AFFIDAVIT
`
`State of Maryland. Montgomery County
`
`I, Marlene 5. Bobka, under oath, hereby depose and state as tollows.
`
`1.
`
`I am the president ofF.O,l._ Inc. dlbla Fol Services, Inc. (‘FOI services‘).
`
`2.
`
`3.
`
`FOI Services is a privetely—he|d corporation organized and operating under the laws of the State of Marytand, with
`its principal place of business at 704 Quince Orchard Road, Suite 275, Garthetsburg, Maryland 20878-1770,
`U.8.A
`
`Fol Services specializes in United States Food 8. Drug Administration (“FDA”) infonnation and maintains a private
`library ofover 150.000 FDA documents obtained under the Freedom of Information Act ('FO1A") in all categories of
`products regulated by FDA. including drugs, biologics veterinary products, foods and medical devices. These
`documents are sold individuallyr. the copies we maintain and sell are faithful reproductions ofthe original
`documents supplied to us by FDA and, except for cover sheets, are not altered in any way. Many U.S. courts have
`accepted our documents as true copies of ofiicial FDA documents.
`
`4. The document attached, FOI Document Number 146008. titted "Peripheral and Central Nervous System Drug
`Advisory Committee Meeting 9/19/1996' was in the possession of FOI Services, and therefore publicly available
`from FDA. and was provided by FOI Services to a third party at least as any as December ‘I4, 2001.
`
`5. The record was kept in the course of our regularly conducted business activity.
`
`6. Making the record was a regular practice of our business activities.
`
`-
`
`THE FOREGOING IS TRUE
`
`v,,{,g.__%
`Marlene S. Bobka
`
`x
`
`:l'_-(ux.
`Date
`
`(9
`
`2,C>i 5/
`
`SUBSCRIBED AND SWO
`
`before me this
`
`fig ,day oflMonth], [Yearl
`
`
`Notary Public
`My/commission expires: 7/2-I {Qb/
`
`AMNEAL
`
`EXHJBIT NO. 1019 Page 1
`
`

`
`EXHIBIT A
`
`Agenda
`
`PERIPHERAL AND CENTRAL NERVOUS SYSTEM DRUGS
`ADVISORY COMITTEE
`
`Meeting #44
`
`Food and Drug Administration
`center for Drug Evaluation and_Research
`Gaithersburg, Maryland
`
`OPEN SESSION
`
`Thursday, September 19, 1996
`Gaithersburg Holiday Inn
`8:30 a.m.
`to Conclusion
`
`I.
`
`8:30 a.m.
`
`Call to Order: Welcome and Information
`
`Sid Gilman, M.D.
`Chairperson
`
`'
`
`Conflict of Interest Statement
`'
`Ermona Mccoodwin
`
`Executive Secretary
`
`II.
`
`To Follow:
`
`Open session
`
`NDA 20-622
`
`COPAXONEO (Copolymer-1 for Injection): Safety
`and Effectiveness in use for Relapsing-Remitting
`Multiple Sclerosis
`
`Ila. FDA Introductory Remarks:
`
`IIb. Sponsor Presentations
`TEVA Pharmaceuticals, USA
`
`Introduction:
`
`Multiple Sclerosis:
`
`Paul Leber, H.D.
`Division Director, DNDP
`
`Russell Katz, H.D.
`Deputy Division Director, DNDP
`1
`
`Carole S. Ben—Haimon, H.D.
`senior Vice President
`TEVA Pharmaceuticals, USA
`
`Kenneth P. Johnson,
`Professor and chair
`
`M.D.
`
`Department of Neurology
`University of Maryland
`School of Medicine
`
`Safety and Efficacy:
`
`Carole S. Ben-Hainon, H.D.
`
`_NMNEAL
`
`EXHIBIT NO. 1019 Page 2
`
`

`
`Page 2
`PCNS Drugs Advisory Committee Meeting
`September 19, 1996
`
`_
`
`_
`
`IIb. Sponsor Presentations:
`
`(continued)
`
`Medical Perspective:
`
`Jerry_wdlinsky, M.D.
`Professor of Neurology, Director
`Multiple Sclerosis Research Group
`University of Texas
`Health Sciences Center
`
`IIC. FDA Response:
`
`FDA Staff
`
`III. Committee Discussion
`
`IV.
`
`OPEN PUBLIC HEARING
`
`v .
`
`committee Recommend at ion ( 5)
`
`VI. Closing Remarks-Information and Followup
`
`NOTE:
`
`There will be a BREAK and/or LUNCH BREAK at the discretion of the Chair.
`
`AMNEAL
`
`EXHIBIT NO. 1019 Page 3
`
`

`
`Meeting #44
`September 19, 1996
`COPAXONE® ___
`
`AMNEAL
`
`EXHIBIT NO 1019 Page 4
`
`

