Bioequivalence Criteria Research Plan

1
Bioequivalence Criteria Research Plan

• Stella G. Machado, Ph.D.
• Office of Biostatistics
• and the
• Replicate Design Technical Committee

Advisory Committee for Pharmaceutical
Science Rockville, Maryland November 29, 2001
2
Background

• Guidances for Industry
• Bioavailability and Bioequivalence Studies for
  Orally Administered Drug Products - General
  Considerations October 2000
• Statistical Approaches to Establishing
  Bioequivalence January 2001
• Advisory Committee for Pharmaceutical Science
  Meeting 9/23/1999
• Discussed FDA plans for further research and
  projects associated with the use of ABE and IBE
  criteria

3
Background continued

• ACPS endorsed plans for furthering mechanistic
  understanding, clinical pharmacology studies,
  influence of outliers on SxF interaction
• ACPS requested creation of research document to
  guide activities during an interim period
• Document sent for review (9/1999) to Population
  and Individual BE Expert Panel
• Draft Research Document modified by Population
  and Individual Working Group of CDERs
  Biopharmaceutics Coordinating Committee in
  response to comments received (4/2000)

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Research Program Overview

• Goal is to provide information to support final
  regulatory decisions regarding criteria for
  comparing BA in BE studies
• Research Plan has 3 projects
• A) Criteria for BE comparisons
• B) Data analyses and Statistical Methodology
• C) Mechanistic understanding of Mean and
  Variances differences between T and R

5
Program overview - continued

• Studies conducted by drug sponsors will be major
  source of data for our evaluations
• General Guidance recommends replicate designs for
  highly variable drugs and modified release dosage
  forms

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A) Criteria for BE comparisons

• Choice of ABE, IBE criteria for BE studies in
  particular types of regulatory submissions IND,
  NDA, ANDA and post-approval supplement filings
• Replicate-designed data sets are analyzed upon
  receipt, and interpreted in light of
  recommendations in Guidance
• These analyses add to knowledge base for
  evaluating performance of approaches

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A) Criteria for BE comparisons - continued

• Identify and evaluate
• clinically important T/R differences in within-
  and between-subject variances, and SxF
  interactions
• importance and impact of mean/variance trade-offs
• other outcomes based on selected disaggregate
  criteria
• study discontinuity aspect of IBE and possible
  resolution

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B) Data Analysis and Statistical Methodology

• Criteria and methods for assessing ABE and IBE as
  laid out in the Guidance are reasonable and valid
  
• open to new approaches - as yet no persuasive
  alternatives have been presented
• Primary objectives
• assess estimation methods in presence of missing
  data
• assess properties of estimates of parameters of
  interest
• assess impact of apparent outlier data on
  properties of aggregate IBE criterion

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B) Data Analysis and Statistical methodology -
continued

• Secondary objectives
• monitor and assess carryover effects using data
  from replicate designs
• assess numbers of subjects and good study designs
  for heterogeneous populations, including both
  genders, different ethnic groups and different
  age ranges

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C) Mechanistic Understanding

• Develop mechanistic understanding as needed for
• important differences in means
• important differences in within subject
  variances for Test and Reference products for
  highly variable and modified release drug
  products
• subject-by-formulation interactions

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Focus for immediate future

• continue evaluation of replicate designed studies
  as received
• address design and other issues via simulation
  studies
• evaluate impact of changing constraint on mean
  difference
• respond to recommendations of ACPS

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Concluding remarks

• some issues in 4/2000 Research Plan were
  addressed and incorporated into Guidances
• now in evaluation phase of data sets and
  performance of estimation methods