LAUSR

We thank Dr. Nicolas for his detailed comments on our article [1]. These we refute from both general and particular perspectives. This response to Dr. Nicholas explains why we do not accept the premises of his reasoning and the deductions he derives, as they lead, in consequence and ineluctably to his wrong conclusions. We reiterate the point made firmly in our article that: when all patients in a population (almost 3 million persons in France in 2017) had been treated with the same licensed Levothyrox® formulation; and when this was administratively and irreversibly switched to a new Levothyrox® formulation, the conclusion must be that this is a switchability issue. Moreover, as we also made previously clear, switchability cannot be established by a classical average bioequivalence (ABE) trial, especially not for a drug like levothyroxine, which has a narrow therapeutic index (NTI). In addition, we reiterate that our article does not present a revised and biased statistical analysis of the bioequivalence (BE) study conducted with old and new formulations of Levothyrox®, using the approach of individual bioequivalence (IBE) instead of ABE. To be clear, we did not undertake any such re-analysis; to repeat, we did not develop an IBE model, as suggested by Dr. Nicolas. Had we done so, our approach would indeed be open to fair criticism. In fact, our approach was rather to count the number of subjects for which the individual exposure ratio (IER) [area under the curve new product/area under the curve old product], calculated using both baseline-adjusted and unadjusted T4 concentrations, was outside the a priori BE range of 0.90–1.11 for the geometric means [2]. In an old but still valuable paper, which presents the results from BE studies, it is recommended that the IER should be reported as a descriptive metric [3]. Such presentation, without any modeling or other testing, reveals the possibility of a red warning signal indicating possible nonindividual BE, when the percentage of IER exceeds 10% [4], i.e., a much lower percentage than the near 70% IER that we calculated for the adjusted IER of Levothyrox®. Like Dr. Nicolas, we are acutely aware of the problems and historical vicissitudes relating to the statistical analyses of an IBE study, as reviewed by Endrenyi et al. [5]. Moreover, this point was clearly acknowledged, when we stated “Individual bioequivalence has been both extensively discussed and challenged and then, finally, not adopted by regulatory authorities”. However, it cannot be asserted that the concept of IBE is either wrong or misplaced, simply because the analysis of IBE studies has, historically, been vigorously debated. Furthermore, it is not correct to claim any inconsistency of IBE because its conclusions may differ from those of an ABE, as previously emphasized by Endrenyi and Midha [6]. The two alternative conclusions, BE or not BE, does not imply any discrepancy, when it is understood that, by their very definitions, ABE and IBE are designed to answer differing questions. Levothyroxine is classified as a NTI drug by many authorities, including the US Food and Drug Administration (FDA) [7], the World Health Organization [8], and the French regulatory agency [9]. Therefore, it is essential that investigation of any new formulation of levothyroxine requires, as for all This reply refers to the article available at https ://doi.org/10.1007/ s4026 2-019-00778 -w.