`
`
`
`VSVJ.VSVJ.
`
`
`
`AMNEALAMNEAL
`
`
`
`EXHIBIT N0: 1019 Page 5EXHIBIT N0: 1019 Page 5
`
`

`
`;*
`
`_'.‘
`
`'
`
`:
`
`Dfle
`
`Fwm
`
`DEPARTMENT OF HEALTH 8!. HUMAN SERVICES
`
`'
`
`September 3, 1996
`
`Ermona HcGoodwin
`
`Executive Secretary (HFD—21)
`
`Pubhc Heanh Senfice
`
`Food and Drug Admfnmratiun
`
`Memorandum
`
`Subieor
`
`comarrras mumuc-.:
`
`COPAXONEG (Copolymer-1, TEVA
`Pharmaceuticals USA)
`NDA 20-622
`
`‘W
`
`Peripheral & Central Nervous System Drugs Advisory Committee
`Members
`
`The enclosed information is provided for your review for the
`September 19 meeting of the PCNS Advisory Committee.
`The
`meeting will be held at the Gaithersburg Holiday Inn (see
`attached directions).
`
`TAB A:
`
`TAB B:
`TAB C:
`
`TAB D:
`TAB E:
`TAB F:
`
`Cover Memo and Directions.
`
`Draft Agenda and Questions, Committee Roster.
`FDA overview of NBA 20-622, Copolymer-1 Injection
`for Patients with Exacerbating-Remitting Multiple
`Sclerosis - Russ Katz, M.D.
`Efficacy Review - Janeth Rouzer—Kammeyer, H.D.
`Safety Review - John Balian, M.D.
`Statistical Review - David Hoberman, Ph.D.
`
`I look forward to seeing you on Thursday, September 19.
`you have any questions please call me.
`
`If
`
`
`
`Ermona HcGo dw n
`
`Executive Secretary
`
`Phone: 301-443-5455
`FAX:
`301-443-0699
`
`e-mail: mcgoodwin0cder.fda.gov
`
`AMNEAL
`
`EXHIBIT NO. 1019 Page 6
`
`

`
`)irections to:
`
`Gaithersburg Holiday Inn
`2 Montgomery Village Avenue
`Gaithersburg, MD 20879
`
`Phone: 301-948-8900
`
`FAX:
`
`301-258-1940
`
`From D.C./Maryland/Virginia
`
`Take Interstate 270 North to Exit 11 — Montgomery Village Exit.
`Go short distance to intersection of Route 355 (Frederick Ave),
`Holiday Inn is cater-corner on the left.
`
`AMNEAL
`
`EXHIBIT NO. 1019 Page 7
`
`

`
`8HVJ.
`
`AMNEAL
`
`EXHIBIT NO. 1019 Page 8
`
`

`
`D"’4Fr
`
`04>
`
`PERIPHERAL AND CbNTRAL NERVOUS SYSTEM DRUGS ADVISORY CUHMITTLH
`Mvut inn) [dd
`
`Food and Drug Administration
`center tor Drug Evaluation and Research
`Ca 1 Lhurfilmr L;
`, Ha! y1.md
`
`OPEN
`
`SHHHKON
`
`Thursday, September 19,
`uaitharehurq Holiday Inn
`H:;u n.m.
`to conriuslon
`
`I996
`
`flzlfi a.n.
`
`Fall
`
`to Ordez: welrome and Inlormatlnn
`Sid Gilmnn, M.D.
`C‘h.A i 1 pm sun
`
`Conflirr of
`
`Interns? Statement
`Ermrma Hmimndu l n
`Executive Secretary
`
`To Follow:
`
`npan fiesaxon
`
`NBA 2U~62."
`
`COPAXONEU (Cupu1ymer~1 Lur Injection)’ Safety
`and ttreutlvanuss in use for Relapsinq—Remittinq
`Hu]t1p)u Sclerosis
`
`[I1‘-
`
`Ilb.
`
`FDA in! rodurrrxry Remarks:
`
`Tn he Annoumzc-d
`
`Sponuur Prenuntntiunn: TLVA Phdzm4CeuLicall, US)
`
`Introduction:
`
`Multiple Suluxuflin:
`
`Carola 5. Ban—Haimun, H.D.
`senior Vice President
`TEVA Ph¢rndc0ulluais, USA
`
`kennath P. Johnson, H.D.
`Professor and Chair
`Ueparnment or Neurology
`Unlvazslty of Harylan
`schuol of Hediuine
`
`Satuty and Efficacy:
`
`Carola 5. Ben-Holman, H.D.
`
`Medical Puzupautlv_:
`
`fl.0.
`Jerry Hulinuky,
`Prutansor of Neurology, Director
`Huintple Sclerosis Research Gxoup
`University of Texas
`Health Sciences Cuntar
`
`AMNEAL
`
`EXHIBIT NO. 1019 Page 9
`
`‘J
`
`1J
`
`[I
`
`
`
`'|!"’I"mu
`
`

