Bioequivalence and other unresolved issues in generic drug substitution.

Background: Substitution of generic drugs for brand-name products is highly controversial and often is met with suspicion by health care providers and patients. Historically, the debate has focused on the issue of bioequivalence, and clinical practice has identified a number of drug classes for which generic substitution should be approached with caution. Current bioequivalence requirements are based on a measure of average bioequivalence; however, there are fears that use of this measure may be inappropriate in the case of a drug with a narrow or wide therapeutic range or high intrasubject or intersubject variability. Under these circumstances, measures of individual and population bioequivalence are proposed to be more accurate than measures of average bioequivalence.

Objective: This paper addresses issues of bioequivalence and other concerns with generic drug substitution.

Methods: I conducted a MEDLINE search of the English-language literature containing the key terms generic, multisource, quality, and brand and published between 1973 and 2003. The names of branded pharmaceuticals whose patents had recently expired (eg, Ventolin HFA, Adalat, Capoten, Tagamet HB 200, and Valium) also were used to search for articles on generic substitution. Reference lists of relevant articles also were searched. Bioequivalence issues are presented together with more general concerns over generic drug substitution, such as consumer perception of risk, differences in product and packaging appearance, and differences in excipients.

Results: The literature reviewed act to highlight a number of different drug categories and patient subpopulations for which generic substitution can still prove to be problematic.

Conclusion: I recommend that health care providers continue to exercise caution in the consideration of generic drug substitution under certain circumstances.