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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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`Food and Drug Administration
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` Silver Spring MD 20993
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`SUPPLEMENT APPROVAL
`REMS ASSESSMENT PLAN REVISION
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` NDA 201655/S-017
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`Tara Chapman, PharmD
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`Director, Regulatory Affairs
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` Endo Pharmaceuticals, Inc.
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` 1400 Atwater Drive
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` Malvern, PA 19355
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`Attention:
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`Dear Dr. Chapman:
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`Please refer to your Supplemental New Drug Application (sNDA) dated and, received February
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`20, 2015, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act (FDCA)
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`for Opana ER (oxymorphone) extended-release tablets
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`We acknowledge receipt of your amendment(s) dated June 12, 2015.
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`This supplemental new drug application provides for proposed modifications to the approved
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`risk evaluation and mitigation strategy (REMS) for Opana ER. This supplement is in response to
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`our February 3, 2015, REMS Modification Notification letter, and our April 9, 2015, email
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`advising you that your proposed REMS modification should also include revised titration
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`information for Dolophine (methadone HCl tablets).
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`We have completed our review of this supplemental application, as amended. It is approved,
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`effective on the date of this letter.
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`RISK EVALUATION AND MITIGATION STRATEGY REQUIREMENTS
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`The REMS for extended release and long-acting (ER/LA) opioid analgesics products, of which
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`Opana ER is a member, was originally approved on July 9, 2012, and the most recent REMS
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`modification was approved on August 19, 2014. The REMS consists of a Medication Guide,
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`elements to assure safe use, and a timetable for submission of assessments of the REMS.
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`In order to ensure the benefits of Opana ER outweigh its risks, we determined that you were
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`required to make the following REMS modifications:
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`Changes to the ER/LA Opioid Analgesics REMS Blueprint for Prescriber
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`Education to incorporate:
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`Reference ID: 3784648
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` NDA 201655/S-017
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` Page 2
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` 1. Product-specific information for a recently approved ER/LA
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` opioid analgesic, Hysingla ER (hydrocodone bitartrate
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` extended-release) tablets
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`2. Newly approved intermediate strengths of fentanyl transdermal
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`systems
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`3. Revised titration information for Dolophine (methadone HCl tablets)
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`Your proposed modified REMS, submitted on June 12, 2015, and appended to this letter, is
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`approved.
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` This REMS uses a single, shared system for the elements to assure safe use and the REMS
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` assessments. This single shared system, known as the ER/LA Opioid Analgesics REMS
` Program, currently includes the products listed on the FDA REMS website, available at
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` http://www.fda.gov/rems.
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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 of the ER/LA Opioid Analgesic REMS Program is
`due annually on July 9. Some aspects outlined in the original REMS assessment plan approved
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`on July 9, 2012, are no longer applicable, as those time-specific elements (special instructions for
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`the 6-month, 12-month, and 24-month assessments) have already been implemented. Therefore,
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`included below is a revised assessment plan intended for all applicants, including those who
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`currently participate in this REMS, as well as those that join the REMS in the future.
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`The revised REMS assessment plan must include, but is not limited to, the following:
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`1) Documentation of the dissemination of Prescriber Letter 3:
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`a) number of prescriber letters electronically sent, received, undeliverable, and
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`opened, and
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`b) number of prescriber letters mailed and undeliverable.
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`2) Prescriber Training: Documentation of the number of prescribers of ER/LA opioid
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`analgesics who have completed REMS-compliant training. Performance goals,
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`based on the 2011 estimate that 320,000 prescribers are active prescribers of
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`ER/LA opioids (prescribers who have prescribed an ER/LA opioid within the last
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`12 months), are as follows:
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`a) Within two years from the time the first REMS-compliant training becomes
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`available, 80,000 prescribers (based on 25% of active prescribers) are to have
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`been trained;
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`b) Within three years from the time the first REMS-compliant training becomes
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`available, 160,000 prescribers (based on 50% of active prescribers) are to have
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`been trained;
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`Reference ID: 3784648
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` NDA 201655/S-017
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` Page 3
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` c) Within four years from the time the first REMS-compliant training becomes
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` available, 192,000 prescribers (based on 60% of active prescribers) are to have
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` been trained.
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`3) Independent Audit: The results of an independent audit of the quality of the content of the
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`educational materials used by the CE providers to provide the REMS-compliant training.
