CENTER FOR DRUG EVALUATION AND RESEARCH
`
`APPROVAL PACKAGE FOR:
`
`APPLICATION NUMBER
`
`NDA 21-574
`
`Administrative] Correspondence Reviews
`
`
`
`APPROVAL PACKAGE FOR:
`
`APPLICATION NUMBER
`
`NDA 21-574
`
`Administrative] Correspondence Reviews
`
`
`
`EXCLUSIVITY SUMMARY for NDA # 21—574
`
`SUPPL # N/A
`
`Trade Name: Fortamet Generic-Name: Metformin HCl extended-
`
`release) Tablets
`
`Applicant Name: Andrx
`
`HFD—510
`
`Approval Date: April 27, 2004
`
`PART I:
`
`IS AN EXCLUSIVITY DETERMINATION NEEDED?
`
`1.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/_VL_/
`
`NO /
`
`/
`
`lb)Is it an effectiveness supplement? YES /
`
`/
`
`NO /_VL_/
`
`If yes, what
`
`type (SE1, 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 /_V_/
`
`N0 /
`
`/
`
`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:
`
`Application contains only BE studies.
`
`Page 1
`
`
`
`d)Did the applicant request exclusivity?
`
`is "yes," how many years of
`If the answer to (d)
`exclusivity did the applicant request?
`
`3 years.
`
`YES /_V/ NO /_/
`
`e)Has pediatric exclusivity been granted for this Active
`Moiety?
`
`IF YOU HAVE ANSWERED l'NO" TO ALL OF THE ABOVE QUESTIONS, GO
`DIRECTLY TO THE SIGNATURE BLOCKS ON Page 9.
`
`YES /'_.// NO /_/
`
`2.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).
`
`YES /_/
`
`NO /I//
`
`(NDA 21—202 Glucophage XR from EMS is 500 mg and 750 mg only.
`NDA 21—574 is 500 mg and 1000 mg).
`
`IF THE ANSWER TO QUESTION 2 IS "YES," GO DIRECTLY TO THE
`
`SIGNATURE BLOCKS ON Page 9.
`
`3. IS this drug product or indication a DESI upgrade?
`
`YES /__/
`
`NO /_s/__/
`
`IF THE ANSWER TO QUESTION 3 IS "YES," GO DIRECTLY TO THE
`
`SIGNATURE BLOCKS ON Page 9
`upgrade).
`
`(even if a study was required for the
`
`PART II: FIVE-YEAR EXCLUSIVITY FOR NEW CHEMICAL ENTITIES
`
`(Answer either #1 or #2, as appropriate)
`
`Page 2
`
`
`
`
`_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.
`
`YES /V/
`
`NO /
`
`/
`
`If "yes," identify the approved drug produCt(s) containing the
`active moiety, and, if known,
`the NDA #(s).
`
`NDA 21—202 Glucophage XR from BMS
`
`2. Combination 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 92E 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.)
`
`NO /V7
`YES /___/
`If "yes," identify the approved drug product(s) containing the
`active moiety, and, if known,
`the NDA #(s).
`
`IF THE ANSWER TO QUESTION 1 OR 2 UNDER PART II IS "NO," GO
`
`DIRECTLY TO THE SIGNATURE BLOCKS ON Page 9.
`III.
`
`IF "YES," GO TO PART
`
`Page 3
`
`
`
`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."
`
`1.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.
`
`YES
`
`/o// NO /_/
`
`IF “NO," G0 DIRECTLY TO THE SIGNATURE BLOCKS ON Page 9.
`
`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
`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.
`
`Page 4
`
`
`
`(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 0N 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?
`
`is "yes," do you personally know
`(1)If the answer to 2(b)
`of any reason to disagree with the applicant‘s
`conclusion?
`If not applicable, answer NO.
`
`YES /.// NO /
`
`/
`
`YES /
`
`/
`
`NO /V/
`
`If yes, explain:
`
`is "no," are you aware of published
`If the answer to 2(b)
`(2)
`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?
