CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`209606Orig1s000
`
`
`OTHER REVIEW(S)
`
`

`

`MEMORANDUM
`REVIEW OF REVISED LABEL AND LABELING
`Division of Medication Error Prevention and Analysis (DMEPA)
`Office of Medication Error Prevention and Risk Management (OMEPRM)
`Office of Surveillance and Epidemiology (OSE)
`Center for Drug Evaluation and Research (CDER)
`
`Date of This Memorandum:
`July 13, 2017
`Requesting Office or Division:
`Division of Hematology Products (DHP)
`Application Type and Number: NDA 209606
`Product Name and Strength:
`Idhifa (enasidenib) Tablets
`50 mg, 100 mg
`Celgene
`June 06, 2017
`2017-17-1
`Leeza Rahimi, Pharm.D.
`Hina Mehta, Pharm.D.
`
`Applicant/Sponsor Name:
`Submission Date:
`OSE RCM #:
`DMEPA Primary Reviewer:
`DMEPA Team Leader:
`
`PURPOSE OF MEMO
`1
`Division of Hematology Products (DHP) requested that we review the revised container labels
`for Idhifa (enasidenib) Tablets (Appendix A) to determine if it is acceptable from a medication
`error perspective. The revisions are in response to recommendations that we made during a
`previous label and labeling review.a Sponsor has accepted most of our previous
`recommendations for the container labels. However, we identified additional areas in the
`container labels that can be improved to increase the readability and clarity of information to
`promote the safe use of the product. We note that the net quantity statement is in close
`proximity of the statement for product strength. We provide letter-ready recommendations for
`the Applicant in Section 3 of this review.
`
` CONCLUSION
`2
`DMEPA concludes that the container labels can be improved to increase the clarity of
`information to promote the safe use of the product. Please see recommendations for the
`Applicant in Section 3 below:
`
`a Rahimi, L. Label and Labeling Review for Idhifa (enasidenib) Tablets (NDA 209606). Silver Spring (MD): FDA, CDER,
`OSE, DMEPA (US); 2017 APR 07. RCM No.: 2017-17.
`
`1
`
`Reference ID: 4124036
`
`

`

`RECOMMENDATIONS FOR CELGENE
`3
`We recommend the following be implemented prior to approval of this NDA:
`1. Relocate the net quantity statement away from the product strength, such as to the
`bottom of the principal display panel. From post-marketing experience, the risk of
`numerical confusion between the strength and the net quantity increases when the net
`quantity statement is located in close proximity to the strength statement.
`
`Reference ID: 4124036
`
`2
`
`

`

`APPENDIX A. LABEL AND LABELING SUBMITTED ON JUNE 6, 2017
`Container labels
`
`Reference ID: 4124036
`
`3
`
`(b) (4)
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`LEEZA RAHIMI
`07/13/2017
`
`HINA S MEHTA
`07/13/2017
`
`Reference ID: 4124036
`
`

