CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`208700Orig1s000
`
`
`OTHER REVIEW(S)
`
`

`

`PMR/PMC DEVELOPMENT TEMPLATE
`For 506B Reportable1 PMRs and PMCs only
`
`This form describes and provides the rationale for postmarketing requirements/commitments (PMRs/PMCs) subject to
`reporting requirements under section 506B of the FDCA.
`Complete this form using the instructions (see Appendix A) and by referring to MAPP 6010.9, “Procedures and
`Responsibilities for Developing Postmarketing Commitments and Requirements.”
`Note: Do not use this template for CMC PMCs. Instead, use the CMC PMC Development Template.1
`
`SECTION A: Administrative Information
`NDA/BLA/Supplement #
`NDA 208700
`PMR/PMC Set (####-#)
`3326-02
`Product Name:
` Lutathera (Lutetium Lu 177 Oxodotreotide)
`Applicant Name:
`Advanced Accelerator Applications USA, Inc. (AAA)
`ODE/Division:
`OHOP/DOP2
`
`SECTION B: PMR/PMC Information
`1. PMR/PMC Description
`Submit cumulative, integrated safety analyses after 5 and after 10 years of follow-up from an
`adequate number of patients enrolled in clinical trials to identify and characterize the risks of
`myelodysplastic syndrome and acute leukemia with Lutathera; include incidence rates, time to
`onset, predisposing factors and outcomes. These safety evaluations should be adequate to
`inform labeling of patient populations at highest risk and to provide evidence-based dose
`modifications and monitoring recommendations.
`
`1 506B “reportable” includes all studies/trials an applicant has agreed upon or is required to conduct related to clinical safety, clinical efficacy,
`clinical pharmacology, or nonclinical toxicology (21 CFR 314.81(b)(2 )(vii) and 21 CFR 601.70(a)). All PMRs are considered 506 “reportable.” A
`separate development template is used for 506 B non-reportable (e.g., chemistry, manufacturing, and controls (CMC)) PMCs, which is located in the
`CST.
`
`1
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`PMR/PMC Development Template
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`Reference ID: 4211485
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`Last Update 06/2017
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`2. PMR/PMC Schedule Milestones2, 3
`
`Section 2 is not applicable as no new studies are being requested.
`Final Analysis Plan Submission:
`Interim Safety Report Submission:
`Final Report Submission:
`
`June 2018
`September 2021
`December 2025
`
`SECTION C: PMR/PMC Rationale
`1. Describe the particular review issue and the goal of the study4 or clinical trial5 in the text box below.
`[Based on the mode of excretion of LUTATHERA, an increased risks of myelodysplastic syndrome and
`acute leukemia are suspected. An increased risk of myelodysplastic syndrome, a precursor of acute
`leukemia was reported in the NETTER-1 trial which supported the approval. However, the proposed
`follow-up time of 5 years following end of treatment for patients in the NETTER-1 trial is not sufficient
`to define the magnitude of the risk since onset of this event may not occur for up to 10 years following
`treatment. Additional follow-up time is required in a defined study population to more precisely estimate
`the risk and the time to onset of this serisous adverse event.]
`
`2. Explain why this issue can be evaluated post-approval and does not need to be addressed prior to approval.
`(Select one explanation below.)
