CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`210259Orig1s000
`
`
`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 210259
`PMR/PMC Set (####-#)
`PMR 3291-1
`Product Name:
`Calquence™ (acalabrutinib) capsules, 100 mg
`Applicant Name:
`Acerta Pharma B.V
`ODE/Division:
`OHOP/DHP
`
`SECTION B: PMR/PMC Information
`1. PMR/PMC Description
`Submit the complete final report and datasets demonstrating clinical efficacy and safety from a
`randomized, double-blind, placebo-controlled, clinical trial of Calquence in combination with standard
`immunochemotherapy versus immunochemotherapy alone in patients with mantle cell lymphoma.
`
`2. PMR/PMC Schedule Milestones2, 3
`Final Protocol Submitted:
`09/2016
`Enrollment Completed Submission: 12/2020
`Trial Completion:
`10/2023
`Final Report Submission:
`04/2024
`
`
`
`
`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
`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.
`
`PMR/PMC Development Template
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`Reference ID: 4174285
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`1
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`Last Update 06/2017
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`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 clinical trial ACE-L-Y-004 is a single arm study of Calquence® (acalabrutinib) monotherapy in
`patients with mantle cell lumphoma. Overall response rate (ORR) defined as CR or PR per nvestigator
`assessed Lugano response criteria was the primary endpoint of the trial and the basis for accelerated
`approval. In this trial the ORR was 80.6% in patients with mantle cell lymphoma who had received
`between 1 and 5 prior therapies The median duration of response was not reached with at least 12 months
`of follow-up for all responders. Overall response rate is a surrogate endpoint likely to predict clinical
`benefit and, with documentation of duration of resposne, has been accepted by the Agency as an endpoint
`for accelerated approval for mantle cell lymphoma and other non-Hodgin lymphomas. This PMR seeks
`to verify efficacy of Calquence® as measured by progression-free survival (PFS) and overall survival
`(OS) in a randomiazed controlled clinical trial, ie (Study ACE-LY-308).
`
`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)
`
`
`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.”
`
`PMR/PMC Development Template
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`Reference ID: 4174285
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`2
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`Last Update 06/2017
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`[If you selected “other reason,” expand on the reason(s) why it is appropriate to conduct the study/trial
`postapproval and why the issue does not need to be addressed prior to approval.]
`
`
`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
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`Reference ID: 4174285
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`Last Update 06/2017
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`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
`[If you selected “other,” expand on the reason(s) why FAERS is not sufficient.]
`
`
`
`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
`[If you selected “other,” expand on the reason(s) why ARIA is not sufficient.]
`
`
`
`
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`PMR/PMC Development Template
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`Reference ID: 4174285
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`4
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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 ” and provide the appropriate responses.]
`
`E] Yes. a study is suflicient [Explain your answer in the textbox and then go to Q. 5]
`
`[Explain why a study is sufficient]
`
`E] No. a study is not sufficient [Select all explanations that apply then go to Q. 4.f]
`
`[:1 Need to minimize bias and/or confounding via randomization
`E] Need for placebo control
`C] 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.).
`E] Need pre-specified and prospective active data collection of the outcome/endpoint of interest
`C] Other
`
`[Ifyou selected “other,” expand on the rmson(s) why a study is not sufficient]
`
`f. E] Because a study is not sufiicient, 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 o_r Q4.a above?
