CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`209803Orig1s000
`209805Orig1s000
`209806Orig1s000
`
`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
`
`PMR/PMC Set (####-#)
`Product Name:
`
`SECTION A: Administrative Information
`NDA/BLA/Supplement #
`NDA 209803
`NDA 209806
`3311-1
`Steglatro (ertugliflozin) tablets
`Segluromet (ertugliflozin and metformin hydrochloride) tablets
`Merck Sharp & Dohme Corp.
`ODE II / DMEP
`
`Applicant Name:
`ODE/Division:
`
`SECTION B: PMR/PMC Information
`1. PMR/PMC Description
`Conduct a 24-week, randomized, double-blind, placebo-controlled, parallel group study of the safety,
`efficacy, and pharmacokinetics (PK) of ertugliflozin as add-on to metformin background therapy for the
`treatment of type 2 diabetes mellitus in pediatric patients ages 10 to 17 years (inclusive), followed by a
`30-week double-blind, controlled extension. Patients will be randomized to receive one of two doses of
`ertugliflozin or placebo once daily. The ertugliflozin doses will be determined using a population PK
`model derived from the Phase 3 program (in adult subjects) for ertugliflozin. As part of the pediatric
`study, sparse blood samples for population PK and exposures-response analysis will be collected. An
`interim analysis of the PK data will be performed during this study to confirm acceptable exposure to
`ertugliflozin with the selected doses.
`
`2. PMR/PMC Schedule Milestones2, 3
`Final Protocol Submission:
`10/2018
`Study Completion:
`03/2026
`Final Report Submission:
`09/2026
`
`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.
`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
`1
`
`PMR/PMC Development Template
`
`Reference ID: 4197464
`
`Last Update 06/2017
`
`

`

`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.
`The goal of this PMR is to establish the safety and efficacy of ertugliflozin in pediatric patients ages 10 to
`17 (inclusive).
`
`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
`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)
`
`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
`
`PMR/PMC Development Template
`
`Reference ID: 4197464
`
`Last Update 06/2017
`
`

`

`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)
`
`PMR/PMC Development Template
`
`3
`
`Reference ID: 4197464
`
`Last Update 06/2017
`
`

`

`Complete Q4.c when FAERS cannot provide 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 ]
` 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 after 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
`
`Complete Q4.d when the ARIA 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 ]
` Cannot identify exposure to the drug(s) of interest in the database.
` 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
`
`PMR/PMC Development Template
`
`Reference ID: 4197464
`
`4
`
`Last Update 06/2017
`
`

`

`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” and provide the appropriate responses.]
`
` Yes, a study is sufficient [Explain your answer in the textbox and then go to Q.5]
`
` No, a study is not sufficient [Select all explanations that apply then go to Q.4.f ]
` 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.).
` Need pre-specified and prospective active data collection of the outcome/endpoint of interest
` Other
`
`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 or Q4.a above?
`[Select ONE OPTION only under either “Type of Study” or “Type of clinical Trial”]
`TYPE OF STUDY
` Drug interaction or bioavailability studies (nonclinical only)
` 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)
` Immunogenicity study (nonclinical)
` Meta-analysis or pooled analysis of previous observational studies
` Nonclinical (animal) study (e.g., genotoxicity, carcinogenicity, reproductive toxicology)
` Nonclinical (in vitro) study (laboratory/microbiology resistance, receptor affinity)
` Pharmacogenetic or pharmacogenomic study
` Pharmacokinetic (PK) and/or pharmacodynamics (PD) study (nonclinical only)
` Quality CMC study (e.g., manufacturing, studies on impurities)
` Quality stability study
` Registry-based observational study
`
`5
`
`PMR/PMC Development Template
`
`Reference ID: 4197464
`
`Last Update 06/2017
`
`

`

` 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)
`* 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
`
`PMR/PMC Development Template
`
`Reference ID: 4197464
`
`6
`
`Last Update 06/2017
`
`

`

`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 Statements8Error! Reference source not found.
`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
`
`PMR/PMC Development Template
`
`Reference ID: 4197464
`
`Last Update 06/2017
`
`

`

`• The trial will emphasize minimizing the risk minimization for participants as the protocol is developed.
`
`3.
`
` 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.
`Refer to DARRTS electronic signature
`
`PMR/PMC Development Template
`
`Reference ID: 4197464
`
`8
`
`Last Update 06/2017
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`ELISABETH A HANAN
`12/19/2017
`
`MARY T THANH HAI
`12/19/2017
`
`Reference ID: 4197464
`
`

