Highly Variable Drugs

1
Highly Variable Drugs Bioequivalence
IssuesFDA Proposal Under Consideration

• Barbara M. Davit, J.D., Ph.D.
• Deputy Director, Division of Bioequivalence (DBE)
• Office of Generic Drugs (OGD)
• Office of Pharmaceutical Sciences (OPS)/CDER
• Advisory Committee for Pharmaceutical Science
• October 6, 2006

2
Discussion topics

• Characteristics of highly variable (HV) drugs
• Present bioequivalence (BE) study approach used
  by the OGD for all drugs
• Disadvantages of using current approach for HV
  drugs
• Reference-scaled average BE approach under
  consideration by FDA
• Advantages/concerns
• Questions for committee

3
HV Drug Characteristics

• Within-subject variability (CVWR) in BE
  parameters AUC and/or Cmax gt 30
• Non-narrow therapeutic index
• Represent about 10 of drugs studied in vivo and
  reviewed by OGD

4
Some reasons for high variability in BE parameters

• Drug substance
• Variable absorption rate
• Low extent of absorption
• Extensive presystemic metabolism
• Drug product
• Inactive ingredient effects
• Manufacturing effects
• Bioanalytical assay sensitivity
• Suboptimal PK sampling
• Impractical to identify mechanism in each case

5
Characteristics of HV drugs evaluated by OGD

• Can use Root Mean Square Error (RSME) to estimate
  within-subject variability in two-way crossover
  studies
• Conclude drug is HV if RMSE gt 0.3
• Using this criterion, about 10 of drugs
  evaluated by OGD are HV drugs of these
• 55 are consistently HV
• 20 are borderline cases
• For the remaining 25, high variability occurs
  sporadically (not HV in most BE studies)

6
BE issues with HV Drugs

• High probability that BE parameters will differ
  when same subject receives a HV drug on more than
  one occasion
• Because of the high variability, a HV drug that
  is truly therapeutically equivalent to the
  reference may not meet BE acceptance criteria

7
Present FDA approach used for BE studies of HV
drugs

• Generally, firms submitting ANDAs for HV drugs
  use the same study design as for drugs with lower
  variability
• Two-way crossover study
• Replicate-design study
• HV drugs must meet same acceptance criteria as
  drugs with lower variability
• 90 CI of AUC and Cmax test/reference ratios must
  fall between limits of 0.8 to 1.25 (80-125)

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Disadvantages of present FDA approach for HV drugs
Approach Disadvantages
Enroll adequate of subjects (N) to show BE in 2-way crossover study Study may require larger N avg. N 47 for HV drugs avg. N 33 for other drugs If study underpowered, must do new study
Replicate-design (4-period) study High dropout rate may need to enroll larger N
Group sequential-design study Must have protocol in place a priori Statistical adjustment
Based on BE studies submitted to OGD in
2003-2005
9
Evolution of new proposal for BE studies of HV
drugs

• Pharmaceutical Sciences Advisory Committee in
  2004 suggested reference-scaled average BE
  approach
• OGD Science Team studied approach by simulating
  outcome of BE studies of HV drugs
• FDA is considering using this approach for BE
  studies of HV drugs

10
New FDA proposal scaled average BE for HV drugs

• Three-period BE study
• Provide reference product (R) twice
• Provide test product (T) once
• Sequences TRR, RRT, RTR
• BE criteria scaled to reference variability
• (µT - µR)2 - ?s2WR lt 0 ? upper BE limit
• Both AUC and Cmax should meet BE acceptance
  criteria

11
Advantages of reference-scaled average BE

• If T variability lt R variability, will benefit
  test product
• If T variability gt R variability, no benefit for
  test product

12
Use of scaled average BE for borderline HV drugs

• Our simulations confirmed that, for a true
  borderline HV drug, either scaled or unscaled
  average BE approach is suitable
• Outcome of a 3-way crossover BE study will be
  similar whether a reference-scaled average BE
  analysis or unscaled average BE analysis is
  conducted
• We define a borderline HV drug as one for
  which, in individual studies, within-subject
  variability in BE parameters is generally
  slightly gt or lt 30, and the average
  within-subject variability is about 30

13
When scaled average BE approach is unsuitable

• HV due to generic product or study conduct
• If due to effects of generic formulation, will
  not benefit from scaled average BE approach
• If T variability gt R variability
• Studies poorly performed
• Burden on applicant to prove to OGD that drug
  substance is HV
• OGD can conclude that scaled average BE approach
  is unacceptable

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Concerns about reference-scaled average BE
Concern Proposed solution
Firms will conduct a replicate-design study, then submit results with both scaled and unscaled BE analyses If CVWR gt 30, FDA will use the reference-scaled average BE approach If CVWR lt 30, FDA will use the unscaled average BE approach
15
Concerns about reference-scaled average BE
Concern Proposed solution
Scaling can allow the resulting AUC and Cmax geometric mean ratios to be either unacceptably low or high Acceptance criteria can include a point estimate constraint
16
Concerns about reference-scaled average BE
Concern Proposed solution
What should be an appropriate number of subjects for a BE study that uses this approach? Should the FDA recommend a minimum number of subjects?
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Acknowledgements

• OGD Working Group
• Mei-Ling Chen
• Dale Conner
• Sam Haidar
• Lai Ming Lee
• Rob Lionberger
• Fairouz Makhlouf
• Devvrat Patel
• Don Schuirmann
• Lawrence Yu

• DBE Research Group
• Beth Fabian-Fritsch
• Sheryl Gunther
• Xiaojian Jiang
• Devvrat Patel
• Keri Suh
• Christina Thompson