`
`‘ Page 1.
`
`llc.
`
`FDA Response:
`
`11!. Committee Diacuaaiun
`
`IV.
`
`UPEN PUBLIC HEARING
`
`To Me Announced
`
`V.
`
`Commlktue ReunmmandaLlun(s)
`
`VI.
`
`cloaxnq Rumarka~lrformation and Followup
`
`There will be a BREAK and/or LUNCH ukhnk at
`
`the discretion of the Chair.
`
`
`
`ml..Ia
`
`LII
`
`gn
`
`1.,
`
`AMNEAL
`
`EXHIBIT NO. 1019 Page 10
`
`

`
`FOOD AND DRUG ADMINISTRATION
`
`QUESTION LIST
`
`PCNS ADVISORY COMMITTEE MEETING
`
`SEPTEMBER 19, I996
`
`COPAXONE@ (COPOLYMER-I); NDA 20-622, Evaluation of Safety and Efficacy in use.
`
`The Division of Neuropharmacological Drug Products has reviewed the New Drug
`Application (NDA) submitted by Teva Pharmaceuticals USA for COPAXONEP and before
`forwarding a recommendation to the Office of Drug Evaluation I, the Division seeks the
`Committee's advice on the following questions:
`
`. Teva Pharmaceuticals has provided results of two controlled clinical
`I
`investigations of Copolymer-I '5 effectiveness in Exacerbaling Remitting Multiple
`Sclerosis. Are these studies adequate and well controlled clinical investigations and
`does each provide evidence that would allow an expert, knowledgeable and
`experienced in the management of patients with MS, to conclude that Copolymer-1
`is an effective treatment for MS?
`
`2. Has the sponsor provided evidence that Copolymer-I is safe when used in the
`treatment of MS?
`
`AMNEAL
`
`EXHIBIT NO. 1019 Page 11
`
`

`
`PERIPHERAL AND CENTRAL NERVOUS SYSTEM DRUGS ADVlSOR¥ COMMITTEE
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`CHAIRPERSON
`
`Gilman, Sid, M.D.
`Professor and Chair
`
`Department of Neurology
`University of Michigan Medical Center
`1500 E. Michigan Center Drive
`Ann Arbor, Michigan 48109
`
`EXECUTIVE SECRETARY
`
`1/31/00
`
`McGoodwin, Errnona
`
`Advisors and_Corisu|tants Staff
`Center for Drug Evaluation and Research
`Food and Drug Administration (HFD-120)
`5600 Fishers-Lane
`
`Rockville, Maryland 20857
`301/443-4695 FAX 301/443-0699
`
`Email‘ mcgoodwin@cder.fda.gov
`
`MEMBERS
`
`Copple, Peggy J.. M D_
`Professor of Pediatrics and Neurology
`Department of Pediatrics
`University of Arizona Health Sciences Center
`1501 N. Campbell Avenue
`Tucson, Arizona 85724
`
`1/31/97
`
`Snead, Orlando Carter III, M.D_
`Head, Division of Neurology
`The Hospital for Sick Children, Room 6544
`Gerrard Wing, 6th Floor
`555 University Avenue
`Toronto, Ontario, Canada M5G1X8
`
`1/31/97
`
`Coyle, Patricia K., M.D.
`Professor of Neurology
`Department of Neurology
`Health Sciences Center
`
`1/31/98
`
`State University of New York at Stony Brook
`Stony Brook. New York l|790
`
`1/31/98
`’
`'
`
`Gennings, Chris, Ph.D.
`Assistant Professor
`Department of Biostatistics
`Medical College of Virginia
`Virginia Commonwealth University
`Box 32, MCV Station
`Richmond, Virginia 23298-0032
`
`Phillips, Ellyn C., B.A., M.S
`President, Amyotropio Lateral Sclerosis
`Association (ALS), Philadelphia Chapter
`980 Harvest Drive, Suite 105
`Blue Bell, Pennsylvania 19422-1961
`
`1/31/99
`
`AUGUST 1996
`
`Zivin, Justin A , M D_, Ph D
`Professor of Neu rosciences
`
`3/31/99
`
`Department of Neurosciences 0624
`University of California, San Diego
`9500 Gilman Drive
`La Jolla, Califomia 92093-0624
`
`Adams, Harold P. Jr., M.D.
`Professor, Department of Neurology
`The University of Iowa
`200 Hawkins Drive #2007 RCP
`
`Iowa City, Iowa 52242-1053
`
`'1l31/00
`
`Drachman, David A., M.D.
`Professor and Chair
`
`1/31/00
`
`Department of Neurology
`University of Massachusetts Medical School
`Room S5-753
`55 Lake Avenue, N.
`Worcester'.'Ni'assachusetts 01655
`
`1/31/00
`
`Kawas. Claudia H., M.D.
`Associate Professor of Neurology
`Department of Geriatric Neurology
`Johns Hopkins University School of Medicine
`5501 Hopkins Bayview Circle
`Asthma and Allergy Building, Room 1882
`Baltimore, Maryland 21224
`
`Khachaturian, Zaven S., Ph.D.
`President
`
`I 1/31/00
`
`Khachaturian, Radebaugh and Associates, |nc._
`8912 Copenhaver Drive
`Potomac, Maryland 20854—3009
`
`AMNEAL
`
`EXHIBIT NO. 1019 Page 12
`
`

