CENTER FOR DRUG EVALUATION AND RESEARCH
`
`APPROVAL PACKAGE FOR:
`
`APPLICATION NUMBER
`
`21-462
`
`Administrative
`
`

`

`Pease, Doroth W
`
`‘rom:
`ant:
`. 0:
`Cc:
`Subject:
`
`Hazarika, Maitreyee
`Tuesday, January 20. 2004 9:20 AM
`Johnson. John R; White Jr, Robert M
`Pease, Dorothy W
`RE: Alimta 120 Day Safety Update
`
`There was an update submitted around May-2003.
`MH
`'
`
`I did go through it while writing up my review.
`
`-----origina! Message-"'-
`From:
`Johnson, John R
`Sent:
`Saturday, January 17, 2004 10:19 AM
`To:
`Peese, Dorothy W
`‘
`Cc:
`Hazarika, Maitreyee; White Jr, Robert M
`Subjects
`Alimta 120 Day Safety Update
`
`Has a 120 Day Safety Update been submitted? If so, has it been reviewed?
`
`John
`
`

`

`NDA/EFFICACY SUPPLEMENT ACTION PACKAGE CHECKLIST
`
`A lication Information
`
`I
`
`.~\ A 21—462
`
`Efficac 'Su- Iement T -e SE-
`
`i Drug: ALIMTA® (pemetrexed, LY231514)
`
`
`
`Su- lement Number
`
`A-
`
`licant: Eli Lilly & Comanv
`
`I RPM: Path~ Garvev, R.Ph.
`
`.
`
`HFD-‘lSO
`
`Phone # 301—594-5766
`
`Reference Listed Drug (NDA #, Drug name):
`
`i
`
`Application Type: ()0 505(1))(1) 0 505(b)(2)
`[ ~2' Application Classifications:
`
`
`() Standard or ) Priority
`_
`-
`Review priority
`F
`
`
`0
`Chern class (NDAs only)
`,.
`1
`
`Orphan designation
`o Other (e.g., orphan, OTC)
`in
`
`
`
` '30 User Fee Goal Dates
`
`March 31, 2004
`
`
`‘ 4°
`Special programs (indicate all that apply)
`'
`()None
`
`Subpart H
`
`l
`()2] CFR 314.510 (accelerated
`approval)
`'
`()Zl CFR 314.520
`(restricted distribution)
`
`'
`
`(X ) Fast Track —Granted 6-10-02
`
`»
`
`.
`
`User Fee exception
`
`’
`
`'
`l
`'
`
`'
`
`i“
`
`p
`
`‘3° Application Integrity Policy (AIP)
`
`
`\
`
`o .
`
`- Applicant is on the AIP
`
`(X ) Rolling Review
`() CMA Pilot 1
`( ) CMA Pilot 2
`User-reexnromanon —
`
`0 .. “User Fee
`_( ) Paid
`,
`0
`User Fee waiver
`( ) Small business
`"
`( ) Public health
`( ) Barrier-to-Innovation
`
`»
`__
`_
`_( ) Other
`‘
`(X ) Orphan designation
`— Granted 8-28-01
`()No-fee 505(b)(2)
`( ) Other
`-
`"
`'-":
`
`.-
`
`.
`
`llYes (X )No
`
`(X )No
`( ) Yes
`
`N/A
`
` 0
`
`0 . This application is on the AIP
`
`
`
`0
`
`Exception for review (Center Director’s memo)
`OC clearance for approval
`
`'.' Debarment certification: verified that qualifying language (e.g., willingly, knowingly) was
`not used in certification & certifications from foreign an ulicants are cosi - ed b US a ent.
`
`
`
`‘1' Patent
`
`( X ) Verified
`
`
`0
`Information: Verify that form FDA-3542a was submitted.
`( X ) Verified
`0
`Patent certification [505(b)(2) applications]: Verify type of certifications
`21 CFR 314.50(i)(l)(r‘)(A)
`submitted.
`.
`()1 ()II
`()III
`()IV
`
`
`
`21 CFR 314.50(i)(1)
`()(ii)
`()(iii)
`
`() Verified
`
`I
`
`For paragraph IV certification, verify that the applicant notified the patent
`holder(s) of their certification that the patent(s) is invalid, unenforceable, or will
`not be infringed (certification of notification and documentation ofreceipt of
`notice).
`
`Versicin: 9.25/03
`
`

