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`MEETING MINUTES
`MEETING DATE: March 1, 2000 TIME: 10:30 AM LOCATION: Conf. Rm. “G"
`
`IND: 40,061
`
`Meeting Request Submission Date: January 25, 2000
`Briefing Document Submission Date: February 16, 2000
`Additional Submission Dates: None
`
`DRUG: MTA (Mu1tiTal-geted Antifolate, LY23 1 S 14)
`
`SPONSORIAPPLICANT: Lilly Research Laboratories
`
`TYPE of NIEETING:
`
`1.
`
`2.
`
`End of Phase 2 (2'“' meeting)
`
`Proposed Indication: For the use ofMTA in patients with mcsothclioma.
`
`FDA PARTICIPANTS:
`
`Richard Pazdur, M.D. — Director, Division of Oncology Drug Products
`. James Krook. M.D. - FDA ODAC Member —pre—meetin only
`John Johnson, M.D. - Medical Team Leader
`Robert White, M.D. - Medical Officer
`David Smith, Ph.D. - Statistical Team Leader
`Doo Young Lee-Ham, Ph.D - Pharmacologyfroxicology Reviewer
`Eric Duffy, Ph.D. — Chemistry Team Leader
`Alvis Dunson
`-Project Manager
`
`INDUSTRY PARTICIPANTS:
`
`Gregory Brophy, Ph.D. — Director, North American Regulatory Affairs, Cancer
`Axel Hanauske, M.D. - Medical Director, MTA Product Team
`Clet Niyikiza, Ph.D. - Research Scientist, Statistician
`Paolo Paoletti, M.D. — MTA Product Team Leader
`James Rusthoven, M.D. - Clinical Research Physician
`Brian Stuglik - MTA Product Team, Chief Operating Oflicer
`John Worzalla - Senior Regulatory Reprensative
`Paul A. Bunn, Jr., M.D. - Consultant, University of Colorado Health Science Center
`Hilary Calvert, M.D. — Consultant. University ofNewcastle, UK.
`
`.
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`. IND 40,061
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`March 1, 2000
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`MeetingMinutes
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`Page 2
`
`MEETING OBJECTIVES:
`
`To discuss changes of vitamin supplementation instituted for the ongoing rnesothelioma
`registration trial.
`QUESTIONS for DISCUSSION with FDA RESPONSE, and DECISIONS REACED:
`Question 13. Does the FDA agree that toxicity and mortality data support a programmatic
`intervention to improve patient safety in LY231S l4 trials and that daily low dose folic acid
`supplementation appropriately serves this purpose?
`
`FDA RESPONSE: The addition ofvitamins to the pivotal tria](s) is at Lilly's risk. We share
`your concerns about toxicity; your options include:
`i. Temporarily closing the trial and conducting a new Phase 1 trial with MTA + vitamins.
`2. Stop the current trial and open a trial using a new protocol and new dose.
`3. Continue the current trial with the addition of vitamins and with a recalculated sample size to
`provide adequate power for comparisons.
`
`- Lilly agrees to option #3.
`_
`0 Afier approximately 150 patients are treated on the revised protocol with vitamin
`supplementation, a survival analyses will be done pooling the approximately 150 patients
`with vitamin supplementation with the approximately 150 patients without vitamin
`supplementation. Lilly will soon submit to FDA a prospective detailed plan for this analysis.
`
`Question 1b. Does the FDA agree that a randomized trial comparing patients receiving
`LY231514 with and without vitamins is no longer
`feasible or advisable given the
`demonstrated toxicity risks to LY231514 patients?
`
`FDA RESPONSE. See 19..
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`Page 3
`Meeting Minutes
`‘ IND 40,061
`Question 2. Do the proposed analyses of efficacy and safety described here for Study .lMCl-I
`sufficiently address the impact of the folic 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. We do not believe the proposed changes would allow us to adequately
`detemiine 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
`weIl—eontrolled trials, There is no standard dose ofvitamins administered to patients and we
`believe this is problematic. Please specify exact dose(s).
`
`- Lilly will provide dosing infonnation for each patient (i.e., patient diary, pill count).
`0 Lilly will provide a revised statistical plan before proceeding with this trial. Specifically, the
`plan should contain information with respect to interim analysis on survival, and the statistics
`tests proposed for analyzing vitamin supplementation. A Type l Error penalty is necessary if
`the trial should be stopped.
`
`comparator in the JMBQ study?
