`NDA 202788/S-021
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`
`
`
`SUPPLEMENT APPROVAL
`
`
`
`
`
`
`
`
` BTcP Pharma, LLC
`
` c/o West Therapeutics Development, LLC
`
` 1033 Skokie Boulevard
`
` Suite 620
` Northbrook, IL 60062
`
`
`
`Attention: Mahlaqa Patel
`
`
`Vice President, Regulatory Affairs and Quality Assurance
`
`
`
`
`Dear Ms. Patel:
`
`Please refer to your supplemental new drug application (sNDA) dated and received July
`
`
`
`25, 2019, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act
`
`
`(FDCA) for Subsys (fentanyl sublingual spray).
`
`
`We also refer to our REMS MODIFICATION NOTIFICATION letter, dated March 27,
`
`2019, 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 determination was based on information contained in
`the REMS assessment reports suggesting many patients prescribed a TIRF medicine
`may not have been opioid-tolerant when they received a new prescription for a TIRF
`
`medicine, as well as recommendations from the August 3, 2018, joint meeting of the
`
`Drug Safety and Risk Management, and the Anesthetic and Analgesic Drug Products
`
`advisory committees.
`
`
`This supplemental new drug application proposes REMS modifications required under
`
`
`
`section 505-1 of the FDCA, consistent with those outlined in the March 27, 2019, letter.
`
`
`We have completed our review of this supplemental application. It is approved, effective
`
`
`on the date of this letter.
`
`
`RISK EVALUATION AND MITIGATION STRATEGY (REMS) REQUIREMENTS
`
`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
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`
`
`September 7, 2017. The REMS consists of a Medication Guide, elements to assure
`safe use, an implementation system, and a timetable for submission of assessments of
`
`the REMS.
`
`
`
`Reference ID: 4721753
`
`

`

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` on
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` NDA 202788/S-021
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` Page 2
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`In order to ensure the benefits of Subsys outweigh its risks, we determined that you
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`
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`were required to make the REMS modifications outlined in our REMS Modification letter
`
`
`dated March 27, 2019.
`
`
`Your proposed modified REMS, submitted to Drug Master File (DMF)
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`December 7, 2020, and appended to this letter, is approved.
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`
`
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`The modifications to the approved REMS must be fully implemented within 120
`
`calendar days of the date of this letter.
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`
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`The REMS uses a shared system for the elements to assure safe use, an
`
`implementation system, and a timeable for assessments of the REMS. This shared
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`system, known as the TIRF REMS program, currently includes products listed on the
`
`FDA REMS, website, available at:
`https://www.accessdata.fda.gov/scripts/cder/rems/index.cfm?event=RemsDetails.page&
`REMS=60
`
`
`Other products may be added in the future if additional NDAs or ANDAs are approved.
`
`
`The timetable for submission of assessments of the REMS must be revised to 12
`
`months from the date of the approval of this REMS modification (December 23, 2020)
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`and annually thereafter.
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`The revised REMS assessment plan must include, but is not limited to, the following:
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`
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`Program Outreach and Communication
`
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`1. Communication (1-year assessment post-modification approval only)
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`a. Sources of the distribution list(s) for the Dear Healthcare Provider Letter to
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`healthcare providers likely to prescribe TIRF medicines
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`b. Number of targeted healthcare providers who can prescribe
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`
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`c. The number of Dear Healthcare Provider letters sent by date(s), medical
`
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`specialty, and method of distribution.
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`i. The number and percentage of emailed letters successfully
`
`
`delivered, opened, and unopened.
`
`ii. The number and percentage of mailed letters successfully delivered
`
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`or returned as undeliverable.
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`iii. The number and percentage of faxed letters successfully delivered
`
`
`or returned as undeliverable.
`
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`d. The number of professional societies sent the Dear Healthcare Provider
`
`
`Letter by date(s) and method of distribution. In addition, include which
`
`
`
`U.S. Food and Drug Administration
`
`
`
`Silver Spring, MD 20993
`
`
`
`www.fda.gov
`
`
`Reference ID: 4721753
`
`(b) (4)
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`

