CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`21-880
`
`MEDICAL REVIEW! S!
`
`

`

`Division Director Summary Review of a New Drug Application
`
`NDA: 21—880
`
`Drug: Revlimid® (lenalidomide) 5 and 10 mg capsules
`Applicant: Celgene Corporation
`Date: December 23, 2005
`
`This new drug application was submitted on April 7, 2005 for the following proposed
`indication: “REVLIMID® is indicated for the treatment of patients with transfusion—
`dependent anemia due to Low- or lntermediate-l-risk myelodysplastic syndromes
`associated with a deletion 5q cytogenetic abnormality with or without additional
`cytogenetic abnormalities.” A major amendment was receivedon September .23, 2005
`and the user fee goal date was extended to January 7, 2006.
`
`Clinical/Statistical Review
`
`The Clinical Review by Maitreyee Hazarika, MD. (efficacy), Edvardas Kaminskas, M.D.,
`(safety), and Rajeshwari Sridhara, Ph.D. was completed on September 26, 2005. The
`submission and recommendations are summarized in the following sections of the review.
`
`9.1 Conclusions.
`
`The NDA submission consisted of two single—arm, phase 2 clinical studies
`relevant to the proposed indication, one very small. The patient population
`consisted of patients with transfusion-dependent anemia due to low or
`intermediate—1 risk MDS associated with del Sq cytogenetic abnormalities with or
`without additional cytogenetic abnormalities. The transfusion entry criterion is
`based on the RBC units transfused in the 8 weeks prior to start of study drug. The
`median number units of RBC transfused was six. The main study enrolled 148
`patients using oral lenalidomide as a single agent given in 2' dose regimens, 10 mg
`daily or 10 mg for 21 days in a 28— day cycle.
`
`The primary endpoint was the determination of RBC transfusion independence. A
`rolling 56 day (8 week) transfusion free period was used for transfusion
`independence response. The RBC transfusion independence response of 67% (99/
`148) was seen with = 1.0 g/dL increase in hemoglobin. These responses lasted for
`a minimum of 8 weeks with a median duration of transfusion independence in
`responders was 52 weeks. Major cytogenetic responses were seen in 43% (52/
`120) patients in whom follow—up bone marrows were present. The study was not
`designed or powered to prospectively compare the efficacy of the 2 lenalidomide
`dosing regimens.
`'
`
`The supportive study had 10 evaluable patients supporting the proposed indication.
`
`

`

`FDA performed an analysis in those patients who met the major eligibility criteria.
`Ninety six patients had transfusion-dependent anemia due to a diagnosis of low or
`intermediate—l risk MDS associated with a del Sq chromosomal abnormality with
`or without additional cytogenetic abnormalities. The results were consistent with
`the ITT population.
`
`The demonstration of the clinical benefit of RBC transfusion independence,
`although substantial, is based mainly on one single—arm, multicenter trial. A
`randomized controlled trial is ongoing at present and the sponsor has a Phase IV
`commitment.
`
`All MDS patients, those with Sq deletion (del Sq) and those without Sq deletion
`(non—del Sq), had adverse events during treatment with lenalidomide. In absence
`of a best supportive care control arm, it is not possible to assign adverse events to
`lenalidomide instead of MDS. The most common reported adverse events were
`neutropenia and thrombocytopenia. They were also the most common grade 3 or
`4 adverse events, the most common serious adverse events ( except for
`pneumonia), the most common events leading to discontinuations from studies,
`and the most common events leading to dose interruptions and dose reductions.
`Less frequently reported were rashes, infectious events, fatigue, bleeding events,
`gastrointestinal events, and others. A very high percentage (about 80%) of
`patients reported grade 3 or 4 events. There was a markedly different adverse
`event profile in the del Sq population from that in non— del Sq population. The del
`Sq patients had approximately twice as high frequencies of neutropenia and of
`thrombocytopenia (all grades and grades 3 — 4 in both cases), a one— third higher
`frequency of infections, and higher incidences of bleeding and of venous
`thromboembolism than non—del Sq patients.
`
`The increased sensitivity to lenalidomide in the del Sq population may account for
`the much greater need for dose reductions and dose interruption of the 10 mg/ day
`starting dose (administered by either of the two schedules) in the del Sq
`population compared to non— del Sq population (80% of patients vs. 47% of
`patients). These data suggest that the starting dose of lenalidomide is too high for
`the del Sq population, and that carefiil monitoring is required for dose adjustment.
`Because neutropenia and thrombocytopenia can occur rapidly and unpredictably
`in some cases, and because the rate of recovery can be delayed, lenalidomide
`should be administered only during the period during which it maintains patients
`free of transfusions. In cases of patients who do not respond to lenalidomide
`treatment, the treatment should be discontinued once a response is unlikely to
`occur (about 16 weeks).
`
`Patients with renal impairment were excluded from the studies. Because
`lenalidomide is mainly excreted by the kidney, renal function should be carefully
`monitored to avoid excess toxicity.
`
`

