`
`Trade Name:
`
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Approval Package for:
`
`APPLICATION NUMBER:
`
`209606Orig1s000
`
`
` Idhifa® tablets, 50 and 100 mg
`
`enasidenib
`
`Celgene Corporation
`
`August 1, 2017
`
`For the treatment of adult patients with relapsed or
`refractory acute myeloid leukemia (AML) with an
`isocitrate dehydrogenase-2 (IDH2) mutation as detected
`by an FDA-approved test.
`
`
`
`Generic or Proper
`Name:
`
`Sponsor:
`
`
`Approval Date:
`
`
`Indication:
`
`
`

`

`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`209606Orig1s000
`
`CONTENTS
`
`Reviews / Information Included in this NDA Review.
`
`
`
`Approval Letter
`Other Action Letters
`Labeling
`REMS
`Officer/Employee List
`Multidiscipline Review(s)
` Summary Review
` Office Director
` Cross Discipline Team Leader
` Clinical
` Non-Clinical
` Statistical
` Clinical Pharmacology
`Product Quality Review(s)
`Clinical Microbiology / Virology Review(s)
`Other Reviews
`Risk Assessment and Risk Mitigation Review(s)
`Proprietary Name Review(s)
`Administrative/Correspondence Document(s)
`
`
`X
`
`X
`
`X
`X
`
`X
`
`X
`X
`X
`X
`
`

`

`
`
`
`
`
`
`
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`209606Orig1s000
`
`
`APPROVAL LETTER
`
`

`

`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`
`
`
`
`
`NDA 209606
`
`
`
`
`
`Food and Drug Administration
`Silver Spring MD 20993
`
`NDA APPROVAL
`
`
`Celgene Corporation
`Attention: Penny Ng, MSc, MBA, RAC
`Director, Regulatory Affairs
`9225 Indian Creek Parkway, Suite 900
`Overland Park, KS 66210
`
`
`Dear Ms. Ng:
`
`Please refer to your New Drug Application (NDA) dated December 30, 2016, received
`December 30, 2016, and your amendments, submitted under section 505(b) of the Federal Food,
`Drug, and Cosmetic Act (FDCA) for Idhifa® (enasidenib) tablets, 50 and 100 mg.
`
`This new drug application provides for the use of Idhifa® (enasidenib) tablets, 50 and 100 mg,
`for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML)
`with an isocitrate dehydrogenase-2 (IDH2) mutation as detected by an FDA-approved test.
`
`We have completed our review of this application, as amended. It is approved, effective on the
`date of this letter, for use as recommended in the enclosed agreed-upon labeling text.
`
`EXPIRATION DATING PERIOD
`
`The drug product is stable for 18 months when stored at 20°C - 25°C (68°F - 77°F); excursions
`permitted between 15°C - 30°C (59°F - 86°F) [see USP Controlled Room Temperature].
`
`CONTENT OF LABELING
`
`As soon as possible, but no later than 14 days from the date of this letter, submit the content of
`labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format using the FDA
`automated drug registration and listing system (eLIST), as described at
`http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm. Content
`of labeling must be identical to the enclosed labeling (text for the package insert, Medication
`Guide). Information on submitting SPL files using eLIST may be found in the guidance for
`industry SPL Standard for Content of Labeling Technical Qs and As, available at
`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
`CM072392.pdf
`
`The SPL will be accessible via publicly available labeling repositories.
`
`
`Reference ID: 4132874
`
`

`

`NDA 209606
`Page 2
`
`
`CARTON AND IMMEDIATE CONTAINER LABELS
`
`Submit final printed carton and immediate container labels that are identical to the carton and
`immediate container labels submitted on July 21, 2017, as soon as they are available, but no
`more than 30 days after they are printed. Please submit these labels electronically according to
`the guidance for industry titled Providing Regulatory Submissions in Electronic Format —
`Certain Human Pharmaceutical Product Applications and Related Submissions Using the eCTD
`Specifications (May 2015, Revision 3). For administrative purposes, designate this submission
`“Final Printed Carton and Container Labels for approved NDA 209606.” Approval of this
`submission by FDA is not required before the labeling is used.
`
`ADVISORY COMMITTEE
`
`Your application for Idhifa® was not referred to an FDA advisory committee because the
`application did not raise significant public health questions on the role of the drug in the
`diagnosis, cure, mitigation, treatment or prevention of disease.
`
`REQUIRED PEDIATRIC ASSESSMENTS
`
`Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all applications for new
`active ingredients, new indications, new dosage forms, new dosing regimens, or new routes of
`administration are required to contain an assessment of the safety and effectiveness of the
`product for the claimed indication(s) in pediatric patients unless this requirement is waived,
`deferred, or inapplicable.
`
`Because this drug product for this indication has an orphan drug designation, you are exempt
`from this requirement.
`
`POSTMARKETING REQUIREMENTS UNDER 505(o)
`
`Section 505(o)(3) of the FDCA authorizes FDA to require holders of approved drug and
`biological product applications to conduct postmarketing studies and clinical trials for certain
`purposes, if FDA makes certain findings required by the statute.
`
`We have determined that an analysis of spontaneous postmarketing adverse events reported
`under subsection 505(k)(1) of the FDCA will not be sufficient to assess a known serious risk of
`differentiation syndrome.
`
`Furthermore, the new pharmacovigilance system that FDA is required to establish under section
`505(k)(3) of the FDCA will not be sufficient to assess this serious risk.
`
`Therefore, based on appropriate scientific data, FDA has determined that you are required to
`conduct the following study:
`
`PMR 3240-1 Conduct a meta-analysis to characterize enasidenib-related differentiation
`syndrome, specifically incidence, appropriate diagnostic criteria, and effective
`
`Reference ID: 4132874
`
`

