Commitment to conduct a limited pharmacokinetic study in patients to characterize the absorption and elimination phases of the 100 mg/mL formulation and to compare the 50 mg/mL versus 100 mg/mL preparations (via crossover).
Single and multiple-dose pharmacokinetics (PK), pharmacodynamics (PD) and safety study in pediatric patients aged 12 to 16 years. Protocol submission by: December 15, 2004 (6 mos. post-approval) Study start: July 15, 2005 (1 year post-approval) Final report submission: July 15, 2007 (3 years post approval)
Conduct a study of Entereg for the acceleration of gastrointestinal recovery in pediatric patients age 0 to 1 month undergoing bowel resection surgery. The study will measure population pharmacokinetic parameters, safety, and time to first tolerated feed while in the hospital.
A deferred pediatric study under PREA for the treatment of schizophrenia in pediatric patients ages 13 to 17. A study of the efficacy and safety of iloperidone tablets in the relevant pediatric population.
To perform Segment III (peri- and post-natal development) studies, as per the ICH M3, S5A, S5B, and S5B(M) Guidances to Industry..
Deferred pediatric study under PREA for the treatment of relief of mild to moderate acute pain in pediatric patients ages 12 to 17 years.
The applicant currently proposes to develop a liquid pediatric formulation and then perform a pharmacokinetic (PK) study in adults comparing the pediatric formulation to an approved pediatric ibuprofen product. The proposed PK study is a single-dose, randomized, open-label, two-way crossover PK study. Approximately 30 healthy male and female subjects, 18 to 45 years of age, will be enrolled. The treatment groups will be: * 10 ml of currently marketed Children's Advil Suspension (equivalent to ibuprofen 200 mg)  * 10 ml of sodium ibuprofen solution (equivalent to ibuprofen 200 mg) The statistical hypothesis to be tested is that sodium ibuprofen pediatric solution is bioequivalent to Children's Advil suspension in the fasted state.
Deferred pediatric studies under PREA for the treatment of chronic hepatitis B virus infection in pediatric patients ages 2 to <12 years of age.
Conduct a labeling comprehension study to ensure that patients are able to read and use the device in the manner specified in them labeling.
Deferred pediatric study under PREA for treating heartburn associated with non-erosive GERD in pediatric patients aged 1 year to 11 years.
You have committed to the conduct of a clinical trial designed to assess the potential effects of apomorphine on the QTc interval. Due to the complexity of the design of this study, submit the protocol for review and discussion prior to study initiation. Protocol Submission Date: October 2004 Study Start Date: April 2005 Final Report Submission Date: October 2006
Studies to determine dosing for neonates to 2 years of age (based on human extrapolation and/or animal models). i. Protocol submission: Within 6 months of the date of this letter ii. Study start: Within 6 months of agreement to the protocol iii. Final study report submission: Within 12 months of initiation of the study
Deferred pediatric study under PREA for the treatment of candidemia and Candida infections in pediatric patients ages 0 to 3 months.
Deferred pediatric study under PREA for the maintenance of remission in Crohn?s disease in pediatric patients ages zero to 17 years of age.
You are required to assess the safety and effectiveness of EQUETRO as a treatment for acute manic and mixed episodes associated with Bipolar I Disorder in pediatric patients ages 10 to 17 (children and adolescents). Due to extensive prior experience with carbamazepine in the treatment of pediatric epilepsy, we do not require either a pediatric pharmacokinetic study or a juvenile animal toxicity study to support this pediatric study.
Deferred pediatric study under PREA for the maintenance of remission of ulcerative colitis in pediatric patients ages 5 to 17 years to evaluate safety, effectiveness, and pharmacokinetics with Apriso (mesalamine granules) in at least two dosing regimens.
Deferred pediatric study under PREA for the management of pain in patients where an opioid analgesic is appropriate in pediatric patients ages 0 to 16 years.
Deferred pediatric study under PREA for the treatment of relief of mild to moderate acute pain in pediatric patients ages 2 to 12 years.
A pediatric study in patients aged 6 - 17 years to obtain pharmacokinetic data pertinent to pediatric dosing of tolvaptan.
Single and multiple-dose pharmacokinetics (PK), pharmacodynamics (PD) and safety study in pediatric patients aged 2 to 11 years. Protocol submission by: December 15, 2004 (6 mos. post-approval) Study start: July 15, 2005 (1 year post-approval) Final report submission: July 15, 2007 (3 years post approval)
Deferred pediatric study under PREA for the treatment of hypertension in pediatric patients ages 6 to 16 years.
Human pharmacokinetic study in adult subjects to compare and evaluate the absorption, distribution and elimination of Ca and Zn-DTPA via inhalation using a commonly available jet type nebulizer (FDA approved model to be selected by the sponsor) with the intravenous route. Data/information on dose delivered and the particle size distribution obtained from the specified nebulizer shall be provided. a. Protocol submission: Within 6 months of the date of final approval of these applications b. Study start: Within 6 months of agreement to the protocol c. Final study report submission: Within 12 months of initiation of the study.
Deferred pediatric study under PREA for the treatment of ulcerative colitis in pediatric patients of all ages.
Deferred pediatric study under PREA for the treatment of HIV in pediatric subjects from 2 to 18 years of age. This study will determine the maraviroc exposure (pharmacokinetics profile) followed by 48 weeks of dosing, with efficacy based on viral load reduction through 48 weeks of dosing, and safety monitored over 96 weeks for pediatric subjects from 2 to 18 years of age to support maraviroc dose selection, safety and efficacy.
To conduct a post-marketing multi-center, randomized, placebo-controlled, large, simple safety study to evaluate the effects of long term use of Perforomist Inhalation Solution in patients with COPD. The objective of this trial would be to determine the risk of fatal and life-threatening respiratory events associated with the long term use of Perforomist Inhalation Solution in patients with COPD.
Deferred pediatric study under PREA for the prevention of acute nausea and vomiting associated with moderately emetogenic cancer chemotherapy in pediatric patients ages 29 days to 16 years.
Completion of a controlled clinical study to verify and describe the clinical benefit of clofarabine in pediatric ALL. Your proposed Phase 3 study to be possibly conducted by the COG does not appear to have a realistic chance of showing a clinical benefit of clofarabine in children with ALL in first relapse. Please submit a new protocol for a study to show clofarabine clinical benefit in children with ALL within 2 months of the date of this letter. Timelines for study start, completion and submission of the study report will also be submitted. Please request a meeting to discuss this protocol within 30 days of receipt of this letter, so that a meeting can be scheduled to occur about one month after receipt of the protocol.
Deferred pediatric study under PREA for the treatment of Irritable Bowel Syndrome with constipation in pediatric patients ages 6 to 17. The design consists of a 12-month multi-center, double-blinded, placebo-controlled safety and efficacy study including a safety evaluation of the effects of lubiprostone treatment on bone growth.
Conduct a descriptive study of the use of Coartem Tablets in non-immune travelers. For a period of five years following approval, collect baseline patient demographic information (including age, weight, height, sex, race, prior medications and concomitant medications, as well as immune status), adverse reactions, including potential nervous system and cardiac adverse reactions, and efficacy outcomes. You should include representation of adults> 65 years, children < or = to 16 years, and overweight patients (BMI > or = to25 kg/m2). Submit yearly reports summarizing data on patients treated with Coartem Tablets within the previous year and the final report integrating information on all patients in the Final Report Submission.
A deferred pediatric study under PREA for the prevention of nausea and vomiting in patients receiving moderately and/or highly emetogenic chemotherapy for up to 5 consecutive days in pediatric patients ages 2 to 17. A study of the efficacy and safety of transdermal granisetron (Sancuso) compared to intravenous granisetron for the prevention of chemotherapy induced nausea and vomiting in 200 pediatric patients aged 2 to 17 years and over 400 patient treatment periods.
Commits to performing an HPA axis suppression study in no less than 60 evaluable subjects (30 adults and 30 adolescents 12 to 17 years of age) using cosyntropin stimulation testing conducted as labeled with pre- and exactly-30-minutes-post-stimulation levels obtained at baseline and 4 weeks. Enrolled subjects should have at least 25% scalp surface area involvement and normal baseline stimulated cortisol levels, and any suppressed subjects should be followed to recovery. Protocol Submission: Within 4 months of receipt of approval letter Study Start: Within 6 months of the date of approval of the protocol Final Report Submission: Within 16 months after date of approval of the protocol
Establish a registry for children aged 2 to < 6 years to enroll approximately 200 patients and follow them for 5 years. Data collection will be at least monthly for renal function and blood pressure and yearly for growth and development. Submit your monitoring scheme for our review and comment.
Forteo User Registry Study (B3D-MC-GHBX[2]) Study B3D-MC-GHBX(2) is a prospective cohort study that will allow voluntary registration of adult Forteo (teriparatide, rPTH[1-34]) users in the United States during a 5 year enrollment period that will be initiated on approval of this supplement. On an annual basis, data collected from the registered patients will be linked with participating cancer registries to ascertain any new cases of osteosarcoma in Forteo-exposed patients. Outcomes will be ascertained through  athologically confirmed cases of osteosarcoma newly reported at any time after the registered patient began Forteo (teriparatide, rPTH[1-34]) treatment.
Commitment to determine whether Quadramet dose adjustment is needed in patients with renal insufficiency since Quadramet is primarily excreted intact in the urine.
Conduct a non-interventional, prospective, observational study to provide additional safety data on important clinical events. The duration of the study will be 5 years from initiation of the study; data will be reviewed on an interim basis every 6 months during the course of the study.
Submit the results of the proposed phase III trial (AALL0434) to be conducted by the Children's Oncology Group to demonstrate nelarabine's clinical benefit.
A deferred pediatric study under PREA for the prevention of nausea and vomiting in patients receiving moderately and/or highly emetogenic chemotherapy for up to 5 consecutive days in pediatric patients ages 2 to 17. A study to examine the pharmacokinetics of granisetron transdermal system (Sancuso) compared to IV dosing in 48 pediatric patients aged 2 to 17 years.
Continuation and modification of your ten-year epidemiological study assessing whether treatment with pioglitazone hydrochloride is associated with an increased risk of bladder cancer in men and women with diabetes.
Deferred pediatric study under PREA for the treatment of type 2 diabetes in pediatric patients ages 11 to 16, inclusive.
A prospective, randomized, active-controlled trial comparing the risk of developing acute kidney injury in patients undergoing bowel cleansing using Visicol or OsmoPrep as compared to patients undergoing bowel cleansing using polyethylene glycol (PEG) containing products.
To evaluate the potential for a serious risk of carcinogenicity, conduct a long-term (2 year) rodent carcinogenicity study in the rat. Submit the carcinogenicity protocol for a Special Protocol Assessment prior to initiating the study.
An open-label pharmacokinetic and safety study or studies of an ageappropriate formulation of Zorvolex in pediatric patients 6 years to less than 17 years of age with acute pain.
An open-label pharmacokinetic and safety study or studies of an ageappropriate formulation of Zorvolex in pediatric patients 2 years to less than 6 years of age with acute pain.
A pharmacokinetic, safety, and efficacy study or studies of an age-appropriate formulation of Zorvolex in pediatric patients 1 year to less than 2 years of age with acute pain.
Commitment to perform a long-term safety and efficacy trial in panic disorder patients to address the questions of maintenance efficacy and of the risks of long-term use. Applicant has agreed to initiate the trials within six months of final agreement on the study design with the Agency and have indicated that a draft protocol will be submitted to the IND by 2/97 for comment and discussion.
To conduct a minimal in vitro genetic toxicology screen (one in vitro mutagenicity assay and one in vitro assay for chromosome damage) to characterize the toxicological safety of the drug product shelf life specifications (stability specifications).
Deferred pediatric study under PREA for the treatment of Stage 3 and Stage 4 chronic kidney disease in pediatric patients ages twelve to sixteen years.
Randomized, double-blind, dose-controlled clinical trial of fospropofol disodium injection in adolescent patients (12 through 18 years old) undergoing upper endoscopy. Pharmacokinetics will be studied using a population PK approach.
Explore potential agonist (direct or indirect) effects on adrenergic tissue.
To conduct pharmacokinetics studies in neonates and children under 2 years of age who do not have mature renal function.
Conduct a study of Entereg for the acceleration of gastrointestinal recovery in pediatric patients age greater than 1 month up to 16 years undergoing bowel resection surgery. The study will measure the time to first tolerated feed, population pharmacokinetic parameters, the proportion of postoperative days with stool passed while in hospital, length of hospital stay, the need for postoperative nasogastric tube insertion for symptoms of postoperative ileus, and safety.
To conduct pharmacokinetic studies to determine what dose adjustments may be needed in patients with renal and liver impairment.
Applicant Holder commits to conduct one or more studies in pediatric patients to address among other things, dosage, administration, instrumentation or other technical features which may affect performance and safety.  Also to evaluate OPTISON specifically in patients with and without cardiac shunts in order to assess safety and efficacy, and to conduct these studies after protocols have been submitted under usual CDER guidance.
Deferred pediatric study under PREA for the treatment of mild to moderate active Crohn's disease involving the ileum and/or the ascending colon in pediatric patients ages 5 to 17 years.
Adult clinical study to address longer-term effectiveness of carbamazepine in Bipolar I Disorder.
Complete study of long-term follow-up (3 years) in 150 patients with myelodysplastic syndromes (MDS) receiving Exjade to evaluate safety (including cardiac, hepatic, endocrine and renal) and hematologic and clinical benefit of Exjade in these patients.
To study the pharmacokinetics, efficacy and safety of tramadol hydrochloride extended-release capsules for the management of moderate to moderately severe chronic pain in pediatric patients ages ¡Ý 2 to 17 years.
A large randomized, double-blind, active- and placebo-controlled trial to compare the risk of clinically significant neuropsychiatric events, including but not limited to suicidality, in individuals using Chantix (varenicline), bupropion, nicotine replacement therapy, or placebo as aids to smoking cessation over 12 weeks of treatment, and to determine whether individuals with prior history of psychiatric disorders are at greater risk for development of clinically significant neuropsychiatric events compared to individuals without prior history of psychiatric disorders while using Chantix (varenicline) as an aid to smoking cessation. The trial should be sufficiently powered to adequately assess clinically significant neuropsychiatric events with each treatment and in both of the two subgroups (i.e., with and without psychiatric disorders).
Clarify the possible effects on developing fetal adrenergic tissue.
A pregnancy registry must be established to evaluate the safety of this product in pregnant women and their offspring. You will be required to evaluate the safety of VIBATIV (telavancin) use during pregnancy by developing and maintaining a prospective, observational pregnancy exposure registry study conducted in the United States. The study should compare pregnancy and fetal/infant outcomes of women exposed to VIBATIV (telavancin) during pregnancy to an unexposed control population. The registry should identify and record major congenital anomalies, minor anomalies that occur in groups of three or more, spontaneous abortions, stillbirths, elective terminations, functional deficits in the child, and any serious pregnancy outcomes. Infants should be assessed through at least the first year of life.
To conduct a clinical trial in pediatric patients aged 2 to < 18 years who have iron deficiency anemia and who are receiving either hemodialysis or peritoneal dialysis. In addition to any other items, the trial will obtain pharmacokinetic (PK), pharmacodynamic (PD) and safety data from at least 50 patients exposed to ferumoxytol. In this trial, patients will be randomized to oral iron (25 patients) or one of two dose ferumoxytol dose regimens (25 patients in each dose cohort). Endpoints will consist of PK, PD, comparisons of hemoglobin changes and safety summaries.
An observational study of the association of azithromycin use with cardiovascular death, compared to amoxicillin or other antibacterial drugs, in one or more study population(s) with sufficient representation of cardiovascular disease and cardiovascular risk factors. The goal is to replicate the analysis conducted in the Ray et al. study published in 2012 in a different population, and to elucidate the risk and potential risk factors for azithromycin-associated  cardiovascular death.
To conduct a clinical trial, per FDA Guidance [Drug Interaction Studies-Study Design, Data Analysis, Implications for Dosing, and Labeling Recommendations], in order to determine the effects of a strong CYP1A2 inhibitor such as fluvoxamine on the PK of Pomalyst (pomalidomide). CYP1A2 inhibition may increase Pomalyst (pomalidomide) exposure.
Collect and analyze data regarding pregnancy outcomes for 10 years after approval of Impavido (miltefosine) in women who become pregnant while taking Impavido (miltefosine) or during 5 months after end of Impavido (miltefosine) therapy
Assessment of efficacy and safety of OraVerse in patients from 2-6 years of age. This study should be a randomized, sham-injection controlled, double-blinded study comparing the times to return of normal sensation and normal function following the injection OraVerse or a sham injection administered to patients undergoing dental procedures requiring the administration of a local anesthetic agent combined with a vasoconstrictor. Specifically, the following clinical endpoints should be assessed using validated metrics: a. Time to return of normal sensation of the lip and, where applicable, the tongue. b. Time to return of normal function for speech, smiling, drinking, eating and not drooling. Safety assessments should include heart rate, blood pressure, oral cavity examinations, assessments for nerve injury, and adverse events. The study should include a minimum of 100 subjects uniformly distributed by age and evenly distributed by treatment within 1-year age groups.
A commitment to conduct a well-controlled, prospective growth study of the effects of Tri-Nasal Spray on growth in Prepubertal children.  The results of this study should be reported to the Agency by January 24, 2003.  Applicant will consult the Division regarding the design and conduct of such a trial.
To adequately assess photosafety to support the drug as described in the 2003 Guidance for Industry: Photosafety Testing.
A safety study in 100 pediatric patients, ages 10-17 years, of single dose cefazolin preoperative prophylaxis using the dose equivalent to 2 gram adult exposure (as determined in the PK study) in pediatric patients.
The sponsor commits to conduct a Phase IV confirmatory clinical study to determine the effect of Luveris on time to clinical pregnancy. The following is the timeline for this commitment: Protocol submission: Accomplished in the October 5, 2004 submission Study start: Within one year of the date of receipt of this action letter Final Report Submission: Within 6 months of the study completion
A single-dose pharmacokinetic and pharmacodynamics trial of empagliflozin in pediatric patients 10 to 17 years (inclusive) with type 2 diabetes mellitus.
Conduct a Long term safety study to further support the administration of Avinza and the safety profile of fumaric acid in high dose patients. The study will be conducted in approximately 100 patients receiving Avinza doses in excess of 500 mg per day including an adequate representation in doses as high as 3-5 gm per day for the treatment of pain. Patients will be followed for 6 months. Protocol Submission: Within 5 months of the date of this letter. Study Start: Within 3 months of receiving comments/approval from FDA on the study protocol. Final Report Submission: Within 33 months of study initiation.
A single dose, pharmacokinetic, open-label, clinical study in healthy lactating women. Concentrations of pregabalin will be assessed in maternal plasma and breast milk so as to estimate potential infant exposure.
Conduct a clinical study to evaluate recurrence or partial response to treatment in patients treated with Metvixia/Aktilite PDT.
Deferred pediatric study under PREA for the management of fibromyalgia in pediatric patients ages 13 to 17.
Deferred pediatric study under PREA for the treatment of partial onset seizures in pediatric patients ages 1 month [44 weeks gestational age] to 16 years.
To provide literature data or perform new studies to describe the safety of Ioxilan in venographic procedures.
Deferred pediatric study under PREA for cleansing of the colon as a preparation for colonoscopy in pediatric patients ages birth to 16 years.
Deferred pediatric studies under PREA for the treatment of cUTI in pediatric patients ages 0-18 years.
Deferred pediatric study under PREA for the treatment of Major Depressive Disorder in pediatric patients ages 7 to 17.
Deferred controlled effectiveness study under PREA for the acute treatment of migraine attacks with or without aura in pediatric patients ages 12 years to 17 years.
To provide information or conduct pharmacokinetics studies in children 2-16 years of age.
Completion of the clinical confirmatory trial required by the Accelerated Approval regulation, as outlined in your submission dated May 13, 1998, and revised as agreed to in your facsimile of May 28, 1998.
Longitudinal studies involving follow up on case report forms and placement of data into a database for periodic analyses to determine length of treatment, safety profile, and other factors related to drug effectiveness. a. Protocol submission: Within 6 months of the date of this letter b. Study start (i.e. the date the database will be ready to accept patient data, should it be necessary): Within 6 months of agreement to the protocol We also remind you of your agreement to provide annual reports of ongoing studies beginning one year from study initiation.
To conduct a clinical trial in pediatric patients aged 2 to < 18 years who have iron deficiency anemia and chronic kidney disease that does not require dialysis. In addition to any other items, the trial will obtain pharmacokinetic (PK), pharmacodynamic (PD) and safety data from at least 50 patients exposed to ferumoxytol. In this trial, patients will be randomized to oral iron (25 patients) or one of two dose ferumoxytol dose regimens (25 patients in each dose cohort). Endpoints will consist of PK, PD, comparisons of hemoglobin changes and safety summaries.
Deferred pediatric study under PREA for the treatment of for short-term treatment (7 to 10 days) of gastroesophageal reflux disease (GERD), as an alternative to oral therapy in patients who are unable to take Protonix (pantoprazole sodium) Delayed-Release Tablets in patients 2 to 16 years of age.
Deferred pediatric study under PREA for the treatment of the control of serum phosphorus in patients with Chronic Kidney Disease (CKD) on dialysis in pediatric patients ages < 1 month to 16 years old.
To conduct a toxicology study of adequate dose and duration to characterize the toxicological safety of the drug product shelf life specifications (stability specifications).
Deferred pediatric study under PREA for the treatment of cSSSI in pediatric patients ages 0 to 17 years.
Deferred pediatric study under PREA for the treatment of GERD in pediatric patients ages 0 to 16.
Submit an analysis of overall survival after 10 years of follow-up for IES.
Conduct a trial to determine the efficacy and safety of the use of deferiprone to treat iron overload in patients with sickle cell disease and transfusional hemosiderosis who have not been adequately treated with available chelating agents. Submit the protocol for review and concurrence prior to commencing. The trial will enroll a sufficient number of patients with sickle cell disease as described above, to provide sufficient evidence to assess the efficacy and safety in the sickle cell disease population described. The trial may enroll patients with other conditions who have developed transfusional iron overload. The trial will stratify for hematologic diagnosis for the randomization. The primary and secondary endpoints will measure changes in cardiac iron concentration and liver iron concentration.
Establish a registry in order to perform an enhanced pharmacovigilance study of agranulocytosis. Submit a protocol to establish the registry and describe procedures for this enhanced pharmacovigilance prior to commencing the study. Procedures should include: Creation of marketing materials to inform and encourage clinicians to report agranulocytosis events to the sponsor; monitoring of all reported cases and active follow-up to characterize the demographics, recent prior blood counts, concomitant medications, co-existing conditions, duration of drug exposure prior to onset, outcomes of the event, and other factors that may help to characterize the agranulocytosis event. Sponsor also will institute procedures to obtain blood samples from patients with reported cases of agranulocytosis to store for later analysis of possible genetic underlying factors that may predict the risk of agranulocytosis. Submit interim reports annually describing the above results.
You will submit a protocol for a prospective study of the effect of buprenorphine on the liver, using a methadone-treated control group. The study should be sufficiently large and of sufficient duration to determine whether buprenorphine causes hepatic dysfunction, and to identify risk factors such as baseline viral hepatitis status, concomitant drug use, or other contributing factors. Protocol Submission: Within 6 months of the date of this letter Study Start: Within 12 months of the date of this letter Final Report Submission: Within 60 months of the date of this letter
To conduct a rodent carcinogenicity study in the mouse. Prior to initiating the study, you will submit and receive agreement on the carcinogenicity protocol under a Special Protocol Assessment (SPA).
Conduct and submit the results of at least one multicenter, randomized clinical trial establishing the superiority of ceritinib over standard therapy in adult patients with ALK-rearranged (ALK-positive) metastatic NSCLC who have been previously treated with crizotinib or in adult patients with previously untreated ALK-positive metastatic NSCLC.
Conduct a clinical trial to evaluate the systemic exposure and safety of 450 mg Zykadia (ceritinib) taken with a meal and 600 mg Zykadia (ceritinib) taken with a light meal as compared with that of 750 mg Zykadia (ceritinib) taken in the fasted state in metastatic ALK-positive NSCLC patients.
To conduct a long-term rodent carcinogenicity study in the rat. Prior to initiating the study, you will submit and receive agreement on the carcinogenicity protocol under a Special Protocol Assessment.
To conduct a Pregnancy Pharmacovigilance Study to collect pregnancy registry data to evaluate pregnancy outcomes and infant outcomes following exposure to vismodegib. This study will include a mechanism to collect, classify, and analyze data on direct exposures (women exposed to vismodegib as treatment) and indirect exposures (women exposed to vismodegib through the seminal fluid of a male partner). The Pregnancy Pharmacovigilance Study will be initiated and functioning at the time of product launch. The registry and study, at a minimum, will include the following key elements (see the Guidance for Industry Establishing Pregnancy Exposure Registries for a detailed description of these elements): * Data collection of prospective and retrospective data points, adequate to produce informative, reliable data outcomes. * Data analysis utilizing descriptive statistics for summarizing data that will fully capture outcomes of concern. Data collected prospectively analyzed separate from data collected retrospectively. * Description of registry procedures including the patient recruitment, along with healthcare provider awareness of potential safety risk and existence of pregnancy registry, and the monitoring of pregnancy and infant outcomes.
To conduct a large, simple, randomized, placebo controlled trial of rasagiline added to standard therapy in approximately 5000 Parkinson's disease patients for a duration of 36 months to assess the relative risk of melanoma.
To study the pharmacokinetics, efficacy and safety of Ryzolt for the the management of moderate to moderately severe chronic pain in pediatric patients ages less than or equal to 2 to 17 years.
Deferred pediatric study under PREA for treating heartburn associated with non-erosive GERD in pediatric patients aged 12 years to 17 years.
Deferred pediatric studies under PREA for the treatment of traveler's diarrhea in pediatric patients ages 3 years to 12 years. Final Report Submission: May 1, 2009.
Deferred pediatric studies under PREA for the treatment of cIAI in pediatric patients ages 0-18 years.
Provide a rationale to support the safe use of the novel excipient cocoyl caprylocaprate that would preclude the submission of preclinical studies.
(2a) If the proposed rationale submitted under Postmarketing commitment number 2 is determined to be inadequate, the following study will be required: A dermal carcinogenicity evaluation of cocoyl caprylocaprate in two species. One of these studies may be conducted in a transgenic mouse model upon concurrence from the Agency.
To cooperate with U.S.-based public health agencies in evaluating data on the use of LEVAQUIN (levofloxacin) in a large U.S population for inhalational anthrax (post exposure) prophylaxis, should an exposure occur. This includes long-term safety data in pediatric patients from treatment greater than 14 days, if such data become available.
Deferred pediatric study under PREA for the treatment of migraine in pediatric patients ages 12 - 17 years.
A 10 year, observational study to prospectively evaluate the incidence of fibrosing colonopathy in patients with cystic fibrosis treated with Creon (pancrelipase) Delayed- Release Capsules in the US and to assess potential risk factors for the event.
A 10 year, observational study to prospectively evaluate the risk of transmission of selected porcine viruses in patients taking Creon (pancrelipase) Delayed-Release Capsules.
Deferred safety and pharmacokinetic pediatric study under PREA in pediatric patients with migraine with or without aura ages 6 years to 11 years. Upon review of additional safety and effectiveness data in pediatric patients ages 12 to 17 years, we will make a determination as to whether or not pediatric studies are practicable for this age range.
Deferred controlled effectiveness study under PREA for the acute treatment of migraine with or without aura in pediatric patients ages 6 years to 11 years. Upon review of additional safety and effectiveness data in pediatric patients ages 12 to 17 years, we will make a determination as to whether or not pediatric studies are practicable for this age range.
Commits to performing a safety and efficacy study in non-Caucasian subjects, with particular attention to subjects of African-American and Asian ethnicity. Protocol Submission: Within 4 months of receipt of approval letter Study Start: Within 6 months of the date of approval of the protocol Final Report Submission: Within 24 months after date of approval of the protocol
A prospective observational cohort study to examine the incidence of pancreatic malignancy and thyroid neoplasm in patients with Type 2 diabetes mellitus initiated on Byetta compared to patients initiated on other antidiabetic agents
Human pharmacokinetic study in pediatric subjects to compare and evaluate the absorption, distribution and elimination of Ca and Zn-DTPA via inhalation using a commonly available jet type nebulizer with the intravenous route after an event in which exposure to trans-uranium isotopes occurred. Data/information on dose delivered and the particle size distribution obtained from the specified nebulizer shall be provided.
Deferred pediatric studies under PREA for the treatment of chronic idiopathic constipation in pediatric patients ages 0 to 17 years.
We are deferring pediatric studies for ages 6-17 years for this application.
Deferred pediatric study under PREA for the treatment of post-operative nausea and vomiting pediatric patients ages 0 to less than 17 years of age.
Deferred pediatric study under PREA for the use of VIREAD treatment, in combination with other antiretroviral agents, of HIV-1 in pediatric patients ages birth to 2 years of age. Due to safety concerns for this age group, we are waiting for completion and review of studies in the 2 to 18 years age group before determining whether it is appropriate to study tenofovir in the birth to 2 years age group.
Sponsor commits to undertake a Phase 4 trial to determine the need for and how to adjust Ferriseltz by body size in pediatric patients.
Deferred pediatric bioavailability study: To Assess the Safety, Tolerability and Pharmacokinetics of Cycloset in 10 to 16 year old Type 2 Diabetic Subjects.
To conduct and submit a final study report for a postmarketing study of thromboembolic events among women prescribed Lybrel compared to women prescribed cyclic oral contraceptives containing 20mcg ethinyl estradiol. The postmarketing study will be a prospective claims database study and will enroll enough participants to achieve 80% power to detect a relative risk of 2.0.
Deferred safety and pharmacokinetic pediatric study under PREA in pediatric patients with migraine with or without aura ages 12 years to 17 years.
To evaluate efficacy and safety of dalteparin in pediatric cancer patients. Studies using dalteparin for venous thromboembolism (VTE) treatment in all age ranges of the pediatric population should be performed.
Conduct clinical trials of ropivacaine usage and pharmacokinetics in children and infants.
To develop and maintain a prospective, observational pregnancy exposure registry study conducted in the United States that compares the pregnancy and fetal outcomes of women exposed to Cymbalta during pregnancy to an unexposed control population. The registry will detect and record major and minor congenital anomalies, spontaneous abortions, stillbirths, elective terminations, and any serious adverse pregnancy outcomes. These events will be assessed among the enrolled women throughout the pregnancy. The events will also be assessed among infants through at least the first year of life. Annual interim reports will be submitted until FDA has acknowledged that sufficient data has been collected.
Determine the no observable effect level on electrocardiographic changes in the dog model.
Randomized, double-blind, dose-controlled clinical trial of fospropofol disodium injection in children (ages 3 up to 12 years old) undergoing sedation for magnetic resonance imaging (MRI). Pharmacokinetics will be studied using a population PK approach.
Deferred long-term open label safety study under PREA in pediatric patients with migraine ages 6 years to 11 years. Upon review of additional safety and effectiveness data in pediatric patients ages 12 to 17 years, we will make a determination as to whether or not pediatric studies are practicable for this age range.
A 24-month oral carcinogenicity study of lumacaftor in rats
Evaluate the safety and treatment response (using sustained virologic response as the primary endpoint) of TECHNIVIE (ombitasvir, paritaprevir, and ritonavir) in a cohort of pediatric subjects 3 to less than 18 years of age with chronic genotype 4 hepatitis C virus infection.
Submit a final report of your analysis of the persistence of treatment-emergent, ombitasvir or paritaprevir resistance-associated substitutions through Post- Treatment Week 48 in ongoing trials of HCV genotype 4 infected subjects.
The preclinical rodent studies found an increased risk for lymphoma and follicular cell thyroid adenoma in the studies evaluating an oral formulation of pimecrolimus. We agree to conduct a registry study of pediatric patients (aged 2-17, with emphasis on the younger ages) with atopic dermatitis followed through adulthood for those who have long-term intermittent treatment with Elidel (pimecrolimus) 1% Cream to assess the risk of developing systemic malignancies. Study proposal for review: April 30, 2002. Report: Every 5 years after the division reviews and accepts the proposal and the study is initiated. Data will be submitted with NDA annual report. b. A preclinical mouse photocarcinogenicity study showed an accelerated rate of development of cutaneous malignancies. We agree to conduct a registry or case-controlled study of sun-exposed adult patients, aged 40 and above, with atopic dermatitis, who have long-term intermittent treatment with Elidel (pimecrolimus) 1%Cream to assess the risk of developing cutaneous malignancies. Study proposal for review: June 30, 2002. Report: Every 5 years after the division reviews and accepts the proposal and the study is initiated. Data will be submitted with NDA annual report.
A commitment to conduct a registry study of pediatric patients with atopic dermatitis to address the risk of developing cutaneous or systemic malignancies in patients who have long term intermittent treatment with Protopic Ointment 0.03% or 0.01%. The proposal for this study will be provided to the Division for review by June 30, 2001.
BioMarin commits to designing and implementing a registry of patients with PKU being treated with Kuvan (sapropterin dihydrochloride) that will be established to obtain longterm clinical status information. Information will be collected on patient demographics, specifics of treatment with Kuvan (sapropterin dihydrochloride), clinical status, neurocognitive assessments, growth and development (for patients who are pre-pubertal at the start of treatment), and adverse events. This registry will be designed so that detailed clinical status information is collected at registry entry and on a six- to twelve-month basis for at least 15 years. BioMarin commits to conducting one sub-study within the registry that will evaluate the effect of Kuvan (sapropterin dihydrochloride) on pregnancy and lactation. The registry data will be analyzed at yearly intervals and the results will be submitted in annual reports for IND 69,708. A registry protocol will be submitted to CDER by May 25, 2008, for concurrence, and the registry will be initiated by November 25, 2008. The final study report under this registry will be submitted to CDER by May 25, 2025.
Deferred pediatric studies under PREA for the adjunctive treatment of partial onset seizures in pediatric patients ages 1 month up to 17 years.
Randomized, double-blind, dose-controlled clinical trial of fospropofol disodium injection in infants and very young children (ages one month up to three years old) undergoing sedation for procedures such as lumbar puncture and/or MRI. Pharmacokinetics will be studied using a population PK approach.
To conduct a study to assess the immunogenicity of Urokinase after primary dosing. Abbott will agree on a study design with CBER prior to initiating the study.
Deferred pediatric study under PREA for the treatment of candidemia and other forms of Candida infections (intra-abdominal abscess and peritonitis) in pediatric patients ages zero months to sixteen years of age.
Conduct a study to comprehensively address device durability and reliability.
Deferred pediatric study(ies) under PREA for the treatment of overactive bladder in the subgroup of pediatric patients with neurologic disease ages 6 to 16 years, 11 months.
Deferred pediatric study under PREA for the treatment of migraine in pediatric patients ages 12 to 17 years old.
A study to bank samples from inflammatory bowel disease patients treated with Simponi (golimumab) for future evaluation to identify genetic mutations and other biomarkers that may predispose them to developing Hepatosplenic T-Cell Lymphoma (HSTCL).
Develop and maintain a prospective, observational pregnancy exposure registry study conducted in the United States that compares the pregnancy and fetal outcomes of women exposed to Savella (milnacipran HCl) during pregnancy to an unexposed control population. The registry will detect and record major and minor congenital anomalies, spontaneous abortions, stillbirths, elective terminations, and any serious adverse pregnancy outcomes. These events will be assessed among the enrolled women throughout the pregnancy. The events will also be assessed among infants through at least the first year of life. Annual interim reports will be submitted until FDA has acknowledged that sufficient data have been collected.
Deferred pediatric study under PREA for the treatment of Gastroesophageal Reflux Disease (GERD): Healing of Erosive Esophagitis, Maintenance of Healing of Erosive Esophagitis, Symptomatic Gastroesophageal Reflux Disease in pediatric patients ages birth to 11 years old.
Deferred pediatric study under PREA for the topical treatment of moderate to severe forms of scalp psoriasis in pediatric patients ages 12 to 17. Final Report Submission: April, 2006
To provide a ribavirin pregnancy registry post-marketing surveillance study. Protocol Submission: Within 2.5 months of the date of this post-approval commitment letter. Follow-up teleconference: Within three months of the date of this post-approval commitment letter. Study Start: Within four months of the date of this post-approval commitment letter or no later than March 31, 2003.
Deferred pediatric study under PREA for the treatment of moderate to moderately severe pain in pediatric patients.
Conduct a systemic bioavailability study using a properly validated assay method to measure methyl aminolevulinate and metabolite (aminolevulinic acid) in plasma under the labeled condition of use in subjects with multiple (8-10) actinic keratosis lesions. Revise your submitted protocol to include the amount of methyl aminolevulinate cream used and include the total body surface area in square centimeters treated for each subject.
Teriparatide Post-Approval Osteosarcoma Surveillance Study (B3D-MC-GHBX). Study B3D-MC-GHBX is an ongoing, case-series study to identify cases of osteosarcoma among men and women 40 years of age and older and determine which cases, if any, have a history of teriparatide treatment. The study was initiated after Forteo (teriparatide, rPTH[1-34]) was first approved in 2002 and will continue with the following changes: * The revised objective of this study will be to identify approximately 1/3 of the incident cases of osteosarcoma annually, in men and women > 40 years of age in the United States, and determine if the patients were exposed to Forteo (teriparatide, rPTH[1-34]). * The duration of the study, which was originally a minimum of 10 years, will be increased to 15 years.
A clinical trial to evaluate the effect of Kapidex (dexlansoprazole) Delayed Release Capsules on bone homeostasis. The primary endpoint will be biomarkers of bone formation and bone resorption. Treatments will include: placebo, dexlansoprazole and esomeprazole.
Deferred pediatric trial under PREA: A randomized, controlled, parallel group superiority trial in pediatric patients ages 10 through 17 years to evaluate the pharmacokinetics of dimethyl fumarate, and the safety and efficacy of dimethyl fumarate compared to an appropriate control for the treatment of relapsing forms of multiple sclerosis.
Deferred pediatric studies under PREA in positron emission tomography (PET) imaging in patients with coronary artery disease and left ventricular dysfunction, when used together with myocardial perfusion imaging, for the identification of left ventricular myocardium with residual glucose metabolism and reversible loss of systolic function in pediatric patients ages greater than 1 year to 16 years old. Final Report Submission: August 5, 2014
Identify dosing adjustments needed in patients with renal insufficiency.
Further explore the specific effects of medication which could interfere with the uptake of Iobenguane Sulfate I 131. This should include a determination of when the medication should be stopped prior to Iobenguane Sulfate I 131 administration and/or whether Iobenguane Sulfate I 131 dose adjustments could overcome the effects of interfering medications.
Gilead agrees to conduct a study examining the effects of LETAIRIS on 6-minute walk distance at peak and trough plasma concentrations, and further agrees to reach agreement on an appropriate study design with the Division.
Deferred pediatric study under PREA for the prophylaxis of invasive Aspergillis and Candida infections in patients, who are at risk of developing these infections in pediatric patients two years to twelve years of age.
To submit the final trial report for Study A8081007 that includes the final analysis of overall survival as specified in the version of Study A8081007 submitted on February 5, 2013, in order to characterize the effects of Xalkori (crizotinib) treatment on overall survival.
Deferred pediatric study under PREA to determine the safety of Zemplar (paricalcitol) for the treatment of secondary hyperparathyroidism associated with chronic kidney disease (CKD) Stage 5 in pediatric patients ages 10 to 16 years receiving peritoneal dialysis or hemodialysis.
Complete an adequate and well-controlled clinical study or studies to better assess the ophthalmologic effects of pregabalin.
Develop an educational outreach program for health care providers and patients, focusing on Yasmin's contraindications in patients with renal or hepatic impairment and inpatients predisposed to hyperkalemia. Protocol Submission: Within 3 months of the date of letter. Study Start: Within 6 months of the date of this letter. Final Report Submission: Within 6 months of the completion of the program. (letter dated 5/11/01)
Firm commits to obtain pharmacokinetic data relevant to children with juvenile rheumatoid arthritis, a post-marketing pharmacokinetic study will be conducted in a suitable number of pediatric patients with juvenile rheumatoid arthritis; or in lieu of such a study, sufficient information from literature and other sources will be submitted that adequately addresses this issue within one year of the approval date. (08/18/00)
To assess the effect of the implant on the corneal endothelium, you will complete a case-controlled study using a subset of approximately 100 patients from Clinical Studies BLP 415-001 and BLP 415-004 who have been implanted with Retisert for at least one year.
Document the presence or absence of Iobenguane Sulfate I 131 in the breast milk and whether or not it crosses the placenta.
Submit the comparative results for the sensitivity and specificity of the CT/MRI scans in the neuroblastoma patients.
Conduct a double-blinded clinical trial testing a single treatment arm of Amitiza versus placebo in male and female patients with Irritable Bowel Syndrome with constipation, utilizing a higher dose than recommended for this indication (e.g., 16 mcg twice daily).
A deferred pediatric study under PREA for the treatment of schizophrenia in pediatric patients ages 13 to 17. A study to obtain pharmacokinetic data and provide information pertinent to dosing of iloperidone tablets in the relevant pediatric population.
Conduct and submit a final report for a non-randomized, controlled, observational study to provide additional safety data regarding the incidence of mortality, liver failure, malignancy, myocardial ischemia or infarction, and rhabdomyolysis, as well as for infections that qualify as a CDC Category C event. Follow-up of subjects will be at least every 6 months for a total of 5 years.
Commitment to continue to collect comprehensive safety data in all ongoing trials. This should include vital signs, electrocardiograms and laboratory data.  The case report forms for these purposes should be reviewed by the division prior to their use.
Submit surveilance reports to evaluate the potential development of resistance to Coartem Tablets. For a period of five years following approval, submit a yearly report describing the reported resistance to a combination ofartemether and lumefantrine in malaria endemic countries as obtained from ongoing resistance monitoring programs on antimalarials collected by international consortia and organizations (e.g., World Health Organization).
A randomized, controlled trial of adequate size and duration to determine whether the use of Uloric is associated with a moderate increase in the risk of serious adverse cardiovascular outcomes as compared to allopurinol.
A study to assess the effectiveness and safety of tolvaptan in the treatment of clinically significant hypervolemic and euvolemic hyponatremia in pediatric patients aged 6 to 17.
Conduct an ophthalmologic study in patients receiving Exjade. Examinations should include distance visual acuity, applanation tonometry, lens photography, and wide angle fundus photography of retina and optic nerve and should be done at baseline (prior to Exjade initiation) and at six month intervals. At least 60 patients should complete 2 years of follow-up.
A randomized, double-blind, placebo-controlled trial to evaluate the effect of long-term treatment with Belviq on the incidence of major adverse cardiovascular events (non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death) in obese and overweight subjects with cardiovascular disease or multiple cardiovascular risk factors. Serial echocardiographic assessments should also be included.
Open label, multicenter single ascending dose study to evaluate pharmacokinetics, safety and tolerability of mirabegron modified release microgranule-based suspension in children from 5 to less than 18 years of age with neurogenic detrusor overactivity (NDO) or overactive bladder (OAB).
Open label, baseline-controlled, multicenter, sequential dose titration study followed by a fixed dose observation period to evaluate pharmacokinetics, safety and efficacy of mirabegron modified release microgranule-based suspension in children from 5 to less than 18 years of age with NDO.
A long-term observational study using electronic healthcare databases with appropriate linkages conducted in United States and European databases to evaluate the incidence of serious cardiovascular outcomes (both individual and composite outcomes) in patients administered Myrbetriq (mirabegron).
A long-term observational study in electronic healthcare databases with appropriate linkages to prospectively evaluate the incidence of new malignant events (excluding non-melanoma skin cancer) in patients using Myrbetriq (mirabegron).
Deferred pediatric study under PREA for the treatment of short-term management of acute post-operative pain in patients requiring opioid analgesia during hospitalization in pediatric patients ages 6 to 16 years of age.
Deferred pediatric study under PREA for the treatment of chronic idiopathic constipation in pediatric patients ages 0 to 18 years. Final Report Submission: January 2, 2008
A rodent carcinogenicity study in the mouse designed according to "FDA Guidance for Industry-Carcinogenicity Study Protocol Submissions". Submit the carcinogenicity protocol for Special Protocol Assessment prior to initiating the study.
Deferred pediatric study under PREA for the treatment of community acquired pneumonia and pelvic inflammatory disease in pediatric patients.
Deferred long-term open label safety study in pediatric patients with migraine with or without aura ages 12 years to 17 years.
Deferred pediatric study under PREA for the treatment of poisoning by organophosphorous nerve agents as well as organophosphorous insecticides in pediatric patients ages birth to less than 17 years.
A commitment to evaluate mangafodipir's effects on blood coagulation in people.
To conduct a study in both adult and pediatric patients to verify and describe the clinical benefit of Cyanokit and to assess its safety when used as indicated.
Pediatric study of an amoxicillin extended-release formulation for the treatment of tonsillitis and/or pharyngitis secondary to Streptococcus pyogenes in pediatric patients two to less than 12 years of age.
Deferred Pediatric Studies Under PREA You have agreed to conduct studies to assess the safety and effectiveness of desvenlafaxine succinate as a treatment for Major Depressive Disorder in pediatric patients ages 7 to 17 (children and adolescents). Both children (ages 7 to 11 years) and adolescents (ages 12 to 17 years) will be equally represented in the samples, and there will be a reasonable distribution of both sexes in these age strata. You have agreed to submit the results of these studies no later than 4.5 years after the date of approval for this NDA.
Deferred pediatric study under PREA for the management of secondary hyperparathyroidism in pediatric patients ages 5 to 18 years with Stage 3 or 4 chronic kidney disease (CKD) not yet on dialysis. Final Report Submission: April 2006
Regarding the hepatic impairment study, you have agreed to evaluate the PK of balsalazide in hepatically-impaired patients if clinically-relevant results are obtained in the renal impairment study.
Determine what dose adjustments are appropriate for pediatric patients with smaller body surface areas.(Fax 11/8/96)
Submit the results of the final analysis of overall survival data from the randomized clinical trial of vandetanib 300 mg vs. placebo in medullary thyroid cancer (Study 58).
Conduct a PK/PD study in adolescents ages = 13 years to 17 years with moderate to severe symptoms of primary Restless Legs Syndrome.
Conduct a double-blind, randomized, placebo-controlled, parallel group efficacy and safety evaluation trial in adolescents = 13 years to 17 years with moderate to severe symptoms of primary Restless Legs Syndrome.
Conduct a fixed-dose, placebo-controlled, double-blinded study that examines multiple doses in late Parkinson's disease. The trial should identify a range of doses inclusive of the lowest effective dose and the lowest maximally effective therapeutic dose.
Longitudinal studies involving follow up of Patient Treatment Data Forms and placement of data into a registry for periodic analyses related to post- marketing drug safety and uses. a. Protocol submission: Within 6 months of the date of final approval of these applications b. Study start (i.e., the date the database will be ready to accept patient data, should it be necessary): Within 6 months of agreement to the protocol c. Agree to submit annual reports of ongoing longitudinal studies beginning one year from study initiation.
Deferred pediatric study under PREA for the use of Palladone (hydromorphone hydrochloride extended-release) Capsules 12-, 16-, 24-, and 32-mg for the management of persistent, moderate to severe pain in opiate-tolerant pediatric patients (0-16 years) requiring continuous, around-the-clock analgesia with a high potency opioid for an extended period of time, generally weeks to months or longer. Final Report Submission: September 24, 2009
A commitment to perform a Phase 4 adrenal suppression study in pediatric patients with large areas of involved skin using ACTH stimulation.  This will be followed by an adrenal suppression study in adult patients with large areas of involved skin using ACTH stimulation only if the pediatric study data show a significant adrenal suppression effect.
Conduct and submit the results of a multicenter, randomized clinical trial confirming the clinical benefit of olaratumab in combination with doxorubicin in patients with soft tissue sarcoma that is not amenable to surgery or radiation.
Deferred pediatric studies under PREA in positron emission tomography (PET) imaging for assessment of abnormal glucose metabolism to assist in the evaluation of malignancy in patients with known or suspected abnormalities found by other testing modalities, or in patients with an existing diagnosis of cancer in pediatric patients ages greater than 1 year to 16 years old. Final Report Submission: August 5, 2014
Deferred pediatric study under PREA for the prevention of postoperative nausea and vomiting (PONV) in pediatric surgical patients ages 0 to <17 years. A PK and safety study to characterize the pharmacokinetics of Zuplenz (ondansetron) oral soluble film in pediatric surgical patients ages 0 to <17 years. An ageappropriate formulation must be developed for younger pediatric patients.
Deferred pediatric study under PREA for the prevention of PONV in pediatric surgical patients ages 0 to <17 years. An adequately powered, well-controlled, and randomized dose-response study to evaluate the safety and efficacy of Zuplenz (ondansetron) oral soluble film compared to standard therapy in pediatric surgical patients ages 0 to <17 years. An age-appropriate formulation must be developed for younger pediatric patients.
Submit the final analysis of safety in the ongoing trial (Protocol NO25026:BRIM3) to provide the potential for new safety signals from longer duration of exposure.
Submit an analysis of secondary malignancies for the proposed adjuvant melanoma trial [G027826: Phase III, Randomized, Double-Blind, Placebo- Controlled Study of Vemurafenib (RO5185426) Adjuvant Therapy in Patients with Surgically-Resected, Cutaneous BRAF Mutant Melanoma at High Risk for Recurrence] annually and one year after the last patient has completed clinical trial treatment.
Follow-up for secondary malignancies from the planned papillary thyroid cancer trial [N025530: An Open-Label, Multi-Center Phase II Study of the BRAF Inhibitor RO5185426 in Patients with Metastatic or Unresectable Papillary Thyroid Cancer (PTC) positive for the BRAF V600 Mutation and Resistant to Radioactive Iodine] annually and one year after the last patient has completed clinical trial treatment.
Conduct a drug interaction trial to evaluate the effect of a strong CYP3A inducer (e.g., rifampin) on the pharmacokinetics of vemurafenib.
A randomized, double-blind, placebo-controlled, parallel group, multicenter clinical trial of the effect of avanafil on spermatogenesis in healthy adult males and adult males with mild erectile dysfunction.
To conduct a field study to evaluate the efficacy and safety of levofloxacin in the event of an attack with the intentional release of Yersinia pestis in the United States.
Deferred requirement for development of an age appropriate formulation for Pertzye (pancrelipase) Delayed-Release Capsules: Develop an age appropriate formulation to allow for dosing to the youngest, lowest weight pediatric patients, including infants less than 12 months of age who will be administered 2,000 to 4,000 lipase units per 120 mL of formula or per breast-feeding. Submit a supplement by June 30, 2014.
A 10 year, observational study to prospectively evaluate the incidence of fibrosing colonopathy in patients with cystic fibrosis treated with Pertzye (pancrelipase) Delayed-Release Capsules in the U.S. and to assess potential risk factors for the event.
An observational study to estimate the prevalence of antibody seropositivity to selected porcine viruses in patients taking Pertzye (pancrelipase) Delayed-Release Capsules compared with an appropriate control group.
A clinical trial to assess the risk of QT prolongation with sublingual buprenorphine, i.e., a thorough QT (tQT) trial. A comparison to methadone at typical treatment doses should be included. It is likely this trial will need to be conducted in opioid-tolerant volunteers or new entrants to opioid dependence treatment.
A multi-phase clinical trial in a hyperphosphatemic pediatric dialysis population, with a placebo-controlled dose-response phase, followed by an open-label titration and maintenance phase, followed by a placebo-controlled randomized withdrawal phase.
Deferred pediatric study under PREA evaluating the use of Lymphoseek guided lymphatic mapping and sentinel lymph node biopsy in the treatment of solid tumors in pediatric patients ages 1 month to 16 years of age.
Develop and validate an appropriate analytical method for determining the individual component phytosterol content in Liposyn II 20% IV Fat Emulsion.
An observational study to evaluate the validity and reproducibility of the Prescription Opioid Misuse and Abuse Questionnaire (POMAQ), which will be used to identify opioid abuse and misuse behaviors among participants who have chronic pain which requires long-term opioid analgesic use.
An observational study to validate measures of prescription opioid Substance Use Disorder and addiction in patients who have received or are receiving opioid analgesics for chronic pain.
Three-month repeat dose toxicity and toxicokinetic study in neonatal rats with a 28-day recovery period to provide safety assessment of Syndros (dronabinol oral solution) for pediatric clinical studies.
Deferred study under PREA to evaluate the pharmacokinetics of Syndros (dronabinol oral solution) for the treatment of chemotherapy induced nausea and vomiting (CINV) in pediatric cancer patients who failed to respond adequately to conventional antiemetic treatments from birth to 17 years of age.
Deferred pediatric study under PREA to evaluate the tolerability and efficacy of Syndros (dronabinol oral solution) for the treatment of chemotherapy induced nausea and vomiting (CINV) in pediatric patients who failed to respond adequately to conventional antiemetic treatments aged birth to 17 years.
Pre-/postnatal developmental toxicology study in rats exposed to Syndros (dronabinol oral solution) to assess the risk of neurotoxicity.
Assess apixaban pharmacokinetics and pharmacodynamics in approximately 50 pediatric subjects aged 0 to less than 18 years, who are at risk for a venous or arterial thrombotic disorder, to determine dosing requirements for subsequent studies in children. Completion and submission of results of Study CV185118 and available data from CV185079 may be used to fulfill this requirement.
Conduct a randomized, open-label, active-controlled, safety and descriptive efficacy study to assess apixaban treatment in 150 pediatric patients evaluable for efficacy and safety, aged 0 to less than 18 years, requiring anticoagulation for the treatment of a venous thromboembolic event (VTE). This trial will also evaluate apixaban pharmacokinetics, anti-Factor Xa activity, and imaging assessment of clot status at the end of treatment in pediatric patients requiring anticoagulation for the treatment of a VTE. Completion and submission of results of Study CV185325 may be used to fulfill this requirement.
A registry to provide long term evaluation of the durability of the treatment effect of the procedure in at least 100 corneal crosslinking-treated subjects at 3 years with a pre-treatment diagnosis of post-refractive corneal ectasia.
Evaluate the pharmacokinetics, safety and treatment response (using sustained virologic response as the primary endpoint) of ombitasvir, paritaprevir, ritonavir, dasabuvir (VIEKIRA XR™) in pediatric patients greater than 3 years of age with chronic hepatitis C virus infection, who weigh at least 42 kg and are able to swallow tablets.
Conduct a repeat dose, pharmacokinetic/pharmacodynamics (PK/PD) study evaluating Adlyxin (lixisenatide) in patients with type 2 diabetes ages 10 to 17 years (inclusive) that are insufficiently controlled with metformin and/or basal insulin. Subjects will be randomized to lixisenatide or placebo. Titration will occur every 2 weeks increasing the dose from 5 mcg to 10 mcg then to 20 mcg.
Conduct a randomized multicenter, active-controlled trial to evaluate the safety and tolerability of AVYCAZ (ceftazidime-avibactam) in children from 3 months to less than 18 years of age with cUTI. The dose for this study will be determined upon review of the data to be submitted by June 2015 from a single-dose, multicenter, non-comparative study assessing the pharmacokinetics of AVYCAZ (ceftazidime-avibactam) in pediatric patients from 3 months to less than 18 years of age.
Conduct a randomized, multicenter, active-controlled trial to evaluate the safety and tolerability of AVYCAZ (ceftazidime-avibactam) in children from 3 months to less than 18 years of age with cIAI. The dose for this study will be determined upon review of the data to be submitted by June 2015 from a single-dose, multicenter, non-comparative study assessing the pharmacokinetics of AVYCAZ (ceftazidime-avibactam) in pediatric patients from 3 months to less than 18 years of age.
Conduct a trial to evaluate the pharmacokinetics, safety and tolerability of AVYCAZ (ceftazidime-avibactam) in children from birth to less than 3 months of age with late-onset sepsis.
Conduct a prospective study over a five-year period after the introduction of AVYCAZ (ceftazidime-avibactam) to the market to determine if decreased susceptibility to AVYCAZ (ceftazidime-avibactam) is occurring in the target population of bacteria that are in the approved AVYCAZ (ceftazidimeavibactam) label.
Conduct a trial or submit data from the Phase 3 trial in cIAI to evaluate the pharmacokinetics, safety, and clinical outcomes in adult patients with baseline renal impairment (creatinine clearance of 50 mL/min or less) receiving AVYCAZ (ceftazidime-avibactam) dosing regimens adjusted for renal function.
A pharmacokinetic/dose ranging study to determine the pediatric doses of Sustol (granisetron) extended-release injection, for subcutaneous use, and a controlled clinical trial with an active comparator to evaluate the efficacy, safety, and tolerability of Sustol (granisetron) extended-release injection, for subcutaneous use, for the prevention of acute and delayed phase nausea and vomiting associated with initial and repeat courses of moderately emetogenic chemotherapy (MEC) or anthracycline and cyclophosphamide (AC) combination chemotherapy regimens in pediatric patients ages 12-17 years old.
A pharmacokinetic/dose ranging study to determine the pediatric doses of Sustol (granisetron) extended-release injection, for subcutaneous use, and a controlled clinical trial with an active comparator to evaluate the efficacy, safety, and tolerability for the prevention of acute and delayed phase nausea and vomiting associated with initial and repeat courses of moderately emetogenic chemotherapy (MEC) or anthracycline and cyclophosphamide (AC) combination chemotherapy regimens in pediatric patients ages 0 to less than 12 years old.
A 1-month, GLP juvenile animal toxicology study of Sustol (granisetron) extended-release injection, for subcutaneous use, conducted in a single species. This study must be completed and submitted for review before initiating pediatric studies in patients ages 0 to less than 12 years.
A multi-center clinical trial to evaluate the dosing and safety of ferric citrate for the treatment of hyperphosphatemia in children ages six months to < 18 years with chronic kidney disease
Develop and validate sensitive and precise assays for the detection of anti-linaclotide antibodies, including IgM, IgG, and IgA, that may be present in the serum at the time of patient sampling. A summary of the validation exercise including supporting data, a summary of the development data supporting assay suitability for parameters not assessed in the validation exercise, and the assay SOP will be provided to FDA.
Provide safety and efficacy data from a 2-year (minimum) clinical study of at least two additional doses of Macugen below 0.3 mg.
You have committed to conduct a pharmacokinetic and pharmacodynamic study to assess the drug interaction potential of apomorphine with alcohol and antihypertensives to include vasodilators (including short-and long-acting nitrates). Protocol Submission Date: September 2004 Study Start Date: December 2004 Final Report Submission Date: 6 months after study completion
Conduct and submit a final study report for a large simple safety study to assess the major clinical outcomes of death, progression of liver disease, and cancer in a broad population of HBV-infected patients using entecavir compared to standard of care over a period of 5 to 10 years of follow-up. The study should be randomized, stratified according to prior treatment, and of sufficient size to detect a 30% difference in cancer outcomes between the two groups. Monitoring by an independent Data Safety Monitoring Board is recommended. Given the anticipated length of the study, it is recommended that the protocol include plans to assess the adequacy of enrollment and submit interim reports of results at yearly intervals.
To cooperate with U.S.-based public health agencies in evaluating data on the use of Levaquin (levofloxacin) in a large U.S. population for inhalational anthrax (post-exposure) prophylaxis, should an exposure occur. This includes long-term safety data from treatment greater than 28 days, if such data becomes available.
Submit comparative LVEF and cardiac safety data for patients enrolled on the adjuvant renal cell carcinoma trial, E2805 titled "A Randomized, Double-Blind Phase III Trial of Adjuvant Sunitinib versus Sorafenib versus Placebo in Patients with Resected Renal Cell Carcinoma". The protocol will be revised to include a plan acceptable to the FDA for ejection fraction monitoring at baseline and follow-up.
Deferred pediatric study under PREA for the treatment of active ulcerative proctitis in pediatric patients ages 12 to 17 years.
A prospective, observational pregnancy outcome study to include fetal and neonatal outcomes and maternal pregnancy complications following a pregnancy exposed to ulipristal acetate (e.g., in case of inadvertent administration to a woman with an unrecognized pregnancy, or in case of emergency contraceptive failure). This study may be conducted by adding a US component to your planned European pregnancy outcome study.
A case-control study of pregnancy loss complications. This study will be conducted as an expansion of the pregnancy outcome study (described under 1673-1), if a signal of concern regarding pregnancy complications is found in that study.
An evaluation of the potential carcinogenicity of DMSO in a 2-year bioassay in the rat.
An evaluation of Fertility and Early Embryonic Development in a single species with DMSO.
An evaluation of Peri-and Postnatal Development in a single species with DMSO.
A clinical pharmacology study to assess pharmacokinetic parameters related to a Belviq dose of 10 mg in pediatric patients ages 7 to 11 years (inclusive). Data from this study should be considered when choosing dose(s) for the safety and efficacy study in this pediatric population.
A 52-week, randomized, double-blind, placebo-controlled pediatric study to evaluate the safety and efficacy of Belviq for the treatment of obesity in pediatric patients ages 12 to 17 years (inclusive). You may not initiate this study until the results of your juvenile animal PMR study and the clinical pharmacology (pediatric patients ages 12 to 17 years) PMR study have been submitted and reviewed by the Agency.
A 52-week, randomized, double-blind, placebo-controlled pediatric study to evaluate the safety and efficacy of Belviq for the treatment of obesity in pediatric patients ages 7 to 11 years (inclusive). You may not initiate this study until results from the Belviq adolescent safety and efficacy PMR study (ages 12 to 17 years) and the clinical pharmacology PMR study (pediatric patients ages 7 to 11 years) have been submitted and reviewed by the Agency.
Provide clinical information from a 1-year (minimum) clinical study to support that there are no adverse effects on the corneal endothelium following the intravitreal administration of Macugen.
Regarding the requested renal impairment study, you have agreed to compare the PK data from the multiple-dose PK study to that obtained from literature on patients with varying degrees of renal impairment that are receiving mesalamine or related prodrugs.  Based on the outcome of the analysis of the multiple-dose PK study, it will be decided whether an additional study is needed to assess PK of balsalazide in patients with varying degrees of renal impairment.
BioMarin commits to designing and implementing a long-term study designed to assess growth and neurocognitive development with treatment with Kuvan (sapropterin dihydrochloride) in patients who are eight years of age or younger at study entry. This study is to include blinded assessments of growth (including standardized measurements of recumbent length or height, weight, and head circumference), and developmental testing (the scales used need to be prospectively agreed upon) at six- to twelve-month intervals over a seven-year period. A study protocol will be submitted to CDER by June 14, 2008, for concurrence, and the study will be initiated by December 14, 2008. The final study report for this study will be submitted to CDER by June 14, 2017.
Zeneca is in the process of gathering and assessing clinical information about the use of propofol in ICU Sedation in children. During the past year, Zeneca has conducted two retrospective post-marketing surveys regarding the use of propofol in pediatric ICU sedation, one in the UK and one in Sweden. The firm anticipates the results from these surveys will be analized before the end of the year. Once the analyses are completed, Zeneca intends to have the data reviewed by an independent panel of experts and they will report the outcome of these reviews to the FDA by end 1Q94. As a result of these reviews, it is anticipated that Zeneca and the FDA and/or the ALSAC will jointly agree an appropriate course of action.
With respect to requested in vivo drug interaction studies, based on the results of the in vitro drug interaction studies, firm agreed to conduct in vivo drug interaction studies in appropriate animal species and evaluate the PK (as deemed necessary).  Based on the outcome of these studies, firm will discuss with the Agency the need for any additional studies.
Deferred clinical efficacy and safety study: A Pivotal, Randomized, Double-Blind, Controlled, Efficacy and Safety Study of the Use of Cycloset for the Treatment of Type 2 Diabetes Mellitus in Children Aged 10 - 16 years with a Diagnosis of Type 2 Diabetes Mellitus.
Sponsor commits to determine if body size adjustments are more appropiate for dosing in the pediatric population.
Commitment to conduct a study to investigate the use of this agent in the pediatric population.
A dose finding, pharmacokinetics and safety trial in subjects with moderate to severe plaque psoriasis between the ages of 6 to 17 years.
A safety and efficacy trial in pediatric subjects with moderate to severe plaque psoriasis between the ages of 6 to 17 years.
Conduct a fixed-dose, placebo-controlled, double-blinded study that examines multiple doses in early Parkinson's disease. The trial should identify a range of doses inclusive of the lowest effective dose and the lowest maximally effective therapeutic dose.
You are required to assess the safety and effectiveness of Geodon as a treatment for bipolar disorder in pediatric patients  ages 10 to 17 (children and adolescents). Final Report Submission: February 11, 2008
Deferred pediatric study under PREA for the treatment of relief of mild to moderate acute pain in pediatric patients ages 1 to 2 years.
Deferred pediatric study under PREA to improve wakefulness in patients with excessive sleepiness associated with narcolepsy in pediatric patients ages 6 to 17.
A 10-year, observational study to prospectively evaluate the risk of transmission of selected porcine viruses in patients taking Zenpep (pancrelipase) Delayed-Release Capsules.
A randomized trial of maintenance treatment with pralatrexate in previously untreated patients with PTCL who have demonstrated a response to CHOP or a CHOP-like regimen. Description of trial: This will be a Phase 3 multi-center, randomized clinical trial of sequential FOLOTYN versus observation in patients with newly diagnosed aggressive peripheral T-cell lymphoma who have responded following initial treatment with CHOPbased chemotherapy. The primary endpoint will be progression-free survival (PFS). The trial will also be sized to detect a realistic difference in survival. Patients will be enrolled prior to initiation of the CHOP-based regimen. Patients responding (CR or PR) after CHOP-based treatment will then be randomized 2:1 to FOLOTYN versus observation.
Deferred pediatric study under PREA for the prevention of nausea and vomiting in pediatric cancer patients ages 4 to <17 years receiving highly emetogenic chemotherapy (HEC). A PK and safety study to characterize the pharmacokinetics of Zuplenz (ondansetron) oral soluble film in pediatric patients ages 4 to <17 years receiving HEC.
A 24-month oral (gavage) carcinogenicity study of glycopyrrolate in mice.
A 24-month oral (gavage) carcinogenicity study of glycopyrrolate in rats.
An assessment and analysis of spontaneous reports of injection site reactions associated with Vivitrol. Following approval, and according to the following timetable, submit the reports (containing both interval-based and comprehensive data) analyzing spontaneous adverse event reports received that describe serious skin reactions. Specialized follow-up should be obtained on these cases to collect additional information on the event. The summaries of reported cases of injection site reactions should include an analysis of patient factors, provider factors and administration technique factors, or any other information that may lead to improved directions for patient selection, needle selection, or administration technique to reduce the risk of serious injection site reactions. When available, provide summaries of pathology and surgical reports.
An efficacy and safety, dose-finding study in children 12 months and older, weighing less than 25 kg, with secondary hypertension.
Conduct a controlled clinical trial to evaluate the efficacy of roflumilast as an add-on therapy to a long-acting beta agonist and inhaled corticosteroid fixed-dose combination therapy in the population of COPD patients for which roflumilast is indicated [severe COPD (FEV1 < 50% predicted) associated with chronic bronchitis and a history of exacerbations]. The design of the trial should be appropriate to demonstrate a clinically relevant beneficial effect of roflumilast as an add-on therapy compared to a long-acting beta agonist and inhaled corticosteroid fixed-dose combination treatment.
Deferred pediatric study under PREA: a 24-month, randomized, active-controlled, parallel group study to evaluate the single and multiple dose pharmacokinetics of fingolimod, and the safety and efficacy of multiple doses of fingolimod compared to interferon beta 1-a-intramuscular (Avonex) for the treatment of relapsing-remitting multiple sclerosis. The efficacy portion of this trial should be designed to show superiority of fingolimod over active control.
A postmarketing observational prospective, parallel cohort study in relapsing multiple sclerosis patients to assess the potentially serious risk of: eye toxicity, cardiac and vascular toxicity, pulmonary toxicity, seizures, serious and opportunistic infections, malignancies, liver toxicity and atypical multiple sclerosis relapse. Specific outcomes examined should include, but not be limited to, macular edema, symptomatic bradycardia, second and third degree atrioventricular block, and lymphoma. The two observed cohorts should consist of 1) patients newly prescribed fingolimod and 2) patients receiving another disease modifying therapy. The study population should be representative of patients with relapsing multiple sclerosis who take disease modifying therapies and should include patients with a history of diabetes or other cardiovascular risk factors. The study design should minimize differences between the cohorts by defining the populations in both cohorts so that they will be similar, by ensuring that both cohorts have similar clinical assessments, and by ensuring that patients who discontinue treatment have continued follow-up. In addition, the study protocol should account for duration of exposure, treatment changes, and loss to follow-up. Sample size should be supported by estimates of the rates of the events of interest.
Develop and maintain a prospective, observational pregnancy exposure registry study conducted in the United States that compares the maternal, fetal, and infant outcomes of women exposed to fingolimod during pregnancy to an unexposed control population. The registry will detect and record major and minor congenital malformations, spontaneous abortions, stillbirths, elective terminations, adverse effects on immune system development, and any other adverse pregnancy outcomes. These outcomes will be assessed throughout pregnancy. Infant outcomes will be assessed through at least the first year of life.
A prospective, randomized, controlled study of fingolimod 0.5 mg, fingolimod 0.25 mg, and an appropriate control, of at least one year duration, to evaluate the efficacy and safety of the drug.
In order to support safe use of clonidine in combination with stimulants in pediatric patients and to provide additional safety information for labeling, you must conduct a juvenile animal study of clonidine in combination with a stimulant as a postmarketing requirement (as communicated in the minutes of our 3/9/2009 meeting).
Conduct a prospective 5-year pre-OLT (orthotopic liver transplant) registry study to collect and analyze data regarding renal function in patients with chronic hepatitis B and decompensated liver disease treated with VIREAD® (tenofovir disoproxil fumarate) and a comparator group taking another nucleoside analogue, such as entecavir.
A randomized trial comparing lapatinib in combination with trastuzumab and an aromatase inhibitor versus trastuzumab in combination with an aromatase inhibitor versus lapatinib in combination with an aromatase inhibitor in postmenopausal women with hormone receptor positive metastatic breast cancer that overexpresses the HER2 receptor.
Conduct a prospective, 3-arm trial evaluating HalfLytely with 5 mg bisacodyl, 2L polyethylene glycol solution plus electrolytes without bisacodyl, and 4L polyethylene glycol solution plus electrolytes without bisacodyl. The trial should evaluate the pharmacokinetics, efficacy and safety of each regimen in cleansing the colon as a preparation for colonoscopy in adults. Collect pharmacokinetic data in a subset of patients.
An adequate, placebo-controlled, double-blind, randomized, add-on design, superiority study to evaluate the safety and efficacy of a single dose of intravenous fosaprepitant, in combination with a 5HT3 antagonist, as compared to standard therapy (a 5HT3 antagonist) in pediatric cancer patients ages 0 to 17 years undergoing treatment with highly emetogenic chemotherapy. You must conduct this study with an age appropriate formulation.
A randomized, double-blind, adequately controlled study of efficacy, pharmacokinetics and pharmcodynamics of IV APAP for the treatment of acute pain in pediatric patients from 0 to 2 years of age.
A prospective, observational study in the United States, which includes a five year period of time after introduction of the TOBI Podhaler to the market to determine if decreased susceptibility to tobramycin is increasing in Pseudomonas aeruginosa from cystic fibrosis (CF) patients. The study will enroll 500 patients.This study should also monitor resistance to these additional antibacterial drugs:meropenem, imipenem, ceftazidime, aztreonam and ciprofloxacin. Within the study, the following treatment emergent pathogens should be evaluated:Staphylococcus aureus, Stenotrophomonas maltophilia, Achromobacter xylosoxidans, and Burkholderia spp. Provide a detailed protocol to the Agency for review and comment prior to commencing the study. Interim reports of changes in P. aeruginosa susceptibility and treatment-emergent pathogens from CF patients should be submitted annually for the duration of the study period.After the first year, the report should be cumulative. The Agency may consider this postmarketing requirement fulfilled after three years if the data do not warrant a longer surveillance period.
A pharmacokinetic analysis to determine a dosing regimen in children from 4 years to less than 16 years of age that provides drug exposure that is similar to the exposure that is effective in adult patients with partial onset seizures. This analysis will require pharmacokinetic data from studies of both adult and pediatric patients. These studies have already been performed.
A pharmacokinetic and safety analysis in children from 1 month to less than 16 years of age to determine whether the bioavailability of the intravenous and oral formulations is similar and to determine an acceptable safety margin of the intravenous formulation when administered at doses that are found acceptable for oral administration. The study should include routine safety monitoring including careful cardiac monitoring before, during, and after infusion. Subjects should be balanced among age cohorts.
A one year, prospective observational cohort study in the United States of CF patients chronically colonized with P. aeruginosa who use TOBI Podhaler as part of their regular care compared to patients using other FDA approved inhaled antipseudomonal antibacterial drugs to assess clinical outcomes, including patients with increased P. aeruginosa minimum inhibitory concentrations to tobramycin at baseline. The study will enroll 500 patients. The clinical outcomes should include use of other antipseudomonal antibacterial drugs, non-respiratory and respiratory-related hospitalizations, mortality, and changes in FEV1% predicted from baseline. This study should also include sputum pharmacokinetics and assess changes in P. aeruginosa sputum log10 CFU/g. Within the study, the following treatment emergent pathogens should be evaluated: Staphylococcus aureus, Stenotrophomonas maltophilia, Achromobacter xylosoxidans, and Burkholderia spp. This study should utilize appropriate approaches to the design and statistical analysis (e.g., baseline covariates, propensity scores) to account for potential differences between the treatment cohorts.
An actual use human factors study to validate the approved Instructions for Use (IFU). The study will enroll 45 patients in total with three age groups of 15 patients each: 6-10 years, 11-17 years, and > 18 years. Only CF patients naïve to use of the Podhaler device will be enrolled. These patients will not be trained prior to reading the IFU and will be observed during the study.
Create adjunct instructions for use using alternative media and validate these instructions for use to ensure the patient can safely and effectively perform the critical tasks for the intended use of this product.
To modify acceptance criteria for the current peptide mapping procedure to include selected peak area and retention times.
Conduct a Phase 3 randomized controlled trial in 1222 patients with hormone-refractory metastatic prostate cancer previously treated with docetaxel comparing cabazitaxel 20 mg/m2 with prednisone versus cabazitaxel 25 mg/m2 with prednisone and powered to preserve 50% of the treatment effect of cabazitaxel 25 mg/m2. The study will include interim analyses for evaluation of drug-related deaths and safety as well as overall survival of the cabazitaxel 25 mg/m2 with prednisone arm versus the cabazitaxel 20 mg/m2 with prednisone arm to potentially discontinue the trial. Submit the protocol for agency review prior to commencing the trial.
In order to verify the clinical benefit of eteplirsen, conduct a 2-year randomized, double-blind, controlled trial of eteplirsen in patients who have a confirmed mutation of the DMD gene that is amenable to exon 51 skipping. Patients should be randomized to the approved dosage of eteplirsen (30 mg/kg weekly) or to a dosage that provides significantly higher exposure, e.g., 30 mg/kg daily. The primary endpoint will be the North Star Ambulatory Assessment.
Deferred pediatric study under PREA for the treatment of type 2 diabetes mellitus in pediatric patients ages 10 to 16 years (inclusive).
Conduct a prospective, randomized clinical trial to demonstrate safety and effectiveness of Dificid (fidaxomicin) compared to vancomycin in pediatric patients (6 months to less than 18 years of age) with C. difficile-associated diarrhea.
Conduct a prospective study over a five-year period after introduction of Dificid (fidaxomicin) to the market to determine if decreased  susceptibility to Dificid (fidaxomicin) is occurring in C. difficile. Provide a detailed protocol describing the study to the Agency for review and comment before commencing the study.
Conduct a prospective, randomized, comparative trial to demonstrate the efficacy of Dificid (fidaxomicin) in the treatment of patients with multiple recurrences of C. difficileassociated diarrhea.
