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`LY231 514 (MTA) End of Phase 2 Meeting with the FDA
`Clinical Issues - Friday, September 25, 1998 at FDA
`
`FDA Participants: Division of Oncoloqy Drug Products
`Rachel Behrman, M.D., Deputy Office Director, ODEI
`Julie Beitz, M.D., Deputy Division Director
`Gang Chen, Ph.D., Statistics Team Leader
`John Johnson, M.D., Medical Team Leader
`Robert Justice, M.D., Oncology Division Director
`Robert White, M.D., Medical Reviewer
`Liang Zhou, Ph.D., Chemistry Team Leader
`Linda McCollum, Consumer Safety Officer
`Lilly Participants:
`Greg Brophy, Ph.D., U.S. Regulatory Affairs
`Steven Hamburger, Ph.D., U.S. Regulatory Affairs
`Robert D Johnson, Ph.D., Pharmacokineticist
`Astra Liepa, Health Outcomes
`Clet Niyikiza, Ph.D., Statistician
`David Seitz, M.D., Ph.D., Medical Advisor
`Gerald Thompson, Ph.D., MTA Product Team Leader
`Jackie Walling, Ph.D., Director of Science, MTA Team
`John Worzalla, U.S. Regulatory Affairs
`Lilly Consultants:
`Ned Patz, M.D., Duke University
`Nicholas Vogeizang, M.D., University of Chicago
`
`Meeting Request Submission Date: July 13, 1998
`Briefing Document Submission Date: July 29, 1998
`Additional Submission Dates: Sept. 8, 1998
`
`Meeting Minutes:
`
`Schedule and Dose: The FDA showed the following acetate:
`
`1. DOSE and SCHEDULE - Do you agree with the proposed dosing schedule
`for single agent MTA studies - specifically the registration studies involving
`NSCLC?
`A. Our agreement is limited to the proposed dosing schedule for single
`agent MIA. There does not appear to be sufficient efficacy advantage
`with the 600 mg/rn2 dose of MTA over the 500 mg/rn2 dose. Also there
`¡s a trend for hematologic toxicity to be greater for the 600 mg/rn2 dose
`of MTA than for the 500 mg/rn2 dose. Therefore, the 500 mg/rn2 dose is
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`recommended unless a dose response for overall response has been
`shown. Alternatively, patients can start at 500 mg/rn2 and the dose can
`be escalated to 600 mg/rn2 if tolerated.
`
`The FDA agreed with the proposed 21 day dosing cycle. There was a
`discussion on the safety profile of the 500 mg/rn2 and 600 mg/rn2 MTA doses
`between Dr. Walling, Dr. White, Dr. Johnson and Dr. Vogeizang. The FDA
`recommended an MTA starting dose of 500 mg/rn2 for single agent studies with
`dose escalation to 600 mg/rn2 allowed. Dr. Walling pointed out that there was no
`significant increase in Grades 3 and 4 neutropenia seen at the 600 mg/rn2 dose
`(48% versus 41% at the 500 mg/rn2 dose, but the increase was not statistically
`significant). Also no excess of toxic deaths has been seen with the 600 mg/rn2
`dose. There is not enough data yet to examine the dose response with respect
`to efficacy, but Lilly agreed to the 500 mg/rn2 starting dose.
`
`The following addition to IA was provided.
`
`FDA recommendation to use 500 mg/rn2 ¡s advice and not a requirement.
`
`Mesothelioma: The FDA showed the following acetate:
`
`1. MTA in Mesothelioma - The indication being pursued is "MTA Injection is
`indicated for the treatment of pleural mesothelioma."
`
`FDA Preliminary comment: Usually, lead indications are approved with two
`studies. Mesothelioma is a rare disease. Depending on the quality of the
`mesothelioma trial design and data, further discussions may convince the
`Agency to accept one mesothelioma study and confirmatory evidence from a
`closely related disease.
`
`2a Do you agree this ¡s an acceptable registration strategy (i.e., patient
`population, patient numbers, endpoints) for accelerated approval for this
`indication?
