FDA issued a draft guidance on March 18, 2014 titled, "Bioavailability and Bioequivalence Studies Submitted in NDAs or INDs - General Considerations." This draft guidance seeks to revise and update FDA's March 2003 guidance titled, "Bioavailability and Bioequivalence Studies for Orally Administered Drug Products -- General Considerations." This document provided guidance for NDAs, INDs, and ANDAs. In December 2013, FDA issued a draft guidance that deal with these issues solely for ANDAs. This week's draft guidance tackles the remaining portion of the subject matter in the 2003 guidance: NDAs and INDs. Like the draft guidance on ANDAs issued in last December, this March 2014 draft guidance should not surprise those familiar with FDA's bioequivalence ("BE") requirements; however, it helpfully clarifies and updates a number of long-standing Agency positions.
The instant draft guidance describes that BE documentation could be useful in the IND and NDA context to compare various formulations implicated at various stages of the application life-cycle. For example, BE studies may be useful in the pre-approval context to compare: (1) formulations used in various stages of clinical trials, (2) clinical trial formulations with formulations used in stability studies; (3) clinical trial formulations with proposed final formulations; and (4) product strength equivalence. In the post-approval context, BE studies are required by FDA under certain circumstances if the innovator makes changes to the formulation.
FDA's draft guidance issued this week also covers methods to document bioavailability and bioequivalence. It is not unexpected that the draft guidance devotes a significant portion to pharmacokinetic studies, laying out considerations relevant to study size, population, moieties to be measured, and pharmacokinetic measures of system exposure, to name a few. The usage of partial measures of exposure has been heavily debated in the past and this draft guidance confirms that they can be used in certain situations. The draft guidance also states, "[t]he time to truncate the partial area should be related to a clinically relevant PD measure." The draft guidance also covers in vitro tests with in vivo correlation, pharmacodynamic studies, comparative clinical studies, and in vitro studies. Further, the draft guidance provides considerations specific to dosage forms, such as solutions (and other solubilized dosage forms), immediate-release products, and modified-release products.
The 2014 draft guidance also covers a number of miscellaneous, "special topics," including considerations relating to: (1) the effects of alcoholic beverages on modified-release products; (2) whether a BE study should measure an enantiomer or a racemate; (3) drug products containing complex mixture active ingredients; (4) drugs with long half-lives; (5) orally administered drugs intended for local action; (6) combination drug products; (7) endogenous substances; and (8) drug products with high intra-subject variability.
Of particular interest are the differences between this March 2014 draft guidance on NDAs and INDs as compared to the 2013 draft guidance on ANDAs. For example, for NDAs and INDs, FDA indicates that assessing food effect on bioavailability can generally be accomplished using fasting BE studies due to the all of the information considered in the context of the NDA application process. On the other hand, FDA recommends using both fed and fasted BE studies for ANDAs. In addition, FDA expanded the section on modified release products and added a number of the "special topics," such as the sections on combination products, effect of alcohol, endogenous substances, and high inter-patient variability, as compared to the March 2003 guidance.