`

`
`
`
`NDA #
`Product
`Set #
`
`PMR Description:
`
`PMR/PMC Development Template
`
`209606
`Idhifa (enasidenib)
`3240
`
` differentiation
`Conduct a meta-analysis to characterize enasidenib-
`syndrome, specifically incidence, appropriate diagnostic criteria, and effective
`treatment based on patient-level data and pooled analyses for on-going trials in
`patients with acute myeloid leukemia: AG221-C-001, AG-120-221-C-001, AG-
`221-AML-004, and AG-221-AML-005. Submit the study report and analysis data
`set.
`
`Preliminary Protocol Submission: 10/2017
`Final Protocol Submission: 01/2018
`Study Completion: 02/2020
`Final Report Submission: 12/2020
`
`
`Schedule Milestones:
`
`
`
`
`1. During application review, explain why this issue is appropriate for a PMR/PMC instead of a pre-approval
`requirement. Check type below and describe.
` Unmet need
` Life-threatening condition
` Long-term data needed
` Only feasible to conduct post-approval
` Prior clinical experience indicates safety
` Small subpopulation affected
` Theoretical concern
` Other
`
`
`
`Relapsed or refractory acute myeloid leukemia (AML) is a life-threatening disease with limited treatment options. Based
`on the extreme unmet need in this population and the apparent clinical benefit from enasidenib in relapsed/refractory
`IDH2+ AML observed on a single-arm trial, it is appropriate to obtain additional needed safety information in a post-
`marketing trial.
`2. Describe the particular review issue and the goal of the study/clinical trial. If the study or clinical trial is a FDAAA
`PMR, describe the risk. If the FDAAA PMR is created post-approval, describe the “new safety information.”
`
`Enasidenib caused a differentiation-like syndrome in 10-20% of patients with AML who received the drug on study AG-
`221-C-001. However, as understanding of the adverse event improved over the course of the study, which resulted in
`changes in recognition and management over time, the true incidence of differentiation syndrome, its component signs
`and symptoms, the timing with respect to initiation of enasidenib, its severity, and the effectiveness of the management
`guidelines recommended in the product label are still not clear. Diagnostic criteria need to be established, and the
`effectiveness of the proposed management guidelines must be demonstrated.
`If the study or clinical trial is a PMR, check the applicable regulation.
`3.
`If not a PMR, skip to 4.
` Accelerated Approval (subpart H/E)
` Animal Efficacy Rule
` Pediatric Research Equity Act
` FDAAA required safety study/clinical trial
`
`
`
`PMR/PMC Development Template
`
`Reference ID: 4123103
`
`
`
`Page 1 of 15
`
`(b) (4)
`
`

`

`If the PMR is a FDAAA safety study/clinical trial, does it: (check all that apply)
` Assess a known serious risk related to the use of the drug?
` Assess signals 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?
`
`
`If the PMR is a FDAAA safety study/clinical trial, will it be conducted as:
` Analysis of spontaneous postmarketing adverse events?
`Do not select the above study/clinical trial type if: such an analysis will not be sufficient to assess or identify
`a serious risk
` Analysis using pharmacovigilance system?
`Do not select the above study/clinical trial type if: the new pharmacovigilance system that the FDA is
`required to establish under section 505(k)(3) has not yet been established and is thus not sufficient to assess
`this known serious risk, or has been established but is nevertheless not sufficient to assess or identify a serious
`risk
` Study: all other investigations, such as investigations in humans that are not clinical trials as defined below
`(e.g., observational epidemiologic studies), animal studies, and laboratory experiments?
`Do not select the above study type if: a study will not be sufficient to identify or assess a serious risk
` Clinical trial: any prospective investigation in which the sponsor or investigator determines the method of
`assigning investigational product or other interventions to one or more human subjects?
`4. What type of study or clinical trial is required or agreed upon (describe and check type below)? If the study or trial
`will be performed in a subpopulation, list here.
`The study will analyze pooled data from trials of enasidenib in AML (AG-221-C-001, C-001, AAML-004, and AML-
`005).
`
`Required
` Observational pharmacoepidemiologic study
` Registry studies
` Primary safety study or clinical trial
` Pharmacogenetic or pharmacogenomic study or clinical trial if required to further assess safety
` Thorough Q-T clinical trial
` Nonclinical (animal) safety study (e.g., carcinogenicity, reproductive toxicology)
` Nonclinical study (laboratory resistance, receptor affinity, quality study related to safety)
` Pharmacokinetic studies or clinical trials
` Drug interaction or bioavailability studies or clinical trials
` Dosing trials
` Additional data or analysis required for a previously submitted or expected study/clinical trial (provide
`explanation):
` Meta-analysis or pooled analysis of previous studies/clinical trials
` Immunogenicity as a marker of safety
` Other (provide explanation):
`Agreed upon:
` Quality study without a safety endpoint (e.g., manufacturing, stability)
` Pharmacoepidemiologic study not related to safe drug use (e.g., natural history of disease, background rates of
`adverse events)
` Clinical trials primarily designed to further define efficacy (e.g., in another condition, different disease severity, or
`subgroup) that are NOT required under Subpart H/E
` Dose-response study or clinical trial performed for effectiveness
` Nonclinical study, not safety-related (specify):
` Other:
`
`
`
`
`
`PMR/PMC Development Template
`
`Reference ID: 4123103
`
`
`
`Page 2 of 15
`
`