Applicant to conduct a Phase 4 study to confirm the clinical benefit of midodrine. Protocol drafts submitted at 7/18/96 meeting.  Protocols are 401, 402 and 403.
Deferred study under PREA to evaluate the pharmacokinetics, healing, maintenance of healing, and symptoms of endoscopy-proven erosive esophagitis (EE) in patients 12 years to 17 years of age.
Deferred pediatric study under PREA for the maintenance of remission of ulcerative colitis in pediatric patients 5 to 17 years of age.
Conduct a randomized, dose-exploration, multicenter clinical trial evaluating the multiple dose PK/PD profile and safety of oral rivaroxaban (tablets or oral suspension) in pediatric patients aged 6 months to < 6 years with VTE.
Conduct a single-dose PK/PD and tolerability trial in pediatric patients age birth to < 6 months with VTE to determine doses of rivaroxaban (oral suspension) that provide similar exposure and/or PD effect to those seen in older pediatric cohorts.
Conduct a dose-exploration, multicenter clinical trial evaluating the multiple dose PK/PD profile and safety of oral rivaroxaban (oral suspension) in pediatric patients aged birth to <6 months with VTE.
A deferred pediatric study under PREA for the treatment of schizophrenia in pediatric patients ages 13 to 17 years. A study to obtain pharmacokinetic data and provide information pertinent to dosing of lurasidone tablets in the relevant pediatric population.
A deferred pediatric study under PREA for the treatment of schizophrenia in pediatric patients ages 13 to 17 years. A study of the efficacy and safety of lurasidone tablets in the relevant pediatric population.
It is not apparent from the trials you have conducted in schizophrenia that the lowest effective dose of lurasidone has been identified. We ask that you further characterize the utilization of lurasidone in the treatment of adults with schizophrenia with a dose lower than 40 mg (e.g. 20 mg daily) through an adequate and well controlled trial.
Conduct a randomized, single-blind, multicenter dose ranging study comparing the safety and efficacy of SUPREP to NuLytely in children (6 months to 2 years).
A long term ( 24 week, 3on/off cycle) postmarketing observational study in 50 patients describing the safety and tolerability of Bethkis in patients with a stable FEV1 >/= 25 to <40% predicted. The following efficacy outcomes should also be collected: sustained FEV improvement, number of exacerbations, anti-pseudomonal use, and planned and unplanned hospitalization and death. Provide a detailed protocol to the Agency for review and comment prior to commencing the study.
Deferred randomized and controlled pediatric study under PREA to evaluate efficacy, safety, and pharmacokinetics of saxagliptin for the treatment of type 2 diabetes mellitus in pediatric patients ages 10 to 16 years.
A randomized, double-blind, controlled trial evaluating the effect of saxagliptin on the incidence of major adverse cardiovascular events in patients with type 2 diabetes mellitus.
A carcinogenicity study of orally administered clobazam in rats.
A carcinogenicity study of orally administered clobazam in mice.
Deferred pediatric study under PREA for the treatment of endoscopically diagnosed esophagitis, including erosive and ulcerative esophagitis and associated heartburn due to GERD for up to 8 weeks in pediatric patients ages birth to 12 years.
Submit the per protocol overall survival follow-up (data cut-off date will be at least 5 years from the date of the last patient randomized) for Trial SSGXVIII/AIO entitled "Short (12 months) versus long (36 months) duration of adjuvant treatment with the tyrosine kinase inhibitor imatinib mesylate of operable GIST with a high risk for recurrence (SSG XVIII/AIO)". Updated OS results including datasets will be provided as an addendum to the full clinical trial report (dated 27-June-2011).
A thorough QTc clinical trial in patients treated with Tygacil (tigecycline).
Deferred pediatric trial under PREA: A randomized, controlled, parallel group superiority trial to evaluate the single and multiple dose pharmacokinetics of teriflunomide, and the safety and efficacy of teriflunomide compared to an appropriate control for the treatment of relapsing forms of multiple sclerosis.
A prospective, observational exposure cohort study conducted in the United States that compares the maternal, fetal, and infant outcomes of women with multiple sclerosis exposed to teriflunomide during pregnancy to unexposed control populations (one with women with multiple sclerosis who have not been exposed to teriflunomide in pregnancy and the other in women without multiple sclerosis). The registry will detect and record major and minor congenital malformations, spontaneous abortions, stillbirths, elective terminations, adverse effects on immune system development, and any other adverse pregnancy outcomes. These outcomes will be assessed throughout pregnancy. Infant outcomes will be assessed through at least the first year of life. Annual interim reports are to be submitted to the Agency.
A pharmacokinetic study in pediatric patients with partial-onset seizures aged 1 month to < 24 months. At least 2 maintenance dose levels of FYCOMPA (perampanel) should be evaluated to characterize pharmacokinetic parameters following multiple administration of oral perampanel. Pharmacokinetic data can be obtained and analyzed using either conventional pharmacokinetics methods with intensive sampling or using a population PK approach by collecting sparse samples. Subjects should be balanced among age cohorts. Effort should also be made to balance the gender distributions within each age cohort.
A pharmacokinetic study in pediatric patients with partial-onset seizures aged 2 to < 12 years. At least 2 maintenance dose levels of perampanel should be evaluated to characterize pharmacokinetic parameters following multiple administration of oral FYCOMPA (perampanel). Pharmacokinetic data can be obtained and analyzed using either conventional pharmacokinetic methods with intensive sampling or using a population PK approach by collecting sparse samples. Subjects should be balanced among age cohorts. Effort should also be made to balance the gender distributions within each age cohort.
It is not apparent from the studies you have conducted in bipolar mania that the lowest effective dose of asenapine has been identified. We request that you further characterize the utilization of asenapine in the treatment of adults with acute manic or mixed episodes associated with bipolar I disorder with a dose lower than 10 mg twice daily (e.g. 5 mg twice daily) through an adequate and well controlled trial.
A randomized, double-blind, controlled trial evaluating the effect of Victoza (liraglutide [rDNA origin]) injection on the incidence of major adverse cardiovascular events in patients with type 2 diabetes mellitus. This trial must also assess adverse events of interest including the long-term effects of Victoza (liraglutide [rDNA origin]) injection on potential biomarkers of medullary thyroid carcinoma (e.g., serum calcitonin) as well as the long-term effects of Victoza (liraglutide [rDNA origin]) injection on pancreatitis, renal safety, serious hypoglycemia, immunological reactions, and neoplasms.
Deferred pediatric study under PREA for the prevention of nausea and vomiting in pediatric cancer patients ages 4 to <17 years receiving HEC. An adequately powered, well-controlled, and randomized dose-response study to evaluate the safety and efficacy of Zuplenz (ondansetron) oral soluble film compared to standard therapy in pediatric patients ages 4 to <17 years receiving HEC.
Test for the individual component phytosterol content in all batches of Liposyn II 20% IV Fat Emulsion, manufactured over a three year period, using the method developed under PMR 2142-1. Based on these test results, establish limits for each of the individual component phytosterols in Liposyn II 20% IV Fat Emulsion in the product specification.
Perform phenotypic resistance testing of neuraminidase activity and direct genotypic resistance testing of neuraminidase and hemagglutinin in a study to assess the safety and tolerability of oseltamivir when administered as treatment for influenza in immunocompromised patients.
A clinical trial to assess the risk of QT prolongation with Subutex sublingual tablets, i.e., a thorough QT (tQT) trial. A comparison to methadone at typical treatment doses should be included. It is likely this trial will need to be conducted in opioid-tolerant volunteers or new entrants to opioid dependence treatment.
A clinical trial to assess the risk of QT prolongation with Suboxone sublingual tablets, i.e., a thorough QT (tQT) trial. A comparison to methadone at typical treatment doses should be included. It is likely this trial will need to be conducted in opioid-tolerant volunteers or new entrants to opioid dependence treatment.
Conduct a 3 - arm randomized trial investigating the combination of everolimus with exemestane versus everolimus alone versus capecitabine in patients with estrogen - receptor positive metastatic breast cancer after recurrence or progression on letrozole or anastrazole.
Conduct a randomized, controlled trial to evaluate the risk of major adverse cardiac events with aclidinium bromide in patients with COPD.
A clinical pharmacology trial to assess pharmacokinetic and pharmacodynamic parameters related to Qsymia doses of 3.75 mg/23 mg, 7.5 mg/46 mg, 11.25 mg/69 mg, and 15 mg/92 mg in pediatric patients ages 12 to 17 years (inclusive). Data from this trial should be considered when choosing dose(s) for the safety and efficacy trial in this pediatric population. This trial should not be initiated until after the data from the juvenile animal study have been submitted and reviewed by the Agency.
A 52-week randomized, double-blind, placebo-controlled pediatric trial to evaluate the safety and efficacy of Qsymia for the treatment of obesity in pediatric patients ages 12 to 17 years (inclusive). This trial should not be initiated until after the data from the juvenile animal study have been submitted and reviewed by the Agency.
A clinical pharmacology trial to assess pharmacokinetic and pharmacodynamic parameters related to Qsymia doses of 3.75 mg/23 mg, 7.5 mg/46 mg, 11.25 mg/69 mg, and 15 mg/92 mg in pediatric patients ages 7 to 11 years (inclusive). Data from this trial should be considered when choosing dose(s) for the safety and efficacy trial in this pediatric population. You may not initiate this trial until the results of the Qsymia adolescent safety and efficacy trial have been submitted to and reviewed by the Agency.
A 52-week randomized, double-blind, placebo-controlled pediatric trial to evaluate the safety and efficacy of Qsymia for the treatment of obesity in pediatric patients ages 7 to 11 years (inclusive). You may not initiate this trial until results from the Qsymia adolescent safety and efficacy trial have been submitted to and reviewed by the Agency.
Perform a trial assessing the CSF concentration profile of Teflaro (ceftaroline fosamil) in infants < 2 months of age. A minimum of 12 infants < 2 months of age receiving antibacterials for treatment of late-onset neonatal sepsis must be studied.
Perform a randomized comparison of Teflaro (ceftaroline fosamil) and comparator in infants < 2 months of age with ABSSSI and CABP including patients with infections suspected or demonstrated to be caused by MRSA.
Conduct a prospective study over a five-year period after introduction of Teflaro (ceftaroline fosamil) to the market to determine if decreased susceptibility to Teflaro (ceftaroline fosamil) is occurring in the target bacteria included in the Indications section of the approved Teflaro (ceftaroline fosamil) package insert. Provide a detailed protocol describing the study to the Agency for review and comment before commencing the study.
A bioequivalence trial of Prestalia (perindopril and amlodipine) and ACEON (perindopril erbumine) in healthy volunteers. The proposed trial will provide an accurate estimate of the relative bioavailability of perindopril and the active metabolite perindoprilat to enable appropriate dosing instructions for elderly (age > 65) patients, or for patients with heart failure, renal impairment (creatinine clearance < 60 mL/min), or hepatic impairment.
Submit the final report for the pediatric pharmacokinetic trial entitled “Pharmacokinetics of SFP iron delivered via dialysate in pediatric patients with chronic kidney disease on hemodialysis.”
Efficacy and safety trial of Triferic via hemodialysate in pediatric patients aged less than 18 years with hemodialysis-dependent chronic kidney disease.
Conduct a study to evaluate the safety and efficacy of secukinumab in pediatric subjects ¡Ý 6 years of age with plaque psoriasis.
Deferred pediatric study of pharmacokinetics and safety under PREA for the management of mild to moderately severe pain when the use of an opioid analgesic is appropriate in pediatric patients ages 2 to 17 years.
Deferred pediatric study of pharmacokinetics, safety and efficacy under PREA for the management of mild to moderately severe pain when the use of an opioid analgesic is appropriate in pediatric patients ages one month to 2 years.
A postmarketing pharmacovigilance study of the risk factors, clinical management, and outcome of cases of major bleeding in association with Xarelto (rivaroxaban) use.
A study to determine the feasibility of conducting nonclinical (embryo-fetal development, prenatal and postnatal development, carcinogenicity) studies to assess the potential toxicity of 9 desmethyl-beta dihydrotetrabenazine (1-O-dealkyl DHTBZ, RUS0893). This would entail identifying one or more animal species in which plasma levels of DHTBZ can be achieved (for a sufficient duration) that are similar to or exceed plasma levels observed in humans at the clinically relevant doses of tetrabenazine.
A randomized controlled trial in patients with histologically documented, advanced or recurrent (Stage IIIB and not amenable for combined modality treatment) or metastatic (Stage IV) non-small cell lung cancer (NSCLC) who have not experienced disease progression or unacceptable toxicity during chemotherapy with 4 cycles of platinumbased chemotherapy, comparing erlotinib as maintenance therapy with erlotinib at progression. The primary endpoint should be overall survival. This will be a trial to determine which is superior, erlotinib maintenance or erlotinib at progression. Regarding biomarkers, all eligible patients should have known EGFR by IHC status and EGFR mutation status.
Conduct a randomized, single-blind, multicenter dose-ranging study comparing the safety and efficacy of Prepopik to community standard of care in children (ages 9 years to 16 years). This study will include PK assessments.
Conduct a randomized, single-blind, multicenter dose-ranging study comparing the safety and efficacy of Prepopik to community standard of care in children (ages 2 years to <9 years). This study will include PK assessments.
Conduct a randomized, single-blind, multicenter dose-ranging study comparing the safety and efficacy of Prepopik to community standard of care in children (ages 12 months to <2 years). This study will include PK assessments.
Conduct a retrospective study to identify the risk factors associated with development of persistent deterioration of renal function in patients undergoing colon cleansing with Prepopik in preparation for colonoscopy.
Conduct a randomized, active-controlled, multicenter clinical trial evaluating the safety, efficacy and PK/PD (sparse sampling) of at least 3 months of treatment with oral rivaroxaban (tablets or oral suspension) in pediatric patients aged birth to < 17 years of age who have acute VTE. Patients who require treatment for longer than 3 months will be offered continuation of treatment in an open label extension of this study with treatment duration of up to 12 months. Patients from birth to <6 months of age may be enrolled only after data from a planned interim analysis have shown efficacy and safety of rivaroxaban in the older pediatric age groups. Age distribution of patients in the study should reflect the occurrence of VTE in the pediatric population.
Conduct a confirmatory randomized double blind placebo controlled multicenter Phase 3 trial in subjects with sputum smear-positive pulmonary multidrug resistant tuberculosis (MDR-TB). This trial should assess long term outcomes of failure or relapse or death at least 6 months after all MDR-TB treatment is completed.
Develop a patient registry for bedaquiline-treated patients to assess incidence rates of serious adverse events, including death. The registry should capture the information listed below: a. indication for use, including utilization of expert medical consultation b. Minimum Inhibitory Concentration (MIC) data for baseline and any subsequent MDR-TB isolate (in patients who have relapsed/at end of treatment) c. drug utilization data d. information on the drug distribution mechanisms used e. information on how the drug was actually distributed to patients f. patient outcomes (clinical and microbiologic) g. safety assessments in bedaquiline-treated patients, including deaths h. concomitant medications
Conduct a prospective in vitro study over a five-year period after introduction of SIRTURO (bedaquiline) to the market to determine MICs of MDR-TB isolates to bedaquiline for the first 5 years from marketing. Report interpretation of these MICs once additional quality control testing methods are developed as noted in the required postmarketing studies PMR 1988-03 and PMR 1988-04. Provide a detailed protocol describing the study to the Agency for review and comment before commencing the study.
A clinical pharmacology study to evaluate the pharmacokinetics, pharmacodynamics, and safety of canagliflozin in pediatric patients ages 10 to <18 years with type 2 diabetes mellitus on metformin monotherapy.
A 26-week, randomized double-blind, placebo-controlled study, followed by a 26-week double-blind, placebo- or active-controlled extension, to evaluate the efficacy and safety of canagliflozin compared to placebo in pediatric patients ages 10 to <18 years with type 2 diabetes mellitus, as add-on to metformin and as monotherapy.
An assessment and analysis of all foreign and domestic spontaneous reports of malignancy (pheochromocytoma, Leydig cell tumor, and renal cell carcinoma), fatal pancreatitis, hemorrhagic/necrotizing pancreatitis, severe hypersensitivity reactions (angioedema, anaphylaxis, Stevens-Johnson syndrome), photosensitivity reactions, serious hepatic abnormalities, and pregnancy in patients treated with canagliflozin. The enhanced pharmacovigilance should continue for 10 years from the date of approval for malignancies and 5 years for all other events.
Deferred pediatric study under PREA for the treatment of sedation of non-intubated patients prior to and/or during surgical and other procedures in pediatric patients 0 to 16 years of age.
A study analyzing data from the Registry provided for in the REMS to evaluate the development of visual lesions, timing and risk of the development of concentric field loss, the risk of visual acuity deficits, the potential for progression of the lesions if therapy is continued, and the potential for progression once therapy has been discontinued.
A 10 year, observational study to prospectively evaluate the incidence of fibrosing colonopathy in patients with cystic fibrosis treated with PANCREAZE (pancrelipase) Delayed-Release Capsules in the U.S. and to assess potential risk factors for the event.
A 10 year, observational study to prospectively evaluate the risk of transmission of selected porcine viruses in patients taking PANCREAZE (pancrelipase) Delayed-Release Capsules.
Conduct a clinical trial of patients with progressive, locally advanced or metastatic, treatment-naive or previously treated pancreatic neuroendocrine tumors (pNET) to verify and describe the efficacy and safety of sunitinib.
A prospective cohort study to a) determine the frequency of pregnancy in women of child-bearing age prescribed Qsymia and b) compare the risk of oral clefts, major congenital malformations, and low birth weight in offspring of women exposed to Qsymia during pregnancy with offspring of similar women not exposed to Qsymia during pregnancy.
A drug-use study conducted annually for 7 years with nationally representative and projected data to provide a denominator in order to assess adverse event reporting rates of the known serious risk of congenital malformation (specifically orofacial clefts) in infants exposed to Qsymia during the first trimester of pregnancy, and to assess possible risk factors contributing to the risk. Provide the following about patients prescribed Qsymia: a) the estimated total number of prescriptions and patients dispensed Qsymia per year; b) distribution of patients by age, sex, and BMI; c) distribution of prescribers by specialty; d) average, median, and range for duration of use; e) average and median size of prescriptions; f) prescribed average daily dose; g) frequencies of top 10 concomitant diagnoses (including pregnancy) by age and sex; h) frequencies of top 10 concomitant drugs by age and sex (including contraceptive medications for females of childbearing age).
A randomized, placebo- and active-controlled trial to evaluate changes in renal function in obese adults, who will be randomized to Qsymia (3 dosage strengths) or placebo. The primary objective of the trial will be to assess the change in measured GFR (assessed as urinary clearance of 125I-sodium iothalamate). Depending on the results of short-term Qsymia exposure on measured GFR, longer follow-up of affected individuals may be required.
A randomized, double-blind, placebo-controlled trial to evaluate the effect of long-term treatment with Qsymia on the incidence of major adverse cardiovascular events (non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death) in obese and overweight subjects with cardiovascular disease or multiple cardiovascular risk factors. A subset of individuals should have measurements of bone health assessed by serial radiographic and laboratory measurements. Measurements of autonomic function (heart rate variability, baroreceptor sensitivity) and dynamic testing (24-hour blood pressure and heart rate monitoring) should also be assessed in a subset of individuals.
Conduct a clinical trial (PX-171-007) to evaluate the safety of a 30-minute intravenous infusion of carfilzomib at the dose of 20/56 mg/m squared in patients with multiple myeloma
Conduct a clinical trial in patients with hepatic impairment to assess safety and PK characteristics of carfilzomib administered as a 30 minute infusion. The number of patients enrolled in the trial should be sufficient to detect PK differences that would warrant dosage adjustment recommendations in the labeling. The duration of the trial should be sufficient (several cycles) to reasonably characterize potential safety issues. The PK sampling scheme should be optimized to accurately estimate relevant PK parameters for the parent drug. A data analysis plan must be included in the protocol. Submit your protocol for Agency review and concurrence prior to initiation.
Conduct one or more clinical trials including Phase 3 Protocol 2011-003, supplemented as needed by an additional trial, to evaluate the PK, safety, and efficacy of carfilzomib in patients with varying degrees of renal impairment and those on chronic dialysis following the administration of carfilzomib when given as a 30 minute intravenous infusion at a sufficient dose level that will likely produce comparable exposure and clinical response to those patients without renal impairment who receive carfilzomib doses of 20/56 mg/m squared using the 30 minute infusion as planned in your upcoming Phase 3 trial Protocol 2011-003. Collect PK samples following carfilzomib doses of 56 mg/m squared or highest clinical dose in the protocol. Submit your protocol for Agency review and concurrence prior to initiation.
An assessment and analysis of spontaneous reports of serious hepatic abnormalities, fatal pancreatitis, hemorrhagic/necrotizing pancreatitis, and severe hypersensitivity reactions (angioedema, anaphylaxis, Stevens Johnson Syndrome) in patients treated with Kazano (alogliptin and metformin hydrochloride). Specialized follow-up should be obtained on these cases to collect additional information on the events. This enhanced pharmacovigilance should continue for a period of 5 years from the date of approval for reports of fatal pancreatitis and hemorrhagic/necrotizing pancreatitis, and 10 years from the date of approval for reports of serious hepatic abnormalities and severe hypersensitivity reactions.
A single-dose, open-label, pharmacokinetic trial in breastfeeding women receiving fospropofol for a needed procedure. Concentrations of Lusedra will be assessed in breast milk so as to estimate potential infant exposure.
You will perform a "Thorough QT Study" as described in ICH E14. This study can utilize your extended release formulation or an immediate release formulation. It can utilize a single 0.6 mg dose group and a single administration.
A carcinogenicity study in one animal species in which plasma levels of 9-desmethyl-beta-dihydrotetrabenazine can be achieved that are similar to or greater than plasma levels in humans at clinically relevant doses of tetrabenazine.
A one year prospective, randomized, parallel, active-control arm trial to compare the safety of Topamax (topiramate) with regard to metabolic acidosis, renal stone formation, bone mineral density, and development (i.e. height, weight and sexual) with that of an alternate treatment in pediatric patients ages 2 to 15 years. Dosing for this study should be based on the pediatric monotherapy dosing recommendations in the approved labeling for Topamax (topiramate) and an expected efficacious dose for the comparator.
A safety and efficacy study in pediatric patients with irritable bowel syndrome with constipation ages seven years up to 17 years treated with Linzess (linaclotide).
A clinical trial in adults receiving Linzess (linaclotide) to assess development of antidrug antibody (ADA) responses in patient samples. Validated assays capable of sensitively detecting ADA responses that may be present at the time of patient sampling, developed under PMR 1915-4 above, will be used. Sampling will occur at 0 and 2 weeks, and at 1, 3, 6 and 12 months. Immunogenicity rates and individual patient titers will be evaluated. Adverse events will be collected.
Submit the results of a single-dose pharmacokinetic (PK)/pharmacodynamic (PD) and tolerability trial in pediatric patients aged >/= 6 months to < 17 years with venous thromboembolic event(s) (VTE) in appropriate age cohorts to determine dosing of rivaroxaban (tablets and oral suspension) that will provide similar exposure and/or PD effect compared to recommended doses in adults. Enroll into sequential age cohorts (e.g., beginning with 12 to < 17 years) and use the information from the older age cohorts to inform dosing in the younger age cohorts.
Conduct a randomized, dose-exploration, multicenter clinical trial evaluating the multiple dose PK/PD profile and safety of oral rivaroxaban (tablets or oral suspension) in pediatric patients aged 6 years to <17 years with VTE. Enroll into sequential age cohorts (e.g., beginning with ages 12 to < 17 years) and use the information from the older age cohorts to inform dosing in the younger age cohorts.
Longer duration follow-up: Continue follow-up of patients (on treatment and in protocol defined post-treatment follow-up) and submit a final analysis report of trial AP24534-10-201 with 24 months of minimum follow-up for each patient. If 24 months of follow-up is not possible for certain patients, provide justification for each patient.
A randomized, double-blind, placebo-controlled trial evaluating the effect of canagliflozin on the incidence of major adverse cardiovascular events (MACE) in patients with type 2 diabetes mellitus. The primary objective of the trial should be to demonstrate that the upper bound of the 2-sided 95% confidence interval for the estimated risk ratio comparing the incidence of MACE (non-fatal myocardial infarction, non-fatal stroke, cardiovascular death) observed with canagliflozin to that observed in the placebo group is less than 1.3.
Deferred pediatric study under PREA to assess efficacy of tramadol in pediatric patients 7 to less than 17 years of age.
Deferred pediatric study under PREA to assess the pharmacokinetics, safety and tolerability of tramadol in pediatric patients 7 to less than 17 years of age.
Conduct a trial in 100 evaluable pediatric patients with plaque psoriasis ages 2 to 16 years and 11 months. Evaluate the safety and effect of Topicort (desoximetasone) Topical Spray, 0.25% on the hypothalamic-pituitary-adrenal axis and pharmacokinetics of desoximetasone under maximal use conditions after 4 weeks of treatment. Conduct the trial in sequential cohorts, for example: Cohort 1: age 12 years to 16 years 11 months Cohort 2: age 6 years -11 years and 11 month Cohort 3: age 2 years to 5 years and 11 months
Deferred pediatric study under PREA to evaluate the safety of SITAVIG (acyclovir) in pediatric patients greater than 6 years to less than 18 years of age with recurrent herpes labialis and to assess duration of herpes simplex virus (HSV) episodes in the treated population. At least 100 treated subjects, distributed across the age range, must be evaluated.
A 2-year carcinogenicity study in a single species.
A registry of patients, including infants, with NAGS deficiency being treated with carglumic acid to obtain long-term clinical safety information. Data to be collected will include patient demographics, details of treatment with carglumic acid, other therapies for hyperammonemia, dietary protein management, clinical status, neurocognitive and psychomotor status, growth and development status, and adverse events. Information from this registry should be submitted annually (in annual reports) with a final report submission at 15 years post-pproval.
Conduct a controlled trial (trial of pediatric HBV-infected subjects required under PREA) that elucidates the mechanism of tenofovir's effects on bone. Evaluations of adequate numbers of pediatric subjects must include the following: a. Measurement of renal excretion of calcium, phosphorous, and magnesium through calculation of the renal phosphate threshold (TmP/GFR). b. Measurement of urine bicarbonate, urine n-telopeptide, serum bonespecific alkaline phosphatase, parathyroid hormone, osteocalcin, ctelopeptide, 25 hydroxyvitamin D, 1,25 (dihydroxyvitamin) D levels, albumin, calcium, phosphate, magnesium, and bicarbonate. c. Correlation of renal parameters with measurements of bone mineral density (DEXA).
Conduct a Phase 1/2 single arm clinical trial to investigate the pharmacokinetic, safety, and preliminary efficacy of omacetaxine following fixed dose  administration in patients with chronic phase (CP) or accelerated phase (AP) chronic myeloid leukemia (CML) who have failed two or more TKI therapies. In Cycle 1 evaluate the PK and safety of omacetaxine following a fixed dose administration. Continue treatment, if tolerated, using a fixed dose as long as patients are clinically benefiting from therapy.
Conduct a mass balance trial in humans to determine the disposition and elimination pathways as well as to characterize the major metabolites of omacetaxine following subcutaneous injection. Depending on the results, hepatic and/or renal impairment trials may be required.
Conduct an observational clinical study in pediatric patients treated with Kalydeco (ivacaftor) to evaluate the risk of cataracts. The study should include eye examinations by an ophthalmologist to assess for both visual acuity and cataracts/eye opacities at a minimum of 3-6 months intervals. Patients should be followed for a minimum of 2 years duration.
A rodent carcinogenicity study in the rat designed according to "FDA Guidance for Industry-Carcinogenicity Study Protocol Submissions". Submit the carcinogenicity protocol for Special Protocol Assessment prior to initiating the study.
A study of the effects of carglumic acid on pregnancy and fetal outcomes. This study can be performed as a sub-study within the registry for all patients with NAGS deficiency. Information on pregnancy and fetal outcomes should be submitted annually (in annual reports) and included in the final report submission on the registry at 15 years post-approval.
A long-term prospective observational study (product exposure registry) of patients with homozygous familial hypercholesterolemia (HoFH) treated with Kynamro (mipomersen sodium) to evaluate known and potential serious risks related to the use of Kynamro (mipomersen sodium), including hepatotoxicity (hepatic transaminase elevations, hepatic steatosis), malignancy (hepatocellular adenoma and carcinoma, and fibroma, fibrosarcoma, and fibrous histiocytoma of the skin and subcutis), and new diagnoses of autoimmune disorders (lupus erythematosus, antiphospholipid syndrome, rheumatoid arthritis, glomerulonephritis). The registry will include a sample of patients prescribed Kynamro (mipomersen sodium) and continue for 10 years from the date of last patient enrollment.
An assessment and analysis of spontaneous reports of serious hepatic abnormalities, malignancy, and immune-mediated reactions in patients treated with Kynamro (mipomersen sodium) for a period of 10 years from the date of approval. Specialized follow-up should be obtained on these cases to collect additional information on the reports.
Conduct a drug interaction trial to evaluate the effect of a strong CYP3A4 inhibitor (e.g., ketoconazole) on the pharmacokinetics of vemurafenib.
Conduct a clinical trial in patients with normal hepatic function and patients with pre-existing severe hepatic impairment to assess the effect of severe hepatic impairment on the pharmacokinetics of vemurafenib.
Develop an Investigational Use Only, Companion Diagnostic (IUO CoDx) that reliably detects V600K BRAF mutation in patients with unresectable or metastatic melanoma and conduct an open-label single arm trial with overall response rate and duration of response as the primary endpoints in this population as determined by the diagnostic test.
Deferred pediatric study under PREA for the treatment or prevention of upper gastrointestinal bleeding in critically ill pediatric patients ages 2 to 11 years old and 12 to 16 years old.
Through collaboration with the Antiretroviral Pregnancy Registry, conduct a prospective observational study in order to collect and analyze data on maternal and fetal outcomes in 200 women who become pregnant while taking Truvada® for a pre-exposure prophylaxis (PrEP) indication and choose to continue Truvada during their pregnancies and in 200 women who become pregnant while taking Truvada for PrEP and choose to discontinue it. Collect and analyze data from at least a similarly sized comparator group of pregnant HIV-infected women taking antivirals other than emtricitabine/tenofovir disoproxil fumarate. Data collected on pregnancy outcomes should include but not be limited to: timing of initiation and duration of Truvada or other antiretrovirals, HIV seroconversions in mothers and infants, spontaneous and elective abortions, spontaneous and scheduled pre-term deliveries, stillbirths, infant weight (normal or low) and infant outcomes, including the presence or absence of congenital malformations.
Collect and analyze data from individuals who take Truvada® for pre-exposure prophylaxis (PrEP) of sexually acquired HIV-1 infection and who seroconvert during follow-up. The following data should be collected and the following analyses conducted on data collected from a minimum of 150 seroconverters over a time period not to exceed 3 years: a. Data regarding the presence or absence of signs and symptoms of acute HIV infection at the study visit or since the last study visit when seroconversion is identified. b. Frequency of screening and screening method(s) used for evaluation of the seroconverter, and in general, at that enrollment site. c. Analyses of baseline samples from early seroconverters to evaluate HIV-1 RNA and the presence or absence of resistance. d. Resistance analyses of viral isolates from seroconverters that include population nucleotide sequence analysis followed by ultrasensitive testing (such as ultra-deep sequencing of proviral DNA or allele-specific PCR) if no resistance is identified by population sequencing. This data may be collected from individuals participating in demonstration projects (trials).
Conduct an analysis of data from ongoing and planned demonstration projects (trials) including at least 7000 uninfected individuals taking Truvada for a pre-exposure prophylaxis (PrEP) indication with the objective of examining the association between levels of adherence to the once-daily dosing regimen and risk of seroconversion, resistance development, and renal and skeletal adverse events. Levels of adherence should measure a gradient of adherence levels rather than the simple dichotomy of 'adherent' versus 'non-adherent' using any available data on drug levels as the measure of adherence. Seroconversion will be assessed every three months, and, upon each seroconversion, resistance testing should be performed. Assessment for renal and skeletal adverse events will be performed every three months, including evaluation of available laboratory data. Analyses will be performed by geographic region, including the United States.
In the context of a U.S. Centers for Disease Control and Prevention (CDC) demonstration project (trial) for once-daily Truvada for a pre-exposure prophylaxis (PrEP) indication, validate an adherence questionnaire over the period of the demonstration project (trial) using an objective quantitative measure such as drug levels. In addition, the demonstration project (trial) will utilize subject demographics and responses from a survey on knowledge, attitudes, and behaviors (sexual and nonsexual behaviors related to increased risk of HIV infection) in order to identify baseline characteristics associated with decreasing adherence, as measured via the adherence questionnaire and confirmed objectively by blood drug levels. The demonstration project (trial) will accrue 1200 individuals with an expected follow up of 12 months and use a national demographically representative sample that reflects the same target population described in 1906-4 above.
An 8-week randomized, double blind, placebo-controlled trial in children 5 to 17 years of age with active, mild to moderate ulcerative colitis. The trial will evaluate pharmacokinetics (PK), efficacy for induction of remission, and safety of at least 2 doses of Uceris (budesonide). The effects of 8 weeks of Uceris (budesonide) on the HPA axis will be assessed.
Deferred pediatric study under PREA for the management of fibromyalgia in pediatric patients ages 13 to 17.
Deferred pediatric study under PREA, a randomized, double-blind, placebo-controlled study to evaluate the efficacy, pharmacokinetics, and safety of pregabalin in pediatric patients with fibromyalgia ages 13 through 17 years, inclusive.
Examine patients 0-23 months of age who are referred for an MRI exam with contrast. A sufficient number of subjects will be studied to adequately characterize the pharmacokinetics of the product in this age group. At least 40 patients will be evaluated in this study, and the study must include a sufficient number of subjects to adequately support the safety and efficacy of Dotarem for central nervous system MRI.
A multiple-dose pharmacokinetic trial in children from 2 to less than 18 years of age with juvenile idiopathic arthritis (JIA)
A randomized withdrawal, double-blind, placebo-controlled trial to evaluate the efficacy and safety of tofacitinib in children from 2 to less than 18 years of age with polyarticular-course juvenile idiopathic arthritis.
Controlled clinical trial to evaluate the long term safety of tofacitinib in patients with rheumatoid arthritis. The trial should include two doses of tofacitinib and an active comparator. The trial should be of sufficient size and duration to evaluate safety events of interest, including cardiovascular adverse events, opportunistic infections, and malignancy.
Conduct a study to assess the safety of Zutripro (hydrocodone, chlorpheniramine, and pseudoephedrine combination product oral solution) in approximately 400-450 children 6-17 years of age with symptoms of the common cold. The dose used in this study will be based upon the results of the pharmacokinetic study in children ages 6-17 years.
Conduct a study to assess the safety of Rezira (hydrocodone and pseudoephedrine combination product oral solution) in approximately 400-450 children 6-17 years of age with symptoms of the common cold. The study will be conducted with a formulation containing hydrocodone, chlorpheniramine, and pseudoephedrine. The dose used in this study will be based upon the results of the pharmacokinetic study in children ages 6-17 years.
Conduct a prospective, randomized, placebo-control, double-blinded efficacy/safety trial of Potiga (ezogabine) in children >/=12 years old.
Conduct a long-term open label extension study of ezogabine in children >/=12 years old.
An in vitro study to evaluate whether ezogabine is a substrate for major transporters in the kidney. Refer to the Agency's Guidance (http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM072101.pdf) for more detailed recommendations regarding transporter-based drug-drug interactions.
A controlled urodynamic trial, to include adults of both sexes in a wide range of ages, including the elderly. Pre- and post-drug urodynamic measures should be carefully collected. Urodynamic measurements should include, although not necessarily be limited to, uroflowmetry, multichannel cystometry, electromyography (EMG), and subjective sensory reporting.
To perform a randomized, blinded, controlled trial of previously untreated PTCL patients randomized to treatment with CHOP or to romidepsin plus CHOP, with Progression Free Survival as the primary efficacy endpoint. Final Progression Free Survival (PFS) data will be available at Trial Completion. For efficacy, the final analysis of the primary endpoint, PFS, will be performed when the trial has experienced the planned number of events. Using the same data cutoff date, an interim analysis of Overall Survival will be performed and included in the study report.
A large randomized, double-blind, active- and placebo-controlled trial to compare the risk of clinically significant neuropsychiatric events, including but not limited to suicidality, in individuals using Zyban (bupropion hydrochloride), varenicline, nicotine replacement therapy, or placebo as aids to smoking cessation over 12 weeks of treatment, and to determine whether individuals with prior history of psychiatric disorders are at greater risk for development of clinically significant neuropsychiatric events compared to individuals without prior history of psychiatric disorders while using Zyban (bupropion hydrochloride) as an aid to smoking cessation. The trial should be sufficiently powered to adequately assess clinically significant neuropsychiatric events with each treatment and in both of the two subgroups (i.e., with and without psychiatric disorders).
Observational study to collect long-term safety data in at least 50 pediatric patients with chronic kidney disease on erythropoietin-stimulating agent (ESA) therapy who require iron maintenance treatment for iron deficiency anemia.
Assess the long-term efficacy (and safety) of Exjade® (deferasirox) treatment to a target LIC of 3 mg Fe/g dw followed by one or more treatment holidays until the LIC is >= 5 mg Fe/g dw in patients with NTDT. Follow-up of all subjects for up to 5 years is necessary.
Conduct a trial to assess the long-term efficacy of Exjade® (deferasirox) in patients with NTDT and high LIC. The trial should assess response rates in the subset of patients with baseline LIC values >15 mg Fe/g dw (proportion of patients achieving an LIC <5 mg Fe/g dw and time to achieving an LIC <5 mg Fe/g dw). Follow-up of all subjects for up to 5 years is necessary.
Conduct a prospective, randomized trial in at least 210 patients with low to intermediate risk myelodysplastic syndromes (MDS) receiving Exjade® (deferasirox) for transfusional iron overload (approximately 140) or placebo (approximately 70) to determine the efficacy and safety of Exjade® (deferasirox) in this population. The trial will continue for 3 years from the date the last patient is enrolled.
Establish a registry of children (aged 10 to <18 years old at enrollment) with NTDT and treated with Exjade® (deferasirox) for documented iron overload. Study 2422 will follow at least 40 children for up to 5 years to assess and analyze the long-term safety of treatment with Exjade® (deferasirox), including an assessment of growth, compared to children on a regular transfusion program receiving Exjade® (deferasirox) (based on historical data). Provide annual interim reports on enrollment and outcomes.
Conduct an enhanced pharmacovigilance study (including proactive surveillance and follow-up of spontaneous reports) to characterize the frequency and severity of adverse Events of Special Interest (ESIs), defined as all deaths and severe or serious events of kidney or liver toxicity, in adults receiving Exjade® (deferasirox) for documented iron overload related to multiple transfusions for myelodysplastic syndrome with anemia requiring transfusions. The specifics regarding targeted safety data collection and analysis, case ascertainment, and processes for meaningful surveillance will be detailed in a protocol to be submitted for FDA review and concurrence prior to study initiation. This study does not replace monitoring and reporting as required by regulations.
Assess the long-term safety of Exjade® (deferasirox) in patients with NTDT by conducting a trial of Exjade® (deferasirox) for the treatment of iron overload (LIC >=5 mg Fe/g dw) in non-transfusion dependent thalassemia (NTDT) in patients aged 10 years and greater with up to 5 years total follow-up.
Completion of the planned mass balance trial. Contingent on FDA review of the mass balance results, a clinical pharmacokinetic trial in patients with hepatic impairment may be required. Description of trial: This is an ongoing Phase 1 mass balance clinical trial to evaluate the excretion and metabolic profile of pralatrexate. Patients will receive a fixed dose of 225 mg radio-labeled pralatrexate. Patients will undergo intense sampling of blood, urine, feces, expired air, and other incidental excreta as needed for up to 7 days. Analysis of the samples will be done by liquid scintillation counting for mass balance determination and HPLC for metabolite profiling. Pralatrexate diastereomer concentrations in plasma and urine will be determined in parallel using a validated LCMS/ MS method.
Deferred pediatric study under PREA, a Phase 1 pharmacokinetic and safety study for the treatment of chronic pain in opioid tolerant pediatric patients ages 7 through 17 years.
Deferred pediatric trial under PREA: A prospective, randomized, controlled, double-blind, efficacy/safety study of oxcarbazepine ER for the adjunctive treatment of partial onset seizures in children ages one month to < 2 years. The primary efficacy endpoint during the controlled phase will examine seizure frequency based upon Video/EEG data.treatment of partial onset seizures in children ages one month to < 2 years. The primary efficacy endpoint during the controlled phase will examine seizure frequency based upon Video/EEG data.
Deferred pediatric trial under PREA: A prospective, randomized, controlled, double-blind, efficacy/safety study of oxcarbazepine ER for the adjunctive treatment of partial onset seizures in children ages 2 to <6 years. The primary efficacy endpoint during the controlled phase will examine seizure frequency based upon diary data.
A clinical trial to examine pharmacokinetics and tolerability in children ages 6 months to 4 years using an age appropriate extended release oxcarbazepine formulation.
A clinical trial to examine pharmacokinetics and tolerability in children, ages 1 month to 6 months, using an age appropriate extended release oxcarbazepine formulation.
To change the text on the backing film of the drug product to a darker ink within one year from the date of this approval letter
A 52-week, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of alogliptin when added on to metformin in pediatric patients ages 10 to 17 years (inclusive) with type 2 diabetes mellitus. At least 30% of randomized subjects will be 10-14 years of age, and at least one-third and not more than two-thirds of subjects in both age subsets (10-14 years and 15-17 years) will be female.
A 52-week, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of alogliptin in pediatric patients ages 10 through 17 years (inclusive) with type 2 diabetes mellitus . At least 30% of randomized subjects will be 10-14 years of age, and at least on-third and not more than two-thirds of subjects in both age subsets (10-14 years and 15-17 years) will be female.
An assessment and analysis of spontaneous reports of serious hepatic abnormalities, fatal pancreatitis, hemorrhagic/necrotizing pancreatitis, and severe hypersensitivity reactions (angioedema, anaphylaxis, Stevens Johnson Syndrome) in patients treated with Nesina (alogliptin). Specialized follow-up should be obtained on these cases to collect additional information on the events. This enhanced pharmacovigilance should continue for a period of 5 years from the date of approval for reports of fatal pancreatitis and hemorrhagic/necrotizing pancreatitis, and 10 years from the date of approval for reports of serious hepatic abnormalities and severe hypersensitivity reactions.
A randomized, double-blind, placebo-controlled trial evaluating the effect of Nesina (alogliptin) on the incidence of major adverse cardiovascular events in patients with type 2 diabetes mellitus. The primary objective of the trial is to establish that the upper bound of the 2-sided 95% confidence interval for the estimated risk ratio comparing the incidence of major adverse cardiovascular events observed with Nesina (alogliptin) to that observed in the control group is less than 1.3. The long-term effects of Nesina (alogliptin) on hepatotoxicity, hypersensitivity reactions (including severe cutaneous reactions), serious hypoglycemia, pancreatitis, and renal safety will also be evaluated. The trial must include at least 200 Nesina (alogliptin)-treated patients with moderate renal impairment and 100 Nesina (alogliptin)-treated patients with severe renal impairment
A 52-week, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of alogliptin when added on to metformin in pediatric patients ages 10 to 17 years (inclusive) with type 2 diabetes mellitus. At least 30% of randomized subjects will be 10-14 years of age and at least one-third and not more than two-thirds of subjects in both age subsets (10-14 years and 15-17 years) will be female.
A prospective, randomized, controlled clinical trial that will assess the safety and efficacy of repetitive use of Cysview in the detection of bladder cancer.
Deferred submission of pediatric studies for the long term maintenance treatment of asthma in patients 6 to less than 12 years of age until December 31, 2007.
A long-term prospective observational cohort study (registry) of patients with Cushing's disease treated with Signifor (pasireotide[...]) to evaluate known and potential serious risks related to the use of Signifor (pasireotide [...]), including serious (requiring treatment in Emergency Department, hospitalization, or death) cases of hyperglycemia, liver-related adverse events, events potentially related to QT prolongation, deaths (including causes of death), atypical infections, and adrenal insufficiency. The registry will continue for three years from the date of last patient enrollment
An assessment and analysis of spontaneous reports of serious (resulting in death, hospitalization, life-threatening, or disability) hyperglycemia, acute liver injury, and adrenal insufficiency in patients with Cushing's disease treated with Signifor (pasireotide [...]) for a period of five years from the date of approval. Specialized follow-up should be obtained on these cases to collect additional information on the events.
A multi-center, randomized, clinical trial investigating the management of Signifor (pasireotide [...])-induced hyperglycemia in patients with Cushing's disease treated with Signifor (pasireotide[...]).
Conduct a trial in the >/=12 - 16 year old age group to evaluate the dose effect of phenylephrine hydrochloride injection on blood pressure in patients undergoing general anesthesia and neuroaxial anesthesia. Administration by both the bolus and infusion methods must be studied for the treatment of hypotension. Dosing of phenylephrine should be weight-based since weight may be quite variable in this population. The study should include 50 subjects in the bolus treatment group and 50 subjects in the infusion treatment group. The study should capture, at a minimum, the following information:  * Demographic and medical history information that informs about the subjects¿cardiovascular status. * Concomitant intraoperative and post-operative medications, including their doses and adjustments in inhaled gas concentration or intravenous agent infusion rates. * Interventions used to treat the hypotension, e.g., other pressor agents, intravenous fluid boluses, changes in patient positioning. * Intraoperative events relevant to subjects' physiological status, such as blood loss and fluids administered. * Blood pressures and heart rate, time to onset and maximal response and duration of response should be defined and captured before and during the treatment. * Pharmacokinetics of the proposed product need to be characterized at points relative to the phenylephrine administration.
A prospective, multi-center, long-term, observational, registry study, of short bowel syndrome patients treated with teduglutide in a routine clinical setting, to assess the long-term safety of teduglutide. Design the study around a testable hypothesis to rule out a clinically meaningful increase in colorectal cancer risk above an estimated background risk in a suitable comparator. Select and justify the choice of appropriate comparator population(s) and corresponding background rate(s) relative to teduglutide-exposed patients. Provide sample sizes and effect sizes that can be ruled out under various enrollment target scenarios and loss to follow-up assumptions. The study's primary outcome should be colorectal cancer, and secondary outcomes should include other malignancies, colorectal polyps, bowel obstruction, pancreatic and biliary disease, heart failure, and long-term effectiveness. Patients should be enrolled over an initial 5-year period and then followed for a period of at least 10 years from the time of enrollment. Progress updates of registry patient accrual and a demographic summary should be provided annually. Registry safety data should be provided in periodic safety reports.
An assessment and analysis of spontaneous reports of malignancy, teratogenicity, and hepatic abnormalities in patients treated with Juxtapid (lomitapide) for a period of 10 years from the date of approval. Specialized follow-up should be obtained on these cases to collect additional information on the reports.
A long-term prospective observational study (product exposure registry) of patients with homozygous familial hypercholesterolemia (HoFH) treated with Juxtapid (lomitapide) to evaluate known and potential serious risks related to the use of Juxtapid (lomitapide), including hepatic transaminase elevations, hepatic steatosis, small bowel and hepatic malignancies, teratogenicity, death (including cause of death), and major adverse cardiovascular events (including cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, unstable angina, and revascularization procedures). The registry will continue for 10 years from the date of last patient enrollment.
Open label, single dose pharmacokinetic study of Zecuity (sumatriptan) iontophoretic transdermal system in adolescents 12 to 17 years of age with a history of migraine, which compares the results with appropriate adult historical control data. The number of adolescent migraine patients in this study must be sufficient to adequately characterize the single dose pharmacokinetics of adolescents compared to adults. There must be similar number of patients in the 12 to 14 years and 15 to 17 years age groups. There must be a reasonable distribution of both sexes in this age bracket.
Randomized, double-blind, placebo-controlled, parallel group study to evaluate the effectiveness and safety of a single Zecuity (sumatriptan) iontophoretic transdermal system compared to a single placebo iontophoretic transdermal system in adolescents 12 to 17 years of age with a history of acute migraine. An enrichment design must be used to reduce the placebo effect. The primary efficacy endpoint must be pain freedom at 2 hours. The study must be powered to detect an effect size similar to that seen in the adult population. There must be similar number of patients in the 12 to 14 years and 15 to 17 years age groups. The protocol must allow the use of appropriate rescue medication after a suitable post-dosing interval.
Open label, 12-month study to evaluate the long-term safety of Zecuity in adolescents 12 to 17 years of age with a history of migraine. Safety assessments must include adverse events, subject and investigator skin irritation evaluations, and monitoring of vital signs. The study must evaluate a sufficient number of adolescent migraine patients to be able to characterize the longterm safety of Zecuity when used to treat multiple migraine attacks over one year. Each patient must treat, on average, at least one migraine attack per month for six to twelve months. At a minimum, 200 patients, using an effective dose, must be exposed for six months, and 75 patients, using an effective dose, must be exposed for one year. There must be similar number of patients in the 12 to 14 years and 15 to 17 years age groups.
Deferred pediatric study under PREA: A pharmacokinetic, efficacy, and safety study of Nucynta ER for the management of chronic pain in pediatric patients ages 7 to <17 years.
Clinical trial (existing trial or new clinical trial) in which at least 30 patients are studied. The following examinations should be performed in these patients at baseline, 2 and 6 weeks after drug administration and 2-8 weeks after discontinuation of the therapy (single visit post therapy). 1. Best corrected distance visual acuity 2. Refractive error associated with best corrected distance visual acuity 3. Pupil size under standardized lighting conditions 4. Slit lamp biomicroscopy of the anterior segment 5. Intraocular pressure 6. Ocular coherence tomography of the macula 7. Dilated fundus photography of the retina
Conduct a multiple dose trial in patients to determine how to adjust the crizotinib dose when it is coadministered with a strong CYP3A inhibitor (e.g., ketoconazole).
Conduct a multiple dose trial in patients to determine how to adjust the crizotinib dose when it is coadministered with a strong CYP3A inducer (e.g., rifampin).
Conduct a multiple dose trial to determine the appropriate crizotinib dose in patients with various degrees of hepatic impairment.
To assess the adequacy of the current cut-off, conduct a clinical trial to explore response to crizotinib in ALK-negative patients based on current assay cut-off. This should be compared to historic controls and to the response in ALK-positive patients. Additional biomarkers should be assessed in ALK-negative patients.
To conduct exposure-response analysis for progression free survival, response rate, overall survival and safety endpoints utilizing data from confirmatory trial A8081014 and to submit the analysis plan for review.
An evaluation of the potential carcinogenicity of colchicine in a 2-year bioassay in rat.
An evaluation of the potential carcinogenicity of colchicine in either a 2-year bioassay or 6-month transgenic study in an appropriate mouse model.
A randomized controlled trial to evaluate the effect of long term rifaximin treatment on the gut flora. In vitro susceptibility testing to rifaximin and other antimicrobial drugs must be included.
A randomized, controlled clinical trial to evaluate whether lactulose is required in combination with rifaximin to delay time to onset of episode of overt hepatic encephalopathy.
Deferred pediatric study under PREA in children 12 years to 16 years and 11 months of age with Juvenile Rheumatoid Arthritis (JRA) A safety and population pharmacokinetic (PK) study in adolescents with JRA who are ages 12 years to 16 years and 11 months and require treatment with NSAIDs will be conducted. This study will be a 6 month,  multicenter, open-label study to evaluate the safety and PK of VIMOVO in this age group.
Conduct a long-term safety study of adolescents ages =13 years to 17 years with moderate to severe symptoms of primary Restless Legs Syndrome. The study must provide a descriptive analysis of safety data in pediatric patients during at least 12 months of continuous treatment with gabapentin enacarbil at individualized doses in association with the study described in PMR #1588-2.
Conduct a driving study in adolescent patients of legal driving age who have Restless Legs Syndrome, using diphenhydramine as active control.
A simulated driving trial in healthy adult subjects treated with an appropriate dose of gabapentin enacarbil determined in PMC 1588-12 that includes active comparator and placebo arms.
Conduct a randomized, placebo-controlled, double-blind, parallel-group clinical trial of gabapentin enacarbil at 300 mg/day, 450 mg/day and 600 mg/day in patients with moderate to severe symptoms of RLS.
A randomized, double-blind, placebo-controlled trial evaluating the effect of Tradjenta (linagliptin) tablets on the incidence of major adverse cardiovascular events in patients with type 2 diabetes mellitus. The primary objective of this trial is to establish that the upper bound of the 2-sided 95% confidence interval for the estimated risk ratio comparing the incidence of major adverse cardiovascular events observed with Tradjenta (linagliptin) tablets to that observed in the control group is less than 1.3. Secondary objectives must include an assessment of the long-term effects of Tradjenta (linagliptin) tablets on immunological and , hypersensitivity reactions (including serious skin and/or mucosal reactions), neoplasms, serious hypoglycemia, pancreatitis, and renal safety. For hypersensitivity reactions, especially angioedema, reports should include detailed information on concomitant use of an angiotensin-converting enzyme inhibitor or an angiotensin-receptor blocker. For cases of pancreatitis, serum amylase and/or lipase concentrations with accompanying normal ranges and any imaging reports should be included in the narratives.
A randomized, double-blind study in pediatric patients ages 5 to 17 years using an age-appropriate formulation for the maintenance of remission of ulcerative colitis.
Conduct a study to assess the safety of Vituz (hydrocodone and chlorpheniramine) in approximately 400-450 children ages 6-17 years with symptoms of the common cold. The study can be conducted with a formulation containing hydrocodone, chlorpheniramine, and pseudoephedrine. The dose used in this study will be based upon the pharmacokinetic study in children ages 6-17 years.
An adequately powered safety and efficacy study in pregnant adolescent girls, 12 to 17 years of age, with nausea and vomiting of pregnancy who are appropriate candidates for pharmacologic therapy.
A juvenile neurotoxicity study in neonatal rats intended to assess the potential for Nuedexta to induce apoptotic neuronal degeneration in the human fetus. Dextromethorphan/quinidine should be administered during the postnatal period demonstrated to be the most vulnerable to this lesion.
Deferred submission of your pediatric studies for the treatment of invasive aspergillosis and serious fungal infections caused by Scedosporium apiospermum and Fusarium spp., including Fusarium solani, in patients intolerant of, or refractory to, other therapy, until December 31, 2003.
Conduct a multiple dose trial to determine the appropriate regorafenib dose in patients with severe renal impairment. Submit the final protocol for FDA review before conducting the trial.
A multiple ascending dose clinical trial in healthy adult volunteers to determine the maximum tolerated dose of tramadol and to inform the dosing for a thorough QT trial of tramadol.
A clinical trial in healthy adult volunteers to assess the risk of QT prolongation with tramadol, i.e., a thorough QT (tQT) trial. This trial will provide information on cardiac depolarization and conduction effects of tramadol at therapeutic and supratherapeutic dose regimens. The tQT trial may be conducted as part of the multiple ascending dose trial.
Convene a panel of experts in oncology and neurology to obtain recommendations regarding which patients, if any, who were excluded from the randomized clinical trial because of increased risk of seizure should be evaluated in a postmarketing safety trial. Following the panel's recommendations, conduct a single-arm safety trial to assess the risk of seizure with enzalutamide 160 mg/day in at least 350 patients with metastatic castrate-resistant prostate cancer who are at increased risk for seizure, e.g., patients with a history of seizure (taking/not taking anticonvulsants), loss of consciousness, transient ischemic attack or cerebrovascular accident, arteriovenous malformation in the brain, head trauma with loss of consciousness, treated brain metastases, use of medications which may decrease the seizure threshold, or other risk factors for the development of seizures. The primary endpoint should be the incidence of seizure. Patients should remain on the trial until disease progression, development of a seizure or the development of an unacceptable adverse reaction. The protocol should contain clear stopping rules for an excessive incidence of seizures.
To perform and submit the trial, presently under SPA agreement, TTX404 "A Phase 3, Multicenter, Randomized Study to Evaluate the Substitution of Marqibo (Vincristine Sulfate Liposomes Injection, VSLI) Standard Vincristine Sulfate Injection (VSI) in the Induction, Intensification, and Maintenance Phases of Combination Chemotherapy in the Treatment of Subjects > 60 Years Old with Newly Diagnosed Acute Lymphoblastic Leukemia (ALL)" to address your subpart H commitment according to the timelines below. Any amendments to the SPA trial TTX404 must also be submitted to the PMR.
Due to the complexity of on site preparation of the final drug product, to study and report at six month intervals on the experience of health care practitioners (HCPs) regarding safety or technical problems with preparation of Marqibo in practice settings.
Considering the relative complexity of preparation of Marqibo, to explore methods to simplify preparation of the final drug product, including the possibility of developing a formulation of liposomal encapsulation such that the step of heating of the drug in the pharmacy is eliminated.
A prospective, randomized, controlled, double-blind, efficacy and safety study of FYCOMPA (perampanel) in children ages 2 years to < 12 years for the adjunctive treatment of partial onset seizures with a long term safety extension. The primary efficacy endpoint during the controlled phase will examine seizure frequency based upon diary data. Safety will be evaluated during the controlled phase and long term extension.
Deferred pediatric study under PREA: A prospective, randomized, controlled, double-blind, efficacy and safety study of FYCOMPA (perampanel) for the adjunctive treatment of partial onset seizures in children ages 1 month to < 4 years with a long term safety extension. The primary efficacy endpoint during the controlled phase will examine seizure frequency based upon Video/EEG data. Safety will be evaluated during the controlled phase and long term extension.
A prospective, multiple dose, randomized, controlled, double-blind, safety and efficacy trial of FYCOMPA (perampanel) as adjunctive treatment of partial onset seizures when high doses of Fycompa are added to concomitant treatments in adults on CYP34A inducing antiepileptic drugs (phenytoin, carbamazepine, and oxcarbazepine). The trial will include a long term safety extension. Safety will be evaluated during the controlled phase and long term extension. Safety endpoints will include serious psychiatric and behavioral reactions, and neurologic effects. The efficacy endpoint during the controlled phase will examine seizure frequency based upon diary data. Trial dosages must be selected to produce exposure similar to that experienced by patients receiving 8 and 12 mg of FYCOMPA (perampanel) daily who were on non-inducing concomitant anti-epileptic drugs.
A prospective human physical dependence trial in patients. The subjects should be titrated to the approved therapeutic dose of FYCOMPA (perampanel) of 8-12 mg, and maintained at this dose for an appropriate amount of time. At the end of the treatment, the drug should be abruptly withdrawn. The trial should be adequately designed to allow differentiation of direct drug toxicity from true withdrawal symptoms.
Conduct an observational multi-site inception cohort study of Pomalyst (pomalidomide) users to address the questions detailed below: 1. To determine the failure rate for each of the different types of initial VTE prophylaxis for multiple myeloma patients treated with a Pomalyst(pomalidomide)-containing regimen. 2. To determine the failure rate for each type of VTE treatment for those patients with multiple myeloma and a VTE who continue to receive ongoing treatment with a Pomalyst (pomalidomide)-containing regimen. 3. To determine the failure rate for each type of post-VTE prophylaxis for those patients with multiple myeloma and a VTE who continue to receive ongoing treatment with a Pomalyst (pomalidomide)-containing regimen. This observational study will enroll relapsed and refractory multiple myeloma patients identified through data sources currently part of the current THAL/REV TEE-01 clinical trial; two managed care databases, and a large claims database.
Conduct a clinical trial, per FDA guidance [Pharmacokinetics in Patients with Impaired Hepatic Function: Study Design, Data Analysis, and Impact on Dosing and Labeling], in patients with baseline hepatic impairment to determine the influence of hepatic impairment on the pharmacokinetics (PK) and safety of Pomalyst (pomalidomide).
Conduct a clinical trial, per FDA guidance [Pharmacokinetics in Patients with Impaired Renal Function--Study Design, Data Analysis, and Impact on Dosing and labeling, in patients with baseline renal impairment and those on chronic dialysis], to determine the influence of renal impairment on the PK and safety of Pomalyst (pomalidomide).
A long-term observational safety study of at least 10 years duration comparing patients with HIV-associated lipodystrophy and excess abdominal fat treated with Egrifta compared to a similar group of patients not treated with Egrifta to assess potential safety concerns associated with long-term administration of Egrifta, including but not limited to the occurrence of glucose intolerance/diabetes mellitus, hypersensitivity reactions, malignancies, liver abnormalities, kidney abnormalities, diabetic retinopathy, and major adverse cardiovascular events.
A prospective, randomized, placebo-controlled clinical trial to evaluate if Egrifta increases the risk of development or progression of diabetic retinopathy when administered to HIV-infected patients with lipodystrophy and concomitant diabetes. The primary objective is to compare the percentage of subjects with a 3-step or greater progression in the Early Treatment Diabetic Retinopathy Study (ETDRS) scale after a minimum of three years of treatment with Egrifta versus placebo. The trial will also evaluate the long-term effect of Egrifta on glucose metabolism and conduct blinded adjudication for major adverse cardiovascular events (MACE).
A randomized, double-blind, 26-week, active-controlled clinical trial comparing Dulera (mometasone furoate and formoterol fumarate) Inhalation Aerosol and mometasone furoate to evaluate the risk of serious asthma outcomes (hospitalizations, intubation, death) in 11,700 adult and adolescent patients 12 years of age and older with persistent asthma.
Conduct a pediatric pharmacokinetic, safety, and antiviral activity trial of Stribild with activity based on the results of HIV-1 RNA virologic response and safety monitoring over at least 48 weeks of dosing in pediatric subjects from 12 to < 18 years of age. Include in the trial safety monitoring assessment of potential renal toxicity (to include serial assessments of serum creatinine, serum phosphate, urine glucose, urine protein, calculated creatinine clearance, glomerular filtration rate (GFR) by cystatin C, and calculated fractional excretion of phosphate) and effects on bone (to include serial DEXA assessment).
Conduct a pediatric pharmacokinetic, safety, and antiviral activity trial of Stribild with activity based on the results of HIV-1 RNA virologic response and safety monitoring over at least 48 weeks of dosing in pediatric subjects from 6 to < 12 years of age. Dose selection must be based on pharmacokinetic data for component drugs and must be discussed with FDA prior to initiation of trial. Include in the trial safety monitoring assessment of potential renal toxicity (serial assessments of serum creatinine, serum phosphate, urine glucose, urine protein, calculated creatinine clearance, glomerular filtration rate (GFR) by cystatin C, and calculated fractional excretion of phosphate) and effects on bone (to include serial DEXA assessment).
An open-label pilot study assessing the efficacy and tolerability of Suclear in pediatric patients 12-16 years of age, inclusive. This study will nclude PK assessments.
A randomized, single-blind, multicenter, dose-ranging study comparing the safety and efficacy of Suclear (up to 3 doses) versus community standard of care in pediatric patients 12-16 years of age, inclusive.
A randomized, single-blind, multicenter, dose-ranging study comparing the safety and efficacy of Suclear (up to 3 doses) versus community standard of care in pediatric patients 3-11 years of age, inclusive.
A randomized, single-blind, multicenter, dose-ranging study comparing the safety and efficacy of Suclear (up to 3 doses) versus community standard of care in pediatric patients 1-2 years of age, inclusive.
Assess the systemic exposure and pharmacokinetics of PEG 3350,[...] following oral administration of Suclear in an adequate number of pediatric patients, encompassing all relevant age groups. These assessments may be conducted as part of the PREA required studies listed above.
Assess the systemic exposure and pharmacokinetics of PEG3350, [...] following oral administration of Suclear to adult patients. These assessments may be conducted as part of 1998-6 (above).
Deferred pediatric study under PREA, a randomized, double-blind, placebo controlled study to evaluate the efficacy, pharmacokinetics, and safety of pregabalin in pediatric patients with partial onset seizures ages 1 month through 3 years, inclusive.
Deferred pediatric study under PREA, a randomized, double-blind, placebo-controlled study to evaluate the efficacy, pharmacokinetics, and safety of pregabalin in pediatric patients with partial onset seizures ages 4 through 16 years, inclusive.
Deferred pediatric study under PREA, a 12 month open label extension study to evaluate the safety of pregabalin in pediatric patients with partial onset seizures ages 1 month through 16 years, inclusive.
Testicular toxicity trial to investigate the effects of ganciclovir on spermatogenesis in humans.
Conduct an open-label pilot study assessing the efficacy and tolerability of SUPREP in adolescents (12 years to 16 years). The adult formulation (and any age appropriate reformulations) will be evaluated for tolerability and efficacy in this pilot study.
Conduct a randomized, single-blind, multicenter dose ranging study comparing the safety and efficacy of SUPREP to NuLytely in adolescents (12 years to 16 years).
Conduct a randomized, single-blind, multicenter dose ranging study comparing the safety and efficacy of SUPREP to NuLytely in children (3 years to 11 years).
Conduct a food effect clinical trial, per FDA guidance [Food-effect Bioavailability and Fed Bioequivalence Studies], in order to determine the effect of food on the pharmacokinetics of Pomalyst (pomalidomide). The trial should be conducted in patients age > 60 years old using the commercial formulation of pomalidomide
Conduct a clinical trial, per FDA guidance [Drug Interaction Studies-Study Design, data Analysis, Implications for Dosing, and Labeling Recommendations], in order to determine the effects of a CYP1A2 inducer (such as montelukast) on the PK of Pomalyst (pomalidomide). CYP1A2 induction may decrease Pomalyst (pomalidomide) exposure and result in diminished efficacy.
A randomized, controlled clinical trial to evaluate the safety of rifaximin in patients with hepatic encephalopathy classified as Child-Pugh C, MELD > 19, and MELD > or = to 25 hepatic impairment.
Conduct a prospective, randomized, placebo-control, double-blinded efficacy /safety trial of Potiga (ezogabine) for the treatment of partial-onset seizures in children aged 2 years to <12 years old.
A randomized, double-blind, 26-week, active-controlled clinical trial comparing Symbicort (budesonide and formoterol fumarate dihydrate) Inhalation Aerosol with budesonide HFA to evaluate the risk of serious asthma outcomes (hospitalizations, intubation, death) in 11,700 adult and adolescent patients 12 years of age and older with persistent asthma.
A randomized, double-blind, 26-week, active-controlled clinical trial comparing Advair Diskus (fluticasone propionate and salmeterol xinafoate inhalation powder) and fluticasone propionate inhalation powder to evaluate the risk of serious asthma outcomes (hospitalizations, intubation, death) in 11,700 adult and adolescent patients 12 years of age and older with persistent asthma.
A randomized, double-blind, 26-week, active-controlled clinical trial comparing Advair Diskus (fluticasone propionate and salmeterol xinafoate inhalation powder) and Flovent Diskus (fluticasone propionate inhalation powder) to evaluate the risk of serious asthma outcomes (hospitalizations, intubation, death) in 6200 pediatric patients 4 to 11 years of age with persistent asthma.
Submit the hypothesis for the final Overall Survival (OS) analysis from the required Clinical Trial (PMR), and the final OS analysis will be performed in accordance with the OS plan. The Study Completion refers to the Statistical Analysis Plan for the required Clinical PMR, it will be April 2021.
To complete the ongoing clinical trial CRAD001M2302 entitled "A Randomized, Double-blind, Placebo-controlled Study of RAD001 in the Treatment of Angiomyolipoma in Patients with either Tuberous Sclerosis Complex (TSC) or Sporadic Lymphangioleiomyomatosis (LAM)" to further verify and describe the ultimate clinical outcomes of the duration of objective responses, incidence of nephrectomy and of renal embolization four years after randomization of the last patient in the study, as specified in the original protocol. You will submit the final comprehensive clinical study report, inclusive of all data collected in the clinical trial, as described in ICH E3.
Assess possible cobicistat protease inhibitory activity in vivo by sequencing the protease in virologic failure subjects' isolates from Studies GS-US-236-0102, GSUS- 236-0103, GS-US-236-0121, GS-US-236-0123 and GS-US-236-0128.
Perform a clinical trial to better characterize the incidence of and risk factors for renal adverse events in women. Provide adequate renal monitoring in the proposed trial to assess renal safety employing a renal monitoring algorithm similar to that used in GS-US-236-0102 and GS-US-236-0103. The algorithm will include an assessment of serum creatinine, creatinine clearance by Cockcroft-Gault, glomerular filtration rate (GFR) by cystatin C, serum phosphate, renal phosphate threshold (TmP/GFR), urine protein and urine glucose. The trial will enroll approximately 500 women, in order to assess the relative incidence of and risk factors for renal adverse events in women as compared to men enrolled in other Stribild clinical trials.
Conduct a pharmacokinetic (PK) sub-trial of the renal safety trial in women to evaluate the potential for a drug-drug interaction between Stribild and commonly used oral contraceptives. Intensive pharmacokinetic data on each oral contraceptive, when given alone and when co-administered with Stribild, should be collected in an adequate number of subjects.
A Pharmacokinetics/Pharmacodynamics trial of Sorilux Foam, 0.005% under maximum use conditions in 20 evaluable pediatric subjects with plaque psoriasis of the scalp and body age 12 years to 16 years and 11 months. Evaluate the effect of the product on calcium metabolism in all subjects.
A PK/PD study to characterize aprepitant PK parameters following administration of a single dose of intravenous fosaprepitant, in combination with a 5HT3 antagonist and dexamethasone, in pediatric cancer patients ages 0 to 17 years undergoing treatment with highly emetogenic chemotherapy. You must conduct this study with an age appropriate formulation.
Deferred pediatric study of pharmacokinetics and safety under PREA for the treatment of mild to moderately severe pain when the use of an opioid analgesic is appropriate in pediatric patients ages 2 to 17 years.
Deferred pediatric study of pharmacokinetics, safety and efficacy under PREA for the treatment of mild to moderately severe pain when the use of an opioid analgesic is appropriate in pediatric patients ages one month to 2 years.
Conduct and submit the results of a randomized withdrawal clinical trial to address longer-term efficacy for your drug at appropriate doses.
Deferred, 1-year, pediatric efficacy and safety study under PREA for the treatment of type 2 diabetes in pediatric patients ages 10 to 17 years.
A 10-year, observational study to prospectively evaluate the incidence of fibrosing colonopathy in patients with cystic fibrosis treated with Zenpep (pancrelipase) Delayed-Release Capsules in the US and to assess potential risk factors for the event.
Shire commits to utilize an antibody screening cut point based on a mean + 1.645 standard deviation for assay values from treatment naïve Gaucher patients. Shire will utilize the same methodology to calculate the anti-imiglucerase ECL cut point.
Shire commits to revise the cut point for the confirmatory anti-velaglucerase and anti-imiglucerase screening assays to a level that is less than or equal to the cut point of the screening assay.
Shire commits to re-assess the IgE cut point for the current ECL methodology using a chemically synthesized hybrid control. Shire commits to support assay validation using patient baseline values.
Shire commits to develop an assay to measure the ability of patient antibodies to block the uptake of velaglucerase and imiglucerase into target cells.
A pharmacokinetic trial in patients with severe hepatic impairment (MELD 19 - 25 and MELD > 25). This may be performed as a sub study in the ongoing Phase 3 trial (RFHE3002, A multicenter, open label trial to evaluate the long term safety and tolerability of rifaximin 550 mg BID in subjects with a history of hepatic encephalopathy), or as part of the required clinical trial described under PMR 1615-2.
A pharmacokinetic trial in patients with concurrent renal insufficiency and liver impairment to determine the extent of elevation of systemic exposure of rifaximin which may lead to worsening of hepatic function. The PK data should be collected and analyzed by the degree of renal insufficiency (e.g. creatinine clearance) within a Child- Pugh class/and by MELD score. A population PK approach will be acceptable.
Deferred pediatric study of safety and pharmacokinetics (single- and multipledose) under PREA for the relief of moderate to severe pain in patients requiring a continuous, around-the-clock opioid treatment for an extended period of time in pediatric patients ages 7 to 17 years.
Deferred study of efficacy, safety, and pharmacokinetics (single- and multipledose) under PREA for the relief of moderate to severe acute pain where the use of an opioid is appropriate in patients ages 0-2 years.
Deferred study of safety and pharmacokinetics (single- and multiple-dose) under PREA for relief of moderate to severe acute pain where the use of an opioid is appropriate in patients ages 2-17 years.
A randomized, placebo-controlled, dose-finding study under PREA evaluating at least two doses of linagliptin as monotherapy in pediatric patients ages 10 to 16 years (inclusive).
Deferred randomized and controlled pediatric study under PREA to evaluate efficacy, safety, and pharmacokinetics of linagliptin for the treatment of type 2 diabetes mellitus in pediatric patients ages 10 to 16 years (inclusive) as monotherapy and when added to metformin therapy.
To develop, in consultation with CDRH, a validated test kit for PDGFR gene rearrangements for patients with MDS/MPD.
To develop, in consultation with CDRH, a validated test kit for D816V c-kit mutation in aggressive systemic mastocytosis.
Conduct and submit the results of a multicenter, randomized trial or trials to verify and describe the clinical benefit of nivolumab in combination with ipilimumab in previously untreated adult patients with unresectable or metastatic, BRAF V600 wild-type melanoma.
Multicenter, randomized, double-blind, parallel-group, bupivacaine- and placebo-controlled study to evaluate the safety, efficacy and pharmacokinetic profile of a single intraoperative administration of Exparel for postoperative analgesia in adolescent subjects 12 to less than 17 years old undergoing multiple surgical procedures.
A multicenter, randomized, double-blind, parallel-group, Bupivacaine- and placebo-controlled study to evaluate the safety, efficacy and pharmacokinetic profile of a single intraoperative administration of Exparel for postoperative analgesia in children 6 to 11 years old undergoing multiple surgical procedures.
A multicenter, randomized, double-blind, parallel-group, bupivacaine- and placebo-controlled study to evaluate the safety, efficacy and pharmacokinetic profile of a single intraoperative administration of Exparel for postoperative analgesia in young children 2 to 5 years old undergoing multiple surgical procedures.
A multicenter, randomized, double-blind, parallel-group, bupivacaine- and placebo-controlled study to evaluate the safety, efficacy and pharmacokinetic profile of a single intraoperative administration of Exparel for postoperative analgesia in young children 0 to 1 years old undergoing multiple surgical procedures.
To develop a validated, sensitive, and accurate assay for the assessment of cellular uptake inhibition by cell surface mannose receptors due to the presence of neutralizing antibodies to ELELYSO (taliglucerase alfa) for injection that is expected to be present in the serum at the time of patient sampling. A summary of the validation exercise including supporting data, a summary of the development data supporting assay suitability for parameters not assessed in the validation exercise, and the assay SOP will be provided to FDA.
To conduct an assessment of neutralizing anti-drug antibody (ADA) response and presence of antibodies against plant-specific sugars in ELELYSO (taliglucerase alfa) for injection in patient plasma samples. Validated assays (developed under 1895-1, 1895-2 and 1895-3) capable of sensitively detecting neutralizing ADA responses and antibodies to plant-specific sugars that are expected to be present at the time of patient sampling will be used. The neutralizing ADA response, cellular uptake inhibition and the presence of plant-specific sugar antibodies will be evaluated in all archived sampling time points available from all patients in Phase 3 trials (PB-06-001, PB-06-002, PB-06-003, and PB-06-005). Analysis will evaluate immunogenicity rates and individual patient titers to assess the impact of neutralizing antibody levels, cellular uptake inhibition, and plant-specific sugar antibody levels on parameters of safety as well as on the pharmacokinetics (PK), pharmacodynamics (PD), and efficacy of ELELYSO (taliglucerase alfa) for injection where data are available.
To evaluate the long-term safety and efficacy of ELELYSO (taliglucerase alfa) for injection in a registry of Gaucher disease patients being treated with ELELYSO (taliglucerase alfa) for injection. Detailed clinical status information will be collected at study entry and on an annual basis for 10 years. An interim report will be submitted after completion of the first 5 years of the study.