`YES/
`
`"No/M/
`
`/
`
`If yes, explaini
`
`(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 301
`
`Investigation #2, Study 302
`
`Investigation #3, Study 303
`
`Page 5
`
`
`
`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
`
`YES /
`
`Investigation #2
`
`YES / »
`
`Investigation #3
`
`YES /
`
`/
`
`/
`
`/
`
`NO /s//
`
`No /s//
`
`NO /.//
`
`If you have answered "yes" for one or more
`investigations,
`identify each such investigation and the
`NDA in which each was relied upon:
`
`NDA #
`NDA #
`NDA #
`
`-
`
`-
`
`Study #
`Study #
`Study #
`
`(b)
`
`For each investigation identified as "essential to the
`approval," 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 #1 301
`
`YES /
`
`Investigation #2
`
`302
`
`YES /
`
`Investigation #3
`
`303.
`
`YES /
`
`/
`
`/
`
`/
`
`NO /;//
`
`NO /s//
`
`NO /V7
`
`Page 6
`
`
`
`If you have answered "yes" for one or more
`investigations,
`identify the NDA in which a similar
`investigation was relied on:
`
`NDA #
`
`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 #_1, Study 301 (non—inferiority, efficacy)
`
`Investigation #_2, Study 302 (safety & tolerability)
`
`Investigation #_3, Study 303 (efficacy)
`
`.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.
`
`(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 55,962
`
`YES /V7 !
`
`NO /
`
`/ Explain:
`
`Investigation #2
`
`l
`
`IND 55,962
`
`YES /|// !
`
`NO /
`
`/ Explain:
`
`Page 7
`
`
`
`Investigation #3
`
`IND 55,962
`
`YES /|// 1
`
`l
`
`NO /
`!
`
`/ Explain:
`
`(bl 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?
`
`NO /
`
`/ Explain
`
`NO /
`
`/ Explain
`
`!l I I
`
`..._._.—
`
`Investigation #1
`
`YES /
`
`/ Explain _NA
`
`Investigation #2
`
`YES /
`
`/ Explain _NA
`
`Investigation #3
`
`!
`
`YES /
`
`/ Explain _NA
`
`NO /
`
`/ Explain
`
`(c) Notwithstanding an answer of "yes" to (a) or (b), are
`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 /.//
`
`If yes, explain:
`
`Jena Weber
`DFS
`
`Page 8
`
`
`
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`David Orloff
`
`4/28/04 05:20:48 PM
`
`
`
`
`
`M E M O R A N D U M
`'
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`Public Health Service
`
`Food and Drug Administration
`Center For Drug Evaluation and Research
`
`Page 1 of l
`
`DATE:
`
`'April 28, 2004
`
`FROM:
`
`David G. Orloff, MD.
`Director, Division of Metabolic and Endocrine Drug Products
`
`TO:
`
`'
`
`NDA 21-574
`
`Fortamet (metformin HCl)
`Andrx Labs
`
`SUBJECT:
`
`NDA review issues and recommended action
`
`Background
`This is a brief memorandum at the time of approval of this NDA. It is in follow up to my memo
`of October 17, 2003 addressing the first cycle review of this application for a long-acting form of
`metformin. On the first cycle, the principal deficiency was the failure to provide sufficient data
`to support dosage form equivalence of the 500 mg and 1000 mg tablets. In addition, a number of
`labeling comments were made.
`
`A December 19, 2003, submission constituted a complete response to the first action letter. The
`Biopharmaceutics issues were adequately addressed and OCPB at that time recommended
`approval of the 500 mg dosage strength (to accompany the previously recommendation to
`approve the 1000 mg dosage strength). A second AE letter was issued on February 20, 2004,
`citing incomplete patent certifications related to Glucophage XR.
`
`A February 26, 2004 submission constituted a complete response to the second action letter.
`
`All issues have been addressed. The labeling has been negotiated to final, acceptable form.
`
`Recommendation
`
`This application may be approved.
