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Individual Bioequivalence

Individual Bioequivalence. Lawrence J. Lesko, Ph.D. Director Office of Clinical Pharmacology and Biopharmaceutics. Advisory Committee for Pharmaceutical Science Rockville, Maryland November 29, 2001. Average Bioequivalence (ABE).

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Individual Bioequivalence

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  1. Individual Bioequivalence Lawrence J. Lesko, Ph.D. Director Office of Clinical Pharmacology and Biopharmaceutics Advisory Committee for Pharmaceutical Science Rockville, Maryland November 29, 2001

  2. Average Bioequivalence (ABE) • Used by FDA to approve the marketing of thousands of generic drugs • For a few other drugs, in vivo studies are waived and market access is granted based on in vitro studies • Large amount of empirical evidence suggests that generic drugs are used regularly without problems of safety or efficacy

  3. Individual Bioequivalence (IBE) • Proposed by FDA as an improvement on the study design, informativeness and method of analysis of BE studies • Controversial topic with many debates and public discussion • Has not been universally accepted

  4. Recommendation of ACPS “The committee has concerns with the new criterion (IBE) and recommended use of the ABE criterion for market access, unless there is a compelling reason not to” --Transcript of the minutes of the ACPS meeting, September 23, 1999

  5. Focus

  6. Comparison of BA Measures in BE Studies (Section IV)* “This guidance recommends continued use of an ABE criterion to compare BA measures for replicate and non-replicate design studies of both immediate- and modified-release products. However, sponsors have the option to explain why they would use another criterion (e.g., an IBE criterion for replicate design studies of highly variable drug products). *Guidance for Industry: BA and BE Studies for Orally Administered Drug Products-General Considerations

  7. Implementation of Guidance Recommendations A few sponsors have requested, a priori, in their BE replicate design study protocols that the Agency use IBE“Compelling reason not to” ?: drug and/or drug product is highly variable and want to avoid using large number of test subjects

  8. Discussion Topic #1 Is it reasonable and appropriate for FDA to use ABE for market access, unless there is a compelling reason not to, for an interim period of another year until a final decision is made to use IBE for market access?

  9. Discussion Topic #1: Background • FDA has concerns about using IBE for market access, and unintended consequences of the criterion • ABE fails, IBE passes (greatest concern) • example: Cmax for ANDA drug #2 (is switchability assured?) • mean T/R ratio: 88.5% (up to +15% can pass ABE) • WSV T/R ratio: 1.07 (T modestly more variable than R) • SxF interaction: 0.2 (important defined a priori as > 0.15) • healthy (all male) volunteers (tend to reduce SxF interaction) • Guidance states mean T/R ratio should fall between 80-125% • recommendation of P&IBE Expert Panel (1999)

  10. Discussion Topic #2 The Advisory Committee is asked to comment on the proposal that if the FDA were to use IBE for market access (when there is a compelling reason not to use ABE) during the interim period, the following conditions would apply:

  11. Discussion Topic #2: Constraints • Mean T/R ratio should fall between 85-117.6% (new) • limit the mean-variance trade-off and consequences of scaling • SxF < 0.15 (new) • conclude no significant interaction • Subjects should take into account age, sex and race factors in general population • already recommended by ACPS (9/23/99) and guidance • relevant subsets maximize detection of SxF

  12. Discussion Topic #3 Are there scientific, technical or other reasons not to continue with the recommendations in the General BA/BE guidance to a) conduct replicate design studies for MR dosage forms, and HVD, and b) to use heterogeneous study population (at least 40% male and female subjects, and/or young and elderly subjects)?

  13. Discussion Topic #3: Background • Replicate design studies (what are the questions) • provide empirical evidence of problems with ABE, if any • allow for post hoc analysis of SxF • assess clinical significance of variance differences • Heterogeneous population necessary • conclusions or extrapolations from studies using all male test subjects are uncertain (if exclude relevant subsets) • Larger database needed • scientific and public health rationale to recommend replicate design studies • if IBE should be used to allow market access

  14. Discussion Topic #4 The AC is asked to comment on plans for further research programs and projects associated with the use of ABE and IBE to allow comparison of BA measures and to arrive at a final conclusion and recommendation on (replicate design studies) and IBE.

  15. Discussion Topic #4: Background • Essentially the research program proposed in 1999 with updates (3/00, 11/01) • endorsement of ACPS on 9/23/99 • limited implementation to date • Revise based on new replicated design ANDA and NDA studies • observe behavior of ABE and IBE • dissect reasons for differences in outcomes • mechanistic basis for SxF (excipients etc) • simulation or meta-analysis

  16. Agenda 1. Brief introduction and background to IBE--Mei-Ling Chen, Ph.D., Office of Pharmaceutical Sciences2. Presentation of replicate design BE studies from NDA’s--Mei-Ling Chen, Ph.D.3. Presentation of replicate design BE studies from ANDA’s --Rabi Patnaik, Ph.D., Office of Generic Drugs4. Presentation of research plan--Stella Machado, Ph.D., Office of Biostatistics

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