Influence of point estimates and study power of bioequivalence studies on establishing bioequivalence between generics by adjusted indirect comparisons

Abstract

In summary, the ability to demonstrate interchangeability between generics is dependent not only on the real differences between the products but also on the design of the original generic vs. reference bioequivalence studies being combined, as earmarked by their respective power.

Adjusted indirect comparisons to assess bioequivalence between generic clopidogrel products in Serbia

“…AICs have been adopted as a useful tool for assessing bioequivalence between generic products and their switchability, as well as for comparing originator products from different markets that have previously been shown to be bioequivalent with the same generic product . To our knowledge, this is the first study to compare clopidogrel generic products.…”

“…However, in our opinion it is a reasonable approach for indirect comparisons since C max is usually more variable than AUC and the AICs for C max are notably underpowered. Similarly, other authors have proposed to use a widened acceptance range for the 90% CI of C max due to this limitation . Since the AICs are less precise than the direct comparisons, the 90% CIs obtained in indirect comparison tend to be wider than those that would have been obtained if an in vivo comparison between generics had been performed .…”

“…Furthermore, it is recognised worldwide that differences between formulations in bioequivalence studies do not depend on factors such as sex or race of the healthy volunteers. It is also taken for granted that there is no subject‐by‐formulation interaction or, in other words, the magnitude of the formulation differences does not depend on the covariates defining subgroups of patients …”

“…Clopidogrel generic products were compared using the method of AICs that uses the results from the individual bioequivalence studies for each generic product vs the reference product. The comparison is performed between the pairs of generic products in relative terms since the reference represents the 100% value in all bioequivalence studies, which adjusts the study results . In this study, for each pair of generic products, adjusted indirect comparison is performed in 1 direction, e.g.…”

“…16 Therefore, the adjusted indirect comparisons (AICs) are the most suitable method to assess bioequivalence between generics. [16][17][18][19][20][21] To our knowledge, generic products of clopidogrel have not been compared between themselves, neither indirectly nor directly. Hence, the aim of our study was to investigate the bioequivalence between generic clopidogrel products of the Serbian market, whose bioequivalence data are available in the public domain, using the method of AICs.…”