`

`NDA 21-462
`
`Page 2
`
`
`Exclusivity (approvals only)
`
`() Yes, Application ii
`(X) No
`
`‘
`
`
`Exclusivity summary
`
`}
`6
`Is there an existing orphan drug exclusivity protection for the active moiety for
`i
`the proposed indication(s)7 Refer to 21 CFR 316.3(bj(13jf0r the definition of
`i
`sameness/or an orphan drug (i.e., active moiety). This definition is NOTIhe
`!
`same as that used/or NDA Chemical classification!
`
`
`General Information
`
`
`I
`°1~ Actions
`'
`
`
`
`00A? 0'” ()AE ()NA
`‘
`0
`Proposed action
`
`
`e
`Previous actions (specify type and date for each action taken)
`N/A
`
`(X ) Materials requested in AP letter
`
`
`0
`Status ofadvertising (approvals only)
`' ( ) Reviewed for Sub-art H
`
`
`
`'02. Public communications
`
`
`
`(X) Yes () Not applicable
`_
`'L
`0
`Press Office notified of action (approval only)
`i __________«.__
`|
`
`_
`
`
`
`
`
`.
`( ) None
`(X ) Press Release — FDA ~.
`( ) Talk Paper
`
`
`( ) Dear Health Care Professional
`Letter
`
`
`( X) Other - e-mail burst
`,
`4° Labeling (package insert; patient package insert (ifapplicable), MedGuide (ifapplicable))_
`
`O
`Division's proposed labeling (only if generated after latest applicant submission
`‘
`attached to letter
`of labeling)
`
`
`
`January 12, 2004 submission
`o MOst recent applicant-proposed labeling
`
`September 29, 2003 submission
`
`
`’ O'riginal applicant-proposed labeling
`c
`’
`i
`review of PI — 12-8-03
`L. _.-,~___.____
`
`0
`
`Indicate what types (if any) of information dissemination are anticipated
`
`
`
`-
`
`Labeling reviews (including DDMAC, DMETS, DSRCS) and minutes of
`labeling meetings (indicate dates ofrevicws and meetings)
`
`'
`
`i DPADP review of PI — 11/16/03
`DSRCS review of PP] - 10/14/03
`DMETS review of tradename -
`10/3/03 and 6/10/02
`DDMAC review of PI — 10/1/03
`
`0
`
`Other relevant labeling (e.g., most recent 3 in class, class labeling)
`
`.;. Labels (immediate container & carton labels)
`
`N/A
`
`i
`
`
`0 Division proposed (only if generated after latest applicant submission)
`0 Applicant proposed
`0
`Reviews
`
`September 29, 2003 submission
`Acceptable'ln CMC review
`
`=
`
`-2-_ Post-marketing commitments
`
` 0
`
`commitments Outgoing correspondence (i.e., letters, E-mails, faxes)
`
`Documentation of discussions and/or agreements relating to post-marketing
`
`0 Agency request for post-marketing commitments
`
`‘2' Memoranda and Telecoms
`
`‘2' Minutes ofMeetings
`
`
`EOP2 meeting (indicate date)
`June 25, 1999 and March 1, 2000
`
`Pre~NDA meeting (indicate date)
`
`January 30, 2002
`
`o
`
`o
`
`l
`
`‘
`
`Version: 9/25/03
`
`Included in package
`
`Included in package
`
`

`

`NDA 21-462
`
`Page 3
`
`
`Pre-Approval Safety Conference (indicate date; approvals only)
`-
`Other
`”—
`.
`
`~2~ Advisory Committee Meeting
`
`.
`Date or Meeting
`E1.—
`_____-
`-
`48-hour alert
`N/A
`
`November 13, 2003
`N/A
`
`,
`
`01° Federal Register Notices, DESI documents, NAS/NRC reports (if applicable)
`
`N/A
`
`6-
`
`Summary Reviews (e,g., Office Director, Division Director, Medical Team Leader)
`(indicate datefor each review)
`
`in volume 3 of3
`Division Director 2-4-04
`Medical Team Leader l-24-O4
`
`Summary Application Review .
`
`Clinical Information
`
`.
`
`'i'
`
`.--,
`li." r'i')"
`C rical
`ex e\x(s,l(mdtcate datefor each renew)
`
`.
`BER consult-9-23-03 vol]
`
`_ .,. Microbiology (efficacy) review(s) (indicate datefor each review)
`
`N/A
`
`in MOR 1-29-04 (vol. 3)
`
`
`.20 Safety Update review(s) (indicate date or location ifincorporated in another review)
`0.0
`_ Rile—liian‘agement Plan review(s) (indicate date/location ifincorporated in another rev)
`
` o
`
`’2' Pediatric Page(separate page for each indication addressing status ofall age groups)
`
`n/a
`
`ssssssssss n
`
`4' Biopharmaceutical review(s) (indicate datefor each review)
`Controlled Substance Staff review(s) and recommendation for scheduling (indicate date
`for each review)
`02° Clinical Inspection Review Summary (DSI)
`
`
`Clinical studies
`December 17, 2003 (vol.])
`
`December 5, 2003 (vol. 2)
`
`IV/A
`
` -
`
`
`
`6
`
`Bioequivalence studies
`
`N/A
`
`CMC Information
`
` 1-5—04 (vol. 2)
`
`4‘ CMC review(s) (indicate datefor each review) 1 194“ (vol 2
`
` :
`' Environmental Assessment
`
`' o ' Categorical Exclusion (indicate review date)
`
`
`.__.... ..........._..‘
`_l
`
`pg. 88 of CMC review (vol. 2
`
`9
`
`0
`
`Review 8; FONS] (indicate date of review)
`
`Review 8; Environmental Impact Statement (indicate date ofeach review)
`
`N/A
`
`N/A
`
`November 7, 2003
`
`4° Microbiology (validation of sterilization & product sterility) review(s) (indicate date for
`each review)
`0? Facilities inspection (provide EER report)
`
` Nonclinical Pharm/Tox Information
`
`Pharm'tox review(s),' including referenced IND reviews (indicate date for each review)
`
`
`
`
`
`'2' Nonclinical inspection review summary
`
`N/A
`
`Version: 925/03
`
`
`
`
`
`Methods validation
`
`Date completed: December 8, 2003
`( X ) Acceptable
`( ) Withhold recommendation
`0 Completed -
`(X) Requested
`( ) Not yet recuested
`
`Team Leader review 12-22-03
`
`
`
`(vol. 2)
`December 19, 2003 (vol.2
`
`

