Lilly Research Laboratories
`A Division of Eli Lilly and Company
`
`Lilly Corporate Center
`Indianapolis, Indiana 46285
`317.276.2000
`
`January 25,2000
`
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Division of Oncology Drug Products, HFD-150
`Attn: Mr. Alvis Dunson, Project Manager
`1451 Rockville Pike
`Rockville, Maryland 20852-1448
`
`TYPE A
`MEETING REQUEST
`
`IND # 40,061 - LY231514 (MTA, MultiTargeted Antifolate) Serial No,: 203
`Formal Type A Meeting Request to Discuss Changes of Vitamin
`Supplementation Instituted for the Ongoing Mesothelioma Registration
`Tdal
`
`Reference is made to Eli Lilly and Company’s submissions to the MTA IND
`(#40,061) on November 8 1999 (serial no. 191 ), on November 24, 1999 (serial
`no. 194), on December 3, 1999 (serial no. 195), on December 22, 1999 (serial
`no. 200) and on December 2:2, 1999 (serial no. 201). Additionally the FDA
`Medical Officer has commented on these submissions in FAX communications to
`Lilly on December 21, 1999 and on January 6, 2000.
`
`As per the February 1999 Guidance for Industry, "Formal Meetings with
`Sponsors and Applicants for PDUFA Products", Eli Lilly and Company wishes to
`request a Type A meeting (critical path meeting) to discuss recent changes in
`the ongoing mesothelioma registration trial. Please see the attached "Formal
`Meeting Request" with details regarding the proposed meeting.
`
`I TRIAL EXHIBIT
`
`TX 333
`
`CONFIDENTIAL
`ELAP00013452
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1085-0001
`
`

`
`Food and Drug Administration
`January 25, 2000
`
`Page 2
`
`We again thank Division of Oncology Drug Products for their assistance in the
`development of LY231514. Please call Mr. John Worzalla at (317) 276-5052 or
`me at (317) 277-3799 if there are any questions. Thank you for your continued
`cooperation and assistance.
`
`Sincerely,
`
`ELI LILLY AND COMPANY
`
`~~r~ ~ T. Brophy, Ph.D.
`Director
`U.S. Regulatory Affairs
`
`Enclosure (Formal Meeting Request)
`
`CONFIDENTIAL
`ELAP00013453
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1085-0002
`
`

`
`DEPARTMENT OF HEALTH AND HUMAN SERVICIES
`PUBLIC HEALTH SERVICE
`FOCO AND DRUG ADMINIS T RAT ION
`INVEST IGAT IONAL NEW DRUG APPLICAT ION (IND)
`(TITLE 21, COOE OF FEDERAL REGULATIONS (CFR] PART 312)
`
`FormAp~ove~ OMB No. 0910-0014.
`Exertion Dct~ Sep~e’~t~ 30, 2002.
`See OMB Steepest ~n Re,~rse
`
`NOTE: NO cl’u~ too/De shipl~cl~ dlnlod
`inv~tig~J~n ~ until a~ IND fo~ th(J
`inv(~fig@ion is In ~ff(~ct (21 CFR 312.40),
`
`I O. IND submission should be oonsecutively numb~e~ The initial’~ND s’hould be numbered
`" $ e/ial number: 000o" The next submission (~ 9, ~nendment, report, o~ correslx~ndanoe)
`~ho~Id be numbered "$ e~ial Number: O0 I." $ ub~equent submissions should be
`nurnb~ed oonsecutively in the order in which they ~e subrr~tte~
`
`SERIAL NUMBER
`
`2O3
`
`HIS SUBMISSICN C~NT AJNS THE FOLLOVVING: (’O~o~’~l th~ q~y)
`
`[] INITIAL INVEST~GAtIONAL NEW DRUGAPPLIC~TICN (1ND)
`
`[] RESPCNSE TOCLINICAL HCLD
`
`PROT CCCL AMENDMENT (~):
`
`INFORMATION AMENDMENT ~):
`
`IND SAFETY REPCRT (S):
`
`[] NEW PROTOCCL
`
`[] CHANGI~ IN PROTOCC[.
`
`[] NEW IWESTIC-’~,.TOR
`
`[] C~ EMIS T RY AVll C~C}BI OLOG’Y
`
`[] INIT IAL WRITT EN REPORT
`
`[] P H AR MAOOL OG~/T C~ I OC:L CG’Y
`
`[] FOLLOW-UP TOA WRITTEN REPCRT
`
`[] Q.INICAL
`
`[] RESPCNSE T O FDA RE~;~J EST Fa~ INFORMAT ION
`
`[] ANNUAL REPCRT
`
`[] GI~NERAL CCRRESPONDENCE
`
`[] RECUEST FCg REINSTATEMENT CF INDTHAT IS WITHDRAWN.
`INACT IVATED. T ERMINAT ED OR DI$OCNT INUED
`
`[] C~’HER
`
`CHECK (~ILY IF APPLICABLE
`
`JUSTIFICATION STATEMENT MUST BE SUBMITTED WITH APPLICATION FO~ ANY CHECKED BELOW. REFERTO.THE ~II"EDCFR ¯ ".
`SECTION FOR FURTHERINFO~MA.T. ION~ ; ::- . .: . " . -~ . .- . ." -..- . .. ..:.. .
`
`.[]TREATMENT ’IND 21 a:R 312.35(b) -F-I .TREXTMENT:PROIO(~ 2i CFR312.35i~ [] (:::H’ARGtE REQUESTA~IOT.I’Fi~’,AI:ION 21
`
`CDR/~)BIND/DGO REC~IPI" STAMP
`
`DDR RECEIPT STAMP
`
`DIVISICN ASSIGNMENT:
`
`FOR FDA USE ONLY
`
`IND NUMBER ASSIGNED;
`
`:ORM FDA 1571 (10/99)
`
`PREVIOUS EDfflCN IS C~SCLETE.
`
`PAGE 1 OF 2
`
`CONFIDENTIAL
`ELAP00013454
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1085-0003
`
`