`
`NDA # 21-574
`
`Drug: Fortamet (metformin HCl), Andrx Labs
`Proposal: treatment of type 2 DM
`04/28/04
`
`
`
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`David Orloff
`4/28/04 05:19:19 PM
`MEDICAL OFFICER
`
`
`
`NDA/EFFICACY SUPPLEMENT ACTION PACKAGE CHECKLIST
`
`Dru-:Fortamet metfonnin HClextended—release Tablets RPM: J.Weber
`
`-
`
`Phone # 76422
`
`
`
`
`1 V 505 - 2
`505 o
`A licationTe:
`Reference ListedDru_
`I,A# Dru-
`
`
`
`40 Application Classifications:
`
` 0
`
`(V ) Standard () nontym
`Review priority
`
`
`
`Chem class (NDAs only)
`
`
`
`
`
`
`April 27, 2004
`(V) None
`Subpart H
`() 21 CFR 314.510 (accelerated
`approval)
`
`() 21 CFR 314.520
`
`(restricted distribution)
`
`() Fast Track
`
`Rollin Review
`
`
`
`
`User Fee waiver
` () Small business
`
`( ) Public health
`() Barrier-to—Innovation
`
`
`0%
`
`
`
`
`( ) Orphan designation
`() No-fee 505(b)(2)
`
`
`Other
`
`
`
`Application Integrity Policy (AIP)
`
`
`
`- Applicant is on the AIP
`()Yes
`(5’) No
`
`
`
`
`
`
`
`
`This application is on the AIP
`0
`() Yes
`(I/ ) No
`
`
`
`
`
`Exception for review (Center Director’s memo)
`0
`
`
`
` April 23, 2004 (e-mail via Liz
`
`
`0C clearance for approval
`Dickinson).
`
`
`
`(V) Verified
`Debarment certification: verified that qualifying language (6.g. willingly, knowingly) was
`not used1n certification and certifications from foreign applicants are 00—signed by U.S.
`
`
`
`
`
`
` (V) Verified
`0
`_In__for_mat_ion: Verify. thatpatent in_formation___was submitted
`_
`0
`Patent certification [505(b)(2) app—lications]: Verify type of certifications
`21 CFR 314.50(i)(l)(i)(A)
`
`submitted
`()I
`()II
`()III
`(V)IV
` 21 CFR 314.50(i)(l)
`
`riiz 01.1
`
`
`(V) Verified
`
`
`
`0 User Fee exception
`
`-
`
`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 of receipt of
`notice).
`
`_
`
`'I‘ Exclusivity Summary (approvals only)
`
`
`
`NDA 2 l -5 74
`
`Page 2
`
`
`
` -' '1‘ Administrative Reviews (Project Manager, ADRA) (indicate date ofeach review)
`
`
`
`() Materials requested in AP letter
`.
`H
`
`() Yes () Not applicable
`
`00
`
`
`
`
`
`: Actions
`
`
`
` (V)AP ()AE ()NA
`
` 0 Proposed action
`
`AE letters issued 10/17/03 and
`
`Previous actions (specify type and date for each action taken)
`-
`2/20/04
`
`
`
`
`
`
`0 Status of advertising (approvals only)
`
`
` 0? Public communications
`
`
`
`
`
`
` ’- Press Office notified of action (approval only)
`(V) None
`
`
`() Press Release
`
`
`
`() Talk Paper
`0
`Indicate what types (if any) of information dissemination are anticipated
`
`
`
`() Dear Health Care Professional
`
`
`
`°2° Labeling (package insert, patient package insert (if applicable), MedGuide (if applicable)
`
`- Division’s proposed labeling (only if generated after latest applicant submission
`
`___.__0f_1‘1.~'fili.r_1&;________.____
`0 Most recent applicant-proposed labeling
`
`
`V
`
`
`April 27, 2004
`
`
`Labeling reviews (including DDMAC, Office of Drug Safety trade name review,
`nomenclature reviews) and minutes of labeling meetings (indicate dates of
`reviews and meetin s
`
`
`See Reviews
`
`
`
`
`Original applicant-proposed labeling
`
`
`
`
`0 v
`
`
