Interchangeability between first-line generic antiretroviral products prequalified by WHO using adjusted indirect comparisons

Abstract

BACKGROUND The scaling up of access to antiretroviral therapy, particularly in low- to middle-income countries, was facilitated by the introduction and widespread use of generic antiretroviral medicines and fixed dose combinations. Generic medicines are approved by regulatory authorities based on the demonstration of bioequivalence with the innovator or reference product, as well as meeting quality standards. In clinical practice, however, it is not unusual for generics to be interchanged between each other. This study investigated the differences in bioavailability between WHO-prequalified first-line antiretroviral generics by means of adjusted indirect comparisons to ensure interchangeability between these generics. METHODS Data on 34 products containing emtricitabine, tenofovir disoproxil fumarate, lamivudine and efavirenz in single formulations or fixed dose combinations were included in the analysis. The 90% confidence interval for the adjusted indirect comparisons was calculated using the homoscedastic method that uses the conventional t test, and assumes homogeneity of variances between the studies and small sample sizes. The combined standard deviation of both bioequivalence studies was calculated from the variability of each individual study. RESULTS The adjusted indirect comparisons between generics showed that the differences, expressed as 90% confidence intervals, are less than 30%. Confidence in the interchangeability of two generic products was reduced if the mean difference between the test and reference in the original studies is more than 10%. CONCLUSIONS From a bioequivalence perspective, the generic antiretroviral medicines prequalified by WHO are interchangeable with the reference, as well as between each other without safety or efficacy concerns.