What’s the problem with generic antiepileptic drugs?

Abstract

To decrease health care expenditures, generic substitution is strongly encouraged by states and third-party payers. Since the 1980s, the Food and Drug Administration (FDA) has published the “Orange Book.”1 This easily searchable document, available online at http://www.fda.gov/cder/ob/, explains the FDA’s policy on generics and lists FDA-approved drugs including generic equivalents. The FDA designates a generic drug as therapeutically equivalent to the reference compound (usually the brand-name drug) if it contains the same amount of active ingredient in the same dosage form and meets the same standards for strength, quality, purity, and identity.1 Two pharmacokinetic measures, the area under the drug concentration-time curve (AUC) and maximum concentration (Cmax), are used to determine bioequivalence (and by extension from these surrogate measures, therapeutic equivalence). Equivalence is established when the 90% CI of the ratio of the generic to reference compound for the AUC and Cmax fall within an 80% to 125% range. The in vivo bioequivalence testing is typically done in 24 to 36 healthy adults. Two reviews have been conducted by the FDA, which showed that the average difference between mean AUC and Cmax of the reference and generic compounds was about 3% to 4% (SD about 3).2,3 Notably, in 13 (5.8%) of 224 bioequivalence studies there was a 10% or greater difference in the mean AUCs. …