` Subpart I or H (animal efficacy rule) PMR: Approved under Subpart I or H (animal efficacy rule) authorities;
`postmarketing study/trial required to verify and describe clinical benefit [Skip to Q.5]
` Subpart H or E (accelerated approval) PMR: Approved under Subpart H or E (accelerated approval) authorities;
`postmarketing study/trial required to verify and describe clinical benefit [Skip to Q.5]
` PREA PMR: Meets PREA postmarketing pediatric study requirements [Skip to Q.5]
`FDAAA PMR (safety): Benefit/risk profile of the drug appears favorable; however, there are uncertainties about
`aspects of the drug’s safety profile. Because the investigation will evaluate a serious risk, it meets FDAAA
`requirements for a postmarketing safety study or trial [Go to Q.3]
` PMC (506B reportable): Benefit/risk profile of the drug appears favorable; however, there are uncertainties about
`aspects of the drug’s efficacy profile or other issues. The purpose of the investigation does not meet requirements
`under Subpart I/H , H/E, PREA, or FDAAA to be a PMR, and therefore the investigation is a PMC. [Go to Q.3]
`
`3. For FDAAA PMRs and 506B PMCs only
`
`2 Final protocol, study/trial completion, and final report submissions are required milestones. Draft protocol submissions and interim milestones are
`optional. EXCEPTION: PMRs/PMCs for medical countermeasures may have only draft/final protocol submission dates and no other milestones,
`since the study/trial will only be initiated in the event of an emergency. Interim milestones may include interim report milestones for studies/trials
`that may be of long duration. May include interim subject accrual milestone (e.g., for accelerated approval PMRs). Other milestones should be
`justified in Section D, question 3.
`3 Dates should be numerical (e.g., 05/2016). PREA PMR date format may be MM/DD/YYYY if a day is specified.
`4 A “study” is an investigation that is not a clinical trial, such as an observational (epidemiologic) study, animal study, or laboratory experiment.
`5 A “clinical trial” is any prospective investigation in which the applicant or investigator determines the method of assigning the drug product(s) or
`other interventions to one or more human subjects. Note that under PREA, clinical trials involving pediatric patients are specifically referred to as
`“studies.”
`
`2
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`PMR/PMC Development Template
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`Reference ID: 4211485
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`Last Update 06/2017
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`The study or trial can be conducted post-approval because: [Select all that apply]
` Longer-term data needed to further characterize the safety/efficacy of the drug
` Based on the purpose and/or design, it is only feasible to conduct the study/trial post-approval
` Prior clinical experience (e.g., with other drugs in the class) indicates adequate safety or efficacy data to support
`approval, but some uncertainties about safety or efficacy remain and should be further characterized
` Only a small subpopulation is affected (e.g., patients with severe renal impairment) and effects of the drug in the
`subpopulation can be further evaluated after approval
` Study/trial is to further explore a theoretical concern that does not impact the approval determination
` Other reason (describe in text box below)
`
`4. For FDAAA PMRs only [for PMCs skip to Q.5]. Complete this entire section
`a. The purpose of the study/clinical trial is to: [Select one, then go to Q.4.b ]
`Assess a known serious risk related to the use of the drug
`Assess a signal of serious risk related to the use of the drug
`Identify an unexpected serious risk when available data indicate the potential for a serious risk
`
`Complete Q4.b if the necessary data can only be obtained through a particular type of nonclinical study or clinical
`pharmacology trial. Otherwise complete Q4.c and Q4.d.
`b. FAERS6 and Sentinel’s postmarket ARIA7 system are not sufficient for the purposes described in Q1. and
`Q4.a because the safety issue involves:
`[Select all that apply then to skip to Q.5. If none apply, answer both Q4.c and Q4.d ]
`
` A serious risk of genotoxicity, carcinogenicity, or reproductive toxicity, and these signals are initially best
`assessed through in vitro or animal studies.
` A potential drug interaction resulting in lower/higher drug exposure and resultant serious drug risks, and
`accurate assessment of an interaction is feasible only through in vitro mechanistic studies or clinical
`pharmacokinetic and pharmacodynamics trials.
` The potential for lower/higher drug exposure and resultant serious drug risks in patients with hepatic or
`renal impairment, or other metabolic abnormalities, and accurate assessment is feasible only through in vitro
`mechanistic studies or clinical pharmacokinetic and pharmacodynamics trials.
` An immunologic concern for which accurate assessment requires in vitro development or validation of
`specific assays.
