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`DEPARTMENT OF HEALTH & HUMAN SERVICES
`
`
`
`
`
`Public Health Service
`Food and Drug Administration
`Rockville, MD 20857
`
`Gretchen Toolan
`Director, Regulatory Affairs
`
`
`
`NDA 21-880/S-001
`
`Celgene Corporation
`86 Morris Avenue
`Summit, New Jersey 07901
`
`Attention:
`
`
`
`Dear Ms. Toolan:
`
`Please refer to your supplemental new drug application (NDA) dated December 29, 2005, received
`December 30, 2005, submitted under section 505 (b) of the Federal Food, Drug, and Cosmetic Act for
`Revlimid® (lenalidomide) capsules 5 mg, 10 mg, 15 mg and 25 mg.
`
`We acknowledge receipt of your submissions dated January 4, 13, 18, 27 and 31, 2006; February 24,
`2006; March 10, 14, 22, and 23, 2006; April 6, 7, 18, 21, and 24, 2006; May 2, 5, 9, 10, 15, 19, 22, 24,
`26 and 31, 2006; June 2, 9, 22 and 23, 2006.
`
`This supplemental new drug application, considered for approval under 21 CFR 314.520 (Subpart H),
`provides for the use of Revlimid® 15 mg and 25 mg capsules in combination with dexamethasone for
`the treatment of multiple myeloma patients who have received at least one prior therapy.
`
`We have completed our review of this supplemental application, as amended. It is approved under the
`provisions of 21 CFR 314.520 (Subpart H), effective on the date of this letter, for use as recommended
`in the agreed upon labeling text, required patient labeling, and the components of the RevAssistSM Risk
`Minimization Action Plan (RiskMAP).
`
`We also remind you of your post marketing study commitments specified in your submission dated
`June 26, 2006. These commitments, along with any completion dates agreed upon, are listed below.
`
`A. Conduct an epidemiologic study to address the questions detailed below:
`
`
`1. What is the failure rate for each of the different types of thromboembolic prophylaxis (e.g.
`antiplatelet or anticoagulant therapy) for multiple myeloma patients treated with a lenalidomide-
`containing regimen?
`
`
`2. What is the failure rate for each type of Deep Vein Thrombosis (DVT) treatment (dose-adjusted
`heparin, low molecular weight heparin, coumadin) for those patients with multiple myeloma and
`a DVT who continue to receive ongoing treatment with lenalidomide?
`
`
`3. What is the failure rate for each type of post-DVT thromboembolic prophylaxis for those
`patients with multiple myeloma and a DVT who continue to receive ongoing treatment with
`lenalidomide?
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`
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`NDA 21-880/S-001
`Page 2
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`This prospective epidemiologic study will enroll select patients identified in the RevAssistSM
`program, and collect the necessary additional data on these patients to further evaluate occurrences
`of thrombosis and anticoagulant use. The final details of the design will be as agreed upon between
`the Agency and Celgene.
`
`Protocol Submission:
`Study Start:
`
`
`Final Report Submission:
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`by December 2006
`by June 2007
`by December 2012
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`
`
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`B. Provide updated time to progression (TTP) and survival data for studies MM-009 and MM-010
`when 194 death events have occurred in each study.
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`
`
` Protocol Submission:
`MM-009 original protocol submitted November 26, 2002 Serial No. 92.
`Amendment No. 2 submitted April 29, 2005 Serial No. 550
`
`MM-010 original protocol submitted December 10, 2002, Serial No. 96.
`Amendment No. 2 submitted May 12, 2005, Serial No. 557.
`
`Study Start:
`
`
`MM-009
`
`
`MM-010
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`
`
`
`Final Report Submission:
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`September 22, 2003
`February 11, 2003
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`by December 2008
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`
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`Proposal Submission:
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`
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`by December 2006
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`C. Provide a proposal to assess for QTc prolongation.
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`
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`D. Conduct a bioequivalence study comparing the 25 mg capsule (test) to 5 X 5 mg capsules
`(reference).
`
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`Protocol Submission:
`Study Start:
`
`
`Final Report Submission:
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`by December 2006
`by March 2007
`by December 2007
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`
`
`
`We also remind you of your required post marketing study commitments specified in your submission
`dated December 21, 2005 for Revlimid® for use in myelodysplastic syndromes (MDS), approved on
`December 27, 2005. These commitments, along with any completion dates agreed upon, are listed
`below.
`
`1. The embryo-fetal toxicity assessment of Revlimid® has not been adequately addressed.
`You have agreed to provide adequate information for this assessment in appropriate
`models designed to fully assesses the possible toxicity of Revlimid®. You indicated you
`plan to conduct these studies in two different species that are appropriate to assess the full
`range of thalidomide embryo-fetal effects. As discussed, the rat is not an acceptable
`model. If the study with lenalidomide in the first species shows clear evidence of
`teratogenesis, than a confirmatory study will not be necessary. Although not generally
`considered “definitive” test systems for pharmaceutical products, additional studies of an
`
`