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`NDA 202788/S-021
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`Page 3
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`professional societies distributed the Dear Healthcare Provider Letter or
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`the content of the letter to their respective members.
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`e. Sources of the distribution list(s) for the Dear Pharmacy Letter to inpatient
`
`
`
`and outpatient pharmacies that dispense Schedule II drugs and may be
`involved in dispensing TIRF medicines
`
`f. The number of pharmacies sent the Dear Pharmacy Letter date(s), type of
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`
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`pharmacy, and by method of distribution
`
`
`i. The number and percentage of emailed letters successfully
`
`
`delivered, opened, and unopened.
`
`ii. The number and percentage of mailed letters successfully delivered
`
`
`or returned as undeliverable.
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`iii. The number and percentage of faxed letters successfully delivered
`
`
`or returned as undeliverable.
`
`g. The number of professional societies sent the Dear Pharmacy by dates(s)
`
`
`and by method of distribution. In addition, include which professional
`
`societies distributed the Dear Pharmacy Letter or the content of the letter
`
`
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`to their respective members.
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`h. Date(s) and name(s) of Professional meetings where TIRF REMS
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`
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`materials were disseminated or displayed.
`
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`Program Implementation and Operations
`
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`2. REMS Program Implementation (1-year assessment post-modification
`
`
`approval only)
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`a. Date when the modified TIRF REMS website went live and was fully
`
`
`operational
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`b. Date when healthcare providers who can prescribe could become certified
`
`in the modified REMS
`
`c. Date when pharmacies could become certified in the modified REMS
`
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`d. Date when patients could be enrolled in the modified REMS
`
`
`e. Date when distributors/wholesalers could be registered in the modified
`
`REMS
`
`f. Date when the REMS Call Center for the modified TIRF REMS program
`
`
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`went live and was fully operational
`
`3. REMS Certification and Enrollment Statistics (provide previous, current,
`
`and cumulative reporting periods)
`
`a. Patients (number and percent)
`
`
`i. For the one-year assessment report only:
`
`
`
`
`
`
`U.S. Food and Drug Administration
`
`
`
`Silver Spring, MD 20993
`
`
`
`www.fda.gov
`
`
`Reference ID: 4721753
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`

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`NDA 202788/S-021
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`Page 4
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`1) Patients previously enrolled in the TIRF REMS Access
`
`
`program (i.e. enrolled prior to implementation of the modified
`REMS)
`
`2) Patients re-enrolled (i.e., previously enrolled in the TIRF
`
`REMS Access program and transitioned to new program)
`
`ii. Newly enrolled into the new program
`
`
`iii. Active patients (i.e., received at least one dispensation of a TIRF
`
`product during the reporting period)
`
`iv. For metrics 3.a.i. through iii, stratify by demographics (age, gender,
`
`
`
`ethnicity, race, and geographic region [as defined by US Census]),
`
`around-the-clock opioid(s) (moiety, daily dose, and duration of
`
`greater than seven days), medical reasons related to pain (cancer
`
`
`or non-cancer pain), TIRF medicine use in the prior six months, and
`concomitant benzodiazepines and other central nervous system
`
`(CNS) depressants
`
`v. A summary of the methods of patient enrollment (e.g., online, fax)
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`
`
`
`vi. Number of patients who were unable to become enrolled,
`
`
`
`accompanied by a summary of the reasons they were unable to be
`
`enrolled
`
`b. Healthcare Providers who can Prescribe (number and percent)
`
`
`i.
`For the one-year assessment report only:
`
`
`1) Healthcare providers who can prescribe who previously
`
`
`certified in the TIRF REMS Access program (i.e. enrolled
`prior to implementation of the modified REMS)
`
`2) Healthcare providers who can prescribe who re-certified (i.e.,
`
`previously certified in the TIRF REMS Access program and
`transitioned to new program)
`
`ii. Healthcare providers who can prescribe who are newly certified
`
`
`iii. Active prescribers (i.e. who have prescribed a TIRF at least once
`
`during the reporting period)
`
`For metrics 3.a.i. through iii, stratify by credentials, (e.g., Doctor of
`
`Medicine, Doctor of Osteopathic Medicine, Nurse Practitioner,
`
`Physician Assistant, Other), medical specialty (e.g., Pain
`
`Medicine, Oncology, Internal Medicine, Other, etc.) and
`geographic region [as defined by US Census])
`
`
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`v. A summary of the methods of healthcare provider certification
`
`
`(e.g., online, fax)
`
`
`iv.
`
`
`
`U.S. Food and Drug Administration
`
`
`
`Silver Spring, MD 20993
`
`
`
`www.fda.gov
`
`
`Reference ID: 4721753
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`