`
`6 FDA Adverse Event Reporting System (FAERS)
`7 Active Risk Identification and Analysis (ARIA)
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`PMR/PMC Development Template
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`Reference ID: 4211485
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`Last Update 06/2017
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`Complete Q4.c when FAERS cannotprovide the necessary data and Q4.b does not apply
`
`c. FAERS data cannot be used to fully characterize the serious risk of interest because:
`
`[Select all that apply then go to Q. 4.d ]
`
`X]
`
`E
`
`Assessment of the serious risk necessitates calculation of the rate of occurrence (e.g.. incidence or odds
`
`ratio) of the adverse event(s), and FAERS data cannot be used for such a calculation.
`
`The serious risk of concern has a delayed time to onset. or delayed time to detection afier exposure (e.g..
`
`cancer), and FAERS data are more useful for detecting events that are closely linked in time to initiation of
`
`drug therapy.
`
`The serious risk of concern occurs commonly in the population (e.g.. myocardial infarction) and FAERS
`
`data are more useful in detecting rare serious adverse events for which the background rates are low.
`Other
`
`[The desired information needs to come from a clinical trial]
`
`Complete Q4.d when the ARM system cannot provide the necessary data and Q4.b does not apply.
`
`d. The currently available data within the ARIA system cannot be used to fully characterize the serious risk
`
`of interest because: [Select all that apply then go to Q. 4.e ]
`
`l—I
`
`Cannot identify exposure to the drug(s) of interest in the database.
`
`I:
`
`I:
`
`Serious risk (adverse event) of concern cannot be identified in the database.
`
`The population(s) of interest cannot be identified in the database.
`
`Long—term follow-up information required to assess the serious risk are not available in the database.
`
`Important confounders or covariates are not available or well represented in the database.
`
`The database does not contain an adequate number of exposed patients to provide sufficient statistical power
`
`to analyze the association between the drug and the serious risk of concern.
`
`The purpose of the evaluation is to rule out a modest relative risk. and observational studies, such as an
`
`ARIA analysis. are not well suited for such use.
`Other
`
`X
`
`I:
`
`E I
`
`:
`
`I:
`
`The requested information can only be obtained from a clinical trial.
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`PMR/PMC Development Template
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`Reference ID: 421 1485
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`Last Update 06/2017
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`e.
`
`If FAERS and the ARIA system are not sufficient for the purpose in Q1. and Q4.a, is a study sufficient?
`
`[Select either “Yes” or “No ” andprovide the appropriate responses.]
`
`I: Yes, a study is suflicient [Explain your answer in the textbox and then go to Q. 5]
`
`[Explain why a study is sufficient]
`
`|:] No, a study is not sufficient [Select all explanations that apply then go to Q. 4.f]
`
`I:] Need to minimize bias and/or confounding via randomization
`|:] Need for placebo control
`|:] Need to capture detailed information about covariates or confounders that are either not routinely collected
`
`during the ususal course of medical practice, or are not collected at the frequency needed for assessment
`
`of the safety issue (e. g. hourly blood glucose measures. etc.).
`I: Need pre-specified and prospective active data collection of the outcome/endpoint of interest
`|:] Other
`
`[If you selected “other,” expand on the reason(s) why a study is not sufficient]
`
`f.
`
`|:] Because a study is not sufficient, a clinical trial is required. [Go to Q. 5]
`
`5. For all PMRs and PMCs: What type of study or clinical trial is needed to achieve the goal described in
`
`Q1 fl Q4.a above?