`

`Until definitive toxicology studies have determined that lenalidomide, unlike
`thalidomide, does not pose risk as a human teratogen, the S. T. E. P. S. program
`should be implemented.
`
`The benefit vs. risk profile of lenalidomide treatment in the del Sq population is
`substantial; the incidence of severe adverse events, some life- threatening, is high.
`Therefore, a balanced medical evaluation is required before prescribing
`lenalidomide followed by carefiil monitoring and dose adjustment.
`
`A Black Box Warning should be placed in the label to include the unknown
`pregnancy risk and the recommendation to prevent fetal exposure and should also
`include weekly monitoring of neutropenias and thrombocytopenias.
`
`.
`
`9.2 Recommendation on Regulatory Action
`
`Lenalidomide (Revlimid ®) should receive regular approval for the treatment of
`patients with transfusion dependent anemia due to low or intermediate—l risk
`myelodysplastic syndromes (MDS) associated with a deletion Sq cytogenetic
`abnormality with or without additional cytogenetic abnormalities.
`
`Lenalidomide was brought before the Oncology Drug Advisory Committee on
`Sept 14, 2005. The ODAC committee agreed that the benefit versus risk analysis
`warranted approval.
`-
`
`9.3 Recommendation on Postmarketing Actions
`
`9.3.1 Risk Management Activity
`
`Due to the inadequacy of the reproductive safety assessment, FDA has a concern
`regarding the risk of teratogenicity and the potential fetal exposure to
`lenalidomide. Of concern is also the high incidence and dose modification due to
`neutropenias and thrombocytopenias. The sponsor should implement a risk
`management activity similar to the S. T. E. P. S. program until toxicology studies
`determine that lenalidomide is not a teratogen in species that predict human
`teratogenicity.
`
`A Black Box Warning should be placed in the label to include the unknown
`pregnancy risk and the recommendation to prevent fetal exposure and should also
`include weekly monitoring of neutropenias and thrombocytopenias.
`
`9.3.2 Required Phase 4 Commitments
`
`Not applicable.
`
`9.3.3 Other Phase 4 Requests
`
`

