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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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`NDA 202788/S-018
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`Food and Drug Administration
`Silver Spring MD 20993
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`SUPPLEMENT APPROVAL
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`Insys Development Company, Inc.
`1333 South Spectrum Blvd., Suite 100
`Chandler, AZ 85286
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`Attention:
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`Dear Mr. Sherman:
`
`Please refer to your Supplemental New Drug Application (sNDA) dated June 12, 2017,
`submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act (FDCA) for
`SUBSYS (fentanyl).
`
`We also refer to our REMS Modification Notification letter dated April 10, 2017, informing you
`that the Transmucosal Immediate Release Fentanyl (TIRF) Risk Evaluation and Mitigation
`Strategy (REMS) must be modified to ensure that the benefits of the drug outweigh its risks.
`
`This supplemental new drug application proposes modifications to the approved TIRF REMS to
`align the REMS document and materials with the labeling approved in supplement S-016 on
`December 16, 2016.
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`We have completed our review of this supplemental application. It is approved, effective on the
`date of this letter.
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`RISK EVALUATION AND MITIGATION STRATEGY REQUIREMENTS
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`The REMS for TIRF products, of which SUBSYS is a member, was originally approved on
`December 28, 2011, and the most recent REMS modification was approved on December 24,
`2014. The REMS consists of a Medication Guide, elements to assure safe use, an
`implementation system, and a timetable for submissions of assessments of the REMS.
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`In order to ensure the benefits of SUBSYS outweigh its risks, we determined that you were
`required to make changes to the REMS document, and appended materials consistent with the
`safety label changes approved on December 16, 2016, as well as additional minor modifications.
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`Your proposed modified REMS, submitted to Drug Master File (DMF)
`2017, and appended to this letter, is approved.
`
`Stephen Sherman
`Sr. Vice President, Regulatory Affairs
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` on August 29,
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`Reference ID: 4148996
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`(b) (4)
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`

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`NDA 202788/S-018
`Page 2
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`This REMS uses a shared system for the elements to assure safe use and the REMS assessments.
`This shared system, known as the TIRF REMS Program, currently includes the products listed
`on the FDA REMS website, available at http://www.accessdata.fda.gov/scripts/cder/
`rems/index.cfm?event=RemsDetails.page&REMS=17.
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`Other products may be added in the future if additional NDAs or ANDAs are approved.
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`The timetable for submission of assessments for the TIRF REMS Program remains the same as
`that approved on June 5, 2012.
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`There are no changes to the REMS assessment plan described in our August 21, 2014, REMS
`Assessment Acknowledgment/REMS Assessment Plan Revision letter.
`
`We remind you that in addition to the REMS assessments submitted according to the timetable in
`the approved REMS, you must include an adequate rationale to support a proposed REMS
`modification for the addition, modification, or removal of any goal or element of the REMS, as
`described in section 505-1(g)(4) of the FDCA.
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`We also remind you that you must submit a REMS assessment when you submit a supplemental
`application for a new indication for use as described in section 505-1(g)(2)(A) of the FDCA.
`This assessment should include:
`a) An evaluation of how the benefit-risk profile will or will not change with the new
`indication;
`b) A determination of the implications of a change in the benefit-risk profile for the current
`REMS;
`c) If the new indication for use introduces unexpected risks: A description of those risks
`and an evaluation of whether those risks can be appropriately managed with the currently
`approved REMS.
`d) If a REMS assessment was submitted in the 18 months prior to submission of the
`supplemental application for a new indication for use: A statement about whether the
`REMS was meeting its goals at the time of the last assessment and if any modifications
`of the REMS have been proposed since that assessment.
`e) If a REMS assessment has not been submitted in the 18 months prior to submission of the
`supplemental application for a new indication for use: Provision of as many of the
`currently listed assessment plan items as is feasible.
`f) If you propose a REMS modification based on a change in the benefit-risk profile or
`because of the new indication of use, submit an adequate rationale to support the
`modification, including: Provision of the reason(s) why the proposed REMS
`modification is necessary, the potential effect on the serious risk(s) for which the REMS
`was required, on patient access to the drug, and/or on the burden on the health care
`delivery system; and other appropriate evidence or data to support the proposed change.
`Additionally, include any changes to the assessment plan necessary to assess the
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`Reference ID: 4148996
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`