To evaluate the effect of ELELYSO (taliglucerase alfa) for injection on pregnancy and fetal outcomes, and to collect detailed clinical status information on newborns and infants whose mothers are treated with ELELYSO (taliglucerase alfa) for injection during lactation. This study may be completed as a sub-study within the registry (1895-5). An interim report will be submitted after completion of the first 5 years of the study.
Conduct a trial in 100 evaluable pediatric patients with plaque psoriasis of the scalp and body ages 12 to 16 years, 11 months, to evaluate the safety and effect of Taclonex® (calcipotriene and betamethasone dipropionate) Topical Suspension, 0.005%/0.064% on calcium metabolism. Evaluate the hypothalamic-pituitary axis and pharmackokinetics of the two drug components, calcipotriene and betamethasone dipropionate, in a subset of at least 30 patients treated with Taclonex®  Topical Suspension under maximal use conditions.
Deferred pediatric study under PREA for the treatment of major depressive disorder in pediatric patients aged 7 to 17. Conduct a study to obtain data on the efficacy and safety of vilazodone in the relevant pediatric population. This must be a placebo-controlled and active-controlled (fluoxetine) study. This study must be a fixed-dose study.
Deferred pediatric study under PREA for the treatment of major depressive disorder in pediatric patients aged 7 to 17. Conduct a second study to obtain data on the efficacy and safety of vilazodone in the relevant pediatric population. This must be a placebo-controlled and active-controlled (fluoxetine) study. This study may be a fixed-dose study.
A descriptive observational cohort study of insertion, localization, and removal related events associated with Nexplanon use. The proposed protocol should include details on the study design, methodology, and analysis plan. This study will need to include a minimum of 5,000 patients who received Nexplanon. Interim status reports to include numbers of subjects enrolled and information on insertion and removal events will be submitted to this NDA at least annually.
To complete the clinical trial of hydroxyprogesterone caproate in women with a singleton pregnancy who had a previous spontaneous preterm birth (Protocol #17P-ES-003).
To complete the clinical follow-up study (Protocol #17P-FU-004) of children born to women who participated in Protocol #17P-ES-003.
Conduct an open-label, single dose, single arm, tolerability, PK/PD and safety study of dabigatran etexilate given at the end of standard anticoagulant therapy in children aged less than 1 year old.
A clinical trial to assess the safety, efficacy, and pharmacokinetics of Ravicti (glycerol phenylbutyrate) and its metabolites (PBA, PAA and PAGN) during Ravicti (glycerol phenylbutyrate) treatment in pediatric patients with Urea Cycle Disorders who are under 2 months of age.
A clinical trial to assess the safety, efficacy, and pharmacokinetics of Ravicti (glycerol phenylbutyrate) and its metabolites (PBA, PAA and PAGN) during Ravicti (glycerol phenylbutyrate) treatment in pediatric patients with Urea Cycle Disorders who are ages 2 months to less than 2 years.
A randomized, controlled clinical trial to assess the safety and efficacy of Ravicti (glycerol phenylbutyrate) in patients with Urea Cycle Disorders who are treatment naïve to phenylbutyrate.
A prospective study in the United States which includes the five year period of time after introduction of Cayston (aztreonam for inhalation) to the market to determine if decreased susceptibility to aztreonam is increasing in Pseudomonas aeruginosa from cystic fibrosis (CF) patients. Provide a detailed protocol to the Agency for review and comment before commencing the study. Interim reports of changes in P. aeruginosa susceptibility from CF patients should be submitted annually for five years. After the first year, the report should be cumulative.
Conduct a prospective, randomized, placebo-control, double-blinded efficacy/safety trial of Potiga (ezogabine) for the treatment of partial-onset seizures in children aged 1 month to <2 years old. This study must also utilize endpoints and assessment methods best suited to this pediatric age group.
A five-year prospective epidemiological study using a large healthcare claims database to determine the incidence of thyroid cancer among patients with type 2 diabetes exposed to Victoza (liraglutide [rDNA origin]) Injection and patients with type 2 diabetes not exposed to Victoza (liraglutide [rDNA origin]) Injection, as well as the incidence of serious hypoglycemia, pancreatitis, hypersensitivity, and overall malignant neoplasms.
A medullary thyroid carcinoma case series registry of at least 15 years duration to systematically monitor the annual incidence of medullary thyroid carcinoma in the United States and to identify any increase related to the introduction of Victoza (liraglutide [rDNA origin]) Injection into the marketplace. This study will also establish a registry of incident cases of medullary thyroid carcinoma and characterize their medical histories related to diabetes and use of Victoza (liraglutide [rDNA origin]) Injection.
To conduct a clinical trial that assesses the agreement between Da Tscan imaging results and diagnostic outcomes among non-Caucasian and Caucasian patients. This trial will be designed and conducted in a manner that allows a comparison of the results between non-Caucasian and Caucasian patients.
A Randomized, Multicenter, Double Masked, Parallel-Group Study Assessing Safety and Efficacy of Loteprednol Etabonate Ophthalmic Gel, 0.5% versus Prednisolone Acetate Ophthalmic Suspension, 1% for the Treatment of Intraocular Inflammation Following Cataract Surgery for Childhood Cataract.
Deferred pediatric study under PREA to assess the pharmacokinetics, safety, and tolerability in pediatric patients 6 to 16 years of age with minor soft tissue injuries.
A deferred pediatric study under PREA for the acute treatment of agitation associated with schizophrenia or bipolar I disorder in pediatric patients ages 10 to 17 years. A study to obtain pharmacokinetic data and provide information pertinent to dosing of Adasuve (loxapine) inhalation powder in the relevant population.
A deferred pediatric study under PREA for the acute treatment of agitation associated with schizophrenia or bipolar I disorder in pediatric patients ages 10 to 17 years. A study of the efficacy and safety of Adasuve (loxapine) inhalation powder in the relevant pediatric population.
Conduct a large, non-randomized, open-label, postmarketing observational study to assess the risks of bronchospasm and related respiratory adverse events and serious outcomes (e.g., hospitalization, intubation, mechanical ventilation, or rescue medication for the management of respiratory reactions) associated with Adasuve (loxapine) inhalation powder treatment. The study must have a large sample size (approximately 10,000 patients exposed to Adasuve (loxapine) inhalation powder), in order to adequately characterize the frequency, nature, and severity of the risk of bronchospasm. The study must assess the use of Adasuve (loxapine) inhalation powder as used in clinical practice under the requirements of the REMS for Adasuve (loxapine) inhalation powder and per the product labeling.
A clinical trial to assess the effect of mild, moderate and severe renal impairment on the pharmacokinetics of phentermine.
A juvenile rat toxicology study. The study should utilize animals of an age range and stage(s) of development that are comparable to the intended pediatric population; the duration of dosing should cover the intended length of treatment in the pediatric population. In addition to the usual toxicological parameters, this study should evaluate effects of dimethyl fumarate on growth, reproductive development, and neurological and neurobehavioral development.
A large, long-term, prospective observational study in adult patients with relapsing multiple sclerosis, with the primary objective of determining the nature and incidence of serious infections including opportunistic infections, leiomyomata, malignancies including renal cell cancers, and other serious adverse events including serious renal and hepatic events and other medically significant events occurring with marketed use of Tecfidera (dimethyl fumarate). The study should include characterization of the finding of urinary ketones. A minimum of 5000 multiple sclerosis patients treated with Tecfidera (dimethyl fumarate) should be enrolled and followed for a minimum of 5 years. The final protocol should reflect agency agreement and be submitted prior to starting the study.
Conduct a clinical trial to determine the pharmacokinetics of romidepsin in advanced cancer patients with moderate and severe hepatic impairment. Submit the protocol for agency review prior to commencing the trial.
A pediatric study to evaluate pharmacokinetics (PK), efficacy for symptomatic relief of non-infectious diarrhea, and safety with different doses of Fulyzaq (crofelemer) over a four week period in HIV-positive pediatric patients, ages 1 month to 17 years of age, on anti-retroviral therapy.
A two-year rodent carcinogenicity study of orally administered crofelemer in the rat. The carcinogenicity protocol will be submitted for Special Protocol Assessment (SPA) prior to initiating the study.
An in vivo study in human subjects to evaluate whether crofelemer inhibits CYP 3A4 using a probe that is a pure substrate of CYP 3A4.
Deferred pediatric study under PREA for the treatment of hyperphosphatemia and chronic kidney disease on dialysis in pediatric patients ages 0-18.
Conduct a study to evaluate the effects of Impavido (miltefosine) on spermatogenesis and male hormones in patients with leishmaniasis receiving Impavido (miltefosine) treatment. Evaluations will include semen volume, sperm count, sperm concentration and motility as well as evaluation of total testosterone and FSH.
Conduct a dedicated QT study in leishmaniasis patients receiving Impavido (miltefosine) treatment to evaluate the effects of Impavido (miltefosine) on the QT interval. ECGs and PK samples will be obtained to identify potential effects of Impavido (miltefosine) on the QT interval or other ECG parameters.
Conduct a descriptive study regarding efficacy outcome and adverse reactions in patients with leishmaniasis who weigh more than 75kg.
A milk-only lactation trial in lactating women receiving Linzess (linaclotide) therapeutically to assess concentrations of linaclotide and its active metabolite in breast milk using a validated assay in order to appropriately inform the Nursing Mothers' subsection of the labeling
A prospective, randomized, controlled clinical trial that will assess the safety and efficacy of Cysview in the detection of carcinoma in situ of the bladder.
Deferred pediatric study of pharmacokinetics and safety under PREA for the treatment of moderate to severe pain where an opioid analgesic is appropriate in pediatric patients ages 2 to 17 years.
Deferred pediatric study of pharmacokinetics, safety and efficacy under PREA for the treatment of moderate to severe pain where an opioid analgesic is appropriate in pediatric patients ages birth to 2 years.
Deferred pediatric study under PREA for the treatment of overactive bladder in the subgroup of pediatric patients with neurologic disease ages 6 to 16 years, 11 months.
A single- and repeated-dose pharmacodynamics and pharmacokinetics trial of Giazo tablets administered orally to pediatric patients ages 12 years to less than 17 years with mildly to moderately active ulcerative colitis to support pediatric labeling.
A placebo-controlled clinical trial in female patients with active ulcerative colitis to assess the efficacy of an eight week course of Giazo therapy for the treatment of active disease in this patient population.
A pharmacokinetic trial in patients to evaluate the effect of concomitant therapy with antibiotics commonly used in ulcerative colitis on the metabolism of balsalazide following administration of Giazo.
A dose-ranging clinical trial to evaluate the risk-benefit ratio of Lusedra in patients classified as ASA III or IV, adult patients weighing less than 60 kg, and geriatric patients.
A study in adolescents and younger pediatric patients receiving emetogenic chemotherapy (HEC or MEC) to evaluate fosaprepitant PK, safety, and tolerability.
A drug utilization study to better characterize the reporting rates of adverse events associated with the long-term use of Korlym (mifepristone). These data will provide a denominator for the adverse events of special interest (endometrial hyperplasia and/or vaginal bleeding, retinopathy, and major adverse cardiovascular events) reported through enhanced pharmacovigilance and associated with long-term exposure to Korlym (mifepristone) therapy.
A drug-drug interaction clinical trial to determine a quantitative estimate of the change in exposure of mifepristone following co-administration of ketoconazole (a strong CYP3A4 inhibitor).
A 10 year, observational study to prospectively evaluate the incidence of fibrosing colonopathy in patients with cystic fibrosis treated with Ultresa (pancrelipase) Delayed-Release Capsules in the U.S. and to assess potential risk factors for the event.
An observational study to estimate the prevalence of antibody seropositivity to selected porcine viruses in patients taking Ultresa (pancrelipase) Delayed-Release Capsules compared with an appropriate control group.
Phase 2 open-label trial to evaluate the safety, efficacy and pharmacokinetics of peginesatide injection for maintenance treatment of anemia in pediatric subjects with chronic kidney disease (CKD) on hemodialysis who are currently stable on ESA therapy.
Phase 2 open-label follow-up trial to evaluate the safety, tolerability, and efficacy of peginesatide injection for maintenance treatment of anemia in pediatric subjects with CKD on hemodialysis.
Phase 3 randomized, active-controlled, open-label, multicenter trial to evaluate the efficacy and safety of peginesatide injection for maintenance treatment of anemia in pediatric subjects with CKD on dialysis.
Phase 3 open-label follow-up extension trial to evaluate the safety, tolerability and efficacy of peginesatide injection for maintenance treatment of anemia in pediatric subjects with CKD on dialysis.
Post marketing comparative observational safety study of dialysis patients (both incident and prevalent) receiving Omontys versus a U.S. marketed ESA to assess safety of long term use. Provide the protocol and analysis plan for FDA review and concurrence prior to commencing the study. The between-group comparison must balance by site and by patient characteristics that are important for cardiovascular, stroke and mortality outcome. Pre-specify the study questions, the testable hypothesis and analysis plan.
Conduct a prospective randomized, controlled trial (RCT) of Omontys versus a U.S. marketed ESA in anemic patients with chronic kidney disease (CKD) who are in the time interval around the initiation of dialysis (defined as incident dialysis patients for this purpose) and at least a reasonable proportion (to be decided during the protocol development) who have not received an ESA previously. Continue the trial through the stabilization period on dialysis and the maintenance period on dialysis sufficient to assess the comparative safety (and efficacy) of Omontys using a primary outcome of Major Adverse Cardiovascular Events (MACE) with supporting safety evidence including SAEs, AEs leading to discontinuation, and study/drug discontinuations. Use a blinded independent panel to adjudicate potential MACE events. Stratify randomization for important adverse cardiovascular risk factors. Justify the sample size and risk ratio chosen to evaluate the MACE endpoint. Justify the choice of active control comparator and dosing plan for both treatment arms. Assess transfusion use and identify the reasons that transfusions are given (e.g., active bleeding, pre-op for a procedure, and symptoms).
To conduct a study to determine whether varenicline, as part of an overall smoking cessation program, is effective in achieving and maintaining smoking cessation in tobacco-addicted adolescents, ages 12 through 16, inclusive, to determine a safe and effective dose, and to document the ability of treating physicians to select appropriate patients. You will need to develop a means for determining reliable criteria for appropriate patient selection of tobacco-addicted teens so that teenage smokers who are not addicted will not be recruited, and so that labeling can convey these criteria to physicians who may wish to use the drug in adolescents.
To conduct a prospective epidemiologic cohort study in pregnant women who are smokers and who are exposed to varenicline at the time of conception or any time during pregnancy. This information will be used to assess the potential risk to the fetus and/or live born infant.
Conduct an extension of the randomized, double-blind, active- and placebo controlled trial to compare the risk of clinically significant neuropsychiatric events in individuals using Chantix (varenicline), bupropion, nicotine replacement therapy, or placebo, as aids to smoking cessation. The non-treatment, 28-week extension trial will be aimed at collecting and comparing data on cardiovascular safety for all participants, allowing for a total of 52 weeks of cardiovascular safety data collection.
Deferred pediatric study under PREA, a pharmacokinetic and safety study for the treatment of moderate to severe chronic pain requiring continuous, around-the clock opioid treatment for an extended period of time in pediatric patients ages 7 through 16.
Conduct an open-label trial to evaluate the pharmacokinetics, safety and tolerability of nintedanib in patients with hepatic impairment (Child-Pugh Classification A and B) compared to healthy subjects
Pharmacokinetic, safety, and efficacy study in subjects from birth to 2 years of age.
Deferred pediatric study under PREA for the treatment of major depressive disorder in pediatric patients aged 7 to 17. Conduct a study to obtain data on the efficacy and safety of desvenlafaxine in the relevant pediatric population.
Submit the results of the protocol-specified final analysis of overall survival, along with datasets and analysis SAS programs, from Study 14874, A randomized, double-blind, placebo-controlled phase III study of regorafenib plus best supportive care versus placebo plus best supportive care for subjects with metastatic and/or unresectable gastrointestinal stromal tumors (GIST) whose disease has progressed despite prior treatment with at least imatinib and sunitinib.
Subpart I Confirmatory Studies: We note your commitment to provide, within 1 month of the date of this letter, detailed protocols to address the requirement to conduct postmarketing studies, such as field studies, to verify and describe pyridostigmine's clinical benefit and to assess its safety when used as indicated when such studies are feasible and ethical. We would be happy to meet with you to discuss the design of these protocols prior to their submission.
A randomized dose-comparison trial in patients with progressive metastatic medullary thyroid cancer comparing the safety and activity of oral cabozantinib 140 mg daily to a biologically active and potentially safer lower daily cabozantinib dose. The trial will be designed to test non-inferiority of the lower dose to the approved dose for effect on progression-free survival effect and to assess the comparative safety of the two doses.Safety assessments will include evaluation for all labeled adverse reactions and the analysis plan will provide comparisons of the incidence and severity of the following adverse reactions of cabozantinib: hemorrhage, gastrointestinal and non-gastrointestinal perforations and fistulas, hypertension, diarrhea, oral mucositis/stomatitis, and palmar-plantar erythrodysesthia (PPE) syndrome.
Submit the results of the protocol-specified final analysis of overall survival, along with datasets and analysis programs, from Protocol XL184-301.
Conduct a pediatric safety and antiviral activity study of rilpivirine with activity based on the results of virologic response over at least 48 weeks of dosing and safety monitored over 48 weeks in pediatric subjects from 4 weeks to <12 years of age.
You must conduct a PK trial in children 6 to <12 who may benefit from the drug (i.e., not in otherwise healthy pediatric volunteers). You should conduct a single and multiple dose PK trial that would characterize ibuprofen and phenylephrine profiles following single and multiple dose exposures to assess relative bioavailability compared to historical single ingredient ibuprofen PK data in adults dosed as 200 mg every 4 hours to a maximum of 1,200 mg in a 24-hour period.
You must conduct a PK trial in children 2 to <6 who may benefit from the drug (i.e., not in otherwise healthy pediatric volunteers). You should conduct a single and multiple dose PK trial that would characterize ibuprofen and phenylephrine profiles following single and multiple dose exposures to assess relative bioavailability compared to historical single ingredient ibuprofen PK data in adults dosed as 200 mg every 4 hours to a maximum of 1,200 mg in a 24-hour period.
You must conduct a PK trial in children 6 to <12 who may benefit from the drug (i.e., not in otherwise healthy pediatric volunteers). You should conduct a single and multiple dose PK trial that would characterize ibuprofen, phenylephrine, and chlorpheniramine profiles following single and multiple dose exposures to assess relative bioavailability compared to historical single ingredient ibuprofen PK data in adults dosed as 200 mg every 4 hours to a maximum of 1,200 mg in a 24-hour period.
You must conduct a PK trial in children 2 to <6 who may benefit from the drug (i.e., not in otherwise healthy pediatric volunteers). You should conduct a single and multiple dose PK trial that would characterize ibuprofen, phenylephrine, and chlorpheniramine profiles following single and multiple dose exposures to assess relative bioavailability compared to historical single ingredient ibuprofen PK data in adults dosed as 200 mg every 4 hours to a maximum of 1,200 mg in a 24-hour period.
Deferred pediatric studies under PREA for the cardiac and oncology indications in pediatric patients ages 1 year to 16 years old.
Deferred pediatric study under PREA for the treatment of hypertension in pediatric patients ages 1 to 18.
Deferred pediatric study under PREA for the treatment of Major Depressive Disorder in pediatric patients ages 7 to 17 years. A study of safety and efficacy of Oleptro (trazodone hydrochloride) extended release tablets in the relevant pediatric population. Both children (ages 7 to 11 years) and adolescents (ages 12 to 17 years) will be equally represented in the samples, and there will be a reasonable distribution of both sexes in these age strata.
Randomized, double-blind, dose-controlled clinical trial of fospropofol disodium injection in neonates (less than one month of age) undergoing sedation for procedures such as lumbar puncture, MRI, and/or circumcision. Pharmacokinetics will be studied using a population PK approach.
A randomized, single-blind, multicenter dose-ranging study to obtain pharmacokinetic data and to compare the safety and efficacy of HalfLytely and Bisacodyl Tablet versus NuLYTELY in children (6 - 11 years of age).
Deferred study under PREA to evaluate the pharmacokinetic, pharmacodynamic, and safety profiles of dexlansoprazole in patients 1 month to 11 months of age with endoscopy-proven erosive esophagitis (EE).
Deferred study under PREA to evaluate the pharmacokinetics, healing, maintenance of healing, and symptoms of endoscopy-proven erosive esophagitis (EE) in patients 1 year to 11 years of age.
Deferred study under PREA to evaluate the long-term safety of dexlansoprazole for the healing and maintenance of healing of erosive esophagitis (EE) in pediatric patients 1 month through 11 months of age, who require chronic treatment with dexlansoprazole due to underlying conditions that predispose to chronic gastroesophageal reflux disease and relapsing EE.
Deferred study under PREA to evaluate the long-term safety of dexlansoprazole for the healing and maintenance of healing of erosive esophagitis (EE) in pediatric patients 1 year through 17 years of age, who require chronic treatment with dexlansoprazole due to underlying conditions that predispose to chronic gastroesophageal reflux disease and relapsing EE.
An epidemiological study to address whether this formulation of Oxycodone HCl results in a decrease in misuse and abuse, and their consequences: overdose, death and addiction.
PK/Efficacy/Safety study in pediatric subjects ages 2 years to 17 years 11 months with tinea corporis.
A 2-year dermal rat carcinogenicity study.
Deferred pediatric study under PREA to evaluate the safety and pharmacokinetics of raltegravir in HIV-exposed neonates (born to HIV-infected mothers). This multiple-dose pharmacokinetic and safety study will evaluate raltegravir in addition to the standard of care in HIV-exposed neonates from ages 0 to 4-6 weeks. HIV-exposed neonates will have safety
A randomized and controlled pediatric study under PREA to evaluate the safety, efficacy, and pharmacokinetics of BYDUREON (exenatide extended-release for injectable suspension) for the treatment of type 2 diabetes mellitus in pediatric patients ages 10-17 years (inclusive).
A 2-year study in mice to determine the reversibility of C-cell hyperplasia, the potential of hyperplasia to progress to neoplasia, and GLP-1 receptor expression on C-cells after 6 months of treatment with exenatide for injectable suspension.
A study to evaluate and compare GLP-1 receptor expression/density on human, rat, and mouse thyroid C-cells. This should include evaluation of mouse tissue from PMR 1860-2 following exenatide for injectable suspension treatment for 6 months as well as following 1.5 year recovery.
A study to evaluate the dependence of the GLP-1 receptor for exenatide-induced C-cell hyperplasia and investigate the expression of growth regulatory genes in wild-type and GLP-1 receptor knock-out mice.
A medullary thyroid carcinoma case series registry of at least 15 years duration to systematically monitor the annual incidence of medullary thyroid carcinoma in the United States and to identify any increase related to the introduction of BYDUREON (exenatide for injectable suspension) into the marketplace. This study will also establish a registry of incident cases of medullary thyroid carcinoma and characterize their medical histories related to diabetes and use of BYDUREON (exenatide for injectable suspension).
A randomized, double blind, placebo-controlled trial evaluating the effect of BYDUREON (exenatide extended-release for injectable suspension) on the incidence of major adverse cardiovascular events (MACE) in subjects with type 2 diabetes mellitus (T2DM). The trial must also assess adverse events of interest including the long-term effects of BYDUREON (exenatide extended-release for injectable suspension) on potential biomarkers of medullary thyroid carcinoma (e.g., serum calcitonin) as well as long-term effects on thyroid neoplasms, pancreatitis (including hemorrhagic and necrotizing forms), pancreatic cancer, serious injection site reactions (including nodules), allergic/hypersensitivity events, serious hypoglycemia, and renal disorders.
A randomized trial comparing pralatrexate in combination with systemic bexarotene versus systemic bexarotene alone in patients with cutaneous T-cell lymphoma (CTCL) who are refractory to at least one prior systemic therapy. Description of trial: This will be a Phase 3 multi-center, randomized clinical trial in patients with CTCL. The primary endpoint will be progression-free survival (PFS). Response rate will be a secondary endpoint. Prior to initiation of the Phase 3 trial, a Phase 1 trial will be conducted to determine the maximum tolerated dose (MTD) of the combination.
A clinical pharmacokinetic trial in patients with renal impairment to include patients with severe renal impairment. Description of trial: This will be a Phase 1 clinical trial to evaluate the pharmacokinetics of pralatrexate in relapsed/refractory lymphoma patients (B-cell, T-cell, and Hodgkin's Lymphoma) with mild to severe renal impairment. Three cohorts (N=6 per cohort) will be enrolled in this study for a total of 18 patients. Cohorts will be based on the severity of renal impairment, i.e., cohort A = severely impaired (Creatinine clearance Cockroft-Gault (CrCl C-G) < 30 mL/min), cohort B = moderately impaired (CrCl C-G = 30-50 mL/min), and cohort C = mildly impaired patients (CrCl C-G = 50-80 mL/min). The pralatrexate dose for cohorts A and B will be determined based on the pharmacokinetics experience from the PROPEL study. Cohort C will be dosed at the recommended dose (30 mg/m2) since patients with mild renal impairment were included in the PROPEL trial. Patients will undergo extensive plasma and urine collections following the first dose of FOLOTYN.
Pharmacokinetic and safety study in subjects >2 years to <17 years of age.
A study to determine patient compliance with dosing instructions in the setting of actual clinical use. The study should enroll patients representing the clinical population using the drug, and should assess the incidence, nature, causes, and consequences of departures from dosing instructions. The study should include a comparator group that is taking other drugs approved for insomnia characterized by difficulty with sleep maintenance. Submit a draft protocol approximately 12 months prior to the protocol submission date to allow for time to negotiate the details of the protocol.
Deferred pediatric study of tizanidine for acute treatment of spasticity in pediatric patients ages 0 to 16.
Inclusion of a new target population, men with osteoporosis, in the required postmarketing study entitled, “The Denosumab Global Postmarketing Safety Observational Study"
Inclusion of a new target population, men with osteoporosis, in the required postmarketing study entitled, “The Prolia Postmarketing Active Safety Surveillance Program”
An open-label study to assess the effect of Enstilar® (calcipotriene and betamethasone dipropionate) Foam, 0.005%/0.064% on calcium metabolism in 100 evaluable pediatric subjects aged 12 years to 16 years and 11 months with plaque psoriasis of the scalp and body. Pharmacokinetics (PK) of Enstilar® Foam and assessment of hypothalamic-pituitary axis (HPA) suppression will be conducted in a sub-set of 30 subjects with at least moderate plaque psoriasis under maximal use conditions.
To conduct an adequate and well-controlled long-term maintenance study to evaluate the efficacy and safety of asenapine in the treatment of adults with acute manic or mixed episodes associated with bipolar I disorder. The maintenance study should be appropriately designed to assess the efficacy of asenapine in preventing all types of mood episodes associated with bipolar disorder (depression, mania, and mixed episodes).
A randomized and controlled pediatric study under PREA to evaluate the efficacy and safety of liraglutide for the treatment of type 2 diabetes mellitus in pediatric patients ages 10 to 16 years 11 months. This study must not be initiated until at least 1 month after you have submitted the complete study report for your postmarketing requirement 1583-5 (13-week mouse study to determine if liraglutide-induced focal C-cell hyperplasia depends on a thyroid GLP-1 receptor and rearranged-during-transfection [RET] proto-oncogene activation).
Deferred pediatric trial under PREA to evaluate the safety and efficacy of multiple doses of mometasone MDI in children 5 to 11 years of age with asthma.
A deferred pediatric study under PREA for the treatment of major depressive disorder in pediatric patients ages 12 to 17 years. Conduct a study to obtain data on the pharmacokinetics (PK), efficacy and safety of levomilnacipran in the relevant adolescent population (ages 12 to 17 years). This study must be a placebo-and active-controlled (escitalopram or fluoxetine) fixed-dose study. You should submit data from population PK modeling in adults to justify dose selection and PK sampling schedule for this adolescent study, at least 3 months prior to submitting the protocol. When the appropriate number of PK samples becomes available from this adolescent study (PMR#1943-1), an interim population PK analysis should be conducted to determine the dosing and regimen for the second efficacy and safety study in children and adolescents (ages 7-17 years).
A deferred pediatric study under PREA for the treatment of major depressive disorder in pediatric patients ages 7 to 17 years. Conduct a study to obtain data on the efficacy and safety of levomilnacipran in the relevant pediatric population (ages 7-17 years). This study must be a placebo-and active-controlled (fluoxetine) study. This study may be a fixed-dose study. You should submit data from population PK model using data from adults and adolescents (PMR# 1943-1) to justify the dose(s) and the schedule for sparse PK sampling, at least 3 months prior to submitting the protocol.
To support the use of levomilnacipran in children less than 12 years of age, you must conduct a study to assess the safety of levomilnacipran in juvenile rats. This study must include evaluation of neurological/behavioral development and reproductive development. You should submit the protocol for our comments prior to initiating the study. You may conduct this study concurrently with the pediatric clinical trials.
Test for the individual component phytosterol content in all batches of Clinolipid (lipid injectable emulsion, USP) 20%, manufactured over a three year period, using the method developed under PMR 2085-1. Based on these test results, establish limits for each of the individual component phytosterols in Clinolipid (lipid injectable emulsion, USP) 20% in the product specification.
Develop and validate an appropriate analytical method for measuring phytosterol levels in plasma.
Randomized controlled trial to evaluate the risk of developing essential fatty acid deficiency (EFAD) in pediatric patients, including neonates, receiving either  Clinolipid (lipid injectable emulsion, USP) 20% or standard of care soybean oil based lipid emulsion. Full essential fatty acid profiles should be evaluated according to standards set by major national reference laboratories. Genetic polymorphisms in the fatty acid desaturase genes (FADS) FADS1 and FADS2 should be determined in at least a subset of patients. The cut-off values for EFAD (e.g., suspected, mild and severe) should be established prior to the study. Plasma phytosterol levels should be assessed in patients using validated analytical assay methods developed under PMR 2085-4.
Randomized controlled trial in pediatric patients, including neonates, comparing Clinolipid (lipid injectable emulsion, USP) 20% with a phytosterol-depleted formulation of Clinolipid (lipid injectable emulsion, USP) 20% and another standard-of-care lipid emulsion to evaluate the incidence of liver injury, including either parenteral nutrition-associated liver disease (PNALD) or intestinal failureassociated liver disease (IFALD). This trial should be initiated after the results from PMRs 2085-1, 2085-2, and 2085-6 are available. The phytosterol content of the phytosterol-depleted formulation of Clinolipid (lipid injectable emulsion, USP) 20% should be documented using validated analytical assay methods developed under PMR 2085-1. Plasma phytosterol levels should be assessed in patients using validated analytical assay methods developed under PMR 2085-4.
Randomized clinical trial in hospitalized patients receiving either Clinolipid (lipid injectable emulsion, USP) 20% or other standard-of-care IV lipid emulsions to evaluate clinical safety outcomes of sepsis and mortality. In addition, the trial will evaluate the requirement for ventilator support and length of stay in ICU and hospital.
A randomized, controlled, parallel group, superiority study in pediatric patients ages 10 through 17 years to evaluate the safety and efficacy of glatiramer acetate compared to an appropriate control for the treatment of relapsing forms of multiple sclerosis.
A juvenile animal toxicology study in rats to evaluate the effects of glatiramer acetate on growth, reproductive development, and neurological and neurobehavioral development.
Deferred pediatric study under PREA for the treatment of major depressive disorder in pediatric patients aged 7 to 17. Conduct a study to obtain data on the efficacy and safety of desvenlafaxine in the relevant pediatric population.
Continue follow-up of patients (on treatment and in protocol defined posttreatment follow-up) enrolled in Study 200-WW at least an additional 2 years past the March 28, 2011 cut-off date. Submit the Final Report, which will consist of an updated report containing, at a minimum, data through March 28, 2013.
Deferred pediatric study under PREA for the treatment of acute deep vein thrombosis when administered in conjunction with warfarin sodium in pediatric patients ages one to 16 years.
Deferred pediatric study under PREA for the treatment of acute pulmonary embolism when administered in conjunction with warfarin sodium in pediatric patients ages one to 16 years.
Randomized clinical trial comparing Clinolipid (lipid injectable emulsion, USP) 20% to another standard-of-care IV lipid emulsion, evaluating long-term risk of developing essential fatty acid deficiency (EFAD) and parenteral nutrition associated liver disease (PNALD) in patients receiving chronically-administered total parenteral nutrition (TPN). Plasma phytosterol levels should be assessed in patients using validated analytical assay methods developed under PMR 2085-4.
Based on the data obtained in PMR #1876-1 and PMR#1876-2, submit a toxicological risk assessment for all leachables in the drug product detected during stability. Your risk assessment should include data to justify the safety of the leachables taking into consideration the maximum daily dose of the identified materials for this drug product. In general, we require that any potentially genotoxic or carcinogenic leachables be reduced to levels that would result in NMT 1.5 mcg/day. Non-genotoxic or carcinogenic leachables present at levels that would result in exposures below 5 mcg/day will not require a toxicological risk assessment; however, you must provide adequate toxicology safety justification for compounds detected at levels that would result in greater or equal to 5 mcg/day.
To commit to development and validation of an assay to detect the presence of neutralizing antibodies to Oncaspar. Validation studies will provide an assessment of the sensitivity (in mass units of antibodies), specificity, and reproducibility of the assay. The cutpoint for the assay (the value that discriminates positive samples from negative samples) will be determined by using samples from unexposed patients and validated positive controls. This value will be used to determine the number and percent of patients who develop neutralizing antibodies to the Oncaspar during clinical trials.
Deferred study under PREA to evaluate the pharmacokinetics, pharmacodynamics, and safety of omeprazole in patients 1 month to 11 months of age with erosive esophagitis (EE).
Conduct an open-label, repeated treatment, pediatric study in 130 patients, 12-16 years of age with severe axillary hyperhidrosis that is inadequately managed with topical agents.
Conduct an open-label, randomized, parallel-group, active-controlled, multicenter, non-inferiority efficacy study of dabigatran etexilate versus standard of care for venous thromboembolism treatment in children from birth to less than 18 years of age. Include PK/PD (sparse sampling) in all patients. The anticipated enrollment is 240 evaluable patients for the efficacy analysis. Enroll adequate numbers of patients in 3 age groups, from 12 to <18 years of age, from 2 to <12 years of age, from birth to <2 years of age. Submit the clinical study report with datasets.
Conduct an open label, single arm trial to evaluate safety of dabigatran etexilate for secondary prevention of venous thromboembolism in children aged 0 to less than 18 years. The anticipated enrollment is 100 patients. Submit the clinical study report with datasets.
Phase 2 trial in 50 pediatric patients 1month to 16 years of age to evaluate pharmacokinetics, pharmacodynamics, and safety data in patients with solid tumors without bone marrow involvement. Submit the protocol for Agency review and concurrence prior to beginning the trial and in advance of the final protocol submission date so that agreement on the essential trial elements can be reached.
To conduct an assessment for neutralizing antibodies using the validated assay developed under PMR 3 in all patients with binding antibodies to tbo-filgrastim or native G-CSF and in all patients with evidence of unexplained, persistent neutropenia. Sicor should provide a listing of the clinical trials in which this assessment will be conducted.
Deferred requirement for development of an age appropriate formulation: Develop an age appropriate formulation to allow for dosing for ages 1 to <5 years.
PMR-EC-1206 A Phase II, Open-Label, Multi-Center Study to Compare the Pharmacokinetics of Tacrolimus in Stable Pediatric Allograft Recipients Converted from a Prograf® Based Immunosuppressive Regimen to a Tacrolimus Prolonged Release, Advagraf® Based Immunosuppressive Regimen, Including a Long-Term Follow-Up
Identify an optimal dose of INJECTAFER (ferric carboxymaltose injection) for the pediatric patient population. Conduct one or more pharmacokinetic (PK) and pharmacodynamic (PD) trials in pediatric patients aged 1 to <17 years with iron deficiency anemia sufficient to justify and to characterize the dose to be tested in a confirmatory clinical trial of safety and efficacy. Identify the most relevant PD endpoints to measure.
Determine the safety and efficacy of INJECTAFER (ferric carboxymaltose injection) in pediatric patients aged 1 to <17 years with iron deficiency anemia by conducting a randomized, active-controlled clinical trial.
A randomized, controlled trial to rule out a moderate increase in the risk of serious cardiovascular events with tocilizumab, e.g., stroke, non-fatal MI, cardiovascular death.
An open-label pharmacokinetic and safety study or studies of an age appropriate formulation of indomethacin in pediatric patients 6 through 17 years of age
An open-label pharmacokinetic and safety study or studies of an age appropriate formulation of indomethacin in pediatric patients 2 through 6 years of age
A pharmacokinetic, safety, and efficacy study or studies of an age appropriate formulation of indomethacin in pediatric patients 1 through 2 years of age
Complete the trial and submit the final report of CNTO328MCD2002 “An Openlabel, Multicenter Study to Evaluate the Safety of Long-term Treatment with Siltuximab in Subjects with Multicentric Castleman’s Disease.”
A controlled efficacy and safety study of lurasidone in the treatment of pediatric patients (ages 10 to 17 years) with a diagnosis of depressive episode associated with bipolar disorder
A long-term, open-label safety study of study of lurasidone in the treatment of pediatric patients (ages 10 to 17 years) with a diagnosis of depressive episode associated with bipolar disorder
A placebo-controlled, randomized withdrawal maintenance study of lurasidone in patients with bipolar I disorder
A clinical trial to assess the risk of QT prolongation with Zubsolv sublingual tablet, i.e., a thorough QT (tQT) trial.
A 26-week randomized, double-blind, placebo controlled study of the safety, efficacy, and pharmacokinetics (PK) of Trulicity (dulaglutide) for the treatment of type 2 diabetes mellitus in pediatric patients ages 10 to 17 years (inclusive) with or without concomitant metformin therapy, followed by a 26-week open-label extension. As part of this study, sparse blood samples for population PK and exposures-response analysis will be collected. This trial should not be initiated until after the data from the juvenile toxicity study have been submitted to and reviewed by the Agency.
A study to evaluate dulaglutide toxicity in immature rats.
A medullary thyroid carcinoma registry-based case series of at least 15 years duration to systematically monitor the annual incidence of medullary thyroid carcinoma in the United States and to identify any increase related to the introduction of Trulicity (dulaglutide) into the marketplace. This study will also establish a registry of incident cases of medullary thyroid carcinoma and characterize their medical histories related to diabetes and use of Trulicity (dulaglutide).
A 26-week randomized, controlled trial comparing once weekly Trulicity (dulaglutide), 0.75 mg and 1.5 mg, with insulin glargine on glycemic control in patients with type 2 diabetes mellitus and moderate or severe renal impairment, with a 26-week controlled extension.
Conduct a trial to evaluate the pharmacokinetics, safety and treatment response (using sustained virologic response) of SOVALDI (sofosbuvir) as a component of an antiviral treatment regimen in pediatric subjects 3 through 17 years of age with chronic hepatitis C.
Collect and analyze long-term safety data for subjects enrolled in the pediatric SOVALDI (sofosbuvir) pharmacokinetic, safety and efficacy trial described in 2110-1. Data collected should include at least 3 years of follow-up in order to characterize the long-term safety of sofosbuvir in pediatric subjects, including growth assessment, sexual maturation and characterization of sofosbuvir resistance-associated substitutions in viral isolates from subjects failing therapy.
Establish a pregnancy registry of patients with RA who become pregnant while on anti-rheumatic therapy, including  Adalimumab as well as other medications, which will run for 3 years.
Submit the final report and datasets for the ongoing trial GS-US-334-0153, entitled, “A Phase 3B Randomized, Open-Label, Multi-Center Trial Assessing Sofosbuvir + Ribavirin for 16 or 24 Weeks and Sofosbuvir + Pegylated Interferon + Ribavirin for 12 Weeks in Subjects with Genotype 2 or 3 Chronic HCV Infection”.
Submit the final report and datasets for the ongoing trial GS-US-334-0125, entitled, “A Phase 2, Multicenter, Open-Label, Randomized Study to Investigate the Safety and Efficacy of GS-7977 and Ribavirin Administered for 48 Weeks in Patients Infected with Chronic HCV with Cirrhosis and Portal Hypertension with or without Liver Decompensation”.
Submit an interim report from the ongoing study GS-US-248-0122, entitled, “A Long Term Follow-up Registry for Subjects Who Achieve a Sustained Virologic Response to Treatment in Gilead-Sponsored Trials in Subjects with Chronic Hepatitis C Infection”, with the three year follow-up data from: P7977-1231 (FISSION), GS-US-334-0107 (POSITRON), GS-US-334-0108 (FUSION), GSUS-334-0110 (NEUTRINO), GS-US-334-0133 (VALENCE), GS-US-334-0123 (PHOTON-1).
Genzyme commits to designing and implementing an infantile-onset Pompe disease study to assess growth and development with treatment with alglucosidase alfa, in patients who are less than one year of age at study entry.  This study is to include blinded assessments of growth (including standardized measurements of recumbent length, height, weight, and head circumference), developmental testing (the scales used need to be prospectively agreed upon), auditory and visual screening, neuro-imaging, and antibody assessments at 6- to 12-month intervals over a 10-year period.
Conduct a pediatric trial to evaluate the pharmacokinetics, safety and antiviral activity (efficacy) of abacavir/dolutegravir/lamivudine FDC tablets in HIV infected pediatric subjects 2 years to less than 6 years of age. The safety and antiviral activity (efficacy) of abacavir/dolutegravir/lamivudine FDC tablets in pediatric subjects should be evaluated for a minimum of 24 weeks.
Conduct a pediatric trial to evaluate the pharmacokinetics, safety and antiviral activity (efficacy) of abacavir/dolutegravir/lamivudine FDC tablets in HIV infected pediatric subjects 6 years to less than 12 years of age and in children older than 12 years of age who weigh less than 40 kg. The safety and antiviral activity (efficacy) of abacavir/dolutegravir/lamivudine FDC tablets in pediatric subjects should be evaluated for a minimum of 24 weeks
Conduct a safety and efficacy study in pediatric patients with chronic idiopathic constipation ages ¡Ý 6 Years to <18 Years (SAG/0211PFC-1131)
Conduct a safety and efficacy study in pediatric patients with chronic idiopathic constipation ages ¡Ý 6 Months to < 6 Years.
Collect, analyze, and submit data on subjects with cirrhosis including decompensated cirrhosis who achieve sustained virologic response following treatment with a sofosbuvir-based regimen to evaluate durability of virologic response and to characterize clinical outcomes such as progression or regression of liver disease, liver-related mortality, occurrence of hepatocellular carcinoma, or liver failure requiring liver transplantation. Data collected should include 5 years of follow-up.
Conduct a study of pretreatment molecular subtyping of tumors from patients treated in the postmarketing cardiac safety trial (PMR#2) and submit an exploratory analysis of the relationship of pathological complete response with the different tumor subtypes.
Conduct an open-label pharmacokinetics and safety study of Xartemis XR in pediatric patients ages 12 to less than 17 years with acute pain severe enough to require opioid treatment and for which alternative treatment options are inadequate.
Conduct an open-label pharmacokinetics and safety study of an age-appropriate formulation (oxycodone hydrochloride/acetaminophen) in pediatric patients ages 2 to less than12 years with acute pain severe enough to require opioid treatment and for which alternative treatment options are inadequate.
Conduct a pharmacokinetics, safety, and efficacy study of an age-appropriate formulation (oxycodone hydrochloride/acetaminophen) in pediatric patients ages 0 (birth) to less than 2 years with acute pain severe enough to require opioid treatment and for which alternative treatment options are inadequate.
Develop an age-appropriate formulation of Qudexy XR (topiramate) extendedrelease capsules that can be used in children ages 1 month to less than 2 years old.
A study to evaluate the pharmacokinetics (PK) and tolerability of the ageappropriate formulation of Qudexy XR (topiramate) extended-release capsules, developed in PMR 2137-1, as adjunctive therapy in children ages 1 month to less than 2 years with partial onset seizures (POS).
An adequately controlled study to assess the efficacy and safety of the ageappropriate formulation of Qudexy XR (topiramate) extended-release capsules, developed in PMR 2137-1, as adjunctive therapy in children ages 1 month to less than 2 years with POS.
Submit an enhanced pre and post-natal development study (segment III) in rats to demonstrate the safety of dexlansoprazole on developing bone. The studies must include at least 3 dose levels of dexlansoprazole and a control group and should include toxicokinetic evaluations. The dose levels must be associated with sufficient maternal plasma levels of dexlansoprazole (refer to ICH S5): http://www.ich.org/products/guidelines/safety/article/safety-guidelines.html). This study must also evaluate a subset of pups at maturity to determine the functional outcomes of the prenatal and lactation exposure. If there is inadequate exposure to dexlansoprazole in the pups in the pre- and postnatal study, you should conduct a separate juvenile animal toxicity study with dexlansoprazole.
Complete a clinical trial evaluating the potential for Tafinlar (dabrafenib) capsules to prolong the QT/QTc interval in accordance with the principles of the FDA Guidance for Industry entitled “E14 Clinical Evaluation of QT/QTc Interval Prolongation”. Submit the final report to include central tendency, categorical and concentration-QT analyses, along with a thorough review of cardiac safety data
Complete a clinical pharmacokinetic trial to determine the appropriate Tafinlar (dabrafenib) dose in patients with moderate to severe hepatic impairment in accordance with the FDA Guidance for Industry entitled “Pharmacokinetics in Patients with Impaired Hepatic Function: Study Design, Data Analysis, and Impact on Dosing and Labeling”.
Complete a clinical pharmacokinetic trial to determine the appropriate Tafinlar (dabrafenib) dose in patients with severe renal impairment in accordance with the FDA Guidance for Industry entitled “Pharmacokinetics in Patients with Impaired Renal Function: Study Design, Data Analysis, and Impact on Dosing and Labeling”.
Conduct a drug interaction trial to evaluate the effect of rifampin (a strong CYP3A4 and CYP2C8 inducer) on the repeat dose pharmacokinetics of dabrafenib in accordance with the FDA Guidance for Industry entitled “Drug Interaction Studies – Study Design, Data Analysis, Implications for Dosing, and Labeling Recommendations”. The results of this clinical trial should allow for a determination on how to dose Tafinlar (dabrafenib) capsules with regard to concomitant strong CYP3A4 and CYP2C8 inducers.
Conduct a clinical trial to evaluate if proton pump inhibitors, H2 antagonists and antacids alter the bioavailability of Tafinlar (dabrafenib) capsules. The worst case scenario can be assessed first to determine if further trials of other gastric pH elevating agents are necessary. The trial results should allow for a determination on how to dose Tafinlar (dabrafenib) capsules with regard to concomitant gastric pH elevating agents
Observational study of incidence and risk factors for uterine perforation among users and particularly when related to breastfeeding and timing of postpartum levonorgestrel intrauterine contraceptive system (IUS) [Mirena] insertion in US women.
Conduct a randomized trial that will characterize the incidence, severity and response to treatment of Tecentriq® induced immune-mediated adverse reactions, including immune-mediated pneumonitis.
Deferred pediatric study of safety and pharmacokinetics (single- and multipledose) under PREA for the relief of moderate to severe pain in patients requiring a continuous, around-the-clock opioid analgesic for an extended period of time in pediatric patients ages 7 to 17 years.
A randomized, single-blind, multicenter dose-ranging study to obtain pharmacokinetic data and to compare the safety and efficacy of HalfLytely and Bisacodyl Tablet versus NuLYTELY in children (1 - 5 years of age).
Deferred pediatric study under PREA for the treatment of rheumatoid arthritis in pediatric patients ages 2 to 17 years of age.
Develop an age appropriate formulation of Trokendi XR (topiramate) extendedrelease capsules that can be used in children 1 month to less than 6 years old.
A study to evaluate the pharmacokinetics (PK) and tolerability of an age-appropriate formulation of Trokendi XR (topiramate) extended-release capsules, developed in PMR 2080-1, in children ages 2 years to less than 6 years with partial onset seizures (POS), primary generalized tonic-clonic (PGTC) seizures, and/or Lennox-Gastaut syndrome (LGS), and evaluating bioavailability after administration once daily relative to bioavailability of the reference listed drug, Topamax, given twice daily.
A study to evaluate the PK and tolerability of an age-appropriate formulation of Trokendi XR (topiramate) extended-release capsules, developed in PMR 2080-1, as adjunctive therapy in children ages 1 month to less than 2 years with partial onset seizures (POS).
An adequately controlled study to assess the efficacy and safety of an age-appropriate formulation of Trokendi XR (topiramate) extended-release capsules, developed in PMR 2080-1, as adjunctive therapy in children ages 1 month to less than 2 years with partial onset seizures (POS).
Conduct a trial to evaluate pediatric pharmacokinetics, safety and antiviral activity of dolutegravir in HIV-1 infected integrase strand transfer inhibitor-naïve, pediatric subjects 4 weeks to less than 12 years of age. Initial evaluation of dolutegravir exposure must be performed in an initial pharmacokinetic study or substudy to allow dose selection. Using doses selected based on the pharmacokinetic study/substudy, and agreed upon with the FDA, conduct a longer-term pediatric safety and antiviral activity assessment of dolutegravir plus background regimen assessing activity on the basis of continued HIV-1 RNA virology response and safety monitoring over at least 24 weeks of dosing.
Conduct a trial to evaluate pediatric pharmacokinetics, safety and antiviral activity of dolutegravir in HIV-1 infected subjects, ages 2 years to less than 18 years, who are integrase strand transfer inhibitor (INSTI) experienced with certain INSTI associated resistance substitutions or clinically suspected INSTI resistance. Initial evaluation of dolutegravir exposure must be performed in an initial pharmacokinetic study or substudy to allow dose selection. Using doses selected based on the pharmacokinetic study/substudy, and agreed upon with the FDA, conduct a longer-term pediatric safety and antiviral activity assessment of dolutegravir plus background regimen assessing activity on the basis of continued HIV-1 RNA virology response and safety monitoring over at least 24 weeks of dosing.
Deferred study under PREA to evaluate the pharmacokinetics, pharmacodynamics, and safety of pantoprazole in patients 1 month to 11 months of age with erosive esophagitis (EE).
Deferred study under PREA to evaluate the pharmacokinetics, healing, maintenance of healing, and symptoms of erosive esophagitis (EE) in patients 1 year to 11 years of age.
Deferred study under PREA to evaluate the pharmacokinetics, healing, maintenance of healing, and symptoms of erosive esophagitis (EE) in patients 12 years to 17 years of age.
Propose and conduct an enhanced pharmacovigilance study of data from clinical trials and all postmarketing sources to assess risk factors for, management of, and consequences of all vascular occlusive events that are serious or require medical evaluation or treatment, occurring while patients are receiving ponatinib or within 30 days of the last drug dose.
Conduct a pharmacokinetic trial to determine the appropriate dose of Mekinist (trametinib) in patients with hepatic impairment in accordance with the FDA Guidance for Industry entitled “Pharmacokinetics in Patients with Impaired Hepatic Function: Study Design, Data Analysis, and Impact on Dosing and Labeling.”
A 12-week, randomized, placebo-controlled, dose-ranging efficacy and safety study of mometasone furoate metered dose inhaler (MDI) in the treatment of children ages 5-11 years with persistent asthma.
Conduct a single point vasoconstriction assay (VCA) trial in healthy subjects with adequate bracketing using visual assessment to determine the topical corticosteroid potency classification for Enstilar® (calcipotriene and betamethasone dipropionate) Foam, 0.005%/0.064%.
Deferred pediatric study under PREA to assess the safety and effectiveness of escitalopram oxalate as a treatment of Generalized Anxiety Disorder in pediatric patients ages 7 to 17 (children and adolescents). Both children (ages 7 to 11) and adolescents (ages 12 to 17) should be equally represented in the samples, and there should be a reasonable distribution of both sexes in these age strata.
A juvenile rat study to support use of Lexapro in children less than 12 years of age.
A randomized, double-blind, adequately controlled, multiple fixed doses, parallel group clinical study of Dysport (abobotulinumtoxinA) in botulinum toxin-naïve children age 2-17 years with lower extremity spasticity. The minimum duration of the study is 12 weeks.  The study should be submitted to the FDA for special protocol assessment.
Conduct a pharmacokinetic trial to determine the appropriate doses of Gilotrif® (afatinib) tablets in patients with moderate and severe renal impairment in accordance with the FDA Guidance for Industry entitled “Pharmacokinetics in Patients with Impaired Renal Function: Study Design, Data Analysis, and Impact on Dosing and Labeling.”
Conduct a prospective, observational study to evaluate the incidence of and risk factors for vascular occlusive events when ponatinib is given with or without anticoagulant or antiplatelet agents. Submit a protocol that includes measures to ensure sufficient long-term follow-up to adequately capture late occurring vascular occlusive events and describe measures that minimize loss to follow-up.
Provide long-term follow-up of all patients enrolled in the Phase 1 (AP24534-07-101) and Phase 2 (AP24534-10-201) clinical trials. Assess the long-term safety of ponatinib treatment, including the long-term risk of vascular occlusive events. Include narratives for all cases of vascular occlusion. The final report submission should include text and data sets.
Prepare and submit an integrated safety data and summary (final report submission) from all three clinical trials cited in PMRs 2113-3 and 2113-4 (Phase 1, Phase 2, and Phase 3). Include narratives for all cases of vascular occlusion.
Conduct a randomized, multi-arm trial to characterize the safety of a range of ponatinib doses. The trial should be of sufficient size and duration to inform safe use of Iclusig in chronic phase CML. The trial should also assess the efficacy of the doses investigated. Include a plan for adequate PK sampling to provide exposure-toxicity and exposure-response data sufficient to identify appropriate dose ranges (or exposure targets) for patients with T315I mutation and for patients who have progressed after at least two TKIs and are considered to have no alternative therapy available.
To determine the potential for pharmacokinetic interactions between Erbitux (cetuximab) and carboplatin you will conduct the drug-drug interaction clinical trial, Study I4E-MC-JXBB.
Deferred pediatric study under PREA to determine the safety of Zemplar (paricalcitol) for the treatment of secondary hyperparathyroidism associated with chronic kidney disease (CKD) Stage 5 in pediatric patients ages 0 to 9 years receiving peritoneal dialysis or hemodialysis.
Conduct a prospective, observational study of 250 pregnant women with asthma exposed to Omalizumab that will assess the outcomes in the offspring born to those women who were exposed to Omalizumab during pregnancy and breastfeeding relative to background risk in similar patients not exposed to Omalizumab.  These outcomes will include adverse effects on immune system development, neonatal thrombocytopenia, major birth defects (congenital anomalies), minor birth defects, and spontaneous abortion.
Assessment of pharmacokinetic (PK/PD) parameters and dosing, safety, tolerance and immunogenicity in the pediatric population 2 years to < 17 years with polyarticular JIA.
A randomized, double-blind, placebo-controlled trial evaluating the effect of Trulicity (dulaglutide) on the incidence of major adverse cardiovascular events (MACE) in patients with type 2 diabetes mellitus. The primary objective of the trial should be to demonstrate that the upper bound of the 2-sided 95% confidence interval for the estimated risk ratio comparing the incidence of MACE (non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death) observed with dulaglutide to that observed in the placebo group is less than 1.3. The trial must also assess the following adverse events: thyroid cancer, pancreatic cancer, pancreatitis, immune-mediated reactions (including serious hypersensitivity reactions), serious hypoglycemic events, hepatic events, serious gastrointestinal events, clinically significant supraventricular arrhythmias, clinically significant conduction disorders and worsening renal function.
Conduct an 18-month study in dogs to evaluate the impact of cytoplasmic vacuoles in the adrenal gland and the aortic outflow tract of the heart.
A juvenile rat toxicology study is required to identify the unexpected serious risk of adverse effects of Botox (onabotulinum toxin type A) on postnatal growth and development.  The study should utilize animals of an age range and stage(s) of development that are comparable to the intended pediatric population; the duration of dosing should cover the intended length of treatment in the pediatric population.  In addition to the usual toxicological parameters, this study should evaluate effects of Botox (onabotulinum toxin type A) on growth, reproductive development, and neurological and neurobehavioral development.
Expand the Pediatric IBD Registry (DEVELOP) to include pediatric patients with ulcerative colitis (UC) and indeterminate colitis (IC).
Conduct a multi-center, randomized, blinded, vehicle-controlled study, including pharmacokinetic assessments, with luliconazole cream 1% for the treatment of tinea corporis in pediatric patients 2 years of age and older.
Conduct a maximum use pharmacokinetic safety study in pediatric patients 12 years to 17 years 11 months of age with interdigital tinea pedis and tinea cruris.
Conduct an in vivo drug interaction trial using an appropriate probe substrate to evaluate the inhibition potential of luliconazole for CYP2C19 under maximal use conditions in subjects with tinea cruris and interdigital tinea pedis.
Conduct an in vivo drug interaction trial using an appropriate probe substrate to evaluate the inhibition potential of luliconazole for CYP3A4 under maximal use conditions in subjects with tinea cruris and interdigital tinea pedis. This trial may be omitted if the results from the trial with the CYP2C19 substrate (PMR 2101-3) indicate no significant interaction.
Conduct in vitro assessments to evaluate the following: a. Inhibition potential of luliconazole for enzymes CYP2B6 and CYP2C8 b. Induction potential of luliconazole for enzymes CYP1A2, CYP2B6 and CYP3A Further in vivo assessment to address drug interaction potential may be needed based on the results of these in vitro assessments.
Complete and submit the final results of the ongoing randomized, double-blind, placebocontrolled Phase 3 clinical trial (PCI-32765MCL3002) of ibrutinib in combination with bendamustine and rituximab in patients with newly diagnosed mantle cell lymphoma. Enrollment of approximately 520 patients is expected. The primary endpoint is progression-free survival as assessed by investigators. Overall survival is a key secondary endpoint.
Determine the effect of a broad range of concentrations of ibrutinib on the potential to inhibit platelet function by conducting in vitro studies. Assessment methods should include evaluation of effects on platelet aggregation, including GPIb-mediated aggregation. Evaluation should include samples from subjects with and without concomitant conditions associated with platelet dysfunction (e.g., severe renal dysfunction, use of a concomitant anticoagulant, and use of aspirin).
Conduct an assessment and an analysis of data from clinical trials and all post-marketing sources in order to characterize the risk of serious bleeding in patients treated with Imbruvica®, (ibrutinib) Capsules. The risks of special interest are major hemorrhagic events and their potential association with concomitant use of anti-platelet and/or anticoagulant drugs. Major hemorrhagic events are defined as any one of the following: I. Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intra-articular or pericardial, or intramuscular with compartment syndrome, II. Bleeding causing a fall in hemoglobin level of 20 g/L or more, or leading to transfusion of two or more units of whole blood or red cells, III. Bleeding resulting in a serious adverse drug experience [as per 21 CFR 314.80(a)] This enhanced pharmacovigilance study will include: 1. Targeted and expedited surveillance with a guided collection form (as referenced in Pharmacyclics’ Pharmacovigilance Plan dated August 23, 2013) to obtain additional salient clinical and diagnostic information related to major hemorrhagic events. 2. Submission of Post-marketing 15-day Alert Reports for all initial and follow-up reports of serious hemorrhagic adverse events from clinical trials and all post-marketing sources, including consumer reports, solicited reports, and foreign reports, utilizing the Standardized Medical Dictionary for Regulatory Activities (MedDRA) Query (SMQ) – Haemorrhages. 3. Submission of interval and cumulative analyses, as well as line listing for all major hemorrhagic events (utilizing the SMQ Haemorrhages) from clinical trials and all postmarketing sources, including consumer reports, solicited reports, and foreign reports. 4. The interval and cumulative analyses should assess potential risk factors for cumulative major hemorrhagic events identified from both clinical trials and all postmarketing sources, and an overall assessment about these events in patients treated with Imbruvica® (ibrutinib) Capsules. In the overall assessment, discuss whether the data warrants further detailed assessment, labeling changes and/or other communication about these adverse events.
Determine the effect of ibrutinib on the QT/QTc interval in healthy subjects on one or more therapeutic dose levels. Conduct and submit results of a thorough QT trial to evaluate the effects of ibrutinib on the QT /QTc interval.
An observational study (N = 1200) to assess the long-term safety of radium Ra 223 dichloride 50 kBq/kg every 4 weeks for 6 doses in patients with castrationresistant prostate cancer with bone metastases.
A randomized clinical trial to assess the safety of radium Ra 223 dichloride in patients with castration-resistant prostate cancer, symptomatic bone metastases and no known visceral metastatic disease.
A trial of the short and long-term safety of re-treatment of patients with castration-resistant prostate cancer with bone metastases with radium Ra 223 dichloride.
Optimize the dosing regimen of Xofigo by conducting a randomized Phase 2 clinical trial to evaluate the efficacy and safety of Xofigo at a dose higher than 50 kBq/kg in patients with castration-resistant prostate cancer with bone metastases. Depending on the results of the Phase 2 trial, a randomized Phase 3 trial may be needed to further confirm the appropriateness of the dosing regimen determined in the Phase 2 trial.
Evaluate for cross-reactivity of anti-ecallantide antibodies with TFPI, perform studies to determine if human anti-ecallantide antibodies bind TFPI, and perform suitability studies and epitope mapping of the human anti-ecallantide antibody response if binding is observed.
Conduct a study in pediatric patients, "A Phase II Open-Label Multi-Center Study to Assess the Safety and Efficacy of Certolizumab pegol in Children and Adolescents with Active Crohn's Disease" [Study CDP870-035]. This study is proposed to evaluate the pharmacokinetics, safety and clinical response of pediatric patients, ages 6-17, with moderately to severely active Crohn's disease to treatment with CIMZIA.
A long-term observational study in the U.S. that will include approximately 2000 CIMZIA-treated Crohn's disease patients and 2000 matched controls receiving other treatments for Crohn's disease. Patients will be monitored for ten years.
Conduct pediatric PK, dose selection, safety, and treatment trial(s) in patients from 2 to < 18 years of age. Initial evaluation of telbivudine exposure must be performed in either a pilot trial or lead-in subtrial to allow dose selection, followed by evaluation of treatment of chronic hepatitis B in pediatric subjects from 2 through < 18 years of age with evidence of active liver inflammation. Using doses selected based on the pilot/subtrial and agreed upon with the FDA, conduct a pediatric safety and treatment trial of telbivudine with treatment response based on virologic, biochemical, serologic, and composite endpoints over at least 48 weeks of dosing and safety monitored over at least 48 weeks.
Conduct pediatric PK, dose selection, and treatment trial(s) in patients from birth to < 2 years of age. Trials in pediatric patients 2 to < 18 years age should be completed before determining whether it is appropriate to study telbivudine for HBV in the birth to < 2 years age group. According to experts in pediatric HBV disease (pediatric hepatologists), treatment is rarely initiated in the first two years of life in patients with chronic HBV infection and this group may be waived in the future if this continues to be the consensus at the time the safety data are available from older pediatric patients or if the risk/benefit assessment is not favorable based on that data.
Submit the results of overall survival, along with datasets and analysis programs, after 240 OS events have occurred from Trial 14295, “A Double-Blind, Randomized Phase III Study Evaluating the Efficacy and Safety of Sorafenib Compared to Placebo in Locally Advanced/Metastatic RAI-Refractory Differentiated Thyroid Cancer.”
Complete a pharmacokinetic trial to determine the appropriate dose of Zykadia (ceritinib) in patients with hepatic impairment in accordance with the FDA Guidance for Industry entitled “Pharmacokinetics in Patients with Impaired Hepatic Function: Study Design, Data Analysis, and Impact on Dosing and Labeling.”
Conduct a clinical trial to evaluate the effect of repeat doses of Zykadia (ceritinib) on the single dose pharmacokinetics of midazolam (a sensitive CYP3A4 substrate) in accordance with the FDA Guidance for Industry entitled “Drug Interaction Studies – Study Design, Data Analysis, Implications for Dosing, and Labeling Recommendations.”
Conduct a clinical trial to evaluate the effect of repeat doses of Zykadia (ceritinib) on the single dose pharmacokinetics of warfarin (a sensitive CYP2C9 substrate) in accordance with the FDA Guidance for Industry entitled “Drug Interaction Studies – Study Design, Data Analysis, Implications for Dosing, and Labeling Recommendations.”
Conduct a clinical trial to evaluate if proton pump inhibitors, H2-receptor antagonists, and antacids alter the bioavailability of Zykadia (ceritinib) and to determine how to dose Zykadia (ceritinib) with regard to concomitant gastric acid reducing agents.
Conduct a single dose pharmacokinetic (PK) study in children from 3 months to less than 12 years of age.
Conduct a single dose PK study in neonates/infants from 0 to less than 3 months of age.
Conduct a Phase 3, randomized, comparator-controlled study of dalbavancin in children from 3 months to 17 years of age with ABSSSI.
Conduct a Phase 3, randomized, comparator-controlled study of dalbavancin in neonates/infants from birth to less than 3 months of age with ABSSSI.
Conduct a trial in patients, ages 2 to < 18 years, to evaluate the pharmacokinetic (PK), safety, and tolerability of two new formulations of posaconazole (IV solution and/or new  age-appropriate oral formulation) in immunocompromised pediatric patients with known or expected neutropenia.
Conduct a comparative, double-blind, randomized, multi-center trial, in patients ages 2 to < 18 years, to evaluate the safety, efficacy, and tolerability of posaconazole for the prophylaxis of invasive fungal infections (IFI) in pediatric patients with known or expected neutropenia.
Submit integrated analyses for genotypic and phenotypic resistance for studies AI463048, AI463050, AI463085, AI463901, AI463110, and AI463111, and integrated phenotypic resistance analyses for studies AI463028 and AI463189 in SAS format. The virology data should be submitted following the guidance format.
A prospective, observational, controlled, pregnancy exposure registry study to monitor pregnancies exposed to apremilast with the primary objective to evaluate whether there is any increase in the risk of birth defects.
Pediatric studies under PREA for the treatment of pediatric patients aged two years and older with detrusor overactivity associated with a known neurological condition (e.g., spina bifida).
A study to evaluate the safety of metronidazole gel 1.3% single dose in the treatment of bacterial vaginosis in females 12-<18 years of age.
Conduct a prospective, observational registry study of women with Crohn's disease, rheumatoid arthritis and psoriatic arthritis exposed to Infliximab during pregnancy.  This study will assess the pregnancy outcomes in women who were exposed to Infliximab during pregnancy relative to background risk in similar patients not exposed to Infliximab.
Assess the safety and efficacy of Peginterferon alfa-2a versus a no-treatment control in 110 pediatric HBeAg positive patients chronically infected with the hepatitis B virus, who have compensated liver disease.
An assessment and analysis of spontaneous reports of inadvertent exposure of anyone other than the patient who has been exposed to Valchlor (mechlorethamine) gel 0.016%. Specialized follow-up should be obtained on these cases to collect additional information on the events. This enhanced pharmacovigilance should continue for a period of 2 years from the date of approval. The following components should be assessed and analyzed in a final report:  Expedited reports of both serious and non-serious outcomes for all initial and followup adverse drug experiences resulting from secondary exposure to the skin, mucous membranes, and eyes of individuals other than the patients being treated submitted as Postmarketing 15-day "Alert Reports", A summary and line listing of all secondary exposure events from postmarketing sources, including consumer reports, solicited reports, and foreign reports submitted in each PADER/PBRER; and Documentation of attempts to contact all reporters of events, and obtain findings about the events, including but not limited to the circumstances leading to the exposure, ultimate highest severity of the exposure, and resolution status.
A long-term prospective observational study (product exposure registry) to evaluate potential serious hepatic risks related to the use of Opsumit (macitentan). The registry will include a sample of patients prescribed Opsumit (macitentan) and enroll at least 5000 patients. Patients should be followed for at least 1 year. A target sample size, supported by a sample size calculation, with an explanation of the underlying assumptions for the PAH patient population (e.g. incidence of AST/ALT elevations, study/registry dropout rates) should be included in the protocol. Even if the proposed sample size targeting approach seems reasonable at this time, if the underlying assumptions are not met or there are other concerns, an extension of the registry enrollment may be deemed warranted at a later point by the Agency.
An assessment and analysis of reports of serious hepatic adverse events (to be defined in the protocol) in patients treated with Opsumit (macitentan) submitted according to the schedule outlined below. Specialized follow up should be obtained on these cases to collect additional information on the reports. Summary information should include the total number of cases, a summary of key facts in those cases, with pertinent expert analysis of clinically relevant information from the case series. Hepatic adverse events of special interest will require expedited reporting to the Agency.
Submit the final report and datasets for the ongoing trial GS-US-334-0154, entitled, “A Phase 2b, Open-Label Study of 200 mg or 400 mg Sofosbuvir + RBV for 24 Weeks in Genotype 1 or 3 HCV-Infected Subjects with Renal Insufficiency”, in order to provide dosing recommendations for chronic hepatitis C patients with severely impaired renal function.
Submit the final report and datasets for the ongoing trial GS-US-334-0154, entitled, “A Phase 2b, Open-Label Study of 200 mg or 400 mg Sofosbuvir + RBV for 24 Weeks in Genotype 1 or 3 HCV-Infected Subjects with Renal Insufficiency”, in order to provide dosing recommendations for chronic hepatitis C patients with ESRD.
Submit the final report and datasets for the ongoing trial GS-US-334-0109, entitled, “An Open-Label Study of GS-7977 + Ribavirin with or without Peginterferon Alfa-2a in Subjects with Chronic HCV Infection Who Participated in Prior Gilead HCV Studies”.
Conduct a trial to quantify efavirenz QT prolongation in CYP2B6*6 homozygous and heterozygous subjects.
Develop and validate an appropriate analytical method for determining the individual component phytosterol content in Liposyn III 20% IV Fat Emulsion.
Test for the individual component phytosterol content in all batches of Liposyn III 20% IV Fat Emulsion, manufactured over a three year period, using the method developed under PMR 2143-1. Based on these test results, establish limits for each of the individual component phytosterols in Liposyn III 20% IV Fat Emulsion in the product specification.
Develop and validate an appropriate analytical method for measuring phytosterol levels in plasma.
Randomized controlled trial in pediatric patients, including neonates, comparing Liposyn III 20% IV Fat Emulsion with a phytosterol-depleted formulation of Liposyn III 20% IV Fat Emulsion to evaluate the incidence of liver injury, including either parenteral nutrition-associated liver disease (PNALD) or intestinal failure-associated liver disease (IFALD). This trial should be initiated after the results from PMR 2143-1 are available. The phytosterol content of the phytosterol-depleted formulation of Liposyn III 20% IV Fat Emulsion should be documented using validated analytical assay methods developed under PMR 2143-1. Plasma phytosterol levels should be assessed in patients using validated analytical assay methods developed under PMR 2143-3.
Provide data analyses from the Nordic Database Initiative regarding the occurrence of serious infection, tuberculosis, opportunistic infections, malignancy, hypersensitivity reactions, autoimmune disease, neurologic or demyelinating disease, cardiovascular, gastrointestinal or hematologic adverse events with exposure to ustekinumab.
Establish a U.S.-based prospective, observational pregnancy exposure registry that compares the pregnancy and fetal outcomes of women exposed to Stelara¿ (ustekinumab) during pregnancy to an unexposed control population.  Outcomes of the registry should include major and minor congenital anomalies, spontaneous abortions, stillbirths, elective terminations, adverse effects on immune system development, and other serious adverse pregnancy outcomes.  These outcomes should be assessed throughout pregnancy.  Infant outcomes should be assessed through at least the first year of life.
A randomized and controlled pediatric study under PREA to evaluate the safety, efficacy, and pharmacokinetics of Tanzeum (albiglutide) for the treatment of type 2 diabetes mellitus in pediatric patients ages 10-17 years (inclusive).
An assessment and analysis of spontaneous reports of serious risks related to the use of Myalept (metreleptin) including: fatal or necrotizing pancreatitis, hepatic adverse events, severe hypoglycemia, serious hypersensitivity reactions, serious infections resulting in hospitalization or death, new diagnoses of autoimmune disorders (for instance, autoimmune hepatitis, glomerulonephritis, lupus erythematosus, antiphospholipid antibody syndrome, rheumatoid arthritis), autoimmune disease exacerbation, all cancers (excluding non-melanoma skin cancer) by cancer type, exposed pregnancies and pregnancy outcomes, and all deaths (including causes of death) in patients treated with Myalept (metreleptin) regardless of indication for 10 years from the date of approval.
Conduct a trial in patients, ages 2 to < 18 years, to evaluate the pharmacokinetic (PK), safety, and tolerability of two new formulations of posaconazole (IV solution and/or new ageappropriate oral formulation) in mmunocompromised pediatric patients with known or expected neutropenia.
Conduct a comparative, double-blind, randomized, multi-center trial, in patients ages 2 to < 18 years, to evaluate the safety, efficacy, and tolerability of posaconazole for the prophylaxis of invasive fungal infections (IFI) in pediatric patients with known or expected neutropenia.
Complete a randomized, multicenter, parallel, single-dose study to explore the pharmacokinetics (PK) and pharmacodynamics (PD) of dapagliflozin in children, 10 to 17 years of age with type 2 diabetes mellitus (T2DM) receiving one of the three dose levels of dapagliflozin over the range of 2.5 to 10 mg. At least 30% of randomized subjects in each dose group will be 10 - 15 years of age
A 26-week randomized, double-blind, placebo-controlled study to evaluate the efficacy, safety, and tolerability of dapagliflozin for the treatment of pediatric subjects ages 10 to <18 years of age with type 2 diabetes mellitus (T2DM), as add-on to metformin or as monotherapy, followed by a 26-week double-blind, placebo- or active-controlled extension period (Week 26 to Week 52). At least 30% of randomized subjects will be 10 to 14 years of age and at least one-third and not more than two-thirds of subjects in both age subsets (10 to 14 years and 15 to <18 years) will be female. Secondary safety endpoints should include the effect of dapagliflozin on mineral and bone metabolism, and the effect of dapagliflozin on growth.
Conduct a study to evaluate dapagliflozin in an orthotopic rodent bladder tumor promotion model.
An assessment and analysis of all foreign and domestic spontaneous reports of serious hepatic abnormalities and pregnancy outcomes in patients treated with dapagliflozin. The enhanced pharmacovigilance study should continue for 5 years.
A randomized, double-blind, placebo-controlled trial (the DECLARE trial) evaluating the effect of dapagliflozin on the incidence of major adverse cardiovascular events (MACE) in patients with type 2 diabetes mellitus. The primary objective of the trial should be to demonstrate that the upper bound of the 2-sided 95% confidence interval for the estimated risk ratio comparing the incidence of MACE (non-fatal myocardial infarction, non-fatal stroke, cardiovascular death) observed with dapagliflozin to that observed in the placebo group is less than 1.3. The long-term effects of dapagliflozin on the incidence of liver toxicity, bone fractures, nephrotoxicity/acute kidney injury, breast and bladder cancer, complicated genital infections, complicated urinary tract infections/pyelonoephritis/urosepsis, serious events related to hypovolemia and serious hypersensitivity reactions should also be assessed. The estimated glomerular filtration rate (eGFR) should also be monitored over time to assess for worsening of renal function.
To assess the risk of bladder cancer associated with dapagliflozin, conduct adequate follow-up beyond completion of the cardiovascular outcomes trial (DECLARE) to observe a total of 66 events of bladder cancer, with 80% power to exclude a relative risk of 2.0 for dapagliflozin versus placebo, assuming a 2-sided alpha of 5%.
Conduct a study to evaluate the pharmacokinetics, safety and treatment response (using sustained virologic response) of Olysio™ (simeprevir) as a component of a combination antiviral treatment regimen in pediatric subjects 3 through 17 years of age with chronic hepatitis C.
Long-term safety follow-up in patients with myelofibrosis and lower baseline thrombocytopenia who are receiving longer term treatment with Jakafi. This longer term safety analysis may be based on further followup of ongoing trials or you may propose an alternative strategy to provide this information.
Conduct in-vitro assessments to evaluate the following: 1. Inhibition potential of econazole nitrate for enzymes CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A4. 2. Induction potential of econazole nitrate for enzymes CYP1A2, 2B6 and 3A. Further in-vivo assessment to address drug interaction potential may be needed based on the results of the in-vitro assessment.
