AFFIDAVIT
`
`State of Maryland, Montgomery County
`
`1, Marlene S. Bobka, under oath, hereby depose and state as follows:
`
`1.
`
`I am the president of F.0.I,, Inc. d/bfa FOI Services, Inc. (“F01 Services”),
`
`FOI Services is a privately-held corporation organized and operating under the laws of the State of
`
`Maryland, with its principal place of business at 704 Quince Orchard Road, Suite 275, Gaitheisburg,
`
`Maryland 20878-1770, USA
`
`FOI Services specializes in United States Food & Drug Administration (“FDA”) information and maintains
`a private library of over 150,000 FDA documents obtained under the Freedom of Information Act (“FOIA”)
`
`in all categories of products regulated by FDA, including drugs, biologics, veterinary products, foods and
`
`medical devices. These documents are sold individually; the copies we maintain and sell are faithful
`
`reproductions of the original documents supplied to us by FDA and, except for cover sheets, are not altered
`
`in any way. Many US. courts have accepted our documents as true copies of official FDA documents.
`
`The document attached as Exhibit A, F0] Services’ Document Number 143374 A, titled “[N20622]
`
`Copaxone (Teva Phann): Approval Letter, Review & Evaluation of Clinical Data, Statistical Review,
`
`Pharmacology & Toxicology, Chemistry, FONSI, Environmental Assment, Microbiology” was publicly
`
`available, incorporated into the F01 Services publicly available files, and was provided to a third party at
`
`least as early as April 8, 2005.
`
`FOI Services provided the document attached as Exhibit A to Mylan Pharmaceuticals Inc. on July 17, 2007.
`
`The record attached as Exl1ibitA was kept in the course of our regularly conducted business activity.
`
`Making the record was a regular practice of my job duties and our business activities.
`
`I hereby declare that all statements made herein of my own knowledge are true and correct.
`
`I further declare
`
`that all of my statements are made with the knowledge that willful false statements and the like so made are
`
`punishable by fine or imprisonment, or both, under Section 1001 of Title 18 of the United States Code.
`
`'
`
`r‘_.-
`
`.r._‘--A _
`‘
`r.T'»\
`,.'.-
`-_
`;
`‘ ~ .1
`‘:
`;
`"ll 7 I“ .i~"Li‘5‘i
`--."“-x‘: _
`-.71 ‘-4*‘:
`
`(7
`
` \
`Marlene S, Boblca
`
`December 9 2014
`DEW
`
`SUBSCRIBED AND SWORN before me on December 9, 2014.
`
`Notary Public
`
`MY Commission expires: rd 2’ l Zol 7
`
`AMNEAL
`
`EXHIBIT NO. 1007 Page 1
`
`

`
`EXHIBITA
`
`AMNEAL
`
`EXHIBIT NO. 1007 Page 2
`
`

`
`

`
`
`
` /6 DEPARTM.'EN'l'OFHEALTH5:HIJMANSERVICES PublicHealthService
`
`Food and Drug Adnainistration
`Rocltville MD 20857
`
`N DA 20-622
`
`Tova Pharmaceuticals USA
`Attention: Deborah Jaskot
`
`1510 Delp Drive
`Knlpsville, PA 19443
`
`Dear Ms. Jaskot:
`
`DEG 2 0 lg
`
`-
`
`Please refer to your June 15. 1995 new drug application and your resubmission dated October
`11, 1995 submitted under section 505(1)) of the Federal Food. Drug, and Cosmetic Act for
`Copaxone (glatiramer acetate) injection.
`
`We also refer to an Agency Approvable letter dated October 4, 1996, and we acknowledge
`receipt of your response amendments dated:
`
`October 2, 1996
`
`October 21. 1996
`
`October 31, 1996
`
`November 6, 1996
`
`November 11, 1996
`
`November 27, 1996
`
`This new dnig application provides for the indication of reduction of relapses in patients with
`relapsing—rerI1itting multiple sclerosis.
`
`We have completed the review of this application, as amended, and have concluded that
`adequate information has been presented to demonstrate that the drug product is safe and
`eficctive for use as recommended in the attached version of labeling. Accordingly, the
`application is approved effective on the date of this letter.
`
`Accompanying this letter (ATTACHMENT) is the labeling that should be used for marketing
`this drug product. These revisions are terms of the NDA approval. Marketing the product
`before making the agreed upon revisions in the product’s labeling may render the product
`rnisbranded and an unapproved new drug.
`-
`
`We have the following additional comments:
`
`Chemistry:
`
`We remind you of the following specifications agreed upon in a December 3. 1996 telecon
`between Dr. Paul Leber, Dr. Russell Katz, Dr. Stanley Blum. Dr. Martha Hcimann. and
`Ms. Teresa Wheelous of the Division and Dr. Carol Bcn—Mairnon and Debbie Jaskot of your
`firm:
`
`AMNEAL
`
`EXHIBIT NO. 1007 Page 4
`
`

