FDA is recommending specific research projects that will help demonstrate the bioequivalence of generic versions of complex branded products.

In a May 1 report, the agency calls for research on new methods to determine bioequivalence for several drug classes, including inhalers, nasal sprays and topical drugs. The agency also suggests studies to find new modeling and simulation tools for drug absorption, drug release and other drug development issues.

The document is part of FDA's Critical Path Initiative, which was established in 2004 to identify and alleviate barriers to the development of drugs, biologics and devices. The agency is now addressing the barriers to generic drug research.

"While straightforward tests of blood plasma levels are sufficient to demonstrate bioequivalence for most generic drug candidates, these common tests generally are not appropriate for certain drugs, including asthma inhalers, nasal sprays, and topical skin applications such as anti-fungal creams," FDA's statement on the report says. "As a result, few generic versions are available in these product categories, resulting in less competition and higher prices."

FDA Office of Generic Drugs Director Gary Buehler said in an interview that the report formalizes efforts that have been going on in an informal, nonpublic way. In 2003, the agency developed a generic research program through which it has sponsored research and coordinated research programs at universities and within its own labs to identify ways to make it easier to determine bioequivalence of certain products.

"We know there are products that could have generic competition if there was a bioequivalence scheme people were comfortable pursuing," Buehler said. He added that the agency wants to avoid duplication of research and have people build on each other's work.

FDA lists groups that could potentially collaborate on research, including its Office of Generic Drugs, individual companies, the Generic Pharmaceutical Association, the National Institutes of Health, the National Science Foundation and the National Institute of Standards and Technology. FDA's Critical Path Initiative has been successful in getting various entities to work together. In 2006, more than 40 collaborations and projects were initiated (¹ Also see "“Critical Path” Is On The Road Forward; FDA Reports Industry Activity Is High" - Pink Sheet, 22 January, 2007., p. 29).

The agency specifies four areas of research where these organizations can work together: improving the science underlying the quality by design paradigm, which controls for formulation and manufacturing variables that can change an ingredient's bioavailability; improving the efficiency of current methods to assess bioequivalence of systemically acting drugs, including products that use complex and novel drug delivery technologies; developing methods to assess bioequivalence of locally acting drugs, such as topical and inhalation products; and developing methods to characterize complex drug substances and products.

GPhA VP of Regulatory Affairs Gordon Johnson said he was pleased to see FDA addressing potential problems with products that have not yet come off patent, such as liposomal dosage forms of drugs. The report notes that work on novel bioequivalence methods is needed "to determine if two liposomes with the same composition but produced by different manufacturers have the same therapeutic profile (e.g., by assessing how they deliver drug to relevant tissues)."

The nine-page report suggests research that can be done to assess bioequivalence. For systemically acting drugs, FDA says there may be opportunities for drug applicants to get waivers of in vivo bioequivalence studies for highly soluble and permeable Biopharmaceutics Classification System Class I drugs dosed in rapidly dissolving immediate release products and to expand biowaivers to poorly soluble and highly permeable BCS Class II drugs and highly soluble and poorly permeable BCS Class III drugs.

With regard to highly variable drugs, the report says study designs may be developed that would allow demonstration of bioequivalence with a smaller number of subjects.

Addressing bioequivalence methods for locally acting and targeted delivery drugs, the report says the current method of comparative clinical trials can be prohibitively expensive and is the least efficient way to detect differences in product performance. For inhalation products, the report suggests studying imaging techniques that can quantify the amount of the drug at the site of action. To determine bioequivalence of nasal sprays, the report says particle size distribution tests may be used.

- Brenda Sandburg (b.sandburg@elsevier.com)

FDA Proposes Bioequivalence Research On Inhalers, Other Complex Drugs

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