CENTER FOR DRUG EVALUATION AND RESEARCH
`
`APPROVAL PACKAGE FOR:
`
`APPLICATION NUMBER
`
`NDA 20-785
`
`Approval Letter(s)
`
`CFAD VI 1031-0001
`
`

`
`,,;~ DEPARTMENT OF HEALTH & HUMAN SERVICES
`~-:ff.
`
`Public Health Service
`
`Food and Drug Administration
`Rockville MD 20857
`
`16 July 1998
`
`NDA 20-785
`
`Steve Thomas, Ph.D.
`Celgene Corporation
`7 Powder Hom Drive
`Warren, New Jersey 07059
`
`Dear Dr. Thomas:
`
`Please refer to your December 20, 1996, new drug application (NDA) received on December 20,
`1996, submitted tinder section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act (the Act) for
`Thalomid (thalidomide) Capsules.
`
`Please refer also to your "approv.able" letter dated September 19, 1997. We acknowledge your
`submissions dated September 22, October 21 anCf27, November 4 and 14, December 23 (2), 1997,
`January 2 (2), 7 (2), 9, 14 (2), 20, and 26, February 18, March 11 and 24, Apnl 3 and 21, May 11
`(2) and 18, June 8, and July 7, 1998. The user fee performance goal for the resubmission of this
`application on January 26, 1998 in response to your "approvable" letter is July 27, 1998.
`
`This NDA provides for the use of thalidomide in the acute treatment of the cutaneous manifestations
`of moderate to severe erythema nodosum leprosum (ENL) and as maintenance therapy for
`prevention and suppression of the cutaneous manifestations of ENL recurrences.
`
`We have reviewed this application under the restricted distribution regulations contained in 21 CFR
`314 (Subpart H) and have concluded that restrictions on distribution and use of thalidomide are
`needed to assure safe use of the product. Please see 21. CFR 314.520.
`
`We have completed our review of this application, including the restrictions on the distribution and
`use of this product you suggested in your June 8, 1998 submission to the NDA entitled "System for
`Thalidomide Education and Prescribing Safety (S.T.E.P.S.)." We have concluded that adequate
`information has now been presented to demonstrated that the drug, when marketed in accordance
`with the terms of restricted distribution and use outlined in the June 8, 1998 S.T.E.P.S. document,
`is safe and effective for use as recommended in the attached final labeling text to which you agreed
`on July 15, 1998 in a telephone conversation between yourself and Ms Mary Jane Walling of FDA.
`Accordingly, Wlder the provisions of21 CFR 314.520, this application is approved effective the date
`of this letter.
`
`I
`
`CFAD VI 1031-0002
`
`

`
`.. ·:~
`,
`:·:o
`
`.
`::f:
`--~: ·~,
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`'
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`~~.'-,
`
`Page2
`NDA20-785
`Approval Letter
`16 July 1998
`
`CHANGES TO THE S.T.E.P.S. RESTRICTED DISTRIBUTION PROGRAM:
`
`Please note that the June 8, 1998 S.T.E.P.S. restricted distribution program is an integral part
`of the approved NDA for this product and is an essential component of the terms of this
`NDA's approval by FDA for marketing this product in the United States. As such, any
`proposed change(s) in the S.T.E.P.S. program must be submitted to the FDA as a
`supplement to this NDA and any proposed change(s) must have FDA prior approval before
`implementation. Changing the S.T.E.P.S. program without prior FDA approval may render
`the product misbranded and an unapproved new drug.
`
`FINAL PRINTED LABELING:
`
`The final printed labeling (FPL) for this product must be identical to the attached approved
`final labeling text, including the two informed consent documents (one for male patients and
`one for female patients); the authorization document; and the boxes, holding, bullets, and
`other formatting provisions. 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 twenty copies of the FPL"'as'soon as it is available; however, in no case should
`it be submitted more that thirty days after it is printed. Please individually mount ten copies
`on heavy-weight paper or similar material. For administrative purposes, this submission
`should be designed "FINAL PRINTED LABELING for approved NDA 20-785 ." Approval
`of this submission by FDA is not required before the labeling is used.
`
`FUTURE INSPECTIONS:
`
`In order to monitor the success of compliance with the restricted distribution provisions of
`this approval action, we intend to conduct inspections of the monitoring sites, i.e., the [_
`_
`·
`--
`- -
`-- 2:). as well as Celgene's records during the
`first quarter after product launch. We will meet with you to discuss the inspections within
`one month after completions of the inspections. Inspections and meetings with you will
`continue periodically thereafter as appropriate.
`
`SPECIAL ADVERSE EVENT REPORTING REQUIREMENT:
`
`Please note that, until further notice, ALL reports you receive of a possible human fetal
`exposure to this drug in the United States or of a possible human congenital malformation( s)
`
`CFAD VI 1031-0003
`
`