`
`NDA 20-622
`
`Page 2
`
`RT at peak maximum:
`
`RRT at -2SD:
`
`RRT at «ISD:
`
`RRT at +1SD:
`
`....._.,
`
`.1 __.... ———— —T —,— -
`
`- —-----:7
`
`The approximate molecular weight range of -
`drug product labeling.
`
`is acceptable for use in the
`
`Validation of the regulatory methods has not been completed. At the present time, it is the
`policy of the Center not to withhold approval because the methods are being validated.
`Nevertheless. we expect your continued cooperation to resolve any problems that may be
`identified.
`
`Phase 4 Commitments
`
`We remind you of the Phase 4 commitments specified in the October 4, 1996 approvable
`letter. 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 comrnitments. please submit protocol, data, and final reports to this NDA as
`correspondences. For administrative purposes, all submissions, including labeling
`supplements. relating to these Phase 4 commitments must be clearly designated "Phase 4
`Commitments-"
`
`Should additional information relating to the safety and effectiveness of the drug become
`available. revision . ‘that labeling may be required.
`
`Please submit sixteen copies of the FPL as soon as it is available, in no case more than 30 days
`after it is printed- Please individually mount ten of the copies on heavy weight paper or
`similar material. For administrative purposes this submission should be designated “FINAL
`PRINTED LABELING" for approved NDA 20-622. Approval of this submission by FDA is
`not required before the labeling is used.
`
`Additionally, please submit three copies of the introductory promotional material that you
`propose to use for this product- All proposed materials should be submitted in draft or mock-
`up form, not final print.
`
`AMNEAL
`
`EXHIBIT NO. 1007 Page 5
`
`

`
`NDA 20-622
`
`Page 3
`
`Please submit on: copy to the Division of Neuropharmacological Drug Products 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,
`HI-‘D40
`
`5600 Fishers Linc
`
`Roclcvillc, Maryland 20857
`
`We remind you that you must comply with the requirements for an approved NDA set forth
`under 21 CFR 314.80 and 314.81.
`
`If you have any questions, please contact:
`
`Teresa Wheelous_ R.Ph-
`
`Regulatory Management Officer
`(301) 594-2777
`
`Sincerely yours,
`
`Robert Temple, M-D.
`Director
`
`Office of Drug Evaluation I
`Center for Drug Evaluation and Research
`
`ENCLOSURE
`
`AMNEAL
`
`EXHIBIT NO. 1007 Page 6
`
`

`
`FINAL PRINTED LABELING HAS NOT BEEN SUBMITTED TO THE FDA.
`
`DRAFT LABELING IS NO LONGER BEING SUPPLIED S0 AS TO ENSURE
`
`ONLY CORRECT AND CURRENT INFORMATION IS DISSEMINATED TO THE
`
`PUBLIC .
`
`AMNEAL
`
`EXHIBIT NO. 1007 Page 7
`
`

`
`Memorandum
`
`Department of Health and Human Services
`Public Health Service
`
`
`
`Food and Drug Administration
`Center for Drug Evaluation and Research
`
`
`DATE:
`
`December 18, 1996
`
`FROM:
`
`Paul Labor,
`
`Il.D.
`
`Director,
`Division of Neurophnrmncologlcal Drug Products
`HFD-120
`
`SUBJECT:
`
`NDA 20-622, Cclpaxonafl
`copolyrner-1]
`
`[glntlramnr acetate.
`
`formerly identified no
`
`TO:
`
`File NDA 20-622
`8:
`
`Robert Temple. MD.
`Director, Office of New Drug Evaluation 1
`._—.___._.____—._——.._____.._____.___.__...—._—.__._._____—_._.___—_....._._._.._——...__.._—._.___.___—
`
`This memorandum conveys the Division's recommendation that NDA 20-
`622 for the use of Copaxone0 [glatiramer acetate, formerly identified as
`copolymer-1] in the management of patients with relapsing remitting MS
`be approved.
`
`The sponsor has complied with the conditions of approval enumerated in
`the approvable action letter of October 4, 1996.
`Follow receipt of the
`agency's letter,
`the firm initially sought extensive revisions to the text
`
`labeling proposed in the approvable action letter. However,
`of product
`the
`following discussions between its representatives and Division staff,
`firm agreed that
`to accept, without substantive modification.
`the labeling
`that had been proposed by the agency.
`
`Our Program Management staff have reviewed the latest draft of labeiing,
`and find that, with the exception of a change in official generic namet, it
`conforms in all but a few minor, and in my view ignorable, details to that
`
`The sponsor has seen
`conveyed in the agency's approvable action letter.
`I believe the labeling
`all but our last revision of
`the final draft; again,
`under which Copaxone will be approved for marketing of Copaxone differs
`in only minor details from that the firm last reviewed.
`
`1 necessitated by USAN's ruling that the original generic name,
`
`copolymer—1, was unacceptable.
`
`AMNEAL
`
`EXHIBIT NO. 1007 Page 8
`
`