`
`
`[Select ONE OPTION only under either “Type ofStudy ” o_r “Type of clinical Trial ”]
`
`TYPE OF STUDY
`
`I: Drug interaction or bioavailability studies (nonclinical only)
`I: Epidemiologic (observational) study related to safe drug use
`|:| Epidemiologic (observational) study not related to safe drug use (e.g., natural history of disease, background
`rates of adverse events)
`|:| Innnunogenicity study (nonclinical)
`E] Meta-analysis or pooled analysis of previous observational studies
`I:| Nonclinical (animal) study (e.g., genotoxicity, carcinogenicity, reproductive toxicology)
`I: Nonclinical (in vitro) study (laboratory/microbiology resistance, receptor affinity)
`I: Pharmacogenetic or pharmacogenomic study
`|:| Pharmacokinetic G’K) and/or pharmacodynamics (PD) study (nonclinical only)
`|:I Quality CMC study (e.g., manufacturing, studies on impurities)
`|:| Quality stability study
`
`E] Registry-based observational study
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`PMR/PMC Development Template
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`Reference ID: 421 1485
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`Last Update 06/2017
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` Other (describe)
`
`TYPE OF STUDY
`
`TYPE OF CLINICAL TRIAL
` Combined PK/PD, safety and/or efficacy trial (PREA* PMRs only)
` Dose-response clinical trial
` Dosing trial (e.g., alternative dosing schedule)
` Drug interaction or bioavailability clinical trial (clinical only)
` Immunogenicity trial (clinical)
` Meta-analysis or pooled analysis of previous clinical trials
` Pharmacogenetic or pharmacogenomic clinical trial
` Pharmacokinetic (PK) and/or pharmacodynamic (PD) clinical trial
` Primary efficacy clinical trial (i.e, with a primary efficacy endpoint; to further define efficacy; may include
`secondary safety endpoints)
` Primary safety clinical trial (e.g., to evaluate the long-term safety of a drug; to evaluate drug toxicity in a
`subpopulation; may include secondary efficacy endpoints) – excludes SOT
` Safety outcomes trial (SOT)**
` Thorough Q-T clinical trial
` Other (describe) Additional follow-up time is required in a defined study population to more precisely estimate
`the risk and the time to onset of this serisous adverse event
`* Note that under PREA, clinical trials involving pediatric patients are specifically referred to as “studies.” However, for the
`purposes of this template, PREA investigations are categorized according to the established definitions of “studies” and “trials” (see
`Footnotes 3 and 4).
`** A safety outcomes trial (SOT) is defined as a large, prospective, randomized, controlled trial that is specifically designed and
`adequately powered to test a safety hypothesis using a clinical outcome, generally irreversible morbidity or mortality, as the primary
`trial endpoint. A cardiovascular outcomes trial (CVOT) is an example of an SOT.
`
`SECTION D: PMR/PMC Additional Information
`1. This PMR/PMC applies to other drugs or applications (e.g. drugs in a therapeutic class; different formulations
`of the same drug).
` Yes
` No
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`PMR/PMC Development Template
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`Reference ID: 4211485
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`Last Update 06/2017
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`2. This study or clinical trial focuses on the following special population(s) or circumstance(s):
`[Select all that apply]
` For non-PREA pediatric studies/trials only: Pediatric population
` Geriatric population
` Lactating/nursing mothers
` Medical Countermeasures (e.g. anthrax exposure, bioterrorism)
` Orphan or rare disease population
` Pregnant women
` Racial/ethnic population
` Not applicable
`
`3.
`
`(Complete if applicable) Additional comments about the PMR/PMC (e.g., points or concerns not previously
`described; explanation for inclusion of milestones other than the 3 “core” milestones or draft protocol submission)
`
`SECTION E: PMR/PMC Development Coordinator Statements8
`1. The PMR/PMC is clear, feasible, and appropriate9 because: [Select all that apply]
` The study/clinical trial meets criteria for a PMR or a PMC.
` The objectives of the study/clinical trial are clear from the description of the PMR/PMC.
` The applicant has adequately justified the choice of milestone dates.
` The applicant has had sufficient time to review the PMR/PMC, ask questions, determine feasibility, and contribute
`to the development process.
`
`2.
`
` (If the PMR/PMC is a randomized controlled clinical trial) The following ethical considerations were made
`with regard to:
` There is a significant question about the public health risks of the drug.
