3%
`
`Lilly Research Laboratories
`A DlVlSlOn of Eli Lilly and Company
`
`Lilly Corporate Center
`lndianapolis.
`lndiana 46285
`(317) 276-2000
`
`September 8, 1998
`
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Division of Oncologic Drug Products, HFD-150
`1451 Rockville Pike
`
`Rockville, MD 20852-1448
`
`Subject:
`
`IND 40,061, MTA (LY231514) -- Serial no. 130
`End-of-Phase ll Meeting (mesothelioma and non-small cell lung
`cancer)
`
`Reference is made to our July 29, 1998 (serial no. 126) submission of an End—of—
`Phase 2 briefing document and your August 5, 1998 communication regarding
`two End-of—Phase 2 meetings. The meetings to discuss MTA include a
`discussion on Biopharmaceutic issues (September 23, 1998 at 1:00 P.M.) and a
`second discussion on Clinical issues (September 25, 1998 at 1:00 P.M.)
`concerning the development of MTA for patients with mesothelioma and non-
`small cell lung cancer.
`
`In addition, we would like to withdraw questions 9a, 9b and 9c which requested
`information related to head and neck cancer; our intent is to focus our
`discussions on the development of MTA for mesothelioma and non-small cell
`lung cancer. As the data matures for other tumor types, we plan on having
`similar discussions with you on the appropriate clinical plan for those tumor
`types.
`
`Since the submission of the original briefing document on July 29, 1998, we have
`further refined certain aspects of MTA development. Dr. Hamburger notified Ms.
`McCol|um on August 26, 1998 that the subject letter would be provided in early
`September. This letter details the following changes:
`
`CONFIDENTIAL
`
`ELAPOOOOT714
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`

`
`Food and Drug Administration
`IND 40,061, MTA (LY2315 14)
`September 8, 1998
`
`1)
`
`2) Change from a specific folate, B5 and B12 tablet to an off-the-shelf vitamin
`with a focus on a range of folate content:
`
`3) Changes to the mesothelioma trial, JMCH (Protocol H3E-MC-JMCH, “A
`Randomized Phase 3 Trial of MTA plus Cisplatin versus Cisplatin in Patients
`with Malignant Pleural Mesothelioma’’):
`
`Changes to the NSCLC trial, JMBQ (Protocol H3E-MC-JMBQ, “A Phase 2/3
`Trial of MTA vs Vinorelbine in Patients Previously Treated with Only One
`Platinum Plus Taxane-Based Regiment for Locally Advanced or Metastatic
`Non-Small Cell Lung Cancer”):
`
`Changes to the recruitment strategies for the renal impairment trial, JMAW
`(Protocol H3E-MC—JMAW, “A Phase I Pharmacokinetic Trial of LY231514
`Administered lntravenously Every 3 Weeks in Advanced Cancer Patients with
`Varying Degrees of Renal Function”):
`
`6) Changes in Population Pharmacokinetics analysis plan:
`
`Outlined below are the major changes with brief explanations as to each of
`previously mentioned points. Because of the nature of certain changes
`additional questions are provided (numbering consecutive from the previous
`briefing document).
`Redacted
`
`CONFIDENTIAL
`
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`
`Food and Drug Administration
`IND 40,061, MTA (LY2315 14)
`September 8, 1998
`
`Formulation
`
`Freeze Dried for
`
`Concentrated solution for
`
`ty I e
`
`Concentration
`
`reconstitution for infusion
`Current formulation
`
`infusion.
`Marketed formulation
`
`For JMCH, it is anticipated that the C.S.l. will be available at the initiation of
`this trial. However, if the marketed formulation (C.S.l.) is not available, it is
`our intention to start this trial using the freeze-dried material, and switch to
`the C.S.|. as soon as possible.
`
`Finally, it is our intention when C.S.l. is available that subsequent therapy for
`all patients will be with this formulation; that includes patients already treated
`with the freeze-dried material.
`
`Question 10a: Do you agree that the switch from the freeze-dried material to
`the C.S.l. is not a significant formulation change?
`
`Question 10b: Do you agree that the safety and efficacy data obtained from
`patients receiving any MTA formulation can be integrated across the
`analyses?
`
`Recently, an issue arose regarding impurities in the C.S.l. as described
`below.
`Redacted
`
`CONFIDENTIAL
`
`ELAPOO0O7716
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`

