O
`
`Ully Research Laboratories
`A Division of ELI Lilly arid Company
`
`Ully Corporate Center
`Indianapolis, Indiana 46285
`317276.2000
`
`March 20, 2000
`
`Food and Drug Administration
`Center for Drug Evaluation arid Research
`Division of Oncology Drug Products, HFD-1 50
`AUn: Mr. Alvis Dunson, Project Manager
`1451 Rockville Pike
`Rockville, Maryland 20852-1 448
`
`Meeting Minutes
`
`LY231 514 (MTA, MultiTargeted Antifolate); IND #40,061 Serial No.: 216
`Meeting Minutes from the March 1, 2000 Meeting to Discuss Vitamin
`Supplementation in the Ongoing Mesothelioma Registration Trial
`
`Reference is made to the meeting between the Division of Oncology Drug
`Products (DODP) and Eli Lilly on March 1, 2000 to discuss the issue of vitamin
`supplementation in the mesothelioma registration trial (H3E-MC-JMCI-i; JMCH
`for brevity) for LY231 514. We thank the FDA for granting this meeting and for
`their valuable suggestions at the meeting.
`
`Enclosed are meeting minutes from the March 1 meeting (Attachment 1). These
`minutes reflect the agreed-to minutes that were shown on the acetates during
`the minutes and also provided to Lilly in hard copy by Alvis Dunson of DODP at
`the conclusion of the meeting.
`
`In addition as 000P works toward providing the official meeting minutes of the
`March 1 meeting, Lilly would like to ask for consideration of the following
`clarifications and additions to the minutes:
`
`For Response to Question la:
`
`Lilly would ask that it be noted that the FDA agreed that if a survival benefit for
`the LY231 514 arm be shown at the interim analysis for the mesothelioma
`registration trial (where 150 patients have been supplemented with vitamins) that
`
`CONFIDENTIAL
`ELAP000 14729
`
`TX 337
`
`Lilly Ex. 2109 pg. 1
`Sandoz v. Lilly IPR2016-00318
`
`

`
`a submission may be made for this indication based on these data provided that
`vitamin supplementation did riot have any negative impact on suMvat.
`
`For Response to Question 2:
`
`Lilly is attempting to provide standardized doses of folic acid for each country in
`which the trial is being conducted, and the dose of folic acid wilt be captured on
`the patients' case report forms. Protocol JMCH(d) states for the folic acid dose:
`"Folic acid will be supplied locally as one of the following options, with preference
`in order from option #1 to option #3: 1.) 350 - 600 g folic acid. 2.) A
`multivitamin containing folic acid in the range of 350 .xg to 600 ig is acceptable if
`option #1 is not available. 3.) A dose of folic acid between 350 tg and 1000 tg
`is acceptable only if neither option #1 or option #2 is available." Given the global
`nature of our registration trial and the eventual global availability of LY231514,
`Lilly feels that the dose of folic acid must be recommended as a range of
`acceptable doses. From our research it is clear that tow-dose fotic acid is
`available in a wide variety of preparations and doses worldwide and folic acid
`would riot be available in some countries if the specified dose was other than
`that available in that country.
`
`Lilly would like to make the clarification that it is only tracking supplemental
`doses of folic acid, and it is not attempting to track fotic acid that is ingested
`through the food of patients.
`
`For Response to Question 3b:
`
`Lilly proposes that the Consensus agreement to question 3a should read:
`Patients with any prior chemotherapy regìmen other than one contaìning taxotere
`would be potentially eligible.
`
`Patients who progress on prior therapy will be acceptable in the labeling if Lilly
`excludes such patients from the trial.
`
`Lilly will make a proposal for a study in 1st line NSCLC with LY231514 in
`combination after completion of the appropriate phase 2 study.
`
`Also please note that in response to Question 3b, Lilly made a number of
`comments concerning supporting trials in our recent IND submission (serial no.
`212 ori March 8, 2000).
`
`DODP provided at the March 1 meeting "Additional Comments" and also the
`DODP responses and questions on protocol amendment H3E-MC-JMCH(d) (
`protocol amendment JMCH(d) was submitted to the (ND as serial rio. 206 on
`
`CONFIDENTIAL
`ELAP000 14730
`
`Lilly Ex. 2109 pg. 2
`Sandoz v. Lilly IPR2016-00318
`
`