`

`Celgene has a planned phase 3 study ongoing in Europe in MDS patients with a
`Sq deletion. It is a randomized, double-blind, placebo—controlled 3—arm study
`evaluating a lower dose of 5 mg daily versus 10 mg syncopated. The primary
`endpoint is RBC transfusion independence for 2 26 weeks. At the time of the
`advisory committee meeting, 20 patients had been enrolled.
`
`The safety of lenalidomide in patients with renal impairment should be
`determined.
`
`Reproductive safety assessments in this drug was inadequate as reviewed by the
`Pharmacology/toxicology team. Celgene is required to conduct further tests to
`adequately assess the risk of teratogenicity.
`
`Medical Team Leader’s Review
`
`The Medical Team Leader’s Review by Ann Farrell, MD. was completed on October 4,
`2005. Dr. Farrell’s conclusions and recommendations are quoted below. .
`
`- Based on the strong comments made by several ODAC members stating that
`hematologists and oncologist are experienced enough to appropriately dose
`reduce when toxicity arises and the suggested efficacy in the MDS-003 study, this
`reviewer recommends full approval provided the sponsor agrees to the following:
`
`1) Strong labeling: The labeling should include Black box warnings and bolded
`warnings regarding the prevention of fetal exposures, 80% dose reduction and
`dose delay seen in the del 5 q MDS population, and the 80% grade 3 and 4
`adverse event data seen in MDS- 003. The labeling should also include weekly
`peripheral blood counts without regard to duration.
`
`2) Risk Management Plan: Due to lenalidomide’s structural similarity to
`thalidomide and the inadequate developmental toxicity study, this reviewer
`recommends that a risk management program very similar to that for thalidomide
`be instituted to prevent the risk of fetal exposure until developmental toxicity
`issues have resolved (new studies have been performed and undergone Agency
`review).
`
`3) Submission of the ongoing European study when completed. The sponsor has
`proposed study CC-5013—MDS—004, a randomized, double— blind, placebo-
`controlled, multicenter, 3-arm study of the efficiency and safety of 2 doses of
`lenalidomide (5 mg daily versus 10 mg days 1—21, 7 days rest (28 day cycle))
`versus placebo in red blood cell (RBC) transfiision- dependent subjects with low—
`or intermediate—l-risk myelodysplastic syndromes (MDS) associated with a del Sq
`cytogenetic abnormality. This study will be conducted in Europe. The primary
`endpoint is RBC transfusion independence for = 26 weeks (182 days).
`
`4) Submission of adequate reproductive safety studies for the Agency to review.
`
`

`

`Oncologic Drugs Advisog Committee
`
`This application was presented and discussed at the September 14, 2005 meeting
`of the Oncologic Drugs Advisory Committee. The questions and votes are
`provided below.
`
`1. Randomized controlled trials allow for direct comparisons of treatment
`effects and safety between treatment arms. A single arm study has
`been submitted using an 8— week run—in period to serve as a baseline
`for each patient’s transfusion requirements. A comparison is
`subsequently made to a follow- up 8— week period on Revlimid to
`compare transfusion requirements. Does this study design allow
`adequate characterization of Revlimid’s treatment effect in the
`population described in the proposed indication? (l 1 yes and 4 no)
`
`2.
`
`In this single arm trial, 80% of patients enrolled in MDS-003 had dose
`reductions and/or delays and 80% of patients experienced either grade
`3 or 4 adverse events. Data do not exist on the efficacy and safety of
`lower Revlimid doses. Approval of a drug is contingent upon being
`able to write adequate product labeling, requiring a recommended dose
`and characterization of a safety profile. Do the data provided in this
`single—arrn trial provide a basis for a recommended dose and adequate
`descriptiOn of a safety profile? (2 yes and 13 no).
`
`3. Please characterize the magnitude of Revlimid’s benefit and risk in the
`indication being sought. After this characterization, does this risk/
`benefit analysis warrant approval? (10 yes and 5 no)
`
`4. At this time, lenalidomide, a thalidomide analogue, does not have
`adequate nonclinical studies to assess reproductive/ developmental
`safety. Should a risk/ management program with a goal of no fetal
`exposures to Revlimid be instituted until the nonclinical reproductive/
`developmental safety assessments are addressed? (There was no vote
`on this question.)
`’
`
`Despite the vote on question 2, during the discussion committee members
`expressed the opinion that hematologists and oncologists were
`experienced in monitoring for myelosuppression and lowering or holding
`doses when indicated.
`
`Clinical Inspection Summary
`
`The preliminary Clinical Inspection Summary is dated December 2, 2005. The Division
`of Scientific Investigations concluded the following.
`
`The EIR from the single European site inspected is pending.
`
`