`
`Page3
`NDA 20-785
`Approval Letter
`16 July 1998
`
`following exposure to this drug in the United States inust be reported to the FDA as "serious,
`unexpected" adverse events, (i.e., within 15 calendar days of your receipt of the report.)
`
`.
`PHASE FOUR COivfMITMENTS:
`
`Please be reminded of your Phase 4 commitments specified in your submission dated July
`7, 1998. These commitments, along with any completion dates agreed between Celgene and
`FDA, are listed below:
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`7.
`
`Ongoing Study E003/P for efficacy should be continued and efforts should be made
`to expand the population in order to accrue the full compliment of subjects, as
`stated in our letter to you dated May 12, 1998.
`
`To conduct studies to demonstrate the absence or presence of thalidomide in
`sperm and I or semen.
`
`To conduct rat and mouse carcinogenicity studies.
`
`To conduct a segment I reproditctive toxicity study in rabbits. -
`
`To conduct a segment III reproductive toxicity study in rabbits.
`
`To develop and propose a component qualification test/specification for the
`packaged drug product that will verify the integrity of the blister pack with respect
`to moisture vapor transmission. This should not be considered to be a regulatory
`specification. This commitment should be completed in six months.·
`
`To submit the results of release testing results for lots 0091 N, 0092N and 0149N,
`along with updated stability data for lots DEV 2775, 2800 and 2811, as well as
`release data for lots 0091N, 0092N and 0149N. These results along with
`previously submitted data on the drug substance will be used to evaluate the bulk
`drug and finished product specifications. The timely submission and review of the
`results of ongoing stability testing of lots 0091N, 0092N and 0149N will determine
`.:J expiration period will be granted. ·
`if a . [
`
`8.
`
`To develop and propose a component qualification test/specification for the
`packaged drug product that will verify the integrity of the blister pack with respect
`to moisture vapor transmission. This should not be considered to be a regulatory
`specification. This commitment should be completed in one year.
`
`CFAD VI 1031-0004
`
`