`A. NO. Serial measurement of disease are difficult and inaccurate in
`mesothelioma. Confirmation of responses by FDA is likely to be
`impossible and the clinical benefit of response in mesothelioma is
`uncertain.
`B.. Accelerated approval based on response rate is unlikely. In order to
`gain accelerated approval with the combination of MTA + cisplatin,
`you would have to provide evidence that MTA + cisplatin is better
`than any other combination in response and response duration.
`Survival should be the primary endpoint. Since survival is short in
`this population, it should not take long to reach the endpoint.
`Tumor related symptoms could also be addressed in a blinded trial.
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`A lengthy discussion took place on the issues of response rate and
`unidimensional measurements for mesothelioma. These discussions were led
`by Ors. Vogeizang and Patz. Dr. Vogeizang explained that unidimensional
`measurements can be easily obtained, the number of responders is always low
`and a high correlation was shown in a recent paper between clinical benefit and
`response. Dr. Patz explained how the CT scans can have resolution down to I
`mm, and that the scans would be digitized and blinded and then read only by Dr.
`Patz and a colleague in France. Dr. Patz showed an acetate (#1) with W.H.O.
`guidance on the use of unidimensional measurements and another acetate (#2)
`with a table showing good concordance between uni and bi-dimensional tumor
`measurements. Dr. White noted that there were no mesothelioma studies which
`correlated these measurements. A number of slides with several mesothelioma
`scans were shown and the technique for using unidimensional measurements
`was discussed. A discussion suggesting several ways in which unidimensional
`measurements could be taken at different locations and what changes in these
`measurements would qualify for a response did not sway the FDA concerning
`response rate as the primary endpoint. lt was restated by the FDA that survival
`should be the primary endpoint, but response rate might be considered for
`inclusion in the label.
`
`The FDA recommended using Study JMCH as designed except using survival as
`the primary endpoint with clinical benefit (reduction in pain or dyspnea) as a
`secondary endpoint to qualify for full approval. Thus, if survival was improved.
`but fell short of statistical significance, then response rate plus clinical benefit
`(reduction in pain or dyspnea) might provide additional evidence for approval.
`
`Dr. Walling asked about the censoring rate for the survival study, and the FDA
`responded that 50% or less censoring rate (50% patients alive in the control arm)
`is the minimum, but that 25% censoring rate (25% of patients alive) would be
`better.
`
`The final agreement to points 2a. A and 2a. B above were listed as shown
`below:
`
`2a A. Lilly has access to the technology (Spiral Hi-Res CT scans),
`protocol, and dedicated assessment team in place to adequately
`assess response in mesothelioma
`2a B. We recommend that appropriately designed trials demonstrating
`clinical benefit, i.e., pain reduction breath shortness, etc., (see C & D)
`be the strategy for gaining full approval if survival benefit can't be
`shown instead of response rate for accelerated approval. (See
`previous FDA comments)
`The FDA also agreed that evidence of activity against NSCLC might also
`serve as confirmatory evidence (see FDA preliminary comment above).
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`A discussion was held on the suggestion of blinding for study JMCH. Dr. Justice
`said that approval could be given for an unblinded study. However, the FDA
`also pointed out that it would be easier to get approval with a blinded trial, since
`improved clinical benefit would be considered more robust in context of a blinded
`trial. Again, this was advice fron, the FDA, and it is Lilly's decision as to whether
`or not to do a blinded study.
`
`The following FDA acetate for issue 2b was shown:
`
`2b
`
`Is the design of study (JMCH) adequate and well controlled?
`Yes, with reservations. This would be a better study if it were blinded.
`A randomized trial of MIA + cisplatin vs. cisplatin alone is an adequate
`trial. However the addition of the vitamins to the MIA arm without data
`that efficacy is not reduced is risky. We would like to know the basis for
`your determination that the addition of vitamins will not affect efficacy.