`
`Leber: Copaxone‘3 approval action memorandum.
`
`paga 2
`
`Accordingly, the other requirements of approval having been satisfied,
`application may be approved.
`
`the
`
`4%
`
`Paul Leber, M.D.
`
`December 18, 1996
`
`AMNEAL
`
`EXHIBIT NO. 1007 Page 9
`
`

`
`REQUEST FOR TRADEMARK REVIEW
`
`TO:
`
`Thru:
`
`From:
`
`Labeling and Nomenclature Committee
`‘ -i I
`Attention: Daniel Boring, C . '
`‘bl:
`ll, (827-2333)
`
`
`Paul Lebcr, M.D., D" =
`Division ofNeuropharmacological Drug Products, HI-‘D-120
`
`
`
`Teresa Wheelous, Regulatory Management Officer (594-5535)
`Division ofNeuropharmacologica1 Drug Products, HI-‘D-120
`
`Date:
`
`December 19, 1995
`
`Subject:
`
`Request for Assessment of a Trademark for a Proposed Drug Product
`
`Proposed Trademark: COPAXONE
`
`NDA#: 20-622
`
`c/ ‘-/-17¢
`’
`_,/
`
`/
`
`Established name, including forrfnfiapolymer-1 for injection (IND
`
`
`
`Other trademarks by the same firm for companion products: None
`
`Indications for Use (may be a summary if proposed statement is lengthy):
`Slowing progression of disability and reducing frequency ofrelapses in patients with relapsing-
`remitting multiple sclerosis.
`
`lnitial comments from the submitter: (concerns, observations, etc.)
`
`None.
`
`cc:
`
`NDA 20-622
`
`HFD-1 20ldivisiOn file
`H"D-120fLeber
`
`HFD-I 20fKat.'zJRouzer-Kamrneyer
`HFD-120/SB1urn/Mfleimman
`
`HFD—l20/Wheelous
`
`m:dos‘.wpfiies‘\nda\nomen.con
`final: Dec 19, 1995
`
`AMNEAL
`
`EXHIBIT NO. 1007 Page 10
`
`

`
`DRUG STUDIES IN FEDIATRIC PRIIENTS
`(To be cmpleted for all N~4.E's reconmended for approval)
`
`MJA t 252- 5,22
`
`Trade (generic) names Coggxggg (2_’4gg4;/g3££-/ )
`
`Check any or the following that apply and explain, as necessary, on the next
`page:
`.
`
`l.
`
`2.
`
`A proposed claim in the draft labeling is directed toward a specific
`pediatric illness. The application contains adequate and well-
`controlled studies in pediatric patients to SLppO1't that claim.
`
`The draft labeling includes pediatric dosing information that is not
`based on adequate and well—control1ed studies in children.
`The
`application contains a request under 21 CFR 210.58 or 3la.l26(c) for
`waiver of the requirement at 2l CFR 2Ul.57(f) for name studies in
`children.
`
`_é._.
`
`a.
`
`The application contains data showing that the-course or the
`disease and the effects of the drug are sufficiently similar
`in adults and children to permit extrapolation of the data
`from adults to children.
`The waiver request should be
`granted and a statement to that effect is included in the
`action letter.
`
`o.
`
`The information included in the application does not
`adequately suport the waiver request.
`The request should
`' not be granted and a statement to that effect is included in
`the action letter.
`(Complete #3 or #4 below as appropriate.)
`
`3. Pediatric studies (e.g., dose—findihg, pharmacoxinetic, adverse
`reaction, adequate and well-controlled for safety and efficacy) should
`be done after approval. The drug product has some potential for use
`in children, but there is no reason to expect early widespread
`pediatric use (because, for example, alternative drugs are available
`or the condition is uncommon in children).
`
`a.
`
`The applicant has committed to doing such studies as will be
`required.
`
`IIH
`
`(1) Studies are ongoing.
`(2) Protocols have been submitted and approved.
`(3) Protocols have,been submitted and are under
`review.
`
`{4}
`
`If no protocol has been submitted, on the next
`page explain the status of discussions.
`
`o.
`
`If the sponsor is not willing to do pediatric studies,
`attach copies of FDR's written request that such studies be
`done and of the sponsor's written response to that request.
`
`5:
`
`4. Pediatric studies do not need to be encouraged because the drug
`product has little potential for use in children.
`
`AMNEAL
`
`EXHIBIT NO. 1007 Page 11
`
`

