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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. Introduction -- BE Studies. Usually two-way crossover, single-dose study Normal volunteers Fasting
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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
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)
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
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
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
Reasons for “Failure” of BE Studies • Under-powered study • Unusual study designs • “Outlier” response from one or more subjects • Assay issues • Wrong reference
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
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
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
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
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