`

`Is the PMR/PMC clear, feasible, and appropriate?
` Does the study or clinical trial meet criteria for PMRs or PMCs?
` Are the objectives clear from the description of the PMR/PMC?
` Has the applicant adequately justified the choice of schedule milestone dates?
` Has the applicant had sufficient time to review the PMRs/PMCs, ask questions, determine feasibility, and
`contribute to the development process?
`
`
`
`
`
`5.
`
`
`
` Check if this form describes a FDAAA PMR that is a randomized, controlled clinical trial
`
`If so, does the clinical trial meet the following criteria?
` There is a significant question about the public health risks of an approved drug
` There is not enough existing information to assess these risks
` Information cannot be gained through a different kind of investigation
` The trial will be appropriately designed to answer question about a drug’s efficacy and safety, and
` The trial will emphasize risk minimization for participants as the protocol is developed
`
`PMR/PMC Development Coordinator:
` 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.
`
`
`
`
`
`
`
`PMR/PMC Development Template
`
`Reference ID: 4123103
`
`
`
`Page 3 of 15
`
`

`

`
`
`PMR Description:
`
`PMR/PMC Development Template
`
`
`Characterize the long-term safety of enasidenib in patients with relapsed or
`refractory acute myeloid leukemia (AML). Submit the final study report and
`dataset with three years of follow-up from ongoing Study AG221-C-001, A phase
`1/2, multi-center, open-label, dose-escalation and expansion, safety,
`pharmacokinetic, pharmacodynamics, and clinical activity study of orally
`administered AG-221 in subjects with advanced hematologic malignancies with an
`IDH2 mutation. Include data from approximately 280 patients with relapsed or
`refractory AML.
`
`[Final Protocol Submitted: 10/2015]
`Trial Completion: 05/2019
`Final Report Submission: 03/2020
`
`
`Schedule Milestones:
`
`
`
`1. During application review, explain why this issue is appropriate for a PMR/PMC instead of a pre-approval
`requirement. Check type below and describe.
` Unmet need
` Life-threatening condition
` Long-term data needed
` Only feasible to conduct post-approval
` Prior clinical experience indicates safety
` Small subpopulation affected
` Theoretical concern
` Other
`
`
`
`Relapsed or refractory acute myeloid leukemia (AML) is a life-threatening disease with limited treatment options. Based
`on the extreme unmet need in this population and the apparent clinical benefit from enasidenib in relapsed/refractory
`IDH2+ AML observed on a single-arm trial, it is appropriate to obtain additional needed safety information in a post-
`marketing trial.
`2. Describe the particular review issue and the goal of the study/clinical trial. If the study or clinical trial is a FDAAA
`PMR, describe the risk. If the FDAAA PMR is created post-approval, describe the “new safety information.”
`
`The approval of enasidenib is based on durable CR/CRh and improvements in transfusion requirements in
`relapsed/refractory IDH2+ AML, but enasidenib has been tested in only a limited number of clinically heterogeneous
`patients over a relatively short duration of time with short follow-up, and there is concern that the toxicity profile may not
`be fully understood. While the primary analysis on this study (submitted for NDA review) was performed at a minimum
`follow-up time of 6 months for all patients, the study is still ongoing, and the final study report is planned when all
`subjects have a minimum follow-up time of 12 months. Longer follow-up time will provide a better understanding of
`safety.
`If the study or clinical trial is a PMR, check the applicable regulation.
`3.
`If not a PMR, skip to 4.
` Accelerated Approval (subpart H/E)
` Animal Efficacy Rule
` Pediatric Research Equity Act
` FDAAA required safety study/clinical trial
`
`
`
`PMR/PMC Development Template
`
`Reference ID: 4123103
`
`
`
`Page 4 of 15
`
`

