1. Individual Bioequivalence: Have the Opinions of the Scientific Community Changed? Leslie Z. Benet, Ph.D. University of California San Francisco

2. Individual bioequivalence is a promising, clinically relevant method that should theoretically provide further confidence to clinicians and patients that generic drug products are indeed equivalent in an individual patient.

3. Even today, considering the studies summarized and analyzed by the FDA, the data is inadequate to validate the theoretical approach and provide confidence to the scientific community that the methodology required and the expense entailed are justified.

4. At this time, individual bioequivalence still remains a theoretical solution to solve a theoretical clinical problem. We have no evidence that we have a clinical problem, either a safety or an efficacy issue, and we have no evidence that if we have the problem that individual bioequivalence will solve the problem.

5. Opinions and Recommendations of Former Chair of the FDA Expert Panel on Individual Bioequivalence Leslie Z. Benet, Ph.D. University of California San Francisco NEW TITLE

6. WE DON’T HAVE A PROBLEM Present +25%/-20% Average Bioequivalence criteria are very tight Lack of a problem is not just verified by minimal Phase 4 problems that can be documented, also Many, many studies in special population subsets have been carried out to attempt to demonstrate lack of equivalence for approved generics (and of course efficacy and safety differences), but you don’t see any of these results

7. What are we trying to solve? For wide-therapeutic index, highly variable drugs we should not have to study an excessive number of patients to prove that two equivalent products meet preset (one size fits all) statistical criteria. For all drugs, but particularly for NTI drugs, that a practitioner may transfer a patient from one drug product to another and be assured of comparable safety and efficacy (switchability). To give patients and clinicians confidence that a generic equivalent approved by the regulatory authorities will yield the same outcome as the innovator product.

8. Subject by Formulation Interaction Term Switchability is not a problem for approved generics Note that the “Example 2 Reference Product” showing the large gender difference is still on the market Note in “New Data-NDAs” that the high SxF interaction terms occur when Reference within-SD is greater than within-SD for Test It is not reasonable to expect that sponsors will use subjects representative of the general population in their IBE studies Conclusion – Ignore (delete) SxF term in IBE equation

9. IBE (ignoring SxF) should allow sponsors to gain approval for highly variable (wide- therapeutic index) drugs without using an excessive number of test subjects Note: Chen et al. (2000) suggest that IBE may only save money and time when within-subject CV is greater than ~ 50%

10. Preliminary Recommendation Sponsors may seek bioequivalence approval using either ABE or IBE (with SxF deleted) If an IBE study is carried out and the test product fails, the data or a subset of the data may not be reanalyzed by ABE for approval

11. Perception Problem IBE would allow approval of test products where mean bioavailability may fall outside of 80-125% for reference ABE allows sponsors to gain approval by enrolling a large number of subjects when test and reference means differ by 10-20% and CV% is not large

12. Proposed Point Estimate Criteria (i.e. Allowable Mean Differences) AUCC max Most Drugs and NTI Drugs with  WR > 20% ±10%±20% NTI Drugs± 5%±10% It is probable that AUC criteria for NTI drugs cannot be any lower than proposed here unless USP content uniformity limits are narrowed (which should be considered in any case for NTI drugs). Presented at the AAPS/FDA Workshop March 1998

13. Recommendations Sponsors may seek bioequivalence approval using either ABE or IBE (with SxF deleted) If an IBE study is carried out and the test product fails, the data or a subset of the data may not be reanalyzed by ABE for approval A point estimate criteria on mean AUCs of ±15% and on mean C max of ±20% should be required for both ABE and IBE. Consideration should be given for narrower point estimate criteria for NTI drugs (e.g., AUC ±10%, C max ±15%)