A juvenile dog toxicology study under PREA to identify and characterize the unexpected serious risk of adverse effects of eslicarbazepine acetate on the immune system of the developing organism. The study should utilize animals of an age range and stage(s) of development that are comparable to the intended pediatric population.
A pharmacokinetic and tolerability study in pediatric patients ages 1 month to < 24 months with partial-onset seizures. At least two maintenance dose levels of eslicarbazepine acetate must be evaluated to characterize pharmacokinetic parameters following at least one week of administration for each dose level of oral eslicarbazepine acetate following titration. Pharmacokinetic data must be obtained and analyzed using intensive sampling, sparse sampling, or both approaches. If a sparse sampling approach is used, approximately 3-4 blood samples per patient should be collected to enable adequate characterization of the concentration-time profile. At least 20% of patients must come from the 1-month to 6-month age group, and at least 25% of patients must come from the 6- to 12month and the 12- to 24-month age groups. Effort must be made to balance the gender distribution within each age cohort, with no less than 35% of patients in each gender.
A prospective, randomized, controlled, double-blind, efficacy and safety study of eslicarbazepine acetate in children ages 12 years to <18 years for the adjunctive the treatment of partial onset seizures. The primary efficacy endpoint must examine seizure frequency based upon diary data. Safety must be evaluated. Subgroup analyses of the effect of the concomitant use of enzyme-inducing anticonvulsants (i.e., carbamazepine, phenytoin, phenobarbital or primidone) on the safety and efficacy of eslicarbazepine acetate must be performed.
Evaluate the long-term safety of eculizumab by enrollng all patients with aHUS treated with eculizumab in a Soliris registry program and analyzing outcomes for a period of no less than five years. Submit interim reports annually to the BLA including the specific items listed below. At the end of the five-year period, submit a final report to the BLA that describes the major safety findings from this registry, including the specific items listed below, and propose labeling changes as appropriate. The following data will be collected for each patient receiving eculizumab for the treatment of aHUS: Serious infections, defined as infections necessitating or prolonging hospitalization, or resulting in death. Alexion wil collect follow-up information from these patients to assess the nature of the serious infection, the major features of the clinical sourse, and the survival status.Malignancy, including the nature of the malignancy and the survival status of patients who develop a malignancy. egnancy, including the clinical course of each pregnancy and the detection of congenital abnormalities among babies born to women exposed to eculizumab during the pregnancy.Surival . Occurrence of stroke (yes/no) . Requirement for renal transplant (yes/no) dialysis requirement or increase in the frequency of dialysis (yes/no) . aHUS exacerbation requiring plasma therapy (yes/no) . Discontinuation (yes/no) and, if discontinued, the reason for discontinuation.
Deferred pediatric study under PREA for the treatment of major depressive disorder in pediatric patients aged 7 to 17. Conduct a study to obtain pharmacokinetic, safety, and tolerability data and provide information pertinent to dosing vortioxetine in the relevant pediatric population.
Deferred pediatric study under PREA for the treatment of major depressive disorder in children aged 7 to 11years. Conduct a study to obtain data on the efficacy and safety of vortioxetine in the relevant pediatric population. This must be a placebo-controlled and active-controlled (fluoxetine) study. This study must be a fixed-dose study.
Deferred pediatric study under PREA for the treatment of major depressive disorder in adolescents aged 12 to17 years. Conduct a study to obtain data on the efficacy and safety of vortioxetine in the relevant pediatric population. This must be a placebo-controlled and active-controlled (fluoxetine) study. This study must be a fixed-dose study.
In-vivo pharmacokinetic trial in subjects with severe hepatic impairment compared to healthy subjects using the 5 mg dose.
A controlled trial to evaluate the longer-term (i.e., maintenance) efficacy of vortioxetine in the treatment of adults with major depressive disorder in the US. This trial must include a placebo group and several fixed doses and must utilize a randomized withdrawal design, following an adequate period of stabilization with open-label treatment of vortioxetine. Because the short-term trials appear to show that higher doses have demonstrated better treatment effects in the US population compared to the rest of the world, it is important to establish the dose-response for maintenance in the US. This trial should randomize patients on stable doses of vortioxetine to several different doses (e.g., 5 mg, 10 mg, and 20 mg) of vortioxetine (and to placebo) during the maintenance phase.
Collect long-term safety data for subjects enrolled in the pediatric simeprevir safety, pharmacokinetics and efficacy study. Data collected should include at least 3 years of follow-up in order to characterize the long-term safety of Olysio™ (simeprevir) in pediatric subjects, including growth assessment, sexual maturation and characterization of Olysio™ (simeprevir) resistance-associated substitutions in viral isolates from subjects failing therapy.
Submit the final report and datasets from the ongoing clinical trial TMC435HPC3005 entitled “A Phase 3, Randomized, Double-Blind, Double Dummy, Placebo-Controlled Study Conducted in the Asia-Pacific Region to Investigate the Efficacy, Pharmacokinetics, Safety and Tolerability of TMC435 vs. Placebo as Part of a Treatment Regimen Including Peginterferon alfa-2a and Ribavirin in Treatment-naïve, Genotype 1 Hepatitis C-Infected Subjects.”
Deferred pediatric study under PREA for the maintenance treatment of Major Depressive Disorder (MDD) in subjects age 7 to 17 years
To conduct a prospective, observational study in at least 5000 subjects with multiple sclerosis who are receiving Natalizumab, with each subject followed for at least 5 years, by completing protocol 101-MS-402, "TYGRIS:  TYSABRI® Global Observation Program in Safety."  Biogen Idec will ensure having at least 3000 patients with 4 years of Natalizumab treatment, and will increase the total subject number beyond 5000 if necessary to achieve this.
Conduct a single dose pharmacokinetic (PK) trial in patients =/>1 to 17 years old.
Conduct a single dose PK trial in neonates/infants 0 to <1 year old.
Conduct a Phase 3, randomized, comparator-controlled trial of telavancin in children from birth to 17 years old with gram positive infections.
Deferred pediatric study under PREA: Conduct a pharmacokinetic and safety study of an age-appropriate formulation of hydrocodone extended-release in patients from ages 12 to less than 17 years with moderate-to-severe pain requiring around the clock opioid therapy for an extended period of time.
Deferred pediatric study under PREA: Conduct a pharmacokinetic and safety study of an age-appropriate formulation of hydrocodone extended-release in patients from ages 7 to less than 12 years with moderate-to-severe pain requiring around the clock opioid therapy for an extended period of time.
Conduct one or more studies to provide quantitative estimates of the serious risks of misuse, abuse, addiction, overdose, and death associated with long-term use of opioid analgesics for management of chronic pain, among patients prescribed ER/LA opioid products. Include an assessment of risk relative to efficacy. These studies should address at a minimum the following specific aims: a. Estimate the incidence of misuse, abuse, addiction, overdose, and death associated with long-term use of opioids for chronic pain. Stratify misuse and overdose by intentionality wherever possible. Examine the effect of product/formulation, dose and duration of opioid use, prescriber specialty, indication, and other clinical factors (e.g., concomitant psychotropic medications, personal or family history of substance abuse, history of psychiatric illness) on the risk of misuse, abuse, addiction, overdose, and death. b. Evaluate and quantify other risk factors for misuse, abuse, addiction, overdose, and death associated with long-term use of opioids for chronic pain, including but not limited to the following: demographic factors, psychosocial/behavioral factors, medical factors, and genetic factors. Identify confounders and effect modifiers of individual risk factor/outcome relationships. Stratify misuse and overdose by intentionality wherever possible.
Develop and validate measures of the following opioid-related adverse events: misuse, abuse, addiction, overdose and death (based on DHHS definition, or any agreed-upon definition), which will be used to inform the design and analysis for PMR # 2065-1 and any future post-marketing safety studies and clinical trials to assess these risks. This can be achieved by conducting an instrument development study or a validation study of an algorithm based on secondary data sources.
Conduct a study to validate coded medical terminologies (e.g., ICD9, ICD10, SNOMED) used to identify the following opioid-related adverse events:misuse, abuse, addiction, overdose, and death in any existing post-marketing databases to be employed in the studies. Stratify misuse and overdose by intentionality wherever possible. These validated codes will be used to inform the design and analysis for PMR # 2065-1.
Conduct a study to define and validate “doctor/pharmacy shopping” as outcomes suggestive of misuse, abuse and/or addiction. These validated codes will be used to inform the design and analysis for PMR # 2065-1.
Conduct a clinical trial to estimate the serious risk for the development of hyperalgesia following use of ER/LA opioid analgesics for at least one year to treat chronic pain. We strongly encourage you to use the same trial to assess the development of tolerance following use of ER/LA opioid analgesics. Include an assessment of risk relative to efficacy.
Conduct US surveillance studies for five years from the date of marketing DALVANCE to determine if resistance to dalbavancin has developed in those organisms specific to the indication in the label for ABSSSI.
Conduct studies to define the mechanism(s) of resistance for isolates identified as being resistant to dalbavancin during the surveillance period (five years from the date of marketing).
Deferred pediatric study under PREA to evaluate the pharmacokinetics, pharmacodynamics, and safety of esomeprazole strontium for healing and maintenance of healing of erosive esophagitis (EE) in patients 1 month to 17 years, inclusive. The study must also assess the efficacy of esomeprazole strontium in maintenance of healing of EE, including determination of the dose and treatment duration required to maintain healing of EE in this pediatric population. The study must include an adequate number of patients in different age groups to inform dosing, and to evaluate the effect of esomeprazole strontium on bone, given that pediatric patients undergo different rates of growth depending on age. Baseline and post-treatment bone-related safety assessments must be included.
Deferred pediatric study under PREA to evaluate the safety of esomeprazolen strontium for treating symptomatic gastroesophageal reflux disease (GERD) in patients 1 year to 17 years, inclusive. The study must include an adequate number of patients in different pediatric age groups to evaluate the effect of esomeprazole strontium on bone, given that pediatric patients undergo different rates of growth depending on age. Baseline and posttreatment bone-related safety assessments must be included. This study may not be needed if the data from PMR 2054-1 are adequate to fulfill the requirement.
Deferred pediatric study under PREA to evaluate the pharmacokinetics, pharmacodynamics, and safety of esomeprazole strontium for reducing the risk of NSAIDassociated gastric ulcer in patients 2 years to 17 years, inclusive. The study must include an adequate number of patients in different age groups to inform dosing, and to evaluate the effect of esomeprazole strontium on bone, given that pediatric patients undergo different rates of growth depending on age. Baseline and post-treatment bone-related safety assessments must be included.
Deferred pediatric study under PREA to evaluate the safety and efficacy of esomeprazole strontium in combination with clarithromycin and amoxicillin for the eradication of Helicobacter pylori in symptomatic pediatric patients 2 to 17 years, inclusive, with or without duodenal ulcer disease.
In vitro studies to evaluate the potential inhibitory effects of Kuvan (sapropterin dihydrochloride) activity of major cytochrome P450 enzymes including, but not limited to, CYP3A4 to assess drug interaction potential in humans
In vitro studies to evaluate if Kuvan (sapropterin dihydrochloride) is an inducer of CYP3A4 to assess drug interaction potential in humans
In vitro studies to evaluate the potential effects of Kuvan (sapropterin dihydrochloride) on activity of transporters including p-glycoprotein and breastcancer- resistance protein to assess drug interaction potential in humans
Submit data from controlled extraction studies of [...] to qualitatively and quantitatively determine the chemical species which may migrate into the drug product solution.
Submit leachable data from long-term stability studies with the final drug product formulation (taking into consideration the proposed shelf-life) to qualitatively and quantitatively determine the chemical species which migrate into the drug product solution upon stability.
A multi-center observational study of Humira (adalimumab) in adults with moderately to severely active ulcerative colitis treated in a routine clinical setting, to assess the long-term safety as measured by the incidence of opportunistic infections and malignancies. Long-term effectiveness should be assessed as a secondary goal. The proposed study should follow patients for a period of at least 10 years from time of enrollment in order to ascertain adverse events with longer latency periods such as malignancies. The primary analysis is to summarize safety data for patients on adalimumab and patients on non-biologic immunomodulator therapy. The study should be adequately sized to sufficiently detect a doubling of the risk of lymphoma events in each treatment group. A secondary analysis is to summarize safety data for patients on adalimumab and patients on the combination of adalimumab and non-biologic immunomodulator therapy. In addition, the study is to document and evaluate effects of withdrawal and re-treatment with adalimumab and switching with other tumor necrosis factor (TNF)-blockers or biologics.
A randomized, double-blind, adequately controlled, multiple fixed doses, parallel group clinical study of Dysport (abobotulinumtoxinA) in botulinum toxin-naïve adults with lower extremity spasticity. The minimum duration of the study is 12 weeks.  The study should be submitted to the FDA for special protocol assessment.
Conduct a cell culture study to characterize the antiviral activity of ombitasvir against representative HCV subtype 4b isolates, including those with amino acid variability (relative to subtypes 4a and 4d) at NS5A positions 30 and 93.
Conduct a nationally representative drug utilization study of sufficient detail to characterize use of OxyContin in children aged 17 years and younger. The data from this study will provide a denominator for the risks assessed in PMR #2923-1 and any future safety studies and clinical trials used to assess those risks. The following analyses should be conducted with the data collected: 1) Total number of prescriptions dispensed across all settings of care a. stratify by age group (0-1, 2-5, 6-10, 11-17), indication, setting of care, and prescriber specialty, and geographic location b. provide characteristics of dose dispensed (mean, median, range) 2) Total number of unique patients receiving dispensed prescriptions across all settings of care a. stratify by age group (0-1, 2-5, 6-10, 11-17), indication, setting of care, and prescriber specialty i. provide unique incident users every quarter-year b. patient demographics of users of the product c. clinical characteristics of users of the product (including what percentage of patients are opioid tolerant at the time they get the OxyContin prescription) 3) Duration of therapy (include definitions of allowable gaps in drug therapy in calculating duration of therapy) a. total and stratified by indication b. exploration of possible ‘intermittent’ use c. percentage of patients switching from immediate-release opioids to OxyContin d. percentage of patients switching from other extended-release opioids to OxyContin e. dose adjustments over time
Evaluate the long-term safety of Vimizim in adult and pediatric patients enrolled in the Morquio A Registry for a period of ten years, including but not limited to the occurrence of serious hypersensitivity reactions, anaphylaxis, and changes in antibody status (i.e., detection and titers of binding and neutralizing antibodies, and detection of IgE antibodies). Pregnancy exposure data, including maternal, neonatal and infant outcomes, will also be collected and analyzed. Include incidence rate calculations as part of long-term safety evaluation assessments to monitor and characterize risk of exposure to Vimizim. In addition, assessment of clinical outcomes (e.g., anthropometric measures, progression of skeletal deformities, frequency and time to orthopedic surgeries) will be performed. All safety, immunogenicity, and clinical outcome assessments will be conducted every 6 months. Patients previously enrolled in clinical trials MOR-005 and MOR-007 may be rolled over to this study but will be monitored using the MOR005 and MOR-007 protocols, respectively.
A study to reanalyze banked immunogenicity serum samples from ulcerative colitis trial C13006 and Crohn’s disease trial C13007 to determine the presence of anti-drug antibodies (ADA) using an improved ADA assay format with reduced sensitivity to product interference.
To assess the safety of long-term use of rilonacept in the pediatric patient population by establishing a pediatric registry.  The registry will collect information on growth and development as well as adverse events, particularly serious infections.  The duration of the study will be at least five years.
To commit to providing complete validation data for the anti-Oncaspar ELISA assay. The validation studies will provide an assessment of the sensitivity (in mass units of antibodies), specificity, and reproducibility of the assay. The cutpoint for the assay (the value that discriminates positive samples from negative samples) will be determined by using samples from unexposed patients and validated positive controls. This cut point value will be used to determine the number and percent of patients who develop antibodies to Oncaspar during clinical trials. The assay validation will be performed with insight obtained from Mire-Sluis et al. J. of Immunol. Methods, 2004, 289: 1-16.
To develop validated screening and confirmatory assays to assess for the presence of anti-tbo-filgrastim antibodies.  The validation of the assay should include the sensitivity and specificity for detection of anti-tbo-filgrastim antibodies that are also cross-reactive with native human granulocyte colony stimulating factor (G-CSF).
To conduct an assessment for the presence of anti- tbo-filgrastim and anti-native human G-CSF binding antibodies using the validated assays developed under PMR 2 in at least 426 patients enrolled/to be enrolled in one or more clinical trials, as a substudy.
Centocor commits to designing and implementing a registry of patients with pediatric Crohn's disease being treated with REMICADE that will be established to obtain long-term clinical status and safety information.  Information will be collected on patient demographics, disease characteristics, history of concomitant medications, dose and duration and frequency of REMICADE administration, clinical status, adverse events including dysplasias and malignancies of all types, infections, autoimmune disease, assessment of immunogenicity, and potential effects of antibody formation.  The age range should include patients ages 0 to 19 years.  This registry will be designed so that detailed clinical status information is collected at registry entry and on a 6 month basis for at least 20 years.  Centocor commits to expand the currently existing Pediatric IBD Registry, and will actively encourage both patients and physicians to participate in the registry through an advertisement campaign, that includes a plan for proactive communication of associated risk.  Centocor also commits to recruiting at least 2,000 REMICADE treated pediatric Crohn's patients, which will provide an adequate number of patients to participate in the registry so that outcome measures will be collected and adequate risk assessment can be made.  Centocor commits to provide prompt risk communication for serious adverse events that are reported through the registry.  The registry data will be analyzed at yearly intervals and the results will be submitted in annual reports for BB-IND 5389.
Submit revised labeling, which accurately reflects the immune response to  Sargramostim.
To conduct clinical trial 20070782 entitled "A Randomized, Double-blind, Placebo-controlled Study to Evaluate the Long-term. Safety and Efficacy of Darbepoetin Alfa Administered at 500 ug Once-Every-3-Weeks (Q3W) in Anemic subjects with Advanced Stage Non-small Cell Lung Cancer Receiving Multi-cycle Chemotherapy" to evaluate the impact of darbepoetin alfa on overall survival, progression-free survival, and objective tumor response rate.
To conduct a verification trial to describe clinical benefit attributable to Elaprase (idursulfase) in a cohort of Hunter syndrome patients 5 years of age and younger.At a minimum, this trial will assess longitudinal changes in anthropometric measures (i.e., length/height z-scores, annual growth velocity z-scores, weight zscores) and the progression of skeletal deformities (i.e. joint stiffness, joint contractures) in children being treated with Elaprase (idursulfase). The growth parameters will be followed in these children for a minimum of 5 years from initiation of Elaprase (idursulfase) treatment or until they have reached at least 10 years of age, whichever is longer. The trials will monitor antibody response (binding, neutralizing, and IgE) at least every 6 months. Additionally, the trial will evaluate the relationship between development of immune tolerance and genetic mutations, endogenous enzyme activity level, and anthropometric measures. The trial may be conducted as a separate trial or as a sub-trial under a special protocol within the Hunter Outcome Survey.
To conduct a clinical trial of Herceptin (trastuzumab) in combination with standard chemotherapy, in patients with previously untreated, HER2 overexpressing, metastatic gastric cancer, if the pharmacokinetic trial (PMR #2) definitively demonstrates that the higher Herceptin dose improves efficacy among patients with low exposure after the initial dose, but does not provide adequate safety and efficacy data among patients with higher exposure to support a new dosing regimen for all patients. The objective of the trial will be to further compare the effect of overall survival in patients who demonstrate adequate exposure after one cycle of the approved Herceptin dosing regimen, as determined by a validated assay for Herceptin levels, between those randomized to receive the approved dose and schedule (as evaluated in Trial BO18255) for subsequent treatment cycles and those randomized to receive the investigational (alternate) Herceptin regimen evaluated in the pharmacokinetic trial in PMR #2. The trial will be designed to establish that the alternate dosing regimen is not inferior to the dosing regimen approved for the treatment of gastric cancer with a primary endpoint of survival. A secondary endpoint will be to further characterize the safety profile of the alternate dosing regimen.
Shire commits to evaluating long-term safety and efficacy data in an observational survey (the Hunter Outcome Survey, HOS) of patients with Hunter syndrome being treated with ELAPRASE.  In addition to clinical and laboratory tests that are part of standard medical care for patients with Hunter syndrome, the survey will collect data from patients on the six-minute walk test, from a subset of centers that will have the training and facilities to collect the data in a standardized and reproducible manner, and urinary GAG levels approximately every 6 to 12 months for at least 15 years.  Assessments and data collected in the HOS will include those listed in Table 1 of the Hunter Outcome Survey protocol summary version 1.0, dated October 31, 2005, and in the Safety Specification and Pharmacovigilance Plan documented in the ELAPRASE BLA.  For pediatric patients in the HOS, data to be collected will include standardized and replicated height, weight, and head circumference measurements in conjunction with deformity assessments and patients method of feeding.  The survey will be designed to take advantage of any opportunity to evaluate the effect of ELAPRASE on female reproduction, pregnancy, and lactation.  The HOS data will be analyzed at yearly intervals and the results will be submitted in the IND annual reports.
Pregnancy registry to evaluate pregnancy outcomes for women exposed to Actemra (tocilizumab) during pregnancy.  Utilize the established Organization of Teratology Information Specialists (OTIS) pregnancy registry to evaluate pregnancy outcomes.
To evaluate a prophylactic immune tolerance regimen in a cohort of Hunter syndrome patients treated with Elaprase (idursulfase) who are at high risk of developing persistent neutralizing antibody that could result in diminished clinical benefit. This immune tolerance regimen will be implemented before or concomitant with onset of therapy. The trial will monitor antibody status (binding, neutralizing, and IgE), urinary GAG, and hypersensitivity reactions in patients at regular intervals. Additionally, the trial will evaluate the relationship between development of immune tolerance and genetic mutations, endogenous enzyme activity level, and clinical outcome. Completion of this PMR is pending the outcome of an Advisory Committee Meeting and completion of PMR 3.
Conduct Study Protocol P10-262, an 800-patient observational study, with inclusion of a reference group, of pediatric patients 4 to 17 years of age with moderately to severely active polyarticular juvenile idiopathic arthritis (JIA).
Review post-marketing adverse event surveillance data after one year of commercial distribution and propose revised labeling as warranted.
Evaluate the pediatric pharmacokinetics (PK), safety, and antiviral activity of once daily elvitegravir combined with a background regimen including a protease inhibitor coadministered with ritonavir in HIV-1 treatment-experienced pediatric subjects from 4 weeks to less than 18 years of age. Initial evaluation of elvitegravir exposure (when combined with a protease inhibitor and ritonavir) must be performed to allow dose selection to be agreed upon with the FDA. Evaluation of longer term treatment with elvitegravir, plus background regimen including protease inhibitor and ritonavir, must assess treatment response on the basis of HIV-1 RNA virologic response and conduct safety monitoring over at least 24 weeks of dosing.
Randomized, double-blind, adequate and well controlled, multiple fixed-dose, parallel group clinical trial of Xeomin (incobotulinumtoxinA) in botulinum toxin-naive children age 2-17 years with lower extremity spasticity.  The minimum duration of the trial should be 12 weeks.  You should propose a method to actively monitor for adverse events related to spread of toxin.  The protocol for the trial should be submitted to the FDA as a special protocol assessment (SPA).
Enhanced pharmacovigilance program for reports of malignancy in pediatric, adolescent, and young adult (¿ 30 years of age) patients treated with Remicade (infliximab), for a period of up to 10 years after this notification to collect data that will be analyzed to better define the risk of this serious adverse event.  The enhanced pharmacovigilance program includes the following: 1) active query of reporters to obtain additional clinical information related to malignancy diagnoses; 2) expedited reporting to FDA of all initial and follow-up reports of any malignancy in pediatric and young adult patients.  Interim analyses and summaries of new and cumulative safety information in pediatric and young adult patients must be submitted annually, followed by the final report at the conclusion of the monitoring period.
A randomized, controlled trial evaluating the efficacy, safety, and pharmacokinetics of sugammadex injection when used to reverse neuromuscular blockade induced by either rocuronium or vecuronium must be conducted in pediatric patients ages birth to 17 years old.
Conduct a postmarketing study to analyze the demographic characteristics, concomitant medication use, and comorbid conditions in patients who did not respond to sugammadex reversal in the development program, in postmarket studies that have been conducted, or as described in cases of non-response/lack of efficacy reported as postmarketing adverse events. The goal of the study is to determine the characteristics and profile of patients who would be expected to be non-responders. The study should also assess the occurrence of hypersensitivity or anaphylaxis, prolonged ventilator support and sedation, and anoxia in these patients.
Conduct a postmarketing clinical trial comparing sugammadex to placebo and/or drugs approved for the management of the reversal of the effects of neuromuscular blockade induced by rocuronium or vecuronium in a population of American Society of Anesthesiologists Class 3 and 4 patients. The goal of the trial is characterization of the risks of bradycardia and other cardiac arrhythmias after sugammadex administration in this population that may have more severe outcomes related to cardiac arrhythmias experienced during reversal of neuromuscular blockade. Prespecify the case definition of bradycardia, tachycardia, and the other cardiac arrhythmias of interest.
Conduct a postmarketing clinical trial comparing sugammadex to placebo and/or drugs approved for the management of the reversal of the effects of neuromuscular blockade induced by rocuronium or vecuronium in patients with morbid obesity. The goal of the trial is to evaluate the safety of sugammadex (including the serious adverse outcomes of anaphylaxis or hypersensitivity) and to generate data to support dosing recommendations in morbidly obese patients, specifically whether to dose by actual vs. ideal body weight. Prespecify the case definition of morbid obesity that will establish who will be included in the trial.
Continue the registry of patients with Fabry disease being treated with Agalsidase beta that was established to obtain long-term clinical status information.  This study will be revised so that detailed clinical status information is collected at study entry and on a 6 to12-month basis for at least 15 years.  Conduct a sub-study within the registry that will evaluate the effect of Agalsidase beta on pregnancy and lactation.  The registry data will be analyzed at yearly intervals.  Information will also be collected on clinical status, adverse events, assessment of immunogenicity and potential effects of antibody formation.
A long-term follow-up study to evaluate long-term efficacy and immunogenicity outcomes in a subpopulation of patients in LOTS and LOTS Extension Studies whose response to Lumizyme (alglucosidase alfa) is associated with substantial improvement over baseline in the 6 minute walk test (6MWT) results. This study will be conducted as a sub-study within the ongoing Pompe Registry.
As part of the ongoing Pompe Registry, prospective outcome data will be collected in patients enrolled in the Registry to assess the long-term efficacy of Lumizyme (alglucosidase alfa).
Conduct a dose-ranging study to determine the pharmacokinetics/ pharmacodynamics, safety, and tolerability of Entyvio (vedolizumab) in pediatric patients 5 to 17 years of age with moderately to severely active ulcerative colitis or Crohn’s disease who have failed conventional therapy.
To conduct a study to determine the incidence of cataract surgery associated with Palifermin administration. This study will be a component of the Phase 4 prospective cohort study using the available Center for International Blood and Marrow Transplant Research (CIBMTR) registry databases to evaluate the incidence of cataracts in patients who receive palifermin compared to a matched patient control group who have not received Palifermin. At least 2000 patients in each treatment group (palifermin and non-palifermin matched control) will be actively followed for cataract surgery through at least 5 years or until death.  The interim data will be submitted every 2 years (after study initiation in 2007) for 10 years.
A prospective safety study conducted within the ongoing Pompe Registry to assess the known serious risks of anaphylaxis and severe allergic reactions, and signals of severe cutaneous and systemic immune complex-mediated reactions with Lumizyme (alglucosidase alfa) treatment.
CONFIRMATORY TRIAL - A randomized phase 3 trial of SGN-35 (brentuximab vedotin) in combination with AVD versus ABVD as frontline therapy in patients with advanced Hodgkin Lymphoma. Enrollment of at least 880 patients is expected with a primary endpoint of progression free survival determined by an independent blinded review facility. Overall survival is a key secondary endpoint.
Conduct a study to determine the incidence of cataracts and decreased visual acuity associated with Palifermin administration.  This study will be a component of the clinical study 20040253 conducted in patients with metastatic breast cancer receiving multi-cycle chemotherapy.
Conduct a prospective cohort study using the available International Bone Marrow Transplant Registry (IBMTR) and Autologous Blood and Bone Marrow Registry (ABMTR) databases to evaluate the incidence of secondary malignancies, cancer relapse rates, and survival in patients who receive Palifermin compared to a matched patient control group who have not received Palifermin.
Submit the final efficacy (disease-free survival) and safety results from Trial BO25126 (APHINITY) as defined in your protocol and Statistical Analysis Plan (SAP).
A long-term observational study in administrative databases to prospectively evaluate the incidence of serious infection including skin infection, dermatologic adverse events, and over-suppression of bone turnover in postmenopausal women administered Prolia (denosumab).
Randomized, double-blind, adequately controlled, multiple fixed dose, parallel group clinical trial of Botox (onabotulinum toxin type A) in botulinum toxin-naive children age 2- 17 years with upper extremity spasticity.  The minimum duration of the trial should be 12 weeks.  The protocol for the trial should be submitted to the FDA as a special protocol assessment (SPA).
Provide information on maintenance of response with dosing intervals longer than every 12 weeks among relevant populations (e.g., subjects whose psoriasis is cleared as measured by PGA and PASI or who have minimal psoriasis).  This information will be obtained from a study of at least 300 subjects treated with Stelara¿ (ustekinumab) for a minimum of one year.
Submit safety data assessing distant spread of toxin effects after multiple administrations of Xeomin (incobotulinumtoxinA), during a minimum period of 12 months, collected in at least 100 adult patients. Approximately one half of the patients must be treated for upper and the other half treated for lower limb extremity spasticity.  Patients can be enrolled in either an upper or lower limb safety study, but not both, and should not receive concomitant botulinum toxin injections for another reason. These safety data could come from open-label extensions of the clinical trials you have committed to perform (see below), from separate longer-term open-label safety trials, or from a long-term controlled safety and efficacy trial.  The doses evaluated must be at least as high as those shown effective in these trials, or those commonly used to treat spasticity.
Conduct a Phase 4 study to evaluate the effect of raxibacumab on immunogenicity of anthrax vaccine.
Conduct a pregnancy registry to evaluate pregnancy outcomes for women exposed to Benlysta (belimumab) during pregnancy.
Submit a final report for the long-term, open-label, continuation trial LBSL99.
Submit a final report for the long-term, open-label, continuation trial C1074.
To conduct a Phase 1 study, Protocol 20050252 entitled, "A Phase 1 Study to Evaluate the Safety and Pharmacokinetics of Panitumumab in Children with Refractory Solid Tumors" in children and adolescents (up to 18 yr of age) to provide the initial safety assessment and establish the pharmacokinetics in pediatric patients with solid tumors in which, based on clinical study and published literature information, an EGFr inhibitor drug has been shown to have clinical activity.
A prospective, long-term observational study that will collect safety data, including sexual dysfunction and immunogenicity, from subjects previously treated with XIAFLEX® (collagenase clostridium histolyticum) who were enrolled and treated in Studies AUX-CC-802, AUX-CC-803 and AUX-CC-804.
Enhanced pharmacovigilance program for reports of malignancy in pediatric, adolescent, and young adult (¿  30 years of age) patients treated with Cimzia (certolizumab pegol), for a period of up to 10 years after this notification to collect data that will be analyzed to better define the risk of this serious adverse event.  The enhanced pharmacovigilance program includes the following: 1) active query of reporters to obtain additional clinical information related to malignancy diagnoses; 2) expedited reporting to FDA of all initial and follow-up reports of any malignancy in pediatric and young adult patients.  Interim analyses and summaries of new and cumulative safety information in pediatric and young adult patients must be submitted annually, followed by the final report at the conclusion of the monitoring period.
A study to bank samples for future evaluation to identify genetic mutations and other biomarkers that predispose inflammatory bowel disease (IBD) patients to developing Hepatosplenic T-Cell Lymphoma (HSTCL).
To conduct study protocol P06-134, a 5-year, 5000 patient, multi-center, uncontrolled, observational study of adult patients with Crohn's disease treated in a routine clinical setting with adalimumab.
Perform, complete and submit the full study report for a single-dose study of pharmacokinetics and pharmacodynamics (PK/PD) of edoxaban in pediatric patients at risk for venous thromboembolism (VTE), requiring anticoagulation or recently completing standard of care anticoagulation in accordance with your October 31, 2013 agreed upon Initial Pediatric Study Plan (iPSP).
Perform, complete and submit the full study report for a phase 3 multicenter, randomized, active control study of edoxaban in pediatric patients with documented venous thromboembolism in accordance with your October 31, 2013 agreed upon Initial Pediatric Study Plan (iPSP).
A juvenile rat toxicology study is required to identify the unexpected, serious risk of adverse effects of Xeomin (incobotulinumtoxinA) on postnatal growth and development.  The study should utilize animals of an age range and stage(s) of development that are comparable to the intended pediatric population; the duration of dosing should cover the intended length of treatment in the pediatric population.  In addition to the usual toxicological parameters, this study should evaluate effects of Xeomin (incobotulinumtoxinA) on growth, reproductive development, and neurological and neurobehavioral development.
Phase 2, multicenter study to evaluate the safety, efficacy, and pharmacokinetics of belimumab plus background standard therapy in 100 pediatric subjects ages 5 years to 17 years of age with active systemic lupus erythematosus (SLE).
To conduct a trial that will evaluate the safety, efficacy, PK/PD and immunogenicity of IV golimumab in pediatric patients between the ages 2 to 17 years and 11 monthswith active juvenile idiopathic arthritis (JIA) despite standard therapy with methotrexate.
To conduct a phase 4, randomized, controlled, open label, multicenter parallel group study to assess the all cause mortality and cardiovascular morbidity in anemic patients with chronic kidney disease who are on dialysis and not undergoing dialysis.  The study will enroll patients with a broad range of C-reactive protein blood concentrations and will randomize patients to treatment with either methoxy polyethylene glycol-epoetin beta or another  erythropoiesis-stimulating agent.
CONFIRMATORY TRIAL- A randomized phase 3, double-blind, placebo-controlled trial of SGN-35 (brentuximab vedotin) in combination with CH-P versus CHOP as frontline therapy in patients with CD30-positive mature T- and NK-cell lymphomas including systemic ALCL (sALCL). Enrollment of approximately 300 patients is expected with a primary endpoint of progression free survival as determined by an independent blinded review facility. Overall survival is a key secondary endpoint.
Unless FDA agrees, based on your completion of Postmarketing Commitment Number 1, that it is not appropriate to conduct a pediatric study in pediatric patients age 6 to 11 years, after completing the study described in Postmarketing Commitment Number 2, conduct a pediatric study in pediatric patients age 6 to 11 years for the treatment of Crohn's disease.  This second pediatric study will enroll pediatric patients age 6 to 11 years in a single, open-label arm (dose of TYSABRI will be selected based on results in older pediatric patients), and evaluate safety, pharmacokinetics, and response/remission rates.
Conduct a prospective, observational registry study of women with rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis and plaque psoriasis exposed to Etanercept during pregnancy or within two weeks prior to conception.  This study will assess the outcomes in the offspring born to those women who were exposed to Etanercept during pregnancy relative to background risk in similar patients not exposed to Etanercept.
A prospective pharmacokinetic (PK) study will be conducted to characterize the pharmacokinetics of Lumizyme (alglucosidase alfa) in pediatric patients in the age range of 8 years to 18 years.
Genzyme commits to designing and implementing an immune tolerance protocol in Pompe disease patients who have significant antibody titers, or the presence of neutralizing antibody, and are failing treatment.  Genzyme commits to designing and implementing a preventive immune tolerance protocol in Pompe disease patients at high risk for the development of significant immune responses to the product.  This would involve 1)  establishing the correlation among genotype, the level of  -glucosidase protein (non-enzymatic assay), and the presence and levels of binding, IgE, and neutralizing antibodies over time, using validated assays;  and 2)  developing an immune tolerance regimen that would be implemented before or concomitant with onset of therapy for those at high risk.  Additionally, Genzyme commits to monitoring antibody positive patients, whose immune responses are not associated with loss of efficacy or severe hypersensitivity responses, at regular intervals over an extended period of time (i.e., 18-24 months) to specifically assess if a sub-population of patients become tolerant with routine treatment.
A long-term surveillance study in postmenopausal women administered Prolia (denosumab) to prospectively evaluate the incidence of serious infection including skin infections, dermatologic adverse events, and over-suppression of bone turnover.
Evaluate the pharmacokinetics, safety and antiviral activity (efficacy) of abacavir/dolutegravir/lamivudine FDC tablets in HIV infected pediatric subjects 12 years to less than 18 years of age and weighing at least 40 kg. The safety and antiviral activity (efficacy) of abacavir/dolutegravir/lamivudine FDC tablets in pediatric subjects should be evaluated for a minimum of 24 weeks. A clinical trial in children 12 to less than 18 years of age and weighing at least 40 kg may not be required if dosing recommendation for the FDC tablets can be supported by pediatric trials already conducted with the individual drug products.
BioMarin is required to conduct the following assessments using data from patients enrolled in the ongoing MPS I Registry.  Immunogenicity will be studied using validated anti-Aldurazyme IgG and IgE, and neutralizing assays.  The relationship between the development of antibodies and development of spontaneous immune tolerance with changes in the following will be evaluated:  alpha -L-iduronidase genotype;  endogenous a-L-iduronidase enzyme activity levels; clinical phenotype; allergic reactions; functional assessments; pharmacodynamic measurement (urinary glycosaminoglycans).  Interim analyses of the preceding assessments will be included in yearly updates submitted to IND 7,334, as part of the MPS I Registry annual report.
BioMarin commits to developing an assay to detect anti-Aldurazyme antibody mediated neutralization of enzyme uptake. Such an assay could be developed based on the current cell uptake assay already used for Aldurazyme lot release. BioMarin commits to developing this neutralization assay and submitting a completed validation report.
To assess the serious risks of respiratory depression, accidental injury, overdose, misuse, accidental exposure, and medication errors associated with the use of OxyContin in opioid-tolerant pediatric patients aged 11-17, and to assess the serious risks of respiratory depression, accidental injury, overdose, misuse, accidental exposure, and medication errors associated with the use of the product in children who are either younger than the approved age range or who do not meet the labeled criteria for opioid tolerance, provide reports of all postmarket adverse events occurring in children aged 17 and younger related to respiratory depression, accidental injury, overdose, misuse, accidental exposure, and all medication errors, regardless of outcome. After three years of submitting reports, submit a comprehensive analysis of these adverse event and medication errors reports, and provide an explanation of how you have addressed them.
To develop, validate, and implement a ligand binding assay to supplement the neutralizing bioassay that tests for the presence of neutralizing antibodies in serum samples from patients with generalized lipodystrophy.
To conduct a randomized, multicenter, observation-controlled trial of peginterferon alfa-2b as adjuvant therapy in 1200 patients with ulcerated primary cutaneous melanoma with negative sentinel lymph node biopsy (T1b-T4bN0M0) randomized 1:1 to peginterferon alfa-2b  3.0 mcg/kg SC administered weekly for 24 months or observation alone for 24 months.  The trial will characterize toxicity of treatment, specifically debilitating fatigue, depression, and anorexia, and 	evaluate relapse-free survival (RFS).  Secondary endpoints will include overall survival.  The trial will be powered to detect an increase in RFS rate by 6.8% at 2 years, by 9.4% at 5 years, and by 10% at 10 years.  The trial will be powered to 	detect a hazard ratio of 0.7 for overall survival.  The trial design and statistical analysis plan must adequately address the comments provided to you in our December 10, 2010, letter to IND 7194 regarding proposed trial 18081.
Submit a report of the immunogenicity evaluation of all subjects enrolled in studies of Sargramostim.
To develop a validated cross-reactive immunologic material (CRIM) assay for patients with Hunter syndrome and test patient samples in a cohort of patientsprior to Elaprase (idursulfase) treatment. Results will be correlated with antibody response (binding, neutralizing and IgE), genetic mutations, enzyme activity level, urinary GAG level, hypersensitivity reactions, and clinical outcome in patients who are receiving Elaprase (idursulfase) treatment. Patients with severe genetic mutations, such as complete deletions or large rearrangements, will be represented in the study. Banked patient samples from other clinical studies may be used.
To conduct a multi-center, randomized, controlled, parallel-group study to confirm the optimal methoxy polyethylene glycol-epoetin beta dosage when used for the maintenance treatment of anemia in pediatric patients ages 5 to 17 years who have chronic kidney disease, inclusive of patients undergoing dialysis as well as patients who are not undergoing dialysis.  The protocol for this study has been submitted.
Conduct a one-year, randomized, placebo-controlled clinical trial with Benlysta (belimumab) in 5,000 patients with active, autoantibody-positive systemic lupus erythematosus to evaluate Benlysta's long term safety profile including adverse events of special interest (e.g., mortality, malignancy, serious and opportunistic infections and depression (suicidality)).
A JIA patient safety registry comprised of at least 500 patients.  The protocol for this study should include a plan for more intensive scrutiny for the first 3 years, with annual follow ups (which could be telephonic) assessing for occurrence of malignancies, other autoimmune diseases, and serious infections, for a total of 10 years.  Patients turning 18 years of age or older should continue to be followed until they have completed the 10 year follow-up period.  Information on these patients may be obtained via annual questionnaire/telephonic follow-up with attention to key adverse events rather than full clinic visit with examination. Occurrence of these serious events should be formally compared to the expected rate of these events in historical controls.
A safety and pharmacokinetic trial as a substudy of the DEVELOP registry to evaluate whether trough concentrations at the time of loss of clinical response can be used to identify pediatric UC and Crohn¿s disease patients who have low infliximab exposures and would benefit from a dose increase above that approved without increasing risk of serious adverse events.
Assess the pharmacokinetics, safety, immunogenicity, and efficacy of golimumab in pediatric patients 2 to 16 years of age with active polyarticular juvenile idiopathic arthritis (pJIA).
Based on the results of the Phase 1 protocol 20050252 (i.e., provided that a safe and tolerable dose of Panitumumab can be determined for children), Amgen will conduct a Phase 2 study to further assess the safety and to estimate the anti-tumor activity of Panitumumab in pediatric patients with solid tumors in which, based on clinical study and published literature information, an EGFr inhibitor drug has been shown to have clinical activity.
To conduct an "Antibody Registry Study" that will enroll subjects who have received romiplostim and whose blood samples contain antibodies to either romiplostim or thrombopoietin.  The antibody assays will be performed by Amgen in response to spontaneously submitted requests for the post-marketing blood tests.  As described in the romiplostim prescribing information, a lack or loss of response to romiplostim should prompt the healthcare provider to search for causative factors, including neutralizing antibodies to romiplostim.  In these situations, healthcare providers are to submit blood samples to Amgen for detection of antibodies to romiplostim and thrombopoietin.  The Antibody Registry Study will collect follow-up platelet count and other clinical data sufficient to assess the long term consequences of the detected antibodies.  Patients will be followed until the detected antibodies resolve or stabilize in titer over a several month period of time.  You will conduct this study according to the following timetable:   Protocol Submission: November 2008; Study Start: May 2009; First interim report submission:  May 2010 then annually; Final Report Submission:	Within six months of FDA notification that sufficient data has been collected
Submit safety data assessing distant spread of toxin effects after multiple administrations of Xeomin (incobotulinumtoxinA), during a minimum period of 12 months, collected in at least 100 pediatric patients (ages 2-17 years). Approximately one half of the patients must be treated for upper and the other half treated for lower limb extremity spasticity.  Patients can be enrolled in either an upper or lower limb safety trial, but not both, and should not receive concomitant botulinum toxin injections for another reason. These safety data could come from open-label extensions of the clinical trials you have committed to perform (see below), from separate longer-term open-label safety trials, or from a long-term controlled safety and efficacy trial.  The doses evaluated must be at least as high as those shown effective in these trials, or those commonly used to treat spasticity.
To develop a validated assay for identification of anti-product antibodies that neutralize the bioactivity of tbo-filgrastim.  The validation of the assay should include the sensitivity and specificity for detection of anti- tbo-filgrastim antibodies that are also cross-reactive with and neutralize the bioactivity of native human granulocyte colony stimulating factor (G-CSF).
Deferred pediatric Placebo-Controlled Efficacy and Safety Study under PREA for prophylaxis of headaches in adolescents ages 12 to 17 with chronic migraine. The study must include a prospective baseline observation period of at least 4 weeks followed by a double-blind treatment phase of at least 12 weeks. The study must include an adequate evaluation of dose-response.  The study must take into account adequate (e.g., proportionate to disease population) representation of children of ethnic and racial minorities and allow the use of appropriate rescue treatment.  The protocol for this study must be submitted as a Special Protocol Assessment (SPA) and receive Division concurrence prior to the initiation of the study.
To submit a separate subsection in the Periodic Safety Update Report (PSUR) containing the interim results of the enhanced pharmacovigilance monitoring plan for PML annually for ten years beginning in 2008.  This section will contain the ongoing aspects of postmarketing surveillance described in Sections 3.3.1, 3.3.2, and 3.3.5 of the May 3, 2007, submission.  This PSUR subsection should include, but not be limited to: a. a cumulative summary of all expedited reports of PML which include the results of questionnaires and active attempts to solicit data on such events 	(Section 3.3.1);  b.  the results of ongoing analyses to characterize observed rates of PML within all non-HIV-related specific disease categories in which PML has occurred or occurs after Rituxan administration.  The results of these analyses will include a comparison of the observed rates of PML among those who have and have not 	received Rituxan to detect trends and estimated rates of PML with evaluation for possible risk factors, e.g., duration of Rituxan exposure, (Section 3.3.2); and,  c.  the results of the proposed and ongoing pharmacoepidemiologic evaluations described under section 3.3.5.
To conduct a multi-center, dose-finding study to determine the optimum starting dose of intravenously administered methoxy polyethylene glycol-epoetin beta when used for the maintenance treatment of anemia in pediatric patients ages 5 to 17 years who have chronic kidney disease and are undergoing dialysis.  The protocol for this study has been submitted.
Conduct a deferred pediatric study under PREA to determine whether, compared to placebo, administration of Palifermin decreases the incidence and duration of severe oral mucositis and related sequelae experienced by patients age 3-16 with hematologic malignancies who are receiving myelotoxic therapy.
Conduct a prospective, multi-center registry including 5000 adult psoriasis patients treated with Humira in the United States.  This registry will characterize and assess the incidence of serious adverse events (including serious infections, tuberculosis, opportunistic infections, malignancies, hypersensitivity reactions, autoimmune reactions and deaths) as well as other adverse events of interest in the study cohort.  All enrolled study patients will be evaluated for a period of at least 10 years with comprehensive annual reports provided to the Agency.  Collect data on the patient characteristics, demographics and drug exposure (including dose, duration and time to onset of adverse event).  The collection of data will be via active surveillance methods and data will be validated by a review of medical records as per the guidance for industry titled Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment.
To submit a protocol for review for a prospectively and actively enrolled pregnancy registry that will collect information assessing pregnancy complications and birth outcomes in women with breast cancer exposed to a Herceptin-containing regimen prior to conception or during pregnancy.  Notice of a pregnancy registry and the telephone contact number will be included in the package insert.  A proposal, including a prospective protocol for FDA review will be submitted to FDA by June 30, 2008.  The registry will become active by December 31, 2008, and interim reports of all data collected will be submitted on an annual basis to FDA through December 31, 2019.
A randomized, double-blind, placebo-controlled trial to evaluate the effect of long-term treatment with Contrave (naltrexone hydrochloride/bupropion hydrochloride) extended-release tablets on the incidence of major adverse cardiovascular events (MACE) in obese and overweight subjects with cardiovascular disease or multiple cardiovascular risk factors. The primary objective of this trial should be to demonstrate that the upper bound of the 2-sided confidence interval for the estimated risk ratio comparing the incidence of MACE (non-fatal myocardial infarction, non-fatal stroke, cardiovascular death) observed with Contrave to that observed in the placebo group is less than 1.4. The trial should be designed to provide sufficient data to reflect the “on-treatment” cardiovascular risk associated with Contrave. Sample size calculation should take into account that “on-study” events would be censored 365 days after treatment discontinuation. The ongoing LIGHT trial will not be sufficient to meet this requirement; a new trial is required.
Enhanced pharmacovigilance program for reports of malignancy in pediatric, adolescent, and young adult (< 30 years of age) patients treated with Humira (adalimumab), for a period of up to 10 years after this notification to collect data that will be analyzed to better define the risk of this serious adverse event.  The enhanced pharmacovigilance program includes the following: 1) active query of reporters to obtain additional clinical information related to malignancy diagnoses; 2) expedited reporting to FDA of all initial and follow-up reports of any malignancy in pediatric and young adult patients.  Interim analyses and summaries of new and cumulative safety information in pediatric and young adult patients must be submitted annually, followed by the final report at the conclusion of the monitoring period.
Long-term pediatric study in patients ? 10 years to ? 17 years of age to evaluate the safety and efficacy of BOTOX in the treatment of urinary incontinence due to detrusor overactivity associated with a neurologic condition (e.g. spina bifida or spinal cord injury).
Conduct studies to evaluate the safety and efficacy of ustekinumab in pediatric subjects with plaque psoriasis.
Evaluate long-term safety and efficacy data in a Clinical Surveillance Program (CSP) of patients being treated with Galsulfase.  Detailed clinical status information will be collected at study entry and on an annual basis for at least 15 years.  Serious and severe adverse events among all patients will be collected and submitted through periodic safety update reports as specified by the regulations (21 CFR 600.80).  You will conduct a sub-study within the CSP that will evaluate the effect of Galsulfase on pregnancy and lactation.  You will also conduct a second sub-study within the CSP that will include the enrollment of at least 10 children less than 5 years of age to be treated with 1 mg/kg/week of Galsulfase for at least one year and report the analysis of these data.  The CSP data will be analyzed at yearly intervals and the results will be submitted in your IND annual reports.  Information will also be collected on clinical status, adverse events, assessment of immunogenicity, and potential effects of antibody formation.
Provide clinical information from a 1-year (minimum) clinical trial evaluating the adverse effects, if any, on the corneal endothelium following administration of aflibercept.
To conduct an assessment of anti-drug antibody (ADA) response and neutralizing ADA responses to ipilimumab with a validated assay (required in PMR 2 and 3) capable of sensitively detecting ADA responses in the presence of ipilimumab levels that are expected to be present at the time of patient sampling. The ADA response will be evaluated in at least 300 ipilimumab-treated patients enrolled in the required postmarketing trial (PMR 6) comparing 3 mg/kg versus 10 mg/kg of ipilimumab monotherapy. The final report will include information on the level of ipilimumab in each patient's test sample at each sampling time point.
Assess data anticipated from adults in protocol "TYSABRI Observational Study in Safety in CD (Crohn's disease)" (Postmarketing Commitment Number 4, below) and establish a pediatric study plan that incorporates these new data.  These data must be analyzed, to include an assessment of safety, before the required pediatric studies are initiated.
To identify further genetic determinants of immune-mediated adverse events caused by ipilimumab. DNA samples from the required postmarketing study comparing 3 mg/kg vs. 10 mg/kg ipilimumab monotherapy will be used to conduct genome-wide association analyses. The design of these analyses will be reviewed by FDA and a final report with electronic datasets will be provided.
Conduct a juvenile animal toxicology study of 3 months duration in an appropriate species before initiation of the pediatric  studies in patients 5 to 17 years of age.
Develop and validate an improved immunogenicity assay for detecting neutralizing antibodies to Galsulfase.
Submit safety data assessing distant spread of toxin effects after multiple administrations off Myobloc (botulinum toxin Type B), during a minimum period of 12 months, collected in at least 100 pediatric patients (ages 2-17 years) and 100 adult patients (approximately half  upper, and half lower extremity spasticity). In addition, submit data assessing the effects of Myobloc (botulinum toxin Type B) on blood glucose and alkaline phosphatase as a marker of bone metabolism. These safety data could come from open-label extensions of the clinical studies, from separate longer-term open-label safety studies, or from a long-term controlled safety and efficacy study. The doses evaluated must be at least as high as those shown effective in these studies, or those commonly used to treat spasticity.
Submit safety data assessing distant spread of toxin effects after multiple administrations of Dysport (abobotulinumtoxinA), during a minimum period of 12 months, collected in at least 100 adult patients (approximately half upper, and half lower extremity spasticity). In addition, submit data assessing the effects of Dysport (abobotulinumtoxinA) on blood glucose and alkaline phosphatase as a marker of bone metabolism. These safety data could come from open-label extensions of the clinical studies specified under #5-8 below, from separate long-term open-label safety studies, or from a long-term controlled safety and efficacy study. The doses evaluated must be at least as high as those shown effective in studies specified under #5-8 below, or those commonly used to treat spasticity.
Obtain preliminary safety and activity data and to characterize the pharmacokinetics of Bevacizumab in pediatric patients in Study AVF2117s, a Phase 1, dose-escalation trial, enrolling up to 24 children with relapsed or refractory solid tumors to be conducted by the Children's Oncology Group (COG).
Evaluate long-term safety and activity data in a registry study of patients being treated with Laronidase.  Among other things, the registry data will be used to evaluate the effect of Laronidase on pregnancy and lactation, and potential effects of antibody formation and urinary GAG levels on clinical outcomes.
Conduct a randomized, controlled clinical trial in patients with lupus nephritis to evaluate the efficacy and safety of Benlysta (belimumab).
Submit a final report for the long-term, open-label, continuation trial C1066.
To conduct a study to assess for the immunogenicity of Myalept (metreleptin) in a relevant number of patients receiving metreleptin. The study should include testing for anti-metreleptin and anti-native human leptin binding antibodies at times when antibody responses peak, using a validated assay. The presence of neutralizing antibodies should be assessed using a validated cell-based assay and a validated ligand-binding assay in samples that are confirmed positive for binding antibodies to leptin. All patients with suspected loss of metreleptin efficacy (e.g., worsening glycemic control, increases in triglycerides) or loss of endogenous leptin activity (e.g., severe infections) should be tested for neutralizing activity and followed at least until antibody levels revert to baseline. Antibody titers, neutralizing activity, and associated clinical events should be characterized over time.
A long-term prospective observational study (product exposure registry) of patients treated with Myalept (metreleptin), regardless of indication, to evaluate serious risks related to the use of Myalept (metreleptin), by indication, including: fatal or necrotizing pancreatitis, hepatic adverse events, severe hypoglycemia, serious hypersensitivity reactions, serious infections resulting in hospitalization or death, new diagnoses of autoimmune disorders (for instance, autoimmune hepatitis, glomerulonephritis, lupus erythematosus, antiphospholipid antibody syndrome, rheumatoid arthritis), autoimmune disease exacerbation, lymphoma, all cancers (excluding non-melanoma skin cancer) by cancer type , exposed pregnancies and pregnancy outcomes, and all deaths (including causes of death). After agreement with FDA on a targeted sample size, the registry will include patients prescribed Myalept (metreleptin) and will continue for 10 years from the date of last patient’s enrollment, or September 2029, whichever is later.
Conduct an observational prospective pharmacoepidemiology cohort study (Protocol IM101045B) to assess the short and long-term risk of malignancies and infection in patients with RA treated with Abatacept in comparison to other DMARDs within an existing registry containing patients with rheumatoid arthritis.  Follow-up will be for at least 5 years after the last patient is enrolled.
To evaluate the safety and tolerability of an alternate Herceptin (trastuzumab) dosing regimen that ensures that all patients, inclusive of patients with a Herceptin Cmin of ? 12 mcg/mL on Cycle 1 Day 21 after an initial dose of 8 mg/kg, achieve adequate exposure as reflected by Cmin of at least 12 mcg/mL by Cycle 2 Day 21, and maintain the exposure level throughout the treatment period. This may be achieved either through a specified regimen applied to all patients or through an individualized, pharmacokinetically guided treatment strategy. The pharmacokinetics and tolerability of the alternate Herceptin (trastuzumab) dosing regimen in patients with HER2-overexpressing, metastatic gastric cancer will be determined in a pharmacokinetic trial that enrolls an adequate number of patients to provide an initial assessment of safety.
To conduct a study to evaluate the impact of Oprelvekin dosing on QT interval prolongation.  The study should include up to 60 patients with cancer for whom Oprelvekin is indicated, who will receive Oprelvekin as subcutaneous injections at the recommended dose and schedule (50 µg/kg SC once daily until desired platelet response). Continuous cardiac monitoring (telemetry or Holter monitors) and/or concurrent detailed serial ECG monitoring, electrophysiologic studies, and serum Oprelvekin pharmacokinetic assessments will be performed at multiple timepoints prior to and during Oprelvekin administration.  Timepoints will include, but are not limited to, pre-treatment, the estimated Tmax of Oprelvekin, and a post therapy wash-out time point.  Serial ECGs will be evaluated in triplicate and read by a qualified physician.
Conduct a study to evaluate pediatric pharmacokinetics (PK), safety and antiviral activity of once daily darunavir and cobicistat (DRV/COBI) combined with a background regimen in HIV-1 infected pediatric subjects. Subjects receiving DRV/COBI should be from 3 years to less than 18 years of age. Initial evaluation of DRV/COBI exposure must be performed in an initial PK study or substudy to allow dose selection. Using doses selected based on the PK study or substudy, and agreed upon with the FDA, conduct a longer-term pediatric safety and antiviral activity assessment of DRV/COBI combined with a background regimen, assessing activity on the basis of continued HIV-1 RNA virology response and safety monitoring over as least 24 weeks of dosing.
A clinical trial in healthy subjects evaluating the effect of cobicistat coadministered with darunavir at steady state on the pharmacokinetics of atorvastatin.
Establish a Pregnancy Registry to collect and analyze information for ten years on pregnancy complications and birth outcomes in women with breast cancer exposed to a pertuzumabcontaining regimen within 6 months of conception or during pregnancy. Submit yearly interim reports, which may be included in your annual reports, on the cumulative findings and analyes from the Pregnancy Registry.
A randomized, double blind, placebo-controlled trial evaluating the effect of Tanzeum (albiglutide) on the incidence of major adverse cardiovascular events (MACE) in subjects with type 2 diabetes mellitus. The primary objective of the trial should be to demonstrate that the upper bound of the 2-sided 95% confidence interval for the estimated risk ratio comparing the incidence of MACE (non-fatal myocardial infarction, non-fatal stroke, cardiovascular death) observed with albiglutide to that observed in the placebo group is less than 1.3. This trial must also assess the following adverse events: development of thyroid cancer, hematologic malignancies, pancreatic cancer, pancreatitis, overall injection site reactions, immunological reactions including serious hypersensitive reactions, serious hypoglycemia events, hepatic events, hepatic enzyme elevations (including gamma-glutamyl transpeptidase [GGT]), serious gastrointestinal events, appendicitis, atrial fibrillation/flutter, pneumonia, worsening renal function, and diabetic retinopathy.
A study evaluating gallbladder ejection fractions in albiglutide treated subjects to further characterize the effect of albiglutide on gallbladder motility.
Conduct a PK/PD study in adolescents ages > or equal to 13 years to 17 years with moderate to severe symptoms of primary Restless Legs Syndrome. Using information from this PK study, conduct a clinical trial to assess the efficacy and safety of rotigotine transdermal (Neupro) in adolescents > or equal to 13 years to 17 years with moderate to severe symptoms of primary Restless Legs Syndrome. Develop age appropriate dose(s) in order to then identify the lowest maximally effective dose in this age group. Conduct a long-term safety study of adolescents ages > or equal to 13 years to 17 years with moderate to severe symptoms of primary Restless Legs Syndrome. The study must provide a descriptive analysis of safety data in pediatric patients during at least 12 months of continuous treatment with rotigotine transdermal at individualized doses in association with the trial
Following completion of protocol ALID 02307, patients will be encouraged to enroll in the ongoing MPS I Registry.  BioMarin is required to collect available mortality, immunogenicity, allergic reactions, and growth and development data on this subpopulation for the duration of the Registry to study the potential effects of immune tolerance induction on these outcomes.  Interim reports of this trial will be submitted on a yearly basis, as part of the MPS I Registry annual report to IND 7,334.
To conduct a prospective, observational study in at least 2000 subjects with Crohn's disease who are receiving TYSABRI, with each subject followed for at least five years, by completing protocol, "TYSABRI Observational Study in Safety in CD (Crohn's disease)." You will ensure having at least 1000 patients with two years of TYSABRI treatment, and will increase the total number of patients enrolled beyond 2000 if necessary to achieve this.
Deferred pediatric efficacy study under PREA for the treatment of upper limb spasticity, to decrease the severity of increased muscle tone in the elbow flexors, wrist flexors and finger flexors in pediatric patients ages 2 years through 16 years 11 months.
Conduct ado-trastuzumab emtansine exposure-response analyses for progression-free survival, final overall survival, and safety utilizing data from trial BO25734/TDM4997 (TH3RESA).  The results of the exposure-response analyses from both TH3RESA and BO21977/TDM4370g (EMILIA) will be used to determine whether a postmarketing trial is needed to optimize the dose in patients with metastatic breast cancer who have lower exposure to ado-trastuzumab emtansine conjugate at the approved dose (3.6 mg/kg q3w).  Submit a final report of the exposure-response analyses based on TH3RESA and EMILIA.
A pharmacokinetic and safety study of tocilizumab (TCZ) in patients less than 2 years old with active systemic juvenile idiopathic arthritis (sJIA)
An observational safety study enrolling 500 patients treated with Krystexxa (pegloticase) for one year duration.  Patients enrolled should have hyperuricemia and gout and be refractory to standard uric acid-lowering therapies (e.g., allopurinol).  The study should include the following objectives:   a.  An evaluation of the frequency and severity of infusion reactions, anaphylaxis, and immune complex-related adverse events.  b.  Identification of serious adverse events associated with Krystexxa (pegloticase) therapy.
Centocor agrees to conduct a prospective, multi-center registry including 4000 adult psoriasis patients treated with commercial REMICADE in the United States.  This registry will characterize and assess the incidence of serious adverse events (including serious infection, tuberculosis, opportunistic infections, malignancies, hypersensitivity reactions, autoimmune reactions and deaths) as well as other adverse events of interest in the study cohort.  All enrolled study patients will be evaluated twice yearly for a period of at least 8 years with comprehensive annual reports provided to the agency.  Centocor agrees to collect data on the patient characteristics, demographics and drug exposure (including dose, duration and time to onset of adverse event).  The collection of data will be via active surveillance methods and data will be validated by a review of medical records as per the Guidance for Industry: Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment.
Establish a Pregnancy Registry to collect and analyze information for 10 years on pregnancy complications and birth outcomes in women with breast cancer exposed to ado-trastuzumab-emtansine within 6 months of conception or during pregnancy. Submit yearly interim reports, which may be included in your annual reports, on the cumulative findings and analyses from the Pregnancy Registry.
A study to analyze samples from the Pediatric IBD registry (DEVELOP) and PMR 3 to determine the presence of ADA using the new assay developed in PMC 5.
A long-term safety study in 400 pediatric patients 2-17 years of age with polyarticular JIA (pJIA) treated with tocilizumab to evaluate for the risk of malignancies, serious infections, gastrointestinal perforation, and effects on growth. The study should include a control group of 400 pediatric pJIA patients treated with other biologics as standard of care. Patients should be followed for 5 years.
A juvenile rat toxicology study is required to identify the unexpected serious risk of adverse effects on postnatal growth and development. The study should utilize animals of an age range and stage(s) of development that are comparable to the intended pediatric population; the duration of dosing should cover the intended length of treatment in the pediatric population. In addition to the usual toxicological parameters, this study should evaluate effects of Dysport (abobotulinumtoxinA) on growth, reproductive development, and neurological and neurobehavioral development.
Analyze anti-elosulfase alfa neutralizing antibody titers in patient samples obtained in the completed MOR-004 trial.
Conduct a prospective registry of belatacept use in US adult kidney-only transplant recipients to determine the incidence rates of post-transplant lymphoproliferative disorder PTLD, PTLD in the central nervous system (CNS PTLD), and progressive multifocal leukoencephalopathy (PML) in US adult EBV seropositive kidney transplant recipients treated with belatacept in clinical practice. All US adult kidney transplant centers dispensing belatacept will be asked to participate in the study (i.e., if a center does not respond or declines to participate, the reason(s) for nonparticipation will be identified and documented). Recipient characteristics will be collected, including EBV and CMV serostatus, timing of initiation of belatacept in relation to the transplant, location of the PTLD, and outcome (survival or mortality).  (Protocol Number IM103076)
A study to measure GC-C mRNA levels in duodenal and colonic tissue obtained from children ages 0 to 6 years of age.
Conduct a randomized, double blind, multicenter, comparative study to establish the safety and tolerability profile of ceftolozane/tazobactam compared to that of meropenem in hospitalized children from birth to <18 years with cUTI. The dose for this study will be determined upon review of the data to be submitted by December 2016 from a single-dose, multicenter, non-comparative study assessing the pharmacokinetics (PK) of ceftolozane/tazobactam in pediatric patients ages 0 to <18 years that was initiated in June 2014.
Provide data analyses from the Pregnancy Research Initiative (study C0168T71).
A post-marketing, observational epidemiologic study comparing MOVANTIK (naloxegol) to other treatments of opioid induced constipation in patients with chronic non-cancer pain. The study’s primary outcome is a composite of major adverse cardiovascular events (MACE): cardiovascular (CV) death, nonfatal myocardial infarction, and nonfatal stroke. Secondary outcomes include, but are not limited to, CV death, nonfatal myocardial infarction, and nonfatal stroke separately. Specify concise case definitions and validation algorithms for the primary and secondary outcomes. Justify the choice of appropriate comparator population(s) and estimated background rate(s) relative to MOVANTIK (naloxegol)-exposed patients; clearly define the primary comparator population for the primary objective. Design the study around a testable hypothesis to assess, with sufficient sample size and power, MACE risk among MOVANTIK (naloxegol) users relative to comparator(s) considering important potential confounders including lifestyle risk factors and over the counter (OTC) medications with potential for cardiovascular effects, with a pre-specified statistical analysis method. For the MOVANTIK (naloxegol)-exposed and comparator(s), clearly define the new user clean period, including any exclusion and inclusion criteria. Ensure an adequate number of patients with at least 12 months of MOVANTIK (naloxegol) exposure at the end of the study.
An in vitro study to evaluate the time-dependent/mechanism-based inhibition potential of naloxegol on the hepatic CYP2C8 enzyme.
Deferred pediatric long-term safety study (minimum 12 months) under PREA for the treatment of upper limb spasticity in pediatric patients ages 2 years through 16 years 11 months. The doses evaluated must be at least as high as those shown effective in the pediatric efficacy study (PMR-2), or those commonly used to treat upper limb spasticity in pediatric patients, if an effective dose is not identified in the pediatric efficacy study (PMR-2). The study must assess distant spread of toxin effects, and the effects of Botox on blood glucose and alkaline phosphatase. The study report must include safety information on at least 300 patients who received 2 injections over a 6-month period, with at least 100 patients who received the highest recommended dose (if any), and safety information on at least 100 patients who received 4 injections over a 12-month period, with at least 60 patients who received the highest recommended dose (if any).
An observational study registry in adult patients with moderately to severely active RA that would assess the longer term risks of serious infections, malignancies that have been reported with TNF  blocker therapy, as well as the longer term risk for cardiovascular and thromboembolic events, including congestive heart failure, hypertension, TIA, stroke, tachyarrhythmia, atrial fibrillation, venous thrombosis and phlebitis.
During the conduct of the required postmarketing trial comparing 3mg/kg vs. 10mg/kg ipilimumab monotherapy (PMR 6), you will obtain comprehensive baseline DNA sample acquisition (? 95% of ITT) and conduct pharmacogenomic association analyses to assess the potential clinical utility of CD86 gene polymorphisms as genetic determinants of immune mediated adverse events. You will provide a protocol that addresses SNP selection, data analyses approaches, and other methodological issues. You will provide a Final Report including electronic datasets.
Enroll 4,000 Stelara¿ (ustekinumab)-treated subjects into the Psoriasis Longitudinal Assessment and Registry, (PSOLAR) and follow for 8 years from the time of enrollment.  Subjects will be followed for the occurrence of serious infection, tuberculosis, opportunistic infections, malignancy, hypersensitivity reactions, autoimmune disease, neurologic or demyelinating disease, cardiovascular, gastrointestinal or hematologic adverse events,
Enhanced pharmacovigilance program for reports of malignancy in pediatric, adolescent, and young adult (< 30 years of age) patients treated with Enbrel (etanercept), for a period of up to 10 years after this notification to collect data that will be analyzed to better define the risk of this serious adverse event.  The enhanced pharmacovigilance program includes the following: 1) active query of reporters to obtain additional clinical information related to malignancy diagnoses; 2) expedited reporting to FDA of all initial and follow-up reports of any malignancy in pediatric and young adult patients.  Interim analyses and summaries of new and cumulative safety information in pediatric and young adult patients must be submitted annually, followed by the final report at the conclusion of the monitoring period.
A long-term safety study in 100 pediatric patients 2 to 17 years of age with systemic JIA (SJIA) treated with canakinumab to evaluate for the risks of serious infections, neutropenia, thrombocytopenia, severe injection site reactions, and MAS. The study should include a control group of SJIA patients not receiving canakinumab. Patients should be followed for 5 years.
Evaluate the occurrence of serious infections associated with administration of a prophylactic immune tolerance regimen in a cohort of Morquio A syndrome patients treated with Vimizim (elosulfase alfa) who are at high risk of developing persistent neutralizing antibodies. This immune tolerance regimen will be implemented before or concomitant with the onset of Vimizim (elosulfase alfa) therapy.
A study in inflammatory bowel disease (IBD) patients treated with Humira (adalimumab) in which you will bank tissue or blood samples (as appropriate) and then analyze them to identify genetic mutations and other biomarkers that predispose these patients to developing Hepatosplenic T-Cell Lymphoma (HSTCL).
Conduct a randomized, placebo-controlled, blinded, multicenter study of the induction and maintenance of clinical response and remission by Entyvio (vedolizumab) in pediatric patients 5 to 17 years of age with moderately to severely active ulcerative colitis who have failed conventional therapy.
Conduct a milk-only lactation study in lactating women receiving vedolizumab therapeutically to assess concentrations of vedolizumab in breast milk using a validated assay in order to appropriately inform the Nursing Mother’s subsection of labeling.
Conduct a randomized, placebo-controlled, blinded, multicenter study of the induction and maintenance of clinical response and remission by Entyvio (vedolizumab) in pediatric patients 6 to 17 years of age with moderately to severely active Crohn’s disease who have failed conventional therapy.
Submit safety data assessing distant spread of toxin effects after multiple administrations of Dysport (abobotulinumtoxinA), during a minimum period of 12 months, collected in at least 100 pediatric patients (ages 2-17 years) (approximately half upper, and half lower extremity spasticity). In addition, submit data assessing the effects of Dysport (abobotulinumtoxinA) on blood glucose and alkaline phosphatase as a marker of bone metabolism. These safety data could come from open-label extensions of the clinical studies specified under #5-8 below, from separate long-term open-label safety studies, or from a long-term controlled safety and efficacy study. The doses evaluated must be at least as high as those shown effective in studies specified under #5-8 below, or those commonly used to treat spasticity.
Randomized, double-blind, adequate and well controlled, multiple fixed-dose, parallel group clinical trial of Xeomin (incobotulinumtoxinA) in botulinum toxin-naive adults with lower extremity spasticity. The minimum duration of the trial should be 12 weeks. You should propose a method to actively monitor for adverse events related to spread of toxin. The protocol for the trial should be submitted to the FDA as a special protocol assessment (SPA).
Conduct a randomized, controlled clinical trial to evaluate the efficacy and safety of Benlysta (belimumab) in African-American patients with SLE.
Conduct a one-year, multi-center, randomized, double-blind placebo-controlled trial to evaluate the efficacy, safety and pharmacokinetics of adalimumab in pediatric patients 5 to 17 years of age with moderately to severely active ulcerative colitis. In this trial, the efficacy of adalimumab should be assessed during induction treatment as well as during continued treatment after induction, and pharmacokinetic measurements should be conducted for exposure-response analysis. Also, collect samples for immunogenicity testing (utilizing a validated AAA assay as described in PMR #3 above) and conduct analyses of the impact of immunogenicity on pharmacokinetics, efficacy and safety. The protocol should be agreed upon by the agency prior to the initiation of the trial.
To determine the approximate percent of potential impurities derived from the E. coli cell line used to manufacture metreleptin that are detected by the ELISA to assess for host cell proteins (HCP) in metreleptin drug substance using a sensitive and discriminating assay such as 2D gel electrophoresis to detect impurities that can lead to increased immunogenicity. If the currently validated assay does not detect a majority of proteins distributed evenly throughout a 2D gel electrophoresis or equivalent method, then a new assay to detect HCP will be developed, validated, and implemented. If the current assay provides adequate HCP detection then a protocol for qualification of new HCP kits will be developed, validated, and implemented. The revised specifications together with supporting information will be submitted to your BLA in accordance with 21 CFR 601.12.
Utilizing a validated AAA assay as described in PMR #3 above, you should measure and analyze the immunogenicity profile based on post-dose patient samples from completed study M10-223, the trial conducted under PMR #5, the trial conducted under PMR #6, and the trial conducted under PMC #7.
Pediatric study in patients  10 years to 17 years of age to evaluate the safety and efficacy of BOTOX in the treatment of urinary incontinence due to detrusor overactivity associated with a neurologic condition (e.g. spina bifida or spinal cord injury).
Conduct a clinical trial to further assess the cardiac safety of neoadjuvant anthracycline/taxane-based chemotherapy regimens when administered in combination with neoadjuvant pertuzumab and trastuzumab in patients with locally advanced, inflammatory, or early stage HER2-positive breast cancer.
Randomized, double-blind, adequate and well controlled, parallel group, clinical trial of Xeomin (incobotulinumtoxinA) in botulinum toxin-naive adults with blepharospasm. You should propose a method to actively monitor for adverse events related to spread of toxin. The protocol for the trial should be submitted to the FDA as a special protocol assessment (SPA).
Randomized, double-blind, adequately controlled, multiple fixed dose, parallel group clinical trial of Botox (onabotulinum toxin type A) in botulinum toxin-naïve children age 2- 17 years with lower extremity spasticity.  The minimum duration of the trial should be 12 weeks. The protocol for the trial should be submitted to the FDA as a special protocol assessment (SPA).
Evaluate the pharmacokinetics, safety, and antiviral activity (efficacy) of darunavir and cobicistat fixed dose combination (FDC) age-appropriate formulation in HIV-infected pediatric subjects 3 years to less than 6 years of age and weighing at least 15 kg. The safety and antiviral activity (efficacy) of darunavir and cobicistat FDC age-appropriate formulation in pediatric subjects should be evaluated for a minimum of 24 weeks. A clinical trial in children ages 3 years to less than 6 years may not be required if the dosing recommendation for the FDC age-appropriate formulation can be supported by pediatric trials already conducted with the individual drug products and if the age-appropriate FDC produces similar exposures as the individual components.
Evaluate the pharmacokinetics, safety, and antiviral activity (efficacy) of darunavir and cobicistat fixed-dose combination (FDC) tablets in HIV-infected pediatric subjects 12 years to less than 18 years of age. The safety and antiviral activity (efficacy) of darunavir and cobicistat FDC tablets in pediatric subjects should be evaluated for a minimum of 24 weeks. A clinical trial in children 12 years to less than 18 years of age may not be required if the dosing recommendation for the FDC tablets can be supported by pediatric trials already conducted with the individual drug products and if the FDC produces similar exposures as the individual components.
Evaluate the pharmacokinetics, safety, and antiviral activity (efficacy) of atazanavir and cobicistat fixed-dose combination (FDC) age-appropriate formulation in HIV-infected pediatric subjects 3 years to less than 6 years of age. The safety and antiviral activity (efficacy) of atazanavir and cobicistat FDC ageappropriate formulation in pediatric subjects should be evaluated for a minimum of 24 weeks. A clinical trial in children 3 years to less than 6 years of age may not be required if the dosing recommendation for the FDC age-appropriate formulation can be supported by pediatric trials already conducted with the individual drug products and if the age-appropriate FDC produces similar exposures as the individual components.