`

`If the PMR is a FDAAA safety study/clinical trial, does it: (check all that apply)
` Assess a known serious risk related to the use of the drug?
` Assess signals 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?
`
`
`If the PMR is a FDAAA safety study/clinical trial, will it be conducted as:
` Analysis of spontaneous postmarketing adverse events?
`Do not select the above study/clinical trial type if: such an analysis will not be sufficient to assess or identify
`a serious risk
` Analysis using pharmacovigilance system?
`Do not select the above study/clinical trial type if: the new pharmacovigilance system that the FDA is
`required to establish under section 505(k)(3) has not yet been established and is thus not sufficient to assess
`this known serious risk, or has been established but is nevertheless not sufficient to assess or identify a serious
`risk
` Study: all other investigations, such as investigations in humans that are not clinical trials as defined below
`(e.g., observational epidemiologic studies), animal studies, and laboratory experiments?
`Do not select the above study type if: a study will not be sufficient to identify or assess a serious risk
` Clinical trial: any prospective investigation in which the sponsor or investigator determines the method of
`assigning investigational product or other interventions to one or more human subjects?
`4. What type of study or clinical trial is required or agreed upon (describe and check type below)? If the study or trial
`will be performed in a subpopulation, list here.
`A phase 1/2, open-label,
` study of enasidenib in subjects with relapsed or refractory hematologic malignancies
`harboring an IDH2 mutation.
`
`Required
` Observational pharmacoepidemiologic study
` Registry studies
` Primary safety study or clinical trial
` Pharmacogenetic or pharmacogenomic study or clinical trial if required to further assess safety
` Thorough Q-T clinical trial
` Nonclinical (animal) safety study (e.g., carcinogenicity, reproductive toxicology)
` Nonclinical study (laboratory resistance, receptor affinity, quality study related to safety)
` Pharmacokinetic studies or clinical trials
` Drug interaction or bioavailability studies or clinical trials
` Dosing trials
` Additional data or analysis required for a previously submitted or expected study/clinical trial (provide
`explanation):
` Meta-analysis or pooled analysis of previous studies/clinical trials
` Immunogenicity as a marker of safety
` Other (provide explanation):
`Agreed upon:
` Quality study without a safety endpoint (e.g., manufacturing, stability)
` Pharmacoepidemiologic study not related to safe drug use (e.g., natural history of disease, background rates of
`adverse events)
` Clinical trials primarily designed to further define efficacy (e.g., in another condition, different disease severity, or
`subgroup) that are NOT required under Subpart H/E
` Dose-response study or clinical trial performed for effectiveness
` Nonclinical study, not safety-related (specify):
` Other:
`
`
`
`
`
`PMR/PMC Development Template
`
`Reference ID: 4123103
`
`
`
`Page 5 of 15
`
`(b) (4)
`
`

`

`Is the PMR/PMC clear, feasible, and appropriate?
` Does the study or clinical trial meet criteria for PMRs or PMCs?
` Are the objectives clear from the description of the PMR/PMC?
` Has the applicant adequately justified the choice of schedule milestone dates?
` Has the applicant had sufficient time to review the PMRs/PMCs, ask questions, determine feasibility, and
`contribute to the development process?
`
` Check if this form describes a FDAAA PMR that is a randomized, controlled clinical trial
`
`If so, does the clinical trial meet the following criteria?
` There is a significant question about the public health risks of an approved drug
` There is not enough existing information to assess these risks
` Information cannot be gained through a different kind of investigation
` The trial will be appropriately designed to answer question about a drug’s efficacy and safety, and
` The trial will emphasize risk minimization for participants as the protocol is developed
`
`
`
`
`
`5.
`
`
`
`PMR/PMC Development Coordinator:
` 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.
`
`
`
`
`PMR/PMC Development Template
`
`Reference ID: 4123103
`
`
`
`Page 6 of 15
`
`