`
`Page 2 —~ Drug Studies in Pediatric Patients
`
`-as
`
`5.
`
`If none of the above apply, explain.
`
`
`
`Explain, as necessary,
`
`the foregoing items:
`
`
`
`..~;;‘1-M 1'1/<x{c1;écw
`
`lgnature of Preparer
`
`.
`
`'7[5[% /Q27/'1?’/&
`
`Oat
`
`cc: Orig NDA
`rFD—
`/Div File
`
`NUA Action Package
`
`AMNEAL
`
`EXHIBIT NO. 1007 Page 12
`
`

`
`Consult #532 {l-I1"-D-I20)
`
`COPAXONE copolymer-1 for injection
`
`A review revealed no names which sound like or look like the proposed name. However.
`the Committee was uncertain about the USAN name since it does not appear in the cunent
`USAN handbook nor does it seem to comply with the usual USAN nomenclatun:
`convenuons.
`'
`
`The Committee has no reason to find the proposed name unacceptable. but would suggest
`that the sponsor contact USAN regarding the use of the proposed USAN name.
`
`CDER labeling and Nomenclature Committee
`
`\
`
`.Chair
`
`AMNEAL
`
`EXHIBIT NO. 1007 Page 13
`
`

`
`AUG lOl995
`
`Registered Mail
`Return Receipt Requested
`
`NDA 20-622
`
`Teva Pharmaceuticals. USA
`Attention: Stanley Scheindlin, D.Sc.
`1510 Delp Drive
`Kulpsvllle. Pennsylvania 19443
`
`Dear Dr. Scheindlin:
`
`Please refer to your New Drug Application (NDA) submitted under section 505(b) of
`the Federal Food. Drug. and Cosmetic Act for Copaxone® (Copolymer-1) injection.
`
`On the basis of our initial review of your new drug application referred to above.
`received on June 13. 1995. and acknowledged on July 5. 1995, we have determined
`that the application is not acceptable for filing under 21 CFR 314.101(d)(3) In that it is
`incomplete because it does not contain information required under 21 CFR
`314.50(d)(1)(l and Ii). The critical deficiency resides solely in the chemistry.
`manufacturing. and control section. The deficiency is as follows:
`
`The application fails to contain information necessary to evaluate the identity, quality.
`purity. and strength of the new drug substancefdrug product (21 CFR 314.50(d)(1)(i &
`ii). Specifically, you have not submitted information describing the preparation and
`characterization of critical reference standards required for review of your application.
`
`The materials described as Copolymer-1 markers and Copolymer-1 controls are
`critical primary reference standards for molecular weight determination in the methods
`listed below. No information about these materials, other than a brief paragraph (e.g.
`volume 1.3 pg. 038). has been provided.
`
`ii/l_e_thod go.
`
`We are unable to evaluate the validity of these methods in the absence of information
`establishing the identity of the reference materials. Le. the Copolymer-1 markers and
`controls. The following information is required for each reference sample.
`
`a.
`
`A detailed description of the synthesis and purification of the marker.
`
`AMNEAL
`
`EXHIBIT NO. 1007 Page 14
`
`

`
`NDA 20-822
`
`Page 2
`
`b.
`
`Spectroscopic and physical data to establish the chemical structure and
`
`any pertinent conformational properties, e.g.°‘-helical structure of the
`marker. This should include copies of actual spectra (e.g. NMR. lR,
`M3) for each marker.
`
`c.
`
`All analytical data and relevant calculations used to determine the
`molecular weight distribution of the markers.
`
`Although not reasons for this Refuse to File Action, we have completed a preliminary
`review of your application and have identified the following deficiencies:
`
`Chemistry and Manufacturing:
`
`2.
`
`3.
`
`4.
`
`We note that your application contains no evidence supporting your ability to
`scale up production of the drug substance. Should your application become
`approvable you will be limited to batches no larger than the pilot scale
`presently described until validated process scaleup information and detailed
`analytical data from production size batches of drug substance have been
`provided and reviewed.
`
`Please submit a table linking drug substance lot numbers, drug product lot
`numbers, and study description and number for all lots of drug substance I
`product used in both preclinical and clinical studies. Additionally, we request
`full analytical data for all of these lots including copies of the reverse phase
`
`The following applications and DMFS may not be referenced in support of the
`NDA until the IND and DMF holders submit Letters of Authorization (LoA)
`allowing the Agency to access their files on your behalf:
`
`a.
`
`Currently TEVA is authorized by
`__
`IND _
`to access these applications only for the treatment protocol submitted
`under IND
`
`AMNEAL
`
`EXHIBIT NO. 1007 Page 15
`
`