`
`February 14, 2000). Discussions on the "Additional Comments" and the
`JMCH(d) protocol were held at the March 1 meeting, but these discussions were
`not captured in the minutes. The latter part of Attachment I provides Lilly
`responses to the questions and comments raised in these two additional DODP
`documents. Attachment 2 that is enclosed contains the specific Lilly response to
`the Clinical Benefit Response table that was discussed at the meeting.
`Attachment 2 also contains the Lilly response providing the detailed statistical
`plan for the analysis of the impact of vitamins in the mesothelioma trial JMCH.
`DODP requested this analysis in their response to Questions la and 2 at the
`March 1 meeting, and this was agreed to by Lilly.
`
`We again thank the 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
`
`Gre%ory T. Brophy. Ph.D.
`Diréctor
`U.S. Regulatory Affairs
`
`Enclosures (2)
`Attachment i
`Lilly version of March 1 meeting minutes
`Attachment 2 - Lilly response regarding Clinical Benefit Response and the
`statistical analysis of the effects of vitamins for trial JMCH
`
`CONFIDENTIAL
`ELAP000 14731
`
`Lilly Ex. 2109 pg. 3
`Sandoz v. Lilly IPR2016-00318
`
`

`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`INVESTIGATIONAL NEW DRUG APPLICATION (IND)
`(TULE 21, CODE OF FEDERAL REGULA TFOAPS (CFR) PART 312)
`
`See 0MB Sta(ement on Reverse.
`
`-
`
`investigation is in effect (21 CER 312.40).
`
`1. NAME OF SPONSOR
`EU LILLY AND COMPANY
`
`3. ADDRESS (Number, Street. City, State and zip Code)
`Lilly Corporate Center
`Indianapolis, IN 46285
`
`2. DATE OF SUBMISSION
`March 20, 2000
`
`4. TEL.EPHONE NUMBER
`(lclude Area Code)
`317) 276-2000
`
`5. NAME(S) OF DRUG (include all available names: Tiade, Generic, Chemical. Code)
`Compound LY2315 14 Disodium (MTA)
`
`6. ND NUMBER (If previously assigned)
`]ND 40,061
`
`7. INDICATION(SI (Covered by this subm'ssion/
`Cancer
`
`8. PHASE(S) OF CLINICAL INVESTIGATION TO BE CONDUCTED:
`
`PHASE i D PHASE 2 D
`(Specify)
`9. UST NUMBERS OF ALL INVESTIGATIONAL NEW DRUG APPLICATIONS (21 CFR Part 312). NEW DRUG OR ANTIBIOTIC APPLICATIONS
`(V C Part 314) DRUG MASTER FILES (2? CPA Part 314.420/. AND PRODUCT LICENSE APPLICATIONS (21 CFR Part 601) REFERRED
`TO IN THIS APPLICATION.
`
`3
`
`OTHER NA
`
`NA
`
`10. 1ND submission should be consecutively numbered. The initial IND should be numbered
`'Sena!number: 000. The next submission (e.g., amendment, report, or correspondence)
`should be numbered 'Sedal Number: 007.' Subsequent submissions should be
`numbered consecutively in the orde, in which they are submitted.
`
`SERIAL NUMBER
`
`2 _4_ 6
`
`11. THIS SUBMISSION CONTAINS THE FOLLOWING:
`INITIAL INVESTIGATIONAL NEW
`
`(Check al) that apply)
`DRUG APPUCATION (INDI
`
`RESPONSE
`
`TO
`
`CUNICAL HOLD
`
`PROTOCOL AMENDMENT(S):
`
`INFORMATION
`
`AMENDMENT(S):
`
`IND SAFETY
`
`REPORT(S):
`
`D NEW PROTOCOL
`D CHANGE IN PROTOCOL
`D NEW INVESTIGATOR
`
`CHEMISTRYIMICROBIOLGGY
`
`PHARMACOLOGWTOXICOLOGY
`CUNICAL
`
`D
`
`wR(rrEN REPORT
`INITIAL
`TO A WRITTEN REPORT
`U FOLLOW-UP
`
`D RESPONSE TO FDA REQUEST FOR INFORMATION
`
`D ANNUAL REPORT
`
`GENERAL CORRESPONDENCE
`
`D REQUEST FOR REINSTATEMENT OF IND THAT IS
`
`INACTIVATED. TERMINATED OR DISCONTINUED
`
`WITHDRAWN.
`
`OTHER
`
`(Specify)
`
`CHECK ONLY IF APPLICABLE
`
`JUSTiFICATION STATEMENT MUST BE SUBMITTED WITH APPLICATION FOR ANY CHECKBELOW REFER TO THE CITED FR:.
`SECTION FOR RJRThER INFORMATION.
`- ... ..
`-
`DETh1E« IND 21 CFR 312.35(b) D TREATMENT PROTOCOL 21 CI'S 31235)a) fl CHARGE REQUESTINOTIFICATIÓN 21
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-.
`
`-
`
`CDRIDBIND/DGD RECEIPT STAMP
`
`FOR FDA USE ONLY
`DDR RECEIPT STAMP
`
`DIVISION ASSIGNMENT:
`
`(ND NUMBER ASSIGNED:
`
`FORM FDA 1571 (10/99)
`
`PRBVIOIJS EDON Is oBSOLEtE.
`
`PAGE 1 OF 2
`
`C,)Mt B 1)44
`
`EF
`
`CONFIDENTIAL
`ELAP000 14732
`
`Lilly Ex. 2109 pg. 4
`Sandoz v. Lilly IPR2016-00318
`
`