`

`
`
`PMR Description:
`
`PMR/PMC Development Template
`
`
`Conduct a trial to provide evidence sufficient to characterize the long-term safety
`of enasidenib compared to conventional care regimens in patients with acute
`myeloid leukemia (AML). Submit the final study report and dataset with three
`years of follow-up from Study AG-221-AML-004, A phase 3, multicenter, open-
`label, randomized study comparing the efficacy and safety of AG-221 versus
`conventional care regimens in older subjects with late stage acute myeloid
`leukemia harboring an isocitrate dehydrogenase 2 mutation. Include data from
`approximately 140 patients with relapsed or refractory AML.
`
`[Final Protocol Submitted: 08/2015]
`Trial Completion: 09/2022
`Final Report Submission: 07/2023
`
`
`Schedule Milestones:
`
`
`
`1. During application review, explain why this issue is appropriate for a PMR/PMC instead of a pre-approval
`requirement. Check type below and describe.
` Unmet need
` Life-threatening condition
` Long-term data needed
` Only feasible to conduct post-approval
` Prior clinical experience indicates safety
` Small subpopulation affected
` Theoretical concern
` Other
`
`
`
`Relapsed or refractory acute myeloid leukemia (AML) is a life-threatening disease with limited treatment options. Based
`on the extreme unmet need in this population and the apparent clinical benefit from enasidenib in relapsed/refractory
`IDH2+ AML observed on a single-arm trial, it is appropriate to obtain additional needed safety information in a post-
`marketing trial.
`2. Describe the particular review issue and the goal of the study/clinical trial. If the study or clinical trial is a FDAAA
`PMR, describe the risk. If the FDAAA PMR is created post-approval, describe the “new safety information.”
`
`The approval of enasidenib is based on durable CR/CRh and improvements in transfusion requirements in
`relapsed/refractory IDH2+ AML, but enasidenib has been tested in only a limited number of clinically heterogeneous
`patients over a relatively short duration of time, and there is concern that the toxicity profile may not be fully understood.
`A study conducted in a randomized fashion against conventional care regimens will provide a better understanding of
`safety (including survival) compared to that of supportive care and other available options.
`If the study or clinical trial is a PMR, check the applicable regulation.
`3.
`If not a PMR, skip to 4.
` Accelerated Approval (subpart H/E)
` Animal Efficacy Rule
` Pediatric Research Equity Act
` FDAAA required safety study/clinical trial
`
`
`
`If the PMR is a FDAAA safety study/clinical trial, does it: (check all that apply)
` Assess a known serious risk related to the use of the drug?
` Assess signals 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: 4123103
`
`
`
`Page 7 of 15
`
`

`

`If the PMR is a FDAAA safety study/clinical trial, will it be conducted as:
` Analysis of spontaneous postmarketing adverse events?
`Do not select the above study/clinical trial type if: such an analysis will not be sufficient to assess or identify
`a serious risk
` Analysis using pharmacovigilance system?
`Do not select the above study/clinical trial type if: the new pharmacovigilance system that the FDA is
`required to establish under section 505(k)(3) has not yet been established and is thus not sufficient to assess
`this known serious risk, or has been established but is nevertheless not sufficient to assess or identify a serious
`risk
` Study: all other investigations, such as investigations in humans that are not clinical trials as defined below
`(e.g., observational epidemiologic studies), animal studies, and laboratory experiments?
`Do not select the above study type if: a study will not be sufficient to identify or assess a serious risk
` Clinical trial: any prospective investigation in which the sponsor or investigator determines the method of
`assigning investigational product or other interventions to one or more human subjects?
`4. What type of study or clinical trial is required or agreed upon (describe and check type below)? If the study or trial
`will be performed in a subpopulation, list here.
`A phase 3, randomized, open-label, multi-center study comparing enasidenib to conventional care regimens in subjects
`with IDH2+ AML. The study will collect all adverse events, laboratory test results, response rates, and overall survival.
`
`Required
` Observational pharmacoepidemiologic study
` Registry studies
` Primary safety study or clinical trial
` Pharmacogenetic or pharmacogenomic study or clinical trial if required to further assess safety
` Thorough Q-T clinical trial
` Nonclinical (animal) safety study (e.g., carcinogenicity, reproductive toxicology)
` Nonclinical study (laboratory resistance, receptor affinity, quality study related to safety)
` Pharmacokinetic studies or clinical trials
` Drug interaction or bioavailability studies or clinical trials
` Dosing trials
` Additional data or analysis required for a previously submitted or expected study/clinical trial (provide
`explanation):
` Meta-analysis or pooled analysis of previous studies/clinical trials
` Immunogenicity as a marker of safety
` Other (provide explanation):
`Agreed upon:
` Quality study without a safety endpoint (e.g., manufacturing, stability)
` Pharmacoepidemiologic study not related to safe drug use (e.g., natural history of disease, background rates of
`adverse events)
` Clinical trials primarily designed to further define efficacy (e.g., in another condition, different disease severity, or
`subgroup) that are NOT required under Subpart H/E
` Dose-response study or clinical trial performed for effectiveness
` Nonclinical study, not safety-related (specify):
` Other:
`
`
`
`
`
`PMR/PMC Development Template
`
`Reference ID: 4123103
`
`
`
`Page 8 of 15
`
`