`
`Page 4
`NDA 20-785
`Approval Letter
`16 July 1998
`
`9.
`
`There also remain two outstanding commitments described in our letter of
`September 19, 1997. They are numbers S(a) and 5 (e). Please provide these data
`when available.
`
`Protocols, data, and final reports should be submitted to your IND for this product and a
`copy of the cover letter sent to this NDA. Should an IND not be required to meet your
`Phase 4 commitments, please submit protocol, data, and final reports to this NDA as
`correspondences. In addition, we request under 21 CFR 314.8l(b)(2)(vii) that you include
`in your annual report to this application, a status summary of each commitment. The
`status summary should include the number of patients entered in each study, expected
`completion and submission dates, and any changes in plans since the last annual report.
`For administrative purposes, all submissions, -including labeling supplements, relating to
`these Phase 4 commitments must be clearly designated "Phase 4 Commitments."
`
`PROMOTIONAL ACTIVITIES:
`
`Please note that promotional activities-for this approved NDA are subject to 21 CFR
`314.550. As such, please submit three cbpies of the introductory promotional materials you
`propose to use for this product. All proposed materials should be submitted in draft or
`mock-up form, not final print. Please submit two copies of both the promotional material
`and the final printed labeli_ng or approved final labeling text to:
`
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Division of Drug Marketing, Advertising and Communications,
`HFD-40
`5600 Fishers Lane
`Rockville, Marylan<i 20857
`
`In addition, please note that this product has been approved ONLY for the acute treatment
`of the cutaneous manifestations of moderate to severe erythema nodosum leprosum (ENL)
`and as maintenance therapy for prevention and suppression of the cutaneous manifestations
`of ENL recurrence. It is not approved as monotherapy for the treatment of ENL cutaneous
`manifestations in the presence of moderate to severe neuritis. In addition, the safety and
`efficacy of this product in the treatment of any manifestations of HIV-associated disease
`were not addressed and thus have not been demonstrated in the data you submitted to this
`NDA. Statements in the approved labeling for this product that refer to HIV-seropositive
`
`CFAD VI 1031-0005
`
`

`
`Page 5
`NDA20-785
`Approval Letter
`16July 1998
`
`patients are included in the approved labeling ONLY to provide further safety information
`to the prescriber. Their inclusion is not intended to imply that use of your product is
`approved in this population of patients. As such, please note that statements or implications
`by you that this product may indeed be safe and efficacious in the treatment of diseases or
`patient i}opulations beyond that approved in your application may be considered a violation
`of the promotional provisions of the Act. If you have any questions or concerns about this
`matter, please contact the Center for Drug Evaluation and Research's Division of Drug
`Marketing, Advertising, and Communications.
`
`CHEMISTRY:
`
`Our validation of the chemistry testing methods has not been completed at this time.
`Presently, it is the general policy of the Center not to withhold approval for an application
`because these methods are being validated. Nevertheless, we expect your continued
`cooperation to resolve any problems that may be identified.
`
`MISCELLANEOUS:
`
`Please submit one marketing package of the drug product when it is available .
`
`. Please note that, with this approval action, the oversight of this NDA (20-785) and IND· 48,
`177 is being transferred to the Division of Special Pathogens and Immunologic Drug
`Products, HFD-590. This transfer is being effected because HFD-590 is the division that
`now has primary oversight of immunomodulatory drug products and of products whose
`purpose is to treat diseases caused by mycobacteria. The product covered by NDA 20-785
`and IND 48, 177 clearly meets both of these criteria. As such, it is most appropriate that it
`now be overseen by HFD-590.
`
`CFAD VI 1031-0006
`
`

`
`Page 6
`NDA 20-785
`Approval Letter
`16 July 1998
`
`We remind you that you must comply with the requirements for an approved NDA set forth· under
`21 CFR 314.80, 314.81, 314.520, 314.550, and 314.560.
`
`If you have any questions regarding this NDA, please coritact Mary Jane Walling, Project Manager,
`at (301) 827-2268.
`
`Sincerely,
`
`~14);(_~
`
`Murray M. Lumpkin, M.D.
`Deputy Center Director (Review Management)
`Center for Drug EVlih.iation and Research
`
`CFAD VI 1031-0007
`
`

`
`NDA20-785
`Page7
`
`HFD-2/Lumpkin.
`HFD-105/CSO/W ailing
`HFD-590/Dir/Goldberger
`HFD-530/MO/Bimkrant
`HFD-540/Chem/DeCamp
`HFD-540ff ox/Hill
`HFD.:550/Biopharm/Bashaw
`HFD-95/DDM-DIAB(with labeling)
`DISTRICT OFFICE
`HFD-232
`HFD-40/DDMAC (with labeling)
`HFD-613/0GD (with labeling)
`HFD-735/DPE (with labeling) - for all NDAs and supplements for adverse reaction
`changes.
`HFI-20/Press Office (with labeling)
`HFD-021/ACS (with labeling)
`HFD-830/0NDC/DD
`
`DRAFTED:MJW ALLING:06/01/98
`REVISED:MJWALLING:07 /06/98:7 II 0/98
`
`APPROVAL (AP)
`with Phase 4 committments
`
`CFAD VI 1031-0008
`
`

