Why Were More Than 200 Subjects Required to Demonstrate the Bioequivalence of a New Formulation of Levothyroxine with an Old One?

At the request of French Regulatory Authorities, a new formulation of Levothyrox® was licensed in France in 2017, with the objective of avoiding the stability deficiencies of an existing licensed formulation. Before launching the new formulation, an average bioequivalence (ABE) trial was conducted, having enrolled 204 subjects and selected for interpretation a narrow a priori bioequivalence range of 0.90–1.11. Bioequivalence was concluded. In a previous publication, we questioned the ability of an ABE trial to guarantee the switchability within patients of the new and old levothyroxine formulations. It was suggested that the two formulations should be compared using the conceptual framework of individual bioequivalence. The present paper is a response to those claiming that, despite the fact that ABE analysis does not formally address the switchability of the two formulations, future patients will nevertheless be fully protected. The basis for this claim is that the ABE study was established in a large trial and analyzed using a stringent a priori acceptance interval of equivalence. These claims are questionable, because the use of a very large number of subjects nullifies the implicit precautionary intention of the European guideline when, for a Narrow Therapeutic Index drug, it recommends shortening the a priori acceptance interval from 0.80–1.25 to 0.90–1.11

Global Harmonization of Comparator Products for Bioequivalence Studies

Comparator products should be the products that were shown to be safe and efficacious in pivotal clinical trials to ensure prescribability of generics. The use of a common comparator ensures switchability between generics. The selection of the comparator is a national responsibility and may be different between countries. This paper discusses the current recommendations on selection of comparators, the associated problems, and the possibility of harmonization. Most countries follow the World Health Organization (WHO) recommendations for selecting comparator products and require the comparator product to be obtained from their national markets to ensure switchability between the local comparator and their generics. These recommendations are only feasible in the few countries where the repetition of the bioequivalence study is economically feasible, but they are impracticable in all other countries. Furthermore, the exclusive use of the local comparator to ensure switchability is ethically and scientifically questionable. The innovator product from well-regulated markets should be the global comparator. This harmonization is feasible as the concept already applies in the WHO prequalification program. 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 products