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`NDA 202788/S-021
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`Page 5
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`vii.
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`vi. Number of healthcare providers who can prescribe who were
`
`
`unable to become certified, accompanied by a summary of the
`
`reasons they were unable to be certified
`
`For the 2-year assessment report, conduct an outreach to
`healthcare providers that did not re-certify in the REMS to
`
`ascertain the reasons why they did not re-certify. Submit the
`
`methodology protocol 120 days prior to initiating the outreach.
`
`c. Pharmacies (number and percent)
`
`
`For the one-year assessment report only:
`i.
`
`
`1) Pharmacies previously certified in the TIRF REMS Access
`
`
`program (i.e. enrolled prior to implementation of the modified
`REMS)
`
`2) Pharmacies re-certified (i.e., previously certified in the TIRF
`
`REMS Access program and transitioned to new program)
`
`ii. Pharmacies newly certified into the new program
`
`
`iii. Active pharmacies (i.e., have dispensed a TIRF at least once
`
`during the reporting period)
`
`For metrics 3.a.i. through iii, stratify by pharmacy type (inpatient,
`
`
`chain, independent [retail, mail, institutional], or closed system
`
`[provide identity of closed system entities]) and by geographic
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`region [as defined by US Census])
`
`v. A summary of the methods of pharmacy certification (e.g., online,
`
`
`
`fax)
`
`vi. Number of pharmacies that were unable to become certified,
`
`
`
`accompanied by a summary of the reasons they were unable to
`
`be certified
`
`For the 2-year REMS assessment report, conduct an outreach to
`pharmacies that did not re-certify in the REMS to ascertain the
`reasons why they did not re-certify. Submit the methodology
`
`
`protocol 120 days prior to initiating the outreach.
`
`d. Wholesalers-Distributors (number)
`
`
`i. Previously enrolled (i.e. enrolled prior to implementation of the
`
`modified REMS)
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`ii. Re-enrolled (i.e., enrolled prior to implementation of the modified
`
`REMS and transitioned to new program)
`
`iii. Newly enrolled into the new program
`
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`iv. Active (i.e., distributed a TIRF product during the reporting period)
`
`
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`iv.
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`vii.
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`
`
`U.S. Food and Drug Administration
`
`
`
`Silver Spring, MD 20993
`
`
`
`www.fda.gov
`
`
`Reference ID: 4721753
`
`