`
`12.
`
`CONTENTS OF APPLICATION
`This q~icafion contdns the following items: (Check dl thct
`
`13. I~ ANY PART C~ THE CLINICAL STUDY TOBE CCNDUCTED BY A C~NrRACT RESEARCH CRGANIZATtC~? ~ YES [] NO
`
`IF YES, WILL ANY SPCNSC~ CSLIGATICI~ 8E TRANSFERRED TOTHE CCNTRACT RESEARCH ORGANIZATION? [] YES
`
`[] NO
`
`IF YES, ATTAO-I A STATEMENI CCNTAINING T HE NAME AND ADDRESS ~F THE OONTRACI RESEARCH C~CANIZATIC~,
`IDENTIFICATICN CF THE CLINICAL STUDY. AND A LISTING CF THE C~LIGATICNS TRANSFERRED.
`
`14, FLAME AND T IT LE ~F "~HE PERSC~N RESPONSIBLE FOR NIC~IT CITING T HE OT~IDUC~ AND PROGRESS CF T HE CLINICAL
`lb~ESTI~TICI~S
`~’ames Rusthoven, M.D.
`
`15. NAME~3) AND TiT LE(S) CI= THE PERSON(S) RESPONSIBLE FO~ REVIEW AND EVALUATION O: INF~MATICN RELEVANT TOTHE
`SAFETY OF THE DRUG
`
`Same as #14 Above
`
`I ag~ not to begin clinical inv(~tig~i~ until 30 da~ dt~ FDA’s receipt of the IND unl~s I receive ~li~ nolificdi~ by
`FDA lhc~ the stucl~ may begin. I also ac~ not to begin ~ a~tinue clinical inv~tigali~s ~ed by the IND if th(~e
`stud~ oe pl~r:~d ~ dinlcal hold. I acj’~ thd m l~tituti~al R~i~ B(~’d ORB) thd ~plim w#h the r~iremenl$ set
`f~rth in 21 CFR Pal 56 will I~ r~il~le f~ initial (~d ~tinuing r~-i~ ~d q:~al of each of t~ studes in the
`w~ed dinicd invesfigalion. I a~ee to c~dud the inv=tigc~ion in c,:~ord~ with dl olhet q3plicable rec~Ic~ory
`requitelamt $.
`
`NAME CF SPON~CR O~ SPGN~OR’$ .AUTHOI~IZED
`REPRES ENT AT IVE
`
`Or¢~or~ T. Brophy, £h.D., Dkcctor
`U.S. Regulatory Affairs
`
`18. ADDRESS (Numbs, Strut.
`
`Eli Lilly and Company
`Lig.7 Corl~O_ rate Center
`Indtanapolis, IN 46285
`
`17. SIGNATURE OF SPCNSCI~ CR SPCINSCIR’S AUTHORIZED
`
`19. TELEPHONE N~4BER
`Ondude Are~)
`
`20. DATE
`
`(317) 27"/-3799
`
`January 25, 2000
`
`(WARNIN~ A willfully fdsest@e’n~t is o~twind ol’f~s~ U,S,C. Title 18, S~ 1001 .)
`
`~lc r~ti~ ~r~ f~ tNs ~l~ ~ in~i~ is ~ti~ to ~ 100 ~} ~ r~ l~.t~ti~ f~ r~l~ imtr~i~, -
`
`~ER ~F~99)
`1401 R~lle ~ke
`R~lle MD 20852-I 448
`
`~M FDA 1571 (IOR9]
`
`~R ~F~94)
`5516 ~ds~ L~
`K~i~ ~ 20895
`
`a ~s ~ is ~ r~r~ to r~ ~ t~ o
`~l~i~
`~rmtly vdid
`
`Pl~e DO N~ RETURN ins ~i~i~ tot~s ~s.
`
`PA~ 2 ~ 2
`
`CONFIDENTIAL
`ELAP00013455
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1085-0004
`
`

