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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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`NDA 204063
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`Food and Drug Administration
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`Silver Spring MD 20993
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`NDA APPROVAL
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`Biogen Idec, Inc.
`
`Attention: Nadine D. Cohen, PhD
`
`Senior Vice President, Regulatory Affairs
`
`14 Cambridge Center
`
`Cambridge, MA 02142
`
`
`
`Dear Dr. Cohen:
`
`
`Please refer to your New Drug Application (NDA) dated February 24, 2012, received February
`27, 2012, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act (FDCA)
`for Tecfidera (dimethyl fumarate) delayed-release capsules, 120 mg and 240 mg.
`
`We acknowledge receipt of your amendments dated, as follows:
`
`
`
`
`This new drug application provides for the use of Tecfidera (dimethyl fumarate) delayed-release
`capsules, 120 mg and 240 mg, for the treatment of patients with relapsing forms of multiple
`sclerosis.
`
`Expiration dating periods of 18 months for 120 mg capsules and 9 months for 240 mg capsules
`are assigned to this product based on the data provided in the application.
`
`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.
`
`
` February 29, 2012 (2)
`
`April 13, 2012
`April 16, 2012
`April 26, 2012
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` May 2, 2012
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` May 9, 2012
`May 15, 2012 (2)
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` May 30, 2012
` June 1, 2012
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`June 4, 2012 (2)
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` June 6, 2012
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` June 8, 2012
` June 12, 2012
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`
`
` June 21, 2012
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` June 27, 2012
`June 28, 2012 (2)
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` July 17, 2012
`July 30, 2012 (2)
`
` July 31, 2012
`August 1, 2012
`August 3, 2012
`August 8, 2012
`August 10, 2012
`August 17, 2012
`August 28, 2012
`August 29, 2012 (2)
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`August 30, 2012
`September 14, 2012
`October 1, 2012
`October 5, 2012
`October 9, 2012
`October 10, 2012
`October 18, 2012
`October 23, 2012
`October 24, 2012 (2)
`October 25, 2012
`October 26, 2012
`November 14, 2012
`November 15, 2012
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`November 30, 2012
`December 7, 2012
`December 12, 2012
`January 23, 2013
`January 29, 2013
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` February 7, 2013
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` February 11, 2013
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` February 20, 2013
` February 22, 2013 (2)
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` February 28, 2013
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`March 4, 2013
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`March 5, 2013
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`March 26, 2013
`
`
`Reference ID: 3283381
`
`Biogen Exhibit 2132
`Mylan v. Biogen
`IPR2018-01403
`
`Page 1 of 8
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`

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`NDA 204063
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` Page 2
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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. 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.
`
`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 March 4, 2013, 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 Providing Regulatory Submissions in Electronic Format – Human
`Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications
`(June 2008). Alternatively, you may submit 12 paper copies, with 6 of the copies individually
`mounted on heavy-weight paper or similar material. For administrative purposes, designate this
`submission “Final Printed Carton and Container Labels for approved NDA 204063.”
`Approval of this submission by FDA is not required before the labeling is used.
`
`Marketing the product(s) with FPL that is not identical to the approved labeling text may render
`the product misbranded and an unapproved new drug.
`
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`ADVISORY COMMITTEE
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`Your application for Tecfidera (dimethyl fumarate) was not referred to an FDA advisory
`committee because the safety profile is acceptable for the treatment of patients with relapsing
`
`forms of multiple sclerosis.
`
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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, 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.
`
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`Reference ID: 3283381
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`Page 2 of 8
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`NDA 204063
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` Page 3
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`We are waiving the pediatric study requirement from birth to nine years of age because
`necessary studies are impossible or highly impracticable. This is because the number of
`pediatric patients less than 10 years of age with multiple sclerosis is too small.
`
`Additionally, we are deferring submission of your pediatric study for ages 10 through 17 years
`for this application because this product is ready for approval for use in adults and the pediatric
`study has not been completed.
`
`Your deferred pediatric study required by section 505B(a) of the FDCA is a required
`postmarketing study. The status of this postmarketing study must be reported annually according
`to 21 CFR 314.81 and section 505B(a)(3)(B) of the FDCA. This required study is listed below.
`
`2014-1
`
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`Deferred pediatric trial under PREA: A randomized, controlled, parallel group
`superiority trial in pediatric patients ages 10 through 17 years to evaluate the
`pharmacokinetics of dimethyl fumarate, and the safety and efficacy of dimethyl
`fumarate compared to an appropriate control for the treatment of relapsing forms
`of multiple sclerosis.
`
`
`
`Final Protocol Submission: 11/30/2016
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`Study/Trial Completion:
`10/31/2019
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`Final Report Submission:
`02/28/2020
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`
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`Submit the protocol(s) to your IND, with a cross-reference letter to this NDA. Submit the draft
`protocol at least 3 months prior to the final protocol submission date to allow for review and
`agreement on the protocol design.
`
`Reports of this required pediatric postmarketing study must be submitted as an NDA or as a
`supplement to your approved NDA with the proposed labeling changes you believe are
`warranted based on the data derived from these studies. When submitting the reports, please
`clearly mark your submission "SUBMISSION OF REQUIRED PEDIATRIC
`ASSESSMENTS" in large font, bolded type at the beginning of the cover letter of the
`submission.
