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Highly Variable Drugs – Bioequivalence Issues: FDA Proposal Under Consideration

Highly Variable Drugs – Bioequivalence Issues: FDA 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

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Highly Variable Drugs – Bioequivalence Issues: FDA Proposal Under Consideration

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  1. Highly Variable Drugs – Bioequivalence Issues:FDA 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> 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 > 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%)

  8. Disadvantages of present FDA approach for HV drugs * 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 - Өσ2WR< 0 ; Ө = upper BE limit • Both AUC and Cmax should meet BE acceptance criteria

  11. Advantages of reference-scaled average BE • If T variability < R variability, will benefit test product • If T variability > 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 > or < 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 > 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

  14. Concerns about reference-scaled average BE

  15. Concerns about reference-scaled average BE

  16. Concerns about reference-scaled average BE

  17. 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 Acknowledgements

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