Evaluate the pharmacokinetics, safety, and antiviral activity (efficacy) of atazanavir and cobicistat fixed-dose combination (FDC) age-appropriate formulation in HIV-infected pediatric subjects 6 years to less than 12 years of age The safety and antiviral activity (efficacy) of atazanavir and cobicistat FDC ageappropriate formulation in pediatric subjects should be evaluated for a minimum of 24 weeks. A clinical trial in children 6 years to less than 12 years of age may not be required if the dosing recommendation for the FDC age-appropriate formulation can be supported by pediatric trials already conducted with the individual drug products and if the age-appropriate FDC produces similar exposures as the individual components.
Evaluate the pharmacokinetics, safety, and antiviral activity (efficacy) of atazanavir and cobicistat fixed-dose combination (FDC) age-appropriate formulation in HIV-infected pediatric subjects 12 years to less than 18 years of age. The safety and antiviral activity (efficacy) of atazanavir and cobicistat FDC age-appropriate formulation in pediatric subjects should be evaluated for a minimum of 24 weeks. A clinical trial in children 12 years to less than 18 years of age may not be required if the dosing recommendation for the FDC ageappropriate formulation can be supported by pediatric trials already conducted with the individual drug products and if the age-appropriate FDC produces similar exposures as the individual components.
Conduct an adequate leachable safety assessment for your freeflex® bag container closure system. This assessment must include leachable data from longterm stability studies testing at least three batches at multiple time points over the shelf-life of your drug product. Submit a toxicological risk assessment justifying the safety of the maximum level achieved over the course of stability for any leachable that exceeds 5 mcg/day, taking into consideration the maximum daily dose of the drug product. From a genetic toxicology perspective, any leachable that contains a structural alert for mutagenicity must not exceed 120 mcg/day, or be adequately qualified for safety.
Conduct the deferred pediatric study to assess the pharmacokinetics, safety/tolerability, and antiviral activity of tenofovir alafenamide in HBV infected subjects 12 to less than 18 years of age, followed by a rollover to a long-term, open-label, extension to assess longer-term pediatric safety and antiviral activity.
Conduct the deferred pediatric study to access the pharmacokinetics, safety/tolerability, and antiviral activity of tenofovir alafenamide in HBV infected subjects 2 to less than 12 years of age, followed by a rollover to a long-term, open-label, extension to assess longer-term pediatric safety and antiviral activity.
A postmarketing study that will allow you to test for and control the levels of the following elemental impurities in your product: [...] that are present during the manufacturing process and have the potential to contaminate your product. As part of your post-marketing study, you will need to 1) develop a validated method for testing the finished product for the elemental impurities as stated above, and 2) analyze at least three batches of your product using the validated method.
A prospective, multi-center, long-term, observational study of ulcerative colitis patients treated with Simponi (golimumab) in a routine clinical setting, to assess the long-term safety of Simponi (golimumab). The study’s primary outcome should be the incidence of lymphoma. Design the study around a testable hypothesis to rule out a clinically meaningful increase in lymphoma above an estimated background risk in a suitable comparator. Secondary endpoints should be pre-specified and may include the incidence of other malignancies. Select and justify the choice of appropriate comparator population(s) and corresponding background rate(s) relative to Simponi-exposed patients. Provide sample sizes and effect sizes that can be ruled out under various enrollment target scenarios and loss to follow-up assumptions. Patients should be enrolled over an initial 5-year period and then followed for a period of at least 10 years from the time of enrollment. Progress updates of patient accrual and a demographic summary should be provided in your annual reports. Safety data should be provided in periodic safety reports.
Conduct a study to evaluate the pharmacokinetics of Simponi (golimumab) in pediatric patients 5 to 17 years of age with moderately to severely active ulcerative colitis. Pharmacokinetic measurements should be conducted for exposure-response analysis and compared to adult patients with ulcerative colitis treated with Simponi (golimumab). Also, collect serum samples for immunogenicity testing and conduct analyses of the impact of immunogenicity on the pharmacokinetics of Simponi (golimumab).
Conduct a study to evaluate the effectiveness and safety of Simponi (golimumab) in pediatric patients 5 to 17 years of age with moderately to severely active ulcerative colitis. The study should be designed to establish that the dose regimen(s) of Simponi (golimumab) identified in PMC#4 is(are) effective and safe for induction treatment, as well as for continued treatment after induction. Pharmacokinetic measurements should be conducted for exposure-response analysis. Collect serum samples for immunogenicity testing and conduct analyses of the impact of immunogenicity on pharmacokinetics, efficacy and safety.
Conduct a pharmacokinetic study in healthy volunteers to evaluate the effects of administration methods on pharmacokinetics of cysteamine. This study will compare the pharmacokinetics of cysteamine after administration of Procysbi (cysteamine bitartrate) capsules with water and with orange juice. In addition, this study will evaluate the effects of a concomitant proton pump inhibitor on the pharmacokinetics of cysteamine after administration of Procysbi (cysteamine bitartrate) capsules with water.
Confirm the efficacy and safety of Trulance (plecanatide) treatment in pediatric patients with chronic idiopathic constipation (CIC) who are 2 years to less than 6 years of age by performing a randomized, double-blind, placebo-controlled, parallel group, 12 week treatment study.
Assess the long-term safety of Trulance (plecanatide) in pediatric patients with chronic idiopathic constipation (CIC) who are 2 years to less than 18 years of age and have completed a confirmatory efficacy and safety study with plecanatide.
Submit and analyze quarterly reports until March 2017 of complaints about preparation and use of Treanda Injection (solution) and Treanda for Injection (lyophilized powder).
Conduct a study to evaluate the pharmacokinetics, safety and treatment response (using sustained virologic response) of elbasvir and grazoprevir in pediatric subjects 3 to 17 years of age with chronic hepatitis C infection.
Collect and analyze long-term safety data from pediatric subjects 3 to 17 years of age enrolled in the pediatric elbasvir and grazoprevir safety, pharmacokinetic and efficacy study. Data should be collected for at least 3 years following the end of treatment in order to characterize the long-term safety of elbasvir and grazoprevir including growth assessment, sexual maturation, and characterization of elbasvir and grazoprevir resistance associated substitutions in viral isolates from subjects failing therapy.
Conduct site-directed mutant phenotype analyses of elbasvir against HCV replicons carrying the following NS5A substitutions: K24R (GT1a), H54Y (GT4d), E62D (GT1a), D427N (GT1a). Include cross-resistance analyses with approved NS5A inhibitors.
Conduct site-directed mutant phenotype analyses of grazoprevir against HCV replicons carrying the following NS3 substitutions: I48A/V (GT1a), T185S (GT1a/GT1b), E357G/K (GT1a). Include cross-resistance analyses with approved NS3/4A inhibitors.
Conduct a trial in hepatitis C virus genotype 1a infected subjects with at least one baseline NS5A polymorphism at amino acid position 28, 30, 31, or 93 to evaluate if treatment with elbasvir/grazoprevir and ribavirin for at least 16 weeks reduces the rate of virologic failure and the rate of treatment-emergent drug resistant viral populations. The trial should have adequate representation of subjects with baseline NS5A polymorphisms that have been demonstrated to have the greatest impact on elbasvir/grazoprevir efficacy in clinical trials evaluating recommended regimens.
Evaluate the effect of SLCO1B1 genotype on grazoprevir pharmacokinetics (PK) and response to elbasvir/grazoprevir treatment in patients with chronic hepatitis C virus infection. To evaluate this effect, either conduct a prospective clinical trial with pharmacokinetic and pharmacodynamic endpoints or a retrospective analysis of previously conducted clinical trials with pharmacokinetic data for which stored biospecimens are available. The trial should be enriched or have sufficient numbers of subjects who are homozygous for reduced function alleles (i.e., N130D and V174A), respectively, to adequately assess whether there are differences in PK and treatment responses.
Submit the final report and datasets, including the SVR24 data, for Phase 3 Trial 068 (C EDGE TE).
Submit the final report and datasets, including the SVR24 data, for Phase 2 Trial 048 (C-SALVAGE).
Submit the final report and datasets, including the SVR24 data, for Phase 3 Trial 061 (C-EDGE CO-INFECTION).
Perform genotypic (also phenotypic if qualified) resistance analysis of baseline virus samples from all HBeAg-positive nucleos(t)ide reverse transcriptase inhibitor-experienced subjects and of Week-48 virus samples from all evaluable subjects in Study GS-US-320-0110, regardless of their Week 96 virologic outcome. Genotyping should be conducted using Next Generation Sequence analysis.
Conduct a field study to evaluate the efficacy and safety of ciprofloxacin in the event of an attack with the intentional release of Y. pestis in the United States.
Deferred pediatric study under PREA for the treatment of major depressive disorder in pediatric patients aged 7 to 17. Conduct a study to obtain data on the efficacy and safety of desvenlafaxine in the relevant pediatric population.
Conduct your deferred pediatric study in HIV-1 infected patients 4 weeks to less than 6 years to assess the pharmacokinetics, safety and tolerability, and antiviral activity of an age-appropriate formulation of emtricitabine and tenofovir alafenamide given in combination as DESCOVY fixed dose combination product. Study participants should be monitored for 24 to 48 weeks to assess safety and durability of antiviral response.
Conduct your deferred pediatric study in HIV-1 infected, virologically suppressed patients 6 years to less than 12 years switching from other nucleoside reverse transcriptase inhibitors (NRTIs) to assess the pharmacokinetics, safety, tolerability and antiviral activity of age-appropriate DESCOVY tablets in combination with an approved third antiretroviral drug. Study participants should be monitored for 48 to 96 weeks to assess safety and durability of antiviral response.
A prospective, controlled, non-interventional, long-term cohort study that follows a series of cohorts consisting of new users of Natazia (estradiol valerate and estradiol valerate/dienogest) tablets and new users of oral contraceptives containing other progestins. This study should be conducted by expanding the ongoing European postmarketing comparative safety surveillance study entitled International Active Surveillance Study of Women Taking EV/DNG (INAS-EV) to include US women. The expanded study should enroll a total of at least 50,000 women in the US and Europe, who will be followed for at least three years. The primary objective of the study is to assess the thrombotic risks of short and long-term use of Natazia (estradiol valerate and estradiol valerate/dienogest) tablets and of other oral contraceptives in a study population representative of the actual users of the individual products. The main clinical outcomes of interest are deep venous thrombosis (DVT), pulmonary embolus (PE), acute myocardial infarction, and cerebrovascular accidents. There should be no age restrictions for entry into the study and the study should include younger users (i.e., women less than 18 years of age).
Develop and validate a sensitive and precise assay for the detection of anti-plecanatide antibodies (ADA), including IgM, IgG, and IgA, that may be present in the serum at the time of patient sampling.
Develop and validate assays to evaluate the cross reactivity of anti-plecanatide antibodies to guanylin and uroguanylin.
Develop and validate an assay to evaluate the neutralizing capacity of ADAs detected in the patient samples taking Trulance (plecanatide).
A study to characterize guanylate cyclase-C (G-CC) mRNA expression in duodenal and colonic mucosal biopsies in pediatric patients ages 0 to 6 years undergoing diagnostic gastrointestinal endoscopies as part of their medical care.
Assess development of anti-drug antibody (ADA) responses in patient samples using the immunogenicity serum samples collected in the plecanatide studies (SP304203-00 and SP304203-03 and SP304203-01). Validated assays capable of sensitively and accurately detecting ADA responses, developed under PMR 3117-7, will be used. Evaluate the anti-drug antibody (ADA) rates, individual patient titers and the relationships between ADA status and the safety and efficacy of Trulance (plecanatide).
Use the validated cross reactivity assays developed under PMR 3117-8 to test the ADA positive samples detected under PMR 3117-11. Evaluate the relationships between cross reactivity status and the safety and efficacy of Trulance (plecanatide).
Use the validated neutralizing antibody assay developed under PMR 3117-9 to test the ADA positive samples detected under PMR 3117-11. Evaluate the relationships between neutralizing antibody status and the safety and efficacy of Trulance (plecanatide).
Perform a milk-only lactation trial in lactating women who have received multiple, once daily, doses of Trulance (plecanatide) therapeutically to assess concentrations of plecanatide and its active metabolite in breast milk using a validated assay in order.
A multicenter, randomized, double-blind study evaluating the safety, efficacy and pharmacokinetics of Jublia (efinaconazole) topical solution, 10% versus vehicle in pediatric subjects ages 12 to less than 17 years with onychomycosis of the toenails
A clinical trial to assess the risk of QT prolongation with Bunavail (buprenorphine and naloxone) buccal film.
Conduct a randomized Single-Blind, Multicenter Safety and Efficacy Study of Intravenous to Oral SIVEXTRO (tedizolid phosphate) and Intravenous to Oral Comparator for the Treatment of Acute Bacterial Skin and Skin Structure Infections in Pediatric Patients Aged 12 to <18 Years
Conduct a randomized, Single-Blind, Multicenter Safety and Efficacy Study of Intravenous to Oral SIVEXTRO (tedizolid phosphate) and Intravenous to Oral Comparator for the Treatment of Acute Bacterial Skin and Skin Structure Infections in Pediatric Patients Aged >3 Months to < 12 years.
Conduct an open-Label, Multicenter Study of 10-14 days IV SIVEXTRO (tedizolid phosphate) for hospital-acquired late onset sepsis in full term and preterm neonates and infants aged 5 days to < 3months.
Conduct a Phase 1 Single-Dose Safety and Pharmacokinetic Study of Oral and IV SIVEXTRO (tedizolid phosphate) in Patients 2 years to < 12 years of age.
Conduct a Phase 1 Single-Dose Safety and Pharmacokinetic Study of Oral and Intravenous SIVEXTRO (tedizolid phosphate) in Inpatients Under 2 Years Old.
Conduct US surveillance studies for five years from the date of marketing SIVEXTRO to determine if resistance to tedizolid has developed in those organisms specific to the indication in the label for ABSSSI.
An observational study of pediatric patients from birth to 3 years of age who are administered iothalamate meglumine for clinical evaluation, in order to assess their risk of developing hypothyroidism.
A 24-week, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of empagliflozin for the treatment of pediatric patients 10 to 17 years (inclusive) with type 2 diabetes mellitus as an add-on to metformin, followed by a 28-week double-blind, placebo- or active-controlled extension period. The efficacy and safety study should have at least 30% of randomized subjects 10 to 14 years (inclusive) of age and at least one-third (but not more than two-thirds) of subjects in both age subsets (10 to 14 years [inclusive] and 15 to 17 [inclusive]) will be female. Secondary safety endpoints should include the effect of empagliflozin on mineral and bone metabolism, and the effect of empagliflozin on growth. This trial should not be initiated until after the data from the juvenile animal study have been submitted to and reviewed by the Agency.
A study to evaluate empagliflozin toxicity in juvenile rats.
A randomized, double-blind, placebo-controlled trial evaluating the effect of empagliflozin on the incidence of major adverse cardiovascular events (MACE) in patients with type 2 diabetes mellitus. The primary objective of the trial should be to demonstrate that the upper bound of the 2-sided 95% confidence interval for the estimated risk ratio comparing the incidence of MACE (non-fatal myocardial infarction, non-fatal stroke, cardiovascular death) observed with empagliflozin to that observed in the placebo group is less than 1.3. The long-term effects of empagliflozin on the incidence of liver toxicity, bone fractures, nephrotoxicity/acute kidney injury, breast cancer, bladder cancer, lung cancer, melanoma, complicated genital infections, complicated urinary tract infections/pyelonephritis/urosepsis, serious events related to hypovolemia and serious hypersensitivity reactions should also be assessed. Estimated glomerular filtration rate (eGFR) should also be monitored over time to assess for worsening renal function.
Pediatric studies under PREA for the treatment of overactive bladder in pediatric patients for ages five to 11 years old and adolescents for ages 12 to 17 years old.
Conduct a cell-culture 2-drug combination study to evaluate the anti-HBV activity of tenofovir alafenamide (TAF) in combination with sofosbuvir.
To evaluate potential tenofovir alafenamide (TAF) resistance pathways, sequence the baseline and Week 48 time-points (by population sequencing or NGS) for all evaluable subjects who had HBV DNA >69 IU/mL and provide a study report that includes resistance data analysis.
To evaluate potential tenofovir alafenamide (TAF) resistance pathways and provide a study report that includes resistance data analysis for evaluable samples at baseline, Week 48 and Week 96 and submit the fastq files and analyses for subjects 4296-4510, 5613-1163, and 9035-5187, that had HBV DNA titers at the last PCR assessment that were >159 IU/mL, qualifying them for deep sequencing analysis.
Provide a study report that includes resistance data analysis and submit the fastq files and analyses for subjects 8006-5282 and 8600-4558 who had HBV DNA titers at the last PCR assessment that were >159 IU/mL.
Phenotype Week-48 virus samples from Subjects 4296-5147 and 8758-5188 in the tenofovir alafenamide (TAF) group and Subjects 1507-4546 and 9035-4845 in the tenofovir disoproxil fumarate (TDF) group in Study GS-US-320-0110.
Submit the long-term efficacy, safety and antiviral activity data for Studies GSUS-320-0108 and GS-US-320-0110. Include data and analyses for the entire study population through Week 144.
Provide the results of an analytic validation study for the assay used to identify patients with PD-L1 positive and PD-L1 negative SCCHN in Study CA2090141 to inform product labeling for the device and for nivolumab.
Phase 2, multicenter study to evaluate the safety, efficacy, and pharmacokinetics of belimumab plus background standard therapy in 70 pediatric subjects ages 5 years to 17 years of age with active systemic lupus erythematosus (SLE).
A post-marketing, observational epidemiologic study comparing Relistor (methylnaltrexone bromide) to other treatments of opioid induced constipation in patients with chronic non-cancer pain. The study’s primary outcome is a composite of major adverse cardiovascular events (MACE): cardiovascular (CV) death, nonfatal myocardial infarction, and nonfatal stroke. Secondary outcomes include, but are not limited to, CV death, nonfatal myocardial infarction, and nonfatal stroke separately. Specify concise case definitions and validation algorithms for the primary and secondary outcomes. Justify the choice of appropriate comparator population(s) and estimated background rate(s) relative to Relistor (methylnaltrexone bromide)-exposed patients; clearly define the primary comparator population for the primary objective. Design the study around a testable hypothesis to assess, with sufficient sample size and power, MACE risk among Relistor (methylnaltrexone bromide) users relative to comparator(s) considering important potential confounders including lifestyle risk factors and over the counter (OTC) medications with potential for cardiovascular effects, with a pre-specified statistical analysis method. For the Relistor (methylnaltrexone bromide) -exposed and comparator(s), clearly define the new user clean period, including any exclusion and inclusion criteria. Ensure an adequate number of patients with at least 12 months of Relistor (methylnaltrexone bromide) exposure at the end of the study.
Conduct epidemiologic investigations to address whether the properties intended to deter misuse and abuse of EMBEDA (morphine sulfate and naltrexone hydrochloride extended-release capsules) actually result in a significant and meaningful decrease in misuse and abuse, and their consequences, addiction, overdose, and death, in the community. The postmarketing study program must allow FDA to assess the impact, if any, that is attributable to the abuse-deterrent properties of EMBEDA. To meet this objective, investigations should incorporate recommendations contained in the FDA draft guidance Abuse-Deterrent Opioids—Evaluation and Labeling (January 2013), and proposed comparators need to be mutually agreed upon prior to initiating epidemiologic investigations. There must be sufficient drug utilization to allow a meaningful epidemiological assessment of overall and route-specific abuse deterrence.
Conduct a clinical trial to evaluate the pharmacokinetics, safety, and antiviral activity of peramivir administration in pediatric subjects with acute uncomplicated influenza infection from birth to less than 18 years of age. Include characterization of peramivir resistance-associated substitutions in viral isolates from subjects with prolonged viral shedding.
Analyze and submit the remainder of the clinical resistance data that were not included with the NDA. These include both the HA and NA data for trials BCX1812-201, BCX1812-211, and BCX1812-311.
Conduct a study to determine the cross-resistance to oseltamivir and zanamivir for all of the HA peramivir resistance substitutions that have yet to be evaluated (A/H1N1 HA D129S, R208K; A/H3N2 HA G78D, K189E; B HA T139N, G141E, R162M, D195N, T197N, Y319H). Additionally, determine crossresistance to oseltamivir/zanamivir resistance substitutions (A/H1N1 NA R152K, I122K/T, G248R+I266V, Q312R+I427T, R371K, A/H3N2 NA E41G, I222L/V, Q226H, S247P, HA A28T, K68R, E114K, R124M, N145S, S165N, S186F, N199S, K222T, B NA D198Y, A246D/S/T, G420S).
A postmarketing study that will allow you to test for and control the levels of the following elemental impurities in your product: [...] present during the manufacturing process and have the potential to contaminate your product. As part of your post-marketing study, you will need to 1) develop a validated method for testing thefinished product for the elemental impurities as stated above, and 2) analyze at least threebatches of your product using the validated method.
Assessment of efficacy and safety of OraVerse in patients from 3-6 years of age. This study should be a randomized, sham-injection controlled, double-blinded study comparing the times to return of normal sensation and normal function following the injection OraVerse or a sham injection administered to patients undergoing dental procedures requiring the administration of a local anesthetic agent combined with a vasoconstrictor. Specifically, the following clinical endpoints should be assessed using validated metrics: a. Time to return of normal sensation of the lip and, where applicable, the tongue. b. Time to return of normal function for speech, smiling, drinking, eating and no drooling. Safety assessments should include heart rate, blood pressure, oral cavity examinations, assessments for nerve injury, and adverse events. The study should include a minimum of 100 subjects uniformly distributed by age and evenly distributed by treatment within 1-year age groups.
Submit the complete final report and data from ongoing trial GO28667, a randomized, Phase 3 trial comparing VENCLEXTA (venetoclax) and rituximab with bendamustine and rituximab in patients with relapsed or refractory chronic lymphocytic leukemia (CLL), including CLL with deletion 17p.
Evaluate the effect of hepatic impairment on the pharmacokinetics and safety of VENCLEXTA (venetoclax)compared to subjects with normal hepatic function. Submit a complete final report with all supporting datasets for trial M15-342 entitled, “A Study to Evaluate the Safety and Pharmacokinetics of a Single Dose of Venetoclax in Female Subjects with Mild, Moderate, or Severe Hepatic Impairment.”
Evaluate the effect of VENCLEXTA (venetoclax) co-administration on pharmacokinetics of a probe substrate of P-gp. Submit a complete final trial report with all supporting datasets.
Assessment of Amjevita (adalimumab-atto) for the treatment of Polyarticular juvenile idiopathic arthritis (pJIA) in patients 2 years to less than 4 years of age.
Assessment of Amjevita (adalimumab-atto) for the treatment of pediatric Crohn’s disease in pediatric patients 6 years to 17 years of age.
Assessment of Amjevita (adalimumab-atto) for the treatment of pediatric ulcerative colitis in pediatric patients 5 years to 17 years of age.
Develop a presentation that can be used to accurately administer Amjevita (adalimumab-atto) to pediatric patients who weigh less than 15 kg.
Deferred pediatric study under PREA investigating ORAVIG safety, pharmacokinetics, efficacy and compliance with use instructions in patients with oropharyngeal candidiasis ages > 5 to < or = 17 years.
Evaluate the impact of peramivir resistance-associated substitutions in hemagglutinin (HA) on the effectiveness of influenza vaccine in cell culture assays: • Titrate the neutralization and hemagglutinin inhibition activity of the serum samples from multiple subjects vaccinated with the influenza virus vaccine against recombinant virus with the peramivir resistance substitutions in the HA and their parental virus. A titration of the serum samples should be evaluated using established methods for determining hemagglutination inhibition (HI) as well as virus neutralization (e.g. plaque number reduction or % infected cells based on nuclear NP staining). We recommend performing neutralization assays using different input concentrations of virus to confirm that assay conditions are such that the EC50 value is independent of virus concentration. • Titrate the neutralization and hemagglutinin inhibition activity of the baseline and end of treatment serum samples from multiple subjects treated with peramivir against recombinant virus with the peramivir resistance substitutions in the HA and their parental virus. • Compare the antigenicity of wild type (WT) and HA mutants, selected during peramivir treatment in cell culture, against immune serum (convalescent or vaccine-induced) from human subjects and from animal models vaccinated with inactivated WT virus. Antigenicity should be determined using both HI and neutralization assays.
Submit clinical data from an adequate number of subjects to characterize the effectiveness of peramivir administration in patients with acute uncomplicated influenza B virus infection. These data may be collected from the pediatric study required under PREA or from a new stand-alone clinical trial in a different population. Conduct genotypic resistance analysis of neuraminidase and hemagglutinin using samples directly from subjects without an intervening culture step. Conduct phenotypic analysis, including cross resistance to approved neuraminidase inhibitors.
Conduct a clinical trial to evaluate the pharmacokinetics, safety and antiviral activity of peramivir administration in a predominantly ambulatory setting in elderly subjects aged 65 years or older with influenza infection.
Conduct a clinical trial to evaluate the pharmacokinetics, safety and antiviral activity of peramivir administration in a predominantly ambulatory setting in subjects with influenza infection at higher risk for influenza complications, as defined by the U.S. Centers for Disease Control and Prevention (CDC).
Open-label long term extension study for PMR 2099-#3 (A prospective, randomized, controlled, double- blind, efficacy and safety study of eslicarbazepine acetate in children ages 12 years to <18 years for the adjunctive the treatment of partial onset seizures). Safety must be evaluated. Subgroup analyses of the effect of the concomitant use of enzyme-inducing anticonvulsants (i.e., carbamazepine, phenytoin, phenobarbital or primidone) on the safety of eslicarbazepine acetate must be performed.
A prospective, randomized, controlled, double-blind, efficacy and safety study of eslicarbazepine acetate in children ages 2 years to < 12 years for the adjunctive treatment of partial onset seizures. The primary efficacy endpoint during the controlled phase must examine seizure frequency based upon diary data. Safety must be evaluated during the controlled phase. Subgroup analyses of the effect of the concomitant use of enzyme-inducing anticonvulsants (i.e., carbamazepine, phenytoin, phenobarbital or primidone) on the safety and efficacy of eslicarbazepine acetate must be performed.
Open-label long term extension study for PMR 2099-5 (A prospective, randomized, controlled, double-blind, efficacy and safety study of eslicarbazepine acetate in children ages 2 years to < 12 years for the adjunctive treatment of partial onset seizures). Safety must be evaluated. Subgroup analyses of the effect of the concomitant use of enzyme-inducing anticonvulsants (i.e., carbamazepine, phenytoin, phenobarbital or primidone) on the safety of eslicarbazepine acetate must be performed.
A prospective, randomized, controlled, double-blind, efficacy and safety study of eslicarbazepine acetate for the adjunctive treatment of partial onset seizures in children ages 1 month to < 4 years. The primary efficacy endpoint must examine seizure frequency based upon Video/EEG data. Safety must be evaluated. Subgroup analyses of the effect of the concomitant use of enzyme-inducing anticonvulsants (i.e., carbamazepine, phenytoin, phenobarbital or primidone) on the safety and efficacy of eslicarbazepine acetate must be performed. At least 75% of children in the study should be ¡Ü 2 years old.
Long term extension study for PMR 2099-7 (A prospective, randomized, controlled, double-blind, efficacy and safety study of eslicarbazepine acetate for the adjunctive treatment of partial onset seizures in children ages 1 month to < 4 years). Safety must be evaluated. Subgroup analyses of the effect of the concomitant use of enzyme-inducing anticonvulsants (i.e., carbamazepine, phenytoin, phenobarbital or primidone) on the safety of eslicarbazepine acetate must be performed. At least 75% of children in the study should be ¡Ü 2 years old.
An ex vivo study to determine whether eslicarbazepine interferes with assays for free T3 and T4 as well as total T3, T4, and TSH. Collect blood samples from 30 subjects who have taken a daily dose of at least 1200 mg eslicarbazepine acetate for at least 6 weeks, as well as blood samples from 30 non-eslicarbazepine acetate-exposed age-matched subjects. Subjects must not be taking phenytoin, carbamazepine, or oxcarbazepine (or any other drugs known to displace T4 or T3 from binding proteins). Blood samples collected from eslicarbazepine acetateexposed subjects will be assayed utilizing the clinical trial methods and the most suitable physical separation methodology (e.g., equilibrium dialysis, ultrafiltration, gel filtration) for comparison for serum free T4 and serum free T3 measurements. Blood samples from non-eslicarbazepine acetate-exposed subjects will be spiked with a range of eslicarbazepine and R-licarbazepine concentrations both above and below the known exposures of patients receiving at least eslicarbazepine acetate 1200 mg and assayed utilizing the clinical trial methods and the most suitable physical separation methodology to determine the effect on serum free T3 and T4, as well as effects on serum total T3, T4, and TSH. Results will be evaluated to determine if there is an artifact in the method.
A study based on routine postmarketing safety surveillance, pharmacovigilance and clinical trial reports will characterize clinical and genomic risk factors associated with the development of serious dermatologic reactions in eslicarbazepine acetate-treated patients, including Stevens-Johnson Syndrome, toxic epidermal necrolysis, acute generalized exanthematous pustulosis, and drug rash with eosinophilia and systemic symptoms (DRESS). The study must include a control group of eslicarbazepine-tolerant patients and use high-throughput genotyping approaches to determine whether specific genotypes are associated with the development of these serious skin reactions.
A prospective human physical dependence trial in healthy volunteers in which subjects are titrated to 800 mg of eslicarbazepine acetate and maintained at this dose for four weeks. At the end of the treatment, the drug should be abruptly withdrawn. Withdrawal should be conducted in an inpatient setting with immediate access to physicians capable of managing medical emergencies (e.g., status epilepticus, cardiopulmonary arrest). Withdrawal questionnaires should be administered at the pre-treatment visit, within the last two days of treatment, on the first day post-treatment, on the fourth to fifth day post-treatment, on the tenth to eleventh day post-treatment, and on the twentieth to twenty-first day posttreatment. All adverse events occurring during the withdrawal period are to be collected. Plasma levels of eslicarbazepine should be measured and accompany every administration of withdrawal questionnaires through the fifth day posttreatment.
Deferred pediatric study under PREA for the treatment of schizophrenia in pediatric patients aged 13 to 17. Conduct a study to obtain pharmacokinetic, safety, and tolerability data and provide information pertinent to dosing brexpiprazole in the relevant pediatric population.
To evaluate the safety of palifermin in pediatric hematopoietic stem cell transplant patients in the prospective cohort study 20050187. This will be a component of the phase 4 prospective cohort study using the available Center for International Blood and Marrow Transplant Research (CIBMTR) registry databases. Outcomes to be evaluated for these patients will be overall survival, performance status, incidence of secondary malignancies, cancer relapse rate and days of hospitalization, as well as a comparison between palifermin treated pediatric patients and their matched controls with regards to number of engraftment, acute and chronic graft versus host (GVH), infections, liver complications, clinically significant pancreatitis, renal failure and pulmonary complications. All pediatric patients in each treatment group (palifermin and non palifermin matched control) will be actively followed through at least 5 years or until death.
A clinical pharmacology (Part A) followed by a 52-week randomized, doubleblind and placebo-controlled pediatric study (Part B) under PREA to evaluate the pharmacokinetics, safety, and efficacy of Contrave (naltrexone/bupropion) for the treatment of obesity in pediatric patients ages 12-17 year (inclusive). Part B should not be initiated until after the data from the juvenile animal study (PMR 2778-1) have been submitted to and reviewed by the Agency.
A clinical pharmacology (Part A) followed by a 52-week randomized, double-blind and placebo-controlled pediatric study (Part B) under PREA to evaluate the pharmacokinetics, safety, and efficacy of Contrave (naltrexone/bupropion) for the treatment of obesity in pediatric patients ages 7-11 years (inclusive). Part B should not be initiated until the results of the adolescent pharmacokinetics, safety, and efficacy study (PMR 2778-2) have been submitted to and reviewed by the Agency.
A thorough QT trial designed to rule out small changes in QTc interval (i.e.,upper bound of 90% confidence interval excludes 10 ms), as defined by ICH E14 guidance.
Conduct a study to evaluate the efficacy and long-term safety of mometasone furoate/formoterol fumarate combination MDI (Dulera) and mometasone furoate MDI (Asmanex HFA) in children 5 to 11 years of age.
Six-month oral toxicology study of methacrylic acid copolymer, [...] , in rat. The methacrylic acid copolymer, [...] , should be the same as the excipient in the to-be-marketed product.
Oral absorption study of radiolabeled methacrylic acid copolymer, [...], in rat. The methacrylic acid copolymer, [...], should be the same as the excipient in the to-be-marketed product.
Conduct a multicenter, evaluator blinded, randomized comparator study designed to assess the safety, efficacy and PK of three age dependent doses of IV daptomycin administered for up to 14 days in pediatric patients aged 1 to 17 years, inclusive with cSSSI caused by Gram-positive pathogens.
Complete a clinical pharmacokinetic trial to determine the appropriate dose of cobimetinib in patients with hepatic impairment in accordance with the FDA Guidance for Industry entitled “Pharmacokinetics in Patients with Impaired Hepatic Function: Study Design, Data Analysis, and Impact on Dosing and Labeling.”
Provide an integrated safety analyses from an adequate number of randomized controlled clinical trials using cobimetinib to identify and characterize the risk of retinal pigmented epithelial detachments (RPED) and subsequent sequelae, including the frequency, time course and if needed, dose alteration required to minimize the impact of retinal pigmented epithelial detachments. This will include safety evaluations adequate to inform labeling of patient populations at highest risk and to provide evidence-based dose modification and monitoring recommendations in labeling of RPED events.
Submit the clinical report at the time of the final analysis of Trial GO28141, A Phase III, Double-Blind, Placebo-Controlled Study of Vemurafenib Versus Vemurafenib Plus Cobimetinib (GDC-0973) in Previously Untreated BRAFV600-Mutation Positive Patients with Unresectable Locally Advanced or Metastatic Melanoma (coBRIM) to update the label with mature overall survival data.
Conduct a study to evaluate the pharmacokinetics, safety and treatment response (using sustained virologic response) of ledipasvir/sofosbuvir in pediatric subjects 3 through 17 years of age with chronic hepatitis C.
Conduct a study to evaluate the pharmacokinetics, safety and treatment response (using sustained virologic response) of ledipasvir/sofosbuvir in pediatric subjects 3 through 17 years of age with chronic hepatitis C
Conduct a study to characterize the cell culture antiviral activity of ledipisvir against representative HCV subtype 4b and 4r isolates, including those with amino acid variability (relative to subtypes 4a and 4d) at NS5A positions 28, 30, 31 and 93.
Conduct and submit the results of at least one multicenter, randomized clinical trial establishing the superiority of osimertinib over available therapy as determined by progression-free or overall survival in patients with metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive non-small cell lung cancer (NSCLC)
A clinical trial in healthy subjects evaluating the effect of cobicistat coadministered with darunavir at steady state on the pharmacokinetics of rosuvastatin.
A clinical trial in healthy subjects evaluating the effect of cobicistat coadministered with darunavir at steady state on the pharmacokinetics of the estrogen and progestin components of a combined oral contraceptive.
A 56-week randomized, double-blind, placebo-controlled study to evaluate the safety and efficacy of Saxenda for the treatment of obesity in pediatric patients ages 12 to 17 (inclusive).
A clinical pharmacology study to assess pharmacokinetic and pharmacodynamics parameters of Saxenda in obese pediatric patients ages 7 to 11 years (inclusive).
A 56-week randomized, double-blind, placebo-controlled study to evaluate the safety and efficacy of Saxenda for the treatment of obesity in pediatric patients ages 7 to 11 (inclusive). The trial may not be initiated until results from the Saxenda adolescent safety and efficacy trial have been submitted to and reviewed by the Agency.
A medullary thyroid carcinoma registry-based case series of at least 15 years duration to systematically monitor the annual incidence of medullary thyroid carcinoma in the United States and to identify any increase related to the introduction of Saxenda (liraglutide [rDNA origin] injection) into the marketplace. This study will also establish a registry of incident cases of medullary thyroid carcinoma and characterize their medical histories related to diabetes and use of Saxenda (liraglutide [rDNA origin] injection).
To assess the risk of breast cancer associated with liraglutide in the LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results) cardiovascular outcomes trial. To assess this risk, collect information on baseline cancer risk and potential confounders for all identified cases of breast cancer in the trial, including (but not limited to) prior history of breast cancer, family history of breast cancer, BRCA1/BRCA2 status, age at menopause, history of radiation to the chest, age at menarche, and current/prior use of hormonal therapy.
To assess the risk of breast cancer associated with liraglutide in Trial 1839. To assess this risk, collect information on baseline cancer risk and potential confounders for all identified cases of breast cancer in the trial, including (but not limited to) prior history of breast cancer, family history of breast cancer, BRCA1/BRCA2 status, age at menopause, history of radiation to the chest, age at menarche, and current/prior use of hormonal therapy.
A study evaluating gallbladder ejection fractions in liraglutide-treated subjects to further characterize the effect of liraglutide on gallbladder motility.
An open-label pharmacokinetic and safety study or studies of an age-appropriate formulation of Dyloject (diclofenac sodium) Injection in pediatric patients 2 to less than 17 years of age with acute pain.
A pharmacokinetic, safety, and efficacy study or studies of an age-appropriate formulation of Dyloject (diclofenac sodium) Injection in pediatric patients 1 to less than 2 years of age with acute pain. Conduct the study or studies after the juvenile animal toxicology study of Dyloject is completed (PMR 2839-3).
A juvenile animal study to evaluate the general toxicology of the Dyloject (diclofenac sodium) Injection pediatric formulation to support the safe use of the pediatric formulation prior to initiation of the clinical study in pediatric patients 1 through less than 2 years of age (PMR 2839-2).
Deferred pharmacokinetics (PK) and safety study of Caldolor (ibuprofen) Injection for reduction in fever, or management of mild-to-moderate pain and management of moderate to severe pain as an adjunct to opioid analgesics, in pediatric patients aged birth to 6 months.
Conduct a 12 week, randomized, open-label, pharmacokinetic and pharmacodynamics study of Nucala (mepolizumab) in pediatric patients with asthma 6 years to 11 years of age (Part A of Study 200363).
Conduct a 12 month long-term safety and pharmacodynamics extension study of Nucala (mepolizumab) in pediatric patients with asthma 6 years to 11 years of age (Part B of Study 200363).
Conduct your deferred pediatric study in HIV-infected patients 6 years to less than 12 years to assess the pharmacokinetics, safety and tolerability, and antiviral activity of age-appropriate doses of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide given in combination. At least some of the safety data must be derived from dosing as the GENVOYA® fixed dose combination (duration and number of subjects on GENVOYA® to be agreed upon with the Agency).
Submit the long-term safety and antiviral activity data for Study GS-US-292-0106. Include data and analyses for the entire study population through Week 48 and for all subjects enrolled in the extension phase through 96 weeks of GENVOYA® dosing.
Using appropriate in vitro approaches (including, but not limited to, patch clamp studies of L-type and T-type calcium channels and transporter phenotyping), evaluate the potential mechanism of both pharmacodynamic and pharmacokinetic interactions between sofosbuvir and amiodarone, with and without other hepatitis C virus (HCV) direct acting antiviral drugs (DAA).
Evaluate the effect of hepatic impairment on the pharmacokinetics and safety of Folotyn (pralatrexate). Submit a complete final report with all supporting datasets.
An observational study of pediatric patients from birth to 3 years of age who are administered iohexol for clinical evaluation, in order to assess their risk of developing hypothyroidism.
An observational study of pediatric patients from birth to 3 years of age who are administered diatrizoate meglumine; diatrizoate sodium for clinical evaluation, in order to assess their risk of developing hypothyroidism.
An observational study of pediatric patients from birth to 3 years of age who are administered ioversol for clinical evaluation, in order to assess their risk of developing hypothyroidism.
An observational study of pediatric patients from birth to 3 years of age who are administered ioxilan for clinical evaluation, in order to assess their risk of developing hypothyroidism.
An observational study of pediatric patients from birth to 3 years of age who are administered iopamidol for clinical evaluation, in order to assess their risk of developing hypothyroidism.
An 8-week GLP toxicology study with fertility evaluation in neonatal rats treated with netupitant alone.
A PK/PD dose finding study of netupitant to characterize the netupitant PK/PD relationship for complete response in the delayed phase following oral administration of a single dose of netupitant given concomitantly (in separate formulations) with an oral single administration of palonosetron in pediatric cancer patients ages 0 to17 years undergoing treatment with emetogenic chemotherapy, including highly emetogenic chemotherapy. You must conduct this study with an age appropriate formulation.
An adequate, well-controlled, double-blind, randomized study to evaluate the safety and efficacy of a dose of the netupitant/palonosetron fixed combination compared to standard therapy in pediatric cancer patients ages 0 to 17 years undergoing treatment with emetogenic chemotherapy, including highly emetogenic chemotherapy. You must conduct this study with an age appropriate formulation.
In vivo drug interaction study to evaluate the duration of inhibitory effects of Akynzeo (netupitant and palonosetron) on CYP3A4 enzyme activity beyond 4 days after Akynzeo (netupitant and palonosetron) administration.
Conduct a study to evaluate the pharmacokinetics, safety and treatment response (using sustained virologic response) of ledipasvir/sofosbuvir in pediatric subjects 3 to 17 years of age with chronic hepatitis C.
Collect and analyze long-term safety data for subjects enrolled in the pediatric ledipasvir/sofosbuvir safety, pharmacokinetic and efficacy study. Data collected should include at least 3 years of follow-up in order to characterize the long-term safety of ledipasvir/sofosbuvir including growth assessment, sexual maturation and characterization of ledipasvir/sofosbuvir resistance associated substitutions in viral isolates from subjects failing therapy.
Submit the ledipasvir 2 year rat carcinogenicity study
Submit the final report and datasets for the ongoing trial GS-US-337-0123, entitled “A Phase 2, Multicenter, Open-Label Study to Investigate the Safety and Efficacy of Sofosbuvir/Ledipasvir Fixed-Dose Combination + Ribavirin Administered in Subjects Infected with Chronic HCV who have Advanced Liver Disease or are Post-Liver Transplant”, in order to provide safety data and dosing recommendations for subjects with decompensated cirrhosis and/or in subjects receiving concomitant immunosuppressive agents post-liver transplant (e.g. cyclosporine).
Submit the final report and datasets for the ongoing trial GS-US-337-0115, entitled “A Phase 3, Multicenter, Open-Label Study to Investigate the Safety and Efficacy of Sofosbuvir/Ledipasvir Fixed-Dose Combination for 12 Weeks in Subjects with Chronic Genotype 1 or 4 Hepatitis C Virus (HCV) and Human Immunodeficiency Virus (HIV)-1 Co Infections” in order to obtain additional safety data in subjects receiving concomitant ledipasvir/sofosbuvir and Atripla (or its components) and to provide dosing recommendations for co-infected subjects
Submit an interim report from the ongoing trial GS-US-248-0122, entitled, “A Long Term Follow-up Registry for Subjects Who Achieve a Sustained Virologic Response to Treatment in Gilead-Sponsored Trials in Subjects with Chronic Hepatitis C Infection”, with the three year follow-up data from: GS-US-337-0102 (ION-1), GS-US-337-0109 (ION-2), GS-US-337-0108 (ION-3).
Deferred pediatric study under PREA: Conduct a multicenter clinical evaluation of safety and efficacy in pediatric patients ages 9-17 years of age of Lumason as a contrast agent in pediatric echocardiography. Evaluate the efficacy of Lumason contrasted echocardiography vs. non-contrast echocardiography for left ventricular border delineation in 92 patients (males and females) 9-17 years old. During the clinical evaluation, pharmacokinetic assessments will be performed on 6 patients, 9-12 years old (3 males and 3 females) and 6 patients 12-17 years old (3 males and 3 females).
Complete a pharmacokinetic trial to determine an appropriate dose of osimertinib in patients with mild to moderate hepatic impairment in accordance with the FDA Guidance for Industry entitled “Pharmacokinetics in Patients with Impaired Hepatic Function: Study Design, Data Analysis, and Impact on Dosing and Labeling.” found at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm072123.pdf.
A randomized, double-blind, 26-week, active-controlled clinical trial comparing Foradil Aerolizer (formoterol fumarate inhalation powder) and fluticasone propionate with fluticasone propionate to evaluate the risk of serious asthma outcomes (hospitalizations, intubation, death) in 11,700 adult and adolescent patients 12 years of age and older with persistent asthma.
Conduct an adequate leachable safety assessment for the [...] rubber stopper used in your container closure system. This assessment must include leachable data from long-term stability studies testing at least three batches (taking into cons ideration the proposed shelf- life) to determine if the identified ex tractables leach into the drug product over time. Using this information, conduct a toxicological risk assessment justifying the safety of the leachables, taking into consideration the maximum daily dose of the identified materials for this drug product. For your toxicological risk assessment, any leachable that contains a structural alert for mutagenicity should not exceed [...] mcg/day total daily exposure, or it must be adequately qualified for safety. A toxicological risk assessment should be provided for any non­-genotoxic leachable that exceeds [...]mcg/day.
Study 1: A Phase 2, Open-Label, Multiple Dose Study to Evaluate the Pharmacodynamic Effects, Safety, and Tolerability of Veltassa (Patiromer Sorbitex Calcium) for Oral Suspension in Children and Adolescents 2 to 18 Years of Age with Hyperkalemia
Study 2: A Phase 2, Open-Label, Multiple Dose Study to Evaluate the Pharmacodynamic Effects, Safety, and Tolerability of Veltassa (Patiromer Sorbitex Calcium) for Oral Suspension in Infants and Toddlers Under 2 Years of Age with Hyperkalemia
Submit integrated safety analyses and supporting data from an adequate number of clinical trial(s) to characterize the risk of cardiomyopathy and its sequelae in patients receiving trabectedin; to identify risk factors for development of these sequelae; and to support labeling instructions for dose modification and monitoring. The design of the trial should include a patient population with previous exposure to anthracyclines and have sufficient cardiac monitoring to achieve these objectives.
Submit the final report of the completed clinical pharmacokinetic trial to determine the pharmacokinetics of Yondelis (trabectedin) in patients with hepatic impairment in accordance with the FDA Guidance for Industry entitled “Pharmacokinetics in Patients with Impaired Hepatic Function: Study Design, Data Analysis, and Impact on Dosing and Labeling.”
Deferred pediatric study under PREA for the treatment of schizophrenia in children aged 13 to 17 years. Conduct a Phase 3, Efficacy: multicenter, randomized, double-blind trial with two phases: Phase 1 - placebo- and activecontrolled, short-term (6 weeks) study; Phase 2 – active-controlled long-term extension (26 weeks) study. Goal of both phases is to obtain data on the efficacy and safety of brexpiprazole in the relevant pediatric population.
Deferred pediatric study under PREA for the treatment of schizophrenia in adolescents aged 13 to17 years. Conduct a Phase 3, Safety: open-label, multicenter, long-term (2 years) study to obtain data on the safety of brexpiprazole in the relevant pediatric population.
A placebo-controlled, randomized withdrawal maintenance study of brexpiprazole in patients who require adjunctive treatment of major depressive disorder.
A placebo-controlled, randomized withdrawal maintenance study of brexpiprazole in patients with schizophrenia.
The merged protocol, Study 191622-137, was developed from the pediatric protocol Study 191622-137 (initial study) and Study 191622-138 (long-term extension study), i.e., the originally submitted Post Marketing Required studies per the OAB Approval Letter, dated January 18, 2013. As discussed in the correspondence between the Agency and Allergan on July 16 and 17, 2013, this merger is administrative and intended to make study conduct more efficient for the physicians, patients, and IRB/ethics committees.
Conduct an assessment of neutralizing anti-drug antibody (ADA) response in serum samples of pediatric patients from Study PB-06-006 using a validated assay (developed under PMR 1895-2) that is capable of sensitively detecting ADA responses that interfere with receptor-ligand binding relevant to cellular uptake. This assay will be used to analyze all archived ADA-positive samples available from pediatric patients who participated in Study PB-06-006. In addition, the impact of neutralizing ADA on safety, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy of Elelyso (taliglucerase alfa) will be assessed.
Evaluate the pharmacokinetics (PK), pharmacodynamics (PD), and safety of Elelyso (taliglucerase alfa) in at least 5 patients with body weight less than 15 kg; at least 5 patients with body weight 15-20 kg; and at least 5 patients with body weight 20-25 kg with Type 1 Gaucher disease dosed at 60 units/kg every other week. Steady state PK will be obtained in an open-label study. When applicable, PD measurements for children enrolled in the PK study may be obtained through the taliglucerase alfa registry (PMR 1895-5) and will include organ volumes (spleen and liver) as well as growth (height and weight). This trial will also collect safety data including any serious hypersensitivity reactions, such as anaphylaxis, as well as changes in antibody status (i.e., detection and titers of binding and neutralizing antibodies, and detection of IgE antibodies).
Conduct epidemiologic investigations to address whether the properties intended to deter misuse and abuse of Hysingla ER (hydrocodone bitartrate extended-release tablets) actually result in a significant and meaningful decrease in misuse and abuse, and their consequences, addiction, overdose, and death, in the community. The post-marketing study program must allow FDA to assess the impact, if any, that is attributable to the abuse-deterrent properties of Hysingla ER. To meet this objective, investigations should incorporate recommendations contained in the FDA draft guidance, Abuse-Deterrent Opioids—Evaluation and Labeling (January 2013) and proposed comparators need to be mutually agreed upon prior to initiating epidemiologic investigations. There must be sufficient drug utilization to allow a meaningful epidemiological assessment of overall and route-specific abuse deterrence.
Conduct a study to identify and quantify low molecular weight impurities in the [...]  polyethylene oxide (PEO) products used to manufacture Hysingla ER. Submit a toxicological risk assessment for the exposure to the impurities taking into consideration the maximum theoretical daily dose of Hysingla ER.
An observational study of pediatric patients from birth to 3 years of age who are administered iopromide for clinical evaluation, in order to assess their risk of developing hypothyroidism.
An observational study of pediatric patients from birth to 3 years of age who are administered iodixanol for clinical evaluation, in order to assess their risk of developing hypothyroidism.
An observational study of pediatric patients from birth to 3 years of age who are administered iodipamide meglumine for clinical evaluation, in order to assess their risk of developing hypothyroidism.
An observational study of pediatric patients from birth to 3 years of age who are administered ioxaglate meglumine; ioxaglate sodium for clinical evaluation, in order to assess their risk of developing hypothyroidism.
Pharmacokinetic, efficacy, and safety study or studies of Nucynta for the management of moderate to severe acute pain in pediatric patients ages birth to less than 17 years.
A juvenile rat toxicology study is required to identify the unexpected serious risk of adverse effects on postnatal growth and development. The study should utilize animals of an age range and stage(s) of development that are comparable to the intended pediatric population; the duration of dosing should cover the intended length of treatment in the pediatric population. In addition to the usual toxicological parameters, this study should evaluate effects of Dysport (abobotulinumtoxinA) on growth, reproductive development, and neurological and neurobehavioral development.
A randomized, double-blind, adequately controlled, multiple fixed doses, parallel group clinical study of Dysport(abobotulinumtoxinA) in botulinum toxin-naive children age 2-17 years with upper extremity spasticity. The minimum duration of the study is 12 weeks. The study should be submitted to the FDA for special protocol assessment.
A Pregnancy Pharmacovigilance Study to evaluate pregnancy outcomes and infant outcomes following exposure to Yervoy (ipilimumab). This study will include a mechanism to collect, classify, and analyze data on direct exposures (women exposed to ipilimumab as treatment). There will be interim annual reporting of the data collected from the study. The study, at a minimum, will include the following key elements (see the Guidance for Industry Establishing Pregnancy Exposure Registries for a detailed description of these elements): • Data collection of prospective and retrospective data points, adequate to produce informative, reliable data outcomes. • Data analysis utilizing descriptive statistics for summarizing data that will fully capture outcomes of concern. Data collected prospectively will be analyzed separately from data collected retrospectively.  • Description of procedures including patient recruitment, along with healthcare provider awareness of the potential safety risk and existence of this study, and the monitoring of pregnancy and infant outcomes.
Submit the final clinical report and datasets at the time of final analysis for overall survival (OS) of Trial CA184029, entitled “Adjuvant immunotherapy with anti-CTLA-4 monoclonal antibody (ipilimumab) versus placebo after complete resection of high-risk Stage III melanoma: A randomized, double-blind Phase 3 trial of the EORTC Melanoma Group,” to inform the product label with mature OS data
Submit the final clinical report and datasets of Trial E1609, entitled “A Phase III Randomized Study of Adjuvant Ipilimumab Anti-CTLA4 Therapy Versus High Dose Interferon a-2b for Resected High Risk Melanoma” to inform any change to the recommended dose of Yervoy (ipilimumab) for adjuvant treatment of resected Stage III melanoma patients, if required, based on the final results of Trial E1609.
Conduct a long-term prospective observational study (product exposure registry), which includes a sufficient number of new Potiga-treated patients to assess baseline (i.e., prior to Potiga therapy) ophthalmologic test results and subsequent potential vision loss. This descriptive study should characterize the predictors, development, progression, and stability of retinal pigmentary abnormalities and visual function changes in patients treated with Potiga, and examine the relationship between these retinal abnormalities and skin discoloration. The targeted sample size and duration of the study should be agreed upon with the FDA. Stratified analyses (i.e., prevalent/incident new Potiga users) should be based on ophthalmologic assessments, including visual function evaluation, performed at baseline (prior to Potiga therapy) and at least every six months after initiation of treatment. Assessments should include, at minimum, visual acuity testing and dilated fundus photography. Skin discoloration or discoloration of the palate, sclerae, or conjunctivae should also be noted at each examination. To examine the reversibility of skin discoloration and retinal pigmentary abnormalities and visual changes, ophthalmologic assessments, including visual function evaluation, should be performed every six months after stopping Potiga for a period of time to be agreed upon with the FDA prior to study inception, and the status of any discoloration of the skin palate, sclera, and conjunctiva should also be noted at each of these examinations.
Commitment to support the availability, through the use of clinical trial data, of an in-vitro diagnostic device that is essential to the safe and effective use of crizotinib for patients with ROS1 rearrangements in metastatic non-small cell lung cancer (mNSCLC) tumor specimens.
Complete a clinical trial to evaluate the effect of a strong CYP3A4 inhibitor on the pharmacokinetics of osimertinib. Conduct this trial in accordance with the FDA draft Guidance for Industry entitled “Drug Interaction Studies – Study Design, Data Analysis, Implications for Dosing, and Labeling Recommendations” found at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM292362.pdf.
Complete a clinical trial to evaluate the effect of a strong CYP3A4 inducer on the pharmacokinetics of osimertinib in accordance with the FDA draft Guidance for Industry entitled “Drug Interaction Studies – Study Design, Data Analysis, Implications for Dosing, and Labeling Recommendations” found at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM292362.pdf
Complete a clinical trial to evaluate the effect of repeated doses of osimertinib on the pharmacokinetics of a probe substrate of CYP3A4 in accordance with the FDA draft Guidance for Industry entitled “Drug Interaction Studies – Study Design, Data Analysis, Implications for Dosing, and Labeling Recommendations” found at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM292362.pdf.
Complete a clinical trial to evaluate the effect of repeated doses of osimertinib on the pharmacokinetics of a probe substrate of breast cancer resistant protein (BCRP) in accordance with the FDA draft Guidance for Industry entitled “Drug Interaction Studies – Study Design, Data Analysis, Implications for Dosing, and Labeling Recommendations” found at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM292362.pdf.
A juvenile rat toxicology study is required to identify the unexpected, serious risk of adverse effects of Xeomin (incobotulinumtoxinA) on postnatal growth and development. The study should utilize animals of an age range and stage(s) of development that are comparable to the intended pediatric population; the duration of dosing should cover the intended length of treatment in the pediatric population. In addition to the usual toxicological parameters, this study should evaluate effects of Xeomin (incobotulinumtoxinA) on growth, reproductive development, and neurological and neurobehavioral development.
Randomized, double-blind, adequate and well controlled, multiple fixed-dose, parallel group clinical trial of Xeomin (incobotulinumtoxinA) in botulinum toxinnaïve children age 2-17 years with upper extremity spasticity. The minimum duration of the trial should be 12 weeks. You should propose a method to actively monitor for adverse events related to spread of toxin. The protocol for the trial should be submitted to the FDA as a special protocol assessment (SPA).
A randomized, controlled, clinical trial to evaluate the safety of lesinurad 200mg on a background of concomitant xanthine oxidase inhibitor, with respect to renal function and renal adverse events, in gout patients who have not achieved target serum uric acid with a xanthine oxidase inhibitor alone. Enrollment should be enriched with patients with moderate renal impairment (creatinine clearance 30 to 60 mL/min). The minimum treatment duration should be 2 years. The trial must also include an assessment of cardiovascular (CV) safety based on an independent adjudication of prospectively defined and collected CV events.
Conduct a pediatric study under the Pediatric Research Equity Act (PREA) to evaluate the efficacy and safety, including sparse pharmacokinetic (PK) sampling, of Onzetra Xsail (sumatriptan) for the acute treatment of migraine in pediatric patients of ages 12 to 17 years.
Conduct a pediatric study under the Pediatric Research Equity Act (PREA) for the efficacy and safety of Onzetra Xsail (sumatriptan), including sparse pharmacokinetic sampling, for the acute treatment of migraine in pediatric patients ages 6 to 11 years. Conduct this study after its practicality has been determined based on the review of additional safety and efficacy data from the study of older children of ages 12 to 17 years under PMR 3025-1.
Genzyme commits to designing and implementing a registry of patients with Pompe disease being treated with alglucosidase alfa that will be established to obtain long-term clinical status information.  Information will be collected on patient demographics, specifics of treatment with alglucosidase alfa, clinical status, ventilatory status, motor assessments, adverse events, assessment of immunogenicity, and potential effects of antibody formation.  In patients who are less than one year of age at the start of treatment, information is to be collected on cognitive status, and auditory and visual screening assessments.  This registry will be designed so that detailed clinical status information is collected at registry entry and on a 6- to 12-month basis for at least 15 years.  Genzyme commits to conducting two sub-studies within the registry: one sub-study that will evaluate the effect of alglucosidase alfa on pregnancy and lactation, and one sub-study that will collect information on the clinical status of patients on ventilatory support at the time of entry into the registry.  The registry data will be analyzed at yearly intervals and the results will be submitted in your annual reports for BB-IND 10780.
Submit cumulative safety analyses annually, and for one year after the last patient has completed clinical trial treatment, to identify and characterize the risk of cardiomyopathy and subsequent sequelae, including safety evaluations adequate to inform labeling of patient populations at highest risk for developing these toxicities and to provide evidence-based dose modification and monitoring recommendations, in all ongoing and subsequently initiated randomized controlled clinical trials through 2020 that use Mekinist (trametinib) alone or in combination with other anti-cancer drugs.
Using data from agreed upon studies of the component products, conduct and submit an assessment of safety, pharmacokinetics, and antiviral activity of ODEFSEY® (emtricitabine, rilpivirine, and tenofovir alafenamide) in pediatric patients 6 years to less than 12 years of age OR greater than 25 kg.
An adequate randomized, active control, single-blind trial to evaluate renal dysfunction and laboratory abnormalities in adult patients, including elderly patients, patients with renal impairment, and patients with hepatic impairment taking Suclear prior to colonoscopy. Serial laboratory and clinical assessments will be performed at regular pre-specified intervals for at least 30 days posttreatment.
Conduct and submit the results of a multicenter, randomized trial or trials establishing the superiority of nivolumab over standard therapy in adult patients with unresectable or metastatic melanoma who are refractory to ipilimumab or who have not been previously treated with ipilimumab.
Conduct an embryo-fetal development study in the rat model to assess the potential impact of polyethylene oxide (PEO) on development. The study must be designed to adequately qualify the safety of the low molecular weight PEO components (impurities/degradants) in the PEO used to manufacture Hysingla ER when the product is consumed up to the maximum theoretical daily dose of Hysingla ER.
Conduct an embryo-fetal development study in the rabbit model to assess the potential impact of polyethylene oxide (PEO) on development. The study must be designed to adequately qualify the safety of the low molecular weight PEO components (impurities/degradants) in the PEO used to manufacture Hysingla ER when the product is consumed up to the maximum theoretical daily dose of Hysingla ER
Conduct a pre- and post-natal development study in the rat model to assess the potential impact of polyethylene oxide (PEO) on development. The study must be designed to adequately qualify the safety of the low molecular weight PEO components impurities/degradants) in the PEO used to manufacture Hysingla ER when the product is consumed up to the maximum theoretical daily dose of Hysingla ER.
Conduct a study to determine an appropriate dose and dosing interval for fexofenadine and pseudoephedrine in children, 6 to less than 12 years of age, who may benefit from the pseudoephedrine component of the drug product (i.e., not in otherwise healthy pediatric volunteers) for temporary relief of nasal congestion due to the common cold.
Conduct a study in children 6 to less than 12 years of age to evaluate the efficacy and safety of the pseudoephedrine component, in your combination product, for temporary relief of nasal congestion due to the common cold.
If the studies conducted in children 6 to less than 12 years of age demonstrate safety and efficacy for the intended claim, conduct a study to determine an appropriate dose and dosing interval for use in children, 2 to less than 6 years of age, who may benefit from the pseudoephedrine component of the drug product (i.e., not in otherwise healthy pediatric volunteers) to relieve nasal congestion due to the common cold.
If the studies conducted in children 6 to less than 12 years of age demonstrate safety and efficacy for the intended claim, conduct a study to evaluate the safety of the pseudoephedrine component, in your combination product, for temporary relief of nasal congestion due to the common cold in children 2 to less than 6 years of age. Efficacy of fexofenadine and pseudoephedrine for the age group 2 to less than 6 years may be extrapolated from data in the older age group.
Conduct a clinical trial to evaluate the incidence of intolerable grade 2 and grade 3-5 adverse reactions of an oral starting dose of lenvatinib 14 mg daily with everolimus 5 mg daily compared to the starting dose of lenvatinib 18 mg daily with everolimus 5 mg daily, with a comparable objective response rate. Safety assessments will include the collection of adverse reactions, dose interruptions or modifications, the results of laboratory evaluations, and ECGs. Submit the final study report, datasets, and revised labeling.
Conduct an open-label safety trial in at least 100 evaluable pediatric subjects with mild to moderate atopic dermatitis ages 3 months to < 2 years and at least 5% treatable percent body surface area (%BSA). Evaluate the pharmacokinetics of crisaborole under maximal use conditions in 16 evaluable subjects with moderate atopic dermatitis and at least 35% treatable percent body surface area (%BSA).
Submit the progression-free survival (PFS) and overall survival (OS) analyses with datasets from clinical trial CO-338-014 entitled, “Phase 3 Study of Rucaparib as Switch Maintenance After Platinum in Relapsed High Grade Serous and Endometrioid Ovarian Cancer” (ARIEL3).
Submit the progression-free survival (PFS) and overall survival (OS) analyses with datasets from clinical trial CO-338-043 entitled “A Phase 3 Multicenter, Randomized Study of Rucaparib Versus Chemotherapy in Patients With Relapsed, BRCA Mutant, High Grade Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer,” (ARIEL4).
Conduct a dedicated PK trial in patients with moderate hepatic impairment to determine the appropriate starting dose in patients with moderate hepatic impairment.
Complete the ongoing drug-drug interaction trial CO-338-044 and submit the final study report.
Submit to FDA the appropriate analytical and clinical validation of a companion diagnostic test that will enable the evaluation of patients’ germline BRCA status.
Submit the final report of ongoing mass balance trial CO-338-045.
Conduct a human factors validation study to demonstrate that the user interface of the product can support safe and effective use for the intended users. The human factors validation study should be conducted in patients aged 6 years and older under simulated yet representative of realistic use conditions and include all the critical tasks identified from your updated use-related risk analysis.
Complete the ongoing clinical pharmacokinetic trial to determine an appropriate dose of Lonsurf (trifluridine and tipiracil) in patients with moderate to severe hepatic impairment in accordance with the FDA Guidance for Industry entitled “Pharmacokinetics in Patients with Impaired Hepatic Function: Study Design, Data Analysis, and Impact on Dosing and Labeling.”
Complete the ongoing clinical pharmacokinetic trial to determine an appropriate dose of Lonsurf (trifluridine and tipiracil) in patients with severe renal impairment in accordance with the FDA Guidance for Industry entitled “Pharmacokinetics in Patients with Impaired Renal Function: Study Design, Data Analysis, and Impact on Dosing and Labeling.”
A single-dose, open-label, randomized pharmacokinetic study of ADZENYS XR-ODT (amphetamine extended-release orally disintegrating tablets), in male and female children (4 to less than 6 years of age) with ADHD.
A randomized, double-blind, placebo-controlled, flexible-dose titration study of ADZENYS XR-ODT (amphetamine extended-release orally disintegrating tablets), in children ages 4 to 5 years diagnosed with ADHD.
A one year Pediatric Open-Label Safety Study of patients age 4 to 5 years (at the time of entry into PMR 3029-1 or PMR 3029-2, or at the time of enrollment if directly enrolled into PMR 3029-3) diagnosed with ADHD treated with ADZENYS XR-ODT (amphetamine extended-release orally disintegrating tablets).
Conduct a study to characterize the safety of long-term exposure to Imbruvica based on data and pooled analyses from trials of patients with mantle cell lymphoma and chronic lymphocytic leukemia. Submit 3-year, 4-year, and 5-year safety follow-up data and reports for a minimum population of 1000 patients treated with approved ibrutinib dosing regimens. Datasets should include patientlevel data on ibrutinib dosing, treatment-emergent adverse events, and treatmentemergent laboratory information. This patient set may include approximately 350 patients who continue receiving long-term ibrutinib therapy after completion of primary analysis of the parent study, where study procedures are then limited to collect a minimum of Grade 3+ adverse events, available treatment emergent laboratory data, adverse events leading to treatment discontinuation and SAEs. Study reports should include analyses of adverse event categories listed in the current Warnings and Precautions section of the prescribing information, adverse events leading to treatment discontinuation, and serious adverse events.
Conduct an open-label, single- and multiple-dose, single-treatment, multi-center study to evaluate the pharmacokinetics and safety of XTAMPZA ER (oxycodone) extended-release capsules in patients 7-17 years.
Conduct an open-label, single- and multiple-dose, single-treatment, multi-center study to evaluate the pharmacokinetics and safety of XTAMPZA ER (oxycodone) extended-release capsules in patients 2-7 years.
In order to provide the baseline data to support the hypothesis-testing studies required under PMR 2966-4, conduct a descriptive study that analyzes data on the following: 1) utilization of XTAMPZA ER (oxycodone) extended release capsules and selected comparators. Reports should include nationally-projected quarterly retail dispensing, overall and by age group and census region; AND 2) abuse of XTAMPZA ER (oxycodone) extended release capsules and related clinical outcomes. These studies should utilize multiple data sources in different populations to establish the scope and patterns of abuse for XTAMPZA ER (oxycodone) extended release capsules as well as mutually agreed-upon, selected comparators to provide context. • Data should include route-specific abuse outcomes, be nationally representative or from multiple large geographic areas, and use meaningful measures of abuse. • Additional information, either qualitative or quantitative, from sources such as internet forums, spontaneous adverse event reporting, or small cohort studies may also be included to help better understand abuse of this drug, including routes and patterns of abuse in various populations. • Formal hypothesis testing is not necessary during this phase, but provide information on the precision of abuse-related outcome estimates (e.g. 95% confidence intervals for quarterly estimates) and calculate utilization adjusted outcome estimates where possible.
Conduct formal observational studies to assess whether the properties intended to deter misuse and abuse of XTAMPZA ER (oxycodone) extended release capsules actually result in a meaningful decrease in misuse and abuse, and their consequences, addiction overdose, and death, in post-approval settings. The studies should allow FDA to assess the impact, if any, attributable to the abuse-deterrent properties of XTAMPZA ER (oxycodone) extended release capsules and should incorporate recommendations contained in Abuse-Deterrent Opioids—Evaluation and Labeling: Guidance for Industry (April 2015). Assessing the impact of the abuse-deterrent formulation on the incidence of clinical outcomes, including overdose and death, is critical to fulfilling this PMR. Any studies using electronic healthcare data should use validated outcomes and adhere to guidelines outlined in FDA’s Guidance for Industry and FDA Staff: Best Practices for Conducting and Reporting Pharmacoepidemiologic Safety Studies Using Electronic Healthcare Data.
Conduct a chronic (6-month) repeat-dose general toxicology study in the rat model testing a mixture of beeswax, carnauba wax, and myristic acid that is representative of the drug product composition.
Submit integrated safety analyses from an adequate number of randomized controlled clinical trial(s) using Mekinist (trametinib) to identify and characterize the risk of retinal pigmented epithelial detachments (RPED), including safety evaluations adequate to inform labeling of patient populations at highest risk and to provide evidence-based dose modification and monitoring recommendations in labeling of RPED events.
Submit cumulative safety analyses annually, and for one year after the last patient has completed clinical trial treatment, to identify and characterize the risk of new malignancies, including cutaneous squamous cell carcinoma, in all ongoing and subsequently initiated randomized controlled clinical trials through 2020 that use Tafinlar (dabrafenib) capsules alone or in combination with other anti-cancer drugs. In addition to a cumulative listing of all cases, include the following summary analyses as well as any additional informative analyses of new malignancies in each report: • Incidence rates, overall and stratified by tumor type, for each arm of the trial(s) • Timing of onset in regard to exposure to Tafinlar (dabrafenib) capsules (i.e., timing from first and last dose) • Prognostic features relevant to each tumor type (e.g., clinicopathological features, including pertinent molecular characteristics, as well as disease staging information) • Treatment(s) administered by tumor type  • Outcome
A clinical trial of patients with symptomatic neurogenic orthostatic hypotension to assess sustained effects of droxidopa therapy. The trial design consists of a 3-month, open-label droxidopa treatment period, followed by a 3-month, randomized, double-blind, placebocontrolled, withdrawal period. The primary endpoint will be time to treatment intervention.
Conduct a juvenile toxicity study in rats to support treatment of children and adolescents with AKOVAZ (ephedrine sulfate) injection by IV administration.
Conduct a single open-label study to evaluate the safety and pharmacodynamics/ pharmacokinetics of intravenous ephedrine dosed on a mg/kg basis with provisions for up-titration (dose or frequency) as clinically indicated in patents 12-16 years.
Conduct a fertility and early embryonic development toxicology study in the rat model for ephedrine sulfate.
Conduct an embryo-fetal developmental toxicology study using the rat model for ephedrine sulfate.
Conduct an embryo-fetal developmental toxicology study using the rabbit model for ephedrine sulfate.
Conduct a pre- and post-natal developmental toxicology study in the rat model for ephedrine sulfate.
Conduct an in vivo micronucleus genotoxicity assay with ephedrine sulfate.
Design and conduct a prospective trial and provide the full final report and data sets to evaluate dose reductions in patients who achieve a response or have stable disease in order to optimize the safety and efficacy of chronic administration of Zydelig in patients with follicular or small lymphocytic lymphoma. Include adequate PK sampling to provide dose-response data (for efficacy and safety).
Submit the complete final report and data showing clinical efficacy and safety from trial GS-US-313-0124, a Phase 3, 2-arm, randomized, double-blind, placebo-controlled, parallel-group trial of idelalisib in combination with rituximab in subjects with previously treated indolent non-Hodgkin lymphomas.
Submit the complete final report and data showing clinical efficacy and safety from trial GS-US-313-0125, a Phase 3, 2-arm, randomized, double-blind, placebo controlled, parallel-group trial of idelalisib in combination with bendamustine plus rituximab in subjects with previously treated indolent non-Hodgkin lymphomas.
Conduct a study to characterize the incidence, diagnosis, and effective treatment of Zydelig-related pneumonitis based on data and pooled analyses from randomized trials in iNHL and CLL (0115, 0119, 0124, and 0125).
Conduct a trial to provide evidence sufficient to characterize the long-term safety of Zydelig. Submit the complete final report and data showing long-term safety with 5 years of follow-up from trial 101-99 Phase 1/2 extension study of safety and durability of idelalisib in hematologic malignancies.
Conduct a trial to provide evidence sufficient to characterize the long-term safety of Zydelig when used in combination with other agents such as bendamustine (B) and rituximab (R). Submit the complete final report and data showing long-term safety with 5 years of follow-up from trial GS-US-313-0125, a Phase 3, 2-arm, randomized, double-blind, placebo controlled, parallel-group study of idelalisib in combination with BR in patients with previously treated indolent non-Hodgkin lymphomas.
Conduct a trial to provide evidence sufficient to characterize the long-term safety of Zydelig when used in combination with other agents such as bendamustine (B) and rituximab (R). Submit the complete final report and data showing long-term safety with 5 years of follow-up from trial GS-US-313-0125, a Phase 3, 2-arm, randomized, double-blind, placebo controlled, parallel-group study of idelalisib in combination with BR in patients with previously treated indolent non-Hodgkin lymphomas.
Conduct a trial to provide evidence sufficient to characterize the long-term safety of Zydelig when used in combination with an anti-CD20 drug regimen. Submit the complete final report and data from trial GS-US-312-0119, a Phase 3, randomized, study of idelalisib in combination with ofatumumab in patients with previously treated CLL.
Conduct a trial to provide evidence sufficient to characterize the long-term safety of Zydelig when used in a combination therapy regimen. Submit the complete final report and data showing long-term safety with 5 years of follow-up from trial GS-US-312-0117, a Phase 3, 2 arm, extension study of idelalisib in patients with previously treated CLL.
Deferred pediatric study under PREA: Conduct a pharmacokinetic and safety study of an age-appropriate formulation of oxycodone hydrochloride/naloxone hydrochloride extended-release tablets in patients from ages 7 to less than 17 years with pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.
Conduct epidemiologic investigations to address whether the properties intended to deter misuse and abuse of TARGINIQ ER (oxycodone hydrochloride and naloxone hydrochloride extended-release tablets) actually result in a significant and meaningful decrease in misuse and abuse, and their consequences, addiction, overdose, and death, in the community. The postmarketing study program must allow FDA to assess the impact, if any, that is attributable to the abuse-deterrent properties of TARGINIQ ER (oxycodone hydrochloride/naloxone hydrochloride). To meet this objective, investigations should incorporate recommendations contained in the FDA draft guidance Abuse-Deterrent Opioids—Evaluation and Labeling (January 2013), and proposed study populations and drug comparators need to be mutually agreed upon prior to initiating epidemiologic investigations. There must be sufficient drug utilization to allow a meaningful epidemiological assessment of overall and route-specific abuse deterrence.
Conduct a combination in vivo micronucleus and comet assay for [...] The comet assay portion of the study should include assessment of both stomach and liver tissue and include doses of the drug substance that would be obtained at the maximum recommended daily dose of the drug product and result in adequate toxicity to ensure assay validity.
Conduct a chronic (9-month) repeat-dose general toxicology study in the dog model testing a mixture of beeswax, carnauba wax, and myristic acid that is representative of the drug product composition.
Conduct a fertility and early embryonic development study in the rat model testing a mixture of beeswax, carnauba wax, and myristic acid that is representative of the drug product composition.
Conduct an embryo-fetal development study in the rat model testing a mixture of beeswax, carnauba wax, and myristic acid that is representative of the drug product composition.
Conduct an embryo-fetal development study in the rabbit model testing a mixture of beeswax, carnauba wax, and myristic acid that is representative of the drug product composition.
Conduct a pre- and post-natal development study in the rat model testing a mixture of beeswax, carnauba wax, and myristic acid that is representative of the drug product composition.
Conduct a carcinogenicity assessment in the rat model testing a mixture of beeswax, carnauba wax, and myristic acid that is representative of the drug product composition.