`
`IND Number 40,061
`Sponsor’s Serial Number
`LY231514
`Table of Contents
`
`203
`
`TABLE OF CONTENTS
`
`Page 1
`
`Pages
`
`Cover Letter
`
`Form FDA-1571
`
`Table of Contents
`
`GENERAL CORRESPONDENCE
`
`Formal Meeting Request
`
`1-5
`
`CONFIDENTIAL
`ELAP00013456
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1085-0005
`
`

`
`This document contains trade secrets~ or
`commercial or financial information,
`privileged or confidential, delivered
`inconfidence and rcl|ance that such
`information .will not be made available
`to the public without express written
`consent of Eli Lilly and Company
`
`CONFIDENTIAL
`ELAP00013457
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1085-0006
`
`

`
`Page I
`
`Formal Meetinq Request
`
`1) Product Name and Application Number:
`LY231514 (MTA or MultiTargeted Antifolate); IND # 40,061
`
`2) Chemical Name and Structure:
`Nonproprietary Name: Pemetrexed disodium
`Chemical Nomenclature: N-[4-[2-(2-amino-3,4-dihydro-4-oxo-7H-pyrrolo [2,3-
`d]pyrimidin-5-yl) ethyl]benzoyI-L-glutamic acid disodium salt
`Chemical Structure:
`
`o ~ F.
`
`3) Proposed Indication(s):
`Malignant Pleural Mesothelioma and Non-Small Cell Lung Cancer
`
`4) The Type of Meeting Being Requested:
`Type A
`
`s) Brief Statement of the P~Jrpose of the Meeting:
`Ongoing LY231514 trials, including the ongoing mesothelioma registration trial H3E-
`MC-JMCH (JMCH for brevity), have been modified through addition of vitamins for
`the purpose of promoting patient safety. The Medical Review Officer does not
`support the addition of vitamins to the ongoing registration trial (FDA
`communications to Lilly on December 21, 1999 and January 6, 2000). The sponsor
`seeks a face-to4ace meeting to resolve this impasse and to come to agreement as
`to the implications of the action of adding vitamins for the pivotal registration trial and
`for supporting trials.
`
`Back.qround:
`Recent multivariate analyses (submission serial numbers 191 on November 8, 1999
`and 194 on November 24, 1999) have shown a strong relationship between high
`baseline homocysteine levels and severe toxicity in the LY231514 trials. In
`response to this information, Lilly initially took the action of excluding patients with
`high baseline homocysteine levels from LY231514 trials (serial no. 194 on
`November 24, 1999). Since external consultants were in unanimous agreement that
`
`CONFIDENTIAL
`ELAP00013458
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1085-0007
`
`

