`NDA 021880/S-057
`
`
`
`
` SUPPLEMENT APPROVAL
`
`REMS MODIFICATION
`
`Celgene Corporation
`Attention: Patricia Pretara
`Senior Manager, Regulatory Affairs
`86 Morris Avenue
`Summit, NJ 07901
`
`
`Dear Ms. Pretara:
`
`Please refer to your supplemental new drug application (sNDA) dated
`December 27, 2018, received December 27, 2018, and your amendments, submitted
`under section 505(b) of the Federal Food, Drug, and Cosmetic Act (FDCA) for
`Revlimid® (lenalidomide) capsules.
`
`We acknowledge receipt of your risk evaluation and mitigation strategy (REMS)
`assessment dated July 27, 2018.
`
`This Prior Approval supplemental new drug application provides for the addition of two
`new indications for:
`
` REVLIMID in combination with a rituximab product, is indicated for the treatment
`of adult patients with previously treated follicular lymphoma (FL).
`
` REVLIMID in combination with a rituximab product, is indicated for the treatment
`of adult patients with previously treated marginal zone lymphoma (MZL).
`
`The supplement proposes modifications to the approved Revlimid® risk evaluation and
`mitigation strategy:
` Removes indication statements from REMS materials
`
` Converts the REMS document into the current template
`
`
` Removes prescription forms from the REMS
`
`
`
`APPROVAL & LABELING
`
`We have completed our review of this application, as amended. It is approved, effective
`
`on the date of this letter, for use as recommended in the enclosed agreed-upon
`labeling.
`
`WAIVER OF ½ PAGE LENGTH REQUIREMENT FOR HIGHLIGHTS
`
`Please note that we have previously granted a waiver of the requirements of 21 CFR
`201.57(d)(8) regarding the length of Highlights of Prescribing Information.
`
`
`Reference ID: 4439576
`
`

`

`NDA 021880/S-057
`Page 2
`
`
`CONTENT OF LABELING
`
` As soon as possible, but no later than 14 days from the date of this letter, submit the
`
`content of labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format using
`the FDA automated drug registration and listing system (eLIST), as described at
`FDA.gov.1 Content of labeling must be identical to the enclosed labeling (text for the
`
` Prescribing Information and Medication Guide), with the addition of any labeling
`changes in pending “Changes Being Effected” (CBE) supplements, as well as annual
`
`reportable changes not included in the enclosed labeling.
`
`Information on submitting SPL files using eList may be found in the guidance for
`industry SPL Standard for Content of Labeling Technical Qs and As.2
`
`
`The SPL will be accessible from publicly available labeling repositories.
`
`Also within 14 days, amend all pending supplemental applications that include labeling
`changes for this NDA, including CBE supplements for which FDA has not yet issued an
`action letter, with the content of labeling [21 CFR 314.50(l)(1)(i)] in Microsoft Word
`format, that includes the changes approved in this supplemental application, as well as
`annual reportable changes. To facilitate review of your submission(s), provide a
`highlighted or marked-up copy that shows all changes, as well as a clean Microsoft
`Word version. The marked-up copy should provide appropriate annotations, including
`supplement number(s) and annual report date(s).
`
`We request that the labeling approved today be available on your website within 10
`days of receipt of this letter.
`
`
`REQUIRED PEDIATRIC ASSESSMENTS
`
`Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all applications for
`new active ingredients (which includes new salts and new fixed combinations), new
`indications, new dosage forms, new dosing regimens, or new routes of administration
`are required to contain an assessment of the safety and effectiveness of the product for
`the claimed indication in pediatric patients unless this requirement is waived, deferred,
`or inapplicable.
`
`Because this drug product for this indication has an orphan drug designation, you are
`exempt from this requirement.
`
`
`
`
` 1 http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm
`
`2 We update guidances periodically. For the most recent version of a guidance, check the FDA Guidance
`Documents Database https://www.fda.gov/RegulatoryInformation/Guidances/default.htm.
`
`U.S. Food and Drug Administration
`
`
`Silver Spring, MD 20993
`
`www.fda.gov
`
`Reference ID: 4439576
`
`

