Generic Substitution: Issues for Problematic Drugs

James D. Henderson, PhD, RPh, Richard H. Esham, MD, Department of Physician Assistant Studies, College of Allied Health Professions, and the Division of General Internal Medicine and Geriatrics, University of South Alabama College of Medicine, Mobile.

South Med J. 2001;94(1) 

In This Article


The fundamental principles underlying the concept of bioequivalence and the process of generic substitution can be summarized as follows:

  1. Generic substitution is based on the premise of therapeutic equivalence; that is, the generic product will produce the exact same clinical effects (both therapeutic and toxic) as the reference product when administered under the same conditions in the same dosage in the same patient.

  2. When authorizing generic substitution, the practitioner expects therapeutic equivalence between the generic product and the reference product; therefore, no dosage adjustment or additional monitoring should be required (above and beyond that which would normally occur with the reference product).

  3. Products that are bioequivalent will be therapeutically equivalent.

  4. Bioequivalence is assessed by comparison of bioavailability parameters (Table 2).

It is apparent that the key step in this process is the determination of bioequivalence; the following discussion describes the development of the FDA's criteria for bioequivalence.

The science of bioequivalence testing originated in the early 1970s from the necessity for regulatory guidelines that could be used to declare drug products to be bioequivalent. Originally, it was believed that orally administered products (suspensions, capsules, tablets) whose average bioavailability parameters differed by less than 20% should be therapeutically equivalent. The shortcomings of this approach were immediately evident, since such a criterion would theoretically allow the parameters of generic product A to differ from the reference (innovator) product by +20%, while allowing the parameters of generic product B to differ from the reference product by -20%. The net difference between the two generic products A and B would then be as much as 40% and, therefore, beyond the limits of therapeutic equivalence as originally conceived. To correct for this deficiency, the FDA adopted the "power" approach in the early 1980s. This method tested the null hypothesis (H0) that the generic and reference products were identical, and it evaluated the power of the bioequivalence study to detect a 20% difference between the means of the parameters. If the differences between the mean values of parameters for the two products were not statistically significant (P > .05), and the study power was at least 80%, the products were declared bioequivalent.

However, the power approach had a major flaw because it tested the assumption of identical performance from products that were already known not to be identical. Clearly, the formulations of the reference and generic products are not identical, and differences in the extent and rate of gastrointestinal absorption are expected to occur. Therefore, it was concluded that the statistical test of no difference between the products was not the proper bioequivalence assessment. In 1986, the FDA adopted the currently used decision rule, which tests the more relevant alternative hypothesis (H1). This approach asks: (1) how great are the differences between the generic and reference products? and (2) more specifically, are these differences within limits that would still guarantee bioequivalence and therefore therapeutic equivalence? The determination of bioequivalence using this approach is termed "average bioequivalence."[30]

The statistical method for the average bioequivalence assessment is termed the "two 1-sided tests" procedure. Typically, the data from a single-dose, 2-way crossover bioavailability study are analyzed using a complex statistical model that allows evaluation of the least squares means of the bioavailability parameters and their standard errors. These results are then used to construct the 90% CI for the differences in parameter means. A 90% CI is used, since a 5% statistical error is allowed at both the upper and the lower limits; therefore, the total error is 10%, generating the 90% CI. When the current rule was adopted in 1986, if both the upper and lower limits of the CI were within 20% of the reference mean (80% to 120%), the generic product was declared bioequivalent to the reference product. In 1992, the FDA issued a guidance in which the use of log-transformed data and an upper limit of 125% were adopted. These criteria remain the current rule for bioequivalence decisions.[26]

A recent article underscores the misinformation that persists regarding the FDA criteria for generic drug approval. The article states: "Only 17% of 396 physicians were aware that FDA allows the rate and extent of absorption of a generic drug product to depart from those of the brand-name version by up to 25%. . ."[31] "The determination of average bioequivalence is made by calculating the 90% confidence interval (CI) for the difference between generic and reference products and by requiring that the entire CI lie completely within the lower and upper limits which define bioequivalence. Currently, these limits are 80-125% of the reference product mean value using data after logarithmic transformation."[6] Using these statistical criteria, it is difficult for any generic product whose mean arithmetic bioavailability parameters differ by more than 10% from the reference to meet the CI requirements, and it is virtually impossible to meet the CI requirements if the differences approach 20%. "A generic product that truly differs by -20%/+25% or more from the innovator product with respect to one or more pharmacokinetic parameters would actually have less than a 5% chance of being approved."[2] An FDA study showed that the mean difference for AUC values between test and reference products was 3.5% in the 2-year period following the Waxman-Hatch Act, and that 80% of the absolute differences between generic products approved since 1984 and the corresponding innovator products were within 5%.[32]


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