`

`NDA 21-462
`
`Page 4
`
` Statistical re\'iew(s) of carcinogenicity studies (indicate datefor each review)
`
`
`-& CAC/"ECAC repon
`,
`
`
`Version: 9/25/03
`
`

`

`ITEM 13: PATENT INFORMATION
`
`Page 1
`
`NBA 21 -462
`ALIMTA®
`
`(pemetrexed)
`
`The undersigned declares that the following patents cover the formulation, composition,
`and method of use of ALIMTA, as indicated. This product is the subject of this
`application for which approval is being sought:
`
`
`
`Type of Patent
`(Drug Substance. Drug
`Product, or Method 01 Use
`
`Method of Use
`
`Patent Number
`
`Patent Expiry Date
`
`5.344.932
`5,217,974
`
`Setember 6, 201 l
`March 29, 2011
`
`The above patents are all owned by or exclusively licensed by Eli Lilly and Company,
`Indianapolis, IN.
`
`b ' Q1
`
`
`X—
`-
`Name ot authorized official
`
`'____QcLoh_er_L._2_QQ2____
`
`Date
`
`Director, US Regulatory Affairs
`
`ALI MTA (LY231514)
`
`Patent Intonation
`
`

`

`ITEM 14: PATENT CERTIFICATION
`
`Page 1
`
`NBA 21 -462
`ALIMTA®
`
`(pemetrexed)
`
`Eli Lilly and Company claims a five year periodpf exclusivity for the use of ALIMTA as
`
`provided by C.F.R. 314.108(b)(2). As evidenced by the absence in the Orange Book that
`
`ALIMTA has previously been approvedby the FDA, to the best of Applicant’s
`
`.
`
`knowledge and belief, ALEMTA has not previously been approved under section 505(b)
`
`of the FFDCA. Accordingly, Eli Lilly and Company submits ALLVITA as a new
`
`chemical entity entitled to a five year period of exclusivity as provided by FFDCA
`
`505(c)(3)(D)(ii) and 5050)(4)(D)(ii)(21 U.S.C. 355(c)(3)(D)(ii) and 3550)(4)(D)(ii)).
`
`0. (Lid
`
`Name of authorized official
`
`Director, US Regulatory Affairs
`
`October 1, 2002
`
`Date
`
`i
`
`i
`
`ALIMTA (LY231514)
`
`Patent Certification
`
`

`

`EXCLUSIVITY SUMMARY for NDA #
`
`21-462
`
`SUPPL #
`
`Trade Name
`
`ALIMTA
`
`Generic Name
`
`pemetrexed
`
`Applicant Name
`
`Eli Lilly & Company
`
`HFD- 150
`
`Approval Date
`
`244-04
`
`PART I:
`
`IS AN EXCLUSIVITY DETERMINATION NEEDED?
`
`l.An exclusivity determination will be made for all original
`applications, but only for certain supplements. Complete
`Parts II and III of this Exclusivity Summary only if you
`answer "YES" to one or more of the following questions about
`the Submission.
`'
`‘
`
`a)Is it an original NDA?
`
`YES/ X /
`
`NO /
`
`/
`
`b)Is it an effectiveness supplement? YES /
`
`/
`
`NO /_X_/
`
`If yes, what type(SEl, SE2, etc.)?
`
`c)Did it require the review of clinical data other than to
`support a safety claim or change in labeling related to
`safety?
`(If it required review only of bioavailability
`or bioequivalence data, answer "NO.")
`
`YES /_x_/
`
`NO /___/
`
`If your answer is "no" because you believe the study is a
`bioavailability study and,
`therefore, not eligible for
`exclusivity, EXPLAIN why it is a bioavailability study,
`including your reasons for disagreeing with any arguments
`made by the applicant that the study was not simply a
`bioavailability study.
`
`If it is a supplement requiring the review of clinical
`data but it is not an effectiveness supplement, describe
`the change or claim that is supported by-the clinical
`data:
`
`Page 1
`
`

