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`Lilly Research Laboratories
`A Division 0! Eli Lilly and Company
`
`Lilly Corporate Center
`lndianapolrs, Indiana 46285
`317.276.2000
`
`December 22, 1999
`
`Food and Dn.rg Administration
`Center for Drug Evaluation and Research
`Division of Oncology Drug Products, HFD-150
`do Mr. A|ViS DUHSOFI
`5600 Fishers Lane
`Rockville, MD 20857
`
`Expedited Review Requested
`
`IND 40,061, MTA (LY231514)
`Subject:
`Response to FAX to Lilly from the FDA on December 21, 1999
`
`Serial No. 201
`
`In a FAX sent on December 21, 1999 from Mr. Alvis Dunson to Lilly, it states that the
`FDA Medical Officer reviewing LY231514 does not support the Lilly decision to add
`vitamins to its ongoing pivotal trial in mesothelioma. This FAX from the FDA further
`states that “the pivotal trial in malignant mesothelioma (H3E-MC—JMCH) should not be
`altered at this stage”. Later in the December 21 FAX, it mentions that “the information
`provided in the Annual Report (serial #191) about the toxicities in the trial (pages 45-46)
`does not appear to support the addition of vitamins”.
`
`Lilly has further information regarding toxicity in the mesothelioma registration trial
`(H3E-MC-JMCH) since the annual report that was submitted (serial number no.191) on
`November 8 (the cut-off date for data in the annual report was September 10).
`It is the
`information contained in the additional data discussed below that prompted the action
`to supplement patients with folic acid and vitamin B12 in the ongoing pivotal
`mesothelioma trial.
`
`In response to the Medical Officers comments in the December 21, 1999 FAX (the
`responses below are in the order of the reasons presented by the FDA)
`1) Lilly plans to submit a statistical analysis plan describing how the data can be
`compared before and after vitamin supplementation. Protocol amendment H3E-
`MC-JMCH(c) being sent today under separate cover (serial number 200) describes
`analysis for toxicity in cycles where patients did and did not receive vitamin
`supplementation.
`2) Lilly is committed to completing this 280 patient trial in malignant mesothelioma
`even if the results are positive at interim analysis. The addition of vitamins does not
`signify any change in our commitment to complete this registration trial.
`3) There is additional information concerning toxicity in the mesothelioma registration
`trial since the annual report. As of December 21, 1999 there have been six patient
`deaths reported to Lilly for the mesothelioma registration trial in a total of 129
`
`TRIIL
`EXHIBIT
`
`2262
`
`CONFIDENTIAL
`ELAPOOO13431
`
`Lilly Ex. 2105
`Sandoz V. Lilly IPR2016-00318
`
`2262
`
`Lilly Ex. 2105
`Sandoz v. Lilly IPR2016-00318
`
`

`

`Food and Drug Administration
`December 22, 1999
`
`Page 2
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`patients randomized between the two arms of this trial. The deaths were distributed
`as follows:
`For the patients receiving cisplatin, but not LY231514, there has been one
`death, which has been attributed to progressive disease.
`For the patients receiving LY231514 plus cisplatin, there have been five deaths,
`three of which have been classified as possibly or probably drug related (the
`other two deaths have been attributed to progressive disease).
`
`The “LY231514 Safety Analysis” (submitted as an attachment to the FDA on
`December 3, 1999; serial no. 195) provided evidence for the strong relationship
`between high baseline homocysteine and severe toxicity for patients treated with
`LY231514.
`In the mesothelioma trial, more than 40% of patients have high
`baseline homocysteine levels. Because of the differences observed in mortality in
`the two anns of the trial and knowing that a high proportion of future LY231514
`patients would be at risk for severe toxicity due to their high baseline homocysteine
`level, Lilly felt that action to ensure patient safety was warranted.
`
`Lilly consulted a number of oncology experts regarding this patient safety concern. including
`Drs. Hilary Calvert, Mark Green, Richard Gralla, and Paul Bunn.
`In addition, Lilly consulted
`with Dr. Robert Allen, an expert in the area of folic acid metabolism. These consultants
`were in unanimous agreement that intervention was necessary to promote patient safety in
`the LY231514 trials. They all further suggested that supplementation with folic acid would
`offer the best chance of reducing serious toxicity to the broadest patient population. These
`experts felt that supplementation with low levels of folic acid would not adversely
`affect efficacy of LY231514. There were many discussions as to the optimum way that
`vitamin supplementation would protect the patients from toxicity. Eventually Lilly went with
`the recommendation to supplement with a low amount of folic acid (in the range of the FDA
`recommended daily dietary allowance) together with vitamin B12 (to possibly protect the
`small proportion of patients who might not benefit from folic acid alone). Because Lilly feels
`that the addition of folic acid together with vitamin B12 is necessary for patient safety, we
`are strongly committed to the use of these vitamins in the mesothelioma registration trial.
`We are aware that there are implications of this action for the LY231514 label.
`Lilly believes that the primary endpoint of survival as well as the secondary efficacy
`endpoints for the malignant mesothelioma registration trial will not be negatively
`affected by the supplementation with vitamins. As mentioned in Section 3 of the
`“LY231514 (MTA) Safety Analysis” (attachment to serial no. 195) folic acid has
`ameliorated toxicity in a phase 2 gastric cancer study and there have been several
`patients with confirmed partial responses in this study.
`
`If the Medical Officer still does not support adding vitamins to this ongoing
`mesothelioma registration trial after reviewing the additional toxicity evidence provided
`in this letter, then Lilly would please request a face to face meeting at DODP’s eartiest
`convenience. Due to the impact of such an evaluation for an ongoing registration trial,
`Lilly requests that consideration be given to grant such a meeting as a Type A meeting
`under the February 1999 Guidance for Industry, “Formal Meetings with Sponsors and
`Applicants for PDUFA Products”. The topic for discussion at this meeting would be as
`follows:
`What are the implications of Lilly’s decision to promote safety in patients treated
`with LY231514 by supplementing them with amounts of folic acid in the range of the
`
`CONFIDENTIAL
`ELAPOOO13432
`
`Lilly Ex. 2105
`Sandoz V. Lilly IPR20l6-00318
`
`Lilly Ex. 2105
`Sandoz v. Lilly IPR2016-00318
`
`

`

`Food and Drug Administration
`December 22, 1999
`
`Page 3
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`FDA recommended daily dietary allowance (together with vitamin B12) in the
`ongoing mesothelioma registration trial (H3E-MC—JMCH)?
`If such a meeting is necessary, Lilly will make a submission with details and specific
`questions for this meeting as per the guidance listed above. Lilly will request a meeting
`to occur within 30 days of FDA’s receipt of such a meeting request.
`
`Please contact Mr. John F. Woizalla at (317) 276-5052 or me at (317) 277-3799 if you
`require any additional information or clarification.
`
`Sincerely,
`
`ELI fin! AN; COMPANY
`
`Gregory T. Brophy, Ph.D.
`Director -
`U.S. Regulatory Affairs
`
`CONFIDENTIAL
`ELAPOOO13433
`
`Lilly Ex. 2105
`Sandoz v. Lilly IPR2016-00318
`
`Lilly Ex. 2105
`Sandoz v. Lilly IPR2016-00318
`
`