`
`NDA 20-622
`
`b.
`
`c,
`
`Currently TEVA is authorized by Ben Venue to access this
`DMF
`file for the treatment protocol lND
`_
`only.
`
`submitted in the NDA is for Ben Venue. not TEVA.
`DMF
`This LoA is not transferrable.
`
`Page 3
`
`5.
`
`Please submit available analytical data tables for the drug substance and drug
`product lots on a 3.5 inch diskette in a spreadsheet format (Le. Lotus or
`Excel).
`
`6.
`
`In Section 3.2.6 Drug Substance Stability, please provide the following:
`
`a_
`
`b,
`
`c,
`
`Supportive stability data referenced in this section.
`
`for non-stressed
`_
`Representative t-
`samples and for samples exposed to each stress condition.
`
`Moisture content, acetate content, and amino acid analysis at the end of
`the proposed 6 month retest period or any longer period proposed as an
`expiration date.
`-
`
`7,
`
`ln Section 3.3.7.4, for manufacture of the drug product at Ben Venue
`Laboratories. a Master Formula should be provided and the Formuta Card
`should indicate amounts of drug substance, exciplents, and batch scale.
`
`Pharmacology:
`
`We request that you submit any data you might have addressing the issue of whether
`or not the antibodies produced as the result of administration of Copotymer—’i are
`neutralizing antibodies with respect to drug activity.
`
`Within 30 days of the date of this letter, you may request in writing an informal
`conference about our refusal to file this application. To file this application over
`FD/—'\'s protest, you must avail yourself of this informal conference. We encourage you
`to avail yourself of a meeting with the Agency to discuss your resubrnission. If you have
`any questions please call:
`
`Teresa Wheelous. R.Ph.
`Regulatory Management Officer
`(301) 594-2777
`
`If after the informal conference, you still do not agree with our conclusions, you may
`make a written request to file this application over protest, as authorized by 21 CFR
`
`AMNEAL
`
`EXHIBIT NO. 1007 Page 16
`
`

`
`NDA 20-622
`
`Page 4
`
`3‘l4.101(a)(3). The filing date will be 60 days after the date you requested «mg:
`informal conference.
`
`Under the Prescription Drug User Fee Act of 1992, FDA will refund one-half of the fee
`submitted with this application (25% of the total fee due).
`if you decide to tile this
`application over protest. the filing of this application over protest will be regarded by
`the Agency as a new original application for user fee purposes, and you will be
`assessed a user fee applicable to new submission.
`
`
`
`Paul Leber, MD.
`Director
`
`Division of Neuropharmasological
`Drug Products
`Office of Drug Evaluation l
`Center for Drug Evaluation and Research
`
`AMNEAL
`
`EXHIBIT NO. 1007 Page 17
`
`

`
`_€'.g
`
`NDA 20-522
`
`031- 23 195
`
`Teva Pharmaceuticals USA
`
`Attention: Dr. Stanley Scholndlln
`1510 Delp Drive
`Kulpsvllle, PA 19443
`
`Dear Dr. Scheindlin:
`
`We have received your new drug application resubmitted under section 505(b) of the Federal
`Food, Drug, and Cosmetic Act for the following:
`
`Name oi Drug Product
`
`Copaxone® (Copolymor-1 for Injection)
`
`Therapeutic Classification:
`
`Standard
`
`Date of resubmitted Application:
`
`October 10. ‘I995
`
`Date of Receipt:
`
`October 11, 1995
`
`Our Reference Number:
`
`NDA 20-622
`
`Unless we notify you within 50 days of our receipt date that the application is not sufficiently
`complete to permit a subgstantlve review. this application will be flied under section 505(b) of the
`Act on (60 days from receipt) in accordance with 21 CFR 314.‘lO‘t(a).
`
`Should you have any questions, please contact:
`
`Teresa Wheeloua
`
`Regulatory Management Officer
`Telephone: (301) 594-27T!
`
`Please cite the NDA number listed above at the top of the first page of any communications
`concerning this application.
`
` Paul Laber, M.D.
`
`Director
`
`Division of Neuropharmacologicel
`Drug Products
`Offico 01 Drug Evaluation l
`Center for Drug Evaluation and
`Research
`
`AMNEAL
`
`EXHIBIT NO. 1007 Page 18
`
`