`
`38V.L
`
`AMNEAL
`
`EXHIBIT NO. 1019 Page 13
`
`

`
`MEMORANDUM
`
`DATE:
`
`August 12, 1996
`
`FROM:
`
`TO:
`
`Deputy Director
`Division of Neuropharmacological Drug Products/HFD—12O
`
`Members, Peripheral and Central Nervous Systems Advisory
`Committee
`
`for September 19, 1996 Advisory
`SUBJECT: Background Material
`Committee Meeting to Discuss NDA 20-622, Copolymer-1
`Injection for Patients With Exacerbating-Remitting Multiple
`Sclerosis
`
`Overview
`
`As you know, the PCNS Advisory Committee will meet on September 19,
`1996 to discuss NDA 20-622, Copolymer-1, submitted by Teva
`Pharmaceuticals,
`for use in patients with Exacerbating Ftemitting Multiple
`
`Sclerosis (ER MS). This memo will give an overview of the safety and
`effectiveness data included in the NDA, which will provide the background
`
`for your discussions and deliberations. The package also contains the
`
`detailed reviews of the effectiveness and safety data, performed by Drs.
`
`Janeth Rouzer-Kammeyer and John Balian, respectively, of the Division, as
`well as 2 reviews of
`the effectiveness data performed by Dr. David
`
`Hoberman, mathematical
`
`statistician.
`
`Under separate cover, we are also forwarding a briefing document
`
`prepared by the sponsor.
`
`BACKGROUND OF THE NDA
`
`NDA 20-622, for the use of Copolymer—1 (Cop 1), a 4 amino acid copolymer
`
`of fixed proportion but random order to be injected subcutaneously, was
`submitted by Teva Pharmaceuticals, USA on October 11, 1995. The
`
`it be approved as a treatment for patients with
`sponsor proposes that
`exacerbating-remitting Multiple Sclerosis. As support
`for
`this proposed
`
`AMNEAL
`
`EXHHBIT NO. 1019 Page 14
`
`

`
`claim,
`
`they have sub_mitted reports of 2 adequate and well controlled
`
`trials in patients with this condition.
`
`and is not part of this application. The drug is presumed to exert its anti-
`MS effect via the activation of T—cells at the site of
`injection, which,
`in
`
`turn, are distributed widely to produce systemic effects.
`
`The first controlled trial was performed as a single center trial by Dr.
`Murray Bornstein at the Albert Einstein College of Medicine in the Bronx,
`New York. The results of this trial were published in the New England
`Journal of Medicine on August 13, 1987 (a copy of which is included in the
`
`sponsor's briefing package). On the basis of this study, and the fact that a
`second trial (a multi-center study conducted by the sponsor) was on-
`going, Teva; submitted a Treatment IND request to the Agency on December
`4, 1992. The Treatment IND was granted on 1/5/93.
`
`At the time of submission of the NDA, -the routinely required |ife—time in
`
`vivo
`carcinogenicity studies in 2 animal species had not been completed
`(they are still on-going).
`In multiple discussions (taking place over
`years) with the sponsor prior to the submission of the NDA,
`the Division
`
`repeatedly informed the sponsor that these studies would be required for
`
`approval. The sponsor made a number of arguments to support their view
`that such studies should not be required (including the fact that
`
`Betaseron,
`
`the first approved treatment for MS, which was approved in
`
`CBER, had not had such studies performed), but these arguments were
`
`never felt
`
`to be compelling by the Division. While it was ultimately
`
`decided (based on discussions with Drs. Temple and Woodcock) that the
`application would be filed without
`this information available. Agency
`staff agreed that whether or not the application coyld be approved before
`the results_ of these studies were available would depend upon the
`—.robustness_ of the clinical data.
`
`BORNSTEIN STUDY
`
`-
`
`..J_=l
`This study was performed by Dr. Murray Bornstein (w_ho‘is, unfortunately,
`recently deceased) and colleagues of
`the Albert Einstein College of
`
`AMNEAL
`
`EXHIBIT NO. 1019 Page 15
`
`