`- Division proposed (only if generated afier latest applicant submission)
`0 Applicant proposed
`
`0 Reviews
`
`
`
`Post-marketing commitments
`
`
`
`
`commitments
`Documentation of discussions and/or agreements relating to post-marketing
`
`
` Outgoing correspondence (i.e., letters, E—mails, faxes)
`Memoranda and Telecons
`
`
`
`
`
`
`EOPZ meeting (indicate date)
`
`
`Pre—NDA meeting (indic_a_te date)
`I
`
`
`
`e
`0.0 Advisory Committee Meeting
`
`
`,
`
`0
`0
`
`~Date of Meeting
`48-hour alert
`
`
`
`
`N/A
`
`
`
`'2' Federal Register Notices, DESI documents, NAS, NRC (if any are applicable)
`
`
`
`NDA 2 1 —5 74
`
`Page 3
`
`
`
`~10 Summary Rev1ews (e.g., Ofiice D1rector,D1v1sron Director, Medical Team Leader) 4/27/04
`
`
`
`2/ 12/03; 10/15/03; 2/20/04
`
`
`
`10/ 1 5/03
`
`
`
`Safety Update review(s) (indicate date or location ifincorporated in another review)
`N/A — Deferred
`
`
`Pediatric Page(separate page for each indication addressing status of all age groups)
`
`
`10/29/03
`Statistical review(s) (indicate datefor each review)
`
`
`
`
`
`Biopharmaceutical review(s) (indicate datefor each review)
`3/1/04; 10/7/03
`00
`° Controlled Substance Staff review(s) and recommendation for scheduling (indicate date
`
`
`or each review
`
`Clinical Inspection Review_Summary (D81)
`0
`Clinical studies
`
`'
`
`'2‘ Facilities inspection (provide EER report)
`
`
`
`
`
`
` 6/23/03
`
`
`
`-
`Categorical Exclusion (indicate review date)
`0
`Review & FONSI (indicate date of review)
`
`
`6/23/03
`
`Review & Environmental Impact Statement (indicate date ofeach review)
`0
`NN
`'1' Micro (validation of sterilization & product sterility) review(s) (indicate date for each
`
`
`review
`Date completed:
`
`
`(V Acceptable
`
`Withhold recommendation
`() Completed
`() Requested
`(V) Not yet requested — some have
`been com leted.
`
`'20 Methods validation
`
`
`
`o
`
`0‘. Pharm/tox review(s), including referenced IND reviews (indicate datefor each review)
`6/11/03
`.0 Nonclinical inspection review summary
`
`'
`o
`0.0
`Statistical review(s) of carcinogenicity studies (indicate datefor each review)
`o
`0.9
`CAC/ECAC report
`NA
`
`NA
`
`00
`
`
`
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Jena Weber
`
`4/28/04 09:08:39 AM
`
`
`
`04/27/2004 17:26 FAX
`
`[@001
`
`0K
`
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`
`0349
`912018831893
`
`04/27 17:20
`05'49
`41
`
`TRANSMISSION 0K
`
`TX/RX N0
`RECIPIENT ADDRESS
`DESTINATION ID
`
`ST. TIME
`TIME USE
`PAGES SENT
`RESULT
`
`TELEFAX
`
`T0:
`
`‘
`
`[fl
`
`ATTENTION:
`
`
`
`FROM
`
`Jena M. Weber, Project Manager
`Food & Drug Administration
`Division of Metabolic & Endocrine Drug Products, HFD-510
`5600 Fishers Lane, Rockville, MD 20857-1706
`
`Fax: 301-443-9282
`
`Phone: 301-827-6422
`
`DATE:‘
`
`412 0
`
`'
`
`pAGES: fl
`
`
`
`' #4 Page(s) Withheld
`
`§ 552(b)(4) Trade Secret / Confidential
`
`§ 552(b)(5) Deliberative Process
`
`_‘(_ § 552(b)(5)Draft Labeling
`
`
`
`Division of Metabolic and Endocrine Drug Products
`
`PROJECT MANAGER LABELING REVIEW
`
`Application Numbers: 21-5 74 Fortamet (metformin HCl) Extended-Release Tablets
`500 mg and 1000 mg.