Conduct a carcinogenicity assessment in the mouse model testing the mixture of beeswax, carnauba wax, and myristic acid that is representative of the drug product composition.
Complete a detailed analysis of the beeswax employed in your drug product for potential residual levels of environmental and apicultural sources of contaminants, based on a thorough review of the apicultural practices across the globe and known contaminants in wax. Provide full validated analytical methods used for testing of the contaminants, including the level of detection. Provide a justification of the safety levels of contaminants present and the need for routine testing of the beeswax prior to use in the manufacture of the drug product.
Conduct a study to characterize the levels of [l...] in the final drug product formulation and propose a release specification to adequately control [...] in the drug product.
A long-term, open-label, safety study of adjunctive therapy in patients from 1 month to less than 12 years of age with epilepsy. The purpose of this study is to evaluate the long-term safety of FYCOMPA (perampanel) as adjunctive therapy in the treatment of partial-onset seizures (ages 1 month to less than 12 years) or primary generalized tonic-clonic seizures in pediatric patients (ages 2 to less than 12 years). Doses for this study must be at or above those doses determined to be efficacious by Study 1932-4 (patients 1 month to less than 4 years of age with partial-onset seizures), Study 2922-1 (patients 2 to less than 12 years of age with primary generalized tonic-clonic seizures), and the pharmacokinetic analyses used for the extrapolation of efficacy in pediatric patients 4 to less than 12 years of age with partial-onset seizures. This study may include subjects enrolled in the extension phases of Studies 1932-1, 1932-2, 1932-4, and 2922-1, and may be supplemented as necessary. A minimum of 100 patients must be exposed to study drug for one year at or above the dose or doses identified as effective. Subjects should be balanced among age cohorts to allow for adequate conclusions to be drawn.
Submit the final report and efficacy datasets for Keynote-024, entitled “A Randomized, Open-Label, Phase 3 Trial of MK-3475 versus Platinum-Based Chemotherapy in 1L Subjects with PD-L1 Strong, Metastatic Non-Small Cell Lung Cancer” to update the label with mature overall survival data.
Submit the final report and efficacy datasets for Keynote-042, entitled: “A Randomized, Open Label, Phase III Study of Overall Survival Comparing Pembrolizumab (MK-3475) versus Platinum Based Chemotherapy in Treatment Naïve Subjects with PD-L1 Positive Advanced or Metastatic Non-Small Cell Lung Cancer.”
In order to provide the baseline data to support the hypothesis-testing studies required under PMR 3148-2, conduct a descriptive study that analyzes data on the following: (1) utilization of ARYMO ER and selected comparators. Reports should include nationally-projected quarterly retail dispensing, overall and by age group and census region; AND (2) abuse of ARYMO ER and related clinical outcomes. These studies should utilize multiple data sources in different populations to establish the scope and patterns of abuse for ARYMO ER as well as mutually agreed-upon, selected comparators to provide context. Data should include route-specific abuse outcomes, be nationallyrepresentative or from multiple large geographic areas, and use meaningful measures of abuse. Additional information, either qualitative or quantitative, from sources such as internet forums, spontaneous adverse event reporting, or small cohort studies may also be included to help better understand abuse of this drug, including routes and patterns of abuse in various populations. Formal hypothesis testing is not necessary during this phase, but provide information on the precision of abuse-related outcome estimates (e.g. 95% confidence intervals for quarterly estimates) and calculate utilization-adjusted outcome estimates where possible.
Submit integrated safety analyses of cardiac valve abnormalities based on centralized, blinded, independent review assessment of all echocardiograms from an adequate number of randomized controlled clinical trials that use Tafinlar (dabrafenib) capsules as monotherapy or in combination with other anti-cancer drugs to inform the label regarding incidence rate and natural history of this safety signal.
Submit a final report of follow-up safety data of Xgeva (denosumab) in patients with giant cell tumor of bone enrolled in the ongoing single arm trial through November 2012 for a minimum of five years or until death or lost to follow-up, whichever comes first. Comprehensively collect information regarding survival status, disease progression, serious adverse events, and adverse events of special interest including osteonecrosis of the jaw, pregnancy-related complications, atypical fractures, malignant transformation of giant cell tumor of bone, and secondary malignancies. Perform descriptive analyses of these safety data, including a subset analysis comparing the long-term safety of denosumab in adolescent and adult patients.
Submit the final report including primary datasets, derived datasets, and analysis programs used to generate the safety and efficacy results for the ongoing single arm multicenter trial of denosumab in patients with giant cell tumor of bone. Include an analysis of radiographic response as determined by the local investigator in evaluable patients who received at least one dose of denosumab and underwent at least one postbaseline Computed Tomography (CT) or Magnetic Resonance Imaging (MRI) tumor assessment during the trial. The primary analysis should be conducted after patients enrolled through November 2012 have had the opportunity to complete 12 months of treatment.
A post-marketing, observational epidemiologic study comparing oral Relistor (methylnaltrexone bromide) to other treatments of opioid induced constipation in patients with chronic non-cancer pain. The study’s primary outcome is a composite of major adverse cardiovascular events (MACE): cardiovascular (CV) death, nonfatal myocardial infarction, and nonfatal stroke. Secondary outcomes include, but are not limited to, CV death, nonfatal myocardial infarction, and nonfatal stroke separately. Specify concise case definitions and validation algorithms for the primary and secondary outcomes. Justify the choice of appropriate comparator population(s) and estimated background rate(s) relative to oral Relistor (methylnaltrexone bromide)-exposed patients; clearly define the primary comparator population for the primary objective. Design the study around a testable hypothesis to assess, with sufficient sample size and power, MACE risk among oral Relistor (methylnaltrexone bromide) users relative to comparator(s) considering important potential confounders including lifestyle risk factors and over the counter (OTC) medications with potential for cardiovascular effects, with a pre-specified statistical analysis method. For the oral Relistor (methylnaltrexone bromide)-exposed and comparator(s), clearly define the new user clean period, including any exclusion and inclusion criteria. Ensure an adequate number of patients with at least 12 months of oral Relistor (methylnaltrexone bromide) exposure at the end of the study.
A two-year carcinogenicity study of intravenously administered eteplirsen in rat.
A 26-week carcinogenicity study of eteplirsen, administered by a clinically relevant route, in an appropriate transgenic mouse model.
Pharmacokinetic/safety study of tavaborole topical solution, 5% in 40 pediatric subjects age 12 to 17 years and 11 months with onychomycosis of the toenails. Pharmacokinetic assessments will be done in at least 16 evaluable subjects under maximal use conditions.
Conduct a 52-week, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of saxagliptin vs. placebo, both as add-on therapy to metformin in pediatric patients with inadequate glycemic control on metformin alone. Approximately one-half of the patients must be on metformin extendedrelease therapy at the time of randomization to add-on saxagliptin vs. add-on placebo.
A postmarketing observational cohort study comparing TARGINIQ ER (oxycodone hydrochloride/naloxone hydrochloride) to other drugs approved for the management of pain severe enough to require daily, around-the-clock, longterm opioid treatment and for which alternative treatment options are inadequate. The study’s outcome is serious cardiovascular thromboembolic events; a concise case definition should be provided. Justify the choice of appropriate comparator population(s) and estimated background rate(s) relative to TARGINIQ ER (oxycodone hydrochloride/naloxone hydrochloride) -exposed patients. Design the study around a testable hypothesis to assess, with sufficient sample size and power, a clinically meaningful increase in serious cardiovascular thromboembolic risk above the comparator background rate, using a pre-specified statistical analysis method. For the TARGINIQ ER (oxycodone hydrochloride/naloxone hydrochloride) -exposed and comparator(s)-exposed patients, the study drug initiation period should be clearly defined, including any exclusion and inclusion criteria. Ensure an adequate number of patients with at least six months of TARGINIQ ER(oxycodone hydrochloride/naloxone hydrochloride) exposure at the end of the study.
Submit the final report and datasets for HPC3017 (OPTIMIST 1).
Deferred pediatric study under PREA for the use of Atripla alone as a complete regimen or in combination with other antiretroviral agents for the treatment of HIV-1 infection in pediatric subjects from 6 to less than 12 years of age.
Submit the final report and datasets for HPC3018 (OPTIMIST-2).
To develop a presentation that can be used to directly and accurately administer filgrastim-sndz to pediatric patients who weigh less than 36 kg requiring doses that are less than 0.3 mL (180 mcg), and conduct any necessary human factors studies to evaluate the ability of caregivers to measure the appropriate doses.
Conduct an efficacy and safety study evaluating Repatha (evolocumab) in patients with heterozygous familial hypercholesterolemia (HeFH) ages 10 years to less than 18 years. The study will be a randomized, 6-month, double-blind, placebocontrolled, parallel-group, multicenter efficacy and safety study (Part A) followed by an 18-month open-label extension in patients 10 years to less than 18 years with HeFH on stable lipid-modifying therapy with LDL-C ¡Ý 130 mg/dL (Part B).
Conduct a prospective observational study of pregnant women exposed to Repatha (evolocumab) to evaluate fetal, infant, and childhood outcomes of pregnant women exposed to evolocumab and their live born offspring through the first 5 years of life to estimate incidence rates for the potential safety signals of adverse pregnancy outcomes, embryo-fetal growth and development, and adverse infant and childhood outcomes related to humoral immune suppression. The study should have validated/adjudicated outcomes, a comparator group, be powered to detect the outcomes of interest, and include the justification for the proposed detectable differences in incidence rates.
Conduct a large, randomized, controlled, long-term trial in which the incidence and severity of new-onset diabetes mellitus, injection site reactions, hypersensitivity, immunogenicity, and adverse events potentially related to demyelination with Repatha (evolocumab) will be evaluated.
Conduct a randomized, controlled, long-term trial that prospectively evaluates changes in neurocognitive function with Repatha (evolocumab) treatment. The trial must be adequately powered to exclude a clinically meaningful adverse effect.
Conduct formal observational studies to assess whether the properties intended to deter misuse and abuse of ARYMO ER actually result in a meaningful decrease in misuse and abuse, and their related clinical outcomes, addiction, overdose, and death, in post-approval settings. The studies should allow FDA to assess the impact, if any, attributable to the abuse-deterrent properties of ARYMO ER and should incorporate recommendations contained in Abuse-Deterrent Opioids—Evaluation and Labeling: Guidance for Industry (April 2015). Assessing the impact of the abuse-deterrent formulation on the incidence of clinical outcomes, including overdose and death, is critical to fulfilling this PMR. Any studies using electronic healthcare data should use validated outcomes and adhere to guidelines outlined in FDA’s Guidance for Industry and FDA Staff: Best Practices for Conducting and Reporting Pharmacoepidemiologic Safety Studies Using Electronic Healthcare Data.
Provide a detailed and thoughtful analysis of the risk factors associated with malignant transformation of GCTB and development of new sarcoma and the lifetime and annual incidences of these events in denosumab naïve patients. For this analysis, use data from a minimum of two representative databases in addition to information from published literature. Include subset analyses based on specific risk factors identified from the comprehensive investigation.
Conduct a fertility and early embryonic development toxicology study in the rat model for phenylephrine hydrochloride completed via modern reproductive and developmental toxicology studies, as outlined in the guidance for industry, Detection of Toxicity to Reproduction for Medicinal Products & Toxicity to Male Fertility S5(R2)
Conduct an embryo-fetal developmental toxicology study using the rat model for phenylephrine hydrochloride completed via modern reproductive and developmental toxicology studies, as outlined in the guidance for industry, Detection of Toxicity to Reproduction for Medicinal Products & Toxicity to Male Fertility S5(R2).
Conduct an embryo-fetal developmental toxicology study using the rabbit model for phenylephrine hydrochloride completed via modern reproductive and developmental toxicology studies, as outlined in the guidance to industry, Detection of Toxicity to Reproduction for Medicinal Products & Toxicity to Male Fertility S5(R2).
Conduct a peri- and post-natal developmental toxicology study in the rat model for phenylephrine hydrochloride completed via modern reproductive and developmental toxicology studies, as outlined in the guidance for industry, Detection of Toxicity to Reproduction for Medicinal Products & Toxicity to Male Fertility S5(R2).
A postmarketing study that will allow you to test for and control the levels of the following [...] impurities in your product: [...] that are present during the manufacturing process and have the potential to contaminate your product. As part of your post marketing study, you will need to 1) develop a validated method for testing the finished product for the [...] impurities as stated above, and 2) analyze at least three batches of your product using the validated method
An assessment and analysis of spontaneous reports of serious hepatic abnormalities, fatal pancreatitis, hemorrhagic/necrotizing pancreatitis, and severe hypersensitivity reactions (angioedema, anaphylaxis, Stevens Johnson Syndrome) in patients treated with Oseni (alogliptin and pioglitazone). Specialized follow-up should be obtained on these cases to collect additional information on the events. This enhanced pharmacovigilance should continue for a period of 5 years from the date of approval for reports of fatal pancreatitis and hemorrhagic/necrotizing pancreatitis, and 10 years from the date of approval for reports of serious hepatic abnormalities and severe hypersensitivity reactions.
Conduct a juvenile rat toxicology study to identify the unexpected serious risk of adverse effects of zolmitriptan on postnatal growth and development. The study should utilize animals of an age range and stage(s) of development that are comparable to the intended pediatric population; the duration of dosing should cover the intended length of treatment in the pediatric population. In addition to the usual toxicological parameters, this study must evaluate effects of zolmitriptan on growth, reproductive development, and neurological and neurobehavioral development.
Submit an enhanced pre and post-natal development study (segment III) in rats to demonstrate the safety of lansoprazole on developing bone. The studies must include at least 3 dose levels of lansoprazole and a control group and should include toxicokinetic evaluations. The dose levels must be associated with sufficient maternal plasma levels of lansoprazole (refer to ICH S5): http://www.ich.org/products/guidelines/safety/article/safety-guidelines.html). This study must also evaluate a subset of pups at maturity to determine the functional outcomes of the prenatal and lactation exposure. If there is inadequate exposure to lansoprazole in the pups in the pre- and postnatal study, you should conduct a separate juvenile animal toxicity study with lansoprazole.
Submit an enhanced pre and post-natal development study (segment III) in rats to demonstrate the safety of lansoprazole on developing bone. The studies must include at least 3 dose levels of lansoprazole and a control group and should include toxicokinetic evaluations. The dose levels must be associated with sufficient maternal plasma levels of lansoprazole (refer to ICH S5): http://www.ich.org/products/guidelines/safety/article/safety-guidelines.html). This study must also evaluate a subset of pups at maturity to determine the functional outcomes of the prenatal and lactation exposure. If there is inadequate exposure to lansoprazole in the pups in the pre- and postnatal study, you should conduct a separate juvenile animal toxicity study with lansoprazole.
Submit an enhanced pre and post-natal development study (segment III) in rats to demonstrate the safety of pantoprazole sodium on developing bone. The studies must include at least 3 dose levels of pantoprazole sodium and a control group and should include toxicokinetic evaluations. The dose levels must be associated with sufficient maternal plasma levels of pantoprazole sodium (refer to ICH S5): http://www.ich.org/products/guidelines/safety/article/safety-guidelines.html). This study must also evaluate a subset of pups at maturity to determine the functional outcomes of the prenatal and lactation exposure. If there is inadequate exposure to pantoprazole sodium in the pups in the pre- and postnatal study, you should conduct a separate juvenile animal toxicity study with pantoprazole sodium.
Conduct a long-term safety trial, including assessment of calcium metabolism, of Vectical® (calcitriol) Ointment in 100 evaluable pediatric subjects with plaque psoriasis aged 2 to 16 years and 11 months. Pharmacokinetic/Pharmacodynamic (calcium metabolism) assessment should be performed in at least 9 subjects with plaque psoriasis under maximum use conditions aged 2 to 6 years and 11 months old.
Conduct an open-label study to assess safety, pharmacokinetics, and treatment effect of ACZONE (dapsone) Gel, 7.5% in 100 pediatric subjects aged 9 years to 11 years 11 months with acne vulgaris. Pharmacokinetic assessments will be done in at least 16 evaluable subjects under maximal use conditions.
A prospective, randomized, controlled, double-blind, parallel-group study to compare the safety and efficacy of SMOFLIPID (lipid injectable emulsion) to standard- of- care soybean oil based lipid emulsion in hospitalized neonates including low birth weight and very low birth weight neonates. The study must enroll an adequate number of patients who receive parenteral nutrition (PN) for at least 28 days. Continue treatment for all patients who remain on PN for up to 84 days and follow-up 8 days after receiving the last dose of study treatment. The efficacy evaluation should include anthropomorphic measures and the risk of developing essential fatty acid deficiency (EFAD). Full essential fatty acid profiles should be evaluated according to standards set by major national reference laboratories. Genetic polymorphisms in the fatty acid desaturase genes (FADS) FADS1 and FADS2 should be determined in at least a subset of patients. The cut-off values for EFAD (e.g., suspected, mild and severe) should be established prior to the study. Secondary endpoints should include incidence of major neonatal morbidities, including BPD (bronchopulmonary dysplasia), ROP (retinopathy of prematurity), IVH (intraventricular hemorrhage), PVL (periventricular leukomalacia), NEC (necrotizing enterocolitis), and late-onset sepsis in premature and low birth weight neonates. The study’s safety assessments should include evaluation of the risk of developing parenteral nutritional associated liver disease (PNALD) and parenteral nutrition associated cholestasis (PNAC). Plasma phytosterol levels should be assessed in patients using validated analytical assay methods developed under PMR 3002-5.
Conduct a long-term, postmarketing, observational study to assess the long-term safety of STELARA (ustekinumab) versus other therapies used in the treatment of adults with moderate to severe Crohn’s disease. The study’s primary outcome is malignancy. Secondary outcomes include, but are not limited to, opportunistic infections (e.g., tuberculosis [TB]). Specify concise case definitions, and provide outcome validation for both primary and secondary outcomes. Describe and justify the choice of appropriate comparator population(s) and estimated background rate(s) relative to ustekinumab-exposed patients; clearly define the primary comparator population for the primary objective. Design the study around a testable hypothesis to assess, with sufficient sample size and power, a clinically meaningful increase in malignancy risk above the comparator background rate, with a pre-specified statistical analysis method. For the ustekinumab-exposed and comparator(s), the study drug initiation period should be clearly defined, including any exclusion and inclusion criteria. Ensure adequate number of patients with at least 18 months of ustekinumab exposure at the end of the study. Follow for a period of at least 7 years.
Conduct a dose-ranging trial to determine the pharmacokinetics/pharmacodynamics, safety, and tolerability of STELARA (ustekinumab) induction dosing in pediatric patients 2 to 17 years of age with moderately to severely active Crohn’s disease despite conventional therapy.
Conduct a randomized, controlled, blinded, multicenter trial to evaluate the safety and efficacy of STELARA (ustekinumab) in pediatric patients 2 to 17 years of age with moderately to severely active Crohn’s disease despite conventional therapy.
Conduct a clinical trial to assess whether STELARA (ustekinumab) alters the metabolism or pharmacokinetics of cytochrome P450 (CYP) substrates in Crohn’s disease (CD) patients treated with ustekinumab (e.g., using a cocktail of relevant CYP probe drugs).
[...] Identify and quantitate the impurities. Submit a toxicological risk assessment for the exposure to the impurities taking into consideration the maximum theoretical daily dose of ARYMO ER.
Conduct an embryo-fetal development study in the rat model to assess the potential impact [...] on development. The study must be designed to adequately qualify the safety [...] when the product is consumed up to the MTDD of ARYMO ER.
Conduct an embryo-fetal development study in the rabbit model to assess the potential impact [...] on development. The study must be designed to adequately qualify the safety [...] when the product is consumed up to the MTDD of ARYMO ER.
Conduct a pre- and post-natal development study in the rat model to assess the potential impact [...] on development. The study must be designed to adequately qualify the safety [...] when the product is consumed up to the MTDD of ARYMO ER.
There is some preliminary evidence of [...] which could potentially alter the abuse-deterrent properties of the drug product. [...]
Conduct a controlled efficacy and pharmacokinetics (PK) study in children ages > or equal to 6 years to 11 years with migraine that includes sparse PK samples throughout the efficacy study. Conduct a long-term open-label safety study in pediatric patients with migraine ages > or equal to 6 years to 11 years. The long-term safety study must provide a descriptive analysis of safety data in at least 50 pediatric patients exposed for at least 6 months, treating on average at least one migraine attack per month, at doses evaluated in the efficacy study.
A study to evaluate: 1. patient immune responses, including IgM and IgG isotypes, to eteplirsen, its induced dystrophin protein, and full length dystrophin; 2. the impact of immune responses on product PK and clinical efficacy and safety. The assays for antibodies to eteplirsen, the induced dystrophin, and full length dystrophin should be performed with sampling times optimized to detect early, peak, and late antibody responses, and should be fully validated. 3. for subjects whose serum screens positive for antibodies, the samples should be tested for neutralizing activity, to product activity, and/or product uptake. Antibody titer and persistence should be monitored throughout the duration of the study. 4. in patients who seroconvert, antibody levels should be monitored until they return to baseline. 5. for patients developing hypersensitivity responses, assays to evaluate IgE responses including skin testing or RAST assays should be developed and employed. Until these assays have been fully validated and reviewed by FDA, sufficient samples should be banked and stored under appropriate conditions so as to allow for re-testing if deemed necessary.
Conduct a 2-year controlled trial in patients who have a confirmed mutation of the DMD gene that is amenable to exon 45 or 53 skipping with a phosphorodiamidate morpholino oligomer (PMO) designed to bind to a regulatory site governing splicing of the corresponding exon. The trial should include at least two wellseparated doses of each PMO, with the high dose designed to provide the greatest dystrophin response possible, based upon preliminary dose-finding, with an expectation of acceptable tolerability. The primary objective of this study will be to evaluate the effect of the two PMO doses (combined-active group) compared to control on the North Star Ambulatory Assessment. The secondary objective will be to evaluate dystrophin levels as percent of normal by Western blot, with tissue to be obtained by needle biopsy.
Continue to evaluate the long-term efficacy and safety of XURIDEN (uridine triacetate) in patients currently enrolled in Protocol 401-13-001 every 6 months for a total duration of 2 years in an extension trial. The extension trial should collect data on growth, hematologic indices, and urine biomarkers (orotic acid and orotidine). Growth data should include height, weight, height velocity and weight velocity. Ensure that the growth data are submitted also as z-scores. Provide information on any dose adjustments made during the extension trial, including the dose amount, the reason(s) for the adjustment, and the results of any additional clinical or laboratory assessments performed following dose adjustments.
Conduct a 12-week, randomized, double-blind, parallel-group, placebocontrolled, efficacy and safety study of tiotropium delivered via the Respimat device in children 6-11 years of age with asthma. The study should evaluate at least two doses of tiotropium and include approximately 125 patients per treatment arm.
Conduct a 48-week, randomized, double-blind, parallel-group, placebocontrolled, efficacy and safety study of tiotropium delivered via the Respimat device in children 6 to 11 years of age with asthma. The study should evaluate at least two doses of tiotropium and include approximately 125 patients per treatment arm.
Conduct a study in adult healthy volunteers to assess the pharmacokinetics and bioavailability of multiple age-appropriate tofacitinib XR formulations compared to the tofacitinib IR formulation.
Conduct a pharmacokinetic study in adult healthy volunteers comparing multiple tofacitinib XR formulations to the tofacitinib IR formulations to select a suitable age-appropriate tofacitinib XR formulation that meets the target pharmacokinetic profile.
Conduct a pharmacokinetic study in adult healthy volunteers to establish the equivalence of AUC and similarity in other pharmacokinetic parameters between the proposed commercial age-appropriate tofacitinib XR formulation and tofacitinib IR formulation.
A prospective descriptive observational cohort study of insertion-, localization-, and removal-related serious adverse events and their sequelae associated with PROBUPHINE (buprenorphine hydrochloride) use.
Clinical trial to assess the risk of QT prolongation with subdermal PROBUPHINE (buprenorphine hydrochloride).
Clinical trial to evaluate the effect of scarring or inflammation related to a prior implant on the safety of re-implantation/reinsertion, the potential for migration of implants, and the bioavailability of PROBUPHINE (buprenorphine hydrochloride) when the drug is implanted in a previously used site.
Clinical trial to evaluate the safety, feasibility, and pharmacokinetics of PROBUPHINE (buprenorphine hydrochloride) implantation at alternate body sites. The trial should also evaluate the safety of other methods of inserting PROBUPHINE (buprenorphine hydrochloride) into additional locations on the arm.
Conduct a pediatric trial to evaluate the safety and antiviral activity of COMPLERA(emtricitabine/rilpivirine/tenofovir disoproxil fumarate) FDC tablets in HIV infected pediatric subjects 12 to 18 years old. Safety and antiviral activity (efficacy) of emtricitabine/rilpivirine/tenofovir disoproxil fumarate FDC tablets in pediatric subjects should be evaluated for a minimum of 48 weeks.
Conduct a pediatric trial to evaluate the safety and antiviral activity of COMPLERA (emtricitabine/rilpivirine/tenofovir disoproxil fumarate) FDC tablets in HIV infected pediatric subjects 6 years to less than 12 years old. Safety and antiviral activity(efficacy) of emtricitabine/rilpivirine/tenofovir disoproxil fumarate FDC tablets in pediatric subjects should be evaluated for a minimum of 48 weeks.
Conduct a trial to investigate the effects on mortality of multiple doses of sildenafil in adults with pulmonary arterial hypertension.
Conduct a single-dose pharmacokinetic trial in subjects with mild, moderate, and severe hepatic impairment. Include overweight and obese subjects in the trial population.
Conduct a single-dose pharmacokinetic trial in subjects with mild, moderate, and severe renal impairment. Include overweight and obese subjects in the trial population.
Conduct a drug-drug interaction clinical trial with organic cation transporter 2 (OCT2) substrate, such as metformin, to evaluate the in vivo potential of Contrave constituents (bupropion and naltrexone) to inhibit OCT2. The trial should test the single-dose pharmacokinetics of the organic cation transporter 2 (OCT2) substrate with and without co-administration of Contrave(preferably at steady-state after multiple doses).
Randomized controlled trial to evaluate the safety and efficacy of SMOFLIPID (lipid injectable emulsion) administered for at least 90 days in pediatric patients, compared to standard of care soybean oil based lipid emulsion administered for the same duration. Continue treatment for all patients who remain on parenteral nutrition (PN) for up to 1 year. The study should enroll an adequate number of patients 3 month of age and older. The study’s efficacy assessments should include anthropomorphic measures and evaluation of the risk of developing essential fatty acid deficiency (EFAD). Full essential fatty acid profiles should be evaluated according to standards set by major national reference laboratories. Genetic polymorphisms in the fatty acid desaturase genes (FADS) FADS1 and FADS2 should be determined in at least a subset of patients. The cut-off values for EFAD (e.g., suspected, mild and severe) should be established prior to the study. The study’s safety assessments should include evaluation of the risk of developing parenteral nutritional associated liver disease (PNALD) and parenteral nutrition associated cholestasis (PNAC). Plasma phytosterol levels should be assessed in patients using validated analytical assay methods developed under PMR 3002-5.
Test the three registration stability batches for the individual component phytosterol content in SMOFLIPID (lipid injectable emulsion) using the validated analytical methods.
Test for the individual component phytosterol content in all batches of SMOFLIPID (lipid injectable emulsion) manufactured over a three year period, using the validated analytical method. Based on these test results, establish safety limits for each of the individual component phytosterols in SMOFLIPID (lipid injectable emulsion) product specification.
Randomized clinical trial in hospitalized adult patients receiving either SMOFLIPID (lipid injectable emulsion) or other standard-of-care IV lipid emulsions to evaluate clinical safety outcomes of sepsis and mortality. The trial will also evaluate the requirement for ventilator support and length of stay in ICU and hospital.
Randomized controlled trial in pediatric patients, including neonates, comparing a phytosterol-depleted formulation of SMOFLIPID (lipid injectable emulsion) and another standard-of-care lipid emulsion (100 % soybean oil product) to evaluate the incidence of liver injury, including either parenteral nutrition-associated liver disease (PNALD) or intestinal failure-associated liver disease (IFALD). An adequate number of patients should receive treatment with parenteral nutrition for at least 90 days. This trial should be initiated after the results from PMRs 3002-1, 3002-2, and 3002-3 are available. The phytosterol content of the phytosteroldepleted formulation of SMOFLIPID (lipid injectable emulsion) should be documented using validated analytical assay methods developed under PMR 3002-3. Plasma phytosterol levels should be assessed in patients using validated analytical assay methods developed under PMR 3002-5.
Conduct a study to assess the pharmacokinetics of each drug component of hydrocodone and guaifenesin in children ages 6 to 17 years with symptoms of the common cold.
Conduct a study to assess the safety of hydrocodone and guaifenesin in children ages 6 to 17 years with symptoms of the common cold. The dose used in this study will be based upon the results of the pharmacokinetic study in children ages 6 to 17 years (PMR 2826-1).
A prospective, registry-based observational exposure cohort study conducted in the United States, that compares the maternal, fetal, and infant outcomes of women with multiple sclerosis exposed to Lemtrada (alemtuzumab) during pregnancy to unexposed control populations (one with women with multiple sclerosis who have not been exposed to Lemtrada (alemtuzumab) in pregnancy and the other in women without multiple sclerosis). The registry will detect and record major and minor congenital malformations, spontaneous abortions, stillbirths, elective terminations, and any other adverse pregnancy outcomes. These outcomes will be assessed throughout pregnancy. Infant outcomes, including effects on postnatal growth and development, will be assessed through at least the first year of life.
A pre- and postnatal development (including maternal function) study of Lemtrada (alemtuzumab) in rHu CD52 mouse.
A prospective observational registry study in adult patients with relapsing multiple sclerosis, with the primary objective of determining the necessary duration of monitoring following treatment with Lemtrada (alemtuzumab) for multiple sclerosis and to further inform appropriate monitoring conditions.Events of interest include autoimmune-mediated conditions, malignancies, serious infections including opportunistic infections, and pneumonitis. A minimum of 5000 multiple sclerosis patients treated with Lemtrada (alemtuzumab) should be enrolled and followed for a minimum of 10 years following the first exposure to Lemtrada (alemtuzumab). The protocol should specify an appropriate comparator population(s) to which observed incidence rates will be compared.
A prospective study in adult patients with relapsing multiple sclerosis to assess patient safety during and after Lemtrada (alemtuzumab) infusion in multiple sclerosis patients. Measurements of interest include: 1) Duration of infusion; 2) Vital signs at baseline, during infusion, and during post-infusion observation for each infusion in the infusion cycle; 3) Serious adverse events that occur during and start within 24 hours of infusion; and 4) Serious adverse events that start within 7 days of infusion. A minimum of 300 multiple sclerosis patients treated with Lemtrada (alemtuzumab) should be enrolled.
Submit the final overall survival (OS) data from Trial CA209037, a randomized, open-label, Phase 3 Trial of Nivolumab Versus Investigator’s Choice in Advanced (Unresectable or Metastatic) Melanoma Patients Progressing Post Anti-CTLA-4 Therapy, to provide long-term data that will inform the label on the efficacy of nivolumab as a treatment for patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor.
Conduct epidemiologic investigations to address whether the properties intended to deter misuse and abuse of MORPHABOND (morphine sulfate extended release tablets) actually result in a significant and meaningful decrease in misuse and abuse, and their consequences, addiction, overdose, and death, in the community. The post-marketing study program must allow FDA to assess the impact, if any, that is attributable to the abuse-deterrent properties of MORPHABOND. To meet this objective, investigations should incorporate recommendations contained in the FDA draft guidance, Abuse- Deterrent Opioids—Evaluation and Labeling (January 2013) and proposed comparators need to be mutually agreed upon prior to initiating epidemiologic investigations. There must be sufficient drug utilization to allow a meaningful epidemiological assessment of overall and route-specific abuse deterrence.
Conduct a 9-month repeat-dose oral toxicology study in the nonrodent model characterizing the toxicological potential of [...]
Conduct a 6-month repeat-dose oral toxicology study in the rodent model characterizing the toxicological potential of [...]
Conduct a 2-year rodent oral carcinogenicity assessment of [...]
Randomized clinical trial comparing SMOFLIPID (lipid injectable emulsion) to another standard-of-care IV lipid emulsion, evaluating long-term risk of developing essential fatty acid deficiency (EFAD) and parenteral nutrition associated liver disease (PNALD) in adult patients receiving chronicallyadministered total parenteral nutrition (TPN). Plasma phytosterol levels should be assessed in patients using validated analytical assay methods developed under PMR 3002-5.
An open-label trial of the safety and treatment effects of Sorilux Foam, 0.005% in 75 evaluable pediatric subjects with plaque psoriasis of the scalp and body age 2 years to 11 years and 11 months. Pharmacokinetic/Pharmacodynamic parameters will be evaluated in a subset of at least 25 evaluable subjects under maximum use conditions. The effect of the product on calcium metabolism will be evaluated in all subjects.
An enhanced pharmacovigilance study of ketoacidosis in patients treated with dapagliflozin. The study will include reports of ketoacidosis or diabetic ketoacidosis for a period of 5 years, and will include assessment and analysis of spontaneous reports of ketoacidosis in patients treated with dapagliflozin, with specialized follow-up to collect additional information on these cases.
An enhanced pharmacovigilance study of ketoacidosis in patients treated with canagliflozin. The study will include reports of ketoacidosis or diabetic ketoacidosis for a period of 5 years, and will include assessment and analysis of spontaneous reports of ketoacidosis in patients treated with canagliflozin, with specialized follow-up to collect additional information on these cases.
An enhanced pharmacovigilance study of ketoacidosis in patients treated with empagliflozin. The study will include reports of ketoacidosis or diabetic ketoacidosis for a period of 5 years, and will include assessment and analysis of spontaneous reports of ketoacidosis in patients treated with empagliflozin, with specialized follow-up to collect additional information on these cases.
Conduct a Pharmacokinetic study in Attention Deficit Hyperactivity Disorder (ADHD) patients aged 4 to 5 years old.
Conduct a 6-week, double-blind, placebo-controlled, randomized, parallel-group safety and efficacy study in children with Attention Deficit Hyperactivity Disorder (ADHD) 4 to 5 years of age using methylphenidate ER formulation (QuilliChew ER)
Conduct a 6-month, open-label extension study to obtain additional information on safety and tolerability of methylphenidate ER formulation (QuilliChew ER) in children 4 to 5 years of age with Attention Deficit Hyperactivity Disorder (ADHD)
Develop a presentation that can be used to accurately administer etanercept-szzs to pediatric patients who weigh less than 63 kg.
Develop and validate an assay that is sufficiently sensitive, selective, and specific to reliably detect product specific antibodies of the IgE isotype.
Use the anti-reslizumab IgE assay developed under 3053-1 to test serum samples from patients who had treatment associated anaphylaxis.
Submit a qualification report demonstrating the suitability of the commercial antialpha gal ELISA from [...] that was used to analyze the sera of the four treatment-related anaphylaxis patients.
Conduct a phase 4 observational study to evaluate the efficacy and safety of Neupogen®(filgrastim) in the setting of Hematopoietic syndrome (HS) following acute radiation exposure.
A prospective, long-term, observational study in a routine clinical setting of patients aged 3 weeks or older with bile acid synthesis disorders due to single enzyme defects and patients with peroxisomal disorders, including Zellweger spectrum disorders, who exhibit manifestations of liver disease, steatorrhea, fat soluble vitamin deficiency, or a neuropathic process related to a vitamin deficiency. The purpose of the study is to assess primarily the long term safety of treatment with Cholbam (cholic acid) capsules with respect to incidence rates of worsening cholestasis, steatorrhea leading to poor growth, fat soluble vitamin deficiency, or neuropathic process related to a vitamin deficiency, and the incidence of death and adverse effects on pregnancy, pregnancy outcomes and infant status. Additional evaluations will include dosing regimens and reasons for any dose modifications, weight gain, length/height and developmental outcomes. Specify concise case definitions and validation algorithms for all outcomes. Enroll at least 55 patients (25 receiving cholic acid and 30 not receiving cholic acid) including at least 20 peroxisomal disorder patients with liver dysfunction, steatorrhea, fat soluble vitamin deficiency or a neuropathic process related to the latter. Enroll over an initial 3-year period and follow for a minimum of 10 years from the time of enrollment or until death, whichever comes first.
Conduct a prospective observational study of patients enrolled in the Zinbryta (daclizumab) Risk Evaluation and Mitigation Strategies (REMS) registry, with the primary objective of determining the incidence rates of drug-induced liver injury, serious infections, and immune-mediated disorders, including hepatitis, noninfectious colitis, serious skin reactions, Type I diabetes, thyroid disease, sarcoidosis, and other immune disorders. All patients enrolled in the registry should be followed for the duration of treatment and at least 6 months following discontinuation of treatment. The protocol should specify at least two appropriate comparator populations to which the observed incidence rates will be compared.
Conduct a prospective observational study of patients enrolled in the Zinbryt (daclizumab) REMS registry, with the primary objective of determining the incidence and mortality rates of breast cancer. All patients enrolled in the registry should be followed for a minimum of 10 years or until death following their first exposure to Zinbryta (daclizumab). The protocol should specify at least two appropriate comparator populations to which the observed incidence and mortality rates will be compared.
Conduct a nested case-control study among patients enrolled in the Zinbryta (daclizumab) REMS registry, with the primary objective of determining which clinical attributes are risk factors or protective factors for developing liver disorders and serious skin reactions. Determine whether there are biomarkers that are earlier indicators of liver injury than standard liver function tests. Patient blood samples will need to be analyzed at baseline, 3 months, and 6 months after initiating therapy and possibly when ending therapy. At a minimum, the following potential risk factors must be evaluated: a) Demographic characteristics (age, gender, race). b) Cumulative dose exposure to daclizumab. c) Prior history of immune disorders, including autoimmune hepatitis. d) Genomic risk factors. e) T-cell markers, such as FOX-3, CD-25 and others. f) Other concomitant drug use. g) Comorbidities. h) Prior drug use to treat MS. i) Prior adverse events as a result of MS drug treatment, including drug induced liver injury. j) Exposure to high-dose intravenous methylprednisolone, steroids, and other immunosuppressants. k) Time between exposures (daclizumab, other MS drugs, and immunosuppressants) and development of serious adverse events.
Conduct prospective pregnancy exposure registry cohort analyses in the United States that compare the maternal, fetal, and infant outcomes of women with multiple sclerosis exposed to Zinbryta (daclizumab) during pregnancy with two unexposed control populations: one consisting of women with multiple sclerosis who have not been exposed to Zinbryta (daclizumab) before or during pregnancy and the other consisting of women without multiple sclerosis. The registry will identify and record pregnancy complications, major and minor congenital malformations, spontaneous abortions, stillbirths, elective terminations, preterm births, small-for-gestational-age births, and any other adverse outcomes, including postnatal growth and development. Outcomes will be assessed through at least the first year of life.
Develop and validate an assay with improved sensitivity for the detection of neutralizing antibodies against daclizumab in the presence of daclizumab levels that are expected in samples collected from patients on treatment.
A randomized, placebo-controlled clinical trial to evaluate the safety, efficacy and steady-state pharmacokinetics of OCALIVA (obeticholic acid) in patients with primary biliary cholangitis (PBC) with Child-Pugh Classes B and C hepatic impairment, including Child-Pugh Class C patients with varying levels of Model for End-Stage Liver Disease (MELD) scores. You may conduct this as a standalone trial or in a subset of patients in your confirmatory trial (PMR# 3057-3).
Establish the optimal and safe dose of belinostat in combination with the cyclophosphamide/vincristine/doxorubicin/prednisone (CHOP) regimen. Perform a Phase 1 dose finding trial of belinostat plus CHOP for the treatment of patients with peripheral T-cell lymphoma (PTCL). Enroll a sufficient number of patients to characterize the safety of belinostat in combination with the CHOP regimen. Submit a complete final report with all supporting datasets.
Characterize the comparative efficacy and safety of belinostat when used in combination with a treatment regimen such as CHOP, versus the combination of pralatrexate plus CHOP, versus CHOP alone for the initial therapy of patients with PTCL. Perform a confirmatory, prospective randomized (1:1:1) trial of previously untreated patients with PTCL, with progression free survival (PFS) as the primary efficacy endpoint. Enroll a sufficient number of patients to characterize the efficacy and safety of each drug added to CHOP, versus CHOP alone. The PFS endpoint should be determined by a blinded independent review committee. PFS analysis should be performed when the trial has experienced the planned number of events necessary for trial completion. Using the same data cutoff date as the PFS analysis, perform an interim analysis of overall survival. Submit a complete final report with all supporting datasets.
Conduct an in vitro study to determine the exact contributions of UGT1A1, CYP3A4, CYP2C9, and CYP2A6 in the biotransformation of belinostat to evaluate the potential for higher drug exposure or metabolism to a potentially more toxic metabolite. Submit a complete final report with all supporting datasets.
Characterize the mass balance information for Beleodaq. Submit the final clinical trial report for the ongoing human mass balance trial (Protocol SPI-BEL-12-103 designed to evaluate the excretion route of belinostat in humans. Excretion alterations could lead to increased toxicity. Submit a complete final report with all supporting datasets.
Characterize the PK of belinostat in the presence of strong UGT1A1 inhibitors. Conduct a clinical trial evaluating the influence of strong UGT1A1 inhibitors on the pharmacokinetics of belinostat in patients with cancer. Submit a complete final report with all supporting datasets.
Evaluate the safety and pharmacokinetics of belinostat in patients with wild-type, heterozygous, and homozygous UGT1A1*28 genotypes. The evaluations should be conducted for sufficient duration and in a sufficient number of subjects in order to evaluate safety following multiple dose administration. Submit a complete final report with all supporting datasets.
Characterize the PK and safety of belinostat in the presence of hepatic impairment. Submit the final clinical trial report for the ongoing hepatic impairment trial (Protocol CTEP #8846) that is designed to evaluate the influence of hepatic impairment on the PK and safety of belinostat. Submit a complete final report with all supporting datasets.
Characterize the PK and safety of belinostat in the presence of renal impairment. Conduct a clinical trial in patients with varying degrees of renal impairment to evaluate the pharmacokinetic and safety of belinostat patients with impaired renal function. The trial should be conducted for sufficient duration in order to evaluate safety following multiple dose administration. Submit a complete final report with all supporting datasets.
Submit the final report and datasets for clinical trial entitled “A Phase III, Open-Label, Multicenter, Randomized Study to Investigate the Efficacy and Safety of Atezolizumab (Anti-PD-L1 Antibody) Compared with Docetaxel in Patients with Non-Small Cell Lung Cancer after Failure with Platinum-Containing Chemotherapy” [OAK (GO28915)].
Establish reliability requirements for the combination product EVZIO (naloxone hydrochloride injection) and complete testing that verifies combination product reliability.
Conduct case study analysis of reports of failure of the combination product EVZIO (naloxone hydrochloride injection) to activate, or failure of the combination product to deliver the full-labeled dose. Perform detailed analyses of reported device failures (including reported malfunctions that did, as well as did not result in patient harm). Reports should include a full narrative description of the failure, any subsequent adverse events, the results of root cause analysis performed for the reported failure, and a description of your procedures for monitoring and analyzing the reports.
Conduct a randomized, double-blind, placebo-controlled trial of safety, efficacy, and pharmacokinetics of Zinplava (bezlotoxumab) in pediatric patients from 1 to less than 18 years of age receiving antibacterial therapy for C. difficile infection.
Conduct a study to evaluate the pharmacokinetics, safety and treatment response (using sustained virologic response) of sofosbuvir and velpatasvir in pediatric subjects 12 through less than 18 years of age with chronic hepatitis C virus infection.
Conduct a study to evaluate the pharmacokinetics, safety and treatment response (using sustained virologic response) of sofosbuvir and velpatasvir in pediatric subjects 3 through less than 12 years of age with chronic hepatitis C virus infection.
Conduct a drug interaction trial to evaluate the interaction between sofosbuvir and velpatasvir and atorvastatin.
Submit the final clinical report and datasets for the ongoing trial GS-US-342-1202 (ASTRAL-5), titled “A Phase 3, Open-label Study to Investigate the Efficacy and Safety of Sofosbuvir/GS-5816 Fixed Dose Combination for 12 weeks in Subjects with Chronic Hepatitis C Virus (HCV) and Human immunodeficiency Virus (HIV)-1 Coinfection,” to provide safety data in HIV-1/HCV co-infected subjects receiving sofosbuvir and velpatasvir concurrently with HIV antiretroviral therapy.
Conduct a trial in hepatitis C virus genotype 3 infected subjects with cirrhosis treated with sofosbuvir and velpatasvir to determine if the addition of ribavirin improves the efficacy (i.e., sustained virologic response rate) and reduces the rate of virologic failure.
Collect, analyze, and submit data from the HCV infected subjects with decompensated Child-Pugh Turcotte (CPT) C cirrhosis treated with sofosbuvir/velpatasvir regimen to obtain safety data in a broader decompensated cirrhosis population (genotype 1-6 HCV infection).
Collect, analyze, and submit data on subjects with cirrhosis including decompensated cirrhosis who achieve sustained virologic response following treatment with a sofosbuvir/velpatasvir-based regimen to evaluate durability of virologic response and to characterize clinical outcomes such as progression or regression of liver disease, liver-related mortality, occurrence of hepatocellular carcinoma, or liver failure requiring liver transplantation. Data collected should include 5 years of follow-up.
Conduct site-directed mutant phenotypic analyses of sofosbuvir against an HCV genotype 3 replicon with the following substitutions: NS5B_L314F, NS5B_L314I, and NS5B_L314P.
Conduct a study to evaluate the pharmacokinetics, safety and treatment response (using sustained virologic response) of daclatasvir in combination with other direct acting antivirals in pediatric subjects 3 through 17 years of age with chronic hepatitis C.
Conduct an observational study to characterize the long-term (> 1 year) persistence of treatment-emergent daclatasvir resistance-associated substitutions in hepatitis C virus genotype 3 infected subjects who failed treatment with daclatasvir-containing treatment regimens.
Evaluate the potential mechanism of both pharmacodynamic and pharmacokinetic interactions between amiodarone and HCV direct acting antivirals, including daclatasvir, using a multielectrode array electrophysiology study in human stem-cell derived cardiomyocytes.
Evaluate the effect of individual HCV direct acting antivirals including daclatasvir on the plasma protein binding of amiodarone using the TRANSIL® high sensitivity binding assay to help elucidate the potential mechanism of an interaction between amiodarone and HCV direct acting antivirals.
Conduct a trial in hepatitis C virus genotype 3 infected subjects with cirrhosis treated with daclatasvir plus sofosbuvir to determine if a longer duration of treatment or the addition of ribavirin reduces the rate of virologic failure and the rate of treatment-emergent drug resistant viral populations.
Conduct a dose-finding study (Phase 2) and an efficacy and safety study (Phase 3) evaluating alirocumab in patients with heterozygous familial hypercholesterolemia (HeFH) ages 10 years to less than 18 years. If children younger than age 10 are included, the eligibility criteria should ensure that other available interventions to lower LDL -C have been insufficient. Phase 2 will be a randomized, open-label, 8-week, ascending repeated dose finding study of alirocumab with an optional open-label extension study in patients 10 years to less than 18 years of age with HeFH on stable lipid modifying therapy with LDL-C > or equal to 130 mg/dL. Phase 3 will be a randomized, 6-month, double-blind, placebo-controlled, parallel-group, multicenter efficacy and safety study followed by an 18-month open-label extension in patients 10 years to less than 18 years with HeFH on stable lipid-modifying therapy with LDL-C > or equal to 130 mg/dL. Patients treated in Phase 2, the dose-finding study, will be offered enrollment in Phase 3, the efficacy and safety study.
Conduct a prospective observational study of pregnant women exposed to Praluent to evaluate fetal, infant, and childhood outcomes of pregnant women exposed to Praluent and their live born offspring through the first 5 years of life to estimate incidence rates for the potential safety signals of adverse pregnancy outcomes, embryo-fetal growth and development, and adverse infant and childhood outcomes related to humoral immune suppression. The study should have validated/adjudicated outcomes, a comparator group, be powered to detect the outcomes of interest, and include the justification for the proposed detectable differences in incidence rates.
Conduct a large, randomized, controlled, long-term trial in which the incidence and severity of new- onset diabetes mellitus, injection site reactions, hypersensitivity, immunogenicity, and adverse events potentially related to demyelination with alirocumab treatment will be evaluated.
Conduct a randomized, controlled, long-term trial that prospectively evaluates changes in neurocognitive function with alirocumab treatment. The trial must be adequately powered to exclude a clinically meaningful adverse effect.
To develop an algorithm for decision-making in the presence of loss of efficacy due to antibody response. This should include an examination of the binding of alirocumab-specific neutralizing antibodies to the LDL receptor in patients in whom the presence of anti-drug antibodies are associated with LDL-C levels> 1.5-fold baseline in the absence of other confounding factors (e.g., nonadherence or intentional changes in concomitant LDL-C-lowering medications).
Conduct an epidemiologic study using claims or electronic health records data to evaluate the incidence of angioedema in Black patients treated with Entresto compared to a control drug. A target sample size, supported by sample size calculation, should be included in the protocol.
A multicenter, randomized, double-blind, active-controlled trial to evaluate the effects of Entresto compared to valsartan on cognitive function as assessed by comprehensive neurocognitive battery and PET imaging in patients with chronic heart failure with preserved ejection fraction.
A randomized, placebo-controlled trial to evaluate the safety and efficacy of OCALIVA (obeticholic acid) used as monotherapy in patients with primary biliary cholangitis (PBC) who are intolerant of or non-responsive to ursodeoxycholic acid (UDCA). Enroll patients across all stages of PBC, by the Rotterdam criteria. You may conduct this as a stand-alone trial or in a sub-set of patients in your confirmatory trial (PMR # 3057-3).
A randomized, double-blind, placebo-controlled trial to verify and describe that OCALIVA (obeticholic acid) induced reductions in alkaline phosphatase and/or total bilirubin are associated with improvements in the composite clinical endpoint of progression to cirrhosis, death, transplant, decompensation events and hepatocellular cancer. Your ongoing trial (747-302) should be revised to include patients across the spectrum of stages of primary biliary cholangitis (PBC), including patients with early, moderately advanced and advanced PBC by the Rotterdam criteria, and should be adequately powered to demonstrate benefit in each stage.
Develop a formulation that would allow once daily dosing of OCALIVA (obeticholic acid) for patients with hepatic impairment. Conduct a study in healthy subjects to characterize the bioavailability of the new formulation relative to an approved formulation. Submit your study protocol once you have a new formulation.
Conduct a pharmacokinetic and safety study of an age-appropriate formulation of VANTRELA ER in patients from ages seven to less than 17 years with pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.
In order to provide the baseline data to support the hypothesis-testing studies required under PMR 2981-3, conduct a descriptive study that analyzes data on the following: 1) Utilization of VANTRELA ER and selected comparators. Reports should include nationally-projected quarterly retail dispensing, overall and by age group and census region; AND 2) Abuse of VANTRELA ER and related clinical outcomes. These studies should utilize multiple data sources in different populations to establish the scope and patterns of abuse for VANTRELA ER as well as mutually agreedupon, selected comparators to provide context. Data should include route-specific abuse outcomes, be nationallyrepresentative or from multiple large geographic areas, and use meaningful measures of abuse. Additional information, either qualitative or quantitative, from sources such as internet forums, spontaneous adverse event reporting, or small cohort studies may also be included to help better understand abuse of this drug, including routes and patterns of abuse in various populations. Formal hypothesis testing is not necessary during this phase, but provide information on the precision of abuse-related outcome estimates (e.g., 95% confidence intervals for quarterly estimates) and calculate utilizationadjusted outcome estimates where possible.
Conduct a multiple-dose pharmacokinetic (PK) and tolerability study to explore the range of tolerated doses of Fycompa in patients from 2 to less than 12 years old with epilepsy. A sufficient proportion of subjects must be on background therapy that includes enzyme-inducing AEDs, such as carbamazepine, oxcarbazepine, or phenytoin, which are known to induce perampanel metabolism and decrease its plasma concentrations. PK data will be obtained using a sparse sampling approach. Sufficient PK and tolerability data must be generated from this study before conducting the efficacy and safety study, to inform the dose selection for that study. Sampling must be optimized to ensure adequate characterization of perampanel PK. Using information from the PK study, conduct an adequately powered, controlled, and blinded trial that examines the efficacy and safety of Fycompa in the treatment of primary generalized tonic-clonic (PGTC) seizures in a pediatric population. Because PGTC seizures are less common in this age group, the study population may include the full range of pediatric patients (e.g., patients less than 17 years old). This study must include a minimum of 60% of patients that are 2 to 12 years of age. Information from the PK/tolerability part of this postmarketing requirement, and its resulting protocol-specified dosing, should be provided to the Division prior to the initiation of the efficacy trial, and agreements on dosing should be reached with the Division before the efficacy trial is initiated.
An efficacy, safety and dose-finding study of Qbrelis in hypertensive pediatric patients two years to less than six years of age
A postmarketing, prospective, observational, cohort study of vedolizumab versus other agents for inflammatory bowel disease. The study's primary outcome is serious infections. Secondary outcomes include, but are not limited to, progressive multifocal leukoencephalopathy (PML), malignancy, and specific infections including gastrointestinal and upper respiratory infections. Specify concise case definitions and validation algorithms for both primary and secondary outcomes. Justify the choice of appropriate comparator population(s) and estimated background rate(s) relative to vedolizumab-exposed patients; clearly define the primary comparator population for the primary objective. Design the study around a testable hypothesis to assess, with sufficient sample size and power, a clinically meaningful increase in serious infection risk above the comparator background rate, with a pre-specified statistical analysis method. For the vedolizumab-exposed and comparator(s), the study drug initiation period should be clearly defined, including any exclusion and inclusion criteria. Ensure adequate number of patients with at least 24 months of vedolizumab exposure at the end of the study.
Submit data from the randomized withdrawal period (Epoch 3) of the ongoing phase 3 study, CACZ885N2301 (N2301). Include an assessment of the maintenance of efficacy of canakinumab at a reduced dosing frequency in the study report.
Conduct an open-label, dose-finding, pharmacokinetics, safety and tolerability study of Orbactiv (oritavancin diphosphate) single dose infusion in pediatric subjects less than 18 years of age with suspected or confirmed bacterial infections.
Conduct a multicenter, evaluator-blind, randomized study to evaluate the safety and tolerability of single-dose IV Orbactiv (oritavancin diphosphate) versus  vancomycin for the treatment of pediatric subjects less than 18 years of age with acute bacterial skin and skin structure infections.
Conduct a US surveillance study over a five-year period from the date of marketing Orbactiv (oritavancin diphosphate) to determine if resistance to oritavancin has developed in those organisms specific to the indication in the label for ABSSSI.
A randomized, double blind, multicenter, comparative study to establish the safety and tolerability profile of ceftolozane/tazobactam compared to that of meropenem in hospitalized children from birth to <18 years with cIAI. The dose for this study will be determined upon review of the data to be submitted by December 2016 from the a single- dose, multicenter, non-comparative study to assessing the PK pharmacokinetics (PK) of ceftolozane/tazobactam in pediatric patients ages 0 to <18 years that was initiated in June 2014.
Establish the efficacy and safety of APTIOM when used as monotherapy in the treatment of partial-onset seizures in patients 1 month to <18 years of age. This PMR may be fulfilled by a pharmacokinetic/pharmacodynamic analysis of data collected as part of studies of APTIOM as adjunctive treatment of partial-onset seizures in adults and pediatric patients, and as monotherapy treatment in adults. However, if the data from adjunctive treatment studies are insufficient to support the efficacy and safety of APTIOM as monotherapy for partial-onset seizures in any or all pediatric age subsets, additional clinical studies may be required.
An open-label, long-term safety study to evaluate the long-term safety of APTIOM when used as monotherapy for partial-onset seizures in patients 1 month to <18 years of age.
Conduct formal observational studies to assess whether the properties intended to deter misuse and abuse of VANTRELA ER actually result in a meaningful decrease in misuse and abuse, and their consequences, addiction overdose, and death, in post-approval settings. The studies should allow FDA to assess the impact, if any, attributable to the abuse-deterrent properties of VANTRELA ER and should incorporate recommendations contained in Abuse-Deterrent Opioids— Evaluation and Labeling: Guidance for Industry (April 2015). Assessing the impact of the abuse-deterrent formulation on the incidence of clinical outcomes, including overdose and death, is critical to fulfilling this PMR. Any studies using electronic healthcare data should use validated outcomes and adhere to guidelines outlined in FDA’s guidance for industry and FDA staff, Best Practices for Conducting and Reporting Pharmacoepidemiologic Safety Studies Using Electronic Healthcare Data.
A multiple ascending dose thorough QT (tQT) clinical trial in healthy adult volunteers designed to determine the maximum tolerated dose of hydrocodone bitartrate without co-administration of naltrexone and characterize the effect of VANTRELA ER on cardiac repolarization.
Submit the complete final report and data from a randomized, Phase 3 trial, comparing ibrutinib in combination with bendamustine and rituximab or rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone versus bendamustine and rituximab or rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone in subjects with previously treated follicular lymphoma or marginal zone lymphoma. At least 50 enrolled subjects need to have a diagnosis of marginal zone lymphoma. The primary endpoint is progression-free survival in the overall intent-to-treat population.
Determine the appropriate Trulance (plecanatide) treatment dose for pediatric patients with chronic idiopathic constipation (CIC) who are 12 years to less than 18 years of age by assessing the safety and efficacy of once daily oral plecanatide in an eight (8) week, proof-of-concept, dose-ranging with sparse pharmacokinetic (PK) sampling study.
Determine the appropriate Trulance (plecanatide) treatment dose for pediatric patients with chronic idiopathic constipation (CIC) who are 6 years to less than 12 years of age by assessing the safety and efficacy of once daily oral plecanatide in an eight (8) week, proof-of-concept, dose-ranging with sparse pharmacokinetic (PK) sampling study.
Confirm the efficacy and safety of Trulance (plecanatide) in pediatric patients with chronic idiopathic constipation (CIC) who are 6 years to less than 18 years of age by performing a randomized, double-blind, placebo-controlled, parallel group, 12 week treatment study.
Determine the appropriate Trulance (plecanatide) treatment dose for pediatric patients with chronic idiopathic constipation (CIC) who are 2 years to less than 6 years of age by assessing the safety and efficacy of once daily oral plecanatide in an eight (8) week, proof-of-concept, dose-ranging with sparse pharmacokinetic (PK) sampling study.
Unless FDA agrees, based on your completion of Postmarketing Commitment Number 1 above, that it is not appropriate to conduct a pediatric study in pediatric patients age 12 to 17 years, conduct a pediatric study in pediatric patients age 12 to 17 years for the treatment of Crohn's disease.  This pediatric study will enroll pediatric patients age 12 to 17 years into four study arms (placebo, 3 mg/kg, 4.5 mg/kg, and 6 mg/kg of TYSABRI administered intravenously every 4 weeks), and evaluate safety, efficacy, and pharmacokinetics of natalizumab.
A postmarketing prospective, long-term, observational study to assess the longterm safety of secukinumab compared to other therapies used in the treatment of adults with moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy in a real world clinical setting. The study’s primary outcome is malignancies. Describe and justify the choice of appropriate comparator population(s). Design the study around a testable hypothesis to assess, with sufficient sample size and power, a clinically meaningful increase in malignancy risk above the comparator background rate. Specify concise case definitions and validation algorithms for the primary outcome. Enroll patients over an initial 4-year period and follow for a minimum of 8 years from the time of enrollment. Provide progress updates on registry patient accrual and demographic summary data in your Annual Report, and provide registry safety data in your Periodic Benefit-Risk Evaluation Reports (PBERs) for the reporting period as well as cumulatively, and a complete final study report.
Complete the treatment and evaluation of subjects enrolled in the ongoing CAIN457A2302E1 trial for a duration of 4 years, unless a safety signal is identified that indicates the potential risks of such continued long-term treatment outweigh the benefits. Evaluation of subjects should continue through the end of the trial when achievable (even if treatment is not continued for the duration). Subjects will be followed for the occurrence of serious infection, tuberculosis, opportunistic infections, malignancy, hypersensitivity reactions, autoimmune disease, neurologic or demyelinating disease, cardiovascular, gastrointestinal or hematologic adverse events.
Complete the treatment and evaluation of subjects enrolled in the ongoing CAIN457A2304E1 trial for a duration of 4 years, unless a safety signal is identified that indicates the potential risks of such continued long-term treatment outweigh the benefits. Evaluation of subjects should continue through the end of the trial when achievable (even if treatment is not continued for the duration). Subjects will be followed for the occurrence of serious infection, tuberculosis, opportunistic infections, malignancy, hypersensitivity reactions, autoimmune disease, neurologic or demyelinating disease, cardiovascular, gastrointestinal or hematologic adverse events.
Conduct a clinical trial to assess whether secukinumab alters the metabolism or pharmacokinetics of CYP substrates in psoriasis patients treated with secukinumab.
Conduct a clinical trial to evaluate the treatment effect and safety profile of a higher exposure (e.g., 450 mg) of secukinumab in psoriasis subjects with higher body weight and to explore the option of exposure escalation (e.g., 450 mg) for those who cannot achieve the therapeutic goal at the 300 mg dose.
To develop and maintain a Pregnancy Surveillance Program that collects pregnancy and fetal outcomes of women exposed to romiplostim during pregnancy. Reports from the program will include an analysis of reports on major and minor congenital anomalies, spontaneous abortions, stillbirths, elective terminations, adverse effects on immune system development, platelet number and function, neoplasm formation, bone marrow reticulin formation, thrombotic events, and any serious adverse pregnancy outcomes.
A safety and pharmacokinetic trial as a sub-study of the trial described in PMR #5 above to evaluate trough concentrations of adalimumab and antibody levels (utilizing a validated anti-adalimumab antibody assay as described in PMR #3 above) at the time of loss of clinical remission in patients whose physicians plan to escalate the dose (e.g., decrease the dosing interval to weekly or increase the dosage) in response to loss of remission. Trough concentrations will be evaluated to determine whether patients who have low adalimumab exposures benefit from dose escalation without increasing risk of serious adverse events. The protocol should be agreed upon by the agency prior to initiation of the trial.
Develop and validate anti-ecallantide and anti-P. pastoris-specific human IgE detection assays using a sensitive platform such as ECL.  Such assays should be free from interference by anti-ecallantide IgG antibodies.
Conduct a prospective, observational registry study of 100 rituximab-treated patients with Wegener¿s granulomatosis (WG) or microscopic polyangiitis (MPA) followed for 4 years to evaluate long term safety and retreatment with rituximab or other therapies.
Conduct a trial to determine the efficacy and safety of the use of deferiprone to treat iron overload in patients with sickle cell disease and transfusional hemosiderosis who have not been adequately treated with available chelating agents. Submit the protocol for review and concurrence prior to commencing. The trial will enroll a sufficient number of patients with sickle cell disease as described above, to provide sufficient evidence to assess the efficacy and safety in the sickle cell disease population described. The trial may enroll patients with other conditions who have developed transfusional iron overload. The trial will stratify for hematologic diagnosis for the randomization. The primary and secondary endpoints will measure changes in cardiac iron concentration and liver iron concentration.
Establish a registry in order to perform an enhanced pharmacovigilance study of agranulocytosis. Procedures should include: Creation of marketing materials to inform and encourage clinicians to report agranulocytosis events to the sponsor; monitoring of all reported cases and active follow-up to characterize the demographics, recent prior blood counts, concomitant medications, co-existing conditions, duration of drug exposure prior to onset, outcomes of the event, and other factors that may help to characterize the agranulocytosis event. Sponsor also will institute procedures to obtain blood samples from patients with reported cases of agranulocytosis to store for later analysis of possible genetic underlying factors that may predict the risk of agranulocytosis. Submit interim reports annually describing the above results.
Evaluate the long-term, prospective clinical outcomes of treatment with sebelipase alfa in adult and pediatric patients with LAL deficiency, including but not limited to progression of liver and cardiovascular diseases and changes in anthropometric assessments (i.e., length/height z-scores, and weight z-scores). At a minimum, liver assessments will include results of liver biopsies and imaging studies, changes in liver synthetic function, evidence for clinical progression to end stage liver disease (e.g., assessed by the Model for End-Stage Liver Disease [MELD] score), receipt of liver transplantation, and fatal outcomes. Cardiovascular assessments will include incidence rates of non-fatal stroke, myocardial infarction, and cardiovascular death. Additional evaluations will include dosing regimens administered and reasons for any dose modifications. This trial will also collect data on the occurrence of any serious hypersensitivity reactions, such as anaphylaxis, as well as changes in antibody status (i.e., detection and titers of binding and neutralizing antibodies, and detection of IgE antibodies). Eligible patients will be enrolled over an initial 3-year period and followed for a minimum of 10 years from the time of enrollment or until death, whichever comes first. This trial may be conducted as a separate study or as a substudy within the Lysosomal Acid Lipase registry.
Collect and analyze data related to the home administration of Synribo in order to assess the potential for the serious safety risks of incorrect dose administration and serious adverse events potentially arising from improper distribution, transport, storage, and handling in clinical practice. Identify all potentially correctable system failures and propose remedial measures. Sponsor agrees to submit a protocol acceptable to the Agency that details the process for collection of this data to assess safe use for home administration.
Conduct an in vivo comet assay for [...]
Conduct a pre- and post-natal development toxicology study in the rat model to assess the potential impact of dibutyl sebacate on development.
Provide data on overall response rate with osimertinib from one or more “realworld” cohorts of a minimum of 100 patients who have been selected for treatment on the basis of an EGFR T790M mutation positive result from plasma (ctDNA) using the cobas® EGFR Mutation Test v2. Provide tissue EGFR T790M status on these patients, where available.
Submit the final clinical report and datasets at the time of the final analysis for overall survival (OS) for Trial P006, entitled “A Multicenter, Randomized, Controlled, Three-Arm, Phase III Study to Evaluate the Safety and Efficacy of Two Dosing Schedules of MK-3475 Compared to Ipilimumab in Patients with Advanced Melanoma”, to revise the product label with mature OS data.
Develop and validate an appropriate analytical method for determining measurable amounts of the following 9 phytosterols in Intralipid 20% IV Fat Emulsion: sitosterol, desmosterol, brassicasterol, lanosterol, ergosterol, campesterol, stigmasterol, sitostanol, lathosterol, squalane (a sterol precursor), and cholesterol.
Using the method developed under PMR 3109-1, test for the individual component phytosterol content in at least one batch of Intralipid 20% IV Fat Emulsion manufactured with every new lot of soybean oil over a three year period. Based on these test results, establish limits for each of the individual component phytosterols in Intralipid 20% IV Fat Emulsion in the product specification.
Randomized controlled trial in pediatric patients, including neonates, comparing Intralipid 20% IV Fat Emulsion with a phytosterol-depleted formulation of Intralipid 20% IV Fat Emulsion to evaluate the incidence of liver injury, including either parenteral nutrition-associated liver disease (PNALD) or intestinal failure associated liver disease (IFALD). This trial should be initiated after the results from PMR 3109-3 are available. The phytosterol content of the phytosteroldepleted formulation of Intralipid 20% IV Fat Emulsion should be documented using validated analytical assay methods developed under PMR 3109-1. Plasma phytosterol levels should be assessed in patients using validated analytical assay methods developed under PMR 3109-3.
A randomized, single-blind, multicenter dose-ranging study comparing the safety and efficacy of ColPrep Kit (sodium sulfate, potassium sulfate and magnesium sulfate) for oral solution to an active control or community standard of care in children (ages 11 years to 16 years). This study will include PK assessments.
A randomized, single-blind, multicenter dose-ranging study comparing the safety and efficacy of ColPrep Kit (sodium sulfate, potassium sulfate and magnesium sulfate) for oral solution to an active control or community standard of care in children (ages 2 years to <11 years). This study will include PK assessments.
A randomized, single-blind, multicenter dose-ranging study comparing the safety and efficacy of ColPrep Kit (sodium sulfate, potassium sulfate and magnesium sulfate) for oral solution to an active control or community standard of care in children (ages 12 months to <2 years). This study will include PK assessments.
A two-year carcinogenicity study in one rodent species (CD-1 mice) with subcutaneous administration of nusinersen.
A pre-and postnatal development (including maternal function) study of nusinersen in rodent.
Conduct a clinical trial to test whether the addition of hormonal therapy increases the efficacy of pertuzumab-based therapy in the hormone receptor-positive, HER2-positive metastatic breast cancer population. Study MO27775 (PERTAIN) as designed will be completed to fulfill this post-marketing commitment.
A medullary thyroid carcinoma case series registry of at least 15 years duration to systematically monitor the annual incidence of medullary thyroid carcinoma in the United States and to identify any increase related to the introduction of Tanzeum (albiglutide) into the marketplace. This study will also establish a registry of incident cases of medullary thyroid carcinoma and characterize their medical histories related to diabetes and use of Tanzeum (albiglutide).
Evaluate in a step-wise approach the disease-drug-drug interaction (Disease-DDI) potential for vedolizumab to indirectly affect the exposure of CYP substrate drugs by modulating pro-inflammatory cytokines in patients with ulcerative colitis and Crohn’s disease who are treated with vedolizumab.
To determine the potential for pharmacokinetic interactions between Erbitux (cetuximab) and cisplatin you will conduct the drug-drug interaction clinical trial, Study I4E-MC-JXBA.
Following the assessment of data from Trial CA184024, you will design and conduct a trial to compare the efficacy, with the primary endpoint of overall survival and the safety of ipilimumab at doses of 3mg/kg versus 10mg/kg given as monotherapy every three weeks for four doses in patients with unresectable Stage III or Stage IV melanoma.
Submit the final clinical report and datasets at the time of the final analysis for overall survival (OS) for Trial P002, entitled “Randomized, Phase 2 Study of MK-3475 versus Chemotherapy in Patients with Advanced Melanoma”, to revise the product label with mature OS data.
A 54-week, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of JANUMET XR versus metformin extended-release in pediatric patients who are inadequately controlled on metformin immediate release.
A prospective, observational study designed to quantify the serious risks of misuse, abuse, and addiction associated with long-term use of opioid analgesics for management of chronic pain among patients prescribed ER/LA opioid analgesics. This study must address at a minimum the following specific objectives: a. Estimate the incidence of misuse, abuse, and addiction associated with long-term use of opioid analgesics for chronic pain. Examine the effect of product/formulation, dose and duration of opioid use, prescriber specialty, indication, and other clinical factors (e.g., concomitant psychotropic medications, personal or family history of substance abuse, history of psychiatric illness) on the risk of misuse, abuse, and addiction. b. Evaluate and quantify other risk factors for misuse, abuse, and addiction associated with long-term use of opioid analgesics for chronic pain, including but not limited to the following: demographic factors, psychosocial/behavioral factors, medical factors, and genetic factors. Identify confounders and effect modifiers of individual risk factor/outcome relationships.
An observational study designed to measure the incidence and predictors of opioid overdose and death (OOD), as well as opioid abuse/addiction, using patient health records, insurance claims, and death records. This study must address at a minimum the following specific objectives: a. Estimate the incidence of abuse/addiction, overdose, and death associated with long-term use of opioid analgesics for chronic pain. Stratify overdose by intentionality wherever possible. Examine the effect of product/formulation, dose and duration of opioid use, prescriber specialty, indication, and other clinical factors (e.g., concomitant psychotropic medications, personal or family history of substance abuse, history of psychiatric illness) on the risk of abuse/addiction, overdose, and death. b. Evaluate and quantify other risk factors for abuse/addiction, overdose, and death associated with long-term use of opioid analgesics for chronic pain, including but not limited to the following: demographic factors, psychosocial/behavioral factors, medical factors, and genetic factors. Identify confounders and effect modifiers of individual risk factor/outcome relationships. Stratify overdose by intentionality wherever possible.
A prospective observational study designed to assess the content validity and patient interpretation of the Prescription Opioid Misuse and Abuse Questionnaire (POMAQ). Patient understanding of the concepts of misuse and abuse will also be obtained.
Deferred 3-month cariprazine toxicity study in the juvenile rat starting at the appropriate age that corresponds to children age of 10 years. A dose range finding/toxicokinetic (TK) study should be conducted prior to a definitive toxicity/TK study. TK assessment should include cariprazine and the metabolites DCAR and DDCAR.
Deferred 6-month study in the juvenile dog starting at the appropriate age that corresponds to children age of 10 years. A dose range finding/TK study should be conducted prior to a definitive toxicity/TK study. TK assessment should include cariprazine and the metabolites DCAR and DDCAR.
Deferred pediatric study under PREA (ages 10 to 17 years) with a diagnosis of schizophrenia or bipolar I disorder to obtain pharmacokinetic, safety, and tolerability data to inform the selection of doses in efficacy and safety studies in pediatric patients with schizophrenia and bipolar I disorder.
Deferred pediatric study under PREA for the treatment of schizophrenia in patients aged 13 to 17. A study of the efficacy and safety of cariprazine in the relevant pediatric population.
Deferred pediatric study under PREA for the treatment of bipolar I disorder, manic episodes in patients aged 10 to 17. A study of the efficacy and safety of cariprazine in the relevant population.
Deferred long-term, open-label safety study in pediatric patients with schizophrenia (ages 13 to 17) and bipolar I disorder, recent manic episodes (ages 10 to 17).
An in vivo drug-drug interaction study to assess cariprazine exposure when cariprazine is coadministered with a proton pump inhibitor.
In-vitro evaluation of: 1) inhibition potential of cariprazine, and the metabolites DCAR and DDCAR toward CYP2C8; 2) inhibition potential of DCAR and DDCAR toward CYP2B6 and CYP2C19; 3) induction potential of cariprazine , DCAR and DDCAR toward CYP2B6; 4) induction potential of cariprazine toward CYP3A4 and CYP1A2.
Conduct a placebo-controlled, randomized withdrawal, dose-response trial in adults patients with schizophrenia to assess the long-term, dose-related serious adverse effects of cariprazine, including tardive dyskinesia, akathisia, adrenal dysfunction, and extrapyramidal symptoms. The trial will also assess both the efficacy and tolerability of several fixed doses of cariprazine as maintenance treatment. Patients stabilized on treatment with cariprazine for at least 12 weeks would be randomized to fixed doses of cariprazine. These would include doses lower than those used to achieve a response in the acute phase.
Conduct a placebo-controlled, randomized withdrawal, dose-response trial in adult patients with bipolar I disorder to assess the long-term, dose-related serious adverse effects of cariprazine, including tardive dyskinesia, akathisia, adrenal dysfunction, and extrapyramidal symptoms. The trial will also assess both the efficacy and tolerability of several fixed doses of cariprazine as maintenance treatment. Patients stabilized on treatment with cariprazine for at least 12 weeks would be randomized to fixed doses of cariprazine. These would include doses lower than those used to achieve a response in the acute phase.
A study to assess for the presence of antibodies that bind native double-stranded (ds) DNA among patients treated with Spinraza (nusinersen). The study may be conducted with plasma samples from patients treated with Spinraza (nusinersen) in the clinical development program, including ongoing studies, but should include samples from patients who test negative as well as patients who test positive for antibodies to Spinraza (nusinersen). Among patients who develop anti-drug antibodies, samples should be included from patients shortly after seroconversion as well as from sustained responders. A sensitive assay should be used to assess presence of antibodies to double-stranded (ds) DNA in patient samples.
Enhanced pharmacovigilance program for reports of malignancy in pediatric, adolescent, and young adult (<  30 years of age) patients treated with Simponi (golimumab), for a period of up to 10 years after this notification to collect data that will be analyzed to better define the risk of this serious adverse event.  The enhanced pharmacovigilance program includes the following: 1) active query of reporters to obtain additional clinical information related to malignancy diagnoses; 2) expedited reporting to FDA of all initial and follow-up reports of any malignancy in pediatric and young adult patients.  Interim analyses and summaries of new and cumulative safety information in pediatric and young adult patients must be submitted annually, followed by the final report at the conclusion of the monitoring period.