`
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`APPROVAL PACKAGE FOR:
`
`APPLICATION NUMBER
`
`NDA 20-785
`
`Approvable Letter (s)
`
`CFAD VI 1031-0009
`
`

`
`DEPARTMENT OF HEALTH &. HUMAN SERVICES
`
`Public Health Service
`
`·t ./
`
`Food and Drug Administration
`Rockville MD 20857
`
`SEP I 9 1997
`
`NDA 20-785
`
`Celgene Corporation
`Attention: Steve Thomas, Ph.D.
`7 Powder Horn Drive
`Warren, New Jersey 07059
`
`Dear Dr. Thomas:
`
`Please refer to your new drug application dated December 20, 1996, received December 20,
`1996, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act for
`SYNOVIR (thalidom'ide capsules) Capsules.
`
`We acknowledge receipt of your submissions dated October"'24, 1996; and January 20, 23 and
`28, February 3 and 25, March 6 and 7, April 1 and 25, May 23, June 2, 12, 16, and 17, July
`16 (two) and 25, August 1, 12, 18, 21, 26, 27, and 29 (two), and September 2, 1997. The
`original User Fee goal date for this application was June 20, 1997. Your submission of June
`16, 1997 extended the User Fee goal date to September 20, 1997.
`-------··-----
`We have completed the review of this application <;ts·,s~bmitted:inc;:luding restrictions on
`distribution and use as stated in the NDA, and it j~'approvable. v/;e have reviewed this
`application under the Accelerated Approval Regu\atiQns contain~d .. in 21 CFR 314 (Subpart H)
`and have concluded that the restriction on distribution.and-use ·of thalidomide are needed for
`safety. (See 21 CFR 314.520) We expect that the restrictions under Subpart H will be agreed
`to in writing by both the FDA and Celgene.
`
`Before this application may be approved, however, we will need to reach agreement on the
`wording of the final labeling this product will have and on the specific details of the elements
`of the restricted distribution and educational programs for the product. Therefore, please
`resubmit draft final labeling and details of your restricted distribution and educational program
`incorporating suggestions from the Advisory Committee meeting of September 4 and 5, 1997
`and from the FDA. In addition, please submit data demonstrating that the program will meet
`its stated goals.
`
`Issues surrounding the potential "scheduling" of thalidomide under the provisions of the
`Controlled Substances Act will also need to be resolved prior to approval.
`
`In addition, before this application may be approved, it will be necessary for you to address the
`
`CFAD VI 1031-0010
`
`

`
`NDA 20-785
`Page 2
`
`following issues:
`
`1.
`
`2.
`
`Please submit an amench!1ent to adopt the tighter specifications of t:
`for the assay of bulk thalidomide. This amendment should also indicate if any
`lots of bulk drug have been released for manufacturing with assay results outside
`these limits.
`
`1
`
`Please provide the following additional infonnation as either revisions of or
`clarifications to your analytical methods as follows:
`
`(a)
`
`·(b)
`
`Celgene Method SOP-121 (Thalidomide Assay) should be clarified to
`state what "Sample A" and "Sample B" are, to include approximate
`retention times for all peaks of interest, to define the peaks between
`which resolution is measured, and. to provide a rationale for specifying
`~ , only one of which appears
`two detector wavelengths 1_ [
`"to be used;
`
`Celgene Method SOP-122 (Related Impurities) should-be-clarified to
`define the calculation basis for the relative retentionctime, to provide a
`_-rationale.for. specifying two detector wavelengths. t
`J 1, and
`to be more specific about the retention times of the· impurities to be
`calculated;
`
`(c)
`. -- -
`
`Celgene Method SOP-120 (Dissolution) and Celgene Method SOP-128
`(ContentUnifonnity) should be clarified as described for Method 121.
`
`3.
`
`4.
`
`Based on our statistical review of the data submitted, we have concluded that the
`maximum expiration dating that can be justified at this time--is eighteen months
`for thalidomide. Please request an adjustment of the maximum expii-ation date
`to eighteen months.
`[
`
`J
`
`(a)
`
`(b)
`
`(c)
`
`t
`f
`
`t
`
`]
`
`J
`
`)
`
`CFAD VI 1031-0011
`
`

