Why Bioequivalence of Highly Variable Drugs is an Issue

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Why Bioequivalence of Highly Variable Drugs is an
Issue

• Charles E. DiLiberti
• Vice President, Scientific Affairs
• Barr Laboratories, Inc.
• Presentation to the Advisory Committee for
  Pharmaceutical Sciences
• April 14, 2004

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Definition of Highly Variable Drugs (HVDs)

• Any drug whose rate and extent of absorption
  shows large dose-to-dose variability within the
  same patient
• Commonly understood to include those drugs whose
  intrapatient coefficient of variation (Cmax
  and/or AUC) is approximately 30 or more

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Current Bioequivalence Criteria

• Comparison between test and reference product
• Use natural log transformation of Cmax and AUC
• Criterion 90 confidence intervals about
  geometric mean test/reference ratios for both
  Cmax and AUC must fall within 80 125
• Applies to all systemically acting drugs (i.e.,
  not locally acting) with measurable blood or
  urine levels without regard to the drugs
  inherent variability
• Same criteria used by pioneer firms to support
  formulation changes

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Why Alternative Acceptance Criteria Are Needed
for HVDs

• Reduce human experimentation (number of
  participants) in BE studies
• Prohibitive size of BE studies for some HVDs
  means no generic is available many American
  patients go untreated/undertreated
• Changing criteria to reduce number of
  participants in BE studies on HVDs can be
  accomplished without compromising safety/efficacy
• 80 125 BE criteria not universally implemented
  worldwide

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Foreign BE Criteria
Country/Region AUC 90 CI Criteria Cmax 90 CI Criteria
Canada (most drugs) 80 125 none (point estimate only)
Europe (some drugs) 80 125 75 133
South Africa (most drugs) 80 125 75 133 (or broader if justified)
Japan (some drugs) 80 125 Some drugs wider than 80 125
Worldwide (WHO) 80 125 acceptance range for Cmax may be wider than for AUC
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Types of Drugs That Are Highly Variable

• Includes many therapeutic classes
• Includes both newer and older products
• Potential savings to patients in the billions of
  dollars if generics are approved
• Examples atorvastatin, esomeprazole,
  pantoprazole, clarithromycin, paroxetine (CR),
  risedronate, metaxalone, itraconazole,
  balsalazide, acitretin, verapamil, atovaquone,
  disulfiram, erythromycin, sulfasalazine, etc.

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Fed BE Studies

• Confidence interval criteria now required for BE
  studies under fed conditions
• General paucity of information on variability
  under fed conditions
• Some drugs show much more variability under fed
  conditions than fasting conditions, making them
  HVDs (e.g., esomeprazole, pantoprazole,
  tizanidine)
• May be more HVDs than generally appreciated

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Why Current 80-125 Criteria Are Not Appropriate
For HVDs

• Current criteria are appropriate for drugs with
  low to moderate variability because dose-to-dose
  variability within a patient is comparable to the
  width of the criteria
• Current criteria are not appropriate for HVDs
  because dose-to-dose variability within a patient
  is much larger than the width of the criteria
• HVDs are wide therapeutic index drugs i.e.,
  have shallow dose response curves, and wide
  safety margins
• Modifying BE acceptance criteria for HVDs to
  reduce the number of participants in BE studies
  can be accomplished while maintaining assurance
  of safety and efficacy

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Different HVDs May Require Different Approaches
One Size Does Not Fit All
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Example 1 HVDs Not Subject to Significant
Accumulation at Steady State

• Half-life short with respect to dosing interval
• Examples omeprazole, tizanidine, azathioprine
• Consider reference-scaled criteria for both Cmax
  and AUC
• Dose-to-dose variability within a patient not
  smoothed out at steady state for either Cmax or
  AUC
• Drug exhibits wide dose-to-dose variations in
  blood levels irrespective of chronic dosing
• Same logic applies to HVDs not dosed chronically

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Example 2 HVDs Subject to Significant
Accumulation at Steady State

• Chronically used and with half-life long with
  respect to dosing interval
• Examples itraconazole, metaxalone, acitretin
• Consider reference scaling criteria for Cmax only
• Steady state T/R for AUC same as under single
  dose conditions (assuming linear kinetics) but
  variability in AUC will be reduced at steady
  state ? drug may not have highly variable AUC at
  steady state
• T/R for Cmax will be closer to unity at steady
  state than under single dose conditions, so
  adjusting criteria for Cmax could be accomplished
  without impacting assurance of safety/efficacy

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Example 2 HVDs Subject to Significant
Accumulation at Steady State (contd)

• Alternatively, could permit demonstration of
  bioequivalence with multiple dose steady state
  study
• Not suitable for all drugs due to safety
  concerns, e.g., toxic drugs, inclusion of
  females, etc.

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Special Considerations
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Parallel Studies for Long Half-Life Drugs

• For long half-life drugs, crossover studies may
  not be feasible, necessitating parallel designs
• Powering parallel studies depends on
  between-subject variability, not within-subject
  variability
• Between-subject variability is often large,
  necessitating large BE studies on such products,
  as for HVDs
• High between-subject variability does not
  necessarily imply high within-subject variability
  (HVD) instead it may be due to interindividual
  differences in absorption/metabolism (e.g.,
  genetic polymorphism)
• Multiple dose steady state studies generally not
  feasible
• Consider reference-scaled criteria

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Pooling Data from Multiple Dosing Groups

• Large n required for HVDs often requires two or
  more dosing groups
• FDA currently requires a statistical test for
  poolability of data from multiple dosing groups
  (group x treatment interaction)
• If interaction term is significant, then the
  groups may not be pooled
• If the groups may not be pooled, each group is
  evaluated on its own for confidence interval
  criteria, and is likely to fail due to
  underpowering
• This procedure results in discarding (and having
  to repeat) about 5 of studies based on random
  chance alone
• Even if there were some underlying explanation
  for the statistical significance (e.g.,
  differences in demographics among the dosing
  groups), there is no reason not to use the data
  from all dosing groups (they would be useable if
  the same subjects had been dosed in a single
  group)

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Conclusions

• While current BE acceptance criteria are
  appropriate for drugs with ordinary variability,
  they are not appropriate for HVDs
• Current BE acceptance criteria make it difficult
  or impossible to develop generic equivalents to
  some HVDs, effectively denying treatment to many
  patients
• Practical, scientifically sound, alternative BE
  acceptance criteria could be implemented for HVDs
  to reduce BE study size while maintaining
  assurance of safety and efficacy
• Different approaches may be needed for different
  types of drugs, depending particularly on
  accumulation following multiple dosing
• Other, related situations (e.g., parallel
  studies, multiple dosing groups) should be
  considered in conjunction with any changes to
  acceptance criteria for HVDs