` There is not enough existing information to assess the public health risks of the drug.
`Information about the public health risks cannot be gained through a different kind of investigation.
`
` The trial will be appropriately designed to answer question about a drug’s efficacy or safety.
`
`8 This section is completed by the PMR/PMC Development Coordinator, who is usually the OND division’s Deputy Director for Safety (DDS). See
`DEFINITIONS section of CDER MAPP 6010.9, Procedures and Responsibilities for Developing Postmarketing Requirements and Commitments.
`
`9 See POLICY section of CDER MAPP 6010.9.
`
`7
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`PMR/PMC Development Template
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`Reference ID: 4211485
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`Last Update 06/2017
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`o The uial will emphasize minimizing the risk minimization for participants as the protocol is developed.
`
`3. g This PMR/PMC has been reviewed for clarity and consistency, and is necessary to further refine the safety,
`
`efficacy, or optimal use of a drug, or to ensure consistency and reliability of drug quality.
`
`Insert electronic signature (usually the Deputy Director for Safety)
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`PMR/PMC Development Template
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`Reference ID: 421 1485
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`Last Update 06/2017
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`

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`Appendix A
`PMR/PMC Development Template (FRM-ADMIN-60)
`Instructions for Use
`[click here to return to the template]
`
`Purpose:
`The PMR/PMC Development template (thereafter, template) is a review tool to help the team decide that PMRs/PMCs are
`needed, articulate the rationale for the PMRs/PMCs, obtain initial supervisory concurrence, and to inform discussions
`with the applicant.
`
`Who completes this template:
`The PMR/PMC Development Coordinator (usually the OND division’s Deputy Director for Safety) may delegate the
`initial draft (i.e., filling out) of the template to an assigned reviewer. However, the PMR/PMC Development Coordinator
`is responsible for ensuring the accuracy and completeness of the template and for signing off on the template.
`
`How to complete this template:
`The assigned reviewer and PMR/PMC Development Coordinator should complete the template by following the
`Instructions For Use. The PMR/PMC Development Coordinator will review each PMR/PMC to ensure it is clearly
`written, has an appropriate rationale, and that milestones were appropriately selected to result in timely submission of
`appropriate data to address the issue that prompted the PMR/PMC.
`
`A separate template is completed for each individual PMR and 506B “reportable” PMC.10 The separate templates are
`then combined into one document for archiving (see “How to archive the completed template”).
`
`A draft template should be completed by the date targeted to begin PMR/PMC discussions with the applicant, as
`documented in the Filing Letter. Once concurrence on the PMR/PMC is reached with the applicant, the draft language in
`the template can be finalized.
`
`How to archive the completed template:
`The OND division’s Safety Regulatory Project Manager should ensure appropriate sign-off on the completed template, as
`determined by the division, and that the process below is followed to ensure the completed template is filed correctly.
`
`Completed templates for all PMRs and 506B “reportable” PMCs for a specific application should be combined and filed
`in CDER’s electronic archival system as a single document. 11 This single document should be filed as PMR/PMC
`Development Template before filing the action letter that establishes the PMR(s)/PMC(s).
`
`For (s)NDA/(s)BLA submissions, the completed, signed template should be included in the Action Package.
`
`10 506B “reportable” includes all studies/trials an applicant has agreed upon or is required to conduct related to clinical safety, clinical efficacy,
`clinical pharmacology, or nonclinical toxicology (21 CFR 314.81(b)(2 )(vii) and 21 CFR 601.70(a)). All PMRs are considered 506 “reportable.” A
`separate development template is used for 506 B non-reportable (e.g., chemistry, manufacturing, and controls (CMC)) PMCs.
`11 A single document facilitates data entry by the document room by preventing the need to upload and archive multiple templates.