`

`d)Did the applicant request exclusivity?
`
`YES /_X_/ NO /
`
`/
`
`is "yes," how many years of
`If the answer to (d)
`exclusivity did the applicant request?
`
`5 Years
`
`e)Has pediatric exclusivity been granted for this Active
`Moiety?
`
`YES /
`
`/
`
`NO /_x_/
`
`IF YOU HAVE ANSWERED "NO" TO ALL OF THE ABOVE QUESTIONS, GO
`DIRECTLY TO THE SIGNATURE BLOCKS ON Page 9.
`
`A 4
`
`.Has a product with the same active ingredient(s), dosage form,
`strength,
`route of administration, and dosing schedule
`previously been approved by FDA for the same use? (Rx to OTC)
`Switches should be answered No — Please indicate as such).
`
`If yes, NDA #
`
`Drug Name
`
`YES /
`
`/
`
`NO /_x_/
`
`IF THE ANSWER TO QUESTION 2 IS "YES," GO DIRECTLY TO THE
`
`SIGNATURE BLOCKS ON Page 9.
`
`3.15 this drug product or indication a DESI upgrade?
`
`YES /___/
`
`NO /_x_/
`
`IF THE ANSWER TO QUESTION 3 IS "YES," GO DIRECTLY TO THE
`SIGNATURE BLOCKS ON Page 9
`(even if a study was required for the
`upgrade).
`
`Page 2
`
`

`

`PART II: FIVE-YEAR EXCLUSIVITY FOR NEW CHEMICAL ENTITIES
`
`(Answer either #1 or #2, as appropriate)
`
`1.Single active ingredient product.
`
`Has FDA previously approved under section 505 of the Act any
`drug product containing the same active moiety as the drug
`under consideration? Answer "yes"¢if the active moiety
`(including other esterified forms, salts, complexes, chelates
`or clathrates) has been previously approved, but this
`particular form of the active moiety, e.g.,
`this particular
`ester or salt
`(including salts with hydrogen or coordination
`bonding) or other non—covalent derivative (such as a complex,
`chelate, or Clathrate) has not been approved. Answer "no" if
`the compound requires metabolic conversion (other than
`deesterification of an esterified form of the drug)
`to produce
`an already approved active moiety.
`
`yrs /__/ NO /_x_/
`
`If "yes," identify the approved drug product(s) containing the
`active moiety, and, if known,
`the NDA #(s).
`
`'NDA #
`
`NDA #
`
`NDA #
`
`2.90mbination product.
`
`If the product contains more than one active moiety (as
`_
`defined in Part II, #1), has FDA previously approved an
`application under section 505 containing any 932 of the active
`moieties in the drug product?
`If,
`for example,
`the
`- combination contains one never-before-approved active moiety
`and one previously approved active moiety, answer "yes."
`(An
`active moiety that is marketed under an OTC monograph, bUt
`that was never approved under an NDA,
`is considered not
`previously approved.)
`
`YES /___/
`
`NO /_x_/
`
`Page 3
`
`

`

`If "yes," identify the approved drug product(s) containing the‘
`active moiety, and, if known,
`the NDA #(s).
`
`NDA #
`
`NDA #
`
`NDA #
`
`IF THE ANSWER TO QUESTION 1 OR 2 UNDER PART II IS "NO," GO
`DIRECTLI TO THE SIGNATURE BLOCKS ON Page 9.
`IF "YES,” GO TO PART
`III.
`-
`
`PART III: THREE-YEAR EXCLUSIVITY FOR NDA'S AND SUPPLEMENTS
`
`To qualify for three years of exclusivity, an application or
`supplement must contain "reports of new clinical investigations
`(other than bioavailability studies) essential to the approval of
`the application and conducted or sponsored by the applicant."
`This section should be completed only if the answer to PART II,
`Question 1 or 2, was "yes."
`
`l.Does the application contain reports of clinical
`investigations?
`(The Agency interprets "clinical
`investigations" to mean investigations conducted on humans
`other than bioavailability studies.)
`If the application
`contains clinical investigations only by virtue of a right of
`reference to clinical investigations in another application,
`answer "yes," then skip to question 3(a).
`If the answer to
`3(a)
`is "yes" for any investigation referred to in another
`application, do not complete remainder of summary for that
`investigation.
`
`IF "NO," GO DIRECTLY TO THE SIGNATURE BLOCKS ON Page 9.
`
`YES
`
`/
`
`/
`
`NO /
`
`/
`
`2. A clinical investigation is "essential to the approval" if the
`Agency could not have approved the application or supplement
`without relying on that investigation. Thus,.the
`investigation is not essential to the approval if 1) no
`clinical investigation is necessary to support
`the supplement
`or application in light of previously approved applications
`(i.e.,
`information other than clinical trials,
`such as
`bioavailability data, would be sufficient to provide a basis
`
`Page 4
`
`

`

`for approval as an ANDA or 505(b)(2) application because of
`what is already known about a previously approved product), or
`2)
`there are published reports of studies (other than those
`conducted or sponsored by the applicant) or other publicly
`available data that independently would have been sufficient
`to support approval of the application, without reference to
`the clinical investigation submitted in the application.
`
`For the purposes of this section, studies comparing two
`products with the same ingredient(s) are considered to be
`bioavailability studies.
`
`(a)
`
`is a
`In light of previously approved applications,
`clinical investigation (either conducted by the
`applicant or available from some other source,
`including the published literature) necessary to
`support approval of the application or supplement?
`
`YES /
`
`/
`
`NO /
`
`/
`
`If "no," state the basis for your conclusion that a
`clinical trial is not necessary for approval AND GO
`DIRECTLY TO SIGNATURE BLOCK ON Page 9:
`
`(b) Did the applicant submit a list of published studies
`relevant to the safety and effectiveness of this drug
`product and a statement that the publicly available
`data would not
`independently sUpport approval of the
`application?
`
`(1)
`
`is "yes," do you personally
`If the answer to 2(b)
`know of any reason to disagree with the applicant's
`conclusion?
`If nbt applicable, answer NO.
`
`YES /__/
`
`' NO /
`
`/
`
`YES /_/I
`
`NO /__/
`
`If yes, explain:
`
`Page 5
`
`