`

`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 209803
`PMR/PMC Set (####-#)
`3311-2
`Product Name:
`Steglatro (ertugliflozin) tablets
`Applicant Name:
`Merck Sharp & Dohme Corp.
`ODE/Division:
`ODE II / DMEP
`
`SECTION B: PMR/PMC Information
`1. PMR/PMC Description
`Conduct a randomized, double blind, placebo-controlled trial evaluating the effect of
`ertugliflozin 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 ertugliflozin to that observed in the placebo group is less than 1.3. This trial must
`also assess pregnancy outcomes and the following adverse events: amputations, ketoacidosis,
`complicated genital infections, complicated urinary tract infections, fractures, pancreatitis,
`serious hypersenstivity events, and malignancies. The estimated glomerular filtration rate
`(eGFR) should also be monitored over time to assess effects on renal function.
`
`2. PMR/PMC Schedule Milestones2, 3
`Final Protocol Submission:
`not required because the trial is ongoing
`Trial Completion:
`10/2019
`Final Report Submission:
`12/2020
`
`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.
`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
`1
`
`PMR/PMC Development Template
`
`Reference ID: 4197476
`
`Last Update 06/2017
`
`

`

`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.
`Patients with diabetes mellitus are at increased risk of cardiovascular events and cardiovascular death. As
`a result of concerns that some anti-diabetic drugs may actually increase the risk of cardiovascular
`events/death despite improving glycemic control, the development of new anti-diabetic agents has
`included an assessment of cardiovascular risk. An estimate of cardiovascular risk derived from a meta-
`analysis of cardiovascular data across the Phase 2 and 3 trials with ertugliflozin has provided sufficient
`evidence that ertugliflozin does not unacceptably increase cardiovascular risk above the pre-approval risk
`margin specified in the 2008 FDA Guidance to Industry, “Diabetes Mellitus – Evaluating Cardiovascular
`Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes.” The Guidance also stipulates a more
`stringent risk margin would need to be demonstrated post-approval. This study is intended to fulfill that
`requirement by demonstrating that treatment with ertugliflozin does not result in an unacceptable increase
`in risk for major adverse cardiovascular events (MACE, i.e., cardiovascular death, non-fatal myocardial
`infarction, and non-fatal stroke).
`
`The applicant has already provided sufficient evidence that ertugliflozin does not unacceptably increase
`cardiovascular risk to support marketing, but has not definitively excluded an unacceptable level of
`cardiovascular risk. Therefore, consistent with the above guidance, the primary objective of the required
`postmarketing trial is to establish that the upper bound of the 95% confidence interval for the estimated
`risk ratio comparing the incidence of major adverse cardiovascular events observed with ertugliflozin to
`that observed with placebo is less than 1.3.
`
`Pregnancy outcomes and signals for amputations, ketoacidosis, complicated genital infections,
`complicated urinary tract infections, fractures, pancreatitis, serious hypersensitivity events, and
`malignancies will be further assessed in this trial.
`
`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]
`
`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
`
`PMR/PMC Development Template
`
`Reference ID: 4197476
`
`Last Update 06/2017
`
`

`

`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
`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
`
`PMR/PMC Development Template
`
`Reference ID: 4197476
`
`3
`
`Last Update 06/2017
`
`

`

`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.
`
`Complete Q4.c when FAERS cannot provide 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 ]
` 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 after 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
`
`6 FDA Adverse Event Reporting System (FAERS)
`7 Active Risk Identification and Analysis (ARIA)
`
`PMR/PMC Development Template
`
`4
`
`Reference ID: 4197476
`
`Last Update 06/2017
`
`

`

`Complete Q4.d when the ARIA 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 ]
` Cannot identify exposure to the drug(s) of interest in the database.
` 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
`In general and at this time, observational studies, including an observational study using the ARIA
`system, are not considered sufficient to evaluate the cardiovascular endpoints of interest.
`
`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” and provide the appropriate responses.]
`
` Yes, a study is sufficient [Explain your answer in the textbox and then go to Q.5]
`
` No, a study is not sufficient [Select all explanations that apply then go to Q.4.f ]
` 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.).
` Need pre-specified and prospective active data collection of the outcome/endpoint of interest
` Other
`
`PMR/PMC Development Template
`
`Reference ID: 4197476
`
`5
`
`Last Update 06/2017
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`f.
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` 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 or Q4.a above?
`[Select ONE OPTION only under either “Type of Study” or “Type of clinical Trial”]
`TYPE OF STUDY
` Drug interaction or bioavailability studies (nonclinical only)
` 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)
` Immunogenicity study (nonclinical)
` Meta-analysis or pooled analysis of previous observational studies
` Nonclinical (animal) study (e.g., genotoxicity, carcinogenicity, reproductive toxicology)
` Nonclinical (in vitro) study (laboratory/microbiology resistance, receptor affinity)
` Pharmacogenetic or pharmacogenomic study
` Pharmacokinetic (PK) and/or pharmacodynamics (PD) study (nonclinical only)
` Quality CMC study (e.g., manufacturing, studies on impurities)
` Quality stability study
` Registry-based observational study
` Other (describe)
`
`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)
`* 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).
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`PMR/PMC Development Template
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`Reference ID: 4197476
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`6
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`Last Update 06/2017
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`** 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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`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
` M