`
`i 2.
`
`APPUCATION
`CONTENTS OF
`This application contains the following
`items: (Check all that apply)
`
`. 1.Forni FDA 1571 (21 CFR3I2.23fa)(1)J
`D 2. Table of Contents ¡21 CFR 312.23(a) (2)]
`. 3. Introductory statement ¡21 CFR 312.23(a) (3))
`D 4. GeneraI Investigational plan [21 CFR 312.23(a) (3)]
`D 5. Investigator's brochure (2 1 CFR 312.23(a)(5)J
`u 6.Protocol(s} ¡21 CFR 312.23(a)(6)J
`a a. Study protocol(s) 121 CFR 372.23(a) (6)]
`D b. Investigator data 12 1 CPA 312.23(a)(611i1i)(b)j
`or completed Form(s) FDA i 572
`or completed Form(s) FDA i 572
`. C. Facilities data 121 CFI? 312.23(a)(6)(ii/)(L)J
`D d. Institutional Review Board data ¡2 1 CPA 312.23(a)(6)(ill)(b))
`or completed Form(s) FDA i 572
`D 7. Chemistry, manufacturing, and control data ¡2 1 CFR312.23(a)(7))
`Environmental assessment or claim for exclusion
`(21 CFR 312.23(aJ(71 (iv) (e)]
`8. Pharmacology and toxicology data (21 CFR 312.23(a) (8))
`fl 9. Previous human experience (21 CFR 312.23(a) (.9)]
`D1O.Additional information ¡21 CFR 312.23(a)(1O))
`
`13. IS ANY PART 0F THE CUNICAJ. STUDY TO BE CONDUCTED BY A CONTRACT
`
`RESEARCH ORGANIZATION?
`
`YES
`
`NO
`
`IF YES, WILL ANY SPONSOR OBliGATIONS BE TRANSFERRED TO THE CONTRACT
`
`RESEARCH ORGANIZATION?
`
`YES
`
`NO
`
`IF YES, ATTACH A STATEMENT CONTAINING THE NAME AND ADDRESS OF
`THE CONTRACT RESEARCH ORGANIZATION.
`IDENTIFICATION OF THE CUNICAI. STUDY. AND A USTING OF THE OBUGATIONS
`TRANSFERRED.
`
`14. NAME AND TiTLE OF THE PERSON RESPONSIBLE FOR MONITORING THE CONDUCT AND PROGRESS OF THE CUNICAL
`INVESTIGATIONS
`James Rusthoven, MD.
`
`15. NAME(S) AND TITLE(S) OF THE PERSONIS) RESPONSiBLE FOR REVIEN AND EVALUATION OF INFORMATION RELEVANT TO THE
`SAFETY OF THE DRUG
`Same as #14 Above
`
`I agree not to begin clinical investigations until 30 dcys after FDA's receipt of the IND unless I receive earlier notification by
`FDA that the studies may begin.
`I also agree not o begin or continue clinica! investigations covered by the IPJD if those
`I agree that an Institutional Review Board (IRS) that complies with the requirements set
`studies are placed on clinical hold.
`fourth in 21 CFR Part 56 will be responsible for initial and continuing review and approval of each of the studies in the
`I agree to conduct the investigation in accordance with all other applicable regulatory
`proposed clinical investigation.
`requirements.
`16. NAME OF SPONSOR OR SPONSOR'S AUTHORIZED
`REPRESENTATIVE
`Gregoty T. Brophy Ph.D., Dixector
`U.S. Regulatory Akans
`
`17. SIGNATURE OR SPONSOR OR SPONSOR'S AUTHORIZED
`REPRESENTATIVE
`
`18. ADDRESS (Numbet Street City. Srate and Zip Code)
`Eh Lilly and Company
`Lilly Corporate Center
`rndianapolis, IN 46285
`
`19. TELEPHONE N
`(Ineiude Area
`(317) 277-3799
`
`BER
`
`20. DATE
`
`3/20/2000
`
`(WARNING: A willfully false statement is a cnrrtiflal offense. U.S.C. Title 18. Sec. 1001.)
`Public reporting burden for titis collection of information is estimated to average 100 hours per response, including the time for reviewing instmcons,
`searching existing data sources, gathering and maima'ethg the data needed, and completing reviewing the collection of informatign, Send comments
`regarding this burden estimate or any other aspect of this collection of information. including suggestions for reducrng this burden to:
`Food and Drug Administration
`agency may not conduct or sponsor. and
`Food and Drug Administration
`a person is not required to respond to. a
`COER (HFD.94)
`CBER (HFM99)
`collection ol information unless it displays a
`5516 Nicholson Lane
`1401 Rockvifle Pike
`Kensington, MD 20895
`currently valid 0MB çontrol number.
`Rockville. MD 20852-1448
`
`s
`
`FORM FDA 1571 (10/99)
`
`PAGE 2 OF 2
`
`Please DO NOT RETURN this application to this address.
`
`CONFIDENTIAL
`ELAP000I 4733
`
`Lilly Ex. 2109 pg. 5
`Sandoz v. Lilly IPR2016-00318
`
`

