( .I# I U.S. FOOD & DRUG
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`,.,. .........
`•-..:::::i~
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`ADMINISTRATION
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` NDA 021880/S-63
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` SUPPLEMENT APPROVAL
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` Celgene Corporation
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` Attention: Lisa Suttner
` Director, Regulatory Affairs
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` 86 Morris Avenue
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` Summit, NJ 07901
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`Dear Ms. Suttner:
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`Please refer to your supplemental new drug application (sNDA) dated and received May
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`14, 2021, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act
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`(FDCA) for Revlimid (lenalidomide) capsules.
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`This “Changes Being Effected” sNDA provides for proposed modifications to the
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`approved shared system risk evaluation and mitigation strategy (REMS) for
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`lenalidomide products known as the Lenalidomide REMS Program..
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`We have completed our review of this application, as amended. It is approved, effective
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`on the date of this letter.
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`RISK EVALUATION AND MITIGATION STRATEGY (REMS) REQUIREMENTS
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`The Shared System (SS) REMS for lenalidomide products, of which Revlimid is a
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`member, was originally approved on May 21, 2021. The REMS consists of elements to
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`assure safe use, an implementation system, and a timetable for submission of
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`assessments of the REMS. Your proposed modifications to the REMS consist of
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`removal of the mobile app for physicians, inclusion of the Patient REMS Application,
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`clarifying language regarding the question for prescribers about days of therapy being
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`prescribed, new language for reporting pregnancies, modification to the disclosure
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`language on the Patient-Physician Agreement Forms (PPAFs), and a new election
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`checkbox on the PPAFs for patients to request Lenalidomide REMS education
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`materials.
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`Your proposed modified REMS, submitted on May 14, 2021, amended and appended to
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`this letter, is approved.
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`The timetable for submission of assessments of the REMS remains the same as that
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`approved on September 13, 2015.
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`The revised REMS assessment plan must include, but is not limited to, the following:
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`Reference ID: 4837100
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`

