FDA issued a draft guidance Wednesday that provides its recommendations for generic-drug makers seeking to show bioequivalence to a reference listed drug.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.

The guidance next addresses establishing bioequivalence in different dosage forms, namely: (1) oral solutions, (2) immediate-release capsules and tablets, (3) suspensions, (4) modified-release products, and (5) chewable tablets. For immediate-release and modified-release products, FDA recommends that applicants conduct: (1) a single-dose, fasting studying comparing the highest strength of the test with the reference listed drug ("RLD"), and (2) a single-dose fed [bioequivalence] study comparing the highest strength of the test with the RLD product."

Regarding immediate-release products, FDA explains that applicants may obtain a waiver of an in vivo bioequivalence requirement for one or more strengths of the product if they can show an acceptable bioequivalence study on the designated strength, acceptable in vitro dissolution testing of all strengths, and proportional similarity of the formulations across all strengths. For modified-release products, additional strengths may be demonstrated to be bioequivalent if the applicant can show that: (1) the additional strength is proportionally similar in its active and inactive ingredients to the test product strength that underwent acceptable in vivo studies; (2) the additional strength has the same drug release mechanism as the test product strength that underwent acceptable in vivo studies; and (3) dissolution testing of all strengths is possible.

FDA also provides a "Special Topics" section that addresses various other issues. One such topic involves moieties. In this section, FDA discusses parent drugs versus metabolites, enantiomers versus racemates, and drug products with complex mixtures as the active ingredients. Regarding metabolites, the Agency advises that applicants only measure the parent drug and not the metabolites, unless primary metabolites are formed substantially through presystemic metabolism and contribute significantly to the safety and efficacy of the product. For racemates, FDA only suggests measuring individual enantiomers in bioequivalence studies if: (1) the enantiomers exhibit different pharmacodynamic characteristics, (2) the enantiomers exhibit different pharmacokinetic characteristics, (3) primary efficacy and safety activity reside with the minor enantiomer, and (4) nonlinear absorption is present. And with drug products having complex mixtures as their active ingredients, FDA recommends forgoing quantification of all active components for bioequivalence studies on a small number of markers of rate and extent of absorption.

Those looking for guidance on investigational new drug applications ("INDs") or new drug applications ("NDAs") will have to wait, as this guidance only addresses ANDAs and ANDA supplements. Hopefully the wait will not be too long, as FDA indicates that a separate guidance addressing bioavailability, bioequivalence, and food-effect studies in INDs and NDAs will soon be available.