`

`Is the PMR/PMC clear, feasible, and appropriate?
` Does the study or clinical trial meet criteria for PMRs or PMCs?
` Are the objectives clear from the description of the PMR/PMC?
` Has the applicant adequately justified the choice of schedule milestone dates?
` Has the applicant had sufficient time to review the PMRs/PMCs, ask questions, determine feasibility, and
`contribute to the development process?
`
` Check if this form describes a FDAAA PMR that is a randomized, controlled clinical trial
`
`If so, does the clinical trial meet the following criteria?
` There is a significant question about the public health risks of an approved drug
` There is not enough existing information to assess these risks
` Information cannot be gained through a different kind of investigation
` The trial will be appropriately designed to answer question about a drug’s efficacy and safety, and
` The trial will emphasize risk minimization for participants as the protocol is developed
`
`
`
`
`
`5.
`
`
`
`PMR/PMC Development Coordinator:
` 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.
`
`
`
`
`PMR/PMC Development Template
`
`Reference ID: 4123103
`
`
`
`Page 9 of 15
`
`

`

`
`
`PMR Description:
`
`
`PMR/PMC Development Template
`
`
`Conduct a clinical pharmacokinetic trial to evaluate the effect of multiple doses of
`enasidenib on the single dose pharmacokinetics of sensitive substrates of CYP3A4,
`CYP2D6, CYP2C19, CYP2C9, UGTs, P-gp, and BCRP to address the potential for
`excessive drug toxicity. This trial should be designed and conducted in accordance
`with the FDA Guidance for Industry entitled “Drug Interaction Studies – Study
`Design, Data Analysis, Implications for Dosing, and Labeling Recommendations.”
`
`Preliminary Protocol Submission: 09/2017
`Final Protocol Submission: 12/2017
`Trial Completion: 09/2019
`Final Report Submission: 03/2020
`
`
`Schedule Milestones:
`
`
`
`
`6. During application review, explain why this issue is appropriate for a PMR/PMC instead of a pre-approval
`requirement. Check type below and describe.
` Unmet need
` Life-threatening condition
` Long-term data needed
` Only feasible to conduct post-approval
` Prior clinical experience indicates safety
` Small subpopulation affected
` Theoretical concern
` Other
`
`
`
`Drug interaction studies have not been conducted by the applicant. In vitro studies suggest that enasidenib may inhibit
`metabolism of concomitant medications, which could result in safety adverse events.
`7. Describe the particular review issue and the goal of the study/clinical trial. If the study or clinical trial is a FDAAA
`PMR, describe the risk. If the FDAAA PMR is created post-approval, describe the “new safety information.”
`
`Only a clinical trial will be sufficient to identify an unexpected serious risk of excessive drug toxicity from drug-drug
`interactions of enasidenib with substrates of CYP3A4, CYP2D6, CYP2C19, CYP2C9, UGTs, P-gp, and BCRP. This
`study will address the need for dosing modifications based on concomitant use of drugs that are sensitive substrates for
`certain drug metabolizing enzymes, which could be reflected in labeling.
`
`8.
`
`
`
`If the study or clinical trial is a PMR, check the applicable regulation.
`If not a PMR, skip to 4.
` Accelerated Approval (subpart H/E)
` Animal Efficacy Rule
` Pediatric Research Equity Act
` FDAAA required safety study/clinical trial
`
`If the PMR is a FDAAA safety study/clinical trial, does it: (check all that apply)
` Assess a known serious risk related to the use of the drug?
` Assess signals 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?
`
`
`If the PMR is a FDAAA safety study/clinical trial, will it be conducted as:
` Analysis of spontaneous postmarketing adverse events?
`Do not select the above study/clinical trial type if: such an analysis will not be sufficient to assess or identify
`a serious risk
`
`PMR/PMC Development Template
`
`Reference ID: 4123103
`
`
`
`Page 10 of 15
`
`