`
`IND Number 40,061
`Sponsor's Serial Number 216
`LY2 31514
`Table of Contents
`
`TABLE OF CONTENTS
`
`Cover Letter
`
`Fonn FDA-1571
`
`Table of Contents
`
`GENERAL CORRESPONDENCE
`
`Attachment I - Lilly Version of March 1 Meeting Minutes
`
`Attachment 2 - Statistical Analysis Plan for the Phase 3 Registration
`Study in Malignant Pleural Mesothelioma
`
`Page 2.
`
`Pages
`
`1-3
`
`I
`
`1-6
`
`l-10
`
`CONFIDENTIAL
`ELAP000 14734
`
`Lilly Ex. 2109 pg. 6
`Sandoz v. Lilly IPR2016-00318
`
`

`
`F
`
`This document contains trade secrets, or
`commercial or financial information,
`privileged or confidential delivered
`in confidence and reliance that such
`information will not be made available
`to the public without express written
`consent of Eli Lilly and Company
`
`,
`
`CONFIDENTIAL
`ELAPOoo 14735
`
`Lilly Ex. 2109 pg. 7
`Sandoz v. Lilly IPR2016-00318
`
`

`
`CONFIDENTIAL
`ELAP000 14736
`
`Lilly Ex. 2109 pg. 8
`Sandoz v. Lilly IPR2016-00318
`
`