`
`Food and Drug Administration
`IND 40,061, MTA (LY2315 14)
`September 8, 1998
`
`Our qualification plan is that MTA containing the new related substances will
`not be administered to patients until the new materials have been qualified in
`appropriate Toxicology studies, conducted in compliance with guidance on
`(ICH Guidance QSA, “|mpurities in New Drug Substances”, and ICH
`Guidance Q3B, “lmpurities in New Drug Products”) impurities in new drug
`products. Specifications will be set on the-these new related substances in
`the event that these substances cannot be eliminated in future batches.
`
`Question 10c: Do you agree with this strategy?
`
`As discussed in the original briefing document, homocysteine, an amino acid
`that is a marker for folate deficiency, was shown by multivariate analysis to
`identify patients who might be at risk of developing serious toxicity from MTA
`administration. Thus, it was proposed to test the hypothesis that
`supplementing patients with folic acid (and other associated vitamins such as
`B5 and B12) may ameliorate toxicity associated with MTA.
`
`It was our original plan to utilize a customized vitamin tablet but we have
`altered our plans because of quality and significant regulatory issues outside
`the United States related to obtaining, analyzing and supplying the custom
`formulated vitamin tablets.
`In response to these issues, we have decided to
`utilize over-the-counter multivitamins containing folic acid; therefore, the
`protocols will be amended to use over-the counter vitamin preparations
`containing approximately 400 pg of folic acid, which is the daily U.S.
`Recommended Dietary Allowance (RDA) and at least the RDA for Be and
`B12; the tablets may contain other vitamins which do not impact on the folate
`pathway. Over-the-counter multivitamins containing folic acid will be used in
`both the mesothelioma trial, JMCH, and the NSCLC trial, JMBQ.
`
`a) Thus, the revised version of the international randomized Phase 3 trial
`(Protocol JMCH) of MTA plus cisplatin versus cisplatin in patients with
`malignant pleural mesothelioma will allow a multivitamin containing from
`350 to 600 pg of folic acid; the range reflects the availability of vitamin
`
`.
`
`CONFIDENTIAL
`
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`

`
`Food and Drug Administration
`IND 40,061, MTA (LY23l514)
`September 8, 1998
`
`tablets containing folic acid in different countries. The multivitamin tablets
`containing folic acid will be obtained locally in the country where the trial is
`being conducted, and the type and content of the tablets will be collected.
`
`Question 11a: Do you agree that this is acceptable and that the safety and
`efficacy dataset from this trial will not require any subsetting for this type
`of vitamin tablet?
`
`b) For the revised version of the US randomized trial (JMBQ) in patients with
`non-small cell lung cancer trial, over-the-counter (OTC) vitamin tablets
`containing 400 pg of folic acid will be used in this trial. These multivitamin
`tablets will also contain vitamin B5 and B12 in amounts equal to or
`exceeding the RDA for these two vitamins.
`It is planned to use a specific
`OTC multivitamin from a single vendor for the Phase 2 portion of this trial.
`Then, it is our intent to make a switch to allow for use of any OTC
`multivitamin containing 350 to 600 pg of folic acid and at least the RDA for
`B6 and B12 for the Phase 3 portion of this trial.
`
`Question 11 b: Do you agree that the switch of multivitamin tablet source
`after the Phase 2 portion will not jeopardize our plans to integrate the Phase
`2 and 3 safety and efficacy data as the final analysis?
`
`In addition to administrative changes, please note the following changes that
`have been made to protocol, JMCH:
`
`a) Section 2.2, Secondary Objectives (p. 6952, original page number of
`briefing document):
`0 Addition of 6 month, 1 year and 2 year survival as secondary
`endpoints (median survival is already included as a secondary
`endpoint).
`
`b) Section 3.1, Summary of Study design (p. 6952):
`o
`In section A, addition of “Dexamethasone 4 mg, or equivalent should
`be taken orally twice per day on the day before, the day of, and the
`day after each dose of MTA”.
`In section B, addition of “Dexamethasone 4 mg, or equivalent should
`be taken orally twice per day on the day before, the clay of, and the
`day after each dose of cisplatin’’. Also changed to multivitamin
`containing 350 to 600 pg of folic acid from the originally proposed
`vitamin tablet with specified amounts of folic acid, vitamin B6 and
`vitamin B¢2— this same change was made throughout the protocol.
`
`CONFIDENTIAL
`
`ELAPOOOOT718
`
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`Sandoz v. Lilly IPR2016-00318
`
`