`

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` NDA 202788/S-021
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` Page 6
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`4. TIRF Utilization Data (provide previous, current, and cumulative reporting
`
`periods)
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`a. Number of prescriptions/transactions authorized for dispensing and those
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`dispensed stratified by:
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`i. Prescriber specialty, degree/credentials, and geographic region.
`
`
`ii. Pharmacy type (specialty, central fill, inpatient, chain,
`
`
`
`independent [retail, mail, institutional], or closed system [provide
`identity of closed system entities])
`
`iii. Patient demographics (age, gender, ethnicity, race, and
`
`
`geographic region [as defined by US Census])
`
`
`Identify the source of this information
`iv.
`
`
`
`5. REMS Infrastructure and Performance (provide previous, current, and
`
`cumulative reporting periods)
`
`a. REMS Website
`
`
`i. Number of visits and unique visits to the REMS website
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`
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`ii. Number of REMS materials downloaded or printed for each
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`
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`material
`
`b. REMS program Call Center Report
`
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`i. Number of contacts by stakeholder type (patient/caregiver,
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`
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`healthcare provider, pharmacy, wholesalers/distributors, other)
`
`ii. A table summarizing the most frequently asked questions (e.g.,
`
`
`
`enrollment question) and by stakeholder type (e.g.,
`
`
`patient/caregiver, healthcare provider, pharmacy, wholesalers/
`
`distributors, etc.).
`
`iii. Summary of reasons for calls (e.g., enrollment question) and by
`
`
`reporter (authorized representative, patient/caregiver, healthcare
`
`
`provider, other)
`
`If the summary reason for the call(s) indicates a complaint,
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`
`
`provide details on the nature of the complaint(s) and whether they
`
`indicate potential REMS burden or patient access issues
`
`v. Summary of frequently asked questions (FAQ) by stakeholder
`
`
`type
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`vi. A summary report of corrective actions resulting from issues
`
`
`identified
`
`c. Infrastructure Performance
`
`
`i. Number of times a backup system was used with reason(s) for
`
`
`
`
`each instance (for example, pharmacy level problem, or REMS
`
`
`iv.
`
`
`
`U.S. Food and Drug Administration
`
`
`
`Silver Spring, MD 20993
`
`
`
`www.fda.gov
`
`
`Reference ID: 4721753
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`

`

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` NDA 202788/S-021
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` Page 7
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`vi.
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`database problem) clearly defined and described with description
`
`of corrective actions taken
`
`ii. Number of times unintended system interruptions occurred for
`
`
`
`each reporting period. Describe the number of stakeholders
`
`
`affected, how the issue was resolved, and steps put into place to
`minimize the impact of future interruptions
`
`6. REMS Compliance (current reporting period)
`
`
`a. Audits of pharmacies, wholesalers/distributors, and the REMS program
`
`
`Call Center) will be conducted to ensure that all REMS processes and
`
`procedures are in place, functioning, and support the REMS program, and
`will be submitted with each assessment report. The audit reports are to
`include:
`
`i. A copy of the audit plan used for the reporting period
`
`
`ii. A detailed description of audit findings including the number with
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`no findings, minor, moderate, or serious findings; include
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`information about the root cause of the noncompliance
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`iii. Number of audited sites in each stakeholder category listed
`
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`directly above.
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`iv. Number of audits expected, and the number of audits performed
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`
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`v. Number and types of deficiencies noted for each group of audited
`
`
`
`stakeholders
`
`Include a unique ID for each stakeholder that had deviations to
`track deviations by stakeholder over time.
`
`vii. Documentation of completion of training for relevant staff
`
`
`viii.
`The existence of documented processes and procedures for
`
`
`complying with the REMS
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`ix. Verification that at each audited stakeholder’s site, the designated
`
`
`authorized representative remains the same. If different, include
`
`the number of new authorized representatives and verification of
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`the site’s recertification.
`
`For inpatient hospital pharmacies, also report:
`
`1) The number of units of use of TIRFs ordered per inpatient
`
`
`hospital pharmacy audited per 12-month period
`
`
`2) Verification that processes such as order sets/protocols are
`
`in place to assure compliance with the REMS
`
`For closed systems, also report:
`
`1) Numbers of prescription authorizations per closed system;
`
`
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`x.
`
`
`xi.
`
`
`
`U.S. Food and Drug Administration
`
`
`
`Silver Spring, MD 20993
`
`
`
`www.fda.gov
`
`
`Reference ID: 4721753
`
`