`
`Page 2
`
`the addition of folic acid should lower plasma homocysteine levels and thus offer
`protection to patients, Lilly made the programmatic decision that further development
`of LY231514 would proceed with vitamin supplementation (folic acid together with
`vitamin B12). The decision as to whether this should be applied to an ongoing
`registration trial was carefully considered. We have seen a significant number of
`cancer patients who present with high homocysteine levels, particularly in
`mesothelioma where this proportion of patients can exceed 40%. At the time of the
`decision, mortality in trial JMCH included 5 deaths on the LY231514 plus cisplatin
`arm (3 possibly drug related and 2 attributed to progressive disease) and 1 death
`(attributed to progressive disease) on the cisplatin alone arm. To promote patient
`safety and to not exclude a significant proportion of patients for whom there is no
`approved chemotherapy, the decision was made to include vitamin supplementation
`in the ongoing mesothelioma trial, JMCH (serial no. 195 on December 3, 1999 and
`serial no. 200 on December 22, 1999 for protocol amendment (c) to JMCH). Vitamin
`supplementation was included in the LY231514 plus cisplatin arm as well as the
`cisplatin alone arm to maintain the integrity of the study design.
`
`The amount of folic acid chosen for supplementation (350 to 1000 Izg per day with
`400 p.g as the recommended dose) approximates the amount of folic acid a patient
`with good dietary habits might be expected to ingest on a daily basis. External
`consultants including an expert in folate metabolism were in agreement that this
`amount of added folic acid should be effective in reducing homocysteine levels but
`these low levels should not be detrimental to efficacy. High homocysteine levels are
`often associated with folic acid deficiency and the addition of relatively small
`amounts of folio acid should lower the homocysteine levels in these patients. Since
`the amount of folic acid that will be administered is low, patients who have normal
`levels of homocysteine should not be affected by the addition of this low level of folic
`acid (400 I~g folic acid is the usual amount found in multivitamins in the U.S.). The
`rationale for these steps will be discussed in the briefing document with reference to
`homocysteine and folic acid in the cardiovascular scientific literature. Additionally
`Lilly will give reasons why it no longer feels that a randomized trial with and without
`vitamins, as has been proposed by DODP, is feasible
`
`6) A List of Specific Objectives/Outcomes Expected from the Meeting:
`
`Lilly will show how the addition of vitamins will not affect the statistical evaluation of
`primary endpoint (survival) in the mesothelioma registration trial, JMCH, and come to
`an agreement with the Agency on the incorporation of vitamins into the analysis plan
`of this study. Lilly also plans to have a discussion and come to agreement as to
`proposed changes for the non-small cell lung supporting tdal. In the End of Phase 2
`meeting for LY231514 held on June 25, 1999, the FDA stated in the minutes (sent to
`Lilly on July 23, 1999) that, "We remind you of our agreement that the randomized
`control trial in NSCLC is essential to support the single randomized control tdal in
`mesothelioma.~
`
`CONFIDENTIAL
`ELAP00013459
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1085-0008
`
`

`
`Page
`
`7) Preliminary Proposed Agenda:
`
`¯
`¯
`¯
`
`Safety analysis/rationale for vitamin supplementation
`Statistical implications for JMCH endpoints
`Options for supportive trials
`
`8) Draft of Specific Questions Grouped by Discipline:
`
`Statistical and Medical:
`
`Lilly feels that the strength of the evidence in our safety analysis (serial numbers 191
`on November 8, 1999 and 194 on November 24, 1999) identifying patients with
`elevated baseline homocysteine levels who are at increased risk for severe toxicity
`justifies the routine use of folic acid and vitamin B12. In addition, Lilly believes that it
`would be ethically difficult to justify exposing patients in a control arm to increased
`risk of toxicity with LY231514 without the addition of folic acid and vitamin B12. It will
`likely also be no longer feasible to implement such a design, given the likelihood that
`investigators will likely not risk exposing their patients without the addition of the
`vitamins and the likelihood that patients will not sign consent to participate in such a
`trial.
`
`Question #1 Does the FDA agree that a randomized trial comparing patients
`receiving LY231514 with and without vitamins is no longer feasible or
`considered ethical given the demonstrated toxicity risks to LY231514
`patients?
`
`Lilly strongly believes that the addition of low amounts of folic acid will not
`substantially affect the primary endpoint of survival in the ongoin~ mesothelioma
`registration trial, JMCH. For this reason we propose the following for this trial.
`At completion of the current 280 patient trial, all endpoints (survival, time to
`progression, tumor response rate, clinical benefit and safety) will be analyzed as
`currently stated in the protocol
`
`To address the issue of vitamins on safety the following is proposed. For JMCH,
`approximately 130 patients have already entered the trial (this includes patients on
`Arms A and B).
`Arm A is the LY231514 plus cisplatin arm
`Arm B is the cisplatin alone arm
`These patients enrolled before amendment JMCH(c) did not receive vitamin
`supplementation. The remaining patients (both arms) will receive vitamin
`supplementation. There will be a small group of patients who will have entered the
`trial without vitamin supplementation and who will have begun vitamin
`supplementation sometime after receiving their first cycle of therapy. The toxicity in
`these particular patients will be assessed per cycle as described in protocol
`amendment (c) (serial no. 200 on December 22, 1999 and 201 on December 22,
`1999).
`
`CONFIDENTIAL
`ELAP00013460
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1085-0009
`
`

