ANDA Bioequivalence Studies That Fail to Meet FDA’s Current Bioequivalence Criteria

1. ANDA Bioequivalence Studies That Fail to Meet FDA’s Current Bioequivalence Criteria Dale P. Conner, Pharm.D. Division of Bioequivalence Office of Generic Drugs OPS, CDER, FDA

2. Introduction -- BE Studies • Usually two-way crossover, single-dose study • Normal volunteers • Fasting • BE criteria: 90% CI between 80 and 125% • AUC • Cmax • Fed (point-estimate between 80 and 125)

3. Examples of BE Results

4. Introduction • Definition of “failed” • Sponsors often choose not to submit “failed” studies in ANDAs • Sometimes these contain important information on the to-be-marketed ANDA product

5. Background • For NDAs all human investigations made to show whether or not such drug is safe for use and whether such drug is effective must be submitted (F.D.&C. 505 (b)(1)(A)) • For ANDAs (F.D.&C. 505 (j)) similar language was not included in the Act • Sponsors have interpreted this to mean that “failed” BE studies need not be submitted in ANDAs

6. Background • Other important considerations • Application may not contain untrue statements of material fact (F.D.&C. 505(j) (3) (K); 21 CFR 314.127 (a) (13)) • Selective reporting of data may constitute untrue statements of material fact (example FR 32982 June 26,1995) • Failure to report failed studies may be considered selective reporting

7. Reasons for “Failure” of BE Studies • Under-powered study • Unusual study designs • “Outlier” response from one or more subjects • Assay issues • Wrong reference

8. Reasons for “Failure” of BE Studies • Baseline-corrected vs. not corrected • Incorrect statistical analysis • Compliance issues • Formulation that is not truly bioequivalent to the reference

9. Example 1 - Drug X Oral Liquid • Liquid dosage form mixed with beverage prior to administration • ANDA studies performed with one beverage • Additional study in another beverage completed before ANDA approval • Product was not bioequivalent under this labeled administration condition • Study was not submitted before ANDA was approved

10. Example 2 - Drug Y Solid Oral MR • Discovered by Compliance on inspection of another study • First study against a lot (A) of brand product failed -- Cmax (105, 130) • Second study against another lot (B) of brand passed (submitted in ANDA) • Third study performed testing lot A vs. lot B -- failed: Cmax (111, 131) • Problem with RLD

11. Example 3 “Outlier” Response Example • Solid oral dosage form • Standard BE study with 24 normal subjects • One subject’s T/R was ~4 • Point-estimate of other subjects T/R ~1.1 • Study did not pass CI criteria with all subjects • Restudy of subject with 4 other original subjects • Subject’s new T/R = 1.05 ==> subject data dropped from original study

12. Questions • Should sponsors submit the results of all BE studies performed on the to-be-marketed ANDA formulation? • Full reports or complete summaries? • What should FDA do with this information? • Complete review • Brief, but careful, examination