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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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`NDA 211192
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`Food and Drug Administration
`Silver Spring MD 20993
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`NDA APPROVAL
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`Agios Pharmaceuticals, Inc.
`Attention: Jamie Cohen, PhD
`Director, Regulatory Affairs
`88 Sidney Street
`Cambridge, MA 02139
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`Dear Dr. Cohen:
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`Please refer to your New Drug Application (NDA) dated December 21, 2017, received
`December 21, 2017, and your amendments, submitted under section 505(b) of the Federal Food,
`Drug, and Cosmetic Act (FDCA) for Tibsovo® (ivosidenib) tablets; 250 mg.
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`This new drug application provides for the use of Tibsovo® (ivosidenib) tablets for the treatment
`of adult patients with relapsed or refractory acute myeloid leukemia (AML) with a susceptible
`isocitrate dehydrogenase-1 (IDH1) mutation as detected by an FDA-approved test.
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`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.
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`CONTENT OF LABELING
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`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 prescribing information and
`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
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`The SPL will be accessible via publicly available labeling repositories.
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`CARTON AND IMMEDIATE CONTAINER LABELS
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`Submit final printed carton and immediate container labels that are identical to the carton and
`immediate container labels submitted on May 16, 2018, as soon as they are available, but no
`more than 30 days after they are printed. Please submit these labels electronically according to
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`Reference ID: 4294285
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`NDA 211192
`Page 2
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`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 211192.” Approval of this
`submission by FDA is not required before the labeling is used.
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`ADVISORY COMMITTEE
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`Your application for ivosidenib was not referred to an FDA advisory committee because the
`application did not raise significant safety or efficacy issues.
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`REQUIRED PEDIATRIC ASSESSMENTS
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`Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all applications for new
`active ingredients (which includes new salts and new fixed combinations), 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 in pediatric
`patients unless this requirement is waived, deferred, or inapplicable.
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`Because this drug product for this indication has an orphan drug designation, you are exempt
`from this requirement.
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`POSTMARKETING REQUIREMENTS UNDER 505(o)
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`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.
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`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 identify an unexpected serious
`risk of long-term toxicities of ivosidenib or assess a signal of excessive drug toxicity from
`impaired hepatic function on the pharmacokinetics of ivosidenib.
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`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 these serious risks.
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`Finally, we have determined that only a clinical trial (rather than a nonclinical or observational
`study) will be sufficient to assess these risks.
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`Therefore, based on appropriate scientific data, FDA has determined that you are required to
`conduct the following trials:
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`PMR 3444-1 Characterize the long-term safety of ivosidenib 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 AG120-C-001, A Phase 1,
`Multicenter, Open-Label, Dose-Escalation and Expansion, Safety,
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`Reference ID: 4294285
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`NDA 211192
`Page 3
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`Pharmacokinetic, Pharmacodynamic, and Clinical Activity Study of Orally
`Administered AG-120 in Subjects with Advanced Hematologic Malignancies with
`an IDH1 Mutation. Include data from approximately 205 patients with relapsed or
`refractory AML.
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`Include in the final study report the exploratory subgroup analyses and
`corresponding subject level data related to pre- and post-treatment cytogenetics,
`specific IDH1 mutations, and mutation analyses for other genes as obtained under
`the trial protocol.
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`The timetable you submitted on July 13, 2018 states that you will conduct this
`trial according to the following schedule:
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`5/2021
`3/2022
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`Trial Completion:
`Final Report Submission:
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`PMR 3444-2 Complete your ongoing Study AG120-C-012, A Phase 1, open-label, single-dose
`study to evaluate the pharmacokinetics, safety, and tolerability of AG-120 in
`subjects with mild or moderate hepatic impairment or normal hepatic function.
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`The timetable you submitted on July 13, 2018 states that you will conduct this
`study according to the following schedule:
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`Final Report Submission:
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`10/2018
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`PMR 3444-3 Conduct a clinical pharmacokinetic trial to determine an appropriate safe dose of
`ivosidenib in patients with relapsed or refractory acute myeloid leukemia (AML)
`with a susceptible IDH1 mutation as detected by an FDA-approved test with
`hepatic impairment (moderate) dosed with ivosidenib to steady-state vs. patients
`with normal hepatic function dosed with ivosidenib to steady-state. This may be
`performed as a sub-study in the ongoing Phase 1 Study AG120-C-001, A Phase 1,
`Multicenter, Open-Label, Dose-Escalation and Expansion, Safety,
`Pharmacokinetic, Pharmacodynamic, and Clinical Activity Study of Orally
`Administered AG-120 in Subjects with Advanced Hematologic Malignancies with
`an IDH1 Mutation. 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. Depending on the results, a clinical pharmacokinetic trial in
`patients with severe hepatic impairment may be required.
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`The timetable you submitted on July 13, 2018 states that you will conduct this
`study according to the following schedule:
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`Final Protocol Submission: 4/2019
`Trial Completion:
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`11/2022
`Final Report Submission:
`6/2023
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`Reference ID: 4294285
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`NDA 211192
`Page 4
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`Submit clinical protocol(s) to your IND 119341 with a cross-reference letter to this NDA.
`Submit nonclinical and chemistry, manufacturing, and controls protocols and all final report(s) 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).
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`Section 505(o)(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.
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`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(o)(3)(E)(ii) provided that you include the elements listed in 505(o) and
`21 CFR 314.81(b)(2)(vii). We remind you that to comply with 505(o), 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(o) on the date required will be considered a violation of FDCA section
`505(o)(3)(E)(ii) and could result in enforcement action.
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`PROMOTIONAL MATERIALS
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`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 prescribing
`information, Medication Guide, and patient PI (as applicable) to:
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`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
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`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 ).
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`As required under 21 CFR 314.81(b)(3)(i), you must submit final promotional materials, and the
`prescribing information, at the time of initial dissemination or publication, accompanied by a
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`Reference ID: 4294285
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`NDA 211192
`Page 5
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`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.
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`REPORTING REQUIREMENTS
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`We remind you that you must comply with reporting requirements for an approved NDA
`(21 CFR 314.80 and 314.81).
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`MEDWATCH-TO-MANUFACTURER PROGRAM
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`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.
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`POST APPROVAL FEEDBACK MEETING
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`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.
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`If you have any questions, call Laura Wall, Regulatory Project Manager, at (301) 796-2237.
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`Sincerely,
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`{See appended electronic signature page}
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`Richard Pazdur, MD
`Office Director
`Division of Hematology Products
`Office of Hematology and Oncology Products
`Center for Drug Evaluation and Research
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`Enclosure:
`Content of Labeling
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`Reference ID: 4294285
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`Signature Page 1 of 1
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`This is a representation of an electronic record that was signed
`electronically. Following this are manifestations of any and all
`electronic signatures for this electronic record.
`--------------------------------------------------------------------------------------------
`/s/
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`RICHARD PAZDUR
`07/20/2018
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`Reference ID: 4294285
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