`
`NDA 20-785
`Page 3
`
`t
`
`(d)
`
`[
`
`]
`
`J
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`5.
`
`'
`
`(a)
`
`-
`We request that the following studies be conducted as Phase 4 commitments:
`The potential of thalidomide to accumulate in fatty tissue depends upon
`its solubility in lipid containing tissues and lipophilic media. Please
`:provide a commitment to perform,a study·in animals to determine tissue
`levels. This study should also include a determination of the
`octanol-water partition coefficient. Please report your. findings within
`120 days following the date of this letter.
`
`. .. (b)
`
`. .A: ~tudy should be done with thalidomide given at nightto insure that
`diurnal factors are not interfering with pharmacokinetics.
`
`(c) We remind you of your commitment to do a two way cross~over study
`of oral solution versus marketed product. This study has been called
`PK007.
`
`(d)
`
`iv.
`
`In addition, you have agreed to make the following changes to the
`protocol for E003/P:
`I.
`Monitoring blood pressures and pulse while the patients are
`standing and sitting and at the time of peak drug levels.
`Oral and axillary temperatures are both to be measured.
`Fever severity should be noted in temperature ranges.
`Information should be recorded about the concomitant use
`ofaspirin, non-steroidal anti-inflammatory drugs and
`acetaminophen.
`Actual lesion counts should be performed.
`
`n.
`
`iii.
`
`CFAD VI 1031-0012
`
`

`
`NDA 20-785
`Page 4
`
`v.
`
`Severity parameters for ENL lesions should be clearly defined,
`standardized, and used.
`vi. We suggest that the term "not present" or similar term(s) be used
`to denote that an assessment has been made and the particular
`symptom is not present.
`vii. We suggest that clinical assessment should be performed on a
`weekly basis after the first week.
`It was noted in animal tests that the color of the urine changed.
`As part of the standard urinalysis, please note color.
`
`viii.
`
`(e)
`
`Additional solubility information should be obtained and reported not
`later than the first Annual Report. This should include the equilibrium
`aqueous solubility in the pH range of 1-9 and the equilibrium solubility
`as a function of temperature in · c.
`J over the temperature
`,range typically used for recrystallization.
`
`6.
`
`The Labeling and Nomenclature Committee has judged the name "Synovir"
`unacceptable. They noted numerous potential look-alike/sound-alike conflicts
`with SYNACORT, SYNALAR, SYNEMOL, SINEQUAN, .SINEMET and
`CINOBAC. Additionally, "-vir" is the USAN stem -reserved for antic.viral
`products and this product is not a pending anti-viral product. Therefore if you
`intend to use a trade name for this product please submit a new proposed name.
`
`Although notthe basis for the approvability ofthis.application~ the following-issues should be
`addressed in your resubmission:
`
`1.
`
`2.
`
`3.
`
`We recommend initiation of accelerated stability studies for-bottles of 14, 28,
`56, and appropriate multiples of 56 capsules as being more·consistent with
`anticipated clinical usage. An appropriate amendment or supplement should be
`submitted on the completion of three months stability study.
`
`We encourage you to continue efforts to develop an improved non-destructive
`· J
`assay for t
`- -- --
`
`We request that you submit additional information concerning the historical
`control data for CD-1 mice and the formation of corneal crystals. In addition, it
`would be helpful for you to provide a potential explanation for: a) the formation
`of cataracts in the 14 day repeat dose toxicity study and not in the 90 day repeat
`dose toxicity study performed in mice and b) the formation of corneal crystals in
`the 90 day repeat dose toxicity study and not in the 14 day repeat dose toxicity
`
`CFAD VI 1031-0013
`
`