`

`(2)
`
`is "no," are you aware of
`If the answer to 2(b)
`published studies not conducted or sponsored by the
`applicant or other publicly available data that
`could
`independently demonstrate the safety and effectiveness
`of this drug product?
`’
`NO /
`
`YES /___/
`
`/
`
`If yes, explain:
`
`(c)
`
`If the answers to (b)(l) and (b)(2) were both "no,"
`
`identify the clinical investigations submitted in the
`application that are essential to the approval:
`
`InveStigation #1, Study #
`
`Investigation #2, Study #
`
`Investigation #3, Study #
`
`investigations must be "new"
`3.In addition to being essential,
`to support exclusivity.
`.The agency interprets "new clinical
`investigation" to mean an investigation that 1) has not been
`relied on by the agency to demonstrate the effectiveness of a
`previously approved drug for any indication and 2) does not
`duplicate the results of another investigation that was relied
`- on by the agency to demonstrate the effectiveness of a
`previously approved drug product, i.e., does not redemonstrate
`something the agency considers to have been demonstrated in an
`already approved application.
`
`(a)
`
`For each investigation identified as "essential to the
`approval," has the investigation been relied on by the
`agency to demonstrate the effectiveness of a previously
`approved drug product?
`(If the investigation was relied
`on only to support
`the safety of a previously approved
`drug, answer "no.")
`
`Investigation #1
`
`Investigation #2
`
`Investigation #3
`
`YES /
`
`YES /
`
`YES /
`
`/
`
`/
`
`/
`
`NO /
`
`NO /
`
`- NO /
`
`/
`
`/
`
`/
`
`yes" for one or more
`If you have answered
`investigations,
`identify each such investigation and the
`NBA in which each was relied upon:
`
`Page 6
`
`

`

`NDA #
`NDA #
`NDA #
`
`Study #
`Study #
`Study #
`
`(b)
`
`For each investigation identified as "essential to the
`approval,P does the investigation duplicate the results
`of another investigation that was relied on by the agency
`to support the effectiveness of a previously approved
`drug product?
`
`Investigation #1
`
`Investigation #2
`
`Investigation #3
`
`YES /
`
`YES /
`
`YES /
`
`/
`
`/
`
`/
`
`NO /
`
`NO /
`
`NO /
`
`/
`
`/
`
`/
`
`If you have answered "yes” for one or more
`inveStigations,
`identify the NDA in which a similar
`investigation was relied on:
`
`NBA #
`
`NDA #
`
`NDA #
`
`Study #
`
`Study #
`
`‘
`
`Study '#
`
`(c)
`
`identify each
`If the answers to 3(a) and 3(b) are no,
`"new" investigation in the application or supplement that
`is essential to the approval (i.e.,
`the investigations
`listed in #2(c),
`less any that are not "new"):
`
`Investigation #__, Study #
`
`Investigation #__, Study #
`
`Investigation #__, Study #
`
`.To be eligible for exclusivity, a new investigation that is
`essential to approval must also have been conducted or
`sponsored by the applicant.
`An investigation was "conducted
`or sponsored by" the applicant if, before or during the
`conduct of the investigation, 1)
`the applicant was the sponsor
`of the IND named in the form FDA 1571 filed with the Agency,
`or 2)
`the applicant
`(or its predecessor in interest) provided
`substantial support for the study. Ordinarily, substantial
`support will mean providing 50 percent or more of the cost of
`the study.
`
`Page 7
`
`

`

`(a)
`
`For each investigation identified in response to
`question 3(c): if the investigation was carried out
`under an IND, was the applicant identified on the FDA
`1571 as the sponsor?
`
`Investigation #1
`
`IND #
`
`YES
`
`/
`
`/
`
`NO /
`
`/ Explain:
`
`Investigation #2
`
`IND #
`
`YES /
`
`/
`
`NO /
`
`/ Explain:
`
`(b)
`
`For each investigation not carried out under an IND or
`for which the applicant was not identified as the
`sponsor, did the applicant certify that it or the
`applicant's predecessor in interest provided
`substantial support for the study?
`
`Investigation #1
`
`YES /
`
`/ Explain
`
`NO /
`
`/ Explain
`
`Investigation #2
`
`YES /
`
`/ Explain
`
`NO /
`
`/ Explain
`
`Page 8
`
`