`
`Sponsor: Andrx Labs. Inc.
`
`Material Reviewed: Package insert (PI); patient package insert (PPI); carton and container
`labels.
`
`Submission Date: December 17, 2002
`
`Receipt Date: December 19, 2002
`
`Background and Summary Description: 505(b)(2) application. Indicated as an adjunct to diet
`and exercise in the treatment of patients with Type 2 Diabetes Mellitus. May be used in
`monotherpy or in combination with a sulfonylurea or insulin.
`
`Review:
`
`Container Labels: Acceptable as submitted on February 9, 2004.
`
`500 mg; 60 tablet count, NDC 62022-574-60
`1000 mg; 60 tablet count, NDA 62022—575—60
`
`Blister Sample Container: Acceptable as submitted on February 9, 2004.
`
`500 mg; 7 tablet count, NOT FOR SALE, NDA 62022—574—99
`1000 mg; 7 tablet count, NOT FOR SALE, NDC 62022-575-99
`
`Carton: Acceptable as submitted on February 9, 2004.
`
`,
`500 mg; 60 tablet count; NDC 62022-574—60
`1000 mg; 1000 mg; 60 tablet count, NDA 62022-575—60
`
`-
`
`Package Insert and Patient Package Insert (Patient Information): Acceptable as submitted
`on April 27, 2004.
`'
`
`Conclusions: Issue approval (AP) letter; request FPL.
`
`
`
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Jena Weber
`
`4/29/04 11:04:06 AM
`CSO
`
`
`
`__5__ Page(s) Withheld
`
`____( § 552I(b)(4) Trade Secret / “Confidential
`
`+ § 552(b)(5) Deliberative Process
`
` § 552(b)(5) Draft Labeling
`
`3—1: ~03!
`
`‘
`
`
`
`:3; Page(s) Withheld
`
`_‘/_ § 552(b)(4) Trade Secret / Confidential
`
`§ 552(b)(5) Deliberative Process
`
`.
`
`§ 552(b)(5) Draft Labeling
`
`
`
`_( DEPARTMENTOFHEALTH&HUMANSERVICES
`
`PublicHealthService
`
`Food and Drug Administration
`Rockville, MD 20857
`
`34—04
`
`NDA 21-574
`
`Andrx Laboratories
`
`Attention: Josephine Cucchiaro, Ph.D.
`VP, Clinical Research and Regulatory Affairs
`411 Hackensack Avenue, 3rd Fidor
`Hackensack, NJ 07601
`
`Dear Dr. Cucchiaro:
`
`We acknowledge receipt on February 27, 2004, of your February 26, 2004, resubmission to
`your new drug application for FortametTM (metformin HCl) Extended-Release Tablets,
`500 mg and 1000 mg.
`
`We consider this a complete, class 1 response to our February 20, 2004, action letter. Therefore,
`the user fee goal date is April 27, 2004.
`
`All applications for new active ingredients, new dosage forms, new indications, new routes of
`administration, and new dosing regimens are required to contain an assessment of the safety and
`effectiveness of the product in pediatric patients unless this requirement is waived or deferred.
`We reference the deferral granted on April 9, 2002, for the pediatric study requirement for this
`application.
`
`If you have any questions, please call me at 301-827-6422.
`
`,
`
`Sincerely,
`
`{See appended electronic Signature page}
`
`Jena Weber
`
`Regulatory Project Manager
`Division of Metabolic and Endocrine Drug Products
`Office of Drug Evaluation II
`Center for Drug Evaluation and Research
`
`
`
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Jena Weber
`
`3/2/04 02:33:07 PM
`
`
`
`Galliers, Enid M
`
`From:
`Sent: »
`To:
`Cc:
`Subject:
`
`.
`
`Ms. Sass,
`
`Johnson, Steven B
`Friday, February 13, 2004 2:04 PM
`'Patricia.Sass@Andrx.com'
`Galliers, Enid M
`CPB Section of Label and Dissolution Recommendation
`
`ln'addition, We also included the dissolution
`Attached is the Clinical Pharmacology section of the label for NDA 21—574.
`recommendation.