`

` Analysis using pharmacovigilance system?
`Do not select the above study/clinical trial type if: the new pharmacovigilance system that the FDA is
`required to establish under section 505(k)(3) has not yet been established and is thus not sufficient to assess
`this known serious risk, or has been established but is nevertheless not sufficient to assess or identify a serious
`risk
` Study: all other investigations, such as investigations in humans that are not clinical trials as defined below
`(e.g., observational epidemiologic studies), animal studies, and laboratory experiments?
`Do not select the above study type if: a study will not be sufficient to identify or assess a serious risk
` Clinical trial: any prospective investigation in which the sponsor or investigator determines the method of
`assigning investigational product or other interventions to one or more human subjects?
`9. What type of study or clinical trial is required or agreed upon (describe and check type below)? If the study or trial
`will be performed in a subpopulation, list here.
`A Drug-Drug Interactions-perpetrator drug as inhibitors of CYP3A4, CYP2D6, CYP2C19, CYP2C9, UGTs, P-gp, and
`BCRP.
`
`Required
` Observational pharmacoepidemiologic study
` Registry studies
` Primary safety study or clinical trial
` Pharmacogenetic or pharmacogenomic study or clinical trial if required to further assess safety
` Thorough Q-T clinical trial
` Nonclinical (animal) safety study (e.g., carcinogenicity, reproductive toxicology)
` Nonclinical study (laboratory resistance, receptor affinity, quality study related to safety)
` Pharmacokinetic studies or clinical trials
` Drug interaction or bioavailability studies or clinical trials
` Dosing trials
` Additional data or analysis required for a previously submitted or expected study/clinical trial (provide
`explanation):
` Meta-analysis or pooled analysis of previous studies/clinical trials
` Immunogenicity as a marker of safety
` Other (provide explanation):
`Agreed upon:
` Quality study without a safety endpoint (e.g., manufacturing, stability)
` Pharmacoepidemiologic study not related to safe drug use (e.g., natural history of disease, background rates of
`adverse events)
` Clinical trials primarily designed to further define efficacy (e.g., in another condition, different disease severity, or
`subgroup) that are NOT required under Subpart H/E
` Dose-response study or clinical trial performed for effectiveness
` Nonclinical study, not safety-related (specify):
` Other:
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`PMR/PMC Development Template
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`Reference ID: 4123103
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`Page 11 of 15
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`10. Is the PMR/PMC clear, feasible, and appropriate?
` Does the study or clinical trial meet criteria for PMRs or PMCs?
` Are the objectives clear from the description of the PMR/PMC?
` Has the applicant adequately justified the choice of schedule milestone dates?
` Has the applicant had sufficient time to review the PMRs/PMCs, ask questions, determine feasibility, and
`contribute to the development process?
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` Check if this form describes a FDAAA PMR that is a randomized, controlled clinical trial
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`If so, does the clinical trial meet the following criteria?
` There is a significant question about the public health risks of an approved drug
` There is not enough existing information to assess these risks
` Information cannot be gained through a different kind of investigation
` The trial will be appropriately designed to answer question about a drug’s efficacy and safety, and
` The trial will emphasize risk minimization for participants as the protocol is developed
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`PMR/PMC Development Coordinator:
` 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.
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`PMR/PMC Development Template
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`Reference ID: 4123103
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`Page 12 of 15
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`PMR Description:
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`PMR/PMC Development Template
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`Conduct a clinical pharmacokinetic trial to determine an appropriate dose of
`enasidenib in patients with hepatic impairment. This trial should be designed and
`conducted in accordance with the FDA Guidance for Industry entitled
`“Pharmacokinetics in Patients with Impaired Hepatic Function: Study Design, Data
`Analysis, and Impact on Dosing and Labeling.”
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`Final Protocol Submission: 09/2017
`Trial Completion: 11/2018
`Final Report Submission: 05/2019
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`Schedule Milestones:
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`1. During application review, explain why this issue is appropriate for a PMR/PMC instead of a pre-approval
`requirement. Check type below and describe.
` Unmet need
` Life-threatening condition
` Long-term data needed
` Only feasible to conduct post-approval
` Prior clinical experience indicates safety
` Small subpopulation affected
` Theoretical concern
` Other
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`Organ impairment studies have not been conducted by the applicant in subjects with moderate or severe hepatic
`impairment. Based on exposure response for safety data, elevated bilirubin is correlate