`
`NDA 20-622
`
`TEVA Pharmaceuticals USA
`
`Attention: Stanley Schelndlin. Ph.D.
`1510 Delp Drive
`Kulpsville, PA 19443
`
`Please refer to your pending October 10,1995 new drug application resubmitted under section
`505 (b) of the Federal Food, Drug, and Cosmetic Act for Copaxone (oopolymer-1) injection.
`
`We also refer to your amendments dated January 10, 1996 and March 29, 1996.
`
`We have completed our review of the microbiology and chemistry sections of your submission
`and have identified the following deficiencies:
`
`Microbiology:
`
`A.
`
`Provide the following information about the drug product manufactured at Term
`Pharmaceutical Industries:
`
`1.
`
`2.
`
`The bulk drug product prior to filtration is a peptide solution and does not
`contain a. preservative.
`:1) Indicate whether the bulk solution supports microbial growth.
`b) Submit information regarding the total hioburden load and volume of a batch
`of unfiltered built drug solution.
`c) Indicate the kinds of microorganisms that can be recovered from the bulk
`solution.
`
`d) Indicated the rationale for the
`bulk solution. We note that specification of
`substance.
`
`limit number in the unfiltered
`
`_ for the bulk drug
`
`e) Indicate the alert and action limits for the bulk solution at the Tova facility.
`
`The sterilizing filters should ideally be validated with product inoculated with
`the challenge microorganism. Recirculation of drug product solution followed
`by a microbial filter challenge does not demonstrate the capabilities of the filter
`to sterilize the drug product solution. Please submit evidence that indicated that
`the sterilizing filters are capable of sterilizing the bulk solution. Indicted the
`actual CFU of P. diiiiinnta used and recovered for assessing the microbial
`retentivity of the sterilizing filters.
`
`3.
`
`Filtration conditions are not specified in the submission. Describe conditions
`including bulk solution volume and filtration time, temperature, pressure, and
`
`AMNEAL
`
`EXHIBIT N0. 1007 Page 19
`
`

`
`NDA 20-522
`
`Indicated whether one or two
`the set-up used during the filtration process.
`sterilizing filters are used to filter the bulk solution. In the event of a filter
`failure, what actions would be taken?
`
`Indicated storage temperature and conditions during the holding periods for the
`bulk product. Describe the sterilization validation of the holding tank: and vent
`filters.
`
`i
`_ _
`A description of the
`the application. Please describe the
`includ
`
`_
`
`was omitted from
`
`Describe the autoclave loading patterns, the placement of the thermocouples and
`biological indicators during the sterilization validation of the closures,
`equipment, containers and components.
`Identify the
`source. the
`stability of the biological indicators used. Corroborate the microbial counts and
`resistance and provide performance characteristics.
`
`Include a description of the bacterial endotoxin tests used for the product.
`description should include qualification of the laboratory. inhibition and
`enhancement testing and results, determinations of
`concentration
`and maximum valid dilution.
`
`The
`
`Submit information on the sterilization validation of the freeze-drier.
`
`8.
`
`Provide additional information regarding the manufacturing process at the Ben
`Venue Laboratoria facility in Bedford, Ohio.
`
`I.
`
`The validation of the sterilizing filters as conducted at the Teva manufacmring
`facility is inadequate. The sterilizing filters should ideally be validated with
`product inoculated with the challenge microorganism. Recirculation of drug
`product solution followed by a microbial filter challenge does not demonstrate
`the capabilities of. the filter to sterilize the drug product solution. Please
`submit evidence that indicates that the sterilizing filters are capable of
`the bulk solution or that organisms cannot be tested by direct inoculation into
`the product.
`Indicate the actual CFU of P. diminuta used and recovered for
`assessing the microbial retentivity of the sterilizing filters.
`
`Submit information on the sterilization of the freezedricr.
`
`Provide data on the sterilization of the sterilizing and vent filters.
`
`AMNEAL
`
`EXHIBIT NO. 1007 Page 20
`
`

`
`NDA 20-622
`
`3
`
`4.
`
`5.
`
`Specify what are actions #A.N-S—3087—l (p.039 237,241). #AN—S-086 (p. 039
`240), and #AN-S-3-077 (p. 139 250, 252.253).
`Include a description of the bactzrial endotoxin tests used for the product. The
`description should include qualification of the laboratory, inhibition and
`enhancement testing and results. dctcrminations of noninhibitory concentration
`and maximum valid dilution.
`
`Chemistry:
`
`1.
`
`Please provide additional information about thc synthesis of copolymor-1 dmg
`substance:
`
`AMNEAL
`
`EXHIBIT NO. 1007 Page 21
`
`

