FDA Issues Draft Guidance on Bioequivalence Studies Specifically for ANDAs

The U.S. Food and Drug Administration (FDA) on December 4, 2013 issued new draft guidance on bioequivalence studies for drugs submitted under an Abbreviated New Drug Application (ANDA).  In light of the relatively few substantive changes from previous guidance, the main purpose in issuing the new draft appears to be the separation of such guidance according to application type.  It also notes that separate guidance addressing bioavailability and bioequivalence studies for Investigational New Drug Applications (INDs), New Drug Applications (NDAs), and NDA supplements will be available soon.

Substantively, the draft guidance for ANDAs reaffirms that pharmacokinetic studies are the preferred method of establishing bioequivalence.  For most dosage forms the guidance recommends a two-period, two-sequence, two-treatment, single-dose, crossover study.  However, the guidance notes that crossover studies may not always be practical, such as for drugs with long half-lives.  In such circumstances the guidance recommends a single-dose, parallel design, where each treatment is administered to a separate group of subjects.  The guidance also notes that replicate crossover studies may be a useful alternative for highly variable drugs.

The draft guidance covers a number of “Special Topics.”  Of particular note is the recommendation that applicants measure only the parent drug, rather than metabolites, because the concentration-time profile of the parent drug is more sensitive to changes in formulation performance than a metabolite.  Additionally, the FDA warns that a failure to include early sampling times leading to first time-point Cmax values may result in the agency not considering the data.

Comments on the draft guidance for ANDAs are due by March 5, 2014.  Those interested in ANDA law also should watch for the forthcoming draft guidance on bioavailability and bioequivalence for INDs and NDAs.  Comparing the new draft guidances should offer clues as to whether the separation of such guidance by application type is primarily for the sake of convenience, or whether the FDA has more fundamentally altered its approach to bioequivalence and bioavailability studies based on application type.