`
`Medicine in New York under Dr. Bornstein‘s IND. Teva had no involvement
`
`in either the design or conduct of the study, and acquired the data after
`
`the study was completed. As a result,
`
`the records tor this study were
`
`gathered retrospectively, and the sponsor's study report was written on
`the basis of the records that could be recovered. While CRFs were
`
`obtained,
`
`the document that the sponsor has submitted as the protocol
`
`is
`
`in fact a portion of a grant application, dated 10/1/82,
`
`that Dr. Bornstein
`
`completed atter the study was initiated (for example, a statement
`
`in
`
`this ‘‘protocol‘’ notes that 16 pairs of patients are receiving drug and that
`
`many of
`them are completing their 2 year participation in the near future).
`According to Drs. Scheindlin and Ben—Naiman of Teva, Dr. Bornstein
`submitted numerous grant applications for this study, and, again,
`
`according to the sponsor,
`
`the actual original protocol
`
`from which Dr.
`
`Bornstein worked, assuming there is such a written document, was
`unavailable to them. The sponsor asserts that the document
`that they
`have submitted as the protocol contains the most explicit details of
`the
`
`trial and its analysis plan as it was intended to be conducted.
`
`There are, however, some points of
`
`interest related to the document,
`
`it was written long after the trial had begun.
`beyond the fact that
`example,
`it describes the establishment of an External Committee
`composed of 3 people (named in the document) who are unaffiliated with
`the study whose role was to review the data regarding adverse effects.
`However,
`the document also states that they may stop the study not only
`
`For
`
`for toxicity, but also “...because of an overwhelming beneficial eifect”.
`
`Because this statement permitted the inference that a formal
`
`interim
`
`analysis was (to be) done, we called the sponsor, who told us that,
`another grant application dated 2/1/81 contained the results of an
`interim analysis of
`the effectiveness data on 26 patients. Ostensibly,
`nominally significant results were obtained on several measures of
`effectiveness.
`Dr. Bornstein does state,
`in this grant application,
`the
`
`indeed,
`
`following:
`
`I must call attention to the conditions imposed by
`(In this regard,
`its being a blinded study.
`it
`is obviously necessary to disclose the
`data to the site visit
`team and The Committee in order to permit a
`
`this report
`this proposal. The details of
`proper consideration of
`must, however, be treated in strict confidence to avoid jeopardizing
`
`AMNEAL
`
`EXHIBIT NO. 1019 Page 16
`
`

`
`the blinded nature ol
`
`the study itself).
`
`the neurologist responsible
`The sponsor assures us that Dr. Aaron Miller,
`for rating the patients, and who was blinded, had no knowledge of the
`results of the interim analysis.
`Dr. Bornstein, was, of course, unblinded,
`
`and knew the results of
`the interim analysis (as did the other trial
`planners-statisticians, etc.), but he apparently was not
`involved in the
`actual conduct of the trial, according to the sponsor
`
`We have recently recovered a document from Dr. Leber’s files signed by Dr.
`Bornstein on February 1, 1980.
`In a cover letter to his IND dated 8/21/87,
`
`Dr. Bornstein states that
`
`it was this 2/1/80 protocol
`
`that was followed in
`
`to be a portion
`the trial reported in the NEJM. The protocol appears, again,
`of a grant application. The date of the protocol would appear to be
`
`consistent with Dr. Bornstein’s statement
`
`in the 2/1/81 grant application
`
`is largely similar
`the trial began in March, 1980. The 1980 protocol
`that
`to that described in the 1982 document, with one important difference.
`
`The sample size called for in the earlier document
`
`is 40 patients total, as
`
`compared to 50 in the latter document. The 2/1/80 protocol does not
`included a sample size calculation, nor does it describe plans for an
`interim analysis.
`
`These matters take on some importance because it
`actual sample size for the study was Calculated.
`
`is not clear when the
`in the 10/1/82 document
`
`submitted as the protocol,
`
`it states that 50 patients (25 matched pairs)
`
`would give reasonable power and would be the final number of patients
`enrolled. The outcome variable used to calculate sample size, proportion
`
`of patients exacerbation—free for 2 years, was one of
`
`the variables
`
`in the interim
`analyzed and found to be nominally significant (p=0.021)
`analysis. As noted above, the 2/1/80 document, described by Dr. Bornstein
`in 1987 as the protocol used for the trial, calls tor 40 patients (explicitly
`
`describing 20 matched pairs). The sequence of documents in our
`possession as of this date would permit the suggestion that the sample
`size could have been increased based on the results of the interim
`
`analysis reported in 2/1/81. We have also just recently retrieved Dr.
`Bornstein's original
`IND application. The original submission (received in
`January, 1978) proposed a small, open. uncontrolled trial of Cop 1.
`I
`
`cannot
`
`tind in the file a detailed protocol
`
`tor the double blind, placebo
`
`AMNEAL
`
`EXHIBIT NO. 1019 Page 17
`
`