`
`

`
`NDA 20-622
`
`1 0
`
`f.
`
`Shelf-life instructions in patient insert (Vol. 3.14, p. 29)
`
`The shelf-life of COPAXONE' as packaged for sale is 18 momhs when
`stored in a freezer (-20°C to 40°C). This product contains no preservatives
`andshouldbeused innnedhlelyaflerrcconsfimfionordiscnrded. Protect
`COPAXONE' from light.
`
`We would appreciate your pmmpi wrinen response so we can continue our evaluation of your
`NDA.
`'
`
`If you have any questions, please contact:
`
`Teresa Wbcelous. R.Ph.
`
`Regulatory Management Officcr
`(301) 594-2777
`
`Sincere!
`
`Paul Lcbcr. MD.
`Director
`
`Division of Naubphzrmacological Drug Products
`Office of Drug Evaluation I
`Center for Drug Evaluation and Research
`
`AMNEAL
`
`EXHIBIT NO. 1007 Page 23
`
`

`
`u'l
`
`REVIEW AND EVALUATION OF
`
`CLINICAL DATA:
`
`SAFETY
`
`Application Information
`
`NDA # 20-622
`
`Sponsor: Teva Pharmaceuticals
`
`Clock Date
`
`January 30, 1996
`
`Drug Name
`
`Generic Name: Copolymer 1
`
`Proposed Trade Name: Copaxooe
`
`Drug Characterization
`
`Pharmacological Category;
`
`Immunomodulator
`
`Proposed Indication: Treatment of Multiple Sclerosis
`
`NDA Classification:
`
`Dosage Forms, Strengths, and Routes of Administration;
`Subcutaneous-injection, 20 milligram strengths.
`
`Reviewer Information
`
`Safety Reviewer: John Dikran Balian, M.D.
`
`Review Completion Date: 3/14/96
`
`Revised: 7/8/96
`
`AMNEAL
`
`EXHIBIT N0. 1007 Page 24
`
`

`
`TABLE OF CONTENTS
`
`1. Introduction .
`
`.
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`2. Sources for the Review .
`
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`n
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`o
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`3. Methods of Review
`.
`-
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`a. Quality of Submission .
`.
`a.1 Completeness of Submisnion
`b. Quality of Coding .
`.
`.
`.
`c. Review of Study Design Adherenoe
`d. Review of Specific Definitions
`e. Findings From the Audit
`.
`.
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`a
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`-
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`a
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`u
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`v
`u
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`n
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`n
`c
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`n
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`o
`0
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`n
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`4. Quality of Adverse Events Surveillance in the Development
`n
`u
`-
`o
`o
`I
`1
`Program _
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`5. Study Population and Demographics
`-
`u
`a. Extent of Exposure
`.
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`-
`b. Extent of Exposure by Dos
`c. Extent of Exposure by Disease Typ
`d. Demographics
`.
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`n
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`6. Review of Deaths .
`
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`7. Review of Serious Events .
`
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`8. Review of Dropouts -
`a. Overall Pattern of Dropouts
`b. Dropout Secondary to Adverse Events .
`r
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`-
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`Q
`g
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`c
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`o
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`o
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`9. other Safety Findings .
`a.
`ADR Incidence Table And AE
`Lists -
`.
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`b. Dose Response For Common Adverse Events
`:
`c.
`Common and Drug Related Adverse Events .
`.
`d. Adverse Event Incidence Over Phase 2-3 Inteéra
`Primary Database
`.
`.
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`3
`
`xlailfllnnbvhvsbohI'-''
`'~.OlDKD(I)O'JQ
`
`10
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`11
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`12
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`15
`15
`15
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`19
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`20
`20
`20
`21
`22
`22
`22
`22
`23
`24
`24
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`z~.éd'
`o
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`10. Review of Systems .
`.1
`Neurology .
`.2
`Opthalmology
`.3
`Psychiatry .
`.4
`Pulmonary .
`.
`.4
`Cardiovascular
`.5
`.
`Renal
`.
`.
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`.6
`Gastrointestinal
`.7
`Musculoskeletal
`.8
`.9
`.1
`.1
`
`(JJDJDJSDDJQJQJS-Ill-|9Ji1JflJ
`
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`-
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`-
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`Hematologic ..
`.
`Body as a Whole .
`0 Endocrine/Metabolic
`1 Immunology
`
`Copolymcr I Clinical Review
`
`1007 Page 25
`
`

