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

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

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

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

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)

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

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%)

Disadvantages of present FDA approach for HV drugs 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

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

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

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

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%

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

Concerns about reference-scaled average BE Proposed solution Firms will conduct a replicate-design study, then submit results with both scaled and unscaled BE analyses If CVWR > 30%, FDA will use the reference-scaled average BE approach If CVWR < 30%, FDA will use the unscaled average BE approach

Concerns about reference-scaled average BE 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

Concerns about reference-scaled average BE 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?

Acknowledgements OGD Working Group DBE Research 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