`
`Dr. Walling answered this with an acetate (#3) with preclinical data from a murine
`L5178Y/TK-IHx- lymphoma tumor model showing that folic acid at 15 mg/kg (45
`mg/rn2) ameliorates the toxicity of MTA, but it does not affect the efficacy. There
`still was concern from the FDA that folie acid might reduce efficacy. Dr. Walling
`again responded that we are using low doses of folic acid that are ¡n a range
`(350 to 600 j.tg/day which is similar to the 100% RDA of 400 pgIday) that would
`give physiologic levels that might be expected from dietary exposure to folate.
`Thus, if MTA efficacy was negatively impacted by these low levels of folie acid in
`the multivitamins, then the activity of MTA would be compromised by similar
`levels of folate that could be ingested with food in a normal diet. The FDA
`responded that it was Lilly's decision whether or not to use folate.
`
`The following FDA acetates for issues 2c through 2e were shown, but agreement
`as to these had been reached in the discussions noted above:
`
`2c. Do you agree that the choice of primary and secondary endpoints, and the
`analysis plan in study JMCH is acceptable?
`NO. Response rate is not an acceptable primary endpoint in this
`disease. Survival should be the primary endpoint and superior survival
`in the patients on the MIA arm should be the basis for approval.
`Secondary endpoints of response rate, duration of response and time
`to progression could be supportive of the primary endpoint.
`
`2d. Do you agreé that allowing the measurement of unidimensional disease will
`provide sufficient information for determining response rate?
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`A. NO. lt is uncertain that unidimensional disease measurements in
`mesothelioma will provide sufficient information for determining
`response rate.
`
`2e. Do you agree that there will be sufficient safety data to support registration,
`i.e., the studies of MTA and cisplatiri in NSCLC may be used to support the
`safety profile obtained in rnesothelioma?
`A. YES
`
`Next the discussion turned to MTA for non-small cell lung cancer. The FDA
`displayed their first acetate for Issue 3:
`
`3. NSCLC - The indication being pursued is: «MIA Injection is indicated for
`treatment of patients with advanced non-small cell lung cancer (NSCLC)
`whose disease has recurred or progressed foflowing platin- and taxane-
`based therapy."
`3a. Do you agree this is an acceptable registration strategy (i.e., patient
`population, patient numbers, endpoints) for this indication?
`NO. Time to progression is not a sufficient surrogate for clinical
`benefit in NSCLC. Since the interval between disease progression
`and death is short, the primary endpoint should be survival.
`Two randomized, controlled trials will be needed.
`
`Nick Vogelzang began by stating the importance of time to tumor progression for
`patients. He said that when a tumor begins to grow, this is accepted as time to
`switch the therapy, and he added that patients are looking for "no growth of
`tumor - you cannot live with growing tumor". Dr. Justice said that there are
`problems with assessing progression such as the need for frequent tumor
`measurements. Dr. White agreed in part, but said that survival is also important.
`lt was mentioned that a 4 week increase in time to tumor progression would be a
`good result, but the FDA asked how often Lilly was planning on doing tumor
`measurements. Dr. Walling replied that Lilly would be taking scans every 6
`weeks, and Dr. John Johnson pointed out the difficulty in taking measurements
`only every 6 weeks while trying to demonstrate an increase of 4 weeks in time to
`tumor progression. Dr. Justice said that the FDA recognizes time to tumor
`progression, but questioned it as grounds for approval. Dr. Walling said that Lilly
`will accept survival as the primary endpoint. Dr. John Johnson said that the
`Agency will look at other things besides survival if the survival trend is there.
`Thus, he suggested survival as the primary endpoint with time to tumor
`progression as a secondary endpoint.
`
`Thus, the following was agreed to:
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`3a. A Lilly agrees to survival as the primary endpoint with time to
`tumor progression as a secondary endpoint.
`
`Next Dr. John Johnson stated the need for two trials for initial approval; unless
`there is a real clear convincing result in the initial trial, a second trial is needed.
`Dr. Hamburger asked whether a positive phase 2 trial would be acceptable. The
`Agency replied that a phase 2 trial in 2'
`line NSCLC might be acceptable. A 2
`line phase 2 study in the same 2 line patient population could be discussed at
`the pre-NDA meeting, but that the Agency would need to see all the data from
`the phase 2 trial.