`9
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`PMR/PMC Development Template
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`Reference ID: 4211485
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`Last Update 06/2017
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`Instructions:
`
`SECTION A: Administrative Information [Click here to return to Section A of the template]
`Complete each field in section A. Do not leave any fields blank.
`SECTION B: PMR/PMC Information [Click here to return to Section B of the template]
`1. PMR/PMC Description: In the textbox, enter the wording for the PMR/PMC that will go in the letter notifying the
`applicant of the PMR/PMC (e.g., NDA action letter) and will also display in the FDA’s PMR/PMC database. The
`PMR/PMC description should be written clearly enough to result in the applicant’s timely submission of the
`appropriate data to address the issue that prompted the postmarketing study or clinical trial.
`PMR/PMC descriptions are specific to the drug, indication, and issues under evaluation. Nevertheless, PMR/PMC
`descriptions should generally reflect the design of the clinical trial or study (e.g. randomized, double-blind, active
`control trial; registry based prospective cohort study), the population(s) to be studied, the exposure or intervention of
`interest, a comparator group (if applicable), and the study/trial goals and objectives.12
`Avoid limiting the PMR/PMC description to a citation of the name of a specific study or clinical trial that may be
`ongoing (e.g., “Complete trial ABC123, A Randomized, Placebo-Controlled Efficacy Trial of DRUG against
`COMPARATOR”). The study/trial name may be included, but in addition, the PMR/PMC description should describe
`the design features of the study or clinical trial. In this way, should unforeseen developments preclude completion of
`the named study/trial, the PMR/PMC description provides sufficient information for FDA, the applicant, and the
`public to determine the type of study/trial that would be considered sufficient to fulfill the PMR/PMC.
`Certain types of studies and clinical trials are commonly issued as PMRs/PMCs (e.g., drug-drug interaction trials;
`hepatic impairment PK trials). For these, a ‘standard’ PMR/PMC description may be employed [see Appendix B for
`examples].
`
`2. PMR/PMC Milestones: List the PMR/PMC milestones in the specified format.
`Dates should be specified for all milestones. The milestone date format should be MM/YYYY; however, the
`milestone date format for PREA PMRs may be MM/DD/YYYY if a day is specified.
`The Final Protocol Submission, Study/Trial Completion, and Final Report Submission milestones are considered
`“core” PMR/PMC milestones. These are included in every PMR/PMC schedule unless they are not applicable (e.g.,
`study/trial is ongoing; the PMR is for a medical countermeasure study/trial that will not be initiated unless there is an
`emergency).
`The Draft Protocol Submission milestone may be included to ensure sufficient time for FDA review and comment on
`the protocol before it is finalized.13
`
`12 The PMR/PMC description may also include primary and important secondary endpoints, as relevant. Typically the PMR/PMC description should
`not include description of milestones or other indicators of study/trial progress (e.g., frequency of interim reports), as these are described in the
`PMR/PMC timetable. .
`
`13 “Final” implies that the applicant has submitted a protocol, the FDA review team has sent comments to the applicant, and the protocol has been
`revised as needed to meet the goal of the study or clinical trial. Thus, the date for this milestone should be selected to allow for the discussion period
`10
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`PMR/PMC Development Template
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`Reference ID: 4211485
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`Last Update 06/2017
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`“Other” milestones may include interim or annual report submission or subject accrual milestones.
`
`Typically, submission of revised labeling (to reflect results from completed studies/trials are not included as
`PMR/PMC milestones.14
`
`SECTION C: PMR/PMC Rationale [Click here to return to Section C of the template]
`1. Describe the review issue and the goal of the study or clinical trial.
`This section should summarize the rationale for the study/trial. The section should not repeat the description of the
`PMR/PMC provided in Section B.
`The summary should briefly identify the review issue (safety signal for FDAAA PMRs; efficacy or other question for
`non-FDAAA PMRs), cite the source of the data if it includes information external to the application, and explain the
`intent of the study/trial and why we think the results of the PMR/PMC will be important.
