Adjusted indirect treatment comparisons of bioequivalence studies

Abstract

Generic medicines are approved by regulatory authorities based on demonstration of bioequivalence with the innovator, however, current regulatory systems do not require direct comparison between all available generics of the same innovator to ensure interchangeability. As such, interchangeability between generics of the same drug isassumed, although it has not been addressed comprehensively by regulators. Thus, this thesis addresses three main interlinked issues with respect to interchangeability of generic medicines particularly in low- and middle-income countries (LMICs) in a global context.First, this thesis shows that adjusted indirect treatment comparison is a pragmatic approach to identify interchangeable generic products by comparing the different generics that have been demonstrated to be bioequivalent with the same comparator product. Further, in contrast to the ± 20% acceptance range used for direct comparisons, a ± 30% acceptance range is proposed for adjusted indirect comparisons, due to the limited precision of indirect comparisons. The outcome of the indirect comparisons indicates that the antimalarial artemether/lumefantrine, first-line antituberculosis, and first-line antiretroviral generics prequalified by the World Health Organization (WHO) can be interchanged without any safety and efficacy concerns in the clinical settings.To ensure switchability between the generics, the generic and the comparator should not differ significantly (i.e. point estimates should not exceed the 7% difference) and the original studies should be sufficiently powered (i.e. > 80%). In this respect an additional point estimate constraint of ± 10% is proposed, particularly for LMICs where the regulators may not provide guidance to health professionals on the switchability of approved products or when generic substitution is recommended by national governments or the third party reimbursement agencies. A lower point estimate constraint of ±5%, is proposed for NTI drugs, especially where neither generic switching of these drugs is restricted nor narrowed bioequivalence acceptance limits applied.Second, this thesis shows that it is possible to have the necessary arrangements for product registration for generic medicines that will ensure that nationally approved products are of sufficient quality and interchangeable, and to adopt resource-efficient approaches without duplications in LMICs. The collaborative case model in the context of global harmonisation efforts, not only in LMICs, but also in high-income countries demonstrates that collaboration in assessments is feasible and probably the most pragmatic approach that countries in LMICs should use to build capacity and to ensure quality and interchangeable medicines in the market.Third, this thesis shows that most countries follow the WHO recommendations for selecting comparator products and require the comparator product to be obtained from their national markets. These recommendations are only feasible in the few countries where the repetition of the bioequivalence study is profitable, but they are impracticable in all other countries, especially LMICs. Therefore, this thesis proposes that the innovator product from well-regulated markets should be the global comparator as it is ineffectual to harmonize only the requirements for performing bioequivalence studies, if such a study has to be repeated for every single country simply because of the different comparator product.