`
`3.12
`
`.
`.
`.
`a.11.1 Systemic Reaction .
`I
`I
`:
`n
`-
`I
`0
`I
`I
`I
`-
`I
`I
`O
`a.12.1 Injection Site Reaction .
`
`11. Laboratory Findings, ECG and vital Signs
`a. Laboratory Findings .
`.
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`a.1 Serum Chemistry .
`.
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`a.2 Hematology
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`a.3 Urine Analysis
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`b. ECG Findings
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`c. Vital Signs .
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`12. Effect of Age and Gender on Adverse Event Incidence .
`
`13.
`
`Important Events Considered Not Drug Related
`
`14. Human Reproductive Data .
`
`IS. Overdose Experience .
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`16. withdrawal Phenomenon/Abuse Potential
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`17. Summary of Drug Interactions
`a. Drug-Demographic Interactions .
`b. Drug-Disease Interactions .
`.
`-
`c. Drug-Drug Interactions
`.
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`I3. Labeling Review .
`
`.
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`19. Conclusions .
`
`.
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`.'.
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`20- Recommendations .
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`APPENDICES...-....................
`
`5.b.1 Number of Patients with RR—MS Exposed to 20 mg
`Cop—1 Daily - Duration of Exposure (Trials 01~
`9001/9001.2, BR~1, 01-9002, 1110-1, 1110-2, BR—3)
`S.b.2 Duration of Exposure: 30 mg Cop-1 Daily CP-MS,
`Controlled Study ER-2 .
`.
`.
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`.
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`S.d.1 Demographics: All Studies in RR-MS Patients
`(9001/90013, BR-]., 9002, 1110-1, 1110-2 and BR-3)
`5-d.2 Demographics: Controlled Studies in RR-MS
`.
`.
`.
`.
`Patients (9001/90013 and BR-1)
`.
`.
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`S.d.3 Demographics: Controlled Study in CP—MS Patients
`(BR—2).........-........
`.
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`6.1 Summary of Patient Deaths
`7.b.1 Adverse Experiences for which any Patient
`Discontinued Therapy
`.
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`7.b.2 Adverse Experiences For which Any Patient
`.
`.
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`Discontinued Therapy, Study BR—2
`.
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`9.a_1 Incidence of Adverse Clinical Experiences (2 1%)
`Controlled Study 9001/90012 .
`.
`.
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`
`33
`33
`33
`33
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`34
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`34
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`34
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`36
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`36
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`37
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`38
`
`39
`
`39
`40
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`41
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`42
`
`43
`
`Copr'
`
`‘~.rICIin‘
`
`Review
`
`.AbflNEAflg
`
`EXHHHTNO.Hm7
`
`Page26
`
`

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`49
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`53
`56
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`60
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`61
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`62
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`63
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`66
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`69
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`9.3.2 Incidence of Adverse Clinical Experiences (2 2%)
`Controlled Study BR-1 .
`.
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`9.a.3 Incidence of Adverse Clinical Experiences (22%)
`Controlled Study BR-2
`.
`.
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`9.d.1 other Adverse Events Observed During the
`.
`.
`Premarketing Evaluation of Copolymer-1
`.
`.
`.
`.
`10.b.1 Cases of Systemic Reactions .
`.
`.
`.
`.
`11.a.1.1 Incidence of Clinically significant Blood
`Chemistry Abnormalities(9001/90013 BR—1 and BR-2}
`11.a.2.1 Incidence of Clinically Significant Hematology
`Abnormalities .
`.
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`11.c.1 Incidence of Clinically Significant Vital Sign '
`Abnormalities .
`.
`13.1 Serious Adverse Exneriences éonsidered Unlikely to‘
`be Related to Study Drug
`.
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`13.2 Hospitalizations Considered Unlikely to be Related
`to Study Drug .
`.
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`13.1 Serious Adverse Experiences Considered.Possib1y
`Related to Study Drug .
`.
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`Cop-olymcr I Clnmcal Rcvacw
`
`AMNEAL
`
`EXHIBIT NO. 1007 Page 27
`
`

`
`1. Introduction
`
`is a chronic inflammatory disease
`Multiple Sclerosis (MS)
`affecting the central nervous system (CNS). Myelin basic protein
`(MBP),
`the protective sheath that surrounds the axons of the CNS
`is the target for demyelination in MS. The animal model for MS,
`experimental allergic encephalomyelitis (EAE)
`is an autoimmune
`neurological disease induced by injections of MBP. The
`imunological processes in EAE are similar to those seen in human
`MS patients.
`
`is a synthetic copolymer of 4 amino acids {L-
`Copolymer—1 (Cop—1)
`alanine, L—lysine, L-glutamic acid and L-tyrosine) in specific
`ratios but random order. These same 4 amino acids form the basic
`composition of the MBP. Cop—1 has been shown to be effective
`agains