`

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` NDA 202788/S-021
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` Page 8
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`2) Numbers of prescriptions dispensed that did not receive
`
`
`REMS authorization
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`xii. Describe any corrective actions taken for any non-compliance as
`
`
`identified above during the audits as well as preventative
`measures that were developed because of uncovering these non­
`compliance events
`
`1) For those with deficiencies noted, report the number that
`
`
`successfully completed a corrective and preventive action
`(CAPA) plan within one month of the audit.
`
`
`2) For any that did not complete the CAPA within one month of
`
`
`the audit, describe additional actions taken.
`
`b. Description of number, specialties, and affiliations of the personnel that
`
`
`
`constitute the Non-Compliance Review Team (NCRT) as well as the Non-
`
`Compliance Working Group
`
`c. For each non-compliance event, provide the source of the report, a
`
`
`
`
`description of the event, the cause of the event, if any patient harm
`
`
`
`resulted, and any corrective actions taken. Also provide a summary of
`
`non-compliance identified by stakeholder, including but not limited to:
`
`i.
`For Prescribers, provide:
`
`
`1) Number of prescribing healthcare providers who were non-
`
`
`compliant with TIRF REMS requirements
`
`2) Number of prescriptions written by non-certified healthcare
`
`
`providers
`
`3) Number of healthcare providers that were suspended or de­
`
`
`certified and reasons for decertification. Include if any
`
`healthcare providers were re-certified.
`
`For Pharmacies provide:
`
`1) Number and types of pharmacies for which non-compliance
`
`
`with the REMS is detected
`
`2) Number and type of non-certified pharmacies that dispensed
`
`TIRFs and the number of incidents for each
`
`
`3) Number of TIRF prescriptions dispensed that were written by
`
`
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`non-certified prescribers and include steps taken to prevent
`
`future occurrences
`
`4) Number of prescriptions dispensed by non-certified
`
`
`pharmacies and include steps taken to prevent future
`
`occurrences
`
`
`ii.
`
`
`
`U.S. Food and Drug Administration
`
`
`
`Silver Spring, MD 20993
`
`
`
`www.fda.gov
`
`
`Reference ID: 4721753
`
`

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` NDA 202788/S-021
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` Page 9
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`5) Number of times certified pharmacies dispensed TIRFs to
`
`
`unenrolled patients
`
`6) Number of times a TIRF prescription was dispensed
`
`
`because a pharmacy (closed or open system) was able to
`bypass REMS edits and if any such events occurred,
`
`describe how these events occurred and were identified
`
`7) Number of TIRF prescriptions dispensed to non-enrolled
`
`
`patients and the actions taken to prevent future occurrences
`
`8) Number of pharmacies suspended or decertified by
`
`
`
`pharmacy type, the reasons for such actions, and actions to
`address non-compliance
`
`For Wholesalers/distributors provide:
`
`1) The number of enrolled wholesalers/distributors for which
`
`non-compliance with the REMS is detected
`
`2) Number of times TIRF products were distributed to a non-
`
`
`certified pharmacy or directly to patients, and actions taken
`
`to recover the TIRF product
`
`
`3) Number of wholesalers suspended or de-enrolled, reasons
`
`
`
`for such action, and actions to address non-compliance
`
`For patients provide:
`
`1) Number of patients unenrolled, and reasons for such
`
`
`
`2) Number of patients not enrolled in the REMS who were
`
`
`dispensed TIRFs
`
`d. For each non-patient stakeholder referred to in section 6.c. above:
`
`
`i. Describe any moderate or serious non-compliance with the REMS
`
`that occurred during the first year of transitioning to the modified
`
`REMS
`
`ii. Provide an assessment of stakeholder compliance in following the
`
`proposed transition plan in transitioning to the modified REMS
`
`e. For each reporting period, include a copy of the non-compliance plan used
`
`during that reporting period
`
`f. Number of times a TIRF was prescribed to an opioid non-tolerant
`
`
`
`individual by falsifying information. Include what was done to minimize
`such instances; if any such events occurred, describe how these events
`
`
`were identified
`
`
`iii.
`
`
`iv.
`
`
`
`
`
`U.S. Food and Drug Administration
`
`
`
`Silver Spring, MD 20993
`
`
`
`www.fda.gov
`
`
`Reference ID: 4721753
`
`