`

`(b), are
`(c) Notwithstanding an answer of "yes" to (a) or
`there other reasons to believe that the applicant
`should not be credited with having "conducted or
`sponsored" the study?
`(Purchased studies may not be
`used as the basis for exclusivity. However,
`if all
`rights to the drug are purchased (not just studies on
`the drug),
`the applicant may be considered to have
`sponsored or conducted the studies sponsored or
`conducted by its predecessor in interest.)
`
`YES /
`
`/
`
`NO / X
`
`/
`
`If yes, explain:
`
`.
`
`Dotti Pease
`
`-
`
`2-12-04
`
`Signature of Preparer
`Title:
`
`Date
`
`Richard Pazdur, M.D.
`
`Signature Division Director
`
`'
`
`Date
`
`.
`"
`cc:
`Archival NDA
`
`.
`
`HED-
`HFD-
`
`/Division File
`/RPM
`
`HFD—6lO/Mary Ann Holovac
`HFD—lO4/PEDS/T.Crescenzi
`
`Page 9
`
`

`

`This is a representation of an electronic record that was signed electronicaliy and
`this page is the manifestation of the electronic signature.
`
`Richard Pazdur
`
`12/12/04 09:23:20 AM
`
`

`

`)
`W
`(
`PEDIATRIC PAGE
`PM 9%
`(Complete for all APPROVED original applications and efficacy supp“;emems h _
`J
`"\ é~ I" i‘
`
`NDA # : 21-462
`
`Supplement Type (e.g. SE5):
`
`Supplement Number:
`
`Stamp Date:
`
`9—30-2003
`
`Action Date:
`
`3-31-2003
`
`HFD -150
`
`Trade and generic names/dosage form: ALIMTA® emetrexed
`
`
`Applicant:
`
`Eli Lilh 8; Companv
`
`Indication(s) previously approved:
`
`N/A
`
`Therapeutic Class:
`
`50 l 0 la 0 (1‘35" C
`Avgfiq LVVCU+Q
`
`Each approved indication must have pediatric studies: Completed, Deferred, and/or Waived.
`
`Number of indications for this application(s):
`
`Indication #1: Alimtain combination with cisplatin (or the indication of malignant pleural
`mesothelioma
`
`Is there a full waiver for this indication (check one)?
`
`X Yes: Please proceed to Section A.
`
`Completed
`Partial Waiver
`D No: Please check all that apply:
`_
`'
`NOTE: More than one may apply
`Please proceed to Section B, Section C, and/or Section D and complete as necessary.
`
`Deferred
`
`I Section A: Fully Waived Studies
`
`Reason(s) for full waiver:
`
`.
`
`‘
`
`I
`
`D Products in this class for this indication have been studied/labeled for pediatric population
`0 Disease/condition does not exist in children
`
`D Too few children with disease to study
`0 There are safety concerns
`X Other:
`Orphan desioI nation
`
`-
`
`Ifstudies arefully waived, then pediatric information is completefor this indication. Ifthere is another indication, please see
`Attachment A. Otherwise, this Pediatric Page is completgand should be entered into DFS.
`
`Section B: Partially Waived Studies
`
`Age/weight range being partially waived:
`
`
`
`
`Min
`Max
`
`kg
`kg
`
`Reason(s) for partial waiver:
`
`mo.
`mo.
`
`yr.
`yr.
`
`Tanner Stage
`Tanner Stage
`
`Products in this class for this indication have been studied/labeled for pediatric population
`Disease/condition does not exist in children
`
`Other:hm—UDUDDDD
`
`Too few children with disease to study
`There are safety concerns
`Adult studies ready for approval
`Formulation needed
`
`

`

`NDA 21-462
`
`Page 2
`
`Ifstudies are deferred, proceed to Section C. Ifstudies are completed, proceed to Section D. Otherwise, this Pediatric Page is
`complete and should be entered into DFS.
`
`Section C: Deferred Studies
`
`.
`
`Age/weight range being deferred:
`
`Min
`Max
`
`.
`
`kg
`kg
`
`mo.
`mo.
`
`yr.
`yr.
`
`Tanner Stage
`Tanner Stage
`
`Reason(s) for deferral:
`
`D Products in this class for this indication have been studied/labeled for pediatric population
`Cl Disease/condition does not exist in children
`0 Too few children with disease to study
`B There are safety concerns
`Cl Adult studies ready for approval
`Cl Formulation needed
`Other:
`
`Date studies are due (mm/dd/yy):
`
`Ifstudies are completed, proceed to Section D. Otherwise, this Pediatric Page is complete and should be entered into DFS.
`
`l Section D: Completed Studies
`
`,
`
`.
`
`I
`
`Age/weight range of completed studies:
`
`Min
`Max
`
`Comments:
`
`kg
`kg
`
`mo.
`mo.
`
`yr.
`yr.
`
`
`Tanner Stage
`
`Tanner Stage
`
`Ifthere are additional indications, please proceed to Attachment A. Otherwise, this Pediatric Page is complete and should be entered
`into DFS.
`'
`
`This page was completed by:
`
`{See appended electronic signature page}
`
`Regulatory Project Manager
`
`cc: NDA
`HFD-950/ Terrie Crescenzi
`HFD-960/ Grace Carmouze
`
`(revised 9-24-02)
`
`FOR QUESTIONS ON COMPLETLVG THIS FORM CONTACT, PEDIATRIC TEAIVI, HFD-960
`301-594-7337
`
`

