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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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` NDA 21880/S-044
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`Food and Drug Administration
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` Silver Spring MD 20993
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`SUPPLEMENT APPROVAL
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`Celgene Corporation
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`Attention: Marion Ceruzzi, Ph.D.
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`Senior Director, Regulatory Affairs
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`400 Conneli Drive, Suite 2000
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`Berkeley Heights, NJ 07922
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`Dear Dr. Ceruzzi:
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`Please refer to your Supplemental New Drug Applications (sNDA) dated June 23, 2015, received
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`June 23, 2015, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act
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` This “Changes Being Effected” supplemental new drug application provides for modifications to
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` the approved Revlimid® (lenalidomide) risk evaluation and mitigation strategy (REMS).
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`APPROVAL
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` We have completed our review of this supplemental application. It is approved, effective on the
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` date of this letter.
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`REQUIRED PEDIATRIC ASSESSMENTS
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`Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all applications for new
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`active ingredients, new indications, new dosage forms, new dosing regimens, or new routes of
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`administration are required to contain an assessment of the safety and effectiveness of the
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`product for the claimed indication(s) in pediatric patients unless this requirement is waived,
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`deferred, or inapplicable.
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`Because none of these criteria apply to your application, you are exempt from this requirement.
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`RISK EVALUATION AND MITIGATION STRATEGY (REMS) REQUIREMENTS
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` The REMS for Revlimid ® (lenalidomide) Capsules was originally approved on August 3, 2010,
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` and the most recent modification was approved on February 17, 2015. The REMS consists of
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` elements to assure safe use (ETASU), an implementation system, and a timetable for submission
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` of assessments of the REMS.
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`Reference ID: 3818851
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` NDA 21880/S-044
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` Page 2
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` Your proposed modifications to the REMS consist of inclusion of mobile applications into the
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` REMS materials to provide an additional platform to accomplish internet-capable REMS
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`Your proposed modified REMS, submitted on June 23, 2015, and appended to this letter, is
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`approved.
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`The timetable for submission of assessments of the REMS must be revised to include submission
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`of an assessment by August 3, 2016, and every 2 years thereafter.
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`The revised REMS assessment plan must include, but is not limited to, the following list.
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`Additions are noted by underline and deletions are noted by strikethrough.
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`1. Pregnancies:
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`a. Number of pregnancies reported during the REMS assessment reporting period and
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`annually for each REMS reporting period
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`b. Outcome of each pregnancy
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`c. Follow-up of outstanding pregnancy reports from previous assessment reporting
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`period
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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 Benefit-Risk
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`Evaluation Report (PBRER) that provides information on worldwide pregnancies.
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`Discussion of any new information provided in the PSUR or PBRER regarding
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`pregnancy
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`2. Reporting on the restricted distribution program:
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`a. The number of pharmacies and physicians certified, and patients enrolled during
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`the current REMS assessment reporting period and during each previous REMS
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`assessment reporting period
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`b. Patient demographics for the current REMS assessment reporting period and for
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`previous REMS assessment reporting periods to include gender, age, diagnosis,
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`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 during this REMS assessment
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`reporting period and for previous REMS assessment reporting periods
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`3. Documentation of safe use conditions
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`Based on information collected through patient enrollment and mandatory surveys that are
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`used to document safe use conditions, provide information on:
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`a. Flagged prescriptions/documentations of safe use of particular interest include
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`those that have the potential of allowing pregnant patients access to the drug, and
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`those that result in a delay or interruption of treatment. Provide the following,
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`relative to flagged prescriptions/documentations of safe use:
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`Reference ID: 3818851
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` i. A summary of identified flags, the reasons for the flags, and the actions
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` taken to correct. Provide for the reporting period; and summarize findings
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` from each previous assessment report.
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` ii. The number and proportion of flagged prescriptions intended for an FRP
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` due to lack of documentation of a negative pregnancy test, positive
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` pregnancy test, and/or a delay in obtaining a pregnancy test.
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` iii. The number and proportion of flags that caused a delay in treatment
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` initiation or a gap in therapy for patients. The time to resolution of flags
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` (mean, minimum, maximum) and include a graph of time to resolution
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` versus numbers of prescriptions (or number of mandatory surveys
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` conducted to document safe use conditions) for the reporting period and
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` for each previous reporting period.
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`4. Results from the Pharmacist Risk Assessment Survey Protocol regarding the serious risks
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`and safe-use conditions.
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`5. Using patient survey data, documentation of choice of contraception (information from
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`patients of method/use), and of changes to methods used (numbers of FRP using method at
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`entry and ongoing): numbers/proportions using highly effective form of birth control;
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`number/proportion using other less effective forms of birth control.
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`6. Data on the use of the mobile device application to conduct REMS functions
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`a. Date the mobile application went live
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`b. Number of downloads of the mobile application
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`c. Number, age, and gender of patients using the mobile application for REMS
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`functions, the number of instances of using the mobile application, and the
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`functions conducted via the mobile application.
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`d. Number of prescribers using the mobile application for REMS functions, the
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`number of instances of using the mobile application, and the functions conducted
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`e. Proportion of above functions being conducted via mobile application vs other
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`means (mail, email, fax)
`f. Summary of any feedback obtained on the use of the mobile application by
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`stakeholders during the assessment period
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`7. Data on the pharmacy business-to-business protocol to conduct pharmacy REMS functions
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`a. The number of pharmacies using the business-to-business protocol, and the date
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`the pharmacies began using pharmacy business-to-business protocol
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`b. The number and percentage of REMS transactions using the business-to-business
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`protocol for each pharmacy
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`c. Any problems in implementing the business-to-business protocol for each
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`pharmacy
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`d. Summary of feedback from pharmacies on use of the business-to-business
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`protocol
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` NDA 21880/S-044
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` Page 3
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`Reference ID: 3818851
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` NDA 21880/S-044
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` Page 4
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` 8. The requirements for assessments of an approved REMS under section 505-1(g)(3) include,
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` 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
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` or more such goals or such elements should be modified.
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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). This assessment
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`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;
`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.
`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
`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
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`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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`the REMS supporting document, or if you propose changes to the submitted assessment
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`instruments or methodology, you should update the REMS supporting document to include
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`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
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`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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`Reference ID: 3818851
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` NDA 21880/S-044
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` Page 5
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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 21880 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.
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`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 with elements to assure safe use from using any element to block or delay approval
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`of an application under section 505(b)(2) or (j). A violation of this provision in 505-1(f) could
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`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 the
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`first page of the submission as appropriate:
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`NDA 21880 REMS ASSESSMENT
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`NEW SUPPLEMENT FOR NDA 21880/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 21880/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 21880/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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`or
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`NEW SUPPLEMENT (NEW INDICATION FOR USE)
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`FOR NDA 21880/S-000
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`REMS ASSESSMENT
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`PROPOSED REMS MODIFICATION (if included)
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`Reference ID: 3818851
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` REMS REVISIONS FOR NDA 21880
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` NDA 21880/S-044
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` Page 6
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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
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`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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`If you have any questions, call Ms. Diane Leaman, Safety Regulatory Project Manager, at
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`(301) 796-1424.
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`Sincerely,
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`{See appended electronic signature page}
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`Robert C. Kane, MD
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`Deputy Director for Safety
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`Division of Hematology Products
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`Office of Hematology Oncology Products
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`Center for Drug Evaluation and Research
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`ENCLOSURE
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`Reference ID: 3818851
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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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`ROBERT C KANE
`09/13/2015
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`Reference ID: 3818851
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