`
`controlled trial ultimately performed. However, Dr. Bornstein did submit
`an amendment to the IND dated November 19, 1979,
`in which he described
`
`to enroll
`IM Cop 1,
`a randomized, double blind, placebo controlled trial of
`“approximately 30-40 patients equally divided between the chronic
`progressive and the exacerbating and remitting types.”_
`
`The description of
`
`the protocol given below, however,
`
`is taken from the
`
`10/1/82 grant application. Again,
`
`the 2/1/80 document
`
`is essentially the
`
`same, with the already described differences in sample size and lack of
`
`sample size calculations.
`
`This was a single center, double blind, randomized trial comparing Cop 1,
`
`20 mg SC, given daily,
`
`to placebo in patients with exacerbating-remitting
`
`MS, as defined by usual criteria.
`
`Patients must have had at
`
`least 2 well-
`
`defined attacks a year for the 2 years prior to entry, and must have had a
`
`Kurtzke score of no greater than 6 (this disability scale ranges from 0-
`
`Normal
`
`to 10—death due to MS; a score of 6 means the patient can walk
`
`with assistance; a 7 means the patient
`
`is restricted to wheelchair).
`
`Patients were to be evaluated at 4 weeks after randomization, and then
`
`every 3 months for 2 years.
`
`In addition, whenever an exacerbation
`
`occurred, patients were to be seen by the evaluating neurologist who was
`
`to document
`
`that an objective neurologic deficit was present. There was
`
`no specific definition in the protocol of how an exacerbation was to be
`
`determined. However,
`
`in the description of exacerbations for purposes of
`
`inclusion into the trial,
`
`the protocol suggests that an exacerbation must
`
`be a new neurologic deficit, of greater than 24 hours duration (changed at
`
`some unknown point during the trial
`
`to the requirement for 48 hours
`
`duration), primarily related to a lesion in the white matter, with no other
`identifiable cause.
`
`At each evaluation (routine or exacerbation), various assessments were
`made. These included:
`
`1) Kurtzke Scale-described above
`
`2) Functional Status-8 scales covering:
`
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`
`tract
`a. Pyramidal
`marked quadriparesis
`
`functiohs—(O—normal-5-paraplegia,hemiplegia,
`
`functions—0-normal-5-unable to perform coordinated
`b. Cerebellar
`movements due to ataxia
`
`c. Brainstem functions—0—normal-5-inability to swallow or speak
`
`d. Sensory Functions-0-normal—6-analgesia and anaesthesia to neck
`
`e. Bowel and bladder lunotions-0-normal-5-loss of bladder and
`
`bowel control
`
`l. Visual
`
`functions-O-6
`
`g. Mental
`
`lunctions—0—norma|-5—dementia,
`
`incompetent
`
`h. Other functions-0—none—1 specify any other findings
`
`3) Ambulatory
`
`Index
`
`4) Incapacity Scale-16 functions graded as normal. without aid, with
`
`mechanical aid, with human aid, not able to do.
`
`Other measures and derived measures included:
`
`5) Total Severity Score—each exacerbation is
`
`ranked from 1-3, with 3
`
`being most severe;scores for all exacerbations during the 2 years will be
`added together
`
`6) Mean Severity Score-the mean score will be calculated
`
`7) Total Time in Exacerbation—the total number of weeks spent during
`
`exacerbatiohs over the 2 years
`
`8) Severity-Duration lndex—A combined score of duration and severity
`will be calculated for each bout and “summarized" for each patient.
`
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`
`Prospective patients were to be extensively screened by Dr. Bornstein and
`Dr. Miller, as well as a social worker, who were to ensure that the patient
`was an appropriate candidate for the study.
`
`illness
`Patients were to be “matched” according to age, sex, duration of
`and frequency of attacks.
`Specifically, a given patient was randomized,
`
`and the next patient who “matched" this patient on the 4 mentioned
`
`criteria was automatically assigned the alternate therapy (there was a
`certain amount of variability permitted in the matching maneuver;
`for
`
`example, when matching on the Kurtzke, patients were categorized into 3
`groups; 0—2,3—4, and 5-6). Clearly,
`it was anticipated that the second
`member of a pair could be enrolled into the study considerably later in
`time than the first member.
`
`The protocol
`
`lists 3 outcome measures on which “major analyses" will be
`
`performed (the 1980 and 1982 documents differ in the order in which
`
`these 3 are listed):
`
`1) Frequency of attacks per year
`
`2) Change in the number of attacks in the study years compared to the
`number of attacks in the 2 years prior to study
`
`3) The number of patients in each group having attacks.
`
`Both documents state that the “first outcome measure to be evaluated
`
`will be the occurrence or absence of exacerbations", and, as noted earlier,
`