`

`Application Information (Enter all identifying information for the submission pertaining to this summary)
`
`NDA Number:
`
`21-462
`
`Submission Type: N/A (pilot)
`
`Serial N/A (pilot)
`Number:
`
`Populations included In Application (Please provide infomationfor each category listed belowfrom the primary safety
`database excluding PK studies)
`
`CATEGORY
`
`'
`
`NUMBER EXPOSED To
`STUDY DRUG
`-
`
`Gende
`
`365
`
`. ll Females
`
`NUMBER
`EXPOSED To
`STUDY DRUG
`83
`
`Females
`>50
`
`NUMBER
`EXPOSED To
`STUDY DRL’G
`60
`
`
`
`—-—-———
`—:-m- 23(Hisanic)
`
`Gender-Based Analyses (Please provide informalionfor each calegorj' listed below.)
`Was Analysis Performed?
`
`
`
`
`
`
`
`
`
`#‘rfir‘u.
`-..
`y
`«3'
`
`,
`,'
`
`'
`
`"
`
`‘
`
`included in labeling?
`
` Was gender-based analysis
`
`
`
`Efficacy
`
`X Yes
`
`NO
`
`inadequate #5
`
`Disease
`Absent
`
`Safety
`
`X Yes
`
`No
`
`
`
`Disease
`inadequate #‘s
`Absent
`
`Is a dosing modification based on gender recommended in the label? Yes
`
`X Sponsor
`
`X No
`
`X FDA
`
`If the analysis was completed, who performed the analysis
`' Age-Based Analyses (Please provide infarmationfiyr each category listed below)
`
`
`
`
`
`
`
`_
`
`.
`
`.
`ass
`.
`
`,
`
`V
`
`p
`
`Absent
`
`Absent
`
`
`
`
`
`in labeling?
`
`
`
`Is a closing modification based on age recommended in the label?
`
`Yes
`
`If the analysis was completed, who performed the analysis
`Race-Based Analyses (Please provide informationfor each category listed below)
`
`X Sponsor
`
`X No
`
`X FDA
`
`
`
`Disease
`Absent
`Disease
`Absent
`
`Is a dosing modification based on race recommended in the label?
`
`Was race-based analysis included
`in labelinO"
`YES
`
`
`
`Yes
`
`If the analysis was completed, who performed the analysis
`
`Sponsor
`
`‘
`
`FDA
`
`

`

`In the comment section below, indicate whether an alternate reason (other than “inadequate numbers" or
`“disease absent") was provided for why a subgroup analysis was NOT performed, and/or if other subgroups
`were studied for which the metabolism or excretion of the drug might be altered (including iflabeling was
`modified).
`Comment:
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`.
`John Johnson
`1/8/04 01:27:58 PM
`
`

`

`Debarment
`
`Certification
`
`NDA Application No.2 21-462
`
`Drug Name: Alimta ( pemetrexed)
`
`Pursuant to the provisions of 21 U.S.C. 335a(k)(1), Eli Lilly and Company,
`through Debasish F. Roychowdhury, M.D., hereby certifies that it did not
`and will not use in any capacity the services of any person debarred under
`Section (21) or (b) [21 U.S.C. 335a(a) or (b)] of the Generic Drug
`Enforcement Act of 1992, in connection with the above referenced
`
`application.
`
`3ELl LILLY AND COMPANY
`
`By:
`
`‘3‘
`
`Z: L
`
`Debasish F. Roychowdhury, M.D.
`
`Title: Director, U.S. Regulatory Affairs
`
`Date: September 30, 2002
`
`

`

`97,
`__-»___—_pages redacted from this section bf-
`. the approval package consisted of draft labeling
`
`

`

`Redagte‘d
`
`l7‘
`
`pages of trade
`
`secfétand/or
`
`J‘Confidential
`
`commerCial.
`
`j infommat;on
`
`

`

`Redégted
`
`I {f
`
`,pageg of trade
`
`secfiét and/or
`
`_J:COnfidential
`
`commerCiqu
`
`j’infOrmation
`
`

`

`MEMORANDUM
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINlSTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`DATE:
`
`TO:
`
`,VIA:
`
`'
`
`FROM;
`-
`
`' THROUGH:
`
`October 14, 2003
`
`Richard Pazdur, M.D., Director
`
`Division of Oncologic Drug Products
`HFD- 150
`
`Patty Garvey, Regulatory Health Project Manager
`Division of Oncologic Drug Products
`HFD-ISO
`
`Jeanine Best, M.S.N., R.N., P.N.P.
`.
`Patient Product Information Specialist
`Division of Surveillance, Research, and Communication SUpport
`HEB-410
`
`Toni Piazza-Hepp, Pharm. D., Acting Director
`Division of Surveillance, Research, and Communication Support
`HFD-4lO
`
`SUBJECT:
`
`I
`
`ODS/DSRCS Review of Patient Labeling for Alimta (pemetrexed
`for injection), NDA 21-462
`
`The patient labeling which follows represents the revised risk communication materials of the
`- Patient Labeling for Alimta (pemetrexed for injection), NDA 21-462. We have simplified the
`-'
`__ wording, made it consistent with the PI, and removed other unnecessary information (the
`' purpose of patient information leaflets is to enhance appropriate use and provide important risk
`information about medications, not to provide detailed information about the condition), and put
`it in the format that we are recommending for all patient information. Our proposed changes are .
`known through research and experience to improve risk communication to a broad audience of
`varying educational backgrounds. These revisions are based on draft labeling submitted by the
`sponsor on September 29, 2003. Patient information should always be consistent with the
`prescribing information. All future changes to the Pl should also be reflected in the PM
`
`Comments to the review Division are bolded, italicized, and underlined. We can provide
`marked-up and clean copies of the revised document in Word if requested by the review
`division. Please let us know ifyou have any questions.
`
`INFORMATION FOR PATIENTS AND CAREGIVERS
`
`