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`NDA 202788/S-021
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`Page 10
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`Safe Use Behaviors
`
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`7. Patient Enrollment and Patient Status and Opioid Tolerance Forms
`
`
`
`a. Report on the Patient Enrollment Form and Patient Status and Opioid
`
`Tolerance Form (the “Forms”) (data presented for each individual form as
`
`well as combined):
`
`(For the 1-, 2-, and 3-year assessment reports only) The most
`i.
`
`
`common modes of submission of Forms to the REMS (e.g., Fax,
`
`
`online)
`
`ii. Number of Forms received compared to the number of TIRF
`
`
`prescriptions authorized for dispensing
`
`1) Explain any discrepancies between these two metrics
`
`
`2) Provide a description of the outcome/resolution of such
`
`event
`
`iii. Provide an analysis of cases where multiple submissions of a
`
`
`Form for the same patient were required prior to the pharmacy
`
`dispensing a prescription:
`
`1) Provide the mean, median, and range of the number of re­
`
`
`submissions
`
`2) Provide the reason(s) for the re-submissions grouped by
`
`
`
`
`commonly encountered situations
`
`3) Include an analysis of the number of Forms that were
`
`
`submitted that indicated that the patient was not opioid
`
`tolerant
`
`iv. Number of Forms submitted to the REMS with incomplete,
`
`
`
`
`erroneous, or altered fields; provide:
`
`1) An accounting of the sections of the Forms affected
`
`
`2) A description of the outcome/resolution of any incomplete,
`
`
`erroneous, or altered Forms
`
`For each TIRF dispense authorization (i.e., the prescriber
`
`provided documentation of opioid tolerance), provide the
`following:
`
`1) The number of these prescriptions that were dispensed by
`
`
`
`the pharmacy.
`
`2) For those prescriptions that were not dispensed, provide the
`
`reasons (e.g., patient not opioid tolerant as per the
`
`pharmacist, insurance/financial, etc.)
`
`
`v.
`
`
`
`U.S. Food and Drug Administration
`
`
`
`Silver Spring, MD 20993
`
`
`
`www.fda.gov
`
`
`Reference ID: 4721753
`
`

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`NDA 202788/S-021
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`Page 11
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`vi.
`
`
`For all dispensed TIRF prescriptions, provide an evaluation to
`confirm opioid tolerance based on the specific product, strength,
`
`
`frequency and duration provided on the Forms.
`
`1) Conduct a quarterly analysis of patients prescribed TIRFs to
`
`assess whether they met the threshold for opioid tolerance.
`
`
`Provide the results of these analyses in the annual
`
`
`assessment reports. The performance thresholds for this
`
`analysis have been set as follows:
`
`
`a) By the Year One assessment report, at least 80% of
`
`
`
`
`prescriptions written for TIRFs will be for opioid
`tolerant patients, as defined in labeling
`
`b) By the Year Two assessment report, at least 90% of
`
`
`prescriptions written for TIRFs will be for opioid
`tolerant patients, as defined in labeling
`
`
`c) By the Year Three assessment report, as well as for
`
`
`all subsequent assessment reports, at least 95% of
`
`prescriptions written for TIRFs will be for opioid
`tolerant patients, as defined in labeling
`
`2) Provide the number of prescriptions dispensed as well as the
`
`
`
`number determined to have been dispensed to opioid non-
`tolerant patients.
`
`a) Describe if any such events recurred in the same
`
`patients.
`
`b) Conduct a follow-up in these patients for any adverse
`
`
`events of special interest.
`
`
`Health Outcomes and/or Surrogates of Health Outcomes (data collected per
`
`reporting period)
`
`
`
`
`8. Surveillance Data
`
`
`a. Data from the REMS Patient Registry (REMS Data, Postmarketing
`
`
`Adverse Event Data): Surveillance data focused on Adverse Events of
`
`
`Special Interest (AESI) such as Accidental Exposure, Misuse, Abuse,
`
`Addiction, Overdose, Death, Serious Adverse Event.
`
`
`i. Average number of patients for each enrolled prescriber
`
`
`ii. Reports of inappropriate interchanges between TIRF products (a
`
`switch from a TIRF product to second TIRF product that is not
`
`
`
`initiated at the lowest dose when beginning the second TIRF)
`
`iii. Number and percentage of patients experiencing an Adverse
`
`Event of Special Interest AESI
`
`
`
`U.S. Food and Drug Administration
`
`
`
`Silver Spring, MD 20993
`
`
`
`www.fda.gov
`
`
`Reference ID: 4721753
`
`