`
`NDA 20-785
`Page 5
`
`study performed in mice.
`
`4.
`
`5.
`
`6.
`
`There were two neoplasms observed in the 13 week repeat dose toxicity study
`performed in CD-1 mice. A low dose male had a small alveolar-bronchiolar
`adenoma involving the lung and a high dose female bad a uterine stromal polyp.
`Tumor findings are quite uncommon in a 13 week repeat dose toxicity study. It
`may be true that the two types of observed tumors are relatively common
`spontaneous neoplasms in CD-1 mice, but one would anticipate that these
`tumors are relatively uncommon in CD-1 mice at this early a time in their life
`span. We request that you submit additional information on the historical
`control data for CD-1 mice to validate the claim that the two types of tumors
`observed in this study are relatively common spontaneous neoplasms in CD-1
`mice. In particular, please pay special attention to clarifying at what time point
`in the life span of the CD-1 mice are alveolar-bronchiolar adenomas and uterine
`stromal, polyps observed and what is their frequency level. .One potential
`possibil,ity for the presence of the alveolar-bro:gchiolar adenoma could be due to
`a murine virus infection of that particular anin).al. We request that you provide
`additional:infonnation on the health status of the CD-1 mice used ·in·this.13
`week repeat dose toxicity study.
`. . : .
`We are concerned about the AUC values obtained in the 52 week repeat dose
`toxicity study .in dogs. The maximum AUC obtained in this study (approx. 100
`µg*hr/ml) is substantially lower (approx. 1A X) than was obtained in the 7 day
`repeat dose pharmacokinetics study (approx 400 µg*hr/ml) performed in dogs.
`:.·.· ·;·We0requestthat you submit any additional infonnation·that you: may have to .
`provide an explanation for this observation. In particular, information
`concerning the status of the dogs fed or fasted state prior to dose administration
`would be quite useful. In dogs, the pH in the stomach varies according to how
`recently the dogs have eaten and this could have a dramatic effect on the rate of
`spontaneous hydrolysis· of thalidomide.
`
`We are concerned about the stability of thalidomide (due to spontaneous
`hydrolysis) under the assay conditions for the in vitro genetic toxicology studies
`that investigated the potential for thalidomide to induce mutations. It is unclear
`as to the stability of thalidomide in the media used to conduct the two in vitro
`genetic toxicology studies. We request that you submit information about the
`stability of thalidomide under the conditions of the two in vitro genetic
`toxicology studies conducted for thalidomide. We recommend that you make
`the following modifications to the two carcinogenicity (rat and mouse)
`protocols: a) delete the clinical pathology assessment at week 104 due to these
`results may be confounded by age related toxicities, b) draw blood from a
`
`. -
`
`.··.
`
`CFAD VI 1031-0014
`
`