`
`Food and Drug Administration
`IND 40,061, MTA (LY231514}
`September 8, 1998
`
`o
`
`c) Section 3.4.2.1, Inclusion Criteria (p. 6954):
`0 Addition at end of [1] — ‘‘In case of a discrepancy between the
`assessment of the independent review and the investigator, the
`assessment of the independent reviewer will take precedence.”
`In [3] (p. 6955), for patients who have undergone pleurodesis, if
`bleomycin was used in this procedure, there must be a 1-week delay
`before MTA or cisplatin is administered.
`In [7] alkaline phosphatase, aspartate transaminase and alanine
`transaminase 53.0 times “upper limit of normal” rather than “normal”;
`also alkaline phosphatase, AST and ALT 55 times “upper limit of
`normal” rather than “normal” if liver has tumor involvement. Change to
`“Albumin g3.0 g/dL” from “Albumin _>_2.5 g/dL”.
`
`d) Section 3.4.2.2, Exclusion Criteria (p. 6956):
`0 Addition of [19] — “Inability to discontinue any supplemental vitamins
`(other than those stipulated in the protocol) which contain folic acid.”
`0 Addition of [20] — “Disease which cannot be radiologically imaged.”
`
`e) Section 3.5, Patient Assignment (p. 6957)
`0 Addition - “Each country will be a stratum.”
`
`f) Section 3.9.1.2, Efficacy Criteria (pp. 6964 - 6965):
`- Addition - ‘‘In case of a discrepancy between the assessment of the
`independent panel and that of the investigator, the independent
`pane|’s assessment will take precedence.”
`Under Disease Status, the definition of Evaluable disease was
`changed to read “Unidimensiona||y measurable lesions with clearly
`defined margins, palpable lesions with either diameter greater than 2
`cm, or bone disease.”
`
`Under “Partial Response”, the first sentence was changed to read,
`“Applies only to patients with at least one unidimensionally or
`bidimensionally measurable |esion.”
`
`g) Section 3.10.4, Post Study Follow-Up (p.6971):
`o Addition — “Responding patients will have a follow-up CT scan
`approximately 1 month after the last dose of MTA or cisplatin. All
`patients will be followed approximately every 3 months after the last
`dose of MTA or cisplatin in order to record the date of disease
`progression or death, and any post study chemotherapy, radiotherapy
`or surgical intervention. All patients will be followed until death or they
`are lost to follow-up.
`If alternative anticancer therapy is given, details
`of this will be collected and patients may be censored at that point.”
`
`CONFIDENTIAL
`
`ELAPOO0O7719
`
`Lilly Ex. 2099
`Sandoz v. Lilly IPR2016-00318
`
`

`
`Food and Drug Administration
`IND 40,061, MTA (LY231514)
`September 8, 1998
`‘
`
`h) Section 4.5, Efficacy Analysis (p. 6973):
`- Addition — “While efficacy data as reported by study investigators will
`be presented in the final report, the principal efficacy results will be
`based on the independent review of data.”
`
`4)
`
`In addition to administrative changes, please note the following changes that
`have been made to protocol, JMBQ:
`
`a) Section 2.2, Phase 2: Secondary Objectives (p. 6865)
`0 Addition of time to tumor progression and survival (6 month, 1 year,
`median) as secondary end-points for the phase 2 portion of JMBQ
`
`Section 2.4 of protocol, Phase 3: Secondary Objectives (p. 6865).
`- Addition of survival (6 month, 1 year, 2 year) as secondary end-points
`for the phase 3 portion of JMBQ Median survival is already included as
`a secondary objective in the Phase 3 portion.
`
`Section 2.4 (Phase 3: Secondary Objectives, p. 6865)
`Section 3.10.2 (Qualifications for Analysis, p. 6887)
`Section 4.5 (Efficacy Analysis, p.6889).
`o For Quality of Life assessment, the EORTC QLQ-C80 and the LC13
`symptom scales will be administered at the end of Cycle 2 (6 weeks)
`rather than 2 months.
`
`Section 3.1, Summary of Study Design (p. 6866 - 6867)
`0 Delete fourth sentence in the second paragraph — “lf the Phase 2
`results indicate a tumor response rate less than 10% in the combined
`MTA arms, the trial will be stopped and the conclusion drawn that MTA
`is not worthy of further development for this patient population.”
`Substitute “lithe Phase 2 results indicate a tumor response rate less
`than 10% in the combined MTA arms, and there is also less than a
`50% increase in time to tumor progression as compared to the
`vinorelbine arm, the trial will be stopped and the conclusion drawn that
`MTA is not worthy of further development for this patient population.”
`
`5) The following change will be made to the ongoing Phase 1 trial with MTA in
`cancer patients with varying degrees of renal function (JMAW).
`
`The following will be added at the end of the first paragraph on p. 6753:
`“Due to a toxic death for a patient enrolled in treatment group 4, the
`following strategy will be employed. Treatment group 3 has been split into
`groups 3A and 3B. Safety will be assessed on at least three patients in
`
`CONFIDENTIAL
`
`ELAPOO0O772O
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`Lilly Ex. 2099
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`