`

`NDA 202788/S-021
`
`Page 12
`
`
`
`
`iv.
`
`
`The total number of AESIs reported and total number of each
`AESI (includes cases reported to the TIRF REMS by all sources
`
`
`including phone, REMS Forms, and spontaneous reports received
`directly by the application holders) per report source
`
`
`v. Risk of each AESI, as a cumulative estimate from all patients
`
`
`
`enrolled in the new program, and stratified by:
`
`
`1) REMS Assessment Period
`
`
`2) Patients with and without any concomitant CNS depressant
`
`
`medication at enrollment, as documented on the Patient
`
`Enrollment Form
`
`3) Patients with each specific category of concomitant CNS
`
`
`depressant medication at enrollment
`
`
`4) Type of pain noted at enrollment: cancer pain, non-cancer
`
`
`
`pain
`
`5) Child in the home/caregiver for small children, yes or no
`
`
`vi. Summary of details of AESIs reported, and outcomes of AESIs (if
`
`
`
`known)
`
`vii. Specifically, regarding the Patient Discontinuation Form:
`
`
`1) The number of such forms submitted
`
`
`2) The number reporting AESI or death
`
`
`3) The reasons for discontinuation indicated
`
`
`The number of Targeted AESI Forms expected, the number
`
`completed, and the reasons for this discrepancy
`
`ix. Monitor whether the percentage of patients who experience
`
`
`AESIs is increasing or decreasing over time
`
`b. Surveillance data to monitor events of accidental exposure, misuse,
`
`
`abuse, addiction, overdose, death, and pediatric cases should also be
`
`drawn from poison control center data, including case narratives.
`
`
`i. Depending on results of REMS assessment reports, additional
`
`
`
`surveillance data sources may be required
`
`c. Healthcare data to monitor events of pediatric accidental exposure
`
`requiring medical evaluation. FDA determined that the REMS assessment
`
`
`must include a medical record review of drug-related hospitalizations and
`hospital emergency department visits. Depending on the study results,
`
`administrative claims data may be required in addition to or instead of
`
`medical records data.
`
`
`viii.
`
`
`
`U.S. Food and Drug Administration
`
`
`
`Silver Spring, MD 20993
`
`
`
`www.fda.gov
`
`
`Reference ID: 4721753
`
`