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`NDA 21-880/S-001
`Page 3
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`exploratory nature on the embryo-fetal effects of lenalidomide (e.g., frog embryo assay;
`FETAX assay), may be useful.
`
`Protocol Submission:
`Study Start:
`
`
`Final Report Submission:
`
`06/06
`09/06
`12/07
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`
`
`
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`2. You have agreed to submit the study report and data from the ongoing study, CC-5013-MDS-
`004, a randomized, double-blind, placebo-controlled, multicenter, 3-arm study of the efficacy
`and safety of 2 doses of lenalidomide (5 mg daily versus 10 mg day 21 days of a 28 day cycle)
`versus placebo in red blood cell (RBC) transfusion-dependent patients with low-or
`intermediate-1-risk myelodysplastic syndromes (MDS) associated with a deletion 5q
`cytogenetic abnormality when completed.
`
`Protocol Submission:
`Study Start:
`
`
`Final Report Submission:
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`03/05
`08/05
`12/08
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`3. Following Revlimid® dosing, approximately 2/3 of lenalidomide is excreted as unchanged
`drug in urine. In multiple myeloma patients with mild renal impairment, exposure (plasma
`AUC) was 56% higher than in similar patients with normal renal function who received the
`same dose. Based on these data, you have agreed to conduct a study to determine the
`pharmacokinetics of lenalidomide in subjects with renal impairment. To assist with the
`study design, please refer to the FDA Guidance, "Pharmacokinetics in Patients with
`Impaired Renal Function.”
`
`Protocol Submission:
`Study Start:
`
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`Final Report Submission:
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`11/04
`03/06
`12/07
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`4. Regarding the Evaluation/Surveillance Plan:
`
`
`You have agreed to submit a Pregnancy Exposure follow-up plan which will document your
`plan to follow-up pregnancy exposures to their outcome. This plan may be submitted as a post-
`marketing commitment.
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`Plan submission:
`
`
`
`06/01/06
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`You have agreed to submit an Evaluation Plan of RevAssistSM to FDA within 3 to 6 months of
`approval. Please include, at a minimum, plans to study the Pharmacy Audit Plan, Outcomes of
`Pregnancy Exposures, and the Knowledge Surveys of physicians, nurses, and patients.
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`Plan submission:
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`5. You have agreed to submit all exposed pregnancies within 15 days of receipt as 15 day
`expedited reports.
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`
`
`06/01/06
`
`
`Submit clinical protocols to your IND for this product. Submit nonclinical and chemistry,
`manufacturing, and controls protocols and all study final reports to this NDA. In addition, under 21
`CFR 314.81(b)(2)(vii) and 314.81(b)(2)(viii), you must include a status summary of each commitment
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`NDA 21-880/S-001
`Page 4
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`in your annual report to this NDA. The status summary should include expected summary completion
`and final report submission dates, any changes in plans since the last annual report, and, for clinical
`studies, number of patients entered into each study. All submissions, including supplements, relating
`to these postmarketing study commitments should be prominently labeled “Postmarketing Study
`Commitment Protocol”, “Postmarketing Study Commitment Final Report”, or “Postmarketing
`Study Commitment Correspondence.”
`
`Pursuant to 21 CFR Part 208, FDA has determined that Revlimid® poses a serious and significant
`public health concern requiring distribution of a Medication Guide. The Medication Guide is
`necessary for patients' safe and effective use of Revlimid®. FDA has determined that Revlimid® is a
`product that has serious risks of which patients should be made aware because information concerning
`the risks could affect patients' decisions to use Revlimid®. In addition, patient labeling could help
`prevent serious adverse events related to use of the product. Under 21 CFR 208, you are responsible
`for ensuring that the Medication Guide is available for distribution to patients who are dispensed
`Revlimid®.
`
`The final printed labeling (FPL) must be identical to the enclosed labeling (package insert, Medication
`Guide and immediate container and carton labels). Marketing the product with FPL that is not identical
`to the approved labeling text may render the product misbranded and an unapproved new drug.
`
`Please submit an electronic version of the FPL according to the guidance for industry titled Providing
`Regulatory Submissions in Electronic Format - NDA. Alternatively, you may submit 20 paper copies
`of the FPL as soon as it is available but no more than 30 days after it is printed. Individually mount 15
`of the copies on heavy-weight paper or similar material. For administrative purposes, designate this
`submission “FPL for approved NDA 21-880.” Approval of this submission by FDA is not required
`before the labeling is used.
`
`Submit content of labeling [21 CFR 601.14(b)] in structured product labeling (SPL) format, as
`described at http://www.fda.gov/oc/datacouncil/spl.html, that is identical in content to the enclosed
`labeling text. Upon receipt and verification, we will transmit that version to the National Library of
`Medicine for posting on the DailyMed website.
`
`As part of the approval under Subpart H, we acknowledge that you submitted to the Agency your
`promotional materials (both promotional labeling and advertisements) that are to be used within the
`first 120 days after approval. In addition, as required by 21 CFR 314.550, after the initial 120 day
`period following this approval, you must submit all subsequent promotional labeling as well as
`advertisements at least 30 days before the intended time of initial distribution of the labeling or initial
`publication of the advertisement. Send one copy to the Division of Drug Oncology Products and two
`copies of the promotional materials and the package insert directly to:
`
`
`Food and Drug Administration
`
`
`Center for Drug Evaluation and Research
`Division of Drug Marketing, Advertising, and Communications
`Food and Drug Administration
`5901-B Ammendale Road
`Beltsville, MD 20705-1266
`
`
`We remind you that you must comply with the reporting requirements for an approved NDA (21 CFR
`314.80 and 314.81).
`
`

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`NDA 21-880/S-001
`Page 5
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`The MedWatch-to-Manufacturer Program provides manufacturers with copies of serious adverse event
`reports that are received directly by the FDA. New molecular entities and important new biologics
`qualify for inclusion for three years after approval. Your firm is eligible to receive copies of reports for
`this product. To participate in the program, please see the enrollment instructions and program
`description details at www.fda.gov/medwatch/report/mmp.htm
`
`If you have any questions, call Carl Huntley, Regulatory Project Manager, at (301) 796-1372.
`
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Robert Justice, M.D.
`Division Director
`Division of Drug Oncology Products
`Office of Oncology Drug Products
`Office of New Drugs
`Center for Drug Evaluation and Research
`Food and Drug Administration
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`
`
`Enclosure -Label
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`

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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.
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` /s/
`---------------------
`Robert Justice
`6/29/2006 07:34:17 PM
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`