`

`
`
`NDA 021880/S-057
`Page 3
`
`
` RISK EVALUATION AND MITIGATION STRATEGY (REMS) REQUIREMENTS
`
`The REMS for Revlimid® (lenalidomide) was originally approved on August 3, 2010, and
`the most recent REMS modification was approved on June 27, 2017. The REMS
`consists of elements to assure safe use, an implementation system, and a timetable for
`submission of assessments of the REMS. Your proposed modifications to the REMS
`consist of the following:
` Removes indication statements from REMS materials
`
` Converts the REMS document into the current template
`
`
` Removes prescription forms from the REMS
`
`
`
`Your proposed modified REMS, submitted on May 3, 2019 and appended to this letter,
`is approved.
`
`The timetable for submission of assessments of the REMS remains the same as that
`approved September 13, 2015.
`
`There are no changes to the REMS assessment plan described in our April 24, 2019
`letter.
`
`We remind you that in addition to the REMS assessments submitted according to the
`timetable in the approved REMS, you must include an adequate rationale to support a
`proposed REMS modification for the addition, modification, or removal of any goal or
`element of the REMS, as described in section 505-1(g)(4) of the FDCA.
`
`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 that last assessment and if any
`modifications of the REMS have been proposed since that assessment.
`U.S. Food and Drug Administration
`
`
`Silver Spring, MD 20993
`www.fda.gov
`
`
`Reference ID: 4439576
`
`

`

`NDA 021880/S-057
`Page 4
`
`
`
`e) If a REMS assessment has not been submitted in the 18 months prior to
`submission of the supplemental application for a new indication for use: Provision
`of as many of the currently listed assessment plan items as is feasible.
`
`f)
`
`
`If you propose a REMS modification based on a change in the benefit-risk profile
`or because of the new indication of use, submit an adequate rationale to support
`the modification, including: Provision of the reason(s) why the proposed REMS
`modification is necessary, the potential effect on the serious risk(s) for which the
`REMS was required, on patient access to the drug, and/or on the burden on the
`health care delivery system; and other appropriate evidence or data to support
`the proposed change. Additionally, include any changes to the assessment plan
`necessary to assess the proposed modified REMS. If you are not proposing
`REMS modifications, provide a rationale for why the REMS does not need to be
`modified.
`
`If the assessment instruments and methodology for your REMS assessments are not
`included in the REMS supporting document, or if you propose changes to the submitted
`assessment instruments or methodology, you should update the REMS supporting
`document to include specific assessment instrument and methodology information at
`least 90 days before the assessments will be conducted. Updates to the REMS
`supporting document may be included in a new document that references previous
`REMS supporting document submission(s) for unchanged portions. Alternatively,
`updates may be made by modifying the complete previous REMS supporting document,
`with all changes marked and highlighted. Prominently identify the submission containing
`the assessment instruments and methodology with the following wording in bold capital
`letters at the top of the first page of the submission:
`
`
`NDA 021880 REMS ASSESSMENT METHODOLOGY
`
`
`An authorized generic drug under this NDA must have an approved REMS prior to
`marketing. Should you decide to market, sell, or distribute an authorized generic drug
`under this NDA, contact us to discuss what will be required in the authorized generic
`
`drug REMS submission.
`
`We remind you that section 505-1(f)(8) of FDCA prohibits holders of an approved
`covered application with elements to assure safe use from using any element to block
`or delay approval of an application under section 505(b)(2) or (j). A violation of this
`provision in 505-1(f) could result in enforcement action.
`
`Prominently identify any submission containing the REMS assessments or proposed
`modifications of the REMS with the following wording in bold capital letters at the top of
`the first page of the submission as appropriate:
`
`
`
`U.S. Food and Drug Administration
`
`
`Silver Spring, MD 20993
`www.fda.gov
`
`
`Reference ID: 4439576
`
`

