Criteria for Evaluating Bio-inequivalence among Drug Products Using Multiple PK Endpoints

1. Criteria for Evaluating Bio-inequivalence among Drug Products Using Multiple PK Endpoints Qian H. Li QMR/OB/OPASS/CDER, FDA

2. Introduction • Why multiple PK endpoints? • Bioequivalence between drugs are established by comparing the rate and extent of drug absorption, which are represented by Cmax, AUCt, and AUC. • Bioequivalence for generic drug approvals has evolved to use AUCt, AUC, and Cmax . • Bio-inequivalence can be established if any one of the PK endpoints are inequivalent in truth. ACPS Meeting

3. Outline • Criterion for bio-inequivalence using one PK endpoint • Strategies for assessing bio-inequivalence using three PK endpoints • Available approaches • Power comparison to show bio-inequivalence • Recommendations ACPS Meeting

4. µT/µR 80% 125% Bio-inequivalence Region Bio-inequivalence Region Bioequivalence Interval Definitions for One Endpoint • Ratios of geometric means µT/µR, • µT the geometric mean of the test product • µR the geometric mean of the reference product • Bioequivalence interval [80%, 125%] • Bio-inequivalence [0, 80%) or (125%, ) ACPS Meeting

5. Test for Bio-inequivalence • Hypotheses for testing bio-inequivalence: H0: 80% µT/µR125% vs. HA: µT/µR < 80% or µT/µR >125% • Perform 2 one-sided tests • H01: µT/µR ≥80% vs. HA1: µT/µR < 80% • H02: µT/µR ≤125% vs HA2: µT/µR >125% • Only need to reject either null • The significance level for each one-sided test is controlled at 0.05 • CRITERION: Reject bioequivalence when the two-sided 90% CI lies completely in either of the two bio-inequivalence regions ACPS Meeting

6. Error Discussion for Bio-inequivalence Criterion • Using 2-sided 90% CI, the error rate is protected at 5% if a 2-sequence and 2-way balanced crossover trial has • >20 subjects and • Within subject standard deviation < 0.7 • Using 2-sided 90% CI, the error rate may be higher than 5% if • Sample size is <20 or • Variance is large • Using 2-sided 95% CI ACPS Meeting

7. Definitions with Three Endpoints AUC Inequivalence Region 125% 125% 80% AUCt Equivalence Region 125% Cmax ACPS Meeting

8. Criterion for Bioequivalence with 3 PK endpoints • Criterion: the 2-sided 90% CIs for the ratios of all three endpoints have to be within [80%, 125%] • The error rate of wrongfully rejecting bio-inequivalence is protected at 5% level. ACPS Meeting

9. Bio-inequivalence with Three Endpoints • Looking for strategies that • Control the error rate of wrongfully rejecting bioequivalence at the rate of 5% • Control the error rate under all correlation structures since the correlation structure is unknown • Assume the variances of test statistics are not large (0.3) ACPS Meeting

10. A Common Misconception • Claim bio-inequivalence when one of the three PK endpoints satisfies the bio-inequivalence criterion for one endpoint; • Inflate error rate of wrongfully rejecting bioequivalence 0.147 if independent 0.082 if highly correlated (correlation is about 0.9) (Note: the error rate is calculated when  is 0.1) • Not acceptable ACPS Meeting

11. A Tough Criterion • Claim bio-inequivalence if all the three PK endpoints satisfy the bio-inequivalence criterion. • Tightly control the error rate under all correlation structures for the three PK endpoints. • Usually does not provide adequate power • Not recommended ACPS Meeting

12. Strategy I • Pre-specify one of the three PK endpoints for bio-inequivalence testing. • For example, test AUCt only, ignore the other two. • Need to pre-specify the endpoint in study protocols • Controls error rate. • Ideal for scenarios when one knows that a specific one PK endpoint is more likely to show bio-inequivalence than others • May have poor power if the wrong endpoint is chosen ACPS Meeting

13. Strategy II • Bonferroni correction: • Ex: Using 2-sided 96.7% confidence intervals (CIs) instead of 2-sided 90% CIs • If one of the three 96.7% CIs fall in the bio-inequivalence regions, then demonstrate bio-inequivalence • Other possible versions • Distribution independent • Ideal for scenarios when one knows that one PK endpoint is more likely to demonstrate bio-inequivalence than others, but do not believe that all endpoints have good power. ACPS Meeting

14. Strategy III • Three confidence intervals with different lengths, a variation to the approach that requires all three endpoints to satisfy the bio-inequivalence criterion of one endpoint. • Control error rate at 5% • Derived based on simulation study and distribution dependent • Ex: (94%, 80%, 65%) • Ideal for scenarios when • one has no idea which PK endpoint is more likely than others to show bio-inequivalence and • All three PK endpoints are inequivalent ACPS Meeting

15. Power Examples • Scenario I: only one endpoint has good power to demonstrate bio-inequivalence • AUCt=5%, AUC=20%, Cmax=90% ACPS Meeting

16. Power Examples • Scenario II: All three endpoints have reasonable power • AUCt=60%, AUC=70%, Cmax=80% ACPS Meeting

17. Power Examples • Scenario III: All three endpoints have equal power • AUCt=80%, AUC=80%, Cmax=80% ACPS Meeting

18. Recommendations • When one knows which endpoint is more likely to show bio-inequivalence, Strategy I should be used. • Pre-specify the endpoint in study protocols, use this endpoint to test bio-inequivalence • Use a two-sided 90% CI • When one knows that one endpoint may have good power, but do not believe that all of them have good power, use Strategy II, Bonferroni correction. • An example of Bonferroni correction is to use a two-sided 96.7% CI. • When one believes that all three endpoints could have reasonable power to show bio-inequivalence, Strategy III could be a good choice. • An example of varying CIs is (94%, 80%, 65%) if normally distributed ACPS Meeting