Regulatory and Study Conditions for the Determination of Bioequivalence of Highly Variable Drugs

Abstract

-Purpose. The FDA Working Group on Highly Variable (HV) Drugs recently presented procedures and conditions for determining the bioequivalence (BE) of HV drug products. They included analysis by the method of scaled average BE (SABE), a switching coefficient of variation of CV S = 30% and a regulatory standardized variation of CV 0 = 25% for applying SABE, and the use of a secondary regulatory criterion restricting to 0.80-1.25 the point estimate for the ratio of the estimated geometric means (GMR) of the two formulations. These conditions are scrutinized in the present communication. Methods. 3-period BE studies were simulated with various statistical and regulatory assumptions. Power curves, obtained by gradually increasing the true GMR, compared performances of the methods of SABE, a constrained point estimate of GMR (PE/GMR), and the composite of these two approaches. The consumer risk of each procedure was evaluated. Results. With CV 0 = 30% and PE/GMR = 0.80-1.25, the composite criterion of BE relied on the confidence limits of SABE. In contrast, with CV 0 = 25% and/or PE/GMR = 0.87-1.15, the composite criterion approached almost completely the features of the GMR point estimate, especially at high within-subject variation. The consumer risk was near 5% with CV 0 = 30% but about 15% when CV 0 = 25%. Conclusions. A constraint on GMR is difficult to justify scientifically. Still, if it is introduced then the condition of CV S = CV 0 = 30% and PE/GMR = 0.80-1.25 is recommended as a composite regulatory criterion. With alternative settings of the conditions, such as the recommended CV 0 = 25% and/or PE/GMR = 0.87-1.15, the composite criterion would reflect almost entirely the GMR point estimate. Also, with CV 0 = 25%, the BE limits are discontinuous at CV S = 30% and, as consequences, the consumer risk is substantially larger than 5%, and the regulatory uncertainty for making a decision about acceptance or rejection is enhanced. These would be undesirable outcomes.

An Exact Procedure for the Evaluation of Reference-Scaled Average Bioequivalence

“…But as reported earlier, this method has a higher than 5% consumer risk (27). This observation was confirmed (28,29).…”

Implementation of a Reference-Scaled Average Bioequivalence Approach for Highly Variable Generic Drug Products by the US Food and Drug Administration

“…As it is possible that, using RSABE, two products can be shown to be bioequivalent but have an estimated GMR outside of the 0.8 to 1.25 range, it is thought that use of the secondary point estimate constraint will improve the confidence of clinicians and patients (15,28). Several simulation studies investigating the relationship between FDA's recommended RSABE approach and study power have shown that, when within-subject variability exceeds 50-60%, the point estimate constraint becomes the dominant regulatory criterion rather than the scaling (43)(44)(45). It has also been shown that applying the point estimate constraint can increase the sample size needed to show BE for drugs with within-subject variability >50-60% (45).…”

“…The FDA sets σ W0 at 0.25, but also proposes an implementation algorithm that does not permit BE limits to scale until the observed within-subject variability reaches the cutoff value of 0.294 for s WR . Endrenyi and Tothfalusi (44) argue that the FDA's approach to RSABE is discontinuous and conducted simulations claiming that, when σ W0 ranges from 0.246 to 0.294, consumer risk is substantially larger than 5% and the regulatory uncertainty about a decision on acceptance or rejection is enhanced. This claim is based on a different definition of consumer risk than FDA uses.…”

Bioequivalence Requirements in the European Union: Critical Discussion

“…This has been done in order to have a smooth transition between scaling and no scaling, and to avoid an excessive consumer risk at intra-subject variability slightly higher than 30%, which are very frequent (31). In contrast, the US-FDA employs a proportionality constant that is more permissive (wider limits) and there is a lack of consistency between the CV that corresponds to that constant and the CV where scaling starts to be acceptable (CV= 30%), which increases the consumer risk.…”