The FDA describes a generic drug as “a copy that is the same as a brand-name drug in dosage, safety, strength, how it is taken, quality, performance, and intended use.”9 The FDA does allow differences in generics that include “shape, scoring configuration, release mechanisms, packaging, excipients (including colors, flavors, preservatives), expiration date. . . .”10
To show that a generic drug has therapeutic equivalence, it must be shown to be bioequivalent to the branded product. The FDA defines bioavailability as “the rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action.”10 The usual study (there can be variations) to test bio- equivalence involves a crossover design using healthy volunteers (usually 24 to 36) who receive single doses of the brand-name or generic drug.
Blood or plasma levels are measured and area under the curve (AUC), peak concentration (Cmax), and time to peak concentration (Tmax) are calculated. The statistics used to evaluate bioequivalence are a bit more complicated than the often quoted range of 80% to 125% of the reference drug. In brief, 90% confidence intervals are calculated for both AUC and Cmax, and it is these intervals that must lie entirely within the 80% to 125% range.10,11 According to the FDA, “The current practice of carrying out 2 one-sided tests at the 0.05 level of significance ensures that there is no more than a 5% chance that a generic product that is not truly equivalent to the reference will be approved.”10 One might construe this to mean that there is a 1 in 20 chance that a drug that is not truly equivalent will be approved. Many issues have been raised about this process of generic approval, including the use of normal volunteers, single-dose testing, the use of average versus individual bioequivalence, and other concerns about study design and how data are selected to be submitted to the FDA.11
Generic alternative Bioequivalent drugs may still not be deemed therapeutically equivalent if “they contain the same therapeutic moiety, but are different salts, esters, or complexes of that moiety or are of different dosage forms or strengths.”9 In such cases, the term “therapeutic alternative” is used. An example of a therapeutic alternative (not AB-rated) is Osmotica’s venlafaxine extended-release tablet, which was FDA approved in May 2008 for MDD and social anxiety disorder to compete with Wyeth’s Effexor XR capsules (whose extended-release formulation continues to be patent-protected). Apparently, because it is not therapeutically equivalent, the Osmotica product cannot be substituted for Effexor XR in many states without prescriber consent.12
Given the large number of generic manufacturers, both within the United States and abroad, the FDA faces a daunting task to ensure the quality of all generics. In September 2008, it issued a ban on the import from India of 30 generics manufactured by Ranbaxy Laboratories because of manufacturing problems at 2 plants.13 The FDA safety net is stretched thin, however, and it remains possible that some less than desirable generics could reach the consumer.
For every brand-name drug that goes generic, there seems to be a burst of articles (usually case reports and Internet postings) that indicate that the generic is less effective or tolerable in some patients. Within psychiatry, drugs for which concerns have been expressed include antiepileptics, anxiolytics, antipsychotics (particularly clozapine(Drug information on clozapine)), and antidepressants.14,15