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`Audits must be conducted on a random sample of at least 10% of the training funded under
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`the ER/LA Opioid REMS, and a random sample of REMS-compliant training not funded
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`under the ER/LA Opioid REMS that will be counted as REMS-compliant training for
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`purposes of meeting the milestones in item 2 above and must evaluate:
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`a) whether the content of the training covers all elements of the FDA “blueprint”
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`approved as part of the REMS;
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`b) whether the post-course knowledge assessment measures knowledge of all sections of
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`the FDA “blueprint”; and
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`c) whether the training was conducted in accordance with the Accreditation Council for
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`Continuing Medication Education (ACCME) standards for CE or appropriate standards
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`for accreditation bodies.
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`4) Evaluation of Prescriber Understanding:
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`a) The results of an evaluation of ER/LA opioid prescribers’ awareness and understanding
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`of the serious risks associated with these products and their awareness of appropriate
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`prescribing practices for ER/LA opioids, comparing the awareness and understanding of
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`prescribers who have taken the REMS-compliant training with those who have not
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`taken such training. This evaluation may include, for example, surveys of healthcare
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`providers.
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`b) The results of any long-term evaluation of prescribers of ER/LA opioids who have
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`taken ER/LA Opioid REMS-funded training to determine these prescribers’ knowledge
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`retention and practice changes 6 months to 1 year after they completed the REMS-
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`compliant training.
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`5) Evaluation of Patient Understanding: The results of an evaluation of patients’
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`understanding of the serious risks of these products and their understanding of how to use
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`these products safely. This evaluation may include, for example, surveys of patients.
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`6) Surveillance Results: Results of surveillance and monitoring for misuse, abuse,
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`overdose, addiction, and death. Surveillance needs to include information on changes
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`in abuse, misuse, overdose, addiction, and death for different risk groups (e.g., teens,
`chronic abusers) and different settings (e.g., emergency departments, addiction
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`treatment centers, poison control call centers). The information should be drug-
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`specific whenever possible.
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`7) Drug Utilization Patterns: An evaluation of drug utilization patterns, including: an
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`evaluation of prescribing behaviors of the prescribers of ER/LA opioid analgesics, e.g.,
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`prescriptions to non-opioid tolerant patients, excessive prescriptions for early refills.
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`8) Patient Access: An evaluation of changes in patient access to ER/LA opioid analgesics.
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`Reference ID: 3784648
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` Page 4
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` 9) Methodologies: A description of the data sources and the methodologies used to conduct
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`all of the above described analyses.
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` 10) Goals: The requirements for assessments of an approved REMS under section 505-1(g)(3) of
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`the FDCA include with respect to each goal included in the strategy, an assessment of the
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`extent to which the approved strategy, including each element of the strategy, is meeting the
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`goal or whether one or more such goals or such elements should be modified.
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`Definitions: For purposes of these REMS assessments, the following definitions apply:
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`REMS-compliant training: Training will be considered “REMS-compliant training” if
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`1) it, for training provided by CE providers, is offered by an accredited provider to
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`licensed prescribers, 2) it includes all elements of the FDA “blueprint”, 3) it includes a
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`post-course knowledge assessment of all of the sections of the “FDA blueprint”, and 4) it
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`is subject to independent audit to confirm that conditions of the REMS training have
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`been met.
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`FDA Blueprint: A document entitled, “Blueprint for Prescriber Continuing Education
`Programs Extended-Release and Long-Acting Opioids,” approved as part of this REMS,
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`that contains core messages to be conveyed to prescribers in the training about the risks
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`and appropriate prescribing practices for the safe use of ER/LA opioids.
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`We remind you that in addition to the REMS assessments submitted according to the timetable in
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`the approved REMS, you must include an adequate rationale to support a proposed REMS
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`modification for the addition, modification, or removal of any of goal or element of the REMS,
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`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
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`application for a new indication for use as described in section 505-1(g)(2)(A) of the FDCA.
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`This assessment should include:
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`a) An evaluation of how the benefit-risk profile will or will not change with the new
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`indication;
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`b) A determination of the implications of a change in the benefit-risk profile for the current
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`REMS;
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`c) If the new indication for use introduces unexpected risks: A description of those risks
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`and an evaluation of whether those risks can be appropriately managed with the currently
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`approved REMS.