`the sample size calculations in the 1982 document were based on the
`
`proportion of patients exacerbation free.
`
`This apparent primary outcome
`
`was to be analyzed using McNemar’s test with Edward's corrective factor.
`
`The 1980 document goes on to say that the “second phase of analysis"
`will examine the frequency of exacerbations, while the "third phase" will
`look at the change in frequency in a patient compared to his or her
`previous attack rate. The 1982 document states that, after the primary
`
`outcome,
`
`they will examine the change in attack rate, and,
`
`in the text of
`
`the Statistical Analysis section, does not explicitly discuss in detail
`
`the
`
`analysis of
`
`the frequency of attacks.
`
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`
`RESULTS
`
`Approximately 1000 patients were screened prior to enrollment.
`
`A total
`
`of 50 patients, however, were actually enrolled into the trial, with 25
`
`randomized to each treatment. There were a total of 24 matched pairs.
`with 1 additional unmatched patient randomized to each treatment.
`
`In the NEJM publication,
`
`the authors excluded 2 patients from the efficacy
`
`analysis. They were both placebo patients, who did not complete the 2
`
`years of treatment, and they were excluded because the authors
`
`considered them unevaluable for psychogenic reasons. These exclusions
`resulted in 22 matched pairs and 4 unmatched patients (3 Cop l,
`1 Placebo)
`having been included in the analysis reported in the NEJM.
`In this memo,
`I
`
`will
`
`report
`
`the results of analyses that
`
`include all 50 patients.
`
`A total of 7 patients (3 Cop 1, 4 Pbo) did not complete the full 2 years of
`
`treatment. Two (2) Cop 1 patients withdrew because of ADRS, and 1
`
`withdrew for unspecified reasons.
`
`Two (2) placebo patients were
`
`terminated by the investigator (see above) and 1 each left for
`
`hospitalization due to a relapse and patient decision.
`
`The following describes the results of
`
`the analysis of what appears to
`
`have been the primary outcome; namely,
`
`the proportion of exacerbation-
`
`free patients.
`
`N
`
`25
`25
`
`Cop1
`Pbo
`
`% Exacerbation Free
`
`P—value
`
`14/25 (56%)
`8/25 (32%)
`
`0.18
`
`The p-value reported in the NEJM article for this comparison was 0.039;
`however,
`this analysis was based on 48 patients. The p-value reported
`
`here is the result of an analysis performed by the sponsor (and confirmed
`
`by Dr- Hoberman) that included all 50 patients.
`
`The following chart displays the results of an analysis of exacerbation
`
`frequency.
`
`It should be kept
`
`in mind that
`
`in this analysis, for patients
`
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`
`who did not complete the full 2 years of
`treatment. exacerbation
`frequency was calculated as # of exacerbations/2 years.
`The following
`results were obtained:
`
`N
`
`25
`
`25
`
`Copl
`
`Pbo
`
`Mean Exacerbation Frequency
`
`P-value
`
`(16/25) 0.6
`
`(59/25) 2.4
`
`0.004
`
`Again,
`
`this P-value represents the result ol a Fisher's Exact Test
`
`in his supplementary review
`performed by the sponsor. Dr. Hoberman,
`dated 8/1/96, suggests that a more appropriate analysis would take into
`account the fact
`that randomization was performed within pairs. As such,
`
`he performed an analysis that examined only the 24 matched pairs;
`
`this
`
`is interesting to note, as
`It
`analysis yielded a similar P-value of 0.005.
`Dr. Hoberman points out on page 5 of his 12/22/95 review and illustrates
`
`with Figure 1, only in the placebo group are there patients who had 4 or
`
`more relapses (maximum 8).
`
`inspection of the individual patient data
`
`reveals that this does not represent a marked increase in the number of
`episodes in these placebo patients compared to their previous 2 year
`rates.
`
`The following chart displays the results of
`
`the third of
`
`the
`
`“major”endpoints described in the protocol; namely,
`
`the change in relapse
`
`rate on treatment compared to the rate in the 2 years prior to enrollment
`in the trial:
`
`N
`
`Baseline Rate
`
`Treatment Rate Change
`
`P-value
`
`Cop 1
`Pbo
`
`25
`25
`
`3.8
`4.0
`
`0.6
`2.4
`
`3.2
`1.6
`
`0.025
`
`The p-value obtained was the result of a sign rank test performed by Dr.
`Hoberman.
`
`Other outcomes were examined in this study as well, as noted in the
`
`description of the protocol. Results of some of these are presented below.
`
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`
`Median Time to First Relapse
`
`P-value
`
`Cop 1
`
`Pbo
`
`>700 days
`
`150 days
`
`0.03 (log rank)
`
`Time to Progression
`
`1
`Only 5/25 Cop 1 patients progressed (defined as an increase of at least
`point on the Kurtzke that persisted for 3 months;
`the time to progression
`was the time from treatment onset to the time a persistent change was
`
`first noted). during the trial, compared to 12/25 Placebo patients who