`
`Thus the following was agreed to:
`
`3a. B FDA ¡s willing to discuss at pre-NDA meting. Activity in NSCLC
`with supportive data from same population as 2 trial. We need
`to see data from all trials.
`
`The FDA presented their acetate for issue 3b:
`
`Is the design of study (JMBQ) adequate and well controlled?
`A. Yes, with reservations. A randomized trial of MTA vs vinorelbine is an
`adequate trial; at least 75% of the patients randomized should have
`stage IV disease. However, the addition of the vitamins to the MTA arm
`without data that efficacy is not reduced is risky.
`
`Dr. Walling said that Lilly agrees to this answer for issue 3b regarding the use of
`vinorelbine as a comparator and the need for 75% of patients to have stage IV
`disease. She said that there have been few patients presenting with stage lllb
`disease. The issue of vitamins and efficacy was addressed earlier in the
`mesothelioma discussion.
`
`The acetate for issue 3c was presented by the Agency:
`
`Do you agree that the Thall-Simon-Ellenberg design ¡s adequate to select
`the best MTA regimen ir the Phase 2 portion of JMBQ (Thall et al., 1988)?
`A. NO. Please clarify what you propose. Will the best MTA regimen be
`selected based on efficacy, toxicity or both?
`
`Dr. Walling said that the best MTA regimen will be selected based on toxicity
`only, but there must be efficacy also. If there is no difference in toxicity, then a
`difference of 10% in response rate would be used to select the winner. Finally, if
`toxicity and response rate did not provide a winner, then a 50% increase in time
`to tumor progression would be the deciding factor. Dr. White again brought up
`the issue of a possible negative effect of folio acid on efficacy. Dr. Walling
`responded that we are attempting to provide a small amount of folic acid (the
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`Recommended Daily Allowance) as a dietary supplement to level the playing
`field such that all patients have the same folate status. Dr. Justice said that all
`the MTA patients from botti arms A and B in the Phase 2 portion should be
`included in the final analysis.
`
`The Thall-Simon-Ellenberg design is appropriate and actually conservative; since
`the trial can only be stopped for negative results, the nominal type I error is less
`than 5%.
`
`Thus the following was agreed to as an addition to 3c. A:
`
`3c. A. Best MTA will be selected on toxicity only. All MTA patients will
`be included ¡n the final analysis.
`
`The agency showed the acetate for issue 3d:
`
`3d. Do you agree with the choice of the primary and secondary endpoints as
`well as the statistical analysis plan and methods for the Phase 2 and Phase
`3 portions of study JMBQ?
`NO. All patients should be included in the MTA arm to minimize the need
`for correction in the final analysis.
`Time to progression is not a sufficient surrogate for clinical benefit in
`NSCLC. Since the interval between disease progression and death is
`short, the primary endpoint should be survival.
`
`All patients randomized to both MTA arms in the Phase 2 portion will be included
`in the final Phase 3 analysis; this was agreed to for issue 3d.
`
`The FDA showed the acetate for issue 3e:
`
`3e. Do you agree with our choice of quality of life instrument, symptoms, and
`analysis plan?
`A. Since survival will be the primary endpoint, the contribution of QOL to the
`basis for approval is uncertain.
`
`Dr. Justice said that if survival is equal, and time to tumor progression and
`quality of life are better, then the submission will be viewed fairly. He added that
`the symptom data would be more convincing if the study was blinded. The
`Agency said that their statistics group will provide a written list of comments. Dr.
`John Johnson said that there has never been an approval in the past based on
`QOL. Dr. Beitz suggested that pre-specified symptoms should be tracked. Dr.
`Walling said that Lilly plans to track disease-related symptoms with a sub-set of
`questions from the EORTC QOL instrument.
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`The following was proposed by FDA and agreement was reached to the
`following addition for issue 3e.
`
`3e. A Statistics will provide a written list of specific comments. We are
`willing to revisit this question at the pre-NDA meeting.
`- Pre-specified group of symptoms
`
`The meeting was adjourned.
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