`If you should have any questions, please feel free to contact me at 301.827.9086 or at
`johnsonst@cder.fda.gov.
`
`1 ' is inappropriate for your product given the pH independent
`The proposed dissolution medium, pH L
`In addition, the tolerance specifications are too loose for the 8 and 16-hour
`dissolution characteristics of FORTAMET‘M.
`time points given the data presented to the Agency in both this and the original submission. The interim dissolution
`method and specifications recommended by the Agency for FORTAMETTM 500-mg and 1000-mg tablets are listed in the
`following table:
`
`Apparatus
`.
`‘ Medium
`I
`Volume
`Temperature
`I
`SpeCificatlon—I 1000 mg
`
`3
`
`j
`
`Speed
`.
`
`.
`
`500 mg
`
`‘
`
`;
`
`L
`
`— —
`
`Regards,
`
`Steven
`
`*‘ki’*****5"*************************k****‘k‘k**********i********************
`
`Steven B. Johnson, Pharm.D.
`Senior Clinical Pharmacology and Biopharmaceutics Reviewer
`Division of Metabolic and Endocrine Drug Products
`5600 Fishers Lane
`HFD-870/RM 13317
`Rockville, MD 20857
`
`53
`N21574 CPB
`aling Comments
`
`
`
`.L Page(s) ’Withheld
`
`_
`
`,
`
`§ 552(b)(4) Trade Secret / Confidential
`
`§ 552(b)(5) Deliberative Process
`
`. / § 552(b)(5) Draft Labeling
`
`
`
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Enid Galliers
`
`2/16/04 04:18:56 PM
`CSO
`
`Entered on behalf of Steven B. Johnson, Pharm.D.
`
`
`
`Page 1 of 1
`
`From:
`
`"Johnson
`
`To:
`cc:
`
`"'Patricia.Sass@Andrx.com'" <Patricia.Sass@Andrx.com>
`"Galliers
`'
`
`Date:
`
`Friday, February 13, 2004 02:03PM
`
`Subject: CPB Section of Label and Dissolut ion Recommendation
`
`M M
`
`s. Sass,
`
`Attached is the Clinical Pharmacology section of the label for NDA 21-574.
`In addition, I've also included the dissolution recommendation.
`If you
`should have any questions, please feel free to contact me at 301.827.9086 or
`at johnsonsthder.fda.gov.
`
`is inappropriate
`J
`The proposed dissolution medium, E
`for your product given the pH independent dissolution characteristics of
`FORTAMETTM.
`In addition,
`the tolerance specifications are too loose for the
`8 and 16—hour
`time points given the data presented to the Agency in both
`this and the original submission. The interim dissolution method and
`specifications recommended by the Agency for FORTAMETTM SOO—mg and lOOO—mg
`tablets are listed in the following table:
`
`<<...OLE_Obj...>>
`
`Regards,
`
`Steven
`
`********~k****~k***********~k~k*~k*~k****~k*****-k*‘k***~k**~k*********~k~k**~k~k*‘k****
`
`SteVen B. Johnson, Pharm.D.
`Senior Clinical Pharmacology and Biopharmaceutics Reviewer
`Division of Metabolic and Endocrine Drug Products
`5600 Fishers Lane
`HFD—870/RM 13B17
`Rockville, MD
`20857
`
`<<N21574 CPB Labeling Comments.doc>>
`
`Attachments:
`
`
`
`
`
`Page 1 of 2
`
`$59
`
`From:
`To:
`
`cc:
`
`_
`"Galliers
`“Patricia.Sass@andrx.com'" <Patricia.Sass@andrx.com>
`
`"Misbin, Robert I" <MISBINR@cder.fda.gov>, "Sahlroot, Jon T"
`<SA‘HLROO‘lT@cder.fda.gov>, "Johnson
`
`Date:
`
`Friday, February 13, 2004 03:02PM
`
`Subject: Changes to fortamet labeling
`
`M
`
`Dear Ms. Sass:
`
`Due to technical problems with different versions of MS Word, I am not sending a clean copy of the labeling
`revisions. However, we include revisions marked in red on pages 10-12 of the labeling you submitted on
`December 19, 2003.. in addition, the text and tables regarding the placebo—controled trial on pages 12 - 15
`should be deleted (further described below). Also, a few additional comments which provide acceptable
`alternatives are enclosed. Finally, the CLINICAL PHARMACOLOGY section should be revised as indicated in
`the email sent earlier this afternoon by Dr. Steven Johnson.
