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

Concordet, D; Gandia, P; Montastruc, J-L; Bousquet-Mélou, A; Lees, P; Ferran, A A; Toutain, P-L

Authors

D Concordet

P Gandia

J-L Montastruc

A Bousquet-Mélou

P Lees

A A Ferran

P-L Toutain



Abstract

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.

Citation

Concordet, D., Gandia, P., Montastruc, J., Bousquet-Mélou, A., Lees, P., Ferran, A. A., & Toutain, P. (2019). Why Were More Than 200 Subjects Required to Demonstrate the Bioequivalence of a New Formulation of Levothyroxine with an Old One?. Clinical Pharmacokinetics, 59, 1-5. https://doi.org/10.1007/s40262-019-00812-x

Journal Article Type Commentary
Acceptance Date Aug 1, 2019
Publication Date Aug 21, 2019
Deposit Date Aug 28, 2019
Publicly Available Date Aug 29, 2019
Journal Clinical Pharmacokinetics
Print ISSN 0312-5963
Electronic ISSN 1179-1926
Publisher Adis
Peer Reviewed Peer Reviewed
Volume 59
Pages 1-5
DOI https://doi.org/10.1007/s40262-019-00812-x
Public URL https://rvc-repository.worktribe.com/output/1380800

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