`
`Attachment i - Lilly Version of March 1 Meeting Minutes
`
`FDA Meeting
`
`DATE: March 1, 2000
`
`TIME: 10:30 a.m.
`
`PLACE: Woodmont 2 Bldg.,
`Rockville, MD
`
`IND: 40,061
`
`DRUG: MTA
`
`SPONSOR: Eli Lilly and Company
`
`SUBJECT: To discuss recent changes in the ongoing mesothelioma
`registration trial.
`
`Attendees;
`
`FDA:
`Richard Pazdur (Deputy Directory, Div. of Oncology Drug Products)
`John Johnson (Medical Team Leader)
`Robert White (Medical Officer)
`David Smith (Statistical Reviewer)
`Doo Young Lee-Ham (Pharmacology/Toxicology Reviewer)
`Eric Duffy (Chemistry Team Leader)
`Alvis Dunson (Project Manager)
`
`Lilly:
`Gregory Brophy, Ph.D., Director, U.S. Regulatory Affairs
`Axel Hanauske, M.D. Medical Directory, MTA Product Team
`Clet Niyikiza, Ph.D., Research Scientist, Statistician, MIA Product Team
`Paolo Paoletti, M.D., Product Team Leader, MIA 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. Burin, Jr., M.D., University of Colorado Health Science Center
`Dr. Hilary Calvert, University of Newcastle, U.K.
`
`CONFIDENTIAL
`ELAP000 14737
`
`Lilly Ex. 2109 pg. 9
`Sandoz v. Lilly IPR2016-00318
`
`

`
`Attachment i - Lilly Version of March 1 Meeting Minutes
`
`Question la:
`Does the FDA agree that toxicity and mortality data support a programmatic inteivention to
`improve patient safety in LY231514 trials and that daily low dose fo/Fc acid supplementation
`appropriately seives this purpose.
`
`FDA Response: The addition of vitamins to the pivotal trial(s) is at Lilly's risk. We share your
`concerns about toxicity: your options include:
`
`Temporarily closing the trial and conducting a new Phase i trial with MTA + vitamins.
`Stop the current trial and open a new trial using a new protocol and new dose.
`Continue the current trial with the addition of vitamins and with a recalculated sample size to
`provide adequate power for comparisons.
`
`Consensus Aqreement for Question la
`Lilly agrees to option #3
`After approx. 150 patients are treated on the revised protocol with vitamin
`supplementation, a survival analysis win be done pooling the approx. 150 patients with
`vitamin supplementation with the approx. 150 patients without vitamin
`supplementation
`
`Lilly will soon submit to the FDA a prospective detailed plan for the analysis.
`
`Question lb:
`Does the FDA agree that a randomized trial comparing patients receiving L Y23 1514 with and
`without vitamins is no longer feasible or advisable give the demonstrated toxicity risks to
`LY231514 patients?
`
`FDA Response to Question lb
`See response to la
`
`Question 2:
`Do the proposed analyses of efficacy and safety described here for Study JMCI-1 sufficiently
`address the impact of the folìc acid supplementation intervention on the results of this trial such
`that the trial will qualify as a randomized, well-controlled trial for the mesothelioma and NSCLC
`indications?
`
`FDA Response to Question 2
`We do not believe the proposed changes would allow us to adequately determine the benefit of
`adding vitamins to this trial. The proposed package for registering MTA is weakened by these
`changes. Tampering with the pivotal trials does not strengthen the case for well-controlled trials.
`There is no standard dose of vitamins administered to patients and we believe this is problematic.
`Please specify exact dose(s).
`
`Consensus Aqreement for Question 2
`Sponsor will provide dosing information for each patient (i.e., patient diary, pill count)
`
`CONFIDENTIAL
`ELAP000I 4738
`
`Lilly Ex. 2109 pg. 10
`Sandoz v. Lilly IPR2016-00318
`
`