`The intent of the study/trial is the explanation of what it is that FDA wants to know. Intents include, but are not
`limited to:
`Signal detection (e.g., detecting potential serious risks associated with the drug)
`
`Signal refinement (e.g., checking to determine whether an identified safety signal persists; conducting
`
`surveillance to obtain additional follow-up on a known serious risk)
`Signal evaluation (e.g., obtaining a precise estimate of the serious risk associated with a drug)
`
`
`
`Examples of a PMR/PMC rationale:
`DRUG-X is metabolized through CYPYYYY, which can be inhibited by COMMONDRUGZ. This DDI trial will
`evaluate whether DRUGX levels are sufficiently increased to warrant a dose reduction when used concurrently
`with COMMONDRUGZ, to reduce the severity and/or likelihood of serious adverse effects caused by DRUGX.
`DRUG-Y is intended for chronic use in patients with CONDITIONA. During clinical development of DRUG-Y,
`the maximum duration of patient exposure was 6 months. This long-term efficacy trial will evaluate whether
`positive treatment effects are maintained when exposures exceed 6 months.
`
`2. Explain why this issue can be evaluated post-approval and does not need to be addressed prior to approval.
`This section documents the statutory or regulatory authorities that necessitate that the study or clinical trial be done
`post-approval (e.g., confirmatory trials for accelerated approval), or why the issue does not preclude an approval
`action and can be evaluated after approval without compromising safety and efficacy considerations.
`Only one option should be selected.
`
`3. For FDAAA PMRs and 506B PMCs only
`
`needed to create a well-designed study or clinical trial. See FDA guidance for industry, Postmarketing Studies and Clinical Trials — Implementation
`of Section 505(o)(3) of the Federal Food, Drug, and Cosmetic Act.
`
`14 Exceptions are PREA and Accelerated Approval PMRs, since those authorities necessitate submission of revised labeling to reflect PMR results.
`
`11
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`PMR/PMC Development Template
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`Reference ID: 4211485
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`Last Update 06/2017
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`This section expands on the reasons why the FDAAA PMR or 506B PMC can be conducted post-approval and do not
`need to be addressed prior to approval.
`This section applies only to FDAAA PMRs and 506B “reportable” PMCs because the statutory and regulatory basis is
`sufficient explanation for all other PMRs (i.e., PREA, accelerated approval, and animal rule PMRs).
`
`4. For FDAAA PMRs only
`This section summarizes the statutory purpose of the FDAAA PMRs, the reasons why FAERS15 and Sentinel’s
`ARIA16 system are insufficient for this purpose and, as applicable, why a study is insufficient for this purpose and a
`clinical trial is necessary. FDA must make each of these hierarchical determinations before requiring a FDAAA
`PMR.
`Question 4.a: identify the purpose of the study/clinical trial:
`As mandated by Section 505(o)(3)(A), postmarketing studies and clinical trials may be required for the three purposes
`listed below. Therefore to document the rationale for requiring a FDAAA PMR, you must identify one of the
`following:
` To assess a known serious risk related to the use of the drug
` To assess signals of serious risk related to the use of the drug
` To identify an unexpected serious risk when available data indicates the potential for a serious risk
`Questions 4.b-d: Explanation of whether FAERS and Sentinel’s postmarket ARIA system are sufficient for the
`purposes described in Q1. and Q4.a.
`Studies/trials are required as FDAAA PMRs when FAERS and the ARIA system are determined to be insufficient to
`assess the safety issue. Responses to questions 4.b-d briefly summarize the reasons why FAERS and the ARIA
`system have been determined insufficient.
`The explanation of why FAERS is insufficient to further characterize the serious risk(s) of concern should be
`informed by the FDA draft guidance, Postmarketing Studies and Clinical Trials — Implementation of Section
`505(o)(3) of the Federal Food, Drug, and Cosmetic Act and by discussions with the Division of Pharmacovigilance
`(DPV) in the Office of Surveillance and Epidemiology (OSE).