`

`The studies that were-inspected appear to have been conducted sufficiently well .
`that the data collected can be used to base approval of an NDA. Some data is
`missing, but quantitatively the amount missing should not qualitatively change the
`overall findings. There were also some lapses outside of the data gathering/
`collection efforts such as those related to informed consent documents, etc and
`these failures have already been brought to the attention of the clinical
`investigators and will be emphasized by DSI in the letter to the clinical
`investigators.
`
`No evidence of withholding of serious adverse event including deaths was found.
`
`No follow up is planned.
`
`Although the review noted that the EIR from the German site was pending, the final
`classification was “probably VAI” and that‘‘the data13 acceptable.”
`
`Pharmacology Toxicology Review and Evaluation
`
`The Pharmacology Toxicology Review and Evaluation was completed by M. Anwar
`Goheer, PhD. and Kimberly Benson, Ph.D. (reproductive and developmental toxicology)
`on October 9, 2005. The recommendations and summary of nonclinical findings are
`excerpted below.
`
`1. Recommendations
`
`A. Recommendation on approvability: The non-clinical studies submitted
`to this NDA provide sufficient information to support the use of
`lenalidomide (Revlimid®) in patients with transfusion-dependent anemia
`due to low—or intermediate-~risk myelodysplastic syndromes (MDS)
`associated with a deletion Sq cytogenetic abnormality with or without
`' additional cytogenetic abnormalities.
`
`B. Recommendation for nonclinical studies: Adequate reproductive
`toxicity assessment, specifically embryo—fetal developmental toxicity in
`two species, needs to be conducted.
`
`C. Recommendations on labeling: A separate review will be conducted.
`
`11. Summary of nonclinical findings
`
`A. Brief overview of nonclinical findings: Lenalidomide (3—( 4’
`aminoisoindoline—l-one)—1—piperidine—2, 6— dione; CC-5013; lMiD—3 and
`Revlimid ®) is a thalidomide analogue. It is a racemic mixture of S (—) and
`R (+) forms. The in vitro and in vivo characterization of pharmacological
`properties of lenalidomide had demonstrated that the drug inhibits the
`
`

`

`secretion of pro-inflammatory cytokines (TNF—a, IL- 1 B, IL-6 and IL—12)
`and increases the secretion of anti- inflammatory cytokine (IL-10) from
`peripheral blood mononuclear cells (PBMC), induces T—cell proliferation
`(IL—2, IFN-y), inhibits cell proliferation (MM, Burkitt’s lymphoma) and
`inhibits angiogenesis ( Knight- R, Semin Oncol 2005; 32: 24— 3O &
`Dredge et al., Microvasc Res. 2005; 69: 56— 63). Lenalidomide inhibits the
`expression of cyclooxygenase-2 (COX— 2) but did not affect COX— 1 in
`vitro. This may translate into adverse effects that need to be fully explored
`in clinical trials. In addition to these immune effects, there is evidence that
`thalidomide and its analogues may act directly on tumor cells, via
`inducing apoptosis or G1 growth arrest.
`
`The oral administration of lenalidomide at dose levels of 3, 6 and 12 g/m2
`produced no effects on behavior or general activity in male rats.
`Intravenous administration of the drug at doses up to 400 mg/m2 did not
`produce any significant effect on cardiovascular and respiratory systems
`of the anesthetized dog. In vitro, lenalidomide inhibited the cloned human
`potassium channel (hERG) current by 8% only at the highest
`concentration tested (787 pM).
`
`Lenalidomide did not inhibit or induce any of the major cytochrome P450
`isozymes in vitro and in vivo indicating limited potential for P450—related
`drug-drug interactions. Distribution of radioactivity in the fetal tissues of
`pregnant rat was low after oral administration but fetalbrain showed more
`activity than maternal brain. The highest concentrations were found in the
`kidney (cortex and medulla), liver, spleen and the mucosa of the GI tract
`of rats.
`
`During traditional toxicity assessment, lenalidomide was administered to
`rodents (mice, rats) and non rodents (monkeys) for l, 7, and 28 days and
`13, 26, and 52 weeks. Single dose administration of lenalidomide up to 6
`g/m2 in mice and 12 g/m2 in rats did not cause any adverse effects. Daily
`oral administration of lenalidomide at 6 g/m2 to rats for 28 days was
`associated with moderate to severe tubular nephropathy/ nephritis, which
`was attributed to precipitation of the lenalidomide in the kidney. Once
`daily oral administration of lenalidomide to rats at doses of 450, 900 or
`1800 mg/mz/ day for 26 weeks was mainly associated with reduced body
`‘ weight gain (12%i) for high dose males and reversible pelvic
`mineralization in the kidney of all treated animals.
`
`Oral administration of lenalidomide to cynomolgus monkeys at dose
`levels of 12, 24, 48, or 72 mg/m2/ day for 52 weeks was associated with
`hemorrhage in multiple organs, gastrointestinal tract inflammation and
`lymphoid and bone marrow atrophy. Dosing at 48 and 72 mg/m2/ day was
`discontinued after 20 weeks of treatment due to toxicity and mortalities. A
`reversal of the macroscopic and microscopic findings seen in decedent and
`
`‘
`
`