`
`Attachment 1 - Lilly Version of March 1 Meeting Minutes
`
`Continued FDA Response to Question 2
`
`should submit a revised statistical plan before proceeding with this trial.
`
`Continued Consensus Aqreement for Question 2
`Specifically, the plan should contain information with the interim analysis on survival, and
`the statistics tests proposed for analyzing vitamin supplementation. A Type i error
`penalty is necessary if the trial should be stopped.
`
`Question 3a
`Does the agency support the replacement of vinote/bine with doce faxe! as the comparator in the
`JMBQ study?
`
`FDA Resconse to Question Sa
`No. A new trial should be initiated. A new protocol
`should
`- -
`-
`-
`-
`.
`be submitted. Does the proposed sample size have sufficient power to demonstrate superiority of
`MTA over taxotere? The trial is too small to demonstrate equivalence.
`
`Consensus Aqreement for Question 3
`Taxotere is an acceptable comparator.
`
`Question 3b
`Does the agency agree that these modifications will al/ow Study JMBQ to continue fo sive the
`role of a randomized, well-controlled trial ¡n support of the mesothelioma and second-line NSCLC
`indications, as previously discussed ¡ri the End-of-Phase Il meeting ¡n June of 1999?
`
`FDA Response to Question 3b
`We remind you that two trials in NSCLC will be required to obtain this claim. In addition your eligibility
`in the lung cancer triai should be similar to the taxotere trial in order to gain approval based on equivalence.
`
`Consensus Agreement to Question 3b
`Taxol prior therapy is acceptable with stratification.
`Patients who progress on prior thery will be acceptable in the labeling.
`Sponsor will submit a proposal for i
`line NSCLC.
`
`FDA will get back to sponsor on the number of trials in NSCLC and no commitment is
`made at this meeting.
`
`CONFIDENTIAL
`ELAP000I 4739
`
`Lilly Ex. 2109 pg. 11
`Sandoz v. Lilly IPR2016-00318
`
`

`
`Attachment i - Lilly Version of March 1 Meeting Minutes
`
`Additional Comments from the FDA
`
`Your proposed clinical benefit response is not acceptable. At a minimum you must use the
`Agency's Clinical Benefit Response table listed below for the mesothelioma trial. This table is
`also listed in the meeting minutes dated June 25, 1999. Please note that clinical benefit
`response alone, as measured in this study, will not be a basis for approvaL
`
`Clinical Benefit Response Criteria
`
`change in pain
`Intensity
`
`change in analgesic
`consumption
`change in
`performance status
`(Karnofs/cy)
`
`Weight change
`Dyspnea
`
`Pancrease ca
`GEMZ4R
`
`50% reduction
`
`250% reduction
`
`20 point
`improvement
`
`7% increase
`
`Lilly Mesothelioma
`MTA
`
`¡Omm decrease on
`a 100mm visual
`analog scale
`30% reduction
`
`20 point
`improvement
`
`N/A
`210 mm decrease on
`a 100 mm visual
`ana log scale
`
`FDA
`Recommendations for
`Mesothelioma erial
`250% reduction
`
`50% reduction
`
`220 point
`improvement
`
`250% reduction
`
`Please note the changes proposed in the Clinical Benefit Response as shown in Attachment
`2. Lilly wishes to note that it had already agreed to use the criteria of
`50 % reduction for the
`change in analgesic consumption as agreed to page 6 of the IND submission serial no. 182
`on September 15, 1999 and this was instituted beginning with version (b) of protocol JMCH.
`
`More justification should be submitted than you have presently for the use of MTA + vitamins.
`
`Lilly has provided justification forthe use of folio acid and vitamin B12 in the "LY231514
`(MTA) Safety Analysis" that was part of the IND safety report (submitted to the IND as serial
`#195 on December 3, 1999) and also in the briefing document for this meeting (see IND
`submission #207 on Feb. 16, 2000, p. 12). Further justification was provided to the FDA in
`discussions at the March 1 meeting. Additionally Lilly believes that further analysis of
`patients after a larger number of patients with vitamin supplementation have been accrued
`will justify this safety intervention.
`
`CONFIDENTIAL
`ELAP000I 4740
`
`Lilly Ex. 2109 pg. 12
`Sandoz v. Lilly IPR2016-00318
`
`