`
`. Question 33. Doesthe agency support the replacement ofvinorelbinc with docetaxel as the
`FDA RESPONSE. No. A new trial should be initiated and a new protocol should be submitted.
`Does the proposed sample size have sufficient power to demonstrate superiority ofMTA over
`taxotere? The trial is too small to demonstrate equivalence.
`
`Question 3b. Does the agency agree that these modification will allow Study JMBQ to continue
`to serve the role of a randomized, well-controlled trial in support ofthe rnesothelioma and
`second-line NSCLC indications, as previously discussed in the End-of Phase ll meeting in Jlure
`of 1999?
`
`FDA RESPONSE. We remind you that two trials in NSCLC will be required to obtain this
`claim.
`in addition, your eligibility in the lung cancer trial should be similar to the taxotere trial
`in order to gain approval based on equivalence.
`
`Taxotere is an acceptable comparator.
`Taxol prior therapy is acceptable with stratification.
`Patients who progress on prior therapy will be acceptable in the labeling.
`Sponsor will submit a proposal for 1“ line NSCLC.
`FDA will get back to sponsor on the number of trials in NSCLC and no commitment is made
`at this meeting.
`
`moo ac ammm ac::I7t9
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`Meeting Minutes
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`Page 4
`
`ADDITIONAL COMMENTS.
`
`1. 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 vial. 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
`
`
`
`FDA
`
`
`
`Pancreas ca
`Recommendations for
`GEMZAR
`Mcsothelioma trial
`
` 3 50% reduction
`3 50% reduction
`3 10 mm decrease on
`a 100 mm visual
`analog scale
`3.30% reduction
`
`MTA
` Mesothoma
`
`
`.
`
`A
`
`
`
`change in analgesic
`consumption
`
`3 50% reduction
`
`
`
`3 50% reduction
`
`_ 3 2°P°*“‘
`‘mpmvemem
`
`
`
`change in pain
`intensixy
`
`.
`
`3 20 point
`improvement
`
`2 20 point
`improvement
`
`
`3 10 mm decrease on
`3 50% reduction
`n l00 mm visual
`
`
`analog scale
`
`
`
`
`yspnea.
`
`
`
`—D
`
`2. More justification should be submitted than you have presently for the use of MTA +
`vitamins.
`
`QPR as 28% @8182
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`IND 40,061
`‘
`. March 1, zooo
`
`Meeting Minutes
`
`Page 5
`
`THE PROTOCOL—l-BE-JMCH
`2/ 14/99; serial #206
`
`Revised Protocol Sections
`
`page 3:
`
`A rationale for the B12 injection has not been provided.
`
`Protocol H3E-MC-JMCI-I (cl)
`
`Page 16: A rationale for the dose, timing, and schedule of administration of the vitamins has not
`been provided. What is the evidence that folate/B12 repletion will not stimulate tumor growth
`prior to the administration of chemotherapy?
`
`Page 20: A crcatinine clearance derived with urine collection and serum creatinine may achieve
`the goal ofpatient safety better than calculated creatinine clearance derived by forrnula and
`serum creatinine.
`
`.
`
`Page 30: Are leucovorin and thymidine rescue still
`necessary it‘ vitamins are added to the protocol?
`
`Page 38: In the Disease Status section, delete references to photographs of skin and oral lesions.
`
`Page 51: Data Analysis Methods: there are no specifics for the evaluation of the‘ impact ofvitamins
`on efficacy endpoints.
`
`Page 52: An intent-to-treat analysis should also be performed.
`
`Page 54-56: Since the plan is to complete the accrual ofpatients to the pivotal trial, the 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.
`
`SPF 86 2882 28183
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`IND40,061
`March 1,2000
`The meeting was concluded at 12:30 pm.
`
`MeetingMinutes
`
`Page 6
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`‘
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`600
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`Concurrence Chair:
`
`Alvis Dunson, Project Manager
`Minmes preparer
`
`
`
`Medical Officer
`
`HPR B6 2668 88183
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`34/86/28
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`1
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`MEETING ATTENDANCE
`
`DATE: March 1,2000
`
`TIME: 10:30am
`
`PLACE:WOC2,6"‘Flr,Rm G
`
`IND: 40,061
`
`Drug: MTA
`
`SPONSOR: Eli Lilly and Company
`
`SUBJECT: To discuss recent changes in the ongoing mesothelioma registration
`trial.
`
`Organization
`i."i'r7.%3-
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`gpg 95 gag aazaz
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`321 594 @498
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