`
`-Changes should be made to Table 4 and accompanying text marked in red.
`
`—In addition, the following statement under Table 4
`
`C.
`
`J
`
`3
`
`should be removed entirely or revised to state:
`
`"Results ofthis study also indicated that neither Fortamet nor immediate release metformin were associated
`with weight gain or increase in body mass index"
`
`—Tables 5 and 6 and accompanying text should be removed.
`
`—Q4 in the PPI should be revised to read:
`
`"Fortamet, as well as otherformulations ofmetformin, lowers the amount ofsugar in your blood...etc... "
`<<fortamet label. TS changes. doc>>
`
`Please submit clean and marked—up versions of the revised package insert and patient package insert as
`soon as possible. We can accept secure email submissions but you will need to make an official submission
`also of either paper or electronic labeling.
`
`Regards,
`
`Enid Galliers
`CPMS, DMEDP
`301 ~827—6429
`
`Enid.galliers@fda.hhs.gov
`
`Attachments:
`
`Luau/HA4..." MAJ... A-A- /____:1 1,, ,.
`
`(‘I/mr
`
`l
`
`\Il-A.A.AAA-.__.A_‘A_A
`
`
`
`sung-J.
`
`'o1‘
`
`,9“
`*0v
`:574'..=
`’or1,
`J,"
`
`{g DEPARTMENTOFHEALTH&HUMANSERVICES
`
`PublicHealthService
`
`Food and Drug Administration
`Rockville, MD 20857
`
`NDA21-574
`
`11/31/03
`
`Andrx Laboratories
`Attention: Josephine Cucchiaro, Ph.D.
`VP, Clinical Research and Regulatory Affairs
`411 Hackensack Avenue, 3rd Floor
`Hackensack, NJ 07601
`
`Dear Dr. Cucchiaro:
`
`We acknowledge receipt on December 22, 2003, of your December 19, 2003, resubmission to
`your new drug application for FortametTM (metformin HCl) Extended-Release Tablets, 500 mg
`and 1000 mg.
`
`We consider this a complete, class 1 response to our October 17, 2003, action letter. Therefore,
`the user fee goal date is February 22, 2004.
`
`All applications for new active ingredients, new dosage forms, new indications, new routes of
`administration, and new dosing regimens are required to contain an assessment of the safety and
`effectiveness of the product in pediatric patients unless this requirement is waived or deferred.
`We reference the deferral granted on April 9, 2002, for the pediatric study requirement for this
`application.
`
`If you have any questions, please call me at 301-827—6422.
`
`Sincerely,
`
`{See crpperzded electronic signature page}
`
`Jena Weber
`
`Regulatory Project Manager
`Division of Metabolic and Endocrine Drug Products
`Office of Drug Evaluation II
`Center for Drug Evaluation and Research
`
`
`
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Jena Weber
`
`12/31/03 08:49:37 AM
`
`
`
`DSI CONSULT: Request for Clinical Inspections
`
`Date:
`
`To:
`
`From:
`
`Subject:
`
`February 12, 2003
`
`Andrea Slavin, HFD—46
`
`Jena Weber, Regulatory Project Manager, HFD-5 10
`
`Request for Clinical Inspections
`NDA 21-574
`
`Andrx Laboratories
`
`Fortamet (metformin HCl extended-release) Tablets, 500 mg & 1000 mg.
`
`Protocol/Site Identification;
`
`
`
`
`
`Subjects
`
`
`
`Dr. Robert Misbin requests that any 2 of the 5 sites identified with study 155—302 be inspected.
`The following protocols/sites essential for approval have been identified for inspection.