`

`the terminal sacrifice was noted in 7 week treatment—free recovery animals.
`It is clear that this species is much more sensitive to lenalidomide than
`rodents.
`
`Lenalidomide did not induce mutation in the Ames test, chromosome
`aberrations in cultured human peripheral blood lymphocytes, or. mutation
`at the thymidine kinase (tk) locus of mouse lymphoma L5178Y cells.
`Lenalidomide did induce micronuclei in the polychromatic erythrocytes of
`the bone marrow of male rats.
`
`Reproductive and developmental toxicity: Reproductive studies were
`conducted with lenalidomide, examining the effects on fertility and early
`embryo development, embryo—fetal development, and pre— and post- natal
`development. Only the embryo—fetal development studies are required for
`drugs with oncologic indications. These studies have not been adequately
`conducted at this time. The first study, conducted in a rat, showed very
`slight maternal toxicity and no fetal malformations. The rat, however, is
`not an adequate species for the full assessment of lenalidomide’s
`developmental effects, given the structural similarity to thalidomide.
`Historical data indicates that the rat is not sensitive to the full range of
`thalidOmide’s teratogenic effects.
`
`An additional developmental study was conducted in the rabbit, with a
`concurrent thalidomide dose group. This study had a confounding variable
`with some rabbits not eating prior to the study and all these rabbits had a
`negative outcome in the study. Additionally, the highest dose tested did
`not meet the standard criteria for sufficient drug exposure.
`
`B. Phannacologic activity: Both lenalidomide and thalidomide have been
`shown to increase the secretion of anti— inflammatory cytokine lL—lO from
`LPS—stimulated PBMC, stimulates T—cells proliferation and production of
`IL—2 and IFN-y. Both inhibit the secretion of pro- inflammatory cytokines
`TNF—a, IL-lB, and IL—6. In addition to these immune effects, there is
`evidence that thalidomide and its analogues may act directly on tumor
`cells, via inducing apoptosis or G1 growth arrest. Exact mechanisms of
`action however remain unknown.
`
`C. Nonclinical safety issues relevant to clinical use: Inflammation of the
`gastrointestinal tract and atrophy of the bone marrow, thymus, and
`lymphoid tissues were observed during repeat dose toxicity studies (up to
`12 months) in cynomolgus monkeys. Embryo— fetal developmental
`toxicity has not been adequately addressed. The structural similarity of
`lenalidomide to thalidomide, a known human teratogen, suggests
`developmental risk. Lenalidomide also inhibits expression of COX—2 in
`vitro but not COX—1 . This finding should be fully explored in clinical
`trials.
`
`