`
`NDA 20-785
`Page 6
`
`satellite group of mice (not the animals to be used for the main study) for the
`week 54 clinical pathology assessment, and c) conduct histopathological
`examination of all of the tissues from all of the dose groups in both
`carcinogenicity assays.
`
`7.
`
`8.
`
`We recommend that you resubmit the two carcinogenicity (rat and mouse)
`protocols with the results of their respective 90 day dose range studies to
`support the dose selection for these studies. Please be advised that the two
`carcinogenicity protocols, along with their respective 90 day dose range studies,
`will be submitted to the executive Carcinogenicity Assessment Committee
`(CAC) for evaluation and recommendations. The recommendations from the
`executive CAC evaluation of the two carcinogenicity protocols will be shared
`with you.
`
`We recommend that you include full hematological and clinical chemistry
`profile Pieasurements in both of the reproducti.Ye toxicity dose range finding
`studies in male and female rabbits at appropriate time points in this study (i.e.,
`day 7 and study termination). We recommend that·you evaluate mating
`performance in the reproductive toxicity dose range finding study in male_
`rabbits.
`
`9.
`
`We recommend that you evaluate mating performance in the.Segment I
`reproductive toxicity study in rabbits.
`
`AO. We.recommend that you evaluate a m~asure-ofsexual maturation in the-Segment·
`III reproductive toxicity study in rabbits. It is also- recommended that you
`evaluate some parameters of development in this study (i.e., measurements of
`learning capacity, physical strength, and motor coordination).
`
`>;
`
`11. We recommend that you resubmit the Segment I and III reproductive toxicity
`protocols after completion of the reproductive toxicity dose range finding studies
`to support the dose selection for these studies.
`
`12.
`
`You have yet to fulfill your commitment made in the protocol to analyze fecal
`samples collected during study PK-005. Please provide a time frame for doing
`so.
`
`Under 21 CFR 314.50(d)(5)(vi)(b), we request that you update your NDA by submitting all
`additional safety information you now have regarding your new drug. Please provide updated
`information as listed below:
`
`CFAD VI 1031-0015
`
`

`
`NDA 20-785
`Page 7
`
`1.
`
`2.
`
`3.
`
`Retabulate all safety data including results of trials that were still ongoing at the
`time of NDA submission. The tabulation can tak~ the same form as in your
`initial submission. Tables comparing adverse reactions at the time the NDA
`was submitted vs now will certainly facilitate review.
`
`Retabulate drop-outs with new drop-outs identified. Discuss, if appropriate.
`
`Provide details of any significant changes or findings, if any.
`
`Summarize worldwide experience on the safety of this drug beyond that which
`·4.
`was included in your NDA.
`
`5.
`
`Submit case report forms for each patient who died during clinical studies EOOl
`and E003/P or who did not complete either one of these two studies because of
`an adverse event.
`
`.
`
`.
`Please also update the new drug application with respect to qew reports of relevant safety
`information, including all deaths and any adverse events thatled· to discontinuation of the drug
`and any information suggesting a substantial difference in the rate of ·occurrence· of common
`but less serious adverse events. The update should cover all studies and uses of the drug
`including: (1) those involving indications not being sought in the present submission, (2) other
`dosage forms, and (3) other dose levels, etc.
`
`In addition, please submit three copies of the introductory promotional material that you
`propose to use for this product:.:All proposed 0materialscshould be,submitted in draftor mock(cid:173)
`up form, not final print. Pleased be advised that theregulationsat'.21'CFR 314.550 regarding
`promotional materilals for products approved under Accelerated Approval (Subpart H) will
`apply 'to this product. Please submit one copy to this Division- and -two copies of both the ·
`promotional material and the package insert directly to:
`
`Food and Drug Administration
`Division of Drug Marketing, Advertising and Communications,
`HFD-40
`5600 Fishers Lane
`Rockville, Maryland 20857
`
`Within 10 days after the date of this letter, you are required to amend the application, notify us
`of your intent to file an amendment, or follow one of your other options under 21 CFR
`314.110. In the absence of such action FDA may take action to withdraw the application.
`
`CFAD VI 1031-0016
`
`

`
`NDA 20-785
`Page 8
`
`Under 21CFR314.102(d) of the new drug regulations, you may request an informal or
`telephone conference with the Office to discuss what further steps need to be taken before the
`application may be approved.
`
`The drug may not be legally marketed until you have been notified in writing that the
`application is approved.
`
`If you have any questions, please contact Mary Jane Walling at (301) 827-2268.
`
`Sincerely yours,
`
`-
`
`Michael Weintraub, M.D.
`Director
`.. Office of Drug Evaluation V
`Center for Drug Evaluation and Research
`
`·~.> ....
`~A~f~'..ori- ..
`
`CFAD VI 1031-0017