FDA issued a draft guidance Wednesday that provides its recommendations for generic-drug makers seeking to show bioequivalence to a reference listed drug. The document–Bioequivalence Studies with Pharmacokinetic Endpoints for Drugs Submitted Under an ANDA–does not represent a significant change or shift in FDA policy/opinion, but it covers many approaches and revises and replaces parts of two existing FDA Guidances (see here and here). And, most notably perhaps, the document is a consolidation of many of FDA’s previous opinions and guidances on establishing bioequivalence that concludes with an attachment providing a summary of general approaches for the design and data handling of bioequivalence studies with pharmacokinetic endpoints. The document should provide would-be generic-drug applicants with a good starting place.
FDA’s advice is very general, as the Agency states that companies should see FDA’s product-specific guidances for information on individual drugs. But despite the lack of product-specific advice, the guidance provides significant detail about common study parameters. FDA starts with a general discussion of how best to establish bioequivalence. The Agency notes that applicants can establish bioequivalence using in vivo and/or in vitro methods, which include–in descending order of preference–pharmacokinetic, pharmacodynamic, clinical, and in vitro studies.
Regarding pharmacokinetic studies, FDA suggests that applicants use: (1) a two-period, two-sequence, two-treatment, single-dose, crossover-study design; (2) a single-dose-parallel-study design; or (3) a replicate-study design. To establish bioequivalence from the studies, FDA urges applicants to use the average bioequivalence method of analysis. The guidance provides that, if possible, the study population should consist of enough subjects–18 years and older and representative of the entire population, considering age, sex, and race–to provide adequate statistical power.