`
`[Select ONE OPTION only under either “Type ofStudy” fl “TJpe ofclinical Trial ”]
`
`TYPE OF STUDY
`
`I: Drug interaction or bioavailability studies (nonclinical only)
`[I Epidemiologic (observational) study related to safe drug use
`|:l Epidemiologic (observational) study not related to safe drug use (e.g., natural history of disease, background
`
`
`
`rates of adverse events)
`|:I Immunogenicity study (nonclinical)
`E] Meta-analysis or pooled analysis ofprevious observational studies
`|:| Nonclinical (animal) study (e.g.. genotoxicity, carcinogenicity, reproductive toxicology)
`l:l Nonclinical (in vitro) study (laboratory/microbiology resistance, receptor affinity)
`El Pharmacogenetic or pharmacogenomic study
`|:| Pharmacokinetic (PK) and/or pharmacodynamics (PD) study (nonclinical only)
`1:] Quality CMC study (e.g.. manufacturing. studies on impurities)
`I:| Quality stability study
`I: Registry-based observational study
`|:| Other (describe)
`
`PMR/PMC Development Template
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`Last: Update 06/2017
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`Reference ID: 41 74285
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`TYPE OF CLINICAL TRIAL
`
`
`
`I Combined PK/PD, safety and/or efiicacy trial (PREA * PMS only)
`l:| Dose-response clinical trial
`I: Dosing trial (e. g, alternative dosing schedule)
`|:| Drug interaction or bioavailability clinical trial (clinical only)
`|:| Immunogenicity trial (clinical)
`[:l Meta-analysis or pooled analysis ofprevious clinical trials
`|:| Pharmacogenetic or pharmacogenomic clinical trial
`E] Pharmacokinetic (PK) and/or pharmacodynamic (PD) clinical trial
`IX Primary efficacy clinical trial (i. c. with a primary efficacy endpoint; to firrther define efficacy; may include
`secondary safety endpoints)
`I:| 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
`1:] Safety outcomes trial (SOT)**
`|:I Thorough Q-T clinical trial
`D 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).
`
`E] Yes
`
`[XlNo
`
`2. This study or clinical trial focuses on the following special population(s) or Circumstance“);
`[Select all that apply]
`
`
`
`
`
`For non-PREA pediatric stzldies/h'ials 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
`
`PMR/PMC Development Template
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`Last Up(htc 06/2017
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`Reference ID: 41 74285
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`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)
`
`
`
`
`
`
`
`2.
`
`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.
`
` (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.
`• The trial will emphasize minimizing the risk minimization for participants as the protocol is developed.
`
` 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)
`
`3.
`
`
`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.
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`PMR/PMC Development Template
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`Reference ID: 4174285
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`Last Update 06/2017
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`PMR/PMC DEVELOPMENT TEMPLATE
`For 506B Reportable10 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 210259
`PMR/PMC Set (####-#)
`PMR 2
`Product Name:
`Calquence™ (acalabrutinib) capsule, 100 mg
`Applicant Name:
`Acerta Pharma B.V.
`ODE/Division:
`OHOP/DHP
`
`SECTION B: PMR/PMC Information
`3. PMR/PMC Description
`Conduct a study to characterize the long-term safety of Calquence monotherapy. Submit interim and
`complete final reports showing long-term safety with a minimum of 24 months of follow-up from study
`ACE-LY-004 in patient with mantle cell lymphoma.
`
`4. PMR/PMC Schedule Milestones11, 12
`Trial Completion:
`02/2018
`Final Report Submission:
`12/2018
`
`
`
`
`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, which is located in the
`CST.
`11 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.
`12 Dates should be numerical (e.g., 05/2016). PREA PMR date format may be MM/DD/YYYY if a day is specified.
`
`PMR/PMC Development Template
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`Reference ID: 4174285
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`SECTION C: PMR/PMC Rationale
`6. Describe the particular review issue and the goal of the study13 or clinical trial14 in the text box below.
`In patients treated with Calquence from clinical trial ACE-LY-004, the Applicant reported a median
`duration of exposure of 13.8 months of Calquence monotherapy. Since it is anticipated that patients may
`take Calquence for an indefinite period of time, the exposure to Calquence in the pivotal trial is not
`sufficient to clearly define the type and incidence of adverse events with prolonged therapy. Suspected
`and known risks include hemorrhage, infection, cytopenias, second primary malignancies, atrial
`fibrillation, and tumor lysis syndrome. There is a need to characterize the safety of Calquence with long-
`term use. The goal of this PMR is to characterize the long-term safety of Calquence monotherapy in
`patients with marginal zone lymphoma.
`
`7. 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]
`
`8. 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)
`
`
`
`
`13 A “study” is an investigation that is not a clinical trial, such as an observational (epidemiologic) study, animal study, or laboratory experiment.
`14 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.”