`

`NDA 021880/S-057
`Page 5
`
`
`
`
`
` NDA 021880 REMS ASSESSMENT
`
`
`or
`
`
`NEW SUPPLEMENT FOR NDA 021880 /S-000
`
`CHANGES BEING EFFECTED IN 30 DAYS
`
`PROPOSED MINOR REMS MODIFICATION
`
`
`
`or
`
`
`
`
` NEW SUPPLEMENT FOR NDA 021880/S-000
`
`
` PRIOR APPROVAL SUPPLEMENT
`
`PROPOSED MAJOR REMS MODIFICATION
`
`
`or
`
`
`NEW SUPPLEMENT FOR NDA 021880 /S-000
`
`PRIOR APPROVAL SUPPLEMENT
`
`PROPOSED REMS MODIFICATIONS DUE TO SAFETY LABEL CHANGES
`
`SUBMITTED IN SUPPLEMENT XXX
`
`
`
`
`or
`
`
`NEW SUPPLEMENT (NEW INDICATION FOR USE)
`FOR NDA 021880 /S-000
`
`REMS ASSESSMENT
`
`
`PROPOSED REMS MODIFICATION (if included)
`
`
`
`
` REMS REVISIONS FOR NDA 021880
`
`
`Should you choose to submit a REMS revision, prominently identify the submission
`containing the REMS revisions with the following wording in bold capital letters at the
`top of the first page of the submission:
`
`
`
`To facilitate review of your submission, we request that you submit your proposed
`modified REMS and other REMS-related materials in Microsoft Word format. If certain
`documents, such as enrollment forms, or website screenshots are only in PDF format,
`they may be submitted as such, but Word format is preferred.
`
`SUBMISSION OF REMS DOCUMENT IN SPL FORMAT
`
`
`FDA can accept the REMS document in Structured Product Labeling (SPL) format. If
`you intend to submit the REMS document in SPL format, as soon as possible, but no
`later than 14 days from the date of this letter, submit the REMS document in SPL format
`using the FDA automated drug registration and listing system (eLIST).
`
`U.S. Food and Drug Administration
`
`
`Silver Spring, MD 20993
`www.fda.gov
`
`
`Reference ID: 4439576
`
`

`

`NDA 021880/S-057
`Page 6
`
`
`
`For more information on submitting REMS in SPL format, please email
`FDAREMSwebsite@fda.hhs.gov.
`
`PROMOTIONAL MATERIALS
`
`
`You may request advisory comments on proposed introductory advertising and
`promotional labeling. To do so, submit the following, in triplicate, (1) a cover letter
`requesting advisory comments, (2) the proposed materials in draft or mock-up form with
`annotated references, and (3) the Prescribing Information to:
`
`
`OPDP Regulatory Project Manager
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Prescription Drug Promotion (OPDP)
`5901-B Ammendale Road
`Beltsville, MD 20705-1266
`
`
`Alternatively, you may submit a request for advisory comments electronically in eCTD
`format. For more information about submitting promotional materials in eCTD format,
`see the draft guidance for industry Providing Regulatory Submissions in Electronic and
`Non-Electronic Format-Promotional Labeling and Advertising Materials for Human
`Prescription Drugs.3
`
`
`You must submit final promotional materials and Prescribing Information, accompanied
`by a Form FDA 2253, at the time of initial dissemination or publication
`[21 CFR 314.81(b)(3)(i)]. Form FDA 2253 is available at FDA.gov.4 Information and
`Instructions for completing the form can be found at FDA.gov.5 For more information
`about submission of promotional materials to the Office of Prescription Drug Promotion
`(OPDP), see FDA.gov.6
`
`
`REPORTING REQUIREMENTS
`
`
`We remind you that you must comply with reporting requirements for an approved NDA
`(21 CFR 314.80 and 314.81).
`
`
`
`
`3 When final, this guidance will represent the FDA’s current thinking on this topic. For the most recent
`version of a guidance, check the FDA guidance web page at
`https://www.fda.gov/RegulatoryInformation/Guidances/default.htm.
`
`4 http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM083570.pdf
`
`
`5 http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM375154.pdf
`
`
`6 http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm090142.htm
`
`
`U.S. Food and Drug Administration
`
`
`Silver Spring, MD 20993
`www.fda.gov
`
`
`Reference ID: 4439576
`
`

`

`NDA 021880/S-057
`Page 7
`
`
`If you have any questions, call Laura Wall, Regulatory Project Manager, at 301-796­
`2237.
`
`
`Sincerely,
`
`{See appended electronic signature page}
`
`
`Albert Deisseroth, MD, PhD
`Supervisory Associate Division Director
`Division of Hematology Products
`Office of Hematology and Oncology Products
`Center for Drug Evaluation and Research
`
`
`ENCLOSURES:
`
` Content of Labeling
`o Prescribing Information
`o Medication Guide
` REMS
`
`
`
`
`
`
`U.S. Food and Drug Administration
`
`
`Silver Spring, MD 20993
`www.fda.gov
`
`
`Reference ID: 4439576
`
`
`
`

`

`Signature Page 1 of 1
`--------------------------------------------------------------------------------------------
`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/
`------------------------------------------------------------
`
`ALBERT B DEISSEROTH
`05/28/2019 10:54:44 AM
`
`Reference ID: 4439576
`
`