Implementation of a reference-scaled average bioequivalence approach for highly variable generic drug products by the US Food and Drug Administration

Abstract

Highly variable (HV) drugs are defined as those for which within-subject variability (%CV) in bioequivalence (BE) measures is 30% or greater. Because of this high variability, studies designed to show whether generic HV drugs are bioequivalent to their corresponding HV reference drugs may need to enroll large numbers of subjects even when the products have no significant mean differences. To avoid unnecessary human testing, the US Food and Drug Administration's Office of Generic Drugs developed a reference-scaled average bioequivalence (RSABE) approach, whereby the BE acceptance limits are scaled to the variability of the reference product. For an acceptable RSABE study, an HV generic drug product must meet the scaled BE limit and a point estimate constraint. The approach has been implemented successfully. To date, the RSABE approach has supported four full approvals and one tentative approval of HV generic drug products.

Fig. 1

The 80–125% BE limits are represented along the x-axis as two “goal posts.” The BE limits are compared to the hypothetical 90% CIs of the test/reference BE measure GMRs for two drugs, a drug with normal variability (Drug A) and an HV drug (Drug B). The 90% CIs of the two drugs are represented by colored bars. For drug A (normal variability), the 90% CI (green bar) meets the BE limits. For drug B (HV), the 90% CI (red bar) fails to meet the acceptance limits. As the width of the CI is influenced by the number of study subjects, in the hypothetical case of drug B, it is likely that the study would have met the BE limits if more subjects had been used

Fig. 2

Implied BE limits are plotted as a function of the population reference product within-subject variability of the BE measure. When σ _W0 ≤ 0.25, for an acceptable BE study, the 90% CI of the BE measure test/reference GMRs must fall within the 80–125% limits. When σ _W0 > 0.25, the implied BE limits scale as reference product within-subject variability increases. The slope of this portion of the curve is determined by the value of σ _W0

Fig. 3

Decision tree showing the process by which FDA’s OGD decide whether it is suitable to use RSABE or unscaled ABE. The first condition to be met is that the study protocol must state a priori that RSABE will be the method of statistical analysis

Fig. 4

Outcome of the review of 64 RSABE studies reviewed at the OGD. All but two of the studies met the BE acceptance criteria. For 36 of these studies, there were no other deficiencies related to the BE portion of the ANDA submission. For 26 studies, other miscellaneous deficiencies unrelated to RSABE analysis (most often related to the bioanalytical method used) were present in the BE portion of the submission. One study did not meet the point estimate constraint and thus the study did not meet the RSABE acceptance criteria. Another study could not be analyzed using RSABE because the s _WR for C _max was <0.294. However, when the TOST was applied, the 90% CI for C _max did not fall within the 80–125 limits; thus, this study did not meet the ABE acceptance criteria

Fig. 5

This timeline summarizes the evolution of the RSABE approach at the FDA. The FDA first proposed reference scaling as a component of IBE analysis, although the FDA subsequently decided not to continue implementing IBE. Three years later, in 2004, the FDA began developing RSABE using the scaling approach from IBE. The first ANDA using RSABE was submitted in 2007. The first tentative approval of an HV drug for which RSABE was successfully applied was in 2009. The first full approval of an HV drug supported by acceptable RSABE was in 2011. From 2004 to 2010, FDA scientists published several peer-reviewed scientific articles on RSABE and made a number of presentations at national and international venues. The FDA has also posted a Draft Guidance for Industry with a step-by-step description of how to perform RSABE