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` NDA 021880/S-063
` Page 2
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`Health Outcomes and/or Surrogates of Health Outcomes
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`1. Pregnancies: (per reporting period and cumulatively)
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`a. Number of pregnancies reported
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`b. Outcome of each pregnancy
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`c. Follow-up of outstanding pregnancy reports
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`d. Root cause analysis of each reported pregnancy
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`e. Link to most recent Periodic Safety Update Report (PSUR) or Periodic
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`Benefit-Risk Evaluation Report (PBRER) that provides information on
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`worldwide pregnancies. Discussion of any new information provided in the
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`PSUR or PBRER regarding pregnancy
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`Program Implementation and Operations
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`2. Reporting on the restricted distribution program: (per current and previous two
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`reporting periods and cumulatively; where applicable)
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`a. The number of pharmacies and physicians certified, and patients enrolled
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`b. Patient demographics for the current REMS assessment reporting period to
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`include gender, age, diagnosis, females of reproductive potential (FRP)
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`c. Number of female patients for whom pregnancy testing can be discontinued
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`because menopause has been documented by follicle-stimulating
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`hormone/luteinizing hormone (FSH/LH) levels
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`3. REMS Pharmacy Compliance (per current and previous two reporting periods
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`and cumulatively; where applicable)
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`a. Provide a copy of the Non-Compliance plan to include the following:
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`i. Criteria for non-compliance
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`ii. Actions taken to address non-compliance for each event identified
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`iii. Criteria for de-certification
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`b. Provide a copy of the audit plan
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`c. Report of audit findings
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`The number of audits expected, and the number of audits conducted
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`ii.
`The number and type of deficiencies noted
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`1. Number that successfully completed a corrective and preventative (CAPA)
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`plan within 30 days of receipt of CAPA
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`2. Describe actions taken for any that did not complete the CAPA within 30 days
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`of receipt of CAPA
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`3. Include a unique ID for each pharmacy that had deviations to track deviations
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`over time
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`iii. Documentation of completion of training for relevant staff
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`iv.
`The existence of documented processes and procedure for complying with
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`the REMS
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`d. Non-compliance events: for each event provide the following
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`i. Source of the report
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`ii. Description of the event
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`U.S. Food and Drug Administration
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`Silver Spring, MD 20993
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`www.fda.gov
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`Reference ID: 4837100
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` NDA 021880/S-063
` Page 3
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`iii. Cause of the event
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`iv. Corrective actions taken
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`v. Events:
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`1. Number of lenalidomide prescriptions dispensed that were written by non-
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`certified prescribers
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`2. Number of lenalidomide prescriptions dispensed by non-certified pharmacies
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`3. Number of lenalidomide prescriptions dispensed to de-enrolled or non-
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`enrolled patients
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`4. Number of times a lenalidomide prescription was dispensed because a
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`certified pharmacy bypassed REMS authorization processes
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`5. Number of shipments sent to non-certified pharmacies, sources of the
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`reports, and actions taken to prevent future occurrences
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`6. Number of pharmacies who were de-certified for non-compliance and reasons
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`for de-certification
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`Safe Use Behaviors
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`4. Documentation of safe use conditions (per current and previous two reporting
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`periods and cumulatively; where applicable)
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`Based on information collected from the mandatory surveys (used to document
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`safe use conditions) provide information that could represent potential fetal
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`exposure or that might result in a delay or interruption in treatment.
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`Provide the following in a tabular format:
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`a. The total number of authorization numbers issued and the number of
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`authorization numbers flagged.
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`b. The number and proportion of flagged authorization numbers intended for an
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`FRP due to questions in the mandatory surveys related to pregnancy testing
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`c. The number and proportion of flags that caused a delay in treatment initiation
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`or a gap in therapy for patients due to REMS processes as the proportion of
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`flagged authorization numbers compared to total authorization numbers.
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`Include the time to resolution of flags in days (mean, minimum, maximum) for
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`the reporting period and for each previous reporting period. Include the
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`number of patients with a delay in treatment or a gap in therapy due to REMS
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`processes.
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`Knowledge, Attitude, Behavior
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`5. Inform prescribers, patients, and pharmacists on the serious risks and safe-use
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`conditions for lenadidomide (per current and previous two reporting periods and
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`cumulatively, where applicable)
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`U.S. Food and Drug Administration
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`Silver Spring, MD 20993
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`www.fda.gov
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`Reference ID: 4837100
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`NDA 021880/S-063
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`Page 4
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`a. Ensure that lenalidomide will only be dispensed to patients enrolled in the
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`lenalidomide REMS Program with evidence or other documentation of safe-use
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`conditions
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`i. Number and proportion of total number of unflagged patient survey questions
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`answered relating to knowledge compared to the total number of patient
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`survey questions relating to knowledge reported per patient risk category
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`b. Ensure healthcare providers counsel patients on the benefits and risks of
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`lenalidomide therapy, including risks described in the boxed warnings
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`i. Number and proportion of total number of unflagged prescriber surveys
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`compared to the total number of prescriber surveys reported per risk category
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`c. Educate pharmacies on the risks and safe-use conditions of lenalidomide
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`i.
`Total number of pharmacy quizzes administered
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`ii. Number of pharmacists with a passing rate/Total number of certified
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`pharmacists on the last day of the reporting period
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`6. The requirements for assessments of an approved REMS under section 505-
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`1(g)(3) include, with respect to each goal included in the strategy, an assessment
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`of the extent to which the approved strategy, including each element of the
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`strategy, is meeting the goal or whether one or more such goals or such
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`elements should be modified.
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`We remind you that in addition to the REMS assessments submitted according to the
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`timetable in the approved REMS, you must include an adequate rationale to support a
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`proposed REMS modification for the addition, modification, or removal of any goal or
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`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
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`supplemental application for a new indication for use, as described in section 505-
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`1(g)(2)(A) of the FDCA. 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
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`current REMS;
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`c) If the new indication for use introduces unexpected risks: A description of those
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`risks and an evaluation of whether those risks can be appropriately managed
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`with the currently 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
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`the REMS was meeting its goals at the time of that last assessment and if any
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`modifications of the REMS have been proposed since that assessment.
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`U.S. Food and Drug Administration
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`Silver Spring, MD 20993
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`www.fda.gov
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`Reference ID: 4837100
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`