Conduct a clinical trial to evaluate the impact of hepatic impairment on the pharmacokinetics of Kadcyla (ado-trastuzumab emtansine), total trastuzumab, and DM1-containing catabolites.   Based on the results of this trial, update the approved Kadcyla labeling with recommendations for appropriate use of Kadcyla in patients with hepatic impairment.
Deferred pediatric 12-month Open-Label Safety Study under PREA for prophylaxis of headaches in adolescents ages 12 to 17 with chronic migraine. The study must include at least 300 patients who received two BOTOX treatments at clinically relevant doses over a 6-month period (with at least 100 patients treated at the maximum recommended dose), and at least 100 patients who received four BOTOX treatments at clinically relevant doses over a 12-month period (with at least 60 patients treated at the maximum recommended dose). The study must assess local reactions, distant spread of toxin effects, BOTOX effects on blood glucose, and  BOTOX effects on alkaline phosphatase (as a marker of bone metabolism). The safety study must include an adequate evaluation of immunogenicity.
Genzyme commits to performing additional analyses of the data obtained in the registry of patients with Fabry disease being treated with Agalsidase beta that was established to obtain long-term clinical status information.  Additional analyses of the registry data are to be performed for the purpose of establishing the clinical benefit of Fabrazyme on progression of renal disease and other end-organ disease endpoints in patients with Fabry disease.  Additional analyses to be performed include the following:   a.  Progression of renal disease, including assessment of time of onset of proteinuria, hypertension, chronic renal insufficiency, end-stage renal disease, and death. b.  Exploration of the effects of endogenous alphaGAL activity and genetic mutations on progression of renal disease, the occurrence of significant clinical events, and the development of anti-recombinant-human-alphaGAL (anti-r-halphaGAL) IgG antibodies. c.  Progression of renal disease by age of initiation of ERT with Fabrazyme for age groups such as <10 years of age, greater than or equal to 10 to <15 years of age,  greater than or equal to 15 to 20 years of age, and in 10 year increments at >20 years of age. d.  Progression of renal disease by treatment administered, including ERT with Fabrazyme or no treatment.  Reports will include data on patients who have received other Fabry specific treatments e.  Progression of renal disease by GFR status (>60 ml/min/1.73 m2 or <60 ml/min/1.73 m2) at initiation of ERT with Fabrazyme. f.  Time of first significant clinical event. g.  Analysis of anti-r-halphaGAL IgG antibodies titers on the progression of renal disease and the occurrence of significant clinical events.
An observational study to develop and validate an algorithm using coded medical terminologies and other electronic healthcare data to identify opioid-related overdose and death.
An observational study to develop and validate an algorithm using coded medical terminologies to identify patients experiencing prescription opioid abuse or addiction, among patients receiving an ER/LA opioid analgesic.
An observational study using coded medical terminologies and other electronic healthcare data to define and validate doctor and/or pharmacy shopping outcomes by examining their association with abuse and/or addiction.
An observational study using a validated patient survey to evaluate the association between doctor/pharmacy shopping outcomes and self-reported misuse and abuse.
An observational study using medical record review to evaluate the association between doctor/pharmacy shopping outcomes and patient behaviors suggestive of misuse, abuse and/or addiction.
Conduct a clinical trial to estimate the serious risk for the development of hyperalgesia following the long-term use of high-dose ER/LA opioid analgesics for at least one year to treat chronic pain. Include an assessment of risk relative to efficacy.
Conduct a study to evaluate safety and pharmacokinetics of Sernivo (betamethasone dipropionate) Spray, 0.05% versus Diprolene Lotion, 0.05% in pediatric subjects 12 years to 16 years 11 months of age with moderate to severe plaque psoriasis. Assess potential hypothalamic-pituitary-adrenal (HPA) axis suppression and drug levels of Sernivo Spray, 0.05% and Diprolene Lotion, 0.05%. Study drugs will be applied twice daily under maximal use conditions for 15 or 29 days.
Conduct a study to evaluate the pharmacokinetics, safety and treatment response (using sustained virologic response) of daclatasvir in combination with other direct acting antivirals in pediatric subjects 3 through 17 years of age with chronic hepatitis C virus.
Conduct a study to determine if Tysabri (natalizumab) increases the risk of major congenital malformations. In this study, the risk of fetal and infant outcomes (including malformations) among Tysabri-exposed women identified from the Tysabri Pregnancy Exposure Registry should be compared to the risk among 1) women with multiple sclerosis (MS) exposed to non-Tysabri therapies during pregnancy, 2) women with MS unexposed to any MS therapy during pregnancy, and 3) women without MS. Women with MS exposed to non-Tysabri therapies will be selected from the following: the Avonex Pregnancy Registry, the Tecfidera Pregnancy Registry, the Plegridy Pregnancy Registry, and the European Union Interferon-beta Pregnancy Registry. Women with MS unexposed to any MS therapy and women without MS should be identified from the Nordic pharmacoepidemiology study. The same birth defect classification system must be used across all populations and comparisons. All comparisons are to be summarized in a final study report.
To submit the clinical study report and datasets for the final analysis of overall survival (OS) for Trial CRAD001T2302, entitled “A randomized, double-blind, multicenter, phase III study of everolimus (RAD001) plus best supportive care versus placebo plus best supportive care in the treatment of patients with advanced NET of GI or lung origin - RADIANT-4,” and to include the final OS data in the product label.
Submit the final study report for the stage 2 (GClb versus RClb) of the BO21004/CLL11 trial entitled, “An Open-label, Multi-center, Three Arm Randomized, Phase 3 Study to Compare the Efficacy and Safety of RO5072759 + Chlorambucil (GClb), Rituximab + Chlorambucil (RClb) or Chlorambucil (Clb) Alone in Previously Untreated CLL Patients with Comorbidities” which shall include overall survival results at the end of the study. The final report will provide summary analysis and primary data. Accrual to this trial has been completed.
Submit the final study report for the clinical trial GAO4753g (GADOLIN) entitled, “An open-label, multicenter, randomized, phase 3 study to investigate the efficacy and safety of bendamustine compared with bendamustine+RO5072759 (GA101) in patients with rituximab-refractory indolent non-Hodgkin’s lymphoma” which shall include the overall survival results at the planned final analysis after 226 deaths. The final report will provide summary analysis and primary data. Accrual to this trial has been completed.
A randomized, double-blind, placebo-controlled clinical trial to evaluate the effect of testosterone replacement therapy on the incidence of major adverse cardiovascular events in men. We recommend that this trial also assess other important safety and efficacy outcomes associated with testosterone therapy.
A study in Fischer 344 rats to ascertain the effect of different Natpara (parathyroid hormone) dosing regimens on osteoblast proliferation, as an indicator of relative osteosarcoma risk.
An enhanced pharmacovigilance study of osteosarcoma in patients with hypoparathyroidism treated with Natpara (parathyroid hormone). The study will include reports of osteosarcoma for a period of 15 years from the date of approval, and will include assessment and analysis of spontaneous reports of osteosarcoma in patients treated with Natpara (parathyroid hormone), with specialized follow-up to collect additional information on these cases.
A clinical pharmacology trial to assess the pharmacokinetics (PK) and pharmacodynamic effects (PD) of Natpara (parathyroid hormone) dose and dosing regimen on the control of serum calcium and normalization of calcium excretion in urine. Modeling and simulation using mechanistic model-based assessment of prior PK/PD data should be used to design this trial.
A 26-week randomized, controlled clinical trial to evaluate the longer term safety and effect of an alternative dose(s) and/or dosing regimen(s) of Natpara (parathyroid hormone), including longer term safety with respect to hypercalciuria. This trial should not be initiated until the results from the clinical pharmacology trial (PMR 2856-3) and the nonclinical rat study (PMR 2856-1) have been submitted to and reviewed by the Agency.
Develop and test the stability of a lower (35 or 70 mg) strength ibrutinib capsule in order to allow dose reductions for patients with moderate hepatic impairment for whom ibrutinib treatment is currently not recommended. The lower strength capsule should be sufficiently distinguishable from the 140 mg capsule.
Evaluate the pharmacokinetics, safety and treatment response (using sustained virologic response as the primary endpoint) of ombitasvir, paritaprevir, ritonavir,dasabuvir (Viekira Pak™) in pediatric subjects 3 to less than 18 years of age with chronic hepatitis C virus infection.
Collect and analyze long-term safety data for subjects enrolled in the pediatric ombitasvir, paritaprevir, ritonavir, dasabuvir (Viekira Pak™) pharmacokinetic, safety, and antiviral efficacy study(ies). Data collected should include at least 3 years of follow-up in order to characterize the durability of response to ombitasvir, paritaprevir, ritonavir, dasabuvir (Viekira Pak™) and the long-term safety including growth assessment, sexual maturation, and characterization of resistance associated substitutions in viral isolates from subjects failing therapy.
Submit a final report for ongoing observational study M13-102, "A Follow-up Study to Assess Resistance and Durability of Response to AbbVie Direct-Acting Antiviral Agent (DAA) Therapy in Subjects Who Participated in Phase 2 or 3 Clinical Studies for the Treatment of Chronic Hepatitis C Virus (HCV) Infection."
Conduct an observational study to investigate the safety and efficacy of ombitasvir, paritaprevir, ritonavir, dasabuvir (Viekira Pak™) in a sufficient number of Blacks/African Americans with and without cirrhosis compared to whites/Caucasians.
Submit the final report and datasets for the ongoing clinical trial M14-227 entitled "An Open-Label Study to Evaluate the Safety and Efficacy of ABT- 450/Ritonavir/ABT-267 and ABT-333 with Ribavirin in Adults with Genotype 1 Chronic Hepatitis C Virus Infection and Decompensated Cirrhosis."
To test all banked clinical samples from pivotal clinical trials NIH 991265/20010769 and trial FHA101 for the presence of neutralizing antibodies against leptin using the ligand binding assay developed and validated under PMR#2, and to correlate neutralizing antibodies with clinical events.
To provide an update of efficacy from all 3 treatment arms in Study BCIRG006 at the time when the last patient enrolled reaches 10 years of follow-up, with an interim update of efficacy at 5-years of follow-up.
Conduct a field study to evaluate the efficacy, pharmacokinetics, and safety of raxibacumab use for Bacillus anthracis in the United States.
Conduct a PK/safety study of SC abatacept in polyaricular JIA patients ages 6 to 17 years of age.
Conduct a prospective, observational study utilizing data from the United Network for Organ Sharing (UNOS) on the pattern of belatacept use in US adult kidney-only transplant recipients at transplant and one year post-transplant.  Specifically, the study will assess the prevalence of belatacept use and the characteristics of belatacept users, as related to the risk of PTLD, including Epstein-BarrVirus (EBV) and cytomegalovirus (CMV) serostatus.  In addition, the study will collect information on adult kidney-only transplant recipients who switch to or from belatacept within one year post-transplant.  (Protocol Number IM103074)
A single-center randomized, placebo-controlled and active-controlled thorough QT (TQT) trial in normal (or healthy) subjects. Please refer to ICH E14 guidance to design the trial and submit the protocol to the agency for comments. The doses studied should ensure the clinical concentration-response relationship for QTc prolongation is characterized, including exploration of higher concentrations than those achieved following the anticipated therapeutic dose. Include the highest tolerable dose in the trial. Because N-desmethylsertraline, the primary metabolite of sertraline, has a much longer elimination half-life (62-104 hours) compared to the parent drug (26 hours), conduct the TQT study at steady state.
Conduct a dose-ranging Pharmacokinetics (PK), Safety and Efficacy Study in pediatric subjects 6 to <18 years of age with moderate to severe psoriasis (with a duration of exposure to ixekizumab of at least one year).
Conduct a retrospective cohort study using administrative databases to identify pregnancy outcomes in a cohort of women exposed to ixekizumab and a nonixekizumab systemic medication exposure cohort. The outcomes will include major congenital malformations, spontaneous abortions, stillbirths, and small for gestational age births. This study may use multiple data sources in order to obtain a sufficient sample size as women with psoriasis are counseled to avoid systemic treatments while trying to conceive and during the course of pregnancy.
Conduct a prospective registry-based observational exposure cohort study that compares the maternal, fetal, and infant outcomes of women exposed to ixekizumab during pregnancy to an unexposed control population. The registry will detect and record major and minor congenital malformations, spontaneous abortions, stillbirths, elective terminations, small for gestational age births, and any other adverse pregnancy outcomes. These outcomes will be assessed throughout pregnancy. Infant outcomes, including effects on postnatal growth and development, will be assessed through at least the first year of life.
Conduct a prospective, observational study to assess the long-term safety of ixekizumab compared to other therapies used in the treatment of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy in the course of actual clinical care. The study’s primary outcome is malignancy. Secondary outcomes include, but are not limited to, serious infection, tuberculosis, opportunistic infections, hypersensitivity reactions, autoimmune disease, neurologic or demyelinating disease, cardiovascular, gastrointestinal or hematologic adverse events. Describe and justify the choice of appropriate comparator population(s) for the primary objective. Design the study around a testable hypothesis to assess, with sufficient sample size and power, a clinically meaningful increase in malignancy risk above the comparator background rate(s), with a pre-specified statistical analysis method. Specify concise case definitions and validation algorithms for both primary and secondary outcomes. For the ixekizumab-exposed and comparator(s), clearly define the study drug initiation period and any exclusion and inclusion criteria. Enroll patients over an initial 4- year period and follow for a minimum of 8 years from the time of enrollment.
Conduct a clinical study to assess whether ixekizumab alters the metabolism or pharmacokinetics of CYP substrates in psoriasis patients treated with ixekizumab.
Conduct a Field Study to evaluate the clinical response, pharmacokinetics, and safety profile of Anthim (obiltoxaximab) when used in the treatment of suspected or confirmed cases of inhalational anthrax due to B. anthracis in the United States.
In patients with CKD who are not on dialysis (NOD), conduct one or more trials to determine whether a dosing strategy (e.g. fixed dose strategy) different from that in the approved labeling can further reduce exposure to ESA while preserving the benefit of reducing transfusion use.
Submit the final report and datasets for the ongoing clinical trial M14-226 entitled "An Open-Label Study to Evaluate the Safety and Efficacy of Ombitasvir/ABT- 450/Ritonavir and Dasabuvir with or without Ribavirin (RBV) in Treatment- Naïve Adults with Genotype 1 Chronic Hepatitis C Virus (HCV) Infection, with Severe Renal Impairment or End-Stage Renal Disease."
Submit the final report and datasets for the ongoing Phase 3 clinical trial M11-646 entitled "A Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and Safety of ABT-450/Ritonavir/ABT-267 (ABT- 450/r/ABT-267) and ABT-333 Co-administered with Ribavirin (RBV) in Treatment-Naïve Adults with Genotype 1 Chronic Hepatitis C Virus (HCV) Infection."
Submit the final report and datasets for the Phase 3 clinical trial M13-098 entitled "A Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and Safety of ABT-450/Ritonavir/ABT-267 (ABT-450/r/ABT-267) and ABT-333 Co-administered with Ribavirin (RBV) in Treatment-Experienced Adults with Genotype 1 Chronic Hepatitis C Virus (HCV) Infection."
Submit the final report and datasets for the Phase 3 clinical trial M13-099 entitled "A Randomized, Open-Label Study to Evaluate the Safety and Efficacy of ABT- 450/Ritonavir/ABT-267 (ABT-450/r/ABT-267) and ABT- 333 Coadministered with Ribavirin (RBV) in Adults with Genotype 1 Chronic Hepatitis C Virus (HCV) Infection and Cirrhosis."
Submit the final report and datasets for the Phase 3 clinical trial M13-961 entitled "A Randomized, Double-Blind, Controlled Study to Evaluate the Efficacy and Safety of the Combination of ABT-450/Ritonavir/ABT-267 (ABT-450/r/ABT- 267) and ABT-333 With and Without Ribavirin (RBV) in Treatment-Naïve Adults with Genotype 1b Chronic Hepatitis C Virus (HCV) Infection."
Submit the final report and datasets for the Phase 3 clinical trial M13-389 entitled "A Randomized, Open-Label, Multicenter Study to Evaluate the Safety and Antiviral Activity of the Combination of ABT-450/Ritonavir/ABT-267 (ABT- 450/r/ABT-267) and ABT-333 With and Without Ribavirin in Treatment- Experienced Subjects with Genotype 1b Chronic Hepatitis C Virus (HCV) Infection."
Submit the final report and datasets for the Phase 3 clinical trial M14-002 entitled "A Randomized, Double-Blind, Controlled Study to Evaluate the Efficacy and Safety of the Combination of ABT-450/Ritonavir/ABT-267 (ABT-450/r/ABT- 267) and ABT-333 With and Without Ribavirin (RBV) in Treatment-Naïve Adults with Genotype 1a Chronic Hepatitis C Virus (HCV) Infection."
Submit the final report and datasets for the ongoing clinical trial M12-999 entitled "Open-label, Phase 2 Study to Evaluate the Safety and Efficacy of the Combination of ABT-450/ritonavir/ABT-267 (ABT-450/r/ABT-267) and ABT- 333 With or Without Ribavirin (RBV) in Adult Liver Transplant Recipients with Genotype 1 Hepatitis C Virus (HCV) Infection."
Submit the final report and datasets for the ongoing clinical trial M14-004 entitled "A Randomized, Open-label Study to Evaluate the Safety and Efficacy of ABT- 450/Ritonavir/ABT-267 (ABT-450/r/ABT-267) and ABT-333 Coadministered with Ribavirin (RBV) in Adults with Genotype 1 Chronic Hepatitis C Virus (HCV) Infection and Human Immunodeficiency Virus, Type 1 (HIV-1) Coinfection."
Submit the final report and datasets for the ongoing clinical trial M14-490 entitled "An Open-Label, Single-Arm Study to Evaluate the Safety and Efficacy of Ombitasvir/ABT-450/Ritonavir and Dasabuvir in Adults with Genotype 1b Chronic Hepatitis C Virus (HCV) Infection and Cirrhosis."
A 6-month carcinogenicity study in the transgenic mouse. Submit the carcinogenicity protocol for a Special Protocol Assessment (SPA) prior to initiating the study.
A long-term rodent carcinogenicity study in the rat. Submit the carcinogenicity protocol for a Special Protocol Assessment (SPA) prior to initiating the study.
Provide quarterly reports on the status of any [ ... ]. These reports should include, at a minimum, a summary of the root cause analyses, associated corrective actions, and disposition of all affected DM1 batches.  Also, provide the disposition of any potentially affected finished product batches using these affected DM1 batches.  Submit an interim report documenting that the manufacturing processes have been appropriately controlled at the manufacturing facilities according to Genentech's evaluation.  The interim report should include a request for follow-up inspection(s). Submit a final report with a statement concerning the follow-up performed on the [ ... ] issues during the course of the FDA inspection(s), an update on whether there have been any further instances of [ ... ], and a proposal to prevent [ ...] managed by each site' quality system.
A single-center randomized, placebo-controlled and active-controlled thorough QT (TQT) trial of Remeron (mirtazapine) in normal (or healthy) subjects. Please refer to ICH E14 guidance to design the trial and submit the protocol to the agency for comments. The doses studied should ensure the clinical concentrationresponse relationship for QTc prolongation is characterized, including exploration of higher concentrations than those achieved following the anticipated therapeutic dose at the steady state. Include the highest tolerable dose in the trial.
A single-center, randomized, placebo-controlled and active-controlled thorough QT (TQT) trial of Effexor Extended-Release (venlafaxine hydrochloride) in normal (or healthy) subjects. Please refer to ICH E14 guidance to design the trial and submit the protocol to the agency for comments. The doses studied should ensure the clinical concentration-response relationship for QTc prolongation is characterized, including exploration of higher concentrations than those achieved following the anticipated therapeutic dose. Include the highest tolerable dose in the trial. Because O-desmethylvenlafaxine, the primary metabolite of venlafaxine hydrochloride, has a much longer elimination half-life (11 hours) compared to the parent drug (5 hours), conduct the TQT study at steady state.
An open label pharmacokinetic and safety study of SPRIX in pediatric patients ages 12 to less than 17 years of age
An open label pharmacokinetic and safety study of SPRIX in pediatric patients ages 2 to less than 12 years of age
A pharmacokinetic, safety, and efficacy study of SPRIX in pediatric patients aged 1 month to less than 2 years of age.
Complete Clinical Trial C13008, an open-label trial to determine the long-term safety of Entyvio (vedolizumab) in patients with ulcerative colitis and Crohn’s disease.  Safety evaluations include but are not limited to the occurrence of serious infections including progressive multifocal leukoencephalopathy (PML) and malignancies.
Conduct a prospective, observational pregnancy exposure registry study in the United States that compares the pregnancy and fetal outcomes of women exposed to Entyvio (vedolizumab) during pregnancy to an unexposed control population or collect Entyvio (vedolizumab) pregnancy exposure data by collaborating with an existing disease-based pregnancy registry.
Conduct an open-label trial to assess the clinical significance of the drug-drug interaction between a single 1200 mg IV dose of Orbactiv (oritavancin diphosphate) and warfarin in healthy volunteers.
Conduct an open label trial evaluating the safety of a single 1200 mg IV dose of Orbactiv (oritavancin diphosphate) in patients on concomitant chronic warfarin therapy who are being treated for ABSSSI.
Conduct a single-center, open-label trial to evaluate the effects of a single 1200 mg IV dose of Orbactiv (oritavancin diphosphate) on the results of multiple coagulation tests in healthy volunteers.
Conduct a study to evaluate the effects of oritavancin on phospholipid and nonphospholipid based coagulation tests in vitro.
Conduct a clinical trial to evaluate the effect of renal impairment on eliglustat pharmacokinetics. A reduced design may be used.
Conduct a clinical trial to evaluate the effects of hepatic impairment on eliglustat pharmacokinetics.
Continue to follow patients en rolled in trial CC-5013-MCL-001 for at least 4 years from the date that the last patient enroll ed. Submit a report to the Agency describing the cumulative efficacy and safety data up to this 4 year time point.
Analyze the polyethylene oxide (PEO) product employed in Zohydro ER (hydrocodone bitartrate) for low molecular weight impurities. Identify and quantitate the impurities. Submit a toxicological risk assessment for the exposure to the impurities taking into consideration the maximum theoretical daily dose of Zohydro ER (hydrocodone bitartrate).
Conduct an embryo-fetal development study in the rat model to assess the potential impact of polyethylene oxide (PEO) on development. The study must be designed to adequately qualify the safety of the low molecular weight PEO components (impurities/degradants) in the PEO used to manufacture Zohydro ER (hydrocodone bitartrate) when the product is consumed up to the maximum theoretical daily dose of Zohydro ER (hydrocodone bitartrate).
Conduct an embryo-fetal development study in the rabbit model to assess the potential impact of polyethylene oxide (PEO) on development. The study must be designed to adequately qualify the safety of the low molecular weight PEO components (impurities/degradants) in the PEO used to manufacture Zohydro ER (hydrocodone bitartrate) when the product is consumed up to the maximum theoretical daily dose of Zohydro ER (hydrocodone bitartrate).
Conduct a pre- and post-natal development study in the rat model to assess the potential impact of polyethylene oxide (PEO) on development. The study must be designed to adequately qualify the safety of the low molecular weight PEO components (impurities/degradants) in the PEO used to manufacture Zohydro ER (hydrocodone bitartrate) when the product is consumed up to the maximum theoretical daily dose of Zohydro ER (hydrocodone bitartrate).
Conduct a pharmacokinetic, pharmacodynamics, tolerability and dose ranging study in subjects 6 years through 17 years, to assess safety and to determine the doses to be used in the efficacy study. Age-specific endpoints, i.e. a clinical outcome assessment utilizing Patient Reported Outcomes (PROs) or a PRO instrument to evaluate efficacy of rifaximin for the treatment of irritable bowel disease (IBS) in children, should be developed.
Conduct a randomized, controlled, double-blind study to determine the safety and efficacy of rifaximin in pediatric patients 6 years through 17 years with diarrhea-predominant irritable bowel syndrome (IBS-D).
Conduct in vitro studies to properly determine the IC50 values for the inhibition of OATP1B1, OATP1B3, and OATP1A2 by rifaximin. The in vitro study results will determine the need for subsequent clinical assessments of drug interactions by rifaximin.
Conduct a dose ranging study to determine the safety and effectiveness of eluxadoline in pediatric patients 6 through 17 years with diarrhea-predominant irritable bowel syndrome (IBS-D). The pharmacokinetics of eluxadoline in these pediatric patients should also be characterized.
Conduct a randomized, double-blind study to determine the safety and effectiveness of eluxadoline in pediatric patients 6 through 17 years with diarrheapredominant irritable bowel syndrome (IBS-D).
Conduct an open-label extension safety study of eluxadoline in pediatric patients 6 through 17 years with diarrhea-predominant irritable bowel syndrome (IBS-D) who participated in the dose ranging (# 2901-1) or efficacy (# 2901-2) studies.
A dedicated clinical pharmacology trial to evaluate the impact of renal impairment on eluxadoline pharmacokinetics and the risk for euphoria and other central nervous system (CNS) adverse effects.
A descriptive observational cohort study to evaluate performance of the THI-002 inserter in women receiving Liletta. The study cohort will include a minimum of 1,000 women who receive Liletta using the THI-002 inserter in a variety of clinical settings. The study should enroll representative proportions of nulliparous users and obese women to reflect the overall user population for the labeled indication. The enrolled subjects should be followed for a minimum of three months after insertion to monitor for expulsion, perforation, and infection because these adverse events are more common during this time period and may be related to the inserter or the insertion process. In addition, for women who have the IUS inserted post-partum, data should be collected on time since delivery or pregnancy termination, and on whether they are lactating. IUS removal data are not of primary importance and do not need to be obtained unless the IUS was removed specifically due to an insertion-related adverse event. Data collected in this study will include: „h characterizing ease of insertion, insertion difficulties, and failed insertions, including use of local anesthesia, rigid dilation, and ultrasound guidance adverse events (AEs) such as pain, vasovagal events, excessive bleeding and uterine perforation during insertion and before the subject leaves the healthcare facility after insertion „h subsequent AEs such as pain and bleeding in the 7-14 days after IUS placement „h expulsions, infections, and other more serious AEs that may be delayed but related to the insertion procedure or IUS
A Pregnancy Pharmacovigilance Study to evaluate pregnancy outcomes and infant outcomes following exposure to Odomzo (sonidegib). This study will include a mechanism to collect, classify, and analyze data on direct exposures (women exposed to Odomzo (sonidegib) as treatment) and indirect exposures (women exposed to Odomzo (sonidegib) through the seminal fluid of a male partner). The Pregnancy Pharmacovigilance Study will be initiated and functioning at the time of product launch. There will be interim annual reporting of the data collected from the study. The study, at a minimum, will include the following key elements (see the Guidance for Industry Establishing Pregnancy Exposure Registries for a detailed description of these elements): • Data collection of prospective and retrospective data points, adequate to produce informative, reliable data outcomes. • Data analysis utilizing descriptive statistics for summarizing data that will fully capture outcomes of concern. Data collected prospectively analyzed separate from data collected retrospectively. • Description of procedures including the patient recruitment, along with healthcare provider awareness of potential safety risk and existence of this study, and the monitoring of pregnancy and infant outcomes.
Complete the ongoing pharmacokinetic trial to determine an appropriate dose of Odomzo (sonidegib) in patients with moderate to severe hepatic impairment in accordance with the FDA Guidance for Industry entitled “Pharmacokinetics in Patients with Impaired Hepatic Function: Study Design, Data Analysis, and Impact on Dosing and Labeling.”
Submit the Final Report for the clinical pharmacokinetic (drug interaction) trial to determine how to dose a gastric acid-reducing agent with Odomzo (sonidegib).
Conduct an in vitro study evaluating interactions between dalbavancin hydrochloride and coagulation tests.
A PK/PD study to characterize aprepitant PK parameters following administration of a single dose of intravenous fosaprepitant, in combination with a 5HT3 antagonist and dexamethasone, in pediatric cancer patients ages 0 to 17 years undergoing treatment with highly emetogenic chemotherapy. You must conduct this study with an age appropriate formulation. Use modeling and simulation including the results of the above study to identify 1-Day and 3-Day intravenous fosaprepitant doses in pediatric patients 0 to 17 years of age that provide similar aprepitant PK exposures to pediatric aprepitant doses and exposures which have demonstrated acceptable safety and efficacy profiles in patients receiving single and multi-day chemotherapy regimens, respectively.
Conduct a pharmacoepidemiology study (Protocol IM101045A) to assess the short term (2 years) and potential long-term (4 years) risk of hospitalization due to infection (all hospitalized infections, hospitalized pneumonia, and all opportunistic infections) among patients with RA treated with Abatacept in comparison to other DMARDs within a large cohort of individuals with commercial health insurance.  This study will also characterize patients receiving Abatacept and monitor any off-label use.
To submit an efficacy supplement containing the final study report, including summary analyses and datasets and revised labeling based on the results of study AVF4396g/BO20990 entitled "A Randomized, Double Blind, Placebo Controlled, Multicenter, Phase III Trial of Bevacizumab, Temozolomide and Radiotherapy, Followed by Bevacizumab and Temozolomide Versus Placebo, Temozolomide Followed by Placebo and Temozolomide in Patients with Newly Diagnosed Glioblastoma," which was accepted under a Request for Special Protocol Assessment on December 29, 2008.
Conduct a 12-week, randomized, double-blind, double-dummy, parallel group, placebo-controlled, dose-ranging, efficacy, and safety study in children 5-11 years of age with asthma. The final study report will be submitted as a supplement with the results of the knemometry and HPA axis studies.
Conduct a 2-week randomized, double-blind, placebo-controlled, 2-way crossover, knemometry growth rate study in children 5-11 years of age with asthma.
Conduct a 52-week, randomized, double-blind, parallel group, active controlled, growth study in females 5-<8 years of age and males 5-<9 years of age with asthma.
Conduct a 6-week, randomized, double-blind, parallel group, placebo-controlled, HPA-axis study in children 5-11 years of age with asthma.
A PK-PD bridging simulation study must be conducted to determine the appropriate lacosamide monotherapy regimen for the treatment of partial-onset seizures in the pediatric population > or equal to 1 month to < 17 years of age, and to support efficacy by extrapolation based on PK and efficacy data of lacosamide for adjunctive therapy for partial-onset seizures in pediatrics and adults, and efficacy for monotherapy for partial-onset seizures in adults. If the exposure-response relationship in younger children, e.g., less than 4 years old, is different from the older children and adult populations, this will be considered, and changes will be made accordingly.
An open-label safety and tolerability study using lacosamide as monotherapy in pediatric patients > or equal to 1 month to < 17 years of age.
A safety study of replacement of oral dosing with intravenous dosing administered over 30 to 60 minutes in pediatric patients > or equal to 1 month to < 17 years of age with partial-onset seizures. If safety is acceptable, a replacement study at a faster rate of infusion (15 minutes) must be conducted in this population. Sparse PK samples must be collected to evaluate the pharmacokinetics of lacosamide and its metabolite using PPK approach in this population.
A study that will examine safety and tolerability of an oral loading dose that will allow a more rapid achievement of the final recommended therapeutic dose in pediatric patients ¡Ý 1 month to < 17 years of age.
A study that will examine safety and tolerability of an intravenous loading dose that will allow a more rapid achievement of steady-state exposures of the final recommended therapeutic dose in pediatric patients ¡Ý 1 month to < 17 years of age.
Prospective, randomized (1:1), open-label, parallel group, active controlled, multicenter study to assess safe and effective doses of Kabiven (amino acids, electrolytes, dextrose and lipid injectable emulsion) in pediatric patients aged 2 to 16 years.
To conduct an animal study that will measure the effect of PD-1 inhibition on the magnitude of the primary (first vaccination) and recall (second vaccination) antibody responses to antigen challenge (e.g., tetanus toxoid or KLH). This study will evaluate the effect of PD-1 inhibition on the primary immune response once steady state plasma levels have been achieved and will reassess the magnitude of the recall response after a suitable period in the presence or absence of continued dosing.
A safety assessment of deoxycholic acid treatment in subjects aged 65 years and older. This assessment is to be performed in the ongoing ATX-101-13-28 trial population of subjects aged 65 to 75 years. To the extent possible, all subjects should be continued through the planned end of the trial (even if a full course of treatment is not administered).
Conduct a randomized trial that will characterize the incidence, severity and response to treatment of nivolumab induced immune-mediated adverse reactions to include immune-mediated pneumonitis.
Submit the final report and efficacy datasets for the open-label randomized trial of nivolumab versus docetaxel in patients with previously treated advanced squamous non-small cell lung cancer.
Deferred pediatric assessment under PREA for Truvada (emtricitabine/tenofovir disoproxil fumarate) for the treatment of HIV-1 infection in pediatric subjects from ages 6 years to less than 12 years, weighing at least 17 kg.
A drug interaction trial to determine the effects of sorbitol-containing solutions on lamivudine exposure following administration of lamivudine oral solution. Evaluate bioavailability differences between lamivudine solution administered alone and in combination with other oral solutions containing sorbitol. If an interaction is found, provide an assessment of the potential clinical impact of the interaction and if warranted, provide a revised dosing recommendation for pediatric patients taking lamivudine oral solution.
A multi-center clinical trial to evaluate the dosing and safety of PA-21 for the treatment of hyperphosphatemia in children ages 1 month to 17 years with chronic kidney disease (CKD) stages 4-5 (defined by a glomerular filtration rate <30 mL/min/1.73 m2) or with CKD Stage 5D receiving adequate maintenance hemodialysis (HD) or peritoneal dialysis (PD).
To commit to testing samples from patients treated with Oncaspar for the presence of binding and neutralizing antibodies to Oncaspar using the validated assays discussed in items 1 and 2 in the following study, entitled, "A Multi-Center, Open Label, Phase 1 Study Evaluating the Safety and Tolerability of Intravenous Pegaspargase in Combination with Intravenous Gemcitabine HCl in Patients with Advanced and/or Metastatic Solid Tumors and Lymphoma".
Complete the trial and submit the final report and data to verify and describe the clinical benefit of blinatumomab, including efficacy and safety from Protocol 00103311, a Phase 3 randomized, open-label, active-controlled trial comparing blinatumomab to standard of care for treatment of patients with relapsed or refractory Ph-negative B-cell precursor acute lymphoblastic leukemia (ALL). Enrollment of approximately 400 patients is expected, and the primary endpoint is overall survival.
A randomized, controlled, parallel group superiority trial in pediatric patients ages 10 through 17 years to evaluate the safety and efficacy of Plegridy (peginterferon beta-1a) compared to an appropriate control for the treatment of relapsing forms of multiple sclerosis.
A prospective, observational, exposure cohort study conducted in the United States that compares the maternal, fetal, and infant outcomes of women with multiple sclerosis exposed to Plegridy (peginterferon beta-1a) during pregnancy to unexposed control populations (one with women with multiple sclerosis who have not been exposed to Plegridy in pregnancy and the other in women without multiple sclerosis). The registry will detect and record major and minor congenital malformations, spontaneous abortions, stillbirths, elective terminations, and any other adverse pregnancy outcomes. These outcomes will be assessed throughout pregnancy. Infant outcomes will be assessed through at least the first year of life.
Conduct a trial to evaluate pediatric pharmacokinetics (PK), safety and antiviral activity of once daily atazanavir and cobicistat (ATV/COBI) combined with a background regimen in HIV-1 infected pediatric subjects. Subjects receiving ATV/COBI should be from 3 months to less than 18 years of age. Initial evaluation of ATV/COBI exposure must be performed in an initial PK study or substudy to allow dose selection. Using doses selected based on the PK study/substudy, and agreed upon with the FDA, conduct a longer-term pediatric safety and antiviral activity assessment of ATV/COBI combined with a background regimen, assessing activity on the basis of continued HIV-1 RNA virology response and safety monitoring over as least 24 weeks of dosing.
A clinical trial in healthy subjects evaluating the effect of cobicistat coadministered with atazanavir at steady state on the pharmacokinetics of atorvastatin.
A clinical trial in healthy subjects evaluating the effect of cobicistat coadministered with atazanavir at steady state on the pharmacokinetics of rosuvastatin.
A clinical trial in healthy subjects evaluating the effect of cobicistat coadministered with atazanavir at steady state on the pharmacokinetics of the estrogen and progestin components of a combined oral contraceptive.
In patients with CKD on dialysis, conduct one or more trials to identify an optimal strategy of ESA dose and schedule. These trials should identify the optimal dosing strategy which will demonstrate the superiority of the ESA dosing strategy to minimize hemoglobin (Hb) variability, excursions, rate of change of Hb, and explore providing symptom benefit.
A juvenile animal study with the combination of bupropion and naltrexone to assess post-natal growth and development with additional assessment of behavior, learning and memory.
Conduct a clinical trial designed to determine whether a higher dose of ramucirumab, in combination with paclitaxel, provides superior progression-free survival as compared to the recommended ramucirumab dose in combination with paclitaxel, in patients with previously treated gastric or gastro-esophageal junction adenocarcinoma. The trial will have a safety run-in phase in order to determine if the higher dose is reasonably safe to administer to patients.
Conduct the analysis and submit the complete final report and data showing clinical efficacy and safety from Trial MMY3003, a “Phase 3, 2- arm, Randomized, Parallel-group Trial of Lenalidomide and Dexamethasone with or without Daratumumab in Patients with Previously-treated Multiple Myeloma.”
Conduct the analysis and submit the complete final report and data showing clinical efficacy and safety from Trial MMY3004, a “Phase 3, 2- arm, Randomized, Parallel-group Trial of Bortezomib and Dexamethasone with or without Daratumumab in Patients with Previously-treated Multiple Myeloma.”
Submit the final report of a study conducted to assess the anti-drug antibody (ADA) response to daratumumab with the validated assay developed under PMR 3000-4
Conduct a study to validate an assay for binding antibodies to daratumumab to assess the product’s potential for immunogenic reactions in treated patients. Submit a validation report for the validated, sensitive, and accurate assay for the detection of binding antibodies to daratumumab, including procedures for the accurate detection of binding antibodies to daratumumab in the presence of daratumumab levels expected in the serum or plasma at the time of patient sampling.
Conduct a study to validate an assay for neutralizing antibodies to daratumumab to assess the potential for increased adverse outcome from loss of product effect in treated patients. Submit a validation report for the validated, sensitive, and accurate assay for the detection of neutralizing antibodies to daratumumab, including procedures for the accurate detection of neutralizing antibodies to daratumumab in the presence of daratumumab levels that are expected in the serum or plasma at the time of patient sampling.
Collect, analyze, and submit additional safety data from ongoing clinical trials to characterize the safety of daratumumab in patients with baseline hepatic impairment.
Establish the optimal and safe dose of pralatrexate in combination with the cyclophosphamide/vincristine/doxorubicin/prednisone (CHOP) regimen. Perform a Phase 1 dose-finding trial of pralatrexate plus CHOP for the treatment of patients with peripheral T-cell lymphoma (PTCL). Enroll a sufficient number of patients to characterize the safety of pralatrexate in combination with the CHOP regimen. Submit a complete final report with all supporting datasets.
Characterize the comparative efficacy and safety of pralatrexate when used in combination with a treatment regimen such as CHOP versus the combination of Beleodaq plus CHOP, versus CHOP alone for the initial therapy of patients with PTCL. Perform a confirmatory, prospective randomized (1:1:1) trial of previously untreated patients with PTCL, with progression free survival (PFS) as the primary efficacy endpoint. Enroll a sufficient number of patients to characterize the efficacy and safety of each drug added to CHOP, versus CHOP alone. The PFS endpoint should be determined by a blinded independent review committee. PFS analysis should be performed when the trial has experienced the planned number of events necessary for trial completion. Using the same data cutoff date as the PFS analysis, perform an interim analysis of overall survival. Submit a complete final report with all supporting datasets.
Conduct an open-label, single-arm trial to evaluate the long-term safety of Kalydeco (ivacaftor) in pediatric patients with Cystic Fibrosis (CF) and R117H mutation in the CFTR. The trial will enroll pediatric patients < 18 years of age and who are registered in the US Cystic Fibrosis Foundation (CFF) Patient Registry. Patients will be followed for at least 3 years and long-term efficacy will also be assessed. The trial assessments will comprise the data collected as part of the CFF registry, and outcomes will include deaths, lung transplantation, lung function (FEV1), antibiotic use, CF exacerbations, and hospitalizations. The results of this trial will be presented in the context of observational data on the same outcomes for all patients (adults and pediatrics) in the CFF registry with the R117H mutation who are treated with Kalydeco (ivacaftor).
An open-label pharmacokinetic (PK), and multiple-dose safety and tolerability dose-titration trial of Afrezza in pediatric patients ages 4 to 17 years (inclusive) with type 1 diabetes (Part 1), followed by a prospective, multicenter, open-label, randomized, controlled trial comparing the efficacy and safety of prandial Afrezza to prandial subcutaneous insulin aspart used in combination with subcutaneous basal insulin in pediatric patients 4 to 17 years old (inclusive) with type 1 or type 2 diabetes (Part 2). Part 2 of the trial should include a 4-week run-in phase and a 52-week randomized intervention phase.
Conduct a dose-ranging PK-PD euglycemic glucose-clamp trial to characterize the dose-response of Afrezza relative to subcutaneous insulin in patients with type 1 diabetes. Select at least three to four doses for each route of insulin administration to ensure both the linear and curvilinear portions of the dose-response curves are adequately captured and characterized. Compare the dose-response curves for Afrezza and subcutaneous insulin noting the dose at which the response becomes curvilinear for each. These data may impact labeling recommendations for dosing and thereby mitigate the risk of diabetic ketoacidosis, which has been observed with Afrezza.
A PK-PD eugylcemic glucose-clamp trial to characterize within-subject variability for Afrezza pharmacokinetic (PK) and pharmacodynamic (PD) parameters. These data may impact labeling recommendations for glucose monitoring and thereby mitigate the risk of hypoglycemia, which has been observed with Afrezza.
Conduct a 5-year, randomized, controlled trial in 8,000-10,000 patients with type 2 diabetes to assess the serious potential risk of pulmonary malignancy with Afrezza use. The primary objective of the trial should be to compare the incidence of pulmonary malignancy observed with Afrezza to that observed in the standard of care control group. Secondary endpoints should include mortality due to pulmonary malignancy and all-cause mortality. Randomization to Afrezza or standard of care should be 1 to 1. The patient population should be enriched with respect to lung cancer risk (i.e., predicted incidence of no less than 200/100,000 patient-year). The potential for detection bias should be adequately addressed in the trial design. Subjects who discontinue randomized intervention due to lack of efficacy or tolerability issues should continue to be followed for the outcomes of interest and prospective measures to encourage subject retention and capture outcomes in patients who withdraw or are lost to follow-up should be in place. Glucose control and glycemic rescue should be per standard of care. The trial must also include an assessment of cardiovascular risk based on prospectively defined, collected and independently adjudicated major adverse cardiovascular events or MACE (i.e., cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke). Also include as part of the trial a substudy (also with 1 to 1 randomization to either Afrezza or standard or care) to evaluate the long-term effect of Afrezza on pulmonary function. Patients in the substudy should have pulmonary function tests at baseline and every 6 months until end of treatment.
Conduct a prospective study over a five-year period after the introduction of ZERBAXA (ceftolozane/tazobactam) to the market to determine if decreased susceptibility to ZERBAXA (ceftolozane/tazobactam) is occurring in the target population of bacteria that are in the approved ZERBAXA (ceftolozane/tazobactam) label.
Submit the progression-free survival (PFS) and overall survival (OS) analyses with datasets from clinical trial D0818C00002, SOLO-2, the ongoing randomized doubleblind, placebo-controlled, multi-center trial to assess the efficacy of olaparib maintenance monotherapy in relapsed high grade serous ovarian cancer (HGSOC) patients (including patients with primary peritoneal and/or fallopian tube cancer) or high grade endometrioid cancer with BRCA mutations (documented mutation in BRCA1 or BRCA2 that is predicted to be deleterious or suspected deleterious (known or predicted to be detrimental/lead to loss of function)) who have responded following platinum-based chemotherapy.
Submit the progression-free survival (PFS) and overall survival (OS) analyses with datasets from clinical trial D0816C00010, a randomized trial establishing the superiority of olaparib over physician’s choice single-agent chemotherapy in the treatment of platinum sensitive relapsed ovarian cancer in patients carrying deleterious or suspected deleterious germline BRCA1/2 mutations.
Randomized,-double-blind, adequately controlled, multiple fixed doses, parallel group clinical trials of Myobloc (botulinum toxin Type B) in the following populations: botulinum toxin-naive children age 2-17 years with lower extremity spasticity, botulinum toxin-naive children age 2-17 years with upper extremity spasticity, botulinum toxin-naive adults with lower extremity spasticity, and botulinum toxin-naive adults with upper extremity spasticity. The minimum duration of each trial should be 12 weeks. The protocols for the trials should be submitted to the FDA as special protocol assessments (SPA).
Identify the in vitro metabolic pathways of dichlorphenamide and characterize the potential for P450-mediated drug interactions due to inhibition or induction of these pathways in vitro. Refer to the draft Guidance for Industry: Drug Interaction Studies — Study Design, Data Analysis, Implications for Dosing, and Labeling Recommendations (http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm292362.pdf )regarding conduct of the studies.
Conduct a trial to characterize the pharmacokinetics of dichlorphenamide in healthy volunteers, to include a single ascending dose assessment and a multiple ascending dose assessment, using a dose range of 25 to 200 mg. Pharmacokinetic parameters should include AUC, Cmax, and elimination half-life.
Characterize safety of long-term use in patients treated with Kyprolis (carfilzomib) 20/56 mg/m2 plus dexamethasone. Submit a final report and datasets with safety and efficacy outcomes of current clinical trial 2011-003 (ENDEAVOR) with at least 3 years of follow-up data.
Characterize the comparative safety and efficacy of the 20/27 mg/m2 and the 20/56 mg/m2 regimens of carfilzomib. Submit a study report with safety and efficacy outcomes of SWOG Protocol S1304 and your analysis of what clinical parameters might affect the choice of carfilzomib regimen for a particular patient.
Post-marketing observational study to evaluate the risk for venous thromboembolic events (VTEs) with Lybrel (ethinyl estradiol 20 mcg/levonorgestrel 90 mcg). This study shall evaluate the risk for VTE with Lybrel use compared to an appropriate comparator. The study shall be adequately powered to exclude a two-fold risk, include adequate control for confounding factors, and use a validated VTE definition with adequate positive predictive value (PPV) and sensitivity.
Conduct a study to evaluate the safety of SITAVIG in pediatric patients greater than or equal to 10 years of age to less than or equal to 17 years of age with recurrent herpes labialis and to assess duration of HSV episode in the treated population. At least 20 subjects from ages 10-13 and 80 subjects ages 14-17 must be evaluated.
Submit safety data assessing distant spread of toxin effects after multiple administrations of Botox (onabotulinum toxin A), during a minimum period of 12 months, collected in at least 100 pediatric patients (ages 2-17 years) and 100 adult patients (approximately half upper and half lower limb extremity spasticity).  In addition, submit data assessing the effects of Botox (onabotulinum toxin type A) on blood glucose and alkaline phosphatase as a marker of bone metabolism.  These safety data could come from open-label extensions of the clinical studies, from separate longer-term open-label safety studies, or from a long-term controlled safety and efficacy study.  The doses evaluated must be at least as high as those shown effective in these studies, or those commonly used to treat spasticity.
A juvenile rat toxicology study under PREA to identify the unexpected serious risk of adverse effects of Botox on postnatal growth and development. The study should utilize animals of an age range and stage(s) of development that are comparable to the intended pediatric population; the duration of dosing should cover the intended length of treatment  in the pediatric population. In addition to the usual toxicological parameters, this study [...] must evaluate effects of Botox on growth, reproductive development, and neurological and neurobehavioral development.
Collect and analyze all cases of acute myelogenous leukemia/ myelodysplastic syndrome identified in patients treated with Lynparza (olaparib) on an annual basis. These interim reports should summarize all cases identified up until that reporting date (new cases and those reported in previous years), and should include patients treated with Lynparza on clinical trials and outside of clinical trials (including spontaneous safety reports) to provide an accurate assessment of the long-term incidence and risk of AML/MDS.
Submit the final report for trial D0816C00006 entitled, “An Open-label, Non-randomized, Multicenter, Comparative, and Phase 1 Study of the Pharmacokinetics, Safety and Tolerability of Olaparib Following a Single Oral 300 mg Dose to Patients with Advanced Solid Tumors and Normal Renal Function or Renal Impairment.”
Submit the final report for trial D0816C00005 entitled, “An Open-label, Non-randomized, Multicenter, Comparative, Phase 1 Study to Determine the Pharmacokinetics, Safety and Tolerability of Olaparib Following a Single Oral 300 mg Dose to Patients with Advanced Solid Tumors and Normal Hepatic Function or Mild or Moderate Hepatic Impairment.”
Evaluate the pharmacokinetics, safety, and antiviral activity (efficacy) of atazanavir and cobicistat fixed-dose combination (FDC) age-appropriate formulation in HIV-infected pediatric subjects 3 months to less than 3 years of age. The safety and antiviral activity (efficacy) of atazanavir and cobicistat FDC age-appropriate formulation in pediatric subjects should be evaluated for a minimum of 24 weeks. A clinical trial in children 3 months to less than 3 years of age may not be required if the dosing recommendation for the FDC ageappropriate formulation can be supported by pediatric trials already conducted with the individual drug products and if the age-appropriate FDC produces similar exposures as the individual components.
Conduct a prospective study over a five-year period to determine if decreased susceptibility to Cresemba (isavuconazonium sulfate) is occurring in the target population of organisms that are in the approved Cresemba (isavuconazonium sulfate) label.
Conduct a two-year mouse carcinogenicity study.
Conduct a two-year rat carcinogenicity study
Establish a registry to collect and analyze clinical efficacy-related outcome data on patients treated with isavuconazonium sulfate who have invasive mucormycosis or infection with non-fumigatus aspergillus species.
Conduct a clinical trial to evaluate the incidence of serious and severe (i.e. ¡Ý Grade 3) adverse reactions of an oral starting dose of 20 mg or of 14 mg daily compared to the 24 mg starting dose, with a comparable objective response rate. Safety assessments will include evaluations for all severe or life-threatening (¡Ý Grade 3) and serious adverse reactions and should also include assessments of all adverse reactions.
Conduct a study to compare exposure and safety data from approximately 220 patients who complete treatment with dinutuximab, pooling across dinutuximab lots and by individual lot, with the historical experience observed in approximately 1100 patients treated with ch14.18 (manufactured by SAIC for the National Cancer Institute). Based on these data, provide thoughtful analyses of the risk serious infusion reactions and neuropathy, and the overall safety and tolerability of the marketed product, Unituxin. In addition, assess whether variations in antibody-dependent cell-mediated toxicity across dinutuximab lots alter the safety and tolerability of dinutuximab.
Conduct a single-dose pharmacokinetic study in which the primary objective is to identify the dose(s) of codeine phosphate and chlorpheniramine maleate ER tablet that results in exposures of codeine and chlorpheniramine in children and adolescents 6 to 17 years of age that are similar to the exposures seen in adults at the recommended dose. The population eligible for enrollment should be otherwise healthy children and adolescents with cough/cold symptoms for whom a combination product that includes an opioid antitussive would be an appropriate symptomatic treatment.
Conduct an open-label, multi-dose safety and tolerability study in children and adolescents 12 to 17 years of age. The population eligible for the study would be children and adolescents with cough/cold symptoms for whom a combination product that includes an opioid antitussive would be an appropriate symptomatic treatment. The study will enroll a total of approximately 400 children aged 6 to 17 inclusive in two cohorts (6-11years, 12 to 17 years). The dose used in this study will be based upon the results of the pharmacokinetic study in children and adolescents ages 6 to 17 years.
A prospective, randomized, controlled, double-blinded, efficacy and safety study of brivaracetam for the adjunctive treatment of partial onset seizures in children from 1 month to less than 4 years of age. The primary efficacy endpoint during the controlled phase will examine seizure frequency based upon video/electroencephalographic data. The placebo and drug treatment groups will be compared by inferential statistical methods to identify a treatment effect. Routine safety endpoints should be monitored. Behavioral and cognitive endpoints should be included. Subjects should be balanced among age cohorts.
Long-term safety study of brivaracetam in the adjunctive treatment of partial onset seizures in children from 1 month to less than 16 years of age. Routine safety measures should be monitored. Behavioral and cognitive endpoints should be included. A total of at least 200 patients must be enrolled. Subjects should be balanced among age cohorts.
Submit the final overall survival analysis with datasets from Trial A5481023, PALOMA-3 “A double-blind, phase III trial of fulvestrant with or without palbociclib in pre- and post-menopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer that progressed on prior endocrine therapy.”
Determine the change in overall past 30-day abuse and abuse via specific routes of administration (ROA), including swallowing intact, chewing and swallowing, dissolving and swallowing, snorting, smoking, and injecting, among individuals being assessed for substance abuse using the NAVIPPRO System Addiction Severity Indicator – Multimedia Version (ASI-MV Connect) tool. Change in past 30-day abuse prevalence, both overall and via specific ROA, should be assessed for OxyContin, as well as previously agreed-upon comparator drugs (refer to May 2013 Advice Letter), through both means and trend analyses, comparing the prereformulation to post-reformulation period. A final analysis will be provided on data collected through 12/2015. This study should incorporate the following: • Sensitivity analyses that restrict the study population to a subset of assessment sites that have contributed data consistently throughout the study period (e.g. at least five assessments during each study year); • Assessment and appropriate adjustment (via stratification or other methods) for any observed shifts in the study population across the study period, including shifts in the distribution of geographic regions and treatment modality; • Adjustment for quarterly utilization of each product or product group (in addition to unadjusted analyses), defined as the number of dosage units dispensed within the study catchment area. Additional analyses should be considered to explore the effect of such factors as lag time or non-linear relationship between utilization and abuse rates; • Analysis of ROA for OxyContin and agreed upon comparators, comparing the pre- and post-reformulation periods, among individuals reporting past 30-day abuse of that drug; • Post-reformulation OxyContin abuse rate analyses using 1) Any OxyContin and 2) Reformulated OxyContin only. • Sensitivity analyses that extend the duration of the pre-reformulation period to a minimum of 2.5 years.
Determine the change in the rate of poison center exposure calls, using the Researched Abuse Diversion and Addiction-Related Surveillance (RADARS®) System Poison Center Program. Exposure calls should be grouped as follows: (1) Intentional abuse and misuse, (2) Intentional—all, (3) Suicide, (4) Unintentional—all, and (5)Adverse reaction. Changes in rates, both overall and via specific routes of administration (ROA), should be assessed for OxyContin, as well as previously agreed-upon comparator drugs, through both means and trend analyses, comparing the pre-reformulation to post-reformulation period. A final analysis will be provided on data collected through 12/2015. This study should incorporate the following: • Route-specific means and trend analyses for intentional abuse calls; • The addition of heroin as a comparator, including in route-specific analyses; • Population-adjusted means and trend analyses; • Analyses that account for trends in calls to U.S. poison control centers (e.g. product-related calls as a proportion of exposure calls); • Means and trend analyses that adjust for quarterly utilization of each product or product group, defined as the number of dosage units dispensed within the study catchment area. Additional analyses should be considered to explore the effect of such factors as lag time or non-linear relationship between utilization and abuse rates; • Sensitivity analyses that extend the duration of the pre-reformulation period to a minimum of 2.5 years.
Conduct a comparative single-dose pharmacokinetic and safety trial of azilsartan between infants, children, and adolescents with hypertension and healthy adults. Using data from the PK and safety trial, conduct an efficacy and safety, dose-finding trial in children 6 years to less than 18 years with hypertension.
Conduct an in vivo comet assay in liver to evaluate the potential genetic toxicology of hydrocodone.
Conduct a 2-year bioassay in the rat model to evaluate the carcinogenic potential of hydrocodone.
Conduct a 2-year bioassay in the mouse model to evaluate the carcinogenic potential of hydrocodone.
Deferred study under PREA to evaluate the pharmacokinetics of dexlansoprazole, maintenance of healing, and symptoms of endoscopy-proven erosive esophagitis (EE) in patients 1 year to 11 years of age.
Deferred study under PREA to evaluate the pharmacokinetics of dexlansoprazole, maintenance of healing, and symptoms of endoscopy-proven erosive esophagitis (EE) in patients 12 years to 17 years of age.
Deferred pediatric study under PREA for treating heartburn associated with nonerosive gastroesophageal reflux disease (GERD) in pediatric patients aged 1 year to 11 years.
Deferred pediatric study under PREA for treating heartburn associated with nonerosive gastroesophageal reflux disease (GERD) in pediatric patients aged 12 year to 17 years.
Deferred study under PREA to evaluate the long-term safety of dexlansoprazole for the maintenance of healing of erosive esophagitis (EE) in pediatric patients 1 month through 11 months of age, who require chronic treatment with dexlansoprazole due to underlying conditions that predispose to chronic gastroesophageal reflux disease (GERD) and relapsing EE.
Deferred study under PREA to evaluate the long-term safety of dexlansoprazole for the maintenance of healing of erosive esophagitis (EE) in pediatric patients 1 year through 17 years of age, who require chronic treatment with dexlansoprazole due to underlying conditions that predispose to chronic gastroesophageal reflux disease (GERD) and relapsing EE.
Conduct a trial in moderately to severely active ulcerative colitis patients to evaluate the safety of induction regimens of adalimumab at doses higher than 160/80 mg. In this trial, the efficacy of Humira (adalimumab) should also be assessed, both during induction treatment as well as during continued treatment after induction, and pharmacokinetic measurements should be conducted for exposure-response analysis. In this trial, collecting samples for immunogenicity testing (utilizing a validated anti-adalimumab antibody assay as described in PMR #3 above) and conducting analyses of the impact of immunogenicity on safety, pharmacokinetics, and efficacy is important. The protocol should be agreed upon by the agency prior to the initiation of the trial.
Deferred pediatric study under PREA: Conduct a pharmacokinetic and safety study of an age-appropriate formulation of Hysingla ER in patients from ages 12 to less than 17 years with pain severe enough to require daily, around-theclock, long-term opioid treatment and for which alternative treatment options are inadequate
Conduct an adequate extractable/leachable safety assessment for the [...] gray [...] rubber stopper used in your container closure system. This assessment must include controlled extraction studies to qualitatively and quantitatively determine the chemical species that may migrate into the dosage form, using appropriate solvents that adequately represent the chemical characteristics of the drug product formulation. Additionally, leachable data from long-term stability studies (taking into consideration the proposed shelf-life) should be used to determine if the identified/specified extractables also leach into the drug product over time. Using this information, conduct a toxicological risk assessment justifying the safety of the extractables and leachables, taking into consideration the maximum daily dose of the identified materials for this drug product. For your toxicological risk assessment, any leachable that contains a structural alert for mutagenicity should not exceed [..] mcg/day total daily exposure, or it must be adequately qualified for safety. A toxicological risk assessment should be provided for any non-genotoxic leachable that exceeds 5 mcg/day.
Conduct a field study to evaluate the efficacy and safety of moxifloxacin hydrochloride in the event of an attack with the intentional release of Y. pestis in the United States.
Submit data to assess the pharmacokinetics and safety of Avelox (moxifloxacin hydrochloride) Tablets and IV in pediatric patients 3 months to less than 18 years of age.
Determine the change in the prevalence of self-reported past 30-day abuse of OxyContin and agreed-upon comparators using the The Researched Abuse Diversion and Addiction-Related Surveillance (RADARS®) System Treatment Center Program (Opioid Treatment Program and Survey of Key Informants’ Program). Changes in prevalence should be assessed for OxyContin, as well as previously agreed-upon comparator drugs, through both means and trend analyses, comparing the pre-reformulation to post-reformulation period. A final analysis will be provided on data collected through 12/2015. This study should incorporate the following: • Sensitivity analyses that restrict the study population to a subset of sites that have contributed data consistently throughout the study period (e.g. at least 5 assessments during each study year or some other criterion for consistent participation in the surveillance program); • Adjustment for quarterly utilization of each product or product group, defined as the number of dosage units dispensed within the study catchment area. Additional analyses should be considered to explore the effect of such factors as lag time or non-linear relationship between utilization and abuse rates; • Population-adjusted analyses should also be included; • Sensitivity analyses that extend the duration of the pre-reformulation period to a minimum of 2.5 years.
Determine the change in the incidence of non-fatal and fatal overdose associated with OxyContin exposure relative to the change associated with exposure to appropriate comparators using electronic healthcare data with linkage to an appropriate death registry such as the National Death Index. This study should adhere to the principles as laid out in FDA’s “Guidance for Industry and FDA Staff: Best Practices for Conducting and Reporting Pharmacoepidemiologic Safety Studies Using Electronic Healthcare Data,” including but not limited to guidelines regarding validation of outcomes, exposure definition and ascertainment, and measurement of and control for potential confounders.
Conduct an analysis of safety in a randomized, open-label multi-center clinical trial comparing defibrotide versus best supportive care in the prevention of hepatic veno-occlusive disease in adult and pediatric patients, including all adverse events, laboratory abnormalities and frequent peri-infusion vital signs.
Design and conduct a study and provide the full final report and data sets to evaluate the safety and efficacy of ProvayBlue (methylene blue) for the treatment of methemoglobinemia. The minimal efficacy endpoints should include achieving a 50% reduction in methemoglobin within one hour of the first dose of ProvayBlue (methylene blue) in addition to normalization of the respiratory rate, heart rate and blood pressure within two hours of the first dose of ProvayBlue (methylene blue).
Conduct a clinical trial (or trials) to determine the extent of in vivo drug-drug interaction of ProvayBlue (methylene blue) as a modulator of CYP450 enzyme activity using CYP450 enzyme substrates.
Conduct a clinical trial to determine the effect of hepatic impairment on the pharmacokinetics and safety of ProvayBlue (methylene blue).
Conduct a clinical trial to evaluate the effect of varying degrees of renal impairment on the pharmacokinetics and safety of ProvayBlue (methylene blue) in subjects with renal impairment.
Combine all available pharmacokinetics (PK) data from different patient populations and healthy subjects in an integrated population PK model to evaluate the potential impact of tumor types on the PK of cabozantinib.
Complete the trial and submit the final report for the pediatric pharmacokinetic trial entitled “Pharmacokinetics of SFP iron delivered via dialysate in pediatric patients with chronic kidney disease on hemodialysis.”
Conduct a randomized withdrawal trial comparing pimavanserin 34 mg/day to placebo.
Conduct a randomized placebo-controlled trial or trials with predominantly frail and elderly subjects that would involve exposure of at least 500 subjects to pimavanserin 34 mg daily for a minimum of 8 weeks.
A study in the greater than or equal to 12- to less than 17-year old age group to evaluate the pharmacokinetics, efficacy, and safety of different doses of phenylephrine hydrochloride injection in patients undergoing general anesthesia and/or neuroaxial anesthesia.
Conduct a fertility and early embryonic development toxicology study in the rat model for phenylephrine hydrochloride.
Conduct an embryo-fetal developmental toxicology study using the rat model for phenylephrine hydrochloride.
Conduct an embryo-fetal developmental toxicology study using the rabbit model for phenylephrine hydrochloride.
Conduct a peri- and post-natal developmental toxicology study in the rat model for phenylephrine hydrochloride.
Submit the progression free survival (PFS) and overall survival (OS) data and results from the ongoing Trial A5481008, PALOMA-2, “A Randomized, Multicenter, Double-blind Phase 3 Study of PD-0332991 (Oral CDK 4/6 Inhibitor) Plus Letrozole Versus Placebo Plus Letrozole for the Treatment of Postmenopausal Women with ER (+), HER2 (-) Breast Cancer Who Have Not Received Any Prior Systemic Anti-Cancer Treatment For Advanced Disease” when supplemental application for regular approval is submitted. In addition, submit OS data and results at trial completion.
Submit the final report for your clinical trial A5481013 entitled, “A phase 1, open-label, single dose, parallel-group study to evaluate the pharmacokinetics of palbociclib (PD-0332991) in subjects with impaired hepatic function,” to assessthe effect of moderate and severe hepatic impairment on the pharmacokinetics of palbociclib.
Submit the final report for your ongoing drug interaction trial (A5481039) entitled, “A phase 1, open-label, fixed-sequence, 2-cohort, 2-period study to investigate the effect of modafinil and pioglitazone given as multiple doses on single dose pharmacokinetics of palbociclib (PD-0332991) in healthy volunteers”, to assess the effect of modafinil (a moderate CYP3A inducer) on the pharmacokinetics of palbociclib in healthy volunteers.
Conduct analysis from the ongoing Trial A5481008, PALOMA-2, “A Randomized, Multicenter, Double-blind Phase 3 Study of PD-0332991 (Oral CDK 4/6 Inhibitor) Plus Letrozole Versus Placebo Plus Letrozole for the Treatment of Postmenopausal Women with ER (+), HER2 (-) Breast Cancer Who Have Not Received Any Prior Systemic Anti-Cancer Treatment For Advanced Disease” to determine the prognostic or predictive significance of genetic alterations in the Cyclin D1/CDK4/6/p16/retinoblastoma pathway in ER (+), HER2 (-) breast cancer, specifically the prognostic/predictive significance of the genetic alteration to the safety and efficacy of palbociclib.
Conduct a randomized Phase 2 clinical trial of panobinostat in combination with subcutaneous bortezomib and dexamethasone to characterize the safety and efficacy of at least two different doses of panobinostat. Eligible patients will include patients with relapsed multiple myeloma who have been previously exposed to immunomodulatory agents. The primary objective is to assess the overall response rate (ORR) in all treatment arms according to International Myeloma Working Group (IMWG) criteria by investigator assessment. The trial should include one interim analysis. The results of this trial will be used to inform the dose selection for the confirmatory Phase 3 trial. Submit a final report with full datasets.
Conduct a multicenter, randomized, placebo-controlled Phase 3 trial comparing panobinostat in combination with subcutaneous bortezomib and dexamethasone with subcutaneous bortezomib and dexamethasonein patients with relapsed multiple myeloma who have been previously exposed to immunomodulatory agents. The panobinostat dose selection will be based upon the interim analysis of the trial described in PMR 2181-1. Eligible patients will have previously treated multiple myeloma, 1-3 prior lines of therapy, prior immunomodulatory agent exposure (either thalidomide, lenalidomide, or pomalidomide), and measurable disease. The primary objective is to compare the progression free survival (PFS) in both treatment arms by investigator assessment.
Conduct a single-dose pharmacokinetic study whose primary objective is to identify the dose(s) of Hycofenix oral solution that results in exposures of hydrocodone bitartrate, pseudoephedrine hydrochloride, and guaifenesin in children (6 to 11 years) and adolescents (12 to 17 years) that are similar to the exposures seen in adults at the recommended dose. The population eligible for enrollment should be otherwise healthy children and adolescents with cough/cold symptoms for whom a combination product that includes an opioid antitussive would be an appropriate symptomatic treatment.
Conduct an open-label, multi-dose safety and tolerability study in children (aged 6 to 11) and adolescents (aged 12 to 17 years). The population eligible for the study would be children and adolescents with cough/cold symptoms for whom a combination product that includes an opioid antitussive would be an appropriate symptomatic treatment. The study will enroll a total of approximately 400 children aged 6 to 17 inclusive in two cohorts (6-11years, 12 to 17 years). The dose used in this study will be based upon the results of the pharmacokinetic study in children ages 6 to 17 years.
Conduct a juvenile rat toxicology study to identify the unexpected serious risk of adverse effects of sumatriptan/naproxen on postnatal growth and development. The study should utilize animals of an age range and stage(s) of development that are comparable to the intended pediatric population; the duration of dosing should cover the intended length of treatment in the pediatric population. In addition to the usual toxicological parameters, this study must evaluate effects of sumatriptan/naproxen on growth, reproductive development, and neurological and neurobehavioral development.
Conduct a pharmacokinetics (PK) study in children ages 6 years to 11 years with migraine. Using information from this PK study, conduct a controlled efficacy study in children ages 6 years to 11 years with migraine. Conduct a long-term open-label safety study in pediatric patients with migraine ages 6 years to 11 years. The longterm safety study must provide a descriptive analysis of safety data in at least 50 pediatric patients treated with Treximet for a duration of at least 6 months, treating on average at least one migraine attack per month, at doses evaluated in the efficacy study.
A controlled trial to evaluate the longer-term (i.e., maintenance) efficacy of aripiprazole in the treatment of pediatric patients (6-17 years) Tourette’s Disorder. This trial must include a placebo group and more than one fixed dose and must utilize a randomized withdrawal design, following an adequate period of stabilization with open-label treatment of aripiprazole. Because it is important to establish the dose-response for maintenance, this trial should randomize patients on stable doses of aripiprazole and different doses of aripiprazole (and to placebo) during the maintenance phase.
A controlled trial to evaluate the longer-term (i.e., maintenance) efficacy of lisdexamfetamine in the treatment of adults with binge eating disorder. This trial must be placebo-controlled, utilize a randomized withdrawal design, and include an adequate period of stabilization with open-label treatment of lisdexamfetamine prior to double-blind randomization.
A single pediatric study in at least 60 patients (30 per arm) undergoing cataract surgery
Conduct a 2-AB UHPLC assay on lots of Herceptin®(trastuzumab) derived from the drug substance manufactured at the Roche Penzberg facility without a media depth filter and used to supply the HERA, BCIRG006, and/or ToGA trials, and that are representative of the clinical trial material used in the HERA, BCIRG006, and/or ToGA trials. Submit data from and a final report for the assay. A recent change in the media depth filters used in Herceptin manufacturing is associated with lower levels of afucosylated variants (%aFuc). These variants serve as a surrogate measure of antibodydependent cell mediated cytotoxicity, which has been considered a component of the mechanism of action of trastuzumab.
A dose-ranging study assessing the pharmacokinetics, safety, tolerability, and effectiveness of Varubi (rolapitant) in pediatric patients ages 0-17 years old
A study to evaluate the efficacy and safety of a single oral dose of Varubi (rolapitant) in pediatric patients ages 0-17 years old
In vivo drug interaction study with a sensitive substrate of CYP2D6 to study the duration of CYP2D6 inhibition beyond 7 days after a single dose administration of Varubi (rolapitant)
Conduct an in vivo drug-drug interaction study to measure the effect of strong CYP3A4 inducers (e.g. rifampin) on the exposure to pimavanserin. Depending on the results of the study, a maximum dose could be recommended when CYP3A4 inducers are co-administered with pimavanserin.
Conduct a study of Entereg (alvimopan) for the acceleration of gastrointestinal recovery in pediatric patients aged 0 months to 10 years undergoing partial bowel resection surgery with primary anastomosis. The study will measure population pharmacokinetic parameters, safety, and time to first bowel movement and tolerated feed while in the hospital.
Conduct a phase 4 observational study evaluating the efficacy and safety of Neulasta®(pegfilgrastim) in the setting of Hematopoietic Syndrome (HS) following acute radiation exposure.
Conduct a study of Entereg (alvimopan) for the acceleration of gastrointestinal recovery in pediatric patients aged 10 to 18 years undergoing partial bowel resection surgery with primary anastomosis. The study will measure the time to first tolerated feed and time to first bowel movement while in the hospital, population pharmacokinetic parameters, length of hospital stay, the need for postoperative nasogastric tube insertion for symptoms of postoperative ileus, and safety.
Conduct a randomized phase 3 clinical trial in classical Hodgkin lymphoma that verifies and isolates the clinical benefit of nivolumab for patients with classical Hodgkin lymphoma. The primary endpoint would be progression-free survival as determined by an independent review committee. Overall survival would be a key secondary endpoint.
Characterize complications after allogeneic hematopoietic stem cell transplantation (HSCT) following nivolumab in at least 90 patients with classical Hodgkin lymphoma, of which at least 50% had received nivolumab alone or in combination as the regimen immediately prior to the allogeneic HSCT conditioning regimen. Evaluate toxicities at least through transplant Day 180, and include details of prior nivolumab treatment and the transplant regimen. Characterize toxicities including hyperacute graft-versus-host disease (GVHD), severe (grade III-IV) acute GVHD, febrile syndromes treated with steroids, immune mediated adverse events, pulmonary complications, hepatic veno-occlusive disease, critical illness, and transplant-related mortality. Toxicities may be characterized prospectively, or through a combination of prospective and retrospective data analysis.
Conduct “GO29294: A Phase 3, Open-label, Multicenter, Randomized Study to Investigate the Efficacy and Safety of Atezolizumab Compared with Chemotherapy in Patients with Locally Advanced or Metastatic Urothelial Bladder Cancer After Failure with Platinum-containing Chemotherapy” and provide the datasets with the final report
Develop and validate an assay with improved sensitivity for the detection of neutralizing antibodies against atezolizumab in the presence of atezolizumab levels that are expected to be present in samples at the time of patient sampling. Patient samples should be banked for storage until the improved method is available.
Conduct a clinical trial to evaluate the effect of atezolizumab on thyroid function tests and clinical thyroid disease. Submit the datasets with the completed report.
Submit the median duration of response for patients who responded to atezolizumab on GO29293. This includes all patients and patients whose tumorinfiltrating cells stain IC 2/3 or IC 0/1. Submit the datasets with the completed report.
Conduct an animal study that will measure the effect of PD-L1 inhibition on the magnitude of the primary (1st vaccination) and recall (2nd vaccination) antibody responses to antigen challenge (e.g., KLH). This study will evaluate the effect of PD-L1 inhibition on the primary immune response once steady state plasma levels have been achieved and will reassess the magnitude of the recall response after a suitable period in the presence or absence of continued dosing. The study should include, if possible, an evaluation of cytokine production by T cells at appropriate time-points.
Conduct a study to analyze laboratory data including serum complement, IgE, tryptase, histamine, and human anti-chimeric antibody levels obtained in patients with documented Grade 4 allergic reactions or anaphylaxis from a sufficient number of patients with neuroblastoma to allow for improved characterization of these adverse reactions to better inform product labeling. For each case identified, provide a narrative description that includes a summary of the allergic reaction or anaphylaxis adverse reaction, re-challenge information, and an assessment of whether the clinical presentation and laboratory data obtained were consistent with an allergic reaction or an infusion reaction. In addition, submit datasets used for safety analyses of the laboratory data.
Develop and validate an assay with improved sensitivity for the detection of neutralizing antibodies against dinutuximab in the presence of dinutuximab levels that are expected to be present in samples at the time of patient sampling.
To conduct a study to assess the neutralizing anti-drug antibody responses to dinutuximab with a validated assay capable of sensitively detecting neutralizing antibody responses in the presence of dinutuximab levels that are expected to be present in the blood at the time of patient sampling. The clinical impact of the neutralizing antibody response should be evaluated in at least 300 patients to include an interim report analyzing data from Studies DIV-NB-302, DIV-NB-303 and DIV-NB-201 and a final report analyzing data from Study NANT2011-04.
To conduct a 5-month repeat-dose juvenile animal toxicology study in cynomolgus monkeys that will measure the chronic toxicity of dinutuximab, particularly its effects on the central and peripheral nervous system. Administration of dinutuximab should be reflective of the clinical administration schedule. Incorporate an evaluation of the effect of treatment on the proximal and distal nerves, and evaluation of the C1 level of the spinal cord in this study and include 7-8 slices for histopathological assessment of the brain. Evaluate the potential for long-term effects on nociception and pain threshold at the end of an appropriate recovery period.
Conduct a randomized, double blind, double-dummy, active- and placebo controlled, 4-period crossover dose-ranging study with vilanterol inhalation powder in children 5 to 11 years of age with asthma. Each treatment period will be of one-week duration with at least one-week washout period between treatment periods.
Conduct a 12 week randomized, double-blind, active controlled, safety and efficacy study with fluticasone furoate/vilanterol inhalation powder in children 5 to 11 years of age with asthma.
Conduct a 52 week randomized, double blind, active comparator, safety study with fluticasone furoate/vilanterol inhalation powder in children 5 to 11 years of age with asthma.