`
`
`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 the abuse potential of
`Tecfidera (dimethyl fumarate) or to identify unexpected serious risks of adverse effects on
`postnatal growth and development or unexpected serious risks of serious infections including
`opportunistic infections, leiomyomata, malignancies including renal cell cancers, and other
`serious adverse events including serious renal and hepatic events and other medically significant
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`Reference ID: 3283381
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`Page 3 of 8
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`NDA 204063
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` Page 4
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`events. 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:
`
`2014-2
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`A comprehensive in vitro receptor binding study with dimethyl fumarate and with
`its metabolite monomethyl fumarate. This includes characterizing the affinity of
`dimethyl fumarate and monomethyl fumarate on dopamine, serotonin, GABA
`(gamma-amino-butyric-acid), opioid, NMDA, monoamine, sodium channel,
`calcium channel, and cannabinoid receptor sites, as well as the interaction of
`
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`dimethyl fumarate and of monomethyl fumarate with nitric oxide synthase.
`
`The timetable you submitted on March 5, 2013, states that you will conduct this study
`according to the following schedule:
`
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`Final Protocol Submission: 06/30/2013
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`Study Completion:
`08/30/2013
`
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`Final Report Submission:
`10/30/2013
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`A nonclinical self-administration study to assess abuse potential using dimethyl
`fumarate in animals trained to discriminate the known drug of abuse from saline.
`The animals chosen must demonstrate similar metabolism of dimethyl fumarate
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`and monomethyl fumarate as observed in humans.
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`
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`2014-3
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`
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`The timetable you submitted on March 5, 2013, states that you will conduct this study
`according to the following schedule:
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`Final Protocol Submission: 10/30/2013
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`Study Completion:
`02/28/2014
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`Final Report Submission:
`03/30/2014
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`A nonclinical discrimination study to assess abuse potential using dimethyl
`fumarate in animals trained to discriminate the known drug of abuse from saline.
`The animals chosen must demonstrate similar metabolism of dimethyl fumarate
`and monomethyl fumarate as observed in humans.
`
`The timetable you submitted on March 5, 2013, states that you will conduct this study
`according to the following schedule:
`
`Final Protocol Submission: 03/30/2014
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`Study Completion:
`07/30/2014
`
`
`Final Report Submission:
`08/30/2014
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`
`
`
`2014-4
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`
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`Reference ID: 3283381
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`Page 4 of 8
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`NDA 204063
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` Page 5
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`2014-5
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`2014-6
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`A juvenile rat toxicology study. The study should utilize animals of an age range
`and stage(s) of development that are comparable to the intended pediatric
`population; the duration of dosing should cover the intended length of treatment
`in the pediatric population. In addition to the usual toxicological parameters, this
`study should evaluate effects of dimethyl fumarate on growth, reproductive
`
`development, and neurological and neurobehavioral development.
`
`The timetable you submitted on March 5, 2013, states that you will conduct this study
`according to the following schedule:
`
`Final Protocol Submission: 04/30/2014
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`Study Completion:
`01/31/2016
`
`
`Final Report Submission:
`03/31/2016
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`A large, long-term, prospective observational study in adult patients with
`relapsing multiple sclerosis, with the primary objective of determining the nature
`and incidence of serious infections including opportunistic infections,
`leiomyomata, malignancies including renal cell cancers, and other serious adverse
`events including serious renal and hepatic events and other medically significant
`events occurring with marketed use of Tecfidera (dimethyl fumarate). The study
`should include characterization of the finding of urinary ketones. A minimum of
`5000 multiple sclerosis patients treated with Tecfidera (dimethyl fumarate) should
`be enrolled and followed for a minimum of 5 years. The final protocol should
`reflect agency agreement and be submitted prior to starting the study.
`
`
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`The timetable you submitted on March 5, 2013, states that you will conduct this study
`according to the following schedule:
`
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`Final Protocol Submission: 10/31/2013
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`Study Completion:
`10/30/2022
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`Final Report Submission:
`10/30/2023
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`
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`Submit the protocol(s) to your IND, with a cross-reference letter to this NDA. Submit 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
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`Reference ID: 3283381
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`Page 5 of 8
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`NDA 204063
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` Page 6
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`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.
`
`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
`to:
`
`
`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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`
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`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. For instruction on completing the Form FDA 2253, see page 2 of the Form. 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). We also request that assessment of adverse events related to abuse
`potential be compiled in PSURs with an emphasis on MedDRA terms and frequently used
`verbatim terms, as identified in Appendix B, that report incidents of euphoria-related behaviors,
`impaired attention, cognition, mood, and psychomotor events, and dissociative or psychotic
`behaviors. In addition, we request that all PSURs include specific discussions of events of
`potential renal toxicity, renal cell cancer, leiomyomata, and infections including opportunistic
`infections.
`
`
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`Reference ID: 3283381
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`Page 6 of 8
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`NDA 204063
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` Page 7
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` 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.
`
`
`POST-ACTION FEEDBACK MEETING
`
`New molecular entities and new biologics qualify for a post-action 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 Nicole L. Bradley, PharmD, Regulatory Project Manager, at (301)
`796-1930.
`
`
`
`
`
`Sincerely,
`
` {See appended electronic signature page}
`
`Robert Temple, MD
`Deputy Director
`Office of Drug Evaluation I
`Center for Drug Evaluation and Research
`
`
`
`Enclosures:
`Appendix A: Content of Labeling
`Appendix B: Abuse-Related Adverse Event Terms
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`
`
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`Reference ID: 3283381
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`Page 7 of 8
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`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`ROBERT TEMPLE
`03/27/2013
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`Reference ID: 3283381
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`Page 8 of 8
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