`
`Food and Drug Administration
`IND 40,061, MTA (LY231514)
`September 8, 1998
`
`If there are no patients with
`Treatment group 3A at 150 mg/m2 dose.
`dose-limiting toxicity, then patients will be enrolled into treatment group
`3B. Treatment Group 4 is closed to enrollment until further safety
`information can be assessed for patients in Groups 3A and 3B.
`
`Treatment Group 1A: GFR >79
`Treatment Group 1B: GFR 60-79
`Treatment Group 2:
`GFR 40-59
`Treatment Group 3A: GFR 30-39
`Treatment Group 3B: GFR 20-29 (currently closed until safety assessed
`in 3A)
`Treatment Group 4:
`toxic death)"
`
`GFR < 20 (currently closed to enrollment due to
`
`6) Issue 5. Population Pharmacokinetics, (p. 6752)
`
`Please replace in paragraph 2, sentences 5 - 7 “Our intent is to provide in
`the NDA a discussion of population pharmacokinetics in a stand-alone
`summary using information obtained from the Phase 2 monotherapy studies
`in which appropriate pharmacokinetic assessments were obtained.
`Population phannacokinetics will also be carried out in Study JMBQ.
`Study JMCH (MTA plus cisplatin in mesothelioma) population
`pharmacokinetics for both MTA and cisplatin will be done. The parameters
`selected and types of analyses will be determined when more data is
`available."
`
`In
`
`with:
`
`“The population pharmacokinetic strategy is to provide a separate analysis for
`Phase 2 studies, for NSCLC, and for Mesothelioma.
`In addition, a combined
`analysis will be performed after combining data from Phase 2 studies with
`data from the Mesothelioma study and after combining data from the Phase 2
`studies with data from the NSCLC study.
`In addition, population
`pharmacodynamic analysis will be performed to model the time course of
`neutrophil and platelet counts as a function of time. A combined
`pharmacodynamic analysis will also be performed as described above for the
`pharmacokinetic analysis.”
`
`CONFIDENTIAL
`
`ELAPOOOOT721
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`Lilly Ex. 2099
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`

`
`Food and Drug Administration
`IND 40,061, MTA (LY23l514)
`September 8, 1998
`
`Listed below are our attendees for the following two meetings:
`
`September 23 Biopharmaceutics meeting
`
`Eli Lilly and Company Employees
`Doug Balogh, Ph.D., Senior Development Projects Manager
`Steven Hamburger, Ph.D., Regulatory Research Scientist, Cancer
`Allen Harkness, Senior Regulatory Representative, Chemistry.,
`Manufacturing. and Control
`Robert D Johnson, Ph.D., Senior Pharmacokineticist
`Mary Pat Knadler, Ph.D., Drug Disposition Research Scientist
`Clet Niyikiza, Ph.D., Research Scientist, Statistician
`David Seitz, M.D., Medical Advisor
`Jackie Walling, Ph.D., Director of Science and Operations for MTA Product
`Team
`
`John Worzalla, Senior Regulatory Representative, Cancer
`Consultant to Eli Lilly and Company
`Sharyn Baker, Pharm.D., Cancer Therapy and Research Center -- San
`Antonio Cancer Institute
`
`.
`
`Se tember 25 Medical meetin
`
`Eli Lilly and Company Employees
`Gregory Brophy, Ph.D., Director US Regulatory Affairs
`Steven Hamburger, Ph.D., Regulatory Research Scientist, Cancer
`Astra Liepa, Pharm.D., Health Outcomes Associate
`Clet Niyikiza, Ph.D., Research Scientist, Statistician
`David Seitz, M.D., Medical Advisor
`Anna Maria Storniolo, M.D., Medical Director, Cancer Research
`Gerald L. Thompson, Ph.D., MTA Product Team Leader
`Jackie Walling, Ph.D., Director of Science and Operations for MTA Product
`Team
`
`‘
`
`John Worzalla, Senior Regulatory Representative, Cancer
`Consultants to Eli Lilly and Company
`Ned Patz, M.D., Duke University
`Nicholas Vogelzang, M.D., University of Chicago
`
`CONFIDENTIAL
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`

`
`Food and Drug Administration
`IND 40,061, MTA (LY231514)
`September 8, 1998
`
`7091 . 10
`
`To facilitate our discussions during these two meeting, we request:
`c
`an updated list of the FDA attendees to each meeting.
`o
`a copy of your responses to our questions and any questions or issues that
`you may have prior to each meeting.
`
`If you require any additional information or clarifications, please contact Dr.
`Steven Hamburger at (317) 277-8900 or me at (317) 277-3799.
`
`Sincerely,
`
`ELI LILLY AND COMPANY
`
`1‘
`
`Gregory T. Brophy, Ph.D.
`Director
`
`U.S. Regulatory Affairs
`
`.
`
`cc: Ms. Linda McCo||um (14 desk copies)
`
`CONFIDENTIAL
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`ELAPOOOOT723
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