In vitro studies to evaluate the inhibitory potential of Varubi (rolapitant) on renal transporters, i.e., organic cation transporter 2 (OCT2), multidrug and toxin extrusion (MATE) transporters, organic anion transporter 1 (OAT1), and organic anion transporter 3 (OAT3)
In vitro study to evaluate the inhibitory potential of Varubi (rolapitant) on OATP1B1 and OATP1B3. The in vitro study results will determine the need for a subsequent clinical assessment of a drug interaction between Varubi (rolapitant) and other concomitant medications
Utilize the validated anti-adalimumab antibody (AAA) assay developed under PMR 2517-3 (as described in the FDA Fulfillment of Postmarketing Requirement Letter dated April 1, 2015) to analyze the immunogenicity profile of adalimumab using banked patient samples from Phase 3 trials M11-810 and M11-313. Evaluate the impact of immunogenicity on pharmacokinetics, efficacy, and safety in subjects with hidradenitis suppurativa based on the AAA data generated with the newly validated assay.
Conduct an Enhanced Pharmacovigilance Study to evaluate the risk factors for and outcomes of severe visual loss following exposure to XALKORI (crizotinib). This study will include a mechanism to collect, classify, and analyze data on Grade 4 severe visual loss in patients exposed to crizotinib The study, at a minimum, will include the following key elements: Data collection of retrospective data points (best corrected visual acuity, retinal photographs, visual fields, optical coherence tomography (OCT), and other evaluations as appropriate for new onset of severe visual loss) to produce informative, reliable outcome measures. Data analysis utilizing descriptive statistics for summarizing data that will fully capture the outcome of concern.
A single-dose, open-label, randomized pharmacokinetic study of Dyanavel XR (amphetamine extended release) oral suspension in male and female children (4 to less than 6 years of age) with ADHD in fed condition.
A randomized, double-blind, placebo-controlled, flexible-dose titration study of Dyanavel XR (amphetamine extended-release) oral suspension in children ages 4 to 5 years diagnosed with ADHD.
A one year Pediatric Open-Label Safety Study of patients age 4 to 5 years (at the time of entry into PMR 2970-1 or PMR 2970-2, or at the time of enrollment if directly enrolled into PMR 2970-3) diagnosed with ADHD treated with Dyanavel XR (amphetamine extended release) oral suspension.
Conduct a safety, pharmacokinetics, and hypothalamic-pituitary-adrenal (HPA) axis suppression study of Ultravate (halobetasol propionate) lotion, 0.05% under maximal use conditions in adolescents 12 years to 16 years 11 months of age with plaque psoriasis receiving two weeks of treatment.
Conduct a multicenter, evaluator-blinded, randomized comparator study designed to evaluate the safety, efficacy and pharmacokinetics of IV daptomycin administered for up to 14 days in the treatment of pediatric patients ages 1 to 17 years with S. aureus bacteremia versus standard of care.
Conduct a trial to evaluate pediatric pharmacokinetics, safety and antiviral activity of dolutegravir in HIV-1 infected integrase strand transfer inhibitor-naïve, pediatric subjects weighing less than 15kg and at least 4 weeks in age. Initial evaluation of dolutegravir exposure must be performed in an initial pharmacokinetic study or substudy to allow dose selection. Using doses selected based on the pharmacokinetic study/substudy, and agreed upon with the FDA, conduct a longer-term pediatric safety and antiviral activity assessment of dolutegravir plus background regimen assessing activity on the basis of continued HIV-1 RNA virology response and safety monitoring over at least 24 weeks of dosing.
Conduct a trial to evaluate pediatric pharmacokinetics, safety and antiviral activity of dolutegravir in HIV-1 infected integrase strand transfer inhibitor-naïve, pediatric subjects weighing 15kg to less than 30kg. Initial evaluation of dolutegravir exposure must be performed in an initial pharmacokinetic study or substudy to allow dose selection. Using doses selected based on the study/substudy, and agreed upon with the FDA, conduct a longer-term pediatric safety and antiviral activity assessment of dolutegravir plus background regimen assessing activity on the basis of continued HIV-1 RNA virology response and safety monitoring over at least 24 weeks of dosing.
Conduct a trial to evaluate pediatric pharmacokinetics, safety and antiviral activity of dolutegravir in HIV-1 infected integrase strand transfer inhibitor-naïve, pediatric subjects less than 12 years of age weighing 30 kg to less than 40kg. Initial evaluation of dolutegravir exposure must be performed in an initial pharmacokinetic study or substudy to allow dose selection. Using doses selected based on the pharmacokinetic study/sub-study, and agreed upon with the FDA, conduct a longer-term pediatric safety and antiviral activity assessment of dolutegravir plus background regimen assessing activity on the basis of continued HIV-1 RNA virology response and safety monitoring over at least 24 weeks of dosing.
Conduct a trial to evaluate pediatric pharmacokinetics safety and antiviral activity of dolutegravir in HIV-1 infected pediatric subjects weighing 20 to less than 40kg, who are integrase strand transfer inhibitor (INSTI) experienced with certain INSTI associated resistance substitutions or clinically suspected INSTI resistance. Initial evaluation of dolutegravir exposure must be performed in an initial pharmacokinetic study or substudy to allow dose selection. Using doses selected based on the pharmacokinetic study/substudy, and agreed upon with the FDA, conduct a longer-term pediatric safety and antiviral activity assessment of dolutegravir plus background regimen assessing activity on the basis of continued HIV-1 RNA virology response and safety monitoring over at least 24 weeks of dosing. A minimum of 15 subjects should be enrolled into the study with an equitable distribution of subjects between the 20-30kg and 30-40kg weight-bands.
Conduct a trial to evaluate pediatric pharmacokinetics, safety and antiviral activity of dolutegravir in HIV-1 infected pediatric subjects 12 years to less than 18 years of age and weighing at least 40kg, who are integrase strand transfer inhibitor (INSTI) experienced with certain INSTI associated resistance substitutions or clinically suspected INSTI resistance. Initial evaluation of dolutegravir exposure must be performed in an initial pharmacokinetic study or substudy to allow dose selection. Using doses selected based on the pharmacokinetic study/substudy, and agreed upon with the FDA, conduct a longer-term pediatric safety and antiviral activity assessment of dolutegravir plus background regimen assessing activity on the basis of continued HIV-1 RNA virology response and safety monitoring over at least 24 weeks of dosing. A minimum of 20 subjects should be enrolled into the study.
Conduct a repeat dose, dose ranging pharmacokinetic/pharmacodynamics (PK/PD) study evaluating Rayaldee (calcifediol) in predialysis patients with stage 3 or 4 chronic kidney disease with secondary hyperparathyroidism and 25-OH vitamin D levels < 30 mcg/L and ages 1 month to less than 18 years. The study should include a minimum of 6 weeks of follow up to allow for the estimation of the calcifediol elimination.
Conduct a 16-week, randomized (1:1), placebo-controlled, double-blind, efficacy and safety study evaluating Rayaldee (calcifediol) in predialysis patients with stage 3 or 4 chronic kidney disease with secondary hyperparathyroidism and 25-OH vitamin D levels < 30 mcg/L and ages 1 month to less than 18 years. The study should be stratified by age 1 month to <2 years, 2 to <12 years, and 12 to < 18 years. This trial should not be initiated until the results of the pediatric PK/PD study (PMR 3052-1) have been submitted to and reviewed by the Agency.
A postmarketing study that will allow you to test for and control the levels of the following elemental impurities in your product: [....] present during the manufacturing process and have the potential to contaminate your product. As part of your post-marketing study, you will need to 1) develop a validated method for testing the finished product for the elemental impurities as stated above, and 2) analyze at least three batches of your product using the validated method.
Conduct a prospective observational study utilizing data from the United Network for Organ Sharing (UNOS) on the incidence rates of post-transplant lymphoproliferative disorder (PTLD) in US adult kidney-only transplant recipients who are treated with belatacept compared to recipients treated with calcineurin inhibitor (CNI)-based regimens.  Recipient characteristics will be collected, including EBV and CMV serostatus, location of the PTLD, and outcome (survival or mortality).  Incidence rates of PTLD in belatacept-exposed patients will be quantified beginning when 500 belatacept-exposed patients have at least 1 year of follow-up.  Relative risks of PTLD for belatacept compared to CNI-based regimens will be estimated after 1,000 person years have been accumulated in transplant recipients initiated on belatacept at transplantation.  (Protocol Number IM103075)
Provide evidence sufficient to characterize the long-term safety of ruxolitinib in the treatment of patients with polycythemia vera with splenomegaly from trials CINC424B2301 and INCB18424-256. Submit the complete final reports and data showing long-term safety with 5 years of follow-up. Include a pooled analysis of safety, including the long-term effects of treatment with ruxolitinib on hematocrit.
Conduct a trial to provide evidence sufficient to characterize the long-term safety of ruxolitinib in the treatment of patients with polycythemia vera who do not have splenomegaly and who have had an inadequate response to or are intolerant of hydroxyurea. Submit the complete final report and data showing long-term safety with 5 years of follow-up from a randomized controlled trial comparing ruxolitinib vs best available therapy. In the safety analysis, include the long-term effects of treatment with ruxolitinib on hematocrit.
Establish reliability requirements for the combination product Narcan Nasal Spray (naloxone hydrochloride), and complete testing which verifies the combination product reliability.
Establish procedures for monitoring reports of failure of the combination product Narcan Nasal Spray (naloxone hydrochloride) to activate or failure of the combination product to deliver the full-labeled dose. Provide interim and final reports to the NDA, which contain a detailed analysis of reported device failures (including reported malfunctions that did, as well as did not result in patient harm), full event narratives of the failure and any subsequent adverse events, and the results of root cause analysis performed for the reported failure.
Conduct an adequate leachable safety assessment for the [....] used in your container closure system. This assessment must include leachable data from long -term stability studies testing at least three batches (taking into consideration the proposed shelf- life) to determine if the identified extractables leach into the drug product over time. Using this information, conduct a toxicological risk assessment justifying the safety of the leachables, taking into consideration the maximum daily dose of the identified materials for this drug product. Submit a toxicological risk assessment for any leachable that exceeds 5 mcg/day. From a genetic toxicology perspective, any leachable that contains a structural alert for mutagenicity must not exceed 120 mcg/day for an acute indication, or be adequately qualified for safety. The risk assessment should be based on the maximum level of each leachable detected in long-term stability samples.
Conduct a long-term stability evaluation placing at least three (3) manufactured lots of NARCAN Nasal Spray, 40 mg/mL, on long-term stability evaluation at the following temperatures: a. 2 to 8°C b. 40°C/75% RH - to extend the time points out to 24 months
Conduct an elotuzumab exposure-response analysis for efficacy and safety utilizing data from trial CA204006. The result of the exposure-response analyses from both CA204004 and CA204006 will be used to determine whether a postmarketing trial is needed to optimize the dose in patients with multiple myeloma who have low exposure to elotuzumab at the approved dose (10 mg/kg). Submit a final report of the exposure-response analyses based on CA204004 and CA204006.
Twenty-eight day, daily, repeat dose, oral gavage dose-range finding toxicity study in neonatal rats to provide rationale for dose selection for the three-month neonatal rat toxicity study with Syndros (dronabinol oral solution).
A repeat dose, randomized, active-controlled trial to assess the safety of Sustol (granisetron) extended-release injection, for subcutaneous use, when administered to patients receiving chemotherapy, for 6 cycles.
A 2-year subcutaneous carcinogenicity study in rats with the [...] vehicle used in the formulation of Sustol (granisetron) extended-release injection, for subcutaneous use.
A Syrian Hamster Embryo (SHE) cell transformation assay with the [...] vehicle used in the formulation of Sustol (granisetron) extended-release injection, for subcutaneous use.
An addition to the stability protocol to test the break force, glide force, and peak force of injection of Sustol (granisetron) extended-release injection, for subcutaneous use.
Develop and validate an improved assay for detecting Galsulfase in human plasma.
Randomized controlled trial in pediatric patients, including neonates, comparing Liposyn II 20% IV Fat Emulsion with a phytosterol-depleted formulation of Liposyn II 20% IV Fat Emulsion to evaluate the incidence of liver injury, including either parenteral nutrition-associated liver disease (PNALD) or intestinal failure-associated liver disease (IFALD). This trial should be initiated after the results from PMR 2142-1 are available. The phytosterol content of the phytosterol-depleted formulation of Liposyn II 20% IV Fat Emulsion should be documented using validated analytical assay methods developed under PMR 2142-1. Plasma phytosterol levels should be assessed in patients using validated analytical assay methods developed under PMR 2142-3.
A study to assess the pharmacokinetics of ProAir RespiClick in pediatric asthma patients between the ages 4 to 11 years.
A study to assess the efficacy and safety of two dose levels of ProAir RespiClick in pediatric asthma patients between the ages 4 to 11 years.
A study to assess the chronic dose efficacy and safety of ProAir RespiClick in pediatric asthma patients between the ages 4 to 11 years.
Establish a registry for children aged 2 to < 6 years to enroll approximately 200 patients receiving deferasirox and follow them for 5 years. Collect data at least monthly for renal function and blood pressure and yearly for growth and development, and analyze the data for adverse renal reactions and delayed growth and development. Submit your monitoring scheme for our review and comment.
Conduct a trial to assess the long-term efficacy and safety of deferasirox in patients with NTDT and high LIC. The trial should assess response rates in the subset of patients with baseline LIC values >15 mg Fe/g dw (proportion of patients achieving an LIC <5 mg Fe/g dw and time to achieving an LIC <5 mg Fe/g dw). Follow-up of all subjects for up to 5 years is necessary.
Conduct a trial to assess the long-term efficacy (and safety) of deferasirox treatment to a target LIC of 3 mg Fe/g dw followed by one or more treatment holidays until the LIC is ¡Ý5 mg Fe/g dw in patients with NTDT. Follow-up of all subjects for up to 5 years is necessary.
Conduct a prospective, randomized trial in at least 210 patients with low to intermediate risk myelodysplastic syndromes (MDS) receiving deferasirox for transfusional iron overload (approximately 140 patients) or placebo (approximately 70 patients) to determine the efficacy and safety of deferasirox in this population. The trial will continue for 3 years from the date the last patient is enrolled.
Conduct a study, using your established registry, to evaluate the risk of growth inhibition in children (aged 10 to <18 years old at enrollment) with NTDT and treated with deferasirox for documented iron overload. Follow at least 40 children for up to 5 years to assess and analyze the long-term safety of treatment with deferasirox, including an assessment of growth, compared to children on a regular transfusion program receiving deferasirox (based on historical data). Provide annual interim reports on enrollment and outcomes.
Conduct an enhanced pharmacovigilance study, including proactive surveillance and follow-up of spontaneous reports, to characterize the frequency and severity of adverse Events of Special Interest (ESIs), defined as all deaths and severe or serious events of kidney or liver toxicity, in adults receiving deferasirox for documented iron overload related to multiple transfusions for myelodysplastic syndrome with anemia requiring transfusions. This study does not replace monitoring and reporting as required by regulations.
Complete a study of long-term follow-up (3 years) in 150 patients with myelodysplastic syndromes (MDS) receiving deferasirox to evaluate safety (including cardiac, hepatic, endocrine and renal) and hematologic and clinical benefit of deferasirox in these patients.
Conduct a trial to assess ocular toxicity in patients receiving deferasirox. Examinations should include distance visual acuity, applanation tonometry, lens photography, and wide angle fundus photography of retina and optic nerve and should be done at baseline (prior to deferasirox initiation) and at six month intervals. At least 60 patients should complete 2 years of follow-up.
Conduct a trial to assess the long-term safety of deferasirox in patients with NTDT by conducting a trial of deferasirox for the treatment of iron overload (LIC ¡Ý5 mg Fe/g dw) in non-transfusion dependent thalassemia (NTDT) in patients aged 10 years and greater with up to 5 years total follow-up.
An open-label, 26-week, randomized, controlled efficacy and safety trial comparing Tresiba (insulin degludec injection) with insulin detemir in pediatric patients with type 1 diabetes ages 1 to 17 years (inclusive) using insulin aspart at each meal, followed by a 26-week safety extension.
Conduct a randomized, double-blind, active-controlled trial evaluating the effect of Tresiba (insulin degludec injection) on the incidence of major adverse cardiovascular events (MACE) in subjects with type 2 diabetes mellitus. The primary objective of the trial should be to demonstrate that the upper bound of the 2-sided 95% confidence interval for the estimated risk ratio comparing the incidence of adjudicated MACE (non-fatal myocardial infarction, non-fatal stroke, cardiovascular death) observed with Tresiba to that observed in the comparator group is less than 1.3.
To develop and validate an assay to assess for the presence of anti-degludec antibodies that has a sensitivity consistent with FDA guidance. Your final report should include a summary of the validation exercise including supporting data, a summary of the development data supporting assay suitability for parameters not assessed in the validation exercise, and the assay standard operating procedure (SOP).
To assess the incidence and titers of anti-degludec antibodies in sera from patients treated with Tresiba (insulin degludec injection) in Tresiba (insulin degludec injection) clinical trials and determine whether they are associated with differences in pharmacokinetics parameters (e.g. exposure), efficacy (e.g. hemoglobin A1c, insulin dose), and safety (e.g. hypoglycemia and hypersensitivity). The clinical samples should not be tested until the results from the PMC for anti-degludec antibody assay development and validation have been submitted to and reviewed by the Agency.
An open-label, 16-week, randomized, controlled efficacy and safety trial comparing Ryzodeg 70/30 (insulin degludec and insulin aspart injection) administered once daily with a main meal and insulin aspart for additional meals to insulin detemir, in combination with mealtime insulin aspart at each meal, in pediatric patients with type 1 diabetes mellitus ages 1 to 17 years (inclusive).
To assess the incidence and titers of anti-degludec antibodies in sera from patients treated with Ryzodeg 70/30 (insulin degludec and insulin aspart injection) in Ryzodeg 70/30 (insulin degludec and insulin aspart injection) clinical trials and determine whether they are associated with differences in pharmacokinetics parameters (e.g. exposure), efficacy (e.g. hemoglobin A1c, insulin dose), and safety (e.g. hypoglycemia and hypersensitivity). The clinical samples should not be tested until the results from the PMC for anti-degludec antibody assay development and validation have been submitted to and reviewed by the Agency.
In vitro drug-drug interaction (DDI) studies in media mimicking physiological conditions (i.e., at pH 1.2, 4.5 and 6.8), including appropriate replicates. The DDI studies may be conducted in the absence of potassium, thus representing a “worst case” scenario. If you choose to conduct the in vitro DDI studies in the presence of potassium, the concentration of potassium should not exceed physiologically relevant concentrations. Prior to initiating the studies, you will need to provide information that justifies the experimental conditions under which the studies will be performed. Validated analytical methods must also be used in these in vitro studies, to measure free drug concentrations after incubation with and without Kayexalate (sodium polystyrene sulfonate) using validated analytical methods. Below is a list of drugs that should be tested for an in vitro interaction with Kayexalate (sodium polystyrene sulfonate). Drugs to be tested for an in vitro interaction with Kayexalate: Allopurinol Cinacalcet Lisinopril Rivaroxaban Cyclosporine Amlodipine Ciprofloxacin Lithium Spironolactone Oral Contraceptive (containing ethinylestradiol and norethindrone) Amoxicillin Clopidogrel Metformin Thiamine Ticagrelor Apixaban Digoxin Metoprolol Trimethoprim Prasugrel Aspirin Furosemide Phenytoin Valsartan Dabigatran Atorvastatin Glipizide Quinidine Verapamil Edoxaban Cephalexin Levothyroxine Riboflavin Warfarin Carvedilol
Conduct a 24-week, randomized, controlled efficacy and safety study comparing Adlyxin (lixisenatide) with placebo in patients with type 2 diabetes ages 10 to 17 years (inclusive), followed by a 28-week double-blind controlled extension. Subjects will be on a background of metformin and/or basal insulin at a stable dose. This trial should not be initiated until the results of the pediatric PK/PD study (PMR 3102-1) have been submitted to and reviewed by the Agency.
Deferred pediatric study under PREA for the treatment of HIV-1 infection in pediatric subjects from 2 years to 6 years of age. This study will determine the pharmacokinetic profile, safety, and activity of etravirine in pediatric subjects from 2 years to 6 years of age.
Azelaic acid pre-foam emulsion: 104-week dermal carcinogenicity study in CD-1 mice
Conduct a safety and efficacy study of lubiprostone in pediatric patients with irritable bowel syndrome with constipation (IBS-C) ages 6 years to < 18 years. The design will consist of a 12-week multi-center, double-blinded, placebocontrolled safety and efficacy study.
Conduct an open-label extension safety study of lubiprostone, including a safety evaluation of the effects of lubiprostone treatment on bone growth, in pediatric patients ages 6 years to < 18 years with irritable bowel syndrome with constipation (IBS-C) who participated in the 12-week efficacy study conducted to address PMR 675-3.
Conduct an in vitro study to characterize and quantify the degradants of the immediate release omeprazole of Yosprala at various pHs (i.e., pH 1, 1.5, 2, 2.5, 3, 3.5, 4) following a minimum of 1 hour of exposure at 37°C, and evaluate the differences in the profiles across pHs. Submit the chromatograms and a summary of quantitative data generated during the study.
Conduct a clinical PK trial evaluating the systemic exposures of the omeprazole degradants that are shown to be present at a higher level at pH <3.0 compared to higher pHs in the in vitro studies (PMC #3111-1). This trial will include both Yosprala and the reference product for the omeprazole component of Yosprala. Compare the individual omeprazole degradant exposures between the two products.
The merged protocol, Study 191622-137, was developed from the pediatric protocol Study 191622-137 (initial study) and Study 191622-138 (long-term extension study), i.e., the originally submitted Post Marketing Required studies per the OAB Approval Letter, dated January 18, 2013. As discussed in the correspondence between the Agency and Allergan on July 16 and 17, 2013, this merger is administrative and   intended to make study conduct more efficient for the physicians, patients, and IRB/ethics committees.
A 6-week randomized, double blind, placebo-controlled trial in children 5 to 17 years of age with active, mild to moderate distal ulcerative colitis (extending up to 40 cm from the anal verge). The trial will evaluate pharmacokinetics (PK), efficacy for induction of remission, and safety of at least 2 doses of Uceris (budesonide) rectal foam. The effects of 6 weeks of Uceris (budesonide) rectal foam on the HPA axis will be assessed.
Provide nationally representative drug utilization data to FDA of sufficient detail that use of Truvada® for a pre-exposure prophylaxis (PrEP) indication and individuals using Truvada® for a PrEP indication can both be characterized. These data should be submitted to FDA as specified in the timetable below, for the combination product emtricitabine/tenofovir disoproxil fumarate, and for the single-ingredient products containing emtricitabine or tenofovir disoproxil fumarate, starting at one year following approval of the PrEP indication. The following analyses should be conducted with the data collected: 1) Total number of prescriptions dispensed across all settings of care Reference ID:a. Total number of prescriptions dispensed, stratified by indication, setting of care, and prescriber specialty 2) Total number of unique patients receiving dispensed prescriptions across all settings of care a. Total number of unique patients receiving dispensed prescriptions, stratified by both indication and setting of care i. Unique incident users every quarter-year ii. Unique prevalent users every quarter-year b. Patient demographics of users of the product c. Clinical characteristics of users of the product 3) Duration of therapy, including definitions of gaps in drug therapy a. Total and stratified by indication b. Examination of possible ‘intermittent’ use c. Number of patients switching from PrEP to an HIV treatment regimen 4) Comparison of drug utilization data collected to data collected from demonstration projects (trials) performed in the United States in terms of patient demographics, patient clinical characteristics, prescriber specialties, settings of care, and geographic region (when available).
An Enhanced Pharmacovigilance Study to evaluate the risks factors and clinical sequelae of immune-mediated encephalitis following exposure to OPDIVO (nivolumab). This study will include a mechanism to collect, classify, and analyze data on moderate to severe neurologic deterioration in patients exposed to OPDIVO (nivolumab). The study at a minimum will include the following key elements: a. Data collection of retrospective data points including Brain imaging, specifically magnetic resonance imaging (MRI) with and without gadolinium contrast, and with diffusion weighted imaging (DWI). Results of lumbar puncture including: o Cell counts, protein, glucose o Viral encephalitis panel o JC virus detection o Autoimmune/paraneoplastic encephalitis panel Results of serum studies including: o JC virus detection o Autoimmune/paraneoplastic encephalitis panel o Vitamin deficiency studies [thiamine, niacin, and B12] Results of complete neurologic examinations. Concomitant medication use, including use of steroids or other immunemodulating therapies. b. Data analysis utilizing descriptive statistics for summarizing data that will fully capture the outcome of concern.
Trial1321.3 titled, “A Phase III, Case Series Clinical Study of the Reversal of the Anticoagulant Effects of Dabigatran by Intravenous Administration of 5.0 g Idarucizumab in Patients Treated with Dabigatran Etexilate Who Have Uncontrolled Bleeding or Require Emergency Surgery or Procedures, the REVERSE –AD trial.”
Conduct a prospective, long-term, observational study in STRENSIQ (asfotase alfa) treated patients with perinatal/infantile-onset and juvenile-onset hypophosphatasia (HPP) from ages birth and older. The purpose of the study is to assess the long term safety of treatment with STRENSIQ (asfotase alfa) with respect to incidence rates of severe hypersensitivity reactions (including anaphylaxis), systemic immune complex-mediated reactions and ectopic calcification events. Specify case definitions and validation methods and procedures for all outcomes. Enroll adequate number of patients, including both infantileonset and juvenile-onset-patients, and follow for a minimum of 5 years from the time of enrollment, or until death, whichever comes first.
Develop an assay to directly compare the complement activating capacity of STRENSIQ (asfotase) alfa to that of human IgG1. The assay should be set up under conditions to readily detect complement activation by IgG1. A dose response curve to demonstrate the sensitivity of the assay is recommended
Develop a validated cross-reactive immunologic material (CRIM) assay for patients with hypophosphatasia (HPP) and test patient samples in a cohort of untreated patients. Results should be correlated with antibody response (binding and neutralizing), genetic mutations, enzyme activity level and clinical outcome in patients who are receiving STRENSIQ (asfotase alfa) treatment.
Conduct a safety and efficacy study in pediatric patients with chronic idiopathic constipation ages 2 to 5 years treated with Linzess (linaclotide).
Conduct a safety and efficacy study in pediatric patients with chronic idiopathic constipation ages 6 to 17 years treated with Linzess (linaclotide).
A randomized, double-blind, placebo-controlled, flexible-dose titration study of methylphenidate hydrochloride extended-release capsules (Aptensio XR) in children ages 4 to 5 years diagnosed with ADHD
A single-dose, open-label, randomized pharmacokinetic study of Aptensio XR capsules in male or female children (4 to less than 6 years of age) with ADHD in fed condition.
A one year Pediatric Open-Label Safety Study for patients age 4 to 5 years (at the time of entry into Study 1 or Study 2 or at the time of enrollment if directly enrolled into Study 3) with ADHD.
Perform immunogenicity testing on anti-drug antibody (ADA)-positive samples from clinical studies of type 2 diabetes patients treated with lixisenatide to determine the incidence of neutralizing antibodies (NAb) and anti-lixisenatide antibodies that are cross-reactive with endogenous GLP-1 and glucagon peptides and are capable of neutralizing these endogenous peptides. Assessments should be performed using assays demonstrated to be suitable for their intended purposes through formal validation studies that have been reviewed by the Agency prior to their use in clinical sample analysis. Samples used for these assessments should be archived under suitable conditions until testing, and should include sufficient quantity to allow for completion of required immunogenicity assessments. Study report(s) submitted to the Agency will include evaluation of the impact of NAb and cross-reactive antibodies on patient safety as well as PK, PD, and efficacy of lixisenatide.
Conduct and submit the results of at least one multicenter, randomized clinical trial establishing the superiority of pembrolizumab over available therapy as determined by an improvement in overall survival in patients with metastatic squamous cell carcinoma of the head and neck.
Conduct a pharmacokinetic and safety study of an age-appropriate formulation of Troxyca ER (oxycodone and naltrexone) in patients seven to less than 17 years of age with pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.
In order to provide the baseline data to support the hypothesis-testing studies required under PMR 2965-3, conduct a descriptive study that analyzes data on the following: (1) utilization of TROXYCA ER (oxycodone and naltrexone) and selected comparators. Reports should include nationally-projected quarterly retail dispensing, overall and by age group and census region; AND (2) abuse of TROXYCA ER (oxycodone and naltrexone) and related clinical outcomes. These studies should utilize multiple data sources in different populations to establish the scope and patterns of abuse for TROXYCA ER (oxycodone and naltrexone) as well as mutually agreed-upon, selected comparators to provide context. • Data should include route-specific abuse outcomes, be nationally representative or from multiple large geographic areas, and use meaningful measures of abuse. • Additional information, either qualitative or quantitative, from sources such as internet forums, spontaneous adverse event reporting, or small cohort studies may also be included to help better understand abuse of this drug, including routes and patterns of abuse in various populations. • Formal hypothesis testing is not necessary during this phase, but provide information on the precision of abuse-related outcome estimates (e.g. 95% confidence intervals for quarterly estimates) and calculate utilization-adjusted outcome estimates where possible.
Conduct formal observational studies to assess whether the properties intended to deter misuse and abuse of TROXYCA ER (oxycodone and naltrexone) actually result in a meaningful decrease in misuse and abuse, and their related clinical outcomes, addiction, overdose, and death, in post-approval settings. The studies should allow FDA to assess the impact, if any, attributable to the abuse-deterrent properties of TROXYCA ER (oxycodone and naltrexone) and should incorporate recommendations contained in Abuse-Deterrent Opioids—Evaluation and Labeling: Guidance for Industry (April 2015). Assessing the impact of the abuse-deterrent formulation on the incidence of clinical outcomes, including overdose and death, is critical to fulfilling this PMR. Any studies using electronic healthcare data should use validated outcomes and adhere to guidelines outlined in FDA’s Guidance for Industry and FDA Staff: Best Practices for Conducting and Reporting Pharmacoepidemiologic Safety Studies Using Electronic Healthcare Data.
Conduct and submit the results of at least one multicenter, randomized clinical trial establishing the superiority of alectinib over available therapy in patients with metastatic anaplastic lymphoma kinase positive non-small cell lung cancer (NSCLC).
Complete a pharmacokinetic trial to determine an appropriate dose of alectinib in patients with moderate to severe hepatic impairment in accordance with the FDA Guidance for Industry entitled “Pharmacokinetics in Patients with Impaired Hepatic Function: Study Design, Data Analysis, and Impact on Dosing and Labeling”.
Enhanced Pharmacovigilance Study to Assess and Analyze the Risks of Hypotension, Syncope, Accidents or Injuries, and Fatal Outcomes with Use of Addyi (flibanserin).
Prospective Observational Study to Evaluate the Risk of Appendicitis with the Use of Addyi (flibanserin) in Women Aged 18 to 44.
Pregnancy Registry Study to Evaluate Adverse Pregnancy Outcomes and Birth Defects in Pregnancies Exposed to Addyi (flibanserin).
Maternal-Fetal Outcome Study to Evaluate Adverse Pregnancy Outcomes and Birth Defects in Pregnancies Exposed to Addyi (flibanserin).
Alcohol Interaction Trial in the Target Female Population (Between Ages 18 and 44) to Evaluate the Interaction Between Addyi (flibanserin) and Alcohol Through a “Worst Case Scenario” with Varying Quantities of Alcohol Intake.
Alcohol Interaction Trial in the Target Female Population (Between Ages 18 and 44) to Evaluate the Interaction of the Timing of Alcohol Intake Relative to Addyi (flibanserin) Dosing. Dose(s) to be evaluated in this trial will be selected based on the findings from PMR 2939-5.
Alcohol Interaction Trial in the Target Female Population (Between Ages 18 and 44) to Evaluate the Interaction Between Addyi (flibanserin) and Alcohol Intake in a “Typical Real World Use” Setting. Dose(s) to be evaluated in this trial will be selected based on the findings from PMR 2939-5.
Conduct an open-label study to evaluate the pharmacokinetics and safety of BELBUCA in patients 7 through 16 years with pain severe enough to require daily, around-the-clock, long-term opioid treatment, and for which alternative treatment options are inadequate.
Conduct a multiple ascending dose clinical trial in adults to determine the maximum tolerated dose of BELBUCA without co-administration of naltrexone to inform the dosing for a thorough QT (tQT) trial of BELBUCA.
Conduct a thorough QT trial in adults without naltrexone co-administration to assess the risk of QT prolongation with BELBUCA. This trial will provide information on the conduction effects of BELBUCA on the heart, specifically cardiac repolarization, at therapeutic and supratherapeutic dose regimens. The tQT trial may be conducted as part of the required multiple ascending dose trial (PMR 2982-2).
To submit a final report that includes updated results for overall survival for trial MO18264 (PRIMA), "A Multicenter, Phase III, Open-Label, Randomized Study in Patients with Advanced Follicular Lymphoma Evaluating the Benefit of Maintenance Therapy with Rituxan after Induction of Response with Chemotherapy plus Rituxan in Comparison with No Maintenance Therapy."  The final report should also include the primary and derived datasets and programs used to generate the overall survival results reported.
Deferred pediatric studies under PREA for the reduction of blood pressure in pediatric patients ages 1 to 16 years old.
Conduct a controlled postmarketing study to track adverse events in the recipients of Trima Accel collected platelets stored in 65% Isoplate/ 35% plasma. Adverse events (e.g., transfusion reactions) will be captured through active surveillance of the test and the control products (platelets stored in plasma). Transfusion reactions will be classified and compared by type (e.g., TRALI, febrile non-hemolytic transfusion reaction, allergic reaction, etc.).
Conduct a study to evaluate the immunogenic potential of the terminal heat-treated product.
Conduct a Postmarketing study to further evaluate safety and efficacy of the product in type 3 vWD patients undergoing major surgeries.
Conduct a post-marketing observational study to compare the safety profile of Vivotif® lots with release titers in the range of 6.9 x 109 to 10 x 109 CFU/capsule to lots with release titers in the range of 4 x 109 to 6 x 109 CFU/capsule.
Conduct two clinical trials: Trial 1: A pilot study of the safety and pharmacokinetics of Prolastin-C administered weekly at a dose of 120 mg/kg. Trial 2: An adequately-powered study of clinically meaningful endpoints -Prolastin-C efficacy study using CT scans as the primary endpoint.
Conduct a study to evaluate T.R.U.E. TEST and the seven new allergens in pediatric patients ages six to seventeen.
Final Protocol Submission: November 30, 2016 Study/Trial Completion: To be determined should an event occur. Final Report Submission: To be determined should an event occur.
Submit results from your clinical studies using this product in populations for which your seasonal influenza vaccine is already licensed.
Establish a pregnancy registry that will enroll women exposed to Fluzone Quadrivalent during pregnancy and collect data on their outcomes and newborn health status.
To establish a pregnancy registry that will enroll women exposed to Fluzone Intradermal Quadrivalent during pregnancy and collect data on their outcomes and newborn health status. Annual reports for this registry will be submitted with the Periodic Benefit-Risk Evaluation Report that includes all other Fluzone® influenza vaccines. When the registry has collected data on the outcomes specified in the protocol for 4 years, Sanofi will submit a final study report including information for both Fluzone Intradermal Quadrivalent and Fluzone Quadrivalent vaccine (administered intramuscularly). After submission of the registry report, Sanofi will continue enrolling in the registry pending CBER review of the report and determination that the registry can be discontinued.
Conduct an observational postmarketing safety surveillance study of FluMist Quadrivalent in children 2 years through 8 years of age.
Conduct an observational postmarketing case-control study of the effectiveness of FluMist Quadrivalent in children 2 years through 17 years of age.
Conduct and report the results of a pilot trial to determine the effect of regular administration of the product on one or more clinically meaningful endpoint(s). Examples of acceptable endpoints include pulmonary exacerbations, serial pulmonary functions, and serial quantitative computerized axial tomographic (CT) lung scans.
Contingent on the outcome of the pilot trial described in commitment 3, conduct and report the results of an adequately-powered study of clinically meaningful endpoints(s). Based on the results of the pilot study and the available scientific data at the time that this study is being designed, work with entities maintaining registries of alpha1-proteinase inhibitor deficient patients and with the National Institutes of Health (NIH) to design and conduct an adequately-powered study of a clinically meaningful endpoint(s). The study design could involve a single product or could potentially involve a cooperative simultaneous study of multiple products in parallel arms, using a factorial design.
Conduct a non-interventional 2-armed study to evaluate the safety of Octagam Immune Globulin Intravenous (Human) 5% liquid preparation designed to monitor, analyze and report thrombotic events.
Conduct a randomized study of the product in surgery, comparing the safety and efficacy of the product administered by intermittent bolus infusion versus continuous infusion.
Conduct a pilot trial of clinically meaningful endpoint(s). Examples of acceptable endpoints include pulmonary exacerbations, serial pulmonary functions, and serial quantitative computerized axial tomographic (CT) lung scans.
Based on the results of the pilot study and the available scientific data at the time that this study is being designed, ZLB Behring will work with entities maintaining registries of alpha1-proteinase inhibitor deficient patients and with the National Institutes of Health (NIH) to design and conduct an adequately-powered study of a clinically meaningful endpoint(s).
Conduct a Phase II open-label administration (laboratory personnel will be blinded to group assignment) parallel-group, multicenter study to evaluate the safety and immunogenicity of two doses of Menactra when administered alone at 9 months and concomitantly with Pentacel® at 15 to 18 months of age, entitled, Immunogenicity and Safety Evaluation of Menactra® (Meningococcal [Groups A, C, Y and W-135] Polysaccharide Diphtheria Toxoid Conjugate Vaccine) When Administered to Healthy Subjects at 9 Months and Concomitantly with Pentacel® at 15 to 18 Months of Age, (MTA55).
Conduct a Phase IV, descriptive, epidemiological, safety surveillance study in the United States, entitled, Post-licensure Safety Surveillance Study of Menactra® Vaccine When Administered as a 2-dose Schedule to Children 9 Months through 23 Months of Age, (MTA57).
Work with the FDA, and other public agencies as appropriate, to design and implement a clinical study protocol to include VIGIV dose ranging, and conduct a study to describe the treatment and clinical course of patients receiving VIGIV for complications of vaccinia infection when such a study is feasible, due to the actual or impending widespread use of VIGIV.
Conduct a large scale observational study of US subjects 50 to 59 years of age vaccinated with ZOSTAVAX to assess the long-term effectiveness of the vaccine and better characterize the duration of protection against herpes zoster (HZ).
Collaborate with the cancer registries in four countries in the Nordic Region (Sweden, Norway, Iceland, and Denmark) to assess long-term outcomes following administration of GARDASIL.
Conduct a study in collaboration with the Norwegian Government, if GARDASIL is approved in the European Union and the Government of Norway incorporates HPV vaccination into its national guidelines, to assess the impact of HPV vaccination on the following in Norway: a. the long-term burden of HPV disease including the incidence of HPV 6/11/16/18-related cervical disease; b. the long-term burden of HPV disease caused by types other than HPV 6/11/16/18; c. the overall incidence of cervical HPV disease; d. the incidence of HPV-related cancers and pre-cancers (CIN 2/3, AIS and cervical cancer; VIN 2/3 and vulvar cancer; and VaIN 2/3 and vaginal cancer); and e. the interaction between administration of GARDASIL and pregnancy outcomes, especially congenital anomalies, by linking the vaccination registry with the Medical Birth Registry.
Provide data concerning duration of immunity following administration of GARDASIL from the Nordic Long-Term Follow-up Study.
Conduct an observational safety study in a U.S. Managed Care Organization (MCO) to assess the general short-term safety of the vaccine as it is administered to a larger male population 9 through 26 years of age.
Conduct a long-term evaluation of vaccine effectiveness in males by extending Protocol 020. Study subjects will be follow-up for up to 10 years from day of enrollment into the base study (i.e., Day 1) for the occurrence of external genital lesions.
Conduct ongoing study D-QIV-004 under PREA for active immunization for the prevention of disease caused by influenza A subtype viruses and type B viruses contained in Fluarix® Quadrivalent, in pediatric patients ages 6 months to 35 months of age.
To establish a pregnancy registry to prospectively collect data on spontaneously-reported exposures to Fluarix® Quadrivalent during pregnancy.
A descriptive study of the safety of Pentacel with regard to selected medically attended events in at least 10,000 infants who will be followed from the first dose of Pentacel through approximately 6 months after the fourth dose.
Conduct a prospective cohort study in the military population receiving ACAM2000 to determine general safety information on expected and unexpected adverse events; Additional information on the natural history and clinical outcome of myocarditis and pericarditis after ACAM2000, and information on the adequacy of the risk management program on reducing preventable adverse events.
Implement an enhanced surveillance program to ascertain at least 75% of symptomatic cases of myocarditis and pericarditis after ACAM2000 vaccination.
Implement a myocarditis registry with cases identified from routine surveillance to further understand the natural history of myocarditis and pericarditis after ACAM2000 vaccination, and to evaluate potential risk factors associated with the development of vaccine-related myocarditis and pericarditis.
Deferred pediatric study under PREA to evaluate the safety and immunogenicity of FluLaval Quadrivalent in childeren 6 to 35 months of age.
Establish a pregnancy registry that will enroll women exposed to FluLaval® Quadrivalent during pregnancy and collect data on their outcomes and newborn health status.
Deferred pediatric study under PREA to evaluate the safety and immunogenicity of FluLaval Quadrivalent in children 6 to 35 months of age.
Conduct a study, based on a registry design, to assess the risk of cerebrovascular events in 1,500 patients with prostate cancer who receive sipuleucel-T.
Conduct a study to investigate the cause of hemolysis, especially the specificity of the antibody involved. The study will enroll ITP and/or PID patients.
Initiate a Registry to capture data for any patient who is prescribed CEPROTIN, irrespective of diagnosis.
Establish a pregnancy registry to prospectively collect data on spontaneously-reported exposures to Afluria during pregnancy.
Deferred pediatric study under PREA, to evaluate the immunogenicity and safety of Afluria Quadrivalent in the pediatric population 5 through 17 years of age.
Deferred pediatric study under PREA, to evaluate the immunogenicity and safety of Afluria Quadrivalent in the pediatric population 6 months through 4 years of age.
To establish a pregnancy registry to prospectively collect data on reported exposures to Afluria Quadrivalent during pregnancy and evaluate pregnancy outcomes. The registry will enroll a minimum of 500 evaluable subjects
Conduct ongoing long term efficacy study for HPV-015.
Conduct ongoing long term efficacy study for HPV-040.
Conduct an observational database study using the CPRD GOLD to evaluate the risk of neuroinflammatory/ophthalmic new onset of autoimmune disease(s) (NOAD) and other pre-specified NOAD within 12 months following the administration of the first dose of Cervarix.
Conduct a randomized trial using two regimens for prophylaxis.
Conduct a large-scale observational post-licensure safety study in the U.S to assess the potential serious risk of intussusception and other serious adverse effects (specifically Kawasaki disease, hospitalizations due to acute lower respiratory tract infections, and convulsions) in recipients of approximately 44,000 ROTARIX vaccinated subjects.
Conduct a clinical trial designed to evaluate higher than labeled dose schedules of CINRYZE for routine prophylaxis of angioedema attacks in patients with Hereditary Angioedema (HAE).
Conduct study DoD Active Surveillance in 20,000 patients.
Conduct the DoD Pregnancy Surveillance study.
Conduct study IC51-325 " Long Term Immunogenicity And Safety With Or Without A Booster Dose Following Primary Vaccination With The Japanese Encephalitis Vaccine IC51 (IXIARO®) In A Pediatric Population In JEV - Endemic Countries." An open-label, randomized follow-up study to evaluate use of a booster dose of Ixiaro administered to a subset of children who received a primary series of Ixiaro in Study IC51-323.
Conduct post-marketing assessments of human factors issues that may affect preparation and administration of the 0.25 mL dose.
Evaluate immunogenicity in patients with repeat exposure to ATryn via an immunosurveillance program to detect antibodies to ATryn, endogenous Antithrombin, goat Antithrombin and goat milk proteins.
Conduct a reactogenicity and immunogenicity study under PREA for active immunization for the prevention of disease caused by influenza virus subtypes A and type B contained in Flublok, in children ages 6 years through 17 years.
Conduct a reactogenicity and immunogenicity study under PREA for active immunization for the prevention of disease caused by influenza virus subtypes A and type B contained in Flublok, in children ages 3 years through 5 years.
Establish a pregnancy registry to collect data prospectively on an actively recruited cohort of 600 pregnant women, of whom at least 300 will have been exposed to Flublok. The statistical analysis will include both exposed women and concurrently enrolled women unexposed to Flublok, and it will be adjusted to control for important covariates.
To conduct a confirmatory clinical efficacy and safety study (PSC12) in adults 50 years of age and older for active immunization for the prevention of disease caused by influenza virus subtypes A and types B contained in your investigational quadrivalent influenza vaccine manufactured according to the same process as Flublok.
To conduct an observational postmarketing safety study (PSC13) in approximately 25,000 Flublok recipients 18 years of age and older to further characterize the safety profile of Flublok using recipients of U.S.-licensed, egg-based, trivalent or quadrivalent inactivated influenza virus vaccines as a comparator, with appropriate adjustment or matching for important covariates such as sex and age.
Deferred pediatric study (Study PSC08) under PREA to evaluate the safety and immunogenicity of a Flublok quadrivalent formulation in children ages 6 years through 17 years.
Deferred pediatric study (PSC17) under PREA to evaluate the safety and effectiveness of a Flublok quadrivalent formulation in children ages 6 years through 17 years.
Deferred pediatric safety, immunogenicity and efficacy study (PSC17) in children 3 years through 17 years of age for active immunization for the prevention of disease caused by influenza virus subtypes A and types B contained in Flublok Quadrivalent.
Conduct a study to assess inhibitory antibody formation against C1-Esterase Inhibitor.
To evaluate the safety of the product, establish and maintain a registry for 3 years of patients treated with Berinert for any indication.
Conduct a randomized masked trial that would be adequately powered to more precisely define the efficacy of Berinert for acute facial HAE attacks.
Conduct a postmarketing surveillance study, your "Sentinel Surveillance Plan", to detect potential safety signals and to monitor and analyze uncommon and unexpected medical events occurring within 42 days following vaccination in the first 100,000 military recruits exposed to Adenovirus Type 4 and Type 7 Vaccine, Live, Oral, during the first year post-approval through the use of the Defense Medical Surveillance System (DMSS).
Conduct Study No. V71_18, a randomized, observer-blind, non-inferiority immunogenicity and safety study with AGRIFLU and a US licensed trivalent inactivated Influenza Vaccine in a pediatric population from 3 years to 17 years of age.
Conduct a randomized, observer-blind, immunogenicity and safety study with AGRIFLU and a US licensed trivalent inactivated Influenza Vaccine in a pediatric population from 6 months to less than 3 years of age.
Establish a pregnancy registry to prospectively collect data on spontaneously-reported exposures to AGRIFLU during pregnancy.
Conduct a non-inferiority immunogenicity study with AGRIFLU and a US-licensed trivalent inactivated seasonal influenza vaccine in a population of adults 50 years of age and older.
Conduct a randomized, comparative trial, designed primarily to evaluate the potential for immune interference of concomitant use of MENVEO with Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine and a Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine Adsorbed as currently recommended by the U.S. vaccine schedule for immunization of adolescents.
Conduct a Phase IV self-controlled case-series study to assess the safety of Meningococcal (Groups A, C, Y, and W-135) Oligosaccharide Diphtheria CRM197 Conjugate Vaccine administered to a minimum of 50,000 HMO subjects 11 through 19 years of age to expand the understanding of the safety profile of Meningococcal (Groups A, C, Y, and W-135) Oligosaccharide Diphtheria CRM197 Conjugate Vaccine.
To conduct an open label, descriptive, epidemiological safety surveillance study of MENVEO vaccine in subjects 2 through 10 years of age. The study will include two parts. Part I of the study will begin with the first administration of MENVEO vaccine to a child 2 through 10 years of age (inclusive) who receives medical care at the site where the study is being conducted. Part I will continue for 3 years, or until commencement of Part II, whichever occurs first. Part II of the study will be initiated if there is a recommendation by the Advisory Committee on Immunization Practices (ACIP) for routine use of MENVEO vaccine in at least one birth cohort within the 2 through 10 year age range.
To conduct an open label, descriptive, epidemiological safety surveillance study of MENVEO in children 2 months through 23 months of age. The study will include two parts. Part I of the study will begin with the first administration of MENVEO to a child 2 through 23 months of age who receives medical care at the site where the study is being conducted. Part I will continue for 3 years, or until commencement of Part II, whichever occurs first. Part II of the study will be initiated if there is a recommendation by the Advisory Committee on Immunization Practices (ACIP) for routine use of meningococcal conjugate vaccine in at least one birth cohort within the 2 through 23 months age range. Part II will commence with the effective date of the ACIP recommendation, and will continue until 20,000 children are enrolled, or until 1 year has elapsed, whichever occurs last. If initiated, a final study report for Part II will be submitted 1 year after the last subject has completed study Part II. In the event there is no recommendation for routine use of meningococcal conjugate vaccine in this age group, Part II will be considered fulfilled when Part I is completed.
Establish a U.S. pregnancy registry to collect safety data on spontaneously-reported exposures to Meningococcal (Groups A, C, Y, and W-135) Oligosaccharide Diphtheria CRM197 Conjugate Vaccine during pregnancy and lactation.
Conduct a phase 4 study to verify the clinical benefit by comparing the hemostatic efficacy of RiaSTAP to historical control.
Evaluate efficacy and safety in the peri-operative period in patients with congenital fibrinogen deficiency.
Evaluate efficacy and safety for routine prophylaxis in patients with congenital fibrinogen deficiency.
CSL Behring will conduct phase 4 study BI 3023_4003 to verify the clinical benefit by comparing the hemostatic efficacy of RiaSTAP™ to historical control.
Conduct an observational database study (6096A1-4005) to monitor the impact of Prevnar 13 in preventing overall invasive pneumococcal disease in Northern California Kaiser Permanente members, by estimating the impact of Prevnar 13 routine use on the annual incidence rate of invasive pneumococcal disease during the five-year surveillance period in the study population.
Conduct an observational study (6096A1-4010) to evaluate the impact of Prevnar 13 routine use in reducing acute otitis media (AOM) and nasopharyngeal colonization in young children caused by the serotypes in the vaccine.
Conduct study 6096A1-4018, an ecologic study to assess national trends in health care visits for otitis media in children younger than five years of age. This study will utilize ambulatory health care visit data from annual national surveys conducted by the National Center for Health Statistics.
Conduct a study to evaluate concomitant use of Prevnar 13 and a U.S. licensed inactivated influenza vaccine in subjects greater-than or equal to 50 years of age, pre-immunized with 23-valent pneumococcal polysaccharide vaccine (23vPS).
Conduct a study exploring potential adverse events associated with protein aggregates. This study will evaluate the safety of the product following multiple repeat exposures over a period of at least 6 months of regular weekly administration. It will include design features that will permit the detection of potential adverse events (AEs) due to the presence of protein aggregates in the product. The study will also include viral nucleic acid testing (NAT) and testing for anti-Alpha1-PI antibodies using an appropriately validated assay. The study will also explore epithelial lining fluid analytes and potential adverse events associated with immunogenicity, and viral safety following the use of Kamada's Intravenous, Human Alpha1-PI (GLASSIA) and another commercial Alpha1-PI, in Alpha1-Antitrypsin [Alpha1-PI] Deficient Patients.
Conduct a study investigating Epithelial Lining Fluid of Alpha1-Antitrypsin Deficient Patients for Alpha1-PI and analytes levels following augmentation therapy with GLASSIA. The primary endpoint for this study will be both antigenic and functional Alpha1-PI levels in Epithelial Lining Fluid after 10-12 weeks of treatment.
Conduct a postmarketing clinical program for GLASSIA Investigating the Safety and Efficacy of GLASSIA vs. Placebo and another (Higher) dose of GLASSIA I.V. by Weekly Administration in Alpha1-Antitrypsin Deficient Patients with emphysema and design and conduct a fully statistically powered efficacy study for augmentation therapy with Alpha-1-Proteinase Inhibitor (Human).
Kamada Ltd. commits to conduct and report the results of a Human Factors study, to evaluate the types of problems that patients/caregivers may encounter in self-infusing. This information will be used to revise, as needed, the training program and educational materials for self-infusion/non-healthcare provider caregiver infusion of GLASSIA®.
Conduct Study Hib-097, a comparative safety and immunogenicity clinical trial of primary and booster immunization with Hiberix relative to U.S. licensed control vaccines.
Conduct a study, based on a registry design, to assess the risk of skin cancer in the area of azficel-T injections and the risk of immune-mediated hypersensitivity reactions in 2700 patients who receive azficel-T.
Conduct a Phase IIIb open-label administration (laboratory personnel will be blinded to treatment), parallel-group, controlled, multicenter study to evaluate concomitant administration of MenHibrix with rotavirus, 13-valent pneumococcal conjugate and hepatitis A vaccines administered according to a US recommended vaccine schedule.
Conduct a Phase IV, Multicentre, Open-Label Study to Evaluate the Efficacy and Safety of BIVIGAM in Primary Immune Deficiency Disorders in Children and Adolescents ages 2 to 16.
Conduct a Prospective, non-interventional, active-control, observational safety study to further assess the potential risk of hypotension, hepatic and renal impairment in Biotest-IGIV-treated patients with primary humoral immunodeficiency (PI).
Conduct a deferred pediatric study under PREA for use of EVARREST as an adjunct to hemostasis in patients 1 month to 17 years undergoing intra-abdominal, retroperitoneal, pelvic, and non-cardiac thoracic surgical procedures.
Deferred pediatric study under PREA for use as an adjunct to hemostasis for control of bleeding during liver surgery in the pediatric study for ages 30 days to 18 years.
Deferred pediatric study under PREA for use with manual compression as an adjunct to hemostasis in pediatric patients aged 1 month to less than 18 years undergoing surgery, when control of bleeding by conventional surgical techniques (such as suture, ligature, and cautery) is ineffective or impractical.
Conduct a Post Approval Safety Study (PASS) NN1841-3868: "Use of rFXIII in treatment of congenital FXIII deficiency, a prospective multi-center observational study."
Assess the safety and effectiveness of Allogeneic Cultured Keratinocytes and Fibroblasts in Bovine Collagen for topical (non-submerged) application to a surgically created vascular wound bed in the treatment of mucogingival disorders in pediatric patients ages 12 to 18 years.
Deferred pediatric study under PREA for the treatment of primary immunodeficiency in pediatric patients 2-16 years of age.
Baxter commits to conducting an evaluation of long-term safety study of HYQVIA in 250 patients with PID including up to 50 patients developing antibodies. The duration of the study is 6 years and subjects who become antibody positive will be eligible for further long term safety evaluation and antibody characterization.
Baxter commits to establish and maintain a pregnancy registry to assess a) the course and outcome of the pregnancy, b) the development of the fetus/infant at birth, and c) the development of the infant for two years following birth. The duration of the registry will be six years and will be open to all women who become pregnant while taking HYQVIA.
Conduct a study (Study V58_31) under PREA to evaluate the safety of FLUCELVAX in children ages 4 years to less than 18 years.
Deferred pediatric dose ranging, immunogenicity and safety study (Study V58P16) under PREA in children ages 6 months to less than 4 years.
Deferred pediatric study (Study V58_35) under PREA to evaluate the safety and immunogenicity of FLUCELVAX in children ages 6 months to less than 4 years.
Establish a pregnancy registry to prospectively collect data on spontaneously-reported exposures to FLUCELVAX during pregnancy.
Conduct a randomized, controlled, observer-blind, immunogenicity and safety study in adults comparing three lots of FLUCELVAX produced under manufacturing process 1.1 at the Holly Springs facility.
To conduct a study to evaluate the efficacy, safety and immunogenicity of the quadrivalent formulation of your Influenza Vaccine compared to a non-influenza comparator vaccine in persons 4 years to less than 18 years of age.
Deferred pediatric study (Study V130_10) under PREA to evaluate the safety and immunogenicity of your quadrivalent formulation of Influenza Vaccine in pediatric subjects 6 months to less than 4 years of age.
To establish a pregnancy registry to prospectively collect data on spontaneously-reported exposures to Flucelvax® Quadrivalent or Flucelvax® during pregnancy and collect data on pregnancy outcomes. When the registry has enrolled a minimum of 600 evaluable subjects and collected data on the outcomes specified in the protocol, Seqirus will submit a full study report and continue enrolling in the registry pending CBER review and discussion of registry results with Seqirus.
Conduct an open-label, multicenter, clinical study to investigate safety, tolerability and efficacy of Octaplas in the management of pediatric patients less than 16 years old who require multiple plasma coagulation factors
Cnduct a non-interventional, open-label, multicenter, clinical study to investigate safety, tolerability and efficacy of Octaplas in the management of pediatric patients less than 16 years old who require therapeutic plasma exchange.
Conduct a non-interventional 2-arm study to evaluate the safety of Octaplas versus FFP in patients treated for thrombotic thrombocytopenic purpura (TTP) with special emphasis on monitoring the occurrence of thromboembolic events (TEEs).
Conduct a non-interventional 2-arm study to evaluate the safety of Octaplas versus FFP in patients undergoing orthotopic liver transplantation (LTX) with a special emphasis on hyperfibrinolysis.
Conduct study Q-Pan H5N1=AS03-021 under PREA to evaluate the safety and immunogenicity of Influenza A (H5N1) Virus Monovalent Vaccine, Adjuvanted when administered to healthy persons 6 months to less than 18 years of age.
Conduct study Q-Pan-023 under PREA to evaluate the safety and immunogenicity of Influenza A (H5N1) Virus Monovalent Vaccine, Adjuvanted when administered to healthy children 6 months to less than 36 months of age.
Conduct study Q-Pan-024 under PREA to evaluate the safety and immunogenicity of Influenza A (H5N1) Virus Monovalent Vaccine, Adjuvanted when administered to healthy persons 6 months to less than 18 years of age. Study Q-Pan-024 will be conducted only if study Q-Pan-023 identifies a pediatric dose that is different than that evaluated in study Q-Pan H5N1=AS03-021.
Conduct study Q-Pan-025 under PREA to evaluate the safety and immunogenicity of Influenza A (H5N1) Virus Monovalent Vaccine, Adjuvanted when administered to healthy infants less than 6 months of age.
Establish a pregnancy registry in the U.S. that is able to prospectively collect data on an actively recruited cohort to study the safety of Influenza A (H5N1) Virus Monovalent Vaccine, Adjuvanted during pregnancy. A concept protocol for this pregnancy registry will be prepared under the assumption that the vaccine would be distributed to the general population in the U.S. in an officially-declared H5N1 influenza virus pandemic. Once the circumstances of the vaccine use in an officially-declared H5N1 influenza virus pandemic are determined by the U.S. Government, you will work with the FDA to finalize the protocol and you will initiate the registry.
A retrospective observational cohort study to estimate the risk of thromboembolic events following Vitamin K Antagonist (VKA) reversal among patients treated with Kcentra or Plasma for urgent reversal of VKA therapy in the setting of acute major bleeding.
Conduct a prospective, double-blind, randomized, multicenter study to assess the efficacy of standard and low doses of Kcentra in reversing effects of VKA in subjects with acute major bleeding.
Deferred pediatric study IB1001-02B under PREA for the treatment of hemophilia B in pediatric patients ages 0-12. Final Protocol Submission: Received on November 6, 2015
Evaluate the safety and efficacy of ALPROLIX in study 9HB02PED in the ongoing open-label, multi-center, evaluation of safety, pharmacokinetics, and efficacy in the prevention and treatment of bleeding episodes in pediatric subjects (PTPs) with Hemophilia B.
Evaluate the safety and efficacy of ALPROLIX in study 9HB01EXT, an open-label, multi-center evaluation of the long-term safety and efficacy in the prevention and treatment of bleeding episodes in previously treated patients with Hemophilia B.
Evaluation of long-term efficacy and safety of RIXUBIS in 100 patients of all age groups with hemophilia B, of which at least 25 will be subjects naïve to RIXUBIS.
You agree to re-initiate the BAT patient registry in the event of a mass botulism exposure scenario. The registry will evaluate the safety and clinical benefit of Botulism Antitoxin Heptavalent (A, B, C, D, E, F, G) - (Equine) used to treat adult, pediatric and infant patients with a confirmed or suspected exposure to botulism.
Conduct a patient registry study for 3 years to evaluate safety following BAT administration in adult, pediatric and infant patients with a confirmed or suspected exposure to botulism
Conduct a pharmacokinetic (PK) study in pediatric patients to verify the pediatric dosing recommendations for BAT.
Evaluate the safety and efficacy of Novoeight in previously untreated patients with hemophilia A in Trial NN7008-3809, Safety and efficacy study in prevention and treatment of bleeds in pediatric previously untreated patients with Hemophilia A.
Evaluate the safety and efficacy of Novoeight during long-term treatment of patients with severe and moderately severe hemophilia A in Trial NN7008-3553, Non-interventional safety and efficacy study during long term treatment of severe and moderately severe Hemophilia A.
Conduct a deferred pediatric study (Study 140224) under PREA for immunotherapy for the treatment of grass pollen-induced allergic rhinitis with or without conjunctivitis confirmed by positive skin test or in vitro testing for pollen-specific IgE antibodies for any of the five grass species contained in the product.
To conduct an observational postmarketing study (Study 140225) to further describe the safety profile in approximately 6,000 patients 10 to 65 years of age receiving Sweet Vernal, Orchard, Perennial Rye, Timothy, and Kentucky Blue Grass Mixed Pollens Allergen Extract approximately 4 months before the expected onset of the grass pollen season and throughout the grass pollen season.
Conduct a post-market claims-based study to further describe the safety profile of GRASTEK in marketed use in the United States. The study will enroll all new users of GRASTEK identified through claims data from a large US health insurance database for a period of at least three years from launch of GRASTEK. The study observation period will last for at least 3 years and until at least 10,000 patients are accrued between both post-market studies. Outcomes of interest identified through claims data will be verified using medical record review.
Conduct a post-market electronic medical record study to further describe the safety profile of GRASTEK in marketed use in the United States. The study will enroll all new users of GRASTEK identified through electronic medical records in a large US integrated health system for a period of at least three years from launch of GRASTEK. The study observation period will last for at least 3 years and until at least 10,000 patients are accrued between both post-market studies. This study will include early exposures to GRASTEK, including administration through starter packs provided in physician offices as well as all subsequent exposures.
Conduct study, protocol #P008, under PREA to evaluate both safety and efficacy of RAGWITEK as immunotherapy for the treatment of short ragweed pollen-induced allergic rhinitis, with or without conjunctivitis, confirmed by positive skin test or in vitro testing for pollen specific IgE antibodies for short ragweed pollen in pediatric subjects aged 5 to 17 years.
Conduct study, protocol #P009, under PREA to evaluate safety of RAGWITEK as immunotherapy for the treatment of short ragweed pollen-induced allergic rhinitis, with or without conjunctivitis, confirmed by positive skin test or in vitro testing for pollen specific IgE antibodies for short ragweed pollen in pediatric subjects aged 5 to 17 years.
A postmarket claims-based study to further describe the safety profile of RAGWITEK in marketed use in the United States. The study will enroll all new users of RAGWITEK identified through claims data from a large U.S. health insurance database for a period of at least three years from launch of RAGWITEK. The study observation period will last for at least 3 years and until at least 10,000 patients are accrued between both postmarketing studies. Outcomes of interest identified through claims data will be verified using medical record review.
A postmarket electronic medical record study to further describe the safety profile of RAGWITEK in marketed use in the United States. The study will enroll all new users of RAGWITEK identified through electronic medical records in a large U.S. integrated health system for a period of at least three years from launch of RAGWITEK. The study observation period will last for at least 3 years and until at least 10,000 patients are accrued between both postmarketing studies. This study will include early exposures to RAGWITEK, including administration through starter packs provided in physician offices as well as all subsequent exposures.
To complete the data analysis for trial 8HA02PED, An Open-Label, Multicenter Evaluation of Safety, Pharmacokinetics, and Efficacy of Recombinant Coagulation Factor VIII Fc Fusion Protein, BIIB031, in the Prevention and Treatment of Bleeding Episodes in Pediatric Subjects With Hemophilia A.
To complete ongoing trial 8HA01EXT, An Open-Label, Multicenter Evaluation of the Long-Term Safety and Efficacy of Recombinant Human Coagulation Factor VIII Fusion Protein (rFVIIIFc) in the Prevention and Treatment of Bleeding Episodes in Previously Treated Subjects With Hemophilia A.
To complete trial 99HA306, An Open-Label, Multicenter Evaluation of the Safety and Efficacy of Recombinant Coagulation Factor VIII Fc Fusion Protein (rFVIIIFc) in the Prevention and Treatment of Bleeding in Previously Untreated Patients With Severe Hemophilia A.
Conduct a study consisting of establishment and maintenance of a registry of HAE patients 13 years of age and older who are prescribed RUCONEST without plasma-derived C1 esterase inhibitors to evaluate the incidence of adverse events and time to symptom relief, as well as to characterize hypersensitivity reactions, thrombotic events, and the safety profile in pregnant and nursing women in the treatment of acute attacks of HAE in adult and adolescent patients. The study will continue until either a) three years have elapsed, or b) 100 patients have been enrolled, 35 of whom will be treated with RUCONEST for at least three attacks.
A post-marketing registry study of perioperative management of moderate to severe hereditary factor X deficient patients receiving Coagadex (human factor X concentrate) for major surgical procedures.
To complete the ongoing 10-year study extension of Protocol V503-002 to evaluate the long-term safety, immunogenicity and effectiveness of Gardasil 9 in males and females who were between 9 and 15 years of age at enrollment.
To conduct a 10-year study extension of Protocol V503-001 to evaluate the long-term safety, immunogenicity and effectiveness of Gardasil 9 in women who were 16 to 26 years of age at enrollment.
To conduct an observational study to further characterize the safety profile of Gardasil 9 in approximately 10,000 persons.
To establish a pregnancy registry as described in your final protocol submitted September 16, 2014, to continue for at least 5 years, to prospectively collect data on spontaneously reported exposures to Gardasil 9 occurring within 30 days prior to the last menstrual period or at any time during pregnancy. You will submit annual reports as well as a five-year summary report, after which you will continue enrolling patients in the registry pending CBER review of the report and determination of whether the registry can be discontinued.
To complete the ongoing study V503-010-01 to evaluate the persistence of antibody titers 36 months after vaccination to the nine vaccine-HPV types in GARDASIL 9 in males and females who received 2-dose and 3-dose regimens of GARDASIL 9.
To conduct the confirmatory study (V118_18) to assess efficacy of Fluad aQIV as compared to an active control Tdap vaccine (tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine, adsorbed [Boostrix]) in adults 65 years of age and older
Deferred Pediatric Trial (V118_05) under PREA to evaluate efficacy, safety and immunogenicity of Fluad aQIV when administered to children 6 months to less than 72 months of age.
Deferred pediatric trial (V70_29) under PREA to evaluate the safety and immunogenicity of Fluad when administered to children 6 months to less than 72 months of age.
Deferred pediatric trial (V118_19) under PREA to evaluate the safety and immunogenicity of Fluad aQIV when administered to children 6 years to less than 9 years of age.
Deferred pediatric trial (V118_14) under PREA to evaluate the safety and immunogenicity of Fluad aQIV when administered to infants less than 6 months of age.
To collect additional efficacy and safety data for OBIZUR in adults with acquired hemophilia A in the Treatment Registry study under Protocol 241302, “A Non-Interventional Study of Safety and Effectiveness of Recombinant Porcine Sequence FVIII (OBIZUR) in the Treatment of Bleeding Episodes for Patients with Acquired Hemophilia A.”
Conduct a prospective observational cohort study of 920 IMLYGIC-treated patients to characterize the risk of herpetic infection among patients, close contacts, and healthcare providers; each subject will be followed for 5 years after initiating IMLYGIC (study Protocol #20130193).
Complete the ongoing single-arm trial to evaluate the biodistribution and shedding of IMLYGIC in 60 IMLYGIC-treated subjects (study Protocol #20120324).
Deferred pediatric study under PREA for use as an adjunct to surgical hemostasis for mild to moderate bleeding from small vessels when control of bleeding by standard surgical techniques is ineffective or impractical in pediatric patients ages 0 to 18 years.
To conduct the ongoing study V102_16 to assess the performance of immunologic assays for evaluating the breadth of coverage against diverse Neisseria meningitidis serogroup B strains.
To conduct study V72_72 of BEXSERO among persons 10 years through 25 years of age in the US to confirm effectiveness against a panel of diverse Neisseria meningitidis serogroup B strains.
A deferred pediatric study (V72_57) under PREA to evaluate the safety and immunogenicity of BEXSERO in North American infants 6 weeks through 12 months of age for the prevention of invasive group B meningococcal disease.
A deferred pediatric study (V72_28) under PREA to evaluate the safety and immunogenicity of BEXSERO in infants 2.5 months through 11 months of age and in children 2 years through 10 years of age for the prevention of invasive group B meningococcal disease.
To conduct a safety and immunogenicity study (V72_79) to assess concomitant use of BEXSERO with a second dose of Meningococcal (Groups A, C, Y and W-135) Oligosaccharide Diphtheria CRM197 Conjugate Vaccine in persons 16 years through 18 years of age.
To establish a pregnancy registry for BEXSERO in the US to prospectively collect data on spontaneously reported exposures to BEXSERO occurring within 30 days prior to the last menstrual period or at any time during pregnancy. You will submit annual reports as well as a three-year summary report, after which you will continue enrolling patients in the registry pending CBER review of the report and determination that the registry can be discontinued.
To conduct the ongoing study (B1971009) among persons 10 years to less than 19 years of age to confirm effectiveness against a panel of diverse meningococcal group B strains.
To conduct the ongoing study (B1971016) among persons 18 years to less than 26 years of age to confirm the effectiveness against a panel of diverse meningococcal group B strains.
A deferred pediatric study (B1971017) under PREA to evaluate the safety and immunogenicity of Trumenba in children 2 years to less than 10 years of age for the prevention of invasive group B meningococcal disease.
A deferred pediatric study (B1971035) under PREA to evaluate the safety and immunogenicity of Trumenba in children 12 months to less than 24 months of age for the prevention of invasive group B meningococcal disease.
A deferred pediatric study (B1971051) under PREA to evaluate the safety and immunogenicity of Trumenba in children 1 year to less than 10 years of age for the prevention of invasive group B meningococcal disease.
To conduct the ongoing safety and immunogenicity study (B1971015) to assess concomitant use of Trumenba with Meningococcal (Groups A, C, Y and W-135) Polysaccharide Diphtheria Toxoid Conjugate Vaccine and Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine, Adsorbed in persons 10 years to less than 13 years of age.
To conduct the ongoing controlled study (B1971014) to further describe the safety of Trumenba in persons 10 years to less than 26 years of age.
To conduct a cohort study (B1971052) to examine pregnancy and birth outcomes following vaccination with Trumenba prior to or during pregnancy.
To conduct a study to assess safety, tolerability, and immunogenicity of Trumenba administered on a 0-, 6-month schedule in healthy subjects aged =10 to less than 26 years
A deferred pediatric study under PREA to evaluate the safety and immunogenicity of a 2-dose regimen (0 and 6 months) of Trumenba in children 1 year to less than 10 years of age for the prevention of invasive group B meningococcal disease
GENA-05: Evaluation of immunogenicity, efficacy and safety of Antihemophilic Factor (Recombinant) in previously untreated patients.
GENA-13: Evaluation of long-term immunogenicity, tolerability, and efficacy of Antihemophilic Factor (Recombinant) in previously treated children.
GENA-15: Extension for subjects who completed GENA-05.
GENA-99: Post-licensure trial to document long-term immunogenicity, safety, and efficacy of Antihemophilic Factor (Recombinant) in patients treated in normal clinical practice.
Conduct a field study (protocol AX-003A) to evaluate the efficacy, pharmacokinetics, and safety of Anthrax Immune Globulin (Human) for the treatment of toxemia associated with inhalational anthrax in adult and pediatric patients in combination with appropriate antibacterial drugs. The primary endpoint of this study will be all-cause mortality.
To submit annual progress reports as well as interim clinical summary reports including available cumulative clinical and pharmacokinetic data every three years from use of Anthrax Immune Globulin (Human) in sporadic systemic anthrax cases (protocol AX-003B).
Deferred pediatric study under PREA for the on-demand treatment and control ofbleeding episodes and routine prophylaxis to reduce the frequency of bleeding episodesin pediatric patients ages 0 to less than 12 years (A phase 3 prospective, uncontrolled, multicenter study to evaluate PK, efficacy, safety, and immunogenicity of ADYNOVATE in pediatric previously treated patients (PTPs) less than 12 years of age [clinical study 261202]).
Deferred pediatric study under PREA for the treatment of perioperative management ofbleeding in pediatric patients ages two years to less than 17 years (A phase 3,prospective, open label, multi-center study of efficacy and safety of ADYNOVATE inthe perioperative management of bleeding in PTPs age 2-75 years [clinical study 261204]– PEDIATRIC COMPONENT ONLY).
Deferred pediatric study under PREA for routine prophylaxis to compare the efficacy and safety of two different pharmacokinetics (PK) guided dosing regimens in pediatric patients ages 12 to less than 17 years (A phase 3, prospective, randomized, multi-center clinical study comparing the safety and efficacy of ADYNOVATE following PK-guidedprophylaxis targeting two different FVIII trough levels in subjects with severeHemophilia A [clinical study 261303] - PEDIATRIC COMPONENT ONLY)
Conduct “A phase 3, prospective, open label, multi-center study of efficacy and safety of ADYNOVATE in the perioperative management of bleeding in PTPs age 2-75 years” [clinical study 261204] – ADULT COMPONENT ONLY.
Conduct “A phase 3b, prospective, open label, and multicentercontinuation study of safety and efficacy of ADYNOVATE in the routine prophylaxis of bleeding to reduce the frequency of bleeding episodes in PTPs” age 12 years and above [clinical study 261302].
Conduct “A phase 3, prospective, randomized, multi-center clinical study comparing the safety and efficacy of BAX 855 [ADYNOVATE] following PK-guided prophylaxis targeting two different FVIII trough levels in subjects with severe Hemophilia A” [clinical study 261303] – ADULT COMPONENT ONLY.
Conduct “A phase 3, multi-center, open label study to investigate safety and immunogenicity of ADYNOVATE in previously untreated patients(PUPs)” [clinical study 261203]. This study will evaluate on-demand treatment andcontrol of bleeding episodes in the setting of routine prophylaxis to reduce the frequencyof bleeding episodes, as well as the perioperative management of bleeding.
Collect additional safety and efficacy information of KOVALTRY in patients with hemophilia A in a clinical study in 25 previously untreated patients under Protocol 13400 “A multi-center Phase III uncontrolled open label trial to evaluate safety and efficacy of BAY 81-8973 (KOVALTRY) in children with severe haemophilia A under prophylaxis therapy”
Collect additional safety and efficacy information of KOVALTRY in patients with hemophilia A in an extension clinical study under Protocol 13400 “A multicenter Phase III uncontrolled open-label trial to evaluate safety and efficacy of BAY 81-8973 (KOVALTRY) in children with severe haemophilia A under prophylaxis therapy”
Deferred pediatric study (PXVX-VC-200-006) under PREA for active immunization against disease caused by V. cholerae serogroup O1 in pediatric patients ages 2 years to less than 18 years traveling to cholera-affected areas. This study will evaluate the safety and immunogenicity of VAXCHORA in this age group.
To establish a pregnancy registry for VAXCHORA in the United States to prospectively collect data on spontaneously reported exposures to VAXCHORA occurring within 28 days prior to the last menstrual period or at any time during pregnancy. You will submit annual reports as well as a 5-year summary report, after which you will continue enrolling patients in the registry and submitting annual reports pending CBER review of the reports and determination that the registry can be discontinued.