LAUSR

We are pleased to respond to the letter of Munafo et al. [1] as follows: in our levothyroxine article [2], we concluded that “a statistical analysis conducted in the conceptual framework of individual bioequivalence would have enabled: (i) documentation of possible higher intra-individual variability for the new compared to the old formulation and, hence, possible reconsideration of development of this new formulation” and “(ii) consideration of a possible subject-byformulation interaction, allowing both regulatory authorities and prescribing clinicians to be better placed to manage and systematically supervise all patients during transition from the old to the new formulation”. We are of the firm opinion that a fundamental responsibility of a drug company is to determine and report these two sources of biological variability, when, as is the case for levothyroxine (T4) [a drug having a