`

`The Pharmacology Toxicology Review and Evaluation of December 9, 2005 provided
`recommendations on labeling.
`
`Clinical Pharmacology and Biopharmaceutics Review
`
`The Clinical Pharmacology and Biopharmaceutics Review was completed by Gene
`Williams, PhD. on September 26, 2005. The recommendations and a summary of the
`clinical pharmacology and biopharrnaceutics findings are provided below.
`
`1.1. Recommendations
`
`This NDA is acceptable from the clinical pharmacology and biopharmaceutics
`perspective.
`
`1.2. Identify recommended Phase 4 study commitments if- the NDA is judged
`approvable
`
`Approximately 2/3 of lenalidomide is excreted as unchanged drug in urine
`following Revlimid dosing. In multiple myeloma patients with mild renal
`impairment, exposure (plasma AUC) was 56% higherthan in multiple myeloma
`patients with normal renal function who received the same dose. Based on these
`data, we recommend that a study be conducted to determine the pharrnacokinetics
`of lenalidomide in subjects with renal impairment. The study design should be
`consistent with the FDA Guidance, "Pharrnacokinetics in Patients with Renal
`Impairment."
`
`1.3 Summary of Clinical Pharmacology and Biopharmaceutics Findings (1- 3
`pages)
`
`Lenalidomide is structurally similar to the teratogenic drug thalidomide.
`
`Following oral administration, maximum lenalidomide plasma concentrations
`occur from 0.5 — 4 hours post- dose. Co- administration with food does not alter
`the extent of absorption. Half— life of lenalidomide elimination is approximately 3
`hours and the pharmacokinetic disposition of lenalidomide is, at doses up to 10X
`the recommended clinical dose of 10 mg, linear. Approximately two- thirds of
`lenalidomide is eliminated unchanged through urinary excretion. The process
`exceeds the glomerular filtration rate and'therefore entails an active component.
`In mutliple myeloma patients with mild renal impairment, AUCs were 56%
`higher than in similar patients with normal renal function.
`
`A search for circulating lenalidomide metabolites in human biomaterials (plasma,
`urine or feces) was not performed.
`
`

`

`Results from human in vitro metabolism studies show that lenalidomide is not
`
`metabolized through the cytochrome P450 pathway. Human in vitro metabolism
`studies also show that lenalidomide does not inhibit or induce cytochromes P450.
`
`The pharmacokinetics of lenalidomide in patients with renal impairment or
`hepatic impairment have not been systematically studied. The effects of age on
`the pharmacokinetics of lenalidomide have not been studied. No pharmacokinetic
`data are available in patients below the age of 18 years. The effects of gender on
`the pharmacokinetics of lenalidomide have not been studied. Pharmacokinetic
`differences due to race have not been studied.
`
`Lenalidomide is a BCS Class 3 (high solubility — low permeability) substance.
`Based on the compositional proportionality of the strengths, the dosing regimen
`used in clinical trials, pharamacokinetic linearity, and comparative dissolution
`profiles, the Applicant requests and will be granted a waiver for an in vivo
`bioequivalence study comparing the 5 mg capsule strength studied in efficacy and
`safety studies and the 10 mg strength which will be marketed, in addition to the 5
`mg strength.
`
`Chemistg Review
`
`The Chemistry Review by Haripada Sarker, Ph.D. was completed on December 5, 2005.
`The recommendation and conclusion on approvability follows.
`This application is recommended for APPROVAL from a chemistry,
`manufacturing and controls standpoint because:
`
`The applicant addressed all the deficienCies satisfactorily. The applicant has
`validated the analytical methods for specified impurities and de'gradants. The -
`office of compliance has provided an overall acceptable recommendation ( see
`attached). The following comments regarding retest for the drug substance and
`shelf- life for the drug product should be included in the action letter:
`
`“A retest period of
`“'2
`or the drug substance and a shelf— life of
`twenty four months for the drug product will be granted based on stability data
`provided”
`
`DDMAC Consultation
`
`A DDMAC consultation on the proposed draft labeling by Joseph Grillo was completed
`on September 22, 2005. The comments were discussed during the labeling meetings.
`
`DMETS Consultations
`
`Two DMETS consultations were obtained. The consultation dated June 2, 2005,
`concluded the following.
`
`10
`
`