`
`Attachment i - Lilly Version of March 1 Meeting Minutes
`
`THE PROTOCOL - H3E-JMCH
`2714/99;serial #206
`
`Revised Protocol Sections
`
`Page 3:
`
`A rationale for the Bi 2 injection has not been provided
`
`The rationale for Bi 2 has been provided n the "LV231514 (MTA) Safety Analysis" and in the
`briefing document for the March 1 meeting. This rationale will be added to the protocol with the
`upcoming protocol amendment.
`
`Protocol H3ED-MC-JMCH(d)
`
`Page 16: A rationale for the dose, timing and schedule of administration of the vitamins has not
`been provided. What ¡s the evidence that folate/B12 repletion will not stimulate tumor growth
`prior to the administration of chemotherapy?
`
`The amount of folio acid (350 to 1000 i.tg) being given is in the range of the amount of folic acid
`ingested in a normal diet (estimates of folic acid in the scientific literature are in the range of
`200 to 300 pg per day and the Recommended Dietary Allowance for folic acid is 400 pg daily
`(this is also the typical dose of folic acid found in multivitamins). Thus there should be little it
`any risk of such a low dose of folic acid to stimulate tumor growth. For vitamin B12, literature
`searches found no evidence for stimulation of tumor growth by this vitamin.
`
`Page 20: A creatinine clearance derived with urine collection and serum creatinine may achieve
`the goal of patient safety better than calculated crea finine clearance derived by formula and
`serum creatinine.
`
`Calculated clearance factors in the most important variables such as weight and gender. There
`can be variability in creatinine clearance derived from urine collection due to incomplete urine
`collection and lab variability in determinations of urine and serum creatinine. With both
`methods suffering from inherent flaws, we feel that the calculated clearance is sufficient to
`estimate renal function in patients on this study.
`
`Page 30: Are leucovorin and thymidine rescue still necessary ¡f vitamins are added to the
`protocol?
`
`Leucovonn and thyrnidine may be of benefit for patients who experience severe toxicity despite
`prophylactically receiving folic acid and vitamin B12.
`
`Page 38: In the Disease Status section, delete reference to photographs of skin and oral lesions.
`
`Lilly agrees to delete this reference in the next protocol amendment.
`
`Page 51: Data Analysis Methods: there are no specifics for the evaluation of the impact of
`vitamins on efficacy endpoints.
`
`Lilly has provided this
`
`see Lilly data analysis in Attachment 2.
`
`Page 52: An intent-to-treat analysis should also be performed.
`
`Lilly agrees to this.
`
`CONFIDENTIAL
`ELAP000 14741
`
`Lilly Ex. 2109 pg. 13
`Sandoz v. Lilly IPR2016-00318
`
`

`
`Attachment i - Lilly Version of March 1 Meeting Minutes
`
`Page 54-56: Since the plan is to complete the accrual of patients to the pivotal trial, fije rationale
`for the interim analysis is weak. Lilly may believe that evidence in their interim analysis may
`support early filing and stopping of the triaL The FDA is not convinced that clinical benefit
`response data will warrant early filing. The interim analysis for efficacy endpoints should be
`deleted. Alternatively, Lilly may accrue all the required patients and then perform an interim
`analysis of the first 75 patients per arm.
`
`Lilly agrees that the interim analysis will be performed after accrual cf the first 75 patients on
`each arm that have received vitamin supplementation. If a survival benefit (based on data for
`all patients - both those supplemented with vitamins and those that were not supplemented)
`for the LY231 514 arm is shown at the interim analysis for the mesothelioma registration trial a
`submission may be made for this indication for consideration of full approval based on these
`data. Furthermore, if response rate, time-to-progression, and clinical benefit all show
`statistically significant benefit in the LY231 514 containing arm among patient receiving vitamins
`compared to patients receiving vitamins in the control arm, FDA still agrees to grant accelerated
`approval for LY23151 4 for this indication. The official DODP minutes from the ,June 25, 1999
`End of Phase 2 meeting state, "However, if responses can be convincingly demonstrated and
`there are clinically relevant and statistically significant differences for all three endpoints
`(response rate, time-to-progression, and clinical benefit), the results would be sufficient for
`accelerated approval."
`
`CONFIDENTIAL
`ELAP00014742
`
`Lilly Ex. 2109 pg. 14
`Sandoz v. Lilly IPR2016-00318