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`NDA 202788/S-018
`Page 3
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`proposed modified REMS. If you are not proposing REMS modifications, provide a
`rationale for why the REMS does not need to be modified.
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`If the assessment instruments and methodology for your REMS assessments are not included in
`the REMS supporting document, or if you propose changes to the submitted assessment
`instruments or methodology, you should update the REMS supporting document to include
`specific assessment instrument and methodology information at least 90 days before the
`assessments will be conducted. Updates to the REMS supporting document may be included in a
`new document that references previous REMS supporting document submission(s) for
`unchanged portions. Alternatively, updates may be made by modifying the complete previous
`REMS supporting document, with all changes marked and highlighted. Prominently identify the
`submission containing the assessment instruments and methodology with the following wording
`in bold capital letters at the top of the first page of the submission:
`
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`NDA 202788 REMS CORRESPONDENCE
`(insert concise description of content in bold capital letters, e.g.,
`UPDATE TO REMS SUPPORTING DOCUMENT - ASSESSMENT
`METHODOLOGY
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`An authorized generic drug under this NDA must have an approved REMS prior to marketing.
`Should you decide to market, sell, or distribute an authorized generic drug under this NDA,
`contact us to discuss what will be required in the authorized generic drug REMS submission.
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`We remind you that section 505-1(f)(8) of FDCA prohibits holders of an approved covered
`application with elements to assure safe use from using any element to block or delay approval
`of an application under section 505(b)(2) or (j). A violation of this provision in 505-1(f) could
`result in enforcement action.
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`Prominently identify any submission containing the REMS assessments or proposed
`modifications of the REMS with the following wording in bold capital letters at the top of the
`first page of the submission as appropriate:
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`NDA 202788 REMS ASSESSMENT
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`NEW SUPPLEMENT FOR NDA 202788/S-000/
`CHANGES BEING EFFECTED IN 30 DAYS
`PROPOSED MINOR REMS MODIFICATION
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`or
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`NEW SUPPLEMENT FOR NDA 202788/S-000/
`PRIOR APPROVAL SUPPLEMENT
`PROPOSED MAJOR REMS MODIFICATION
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`or
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`Reference ID: 4148996
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`

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`NDA 202788/S-018
`Page 4
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`NEW SUPPLEMENT FOR NDA 202788/S-000/
`PRIOR APPROVAL SUPPLEMENT
`PROPOSED REMS MODIFICATIONS DUE TO SAFETY LABEL CHANGES
`SUBMITTED IN SUPPLEMENT XXX
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`or
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`NEW SUPPLEMENT (NEW INDICATION FOR USE)
`FOR NDA 202788/S-000/
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`REMS ASSESSMENT
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`PROPOSED REMS MODIFICATION (if included)
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`Should you choose to submit a REMS revision, prominently identify the submission containing
`the REMS revisions with the following wording in bold capital letters at the top of the first page
`of the submission:
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`
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`To facilitate review of your submission, we request that you submit your proposed modified
`REMS and other REMS-related materials in Microsoft Word format. If certain documents, such
`as enrollment forms, are only in PDF format, they may be submitted as such, but the preference
`is to include as many as possible in Word format.
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`If you have any questions, call Mark Liberatore, PharmD; Safety Regulatory Project Manager, at
`(301) 796-2221.
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`REMS REVISIONS FOR NDA 202788
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`Sincerely,
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`{See appended electronic signature page}
`
`Judith A. Racoosin, MD, MPH
`Deputy Director of Safety
`Division of Anesthesia, Analgesia,
` and Addiction Products
`Office of Drug Evaluation II
`Center for Drug Evaluation and Research
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`ENCLOSURE:
`REMS
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`Reference ID: 4148996
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`

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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/
`----------------------------------------------------
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`SHARON H HERTZ on behalf of JUDITH A RACOOSIN
`09/07/2017
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`Reference ID: 4148996
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