`

`NDA 209606
`Page 3
`
`
`
`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.
`
`
`The timetable you submitted on July 21, 2017, states that you will conduct this study according
`to the following schedule:
`
`
`Preliminary Protocol Submission:
`Final Protocol Submission:
`
`Study Completion:
`
`
`Final Report Submission:
`
`
`10/2017
`01/2018
`02/2020
`12/2020
`
`
`Finally, we have determined that only a clinical trial (rather than a nonclinical or observational
`study) will be sufficient to identify an unexpected serious risk of toxicity from longer-term use,
`from interactions with other drugs, or due to impaired hepatic function.
`
`Therefore, based on appropriate scientific data, FDA has determined that you are required to
`conduct the following trials:
`
`PMR 3240-2 Characterize the long-term safety of enasidenib in patients with relapsed or
`refractory acute myeloid leukemia (AML). Submit the final study report and data
`set with 3 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.
`
`
`The timetable you submitted on July 21, 2017, states that you will conduct this trial according to
`the following schedule:
`
`
`
`Trial Completion:
`Final Report Submission:
`
`
`
`
`05/2019
`03/2020
`
`
`PMR 3240-3 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 data set with 3 years
`of follow-up from ongoing 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.
`
`
`
`Include in the final study report the exploratory subgroup analyses and
`corresponding subject-level data related to pre- and post-treatment cytogenetics,
`specific IDH2 mutations, and mutation analyses for other genes (e.g., IDH2,
`
`Reference ID: 4132874
`
`

`

`NDA 209606
`Page 4
`
`
`
`FLT3, NPM1, CEBPA, DNMT3A, NRAS) as obtained under the trial protocol or
`from medical history prior to trial enrollment.
`
`
`The timetable you submitted on July 21, 2017, states that you will conduct this trial according to
`the following schedule:
`
`
`
`Trial Completion:
`Final Report Submission:
`
`
`
`
`09/2022
`07/2023
`
`
`PMR 3240-4 Conduct clinical pharmacokinetic trials 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.”
`
`
`The timetable you submitted on July 21, 2017, states that you will conduct this trial according to
`the following schedule:
`
`
`Preliminary Protocol Submission:
`Final Protocol Submission:
`
`Trial Completion:
`
`
`Final Report Submission:
`
`
`09/2017
`12/2017
`09/2019
`03/2020
`
`
`PMR 3240-5 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.”
`
`
`The timetable you submitted on July 21, 2017, states that you will conduct this trial according to
`the following schedule:
`
`
`Final Protocol Submission:
`Trial Completion:
`
`Final Report Submission:
`
`
`
`
`
`09/2017
`11/2018
`05/2019
`
`
`Submit clinical protocols to your IND 117631 with a cross-reference letter to this NDA. Submit
`nonclinical and chemistry, manufacturing, and controls protocols and all final reports to your
`NDA. Prominently identify the submission with the following wording in bold capital letters at
`the top of the first page of the submission, as appropriate: Required Postmarketing Protocol
`Under 505(o), Required Postmarketing Final Report Under 505(o), Required
`Postmarketing Correspondence Under 505(o).
`
`
`Reference ID: 4132874
`
`