`
`The remaining patients (those who had no vitamin supplementation during their
`entire participation in JMCH and those who were supplemented the entire time they
`participated in JMCH), can be grouped into four categories:
`
`Treatment
`Arm A
`
`Treatment
`Arm B
`
`Group A-vits
`LY231514 + cisplatin
`without vitamins
`
`tead~’ patients1
`
`Group B-vits
`cisplatin alone
`without vitamins
`~ead~’ patientsI
`
`Group A+vits
`LY231514 + cisplatin
`with vitamins
`Ilate patients/
`
`Group B+vits
`cisplatin alone
`with vitamins
`Ilate patients)
`
`Dec. 2, 1999
`
`At the end of the trial (280 qualified patients completed) Lilly proposes to evaluate
`toxicity between early and late patients] in these groups and proceed as follows:
`All endpoints will be analyzed as currently stated in the protocol, and the addition
`of vitamins will be included as a possible cofactor for all analyses.
`Exploratory analyses on toxicity (especially on mortality) for variations between
`early and late patients will be carried out.
`
`Question #2 Is this an acceptable plan for analysis of trial JMCH at
`completion of this presently planned 280 patient trial?
`
`In the End of Phase 2 meeting for LY231514 held on June 25, 1999, the FDA stated
`in the minutes that, %’#e remind you of our agreement that the randomized control
`trial in NSCLC is essential to support the single randomized control trial in
`mesothelioma".
`
`Lilly remains committed to completing a randomized registration study as support for
`the mesothelioma registration trial. Lilly anticipates initiation of registration studies
`for LY231514 in front line NSCLC and in breast cancer in the year 2000.
`
`Due to slow accrual (serial number 186 on October 14, 1999; FDA reply from Dr.
`Robert White to Lilly on Dec. 1,1999) in the present second line NSCLC study
`(H3E-MC-JMBQ comparing LY231514 to vinorelbine) and changes in the practice of
`oncology together with changes in the oncology regulatory landscape (i.e., the
`recent approval of docetaxel for second line NSCLC), Lilly proposes replacing the
`present registration study in second line NSCLC with an entirely new randomized
`registration study for LY231514. We will present details of this trial when the briefing
`document is sent.
`
`CONFIDENTIAL
`ELAP00013461
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1085-0010
`
`

`
`Page 5
`
`Question #3 Will the FDA accept a different supporting trial for the
`mesothelioma indication that is a well-designed, randomized, controlled,
`registration trial, in lieu of the present randomized registration trial H3E-MC-
`JMBQ?
`
`9) List of All Individuals Who Will Attend Including Titles (both sponsor and
`consultants):
`
`Eli Lilly and Company Participants:
`Gregory Brophy, Ph.D., Director, U.S. Regulatory Affairs
`Axel Hanauske, M.D. Medical Director, MTA Product Team
`Clet Niyikiza, Ph.D., Research Scientist, Statistician, MTA Product Team
`Paolo Paoletti, M.D., Product Team Leader, MTA Product Team
`James Rusthoven, M.D., Clinical Research Physician, MTA Product Team
`Brian Stuglik, Director of Operations, MTA Product Team
`John Worzalla, Associate Regulatory Consultant, U.S. Regulatory Affairs
`Consultants to Eli Lilly and Company:
`Dr. Paul A. Bunn, Jr., M.D., University of Colorado Health Science Center
`Dr. Robert H. Allen, M.D., University of Colorado School of Medicine
`
`10) List of Agency Staff Requested:
`
`Gang Chen, Ph.D., Statistics, Team Leader
`Alvis Dunson, Project Manager
`John Johnson, M.D., Medical Team Leader
`Robert Justice, M.D., Supervisory Medical Officer, Oncology
`Richard Pazdur, Division Director, Oncology
`Robert White, M.D., Medical Reviewer
`A member from the Oncology Drug Advisory Committee
`
`11) Approximate Date Supporting Documentation Will be Sent:
`Two weeks prior to the actual meeting date as scheduled by the FDA
`
`12) Suggested Date and Time:
`Weeks of February 28 or March 6
`
`CONFIDENTIAL
`ELAP00013462
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1085-0011