`
`
`Number of
`Site (Name and ‘
`Protocol #
`
`
`Address)
`
`As an
`A Double-Blind, Multicenter,
`
`adjunct to
`Randomized, Parallel Group,
`
`
`diet and
`Phase III Study Comparing the
`
`
`
`
`Total of five sites:
`exer01se for Tolerab111ty and Safety of 2000
`
`
`
`mg and 2500 mg of Metformm 002 003 010 014
`the.
`
`
`
`’
`015’
`’
`’
`treatment
`XT Q.D. to the Same Dose of
`
`
`
`‘
`of patients
`Glucophage B.I.D. in Patients
`
`
`with Type , with Non—Insulin Dependent
`
`
`Diabetes Mellitus (NIDDM).
`2 Diabetes
`
`
`Mellitus. 155—302
`
`
`
`
`
`
`
`
`
`
`
`
`Goal Date for Completion:
`
`We request that the inspections be performed and the Inspection Summary Results be provided
`by (inspection summary goal date) August 15, 2003. We intend to issue an action letter on this
`application by (action goal date) October 1, 2003.
`
`
`
`NDA 21—574
`
`Page 2
`Request for Clinical Inspections
`
`Should you require any additional information, please contact Ms. Jena Weber, at 301-827-6422.
`
`Please note that all sections of this application may be accessed through the Electronic Document
`Room (EDR).
`
`Concurrence: . Robert I. Misbin, M.D., Medical Reviewer, HFD-5 10
`David G. Orloff, M.D., Division Director, HFD—S 10
`
`
`
`This'Is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Robert Misbin
`
`2/14/03 02:49:05 PM
`
`
`
`FROM:DMEDP, Jena Weber, HFD-510
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`PUBLIC HEALTH SERVICE
`REQUEST FOR CONSULTATION
`FOOD AND DRUG ADMINISTRATION
`
` To (Division/Office): DDMAC, Attention: Laura Pincock, PharmD/Jeanine Best,
`
`‘ MSN, HFD42
`
` TYPE OF DOCUMENT Pl/PPl
`DATE OF DOCUMENT: 12/19/03
`1/2/04
`IND No. N/A .
`NDA No. 21 -574
`
`
`
`
`PRIORITY CONSIDERATION: NO
`
`
`
`NAME OF DRUG: Fortamet (metformin
`CLASSIFICATION OF DRUG:Oral
`DESIRED COMPLETION DATE: 2/1/04
`HCI) E-R Tablets
`
`Hypoglycemic agent
`
`
`
`
` NAME OF FlRM:Andl'X
`
`REASON FOR REQUEST
`I. GENERAL
`
`
`
`
`
`D NEW PROTOCOL
`El RESPONSE TO DEFICIENCY LETTER
`El PRE—NDA MEETING »
`
`
`
`I] PROGRESS REPORT
`El END OF PHASE II MEETING
`El FINAL PRINTED LABELING
`
`
`El NEW CORRESPONDENCE
`_
`El RESUBMISSION
`X LABELING REVISION
`
`
`El DRUG ADVERTISING
`El SAFETY/EFFICACY
`El ORIGINAL NEW CORRESPONDENCE
`
`
`El ADVERSE REACTION REPORT
`El PAPER NDA
`El FORMULATIVE REVIEW
`
`
`El MANUFACTURING CHANGE/ADDITION
`El CONTROL SUPPLEMENT
`El OTHER (SPEC/FYBELOW):
`D MEETING PLANNED BY
`
`
`
`'II. BIOMETRICS
`
`STATISTICAL EVALUATION BRANCH
`
`STATISTICAL APPLICATION BRANCH
`
`
`
`
`
`
`El TYPE A OR B NDA REVIEW
`Cl END OF PHASE II MEETING
`III CONTROLLED STUDIES
`'
`"OTOCOL REVIEW
`IER SPECIFY BELOW :
`
`
`
`
`El CHEMISTRY REVIEW
`D PHARMACOLOGY-
`I] BIOPHARMACEUTICS
`CI OTHER (SPECIFY BELOW):
`
`
`
`
`
`
`
`Ill. BIOPHARMACE
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