`

`NDA 202788/S-021
`
`Page 13
`
`
`
`
`d. Death certificate data to monitor drug-related deaths, especially involving
`
`pediatric subjects
`
`e. Regarding spontaneous adverse event reports:
`
`
`i. AESI reports related to specific TIRF products will be reported to
`
`the FDA in accordance with 21 CFR 314.80.
`
`ii. AESI reports are to be linked to the registry and de-duplicated as
`
`
`
`is possible.
`
`iii. AESI reports from an inpatient setting, or outpatient reports that
`
`
`cannot be linked to enrolled patient data will be summarized
`separately.
`
`The FAERS public dashboard is to be utilized.
`
`TIRF product application holders will retrieve AESI reports from
`
`
`
`their respective safety databases and calculate reporting rates.
`
`vi. Each TIRF product application holder is to submit MedWatch
`
`reports in conjunction with un-blinded line listings directly to the
`
`FDA.
`
`
`iv.
`
`v.
`
`
`Knowledge
`
`
`
`9. Periodic Surveys of Prescribers, Pharmacists, and Patients (due with the
`
`2-Year REMS Assessment Report and annually thereafter with each
`
`assessment report)
`
`A Knowledge, Attitude and Behavior (KAB) Survey will be conducted with
`random samples of prescribers, pharmacists, and patients who have prescribed,
`
`
`dispensed, or received a TIRF medicine.
`
`a. Certified Prescriber KAB surveys will assess if prescribers are educated
`
`on the following:
`
`TIRF medicines contain fentanyl. Serious, life-threatening, and/or
`i.
`
`
`fatal respiratory depression has occurred.
`
`ii. Patients must be opioid tolerant to be prescribed a TIRF
`
`Medicine.
`
`iii. Accidental exposure to children and others and may cause severe
`
`or fatal respiratory depression.
`
`iv. Prescribers must counsel their patients on the risk of misuse,
`
`
`
`abuse, addiction, and overdose.
`
`b. Certified Outpatient Pharmacist KAB surveys will assess understanding of
`
`
`
`the following key risk messages:
`
`
`
`
`U.S. Food and Drug Administration
`
`
`
`Silver Spring, MD 20993
`
`
`
`www.fda.gov
`
`
`Reference ID: 4721753
`
`

`

`
`
` NDA 202788/S-021
`
` Page 14
`
`
`
`i.
`
`
`TIRF medicines contain fentanyl. Serious life-threatening, and/or
`
`fatal respiratory depression has occurred.
`
`ii. Patients must be opioid tolerant to be prescribed a TIRF
`
`Medicine.
`
`For each outpatient prescription, the pharmacist must obtain a
`prescription authorization number from the TIRF REMS Access
`
`
`program prior to dispensing each TIRF medicine.
`
`iv. Accidental exposure to children and others and may cause severe
`
`or fatal respiratory depression.
`
`c. Certified Inpatient Pharmacist KAB surveys will assess understanding of
`
`the following key risk messages:
`
`
`TIRF medicines contain fentanyl. Serious, life-threatening, and/or
`i.
`
`
`fatal respiratory depression has occurred.
`
`ii. Develop internal policies and procedures to verify opioid tolerant
`
`
`inpatients who require TIRF medicine while hospitalized.
`
`d. Patient KAB surveys will assess patient understanding of the following key
`
`
`risk messages:
`
`TIRF medicines can cause you to stop breathing which can lead
`i.
`
`to death.
`
`ii. Accidental poisoning by a child or others could cause harm or
`
`
`even death.
`
`10.Knowledge Assessments (provide for each reporting period and
`
`cumulatively)
`
`a. The number of completed post-training knowledge assessments for
`
`
`healthcare providers who can prescribe and pharmacy authorized
`representatives including the method of completion and the number of
`
`attempts to complete.
`
`
`b. A summary of the most frequently missed knowledge assessment
`
`
`
`questions.
`
`c. A summary of potential comprehension or perception issues identified with
`
`the knowledge assessment.
`
`11.The requirement for assessments of an approved REMS under section
`
`
`
`505-1(g)(3) include with respect to each goal included in the strategy, an
`
`assessment of the extent to which the approved strategy, including each
`
`element of the strategy, is meeting the goal or whether one or more goals
`
`or such elements should be modified.
`
`
`iii.
`
`
`
`
`
`U.S. Food and Drug Administration
`
`
`
`Silver Spring, MD 20993
`
`
`
`www.fda.gov
`
`
`Reference ID: 4721753
`
`

`

`
`
` NDA 202788/S-021
`
` Page 15
`
`
`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.
`
`
`
`
`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.
`
`
`
`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 proposed modified REMS. If you are not proposing
`REMS modifications, provide a rationale for why the REMS does not need to be
`m