`

`NDA 209606
`
`Page 5
`
`Section 505(0)(3)(E)(ii) of the FDCA requires you to report periodically on the status of any
`study or clinical trial required under this section. This section also requires you to periodically
`report to FDA on the status of any study or clinical trial otherwise undertaken to investigate a
`safety issue. Section 506B of the FDCA, as well as 21 CFR 314.81(b)(2)(vii) requires you to
`report annually on the status of any postmarketing commitments or required studies or clinical
`trials.
`
`FDA will consider the submission of your annual report under section 506B and
`21 CFR 314.81(b)(2)(vii) to satisfy the periodic reporting requirement under section
`505(0)(3)(E)(ii) provided that you include the elements listed in 505(0) and
`21 CFR 314.81(b)(2)(vii). We remind you that to comply with 505(0), your annual report must
`also include a report on the status of any study or clinical trial otherwise undertaken to
`investigate a safety issue. Failure to submit an annual report for studies or clinical trials required
`under 505(0) on the date required will be considered a violation of FDCA section
`505(0)(3)(E)(ii) and could result in enforcement action.
`
`POSTMARKETING COMMITMENTS NOT SUBJECT TO THE REPORTING
`
`REQUIRENIENTS UNDER SECTION 506B
`
`We remind you of your postmarketing commitment:
`
`PMC 3240—6 Develop and report a control strategy for the drug product to minimize the risk of
`(no)
`
`The timetable you submitted on July 21, 2017, states that you will conduct this study according
`to the following schedule:
`
`CBE-30 submission of Control Strategy:
`Implementation of Control Strategy:
`
`09/2017
`11/2017
`
`Submit clinical protocols to your IND 117631 for this product. Submit nonclinical and
`chemistry, manufacturing, and controls protocols and all postmarketing final reports to this
`NDA. In addition, under 21 CFR 314.81(b)(2)(vii) and 3 l4.81(b)(2)(viii) you should include a
`status summary of each commitment in your annual report to this NDA. The status summary
`should include expected summary completion and final report submission dates, any changes in
`plans since the last annual report, and, for clinical studies/trials, number of patients entered into
`each study/trial. All submissions, including supplements, relating to these postmarketing
`commitments should be prominently labeled “Postmarketing Commitment Protocol,”
`“Postmarketing Commitment Final Report,” or “Postmarketing Commitment
`Correspondence.”
`
`Reference ID: 41 32874
`
`

`

`NDA 209606
`Page 6
`
`
`PROMOTIONAL MATERIALS
`
`You may request advisory comments on proposed introductory advertising and promotional
`labeling. To do so, submit, in triplicate, a cover letter requesting advisory comments, the
`proposed materials in draft or mock-up form with annotated references, and the package insert,
`Medication Guide, and patient PI (as applicable) to:
`
`
`OPDP Regulatory Project Manager
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Prescription Drug Promotion
`5901-B Ammendale Road
`Beltsville, MD 20705-1266
`
`
`Alternatively, you may submit a request for advisory comments electronically in eCTD format.
`For more information about submitting promotional materials in eCTD format, see the draft
`Guidance for Industry (available at:
`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
`CM443702.pdf).
`
`As required under 21 CFR 314.81(b)(3)(i), you must submit final promotional materials, and the
`package insert, at the time of initial dissemination or publication, accompanied by a Form FDA
`2253. Form FDA 2253 is available at
`http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM083570.pdf.
`Information and Instructions for completing the form can be found at
`http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM375154.pdf. For
`more information about submission of promotional materials to the Office of Prescription Drug
`Promotion (OPDP), see http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm090142.htm.
`
`REPORTING REQUIREMENTS
`
`We remind you that you must comply with reporting requirements for an approved NDA
`(21 CFR 314.80 and 314.81).
`
`MEDWATCH-TO-MANUFACTURER PROGRAM
`
`The MedWatch-to-Manufacturer Program provides manufacturers with copies of serious adverse
`event reports that are received directly by the FDA. New molecular entities and important new
`biologics qualify for inclusion for three years after approval. Your firm is eligible to receive
`copies of reports for this product. To participate in the program, please see the enrollment
`instructions and program description details at
`http://www.fda.gov/Safety/MedWatch/HowToReport/ucm166910.htm.
`
`
`Reference ID: 4132874
`
`

`

`NDA 209606
`Page 7
`
`
`POST APPROVAL FEEDBACK MEETING
`
`New molecular entities and new biologics qualify for a post approval feedback meeting. Such
`meetings are used to discuss the quality of the application and to evaluate the communication
`process during drug development and marketing application review. The purpose is to learn
`from successful aspects of the review process and to identify areas that could benefit from
`improvement. If you would like to have such a meeting with us, call the Regulatory Project
`Manager for this application.
`
`If you have any questions, call Jennifer Lee, Regulatory Project Manager, at (240) 402-4622.
`
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Richard Pazdur, MD
`Director
`Office of Hematology and Oncology Products
`Center for Drug Evaluation and Research
`
`
`
`Enclosure:
`Content of Labeling
`
`Reference ID: 4132874
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`RICHARD PAZDUR
`08/01/2017
`
`Reference ID: 4132874
`
`