`

`In summary, DMETS has no objection to the use of the proprietary name of
`Revlimid from a safety perspective. This is considered a final decision. However,
`if the approval of the NDA is delayed beyond 90 days from the signature date of
`this document, the name with its associated labels and labeling must be re-
`evaluated. A re—review of the name before NDA approval will rule out any
`objections based upon approvals of other proprietary and/ or established names
`from the signature date of this document. In addition, DMETS recommends
`implementation of the label and labeling revisions outlined in this memo to
`minimize potential errors with the use of this product. DMETS also recommends
`that the division consider submitting the patient package insert to the Division of
`Surveillance, Research and Communication Support for review and comment.
`DDMAC finds the name of Revlimid acceptable from a promotional perspective.
`
`A second DMETS consultation was completed on December 14, 2005. The consultation
`again concluded the following.
`
`In summary, DMETS has no objection to the use of the proprietary name of
`Revlimid from a safety perspective. In addition, DMETS recommends
`implementation of the label and labeling revisions outlined in this memo to
`minimize potential errors with the use of this product. DDMAC found the
`proprietary name of Revlimid acceptable from a promotional perspective in both
`the initial review and this re— review. This is considered a final decision...
`
`DMETS labeling comments were conveyed to the applicant and revised labeling was
`submitted and reviewed.
`
`DSRCS Medication Guide Review
`
`The DSRCS consultation on the Medication Guide was completedon December 7, 2005.
`The applicant agreed to the recommended revisions to the Medication Guide.
`
`RevAssistSM Program and Office of Drug Safety Consultations
`
`This application is being considered for approval under 21 CFR 314.520 (Subpart H).
`Distribution of the drug will be restricted to licensed prescribers who are registered in the
`RevAssistSM program and understand the potential risk of teratogenicity if lenalidomide
`is used during pregnancy. The primary goal ofthe RevAssistSM program is to prevent
`fetal exposures, pending complete and adequate preclinical characterization of the
`teratogenic potential of lenalidomide.
`
`The RevAssistSM program includes the following components:
`
`1. Registration in the RevAssistSM program of prescribers, pharmacies, nurses, and
`patients who agree to specific responsibilities and requirements in order to
`distribute, prescribe, dispense, and use Revlimid®.
`
`ll
`
`