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`d) If a REMS assessment was submitted in the 18 months prior to submission of the
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`supplemental application for a new indication for use: A statement about whether the
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`REMS was meeting its goals at the time of that the last assessment and if any
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`modifications of the REMS have been proposed since that assessment.
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`e) If a REMS assessment has not been submitted in the 18 months prior to submission of the
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`supplemental application for a new indication for use: Provision of as many of the
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`currently listed assessment plan items as is feasible.
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`Reference ID: 3784648
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` NDA 201655/S-017
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` Page 5
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`f) If you propose a REMS modification based on a change in the benefit-risk profile or
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` because of the new indication of use, submit an adequate rationale to support the
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` modification, including: Provision of the reason(s) why the proposed REMS
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` modification is necessary, the potential effect on the serious risk(s) for which the REMS
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` 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.
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`Additionally, include any changes to the assessment plan necessary to assess the
`proposed modified REMS. If you are not proposing REMS modifications, provide a
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`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
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`instruments or methodology, you should update the REMS supporting document to include
`specific assessment instrument and methodology information at least 90 days before the
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`assessments will be conducted. Updates to the REMS supporting document may be included in a
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`new document that references previous REMS supporting document submission(s) for
`unchanged portions. Alternatively, updates may be made by modifying the complete previous
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`REMS supporting document, with all changes marked and highlighted. Prominently identify the
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`submission containing the assessment instruments and methodology with the following wording
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`in bold capital letters at the top of the first page of the submission:
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`NDA 201655 REMS CORRESPONDENCE
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`(insert concise description of content in bold capital letters, e.g.)
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`UPDATE TO REMS SUPPORTING DOCUMENT - ASSESSMENT
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`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,
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`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
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`application from using any element to assure safe use to block or delay approval of an
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`application under section 505(b)(2) or (j) or to prevent application of such element under 505­
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`1(i)(1)(B) to a drug that is subject of an ANDA. 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
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`first page of the submission as appropriate:
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`NDA 201655 REMS ASSESSMENT
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`NEW SUPPLEMENT FOR NDA 201655/S-000/
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`CHANGES BEING EFFECTED IN 30 DAYS
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`PROPOSED MINOR REMS MODIFICATION
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`Reference ID: 3784648
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` NDA 201655/S-017
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` Page 6
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` or
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`NEW SUPPLEMENT FOR NDA 201655/S-000
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`PRIOR APPROVAL SUPPLEMENT
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`PROPOSED MAJOR REMS MODIFICATION
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`or
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`NEW SUPPLEMENT FOR NDA 201655/S-000
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`PRIOR APPROVAL SUPPLEMENT
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`PROPOSED REMS MODIFICATIONS DUE TO SAFETY LABEL CHANGES
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`SUBMITTED IN SUPPLEMENT XXX
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`NEW SUPPLEMENT (NEW INDICATION FOR USE)
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`FOR NDA 201655/S-000
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`REMS ASSESSMENT
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`PROPOSED REMS MODIFICATION (if included)
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`REMS REVISIONS FOR NDA 201655
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`Should you choose to submit a REMS revision, prominently identify the submission containing
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`the REMS revisions with the following wording in bold capital letters at the top of the first page
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`of the submission:
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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
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`as enrollment forms, are only in PDF format, they may be submitted as such, but the preference
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`is to include as many as possible in Word format.
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`If you do not submit electronically, please send 5 copies of REMS-related submissions.
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`REPORTING REQUIREMENTS
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`We remind you that you must comply with reporting requirements for an approved NDA
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`(21 CFR 314.80 and 314.81).
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`Reference ID: 3784648
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` NDA 201655/S-017
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` Page 7
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` If you have any questions, call Mark Liberatore, PharmD, Safety Regulatory Project Manager, at
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`Sincerely,
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`{See appended electronic signature page}
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`Judith A. Racoosin, MD, MPH
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`Deputy Director of Safety
`Division of Anesthesia, Analgesia,
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`and Addiction Products
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`Office of Drug Evaluation II
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`Center for Drug Evaluation and Research
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`ENCLOSURE:
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`REMS
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`Reference ID: 3784648
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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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`JUDITH A RACOOSIN
`06/26/2015
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`Reference ID: 3784648
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