Authors’ Reply to Krebs-Brown et al. Comment on: “Why Were More Than 200 Subjects Required to Demonstrate the Bioequivalence of a New Formulation of Levothyroxine with an Old One?”

Abstract

As a preliminary response to , we remind readers that Clinical Pharmacokinetics does not publish 'opinions'. Rather, in a section of the journal entitled "Current Opinion", it publishes regular articles and these are subjected, like all articles accepted by the journal, to a peer-review evaluation. We also remind readers that the bioequivalence (BE) trial that we have commented on has itself been published in a journal entitled Current Medical Research and Opinion (Gottwald-Hostalek, Uhl, Wolna, & Kahaly, 2017). As a first comment, we ask readers to note that we have not downgraded this BE trial to the status of a Merck-Serono opinion, despite the title of this journal.However, the Letter to the Editor from Krebs-Brown et al. does offer an opinion, under the guise of seeking "further clarification". The five co-authors of the Krebs-Brown et al. "comment" are employees of the company that developed and successively marketed the old and new formulations of levothyroxine, on which we have commented in our two previous articles in Clinical Pharmacokinetics. We take it that the opinions expressed by Krebs-Brown et al. are those also of their employer, or at least sanctioned by the company. We are pleased now to answer the Merck Serono employees' opinions. In seeking to denigrate our balanced conclusions with their opinions, they fail to answer both the arguments we have put forward and conclusions reached. Inappropriate and confrontational as they may be, we choose to pass over the comments of Krebs-Brown et al. "Without wanting to appear petty, we should point out that the paper contains several inaccuracies and misrepresentations … we would like to distance ourselves from …. This implies that sponsors and planners of ABE trials inherently display a callous attitude to participants in such a trial, an accusation we must strongly protest". We choose rather to focus on the underlying science on which our conclusions are based.We re-affirm our previous comments on the question of switchability. This was the key issue to stimulate debate, when replacement of the old formulation (OF) by a new formulation (NF) of Levothyrox ® was imposed on millions of patients. Now, we are pleased to note that Merck Serono acknowledges that "it is unclear how to interpret the percentage of observed individual exposure ratio (IER) outside of this range" (i.e. the a priori BE range). Krebs-Brown et al. do not deny, in their response, that there was in their trial a large number of subjects outside the a priori BE range. Of significance is their acknowledgement that they are unable to interpret their own average BE (ABE) results on the question of switchability. Whilst there is indeed no regulatory recommendation on this point, this is not sufficient reason to simply ignore it.This question of the number of individual exposure ratios outside the a priori BE range, as a possible weakness of an ABE study, has been addressed both very early and subsequently in the long history of BE. Using simulations, it was shown, in a cross-over trial condu...