`

`3
`__.—_-___-_pages redacted from this'section Of.
`v the-approval package consisted of draft labeling
`
`

`

`nnnnnnnnnnnnnnnnnounc-n-n-n-u-u-n-n-u-nsou-g-..a.n.-no.~-o..---.----o--o--.---n--u-poo-ou--n-g-nuuusuuupaunn-----.-.o
`
`This is'a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`,
`Jeanine Best
`.
`-10/14/03 11:24:05 AM
`DRUG SAFETY OFFICE REVIEWER
`
`7 Toni Piazza Hepp
`10/14/03 04:52:02 PM
`DRUG SAFETY OFFICE REVIEWER
`
`

`

`
`
`DIVISION OF MEDICATION ERRORS AND TECHNICAL SUPPORT
`OFFICE OF DRUG SAFETY
`
`(DMETS; HFD-420)
`
`CONSULTATION RESPONSE
`
`DATE RECEIVED: July 11, 2003
`
`DUEDATE: October 10, 2003
`
`ODS CONSULT #: 01-0063-1
`
`T0:
`
`_
`
`_
`
`Richard Pazdur, MD.
`Director, Division of Oncology Drug Products
`HFD-ISO
`
`THROUGH: Patricia Garvey
`Project Manager, Division of Oncology Drug Prodhcts
`HFD-150
`'
`
`PRODUCT NAME:
`
`NDA SPONSOR: Eli Lilly and Company
`
`Alimta (Pemetrexed Disodium for Injection)
`500 mg/Vial
`
`NDA#: 21-462
`
`SAFETY EVALUATOR: Charlie Hoppes, R.Ph., MPH.
`
`ll
`
`,
`
`SUMMARY: In response to a consult from the Division of Oncology Drug Products, (HFD-lSO‘, the Division of
`Medication Errors and Technical Support (DMETS) conducted a re-review of the proposed proprietary name
`“Alimta” to determine the potential for confusion with approved proprietary and established names as well as
`ending names.
`.
`
`RECOMMENDATIONS:
`
`. DDMAC finds the proposed name, Alimta, acceptable from a promotional perspective.
`
`l. DMETS has no objection to the use of the proprietary name Alimta. ODS considers this a final review.
`However, if the approval of the NDA is delayed beyond 90 days from the date of this review, the name must
`be re-evaluated. A re-review ofthe name before NDA approval will rule out any objections based upon
`approvals of other proprietary/established names from this date forward.
`. DMETS recommends implementation of the labeling revisions as outlined in Section III ofthis review.
`
`[SI
`
`/3/
`
`Carol Holquist, R.Ph.
`Deputy Director
`DivisiOn of Medication Errors and Technical Support
`Office of Drug Safety
`Phone: (301) 827-3242
`
`
`Fax:
`
`
`(301 443-9664
`
`’
`
`Jerry Phillips, R.Ph.
`Associate Director
`Ofiice of Drug Safety
`Center for Drug Evaluation and Research
`Food and Drug Administration
`
`‘
`1
`
`
`
`
`
`
`
`

`

`Division of Medication Errors and Technical Support (DMETS)
`Office of Drug Safety
`HEB-420; Rm. Parklawn Room 6-34
`
`Center for Drug Evaluation and Research
`
`PROPRIETARY NAME REVIEW
`
`DATE OF Ravrrawr
`
`September 25, 2003
`
`NDA#
`
`21-462
`
`NAME OF DRUG:
`
`Alimta (Pemetrexed Disodium for injection) 500 mg/Vial
`
`’NDA HOLDER:
`
`Eli Lilly and Company
`
`I. INTRODUCTION:
`
`This consult is written in response to a request from the Division of Oncology Drug Products (HF D-.4
`150)
`for _a re-review of the proposed proprietary name Alimta. DMETS previously reviewed Alimta
`in a review dated May 17, 2002, and had no objections to the use ofthe proprietary name (ODS
`consult #021-0063). Container labels, carton and professional package insert labeling were
`reviewed for possible interventions in minimizing medication errors.
`
`PRODUCT INFORMATION
`
`Alimta (Premetrexed Disodium) is a folate antagonist proposed for the treatment of malignant pleural
`mesothelioma in combination with cisplatin. The recommended dose is 500 mg/m2 over 10 minutes
`once every 21 days followed approximately 30 minutes later by a 2 hour infusion of 75