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`NDA 021880/S-063
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`Page 5
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`e) If a REMS assessment has not been submitted in the 18 months prior to
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`submission of the supplemental application for a new indication for use: Provision
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`of as many of the currently listed assessment plan items as is feasible.
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`f) If you propose a REMS modification based on a change in the benefit-risk profile
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`or because of the new indication of use, submit an adequate rationale to support
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`the 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
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`REMS was required, on patient access to the drug, and/or on the burden on the
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`health care delivery system; and other appropriate evidence or data to support
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`the proposed change. Additionally, include any changes to the assessment plan
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`necessary to assess the proposed modified REMS. If you are not proposing
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`REMS modifications, provide a rationale for why the REMS does not need to be
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`modified.
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`If the assessment instruments and methodology for your REMS assessments are not
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`included in the REMS supporting document, or if you propose changes to the submitted
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`assessment instruments or methodology, you should update the REMS supporting
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`document to include specific assessment instrument and methodology information at
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`least 90 days before the assessments will be conducted. Updates to the REMS
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`supporting document may be included in a new document that references previous
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`REMS supporting document submission(s) for unchanged portions. Alternatively,
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`updates may be made by modifying the complete previous REMS supporting document,
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`with all changes marked and highlighted. Prominently identify the submission containing
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`the assessment instruments and methodology with the following wording in bold capital
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`letters at the top of the first page of the submission:
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`NDA 021880 REMS ASSESSMENT METHODOLOGY
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`(insert concise description of content in bold capital letters, e.g.,
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`ASSESSMENT METHODOLOGY, PROTOCOL, SURVEY METHODOLOGIES,
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`AUDIT PLAN, DRUG USE STUDY)
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`An authorized generic drug under this NDA must have an approved REMS prior to
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`marketing. Should you decide to market, sell, or distribute an authorized generic drug
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`under this NDA, contact us to discuss what will be required in the authorized generic
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`drug REMS submission.
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`We remind you that section 505-1(f)(8) of FDCA prohibits holders of an approved
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`covered application with elements to assure safe use from using any element to block
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`or delay approval of an application under section 505(b)(2) or (j). A violation of this
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`provision in 505-1(f) could result in enforcement action.
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`Prominently identify any submission containing the REMS assessments or proposed
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`modifications of the REMS with the following wording in bold capital letters at the top of
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`the first page of the submission as appropriate:
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`U.S. Food and Drug Administration
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`Silver Spring, MD 20993
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`www.fda.gov
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`Reference ID: 4837100
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`

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` NDA 021880/S-063
` Page 6
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`NDA 021880 REMS ASSESSMENT
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`or
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`NEW SUPPLEMENT FOR NDA 021880/S-000
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`CHANGES BEING EFFECTED IN 30 DAYS
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`PROPOSED MINOR REMS MODIFICATION
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`or
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`NEW SUPPLEMENT FOR NDA 021880/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 021880/S-000
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`PRIOR APPROVAL SUPPLEMENT
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`PROPOSED REMS MODIFICATIONS DUE TO SAFETY LABELING
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`CHANGES SUBMITTED IN SUPPLEMENT XXX
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`or
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`NEW SUPPLEMENT (NEW INDICATION FOR USE)
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`FOR NDA 021880/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 021880
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`Should you choose to submit a REMS revision, prominently identify the submission
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`containing the REMS revisions with the following wording in bold capital letters at the
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`top of the first page of the submission:
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`To facilitate review of your submission, we request that you submit your proposed
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`modified REMS and other REMS-related materials in Microsoft Word format. If certain
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`documents, such as enrollment forms, or website screenshots are only in PDF format,
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`they may be submitted as such, but Word format is preferred.
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`SUBMISSION OF REMS DOCUMENT IN SPL FORMAT
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`FDA can accept the REMS document in Structured Product Labeling (SPL) format. If
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`you intend to submit the REMS document in SPL format, as soon as possible, but no
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`U.S. Food and Drug Administration
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`Silver Spring, MD 20993
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`www.fda.gov
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`Reference ID: 4837100
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`

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` NDA 021880/S-063
` Page 7
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`later than 14 days from the date of this letter, submit the REMS document in SPL format
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`using the FDA automated drug registration and listing system (eLIST).
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`For more information on submitting REMS in SPL format, please email
`FDAREMSwebsite@fda.hhs.gov.
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`If you have any questions you may contact Felicia Diggs, Safety Regulatory Project
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`Manager, at (240) 402-4932 or via email at Felicia.Diggs@FDA.HHS.gov.
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`Sincerely,
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`{See appended electronic signature page}
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`Abhilasha Nair, M.D.
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`Supervisory Associate Director for Safety (acting)
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`Office of Oncologic Diseases
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`Center for Drug Evaluation and Research
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`ENCLOSURE:
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`REMS
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`U.S. Food and Drug Administration
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`Silver Spring, MD 20993
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`www.fda.gov
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`Reference ID: 4837100
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`

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`Signature Page 1 of 1
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`This is a representation of an electronic record that was signed
`electronically. Following this are manifestations of any and all
`electronic signatures for this electronic record.
`--------------------------------------------------------------------------------------------
`/s/
`------------------------------------------------------------
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`ABHILASHA NAIR
`08/05/2021 02:02:34 PM
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`.
`Reference ID: 4837100
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`(
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