Adjusted Indirect Treatment Comparison of the Bioavailability of WHO-Prequalified First-Line Generic Antituberculosis Medicines

Abstract

Approval of generic medicines is based on bioequivalence with the innovator product, but it is not unusual for generics to be interchanged with each other. This study investigated the differences in bioavailability between World Health Organization-prequalified antituberculosis generics by means of indirect comparisons to ensure interchangeability between these diverse generics. Data on 22 products containing isoniazid, rifampicin, pyrazinamide, or ethambutol in single- or fixed-dose combination were included. The indirect comparison between generics shows that the differences, expressed as 90% confidence intervals, are always less than 30%. Furthermore, assurances regarding interchangeability of two generic products are reduced when either the point estimate ratios in the original studies are shifted from unity by more than 5% or when the width of the 90% confidence interval is large. From a bioequivalence perspective, not only are the generics bioequivalent with the reference but also all these generics can be interchanged without safety/efficacy concerns.

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

“…Products meeting the proposed acceptance criteria can be interchanged as necessary with little concern regarding possible shifts in the quality of therapy as observed by the patient or treating professional. As suggested previously [9], this work indicates that the best way to gain greater assurance of generic interchangeability, when necessary, is to place a constraint on the point estimates in the original generic vs. reference product bioequivalence studies.…”

“…This was observed in Gwaza et al [9] by comparing a diverse group of prequalified firstline tuberculosis (TB) medicines in order to explore the utility of the recommended approach for conducting adjusted indirect comparisons. On one hand, the study found that the TB products being compared could be interchanged as necessary without significant concern regarding possible shifts in the quality of therapy.…”

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.…”

“…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.…”

“…Direct comparisons between generics are not performed as there is no regulatory requirement for conducting these studies since they are not practical . Therefore, the adjusted indirect comparisons (AICs) are the most suitable method to assess bioequivalence between generics . To our knowledge, generic products of clopidogrel have not been compared between themselves, neither indirectly nor directly.…”