`The explanation of why the ARIA system is insufficient to further characterize the serious risk(s) of concern should
`be informed by discussions with the Division of Epidemiology (DEPI) in OSE, the DEPI ARIA Sufficiency
`Memorandum, and the aforementioned FDA guidance. It is acceptable to excerpt text from the ARIA Sufficiency
`Memorandum.
`Question Q4.e: Determination of whether a study is sufficient for the purposes described in Q1. and Q4.a.
`The explanation of why a study is (or is not) sufficient to further characterize the serious risk(s) of concern should be
`informed by the nature of the study (e.g., an animal study is the generally accepted standard for assessment of
`genotoxicity) and relevant discussions with other scientific disciplines such as Clinical Pharmacology,
`Pharmacology/Toxicology, and DEPI.
`
`15 FDA Adverse Event Reporting System (FAERS)
`16 Active Risk Identification and Analysis (ARIA)
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`12
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`PMR/PMC Development Template
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`Reference ID: 4211485
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`Last Update 06/2017
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`Examples of situations when an observational study may not be sufficient, and a clinical trial required, in include (but
`are not limited to):
` Need to minimize bias and/or confounding via randomization
` Need for placebo control
` Need to capture detailed information about covariates or confounders that are either not routinely collected during
`the ususal course of medical practice, or not collected at the frequency needed for assessment of the safety issue
`(e.g. hourly blood glucose measures, etc.).
` Need pre-specified and prospective active data collection of outcome(s)/endpoint(s)
`
`Question Q4.f: Conclusion that only a clinical trial is sufficient for the purposes described in Q1. and Q4.a.
`Under FDAAA, when FAERS, the ARIA system, and a study are considered insufficient, then a clinical trial is
`necessary for the specified purposes.
`
`5. For all PMRs and PMCs: What type of study or clinical trial is needed to achieve the goal?
`This section should be completed for all PMRs and PMCs.
`Select the best summary description of the type of postmarketing study or clinical trial. Select only ONE option
`under either “type of study” or “type of clinical trial.” Do not choose a option under both categories.
`
`SECTION D: PMR/PMC Additional information [Click here to return to Section D of the template]
`This section provides additional information about the PMRs and PMCs.
`1. Does this PMR/PMC apply to other drugs (e.g. drugs in a therapeutic class)?
`Select “yes” if the PMR/PMC will apply to other drugs in the same therapeutic class or different formulations of the
`same drug.
`
`2. This study or clinical trial focuses on the following special population or circumstances:
`Select the appropriate box(es) if the study or trial focuses on a special population. If not, select “not applicable.”
`
`3.
`
`(Complete if applicable) Additional comments about the PMR/PMC.
`Complete this text box only if there are additional comments to add about this PMR or PMC (e.g., points or concerns
`not previously described; explanation for inclusion of additional milestones besides the 3 “core” milestones).
`Note: Additional milestones also must be tracked by the division (see MAPP 6010.2, Responsibilities for Tracking
`and Communicating the Status of Postmarketing Requirements and Commitments).
`If nothing additional to add, leave text box blank.
`
`SECTION E: PMR/PMC Development Coordinator Statements [Click here to return to Section E of the template]
`This section is completed only by the the PMR/PMC Development Coordinator (usually the OND division’s Deputy
`Director for Safety) who will sign off on the completed Development Template.
`
`1. The PMR/PMC is clear, feasible, and appropriate because (select all that apply):
`Select the considerations FDA made to determine that the study or clinical trial is feasible to conduct, appropriately
`described, and informed by discussions with the applicant.
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`13
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`PMR/PMC Development Template
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`Reference ID: 4211485
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`Last Update 06/2017
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`2. The following ethical considerations were made with regard to randomized, controlled, clinical trials:
`This section is only completed if the PMR/PMC is for a rand