`

`2.
`
`3.
`
`4.
`
`Implementation of an educational program and associated materials which
`describe the risks and benefits of Revlimid® and the required activities for
`prescribers, pharmacies, nurses, and patients.
`Implementation of a reporting and data collection system for safety surveillance
`including reporting of pregnancy exposures in real time, a pregnancy exposure
`plan, pharmacy audits, voluntary follow-up surveys of prescribers and patients,
`and update reports to the FDA.
`Implementation of a plan to monitor, evaluate, and improve minimizationof drug
`exposure during pregnancy and compliance with restrictions for safe use under
`the RevAssistSM program.
`
`The Office of Drug Safety Review of the RevAssistSM Risk Minimization Action Plan
`submitted on September 30, 2005 was completed on December 15, 2005. The Executive
`Summary of the consultation is provided below.
`
`This consult follows a request from the Division of Oncologic Drug Products for
`the Office of Drug Safety (ODS) to review, comment, and compare the
`Lenalidomide Risk Minimization Action Plan (RevAssistSM) to the System for
`Thalidomide Education and Prescribing Safety (S.T.E.P.S.® ) .
`
`Lenalidomide is an immunomodulatory drug being developed for treatment of ‘
`patients with transfusion— dependent anemia due to low— or intermediate- 1 risk
`myelodysplastic syndromes (MDS). Because of the structural similarity between
`thalidomide and lenalidomide, there is a concern that this product carries the same
`risk for teratogenicity as has been demonstrated with thalidomide. The Sponsor
`was informed that until such time as more definitive animal studies rule out a risk
`for teratogenicity, a RiskMAP similar to S.T.E.P.S will be required for approval
`and marketing of lenalidomide.
`
`We conclude that the ReVAssist program overall looks comparable to S.T.E.P.S.
`based on the side-by—side comparison and therefore is acceptable to us for interim
`use until the questionable teratogenicity of lenalidomide is fully characterized and
`resolved. There are several outstanding issues that should be resolved prior to
`approval. The educational materials for patients and prescribers submitted to date
`do not adequately describe the RiskMAP components and requirements. The
`Sponsor should also submit a Pregnancy Exposure follow—up plan. A more
`complete list of comments and recommendations is included in section 7, pgs 9—
`10 of this document.
`
`If animal or human teratogenicity is demonstrated, we would suggest the program
`be modified to reflect state-'of—the—art pregnancy prevention risk management
`standards in pregnancy testing (e.g., sensitivity to 25 mIU/mL) and contraceptive
`methods (e.g. removal of all references to poorly effective contraceptive
`techniques
`_ , as well as a clear definition of females of
`child— bearing potential. Currently, the standards being implemented for the
`iPLEDGE program represent the Agency’s recommendations of the best available
`
`12
`
`

`

`standards. If adequate animal teratogenicity testing is reassuring about fetal risks
`such that the RevAssist program to prevent pregnancy exposures is discontinued,
`we recommend a pregnancy registry be established to monitor for potential
`human teratogenicity.
`
`The comments and recommendations were communicated to the sponsor. On December
`21, 2005 ODS provided another consultation on the RevAssist education materials
`submitted on December 15, 2005 and on Celgene’s responses to FDA’s December 12,
`2005 correspondence concerning RevAssist. The comments and recommendations were
`communicated to the applicant. A teleconference between FDA (ODS and DDOP) was
`held on December 20, 2005. Agreement was reached on the RevAssist program during
`that telecon.
`'
`
`Post—Marketing Commitments
`
`The applicant has agreed to the following post—marketing commitments:
`
`December 15, 2005 commitment: establish a pregnancy registry to monitor for
`potential human teratogenicity if animal teratogenicity testing indicates that the
`RevAssistSM program for monitoring fetal exposure is unnecessary.
`
`December 21, 2005 commitments:
`
`1. The embryo—fetal toxicity assessment of Revlimid has not been adequately
`addressed. You will need to provide adequate information for this
`assessment in appropriate models that firlly assesses the possible toxicity of
`Revlimid. These studies should be conducted in two different species that are
`appropriate to aSsess the full range of thalidomide embryo—fetal effects. 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 exploratory
`nature on the embryo—fetal effects of lenalidomide (e. g., ‘
`~—
`,
`assay;
`-/
`assay), though not required, may be usefirl.
`'
`
`Protocol Submission:
`
`Study Start:
`Final Report Submission:
`
`06/06
`
`09/06
`12/07
`
`Submission of 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—l-risk myelodysplastic syndromes
`(MDS) associated with a deletion 5q cytogenetic abnormality when completed.
`
`13
`
`

`

`Protocol Submission:
`
`Study Start:
`Final Report Submission:
`
`03/05
`
`08/05
`12/08
`
`Following Revlimid dosing, approximately 2/3 of lenalidomide is excreted as
`unchanged drug in urine. 1n multiple myeloma patients with mild renal
`impairment, exposure (plasma AUC) was 56% higher than in similar patie