FDA Locally Active Drug BA/BE Guidances Slated for Release In About A Year

Four FDA guidances on drug bioavailability and bioequivalence, including three focused on "locally active drug products," are expected to be issued "in the next year or so," Center for Drug Evaluation and Research Deputy Director for Pharmaceutical Science Roger Williams, MD, told an International Generic Pharmaceutical Alliance conference in Rome June 5.

The locally active drug guidances will address three formulation types: topical, oral inhalation and nasal inhalation, Williams said. He characterized the fourth document as a "general" guidance for oral drug products.

"There is a tremendous amount of science going on in these areas, and...these guidances will...gel very nicely in terms of a 'how to' sort of approach" to bioavailability and bioequivalence issues, Williams explained. The documents also are intended to"fit well" with the World Health Organization multi-source guidance as well as guidances from the European Medicines Evaluation Agency and its working groups, he noted.

FDA's Dermatologic and Ophthalmic Drugs Advisory Committee met March 20 to discuss methods of determining bioequivalence for topical dermatologic products that should be included in the topical products guidance. The committee recommended against the use of skin-stripping tests as a replacement for comparative clinical trials to determine bioequivalence ("The Pink Sheet" March 30, p. 11).

Williams also reported that FDA's recently formed Complex Drug Substances Coordinating Committee will be developing agency policy on equivalency for products such as natural source conjugated estrogens.

"The allowance for generic substitution of [natural source conjugated estrogens] was and is very difficult for the U.S. It causes a lot of challenges in terms of figuring out what is equivalent in terms of the active moiety," he said.

In May 1997, FDA concluded that it could not approve ANDAs for synthetic generics for Wyeth's Premarin because the drug had not been adequately characterized.

The Complex Drug Substances Coordinating Committee also will evaluate products such as recombinant DNA-derived cell metabolites, Williams said. "If you look throughout the rest of the coordinating committee, you will see a lot of other areas of future contention and debate," he added.

Williams also suggested that FDA may be re-evaluating its plan to augment its pharmaceutical equivalence standards with "individual bioequivalence" parameters. FDA "is working very vigorously with the industry now, with its academic partners, to see if we can come to a good understanding of how to move forward on this criterion, if it is appropriate," he said.

Both the branded and generic drugs industries have questioned the need for new bioequivalence standards that would permit reference product variability to define the statistical range for drug bioequivalence data.

In March 2 comments, the Pharmaceutical Research & Manufacturers of America argued that FDA had not presented "convincing rationale" for the proposed move away from the current averaging system. Generic associations concurred that the "need for a new guidance has not been adequately explained."

Williams assured IGPA members that a shift to individual bioequivalence would have the same level of impact on generic and branded manufacturers.

"The concept of 'switchability' affects the pioneer just as it effects the generic," he said, citing the incidence of post-approval changes to a drug. "It is not a generic vs. innovator issue. It goes back to that whole goal of ensuring stability, quality and performance parameters during the period [a product] is in the marketplace."

Williams also touched on FDA's current Waxman-Hatch "battles," which he said "are an enormous resource burden for the agency." The FDAer commented that "the problem arises when a pioneer manufacturer sees the loss of a very successful monopoly-protected market."

In addition to Waxman-Hatch legislative challenges and debates related to patents and exclusivity, pharmaceutical equivalence and bioequivalence, the agency is seeing "new debates about excipients and specification" and challenges at the state level, Williams said.