`
`progressed. The p-value for the comparison between the 2 groups on this
`measure was 0.023.
`
`Proportion of Patients With Change From Baseline on Kurtzke
`
`A comparison of
`
`the proportion of patients who worsened as measured by
`
`the Kurtzke (see Figure 2 of Dr. Hoberman’s 12/22/95 review) yielded a p-
`value of 0.13. A comparison of the proportion of patients who improved on
`
`the Kurtzke yielded a p-value of
`
`.2.
`
`As noted above in the description of the protocol, at some point in the
`
`conduct of the trial
`
`(it
`
`is not clear to us when),
`
`the duration of
`
`persistence of a new neurologic deficit necessary to declare this new
`deficit an exacerbation changed from 24 to 48 hours. The records of
`
`patients who had had an exacerbation declared under the 24 hour rule were
`reviewed after the fact and were to have been re-classified as an
`
`exacerbation if
`
`the records showed that
`
`the new deficit had,
`
`in fact,
`
`persisted for at least 48 hours. The sponsor claims that all episodes
`classified as exacerbations under the 24 hour rule also were classified as
`
`exacerbations when the 48 hour rule was applied.
`
`The retrospective nature of
`the re-classification raised one issue.
`Specifically,
`the protocol required that patients be seen by the study
`neurologist as soon as possible after the onset of a new deficit. so that
`
`the neurologist could document objective neurologic signs (one criterion
`
`10
`
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`
`necessary to call
`
`the deficit an exacerbation).
`
`If
`
`this visit occurred less
`
`than 48 hours after the onset of the deficit, and objective signs were
`present,
`the event could rightly be classified as an exacerbation by the 24
`hour rule, but not by the 48 hour rule. Given this, we asked the sponsor to
`document that all
`re-classified exacerbations had,
`in fact, had a visit
`
`occurring in proximity to the onset of
`
`the deficit but at
`
`least 48 hours
`
`after its onset, so that we could be assured that all of the “24 hour
`
`exacerbations” were truly also exacerbations by the new rule. The
`sponsor was unable to produce such documentation.
`
`STUDY 9001
`
`This was a multi—center,
`
`randomized. double blind, placebo controlled
`
`trial comparing Copolymer 1, given as 20 mg subcutaneously,
`
`to placebo in
`
`patients with exacerbating remitting MS.
`
`Two hundred forty (240) patients similar to those enrolled in the
`
`Bornstein study were to be enrolled into the trial. The primary outcome
`was to be the “...number of relapses during a fixed period of treatment".
`
`The primary analysis of this primary outcome was to be performed on the
`
`evaluable patient subset, defined as lhose patients who do not violate the
`
`protocol and who completed the full
`
`treatment period. Although the
`
`primary analysis was to be based on the evaluable subset,
`
`the protocol did
`
`state that an analysis of
`
`the intent
`
`to treat population would also be
`
`performed.
`
`The protocol called for an interim analysis to be performed on the primary
`outcome for the evaluable subset when all patients either completed 12
`
`months in study or prematurely discontinued treatment. The stopping rule
`for effectiveness was to be based on the method of Lan and DeMets.
`
`In this trial, a relapse (exacerbation) was defined as the appearance of
`
`one or more new neurologic deficits or the re-appearance of one or more
`
`least 48 hours. The
`previously observed abnormalities, persisting for at
`deficit must have been preceded by a stable or improving neurologic
`
`condition for the 30 days prior to the onset, and must have been
`
`documented by objective signs. The objective change must have been
`
`11
`
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`
`accompanied by an increase of at least 0.5 on the Kurtzke or an increase of
`
`at least one grade in at least 2 of the Functional Systems (F8) or 2 grades
`in at least 1 FS.
`
`Patients were to be assessed using the Kurtzke, FS, Ambulation Index, a
`
`Patients were to
`laboratory tests.
`Neuropsychological Profile, and other
`be seen every 3 months. at which the first 3 tests listed above were
`
`performed, and at the 12 and 24 month evaluations the Neuropsychological
`
`including a
`Profile was administered, as well as additional assessments,
`Quality of Life questionnaire.
`Patients were to be seen at these times by
`
`a blinded Examining Neurologist who was to evaluate the patient without
`
`verbal communication regarding symptoms and who did not have access to
`prior evaluations. They were also seen by a blinded Treatment Neurologist
`who was to assess adverse events and make treatment decisions (e.g.,
`
`acute treatments for a relapse).
`
`Patients who discontinued were to be
`
`seen at specified int