`
`PMR/PMC Development Template
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`Reference ID: 4174285
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`9. 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. FAERS15 and Sentinel’s postmarket ARIA16 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.
`
`
`
`
`15 FDA Adverse Event Reporting System (FAERS)
`16 Active Risk Identification and Analysis (ARIA)
`
`PMR/PMC Development Template
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`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
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`Reference ID: 4174285
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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” and provide the appropriate responses.]
`
`E] Yes. a study is suflicient [Explain your answer in the textbox and then go to Q. 5]
`
`[X] No. a study is not sufficient [Select all explanations that apply then go to Q. 4.f]
`
`[:1 Need to minimize bias and/or confounding via randomization
`E] Need for placebo control
`[X 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.).
`X] Need pre-specified and prospective active data collection of the outcome/endpoint of interest
`C] Other
`
`[Ifyou selected “other,” expand on the reason(s) why a study is not sufficient]
`
`f.
`
`[X] Because a study is not sufiicient, a clinical trial is required. [Go to Q. 5]
`
`10. For all PMRs and PMCs: What type of study or clinical trial is needed to achieve the goal described in
`
`Q1 o_r Q4.a above?
`
`[Select ONE OPTION only under either “Type ofStudy” fl “TJpe ofclinical Trial”]
`
`TYPE OF STUDY
`
`I: Drug interaction or bioavailability studies (nonclinical only)
`[I Epidemiologic (observational) study related to safe drug use
`|:l Epidemiologic (observational) study not related to safe drug use (e.g., natural history of disease, background
`
`
`
`rates of adverse events)
`|:I Immunogenicity study (nonclinical)
`E] Meta-analysis or pooled analysis ofprevious observational studies
`|:| Nonclinical (animal) study (e.g.. genotoxicity, carcinogenicity, reproductive toxicology)
`l:l Nonclinical (in vitro) study (laboratory/microbiology resistance, receptor affinity)
`El Pharmacogenetic or pharmacogenomic study
`|:| Pharmacokinetic (PK) and/or pharmacodynamics (PD) study (nonclinical only)
`1:] Quality CMC study (e.g.. manufacturing. studies on impurities)
`I:| Quality stability study
`I: Registry-based observational study
`|:| Other (describe)
`
`PMR/PMC Development Template
`
`Last: Update 06/2017
`
`Reference ID: 41 74285
`
`

`

`TYPE OF CLINICAL TRIAL
`
`
`
`I Combined PK/PD, safety and/or efiicacy trial (PREA * PMS only)
`l:| Dose-response clinical trial
`I: Dosing trial (e. g, alternative dosing schedule)
`|:| Drug interaction or bioavailability clinical trial (clinical only)
`|:| Immunogenicity trial (clinical)
`[:l Meta-analysis or pooled analysis ofprevious clinical trials
`|:| Pharmacogenetic or pharmacogenomic clinical trial
`E] Pharmacokinetic (PK) and/or pharmacodynamic (PD) clinical trial
`l:| Primary efficacy clinical trial (i. c. with a primary efficacy endpoint; to firrther define efficacy; may include
`secondary safety endpoints)
`XI 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
`1:] Safety outcomes trial (SOT)**
`|:I Thorough Q-T clinical trial
`D 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
`
`4. This PMR/PMC applies to other drugs or applications (e.g. drugs in a therapeutic class; different formulations
`of the same drug).
`
`E] Yes
`
`[XlNo
`
`5. This study or clinical trial focuses on the following special population(s) or Circumstance“);
`[Select all that apply]
`
`
`
`
`
`For non-PREA pediatric stzldies/h'ials 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
`
`PMR/PMC Development Template
`
`Last Up(htc 06/2017
`
`13
`
`Reference ID: 41 74285
`
`

`

`
`6. (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)
`
`
`
`
`
`
`
`5.
`
`SECTION E: PMR/PMC Development Coordinator Statements17
`4. The PMR/PMC is clear, feasible, and appropriate18 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.
`
` (If the PMR/PMC is a randomized controlled clinical trial) The following ethical considerations were made
`with regard to:
`•