Comment on “Levothyrox^® New and Old Formulations: Are they Switchable for Millions of Patients?”

Excerpt

In a recent ‘Current Opinion’ paper in Clinical Pharmacokinetics, Concordet et al. [1] postulated that the within-subject variance (WSV) and variance estimating subject-by-formulation interaction for a new formulation should be assessed in order to estimate the appropriateness of the new formulation [1]. In this respect it is relevant to remind readers that a few decades ago individual bioequivalence (IBE) and population bioequivalence (PBE) were heavily discussed in the scientific field and also drew the attention of regulatory agencies. The potential of IBE/PBE to replace ABE as regulatory requirement had been investigated by the US Food and Drug Administration (FDA) [2, 3], as indeed referenced by the authors. However, IBE/PBE were, in the end, not adopted by the FDA, nor by any other agency around the world. The reasons for not adopting IBE/PBE are not mentioned by Concordet et al. [1]; however, the authors considered it is not acceptable, for example, because no evidence for failure of average bioequivalence (ABE) for approved generics had been reported. In our opinion, the most critical reason for not adopting IBE/PBE is that the proposed criteria using a mixed-scaling aggregate strategy would lead to a relaxation of the 80–125% (and equally a 90–111%) ABE standard [4, 5], indicating IBE/PBE may not be better than the ABE study in terms of evaluating interchangeability of generic drugs/formulations. Furthermore, a positive correlation between the WSV and the estimation of the variance for the subject-by-formulation interaction was identified, which consequently eliminated the possibility of using a constant cut-off (such as 0.0225, as suggested by the FDA) as a basis for demonstrating substantial subject-by-formulation interactions [6]. Additional support for not applying IBE/PBE has come from a study published recently by us [7], where the variance of subject-by-formulation interaction was investigated together with WSV as well as between-subject variability in a selection of replicated bioequivalence studies. The study showed that the variance of subject-by-formulation interaction can be considered negligible. The results clearly indicate that the difference in exposure after switching to a generic drug is almost exclusively due to the WSV in the pharmacokinetics of the active substance. Therefore, overall we do not see a benefit of requesting an IBE instead of an ABE study as the regulatory requirement. The ABE approach does not allow a wide variance for the subject-by-formulation interaction compared with the IBE approach, even though the variance of subject-by-formulation interaction is not the criterion to be evaluated. It is fully understood that IBE is more straightforward from a patient or doctors’ perspective and more comparable with the clinical situation than the ABE; however, this does not mean it is the best method as a regulatory requirement for drug assessments. …