NDA 21240

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NDA 21-240

• Study MP-US-M01

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Federal Food, Drug, and Cosmetic Act of 1962

• Substantial Evidence Adequate and
  well-controlled investigations
• Modernization Act 1997
• Data from one adequate and well controlled
  clinical investigation and confirmatory evidence
  can be considered substantial evidence by the
  Agency

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Reasons a Single Study is Generally Not Adequate

• Any trial may be subject to unanticipated,
  undetected, systematic biases that could lead to
  flawed conclusions
• Inherent variability may produce a positive trial
  by chance alone
• 1/40 studies of ineffective drugs will be
  positive (p0.05)

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Causes of False-Positive Studies (Tannock, JCO
Nov 2000)

• Chance
• Prognostic Factor Imbalances
• Multiplicity
• Low Prior Probability a New Treatment will be a
  Therapeutic Advance
• 1/3 positive trials are false positive in this
  hypothetical setting

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Hypothetical Situation - Low Prior Probability of
Therapeutic Advance
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Role of Tamoxifen in the Treatment of Metastatic
Melanoma

• Cocconi, et al NEJM August 1992.
• Dacarbazine Tamoxifen vs. Dacarbazine
• Survival 48 weeks vs. 29 weeks, p0.02
• Subsequent Non-Confirmatory Trials
• ECOG (Falkson, et al JCO May 1998)
• Intergroup (Chapman, et al JCO 1999)
• NCI Canada (Rusthoven, et al JCO 1996)
• Mayo (Creagan, et al JCO June 1999)
• U. Pittsburgh (Agarwala, et al Cancer 1999)

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FDA Guidance for IndustryProviding Clinical
Evidence of Effectiveness for Human Drug and
Biological Products

• Reliance on a single study whether alone or with
  substantiation from related trial data leaves
  little room for study imperfections or
  nonsupportive information
• Limited to where confirmation would be
  practically or ethically impossible

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What Makes a Single Study Persuasive?

• Large, multicenter study
• Appropriate Design
• Flawless conduct
• Minimal possibility of bias due to baseline
  imbalances, unblinding and post-hoc changes in
  analysis

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What Makes a Single Study Persuasive?

• Results should reflect a clear hypothesis
  documented in the protocol
• Statistically persuasive

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NDA 21-240Study MP-US-M01
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Review

• Randomized, Controlled Multicenter Trial, BUT it
  is a Single Trial
• ITT Analysis of the Primary Endpoint was not
  Statistically Significant

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• Apparent Survival Benefit in a Subset Analysis -
  Liver Metastases
• BUT there were imbalances in prognostic factors
  favoring the histamine/IL-2 arm
• AND the FDAs adjusted analyses showed that
  imbalances influenced the observed treatment
  effect

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Questions

• Does the survival difference in the planned
  primary analysis of this single study, the ITT
  analysis of survival, represent substantial
  evidence of the efficacy of histamine
  dihydrochloride as an adjunctive treatment with
  IL-2 for patients with metastatic melanoma?

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Questions

• Does the survival difference observed in the
  subgroup of patients with liver metastases in
  this single study represent substantial evidence
  of the efficacy of histamine dihydrochloride as
  an adjunctive treatment with IL-2 for patients
  with melanoma that has metastasized to the liver?

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Questions

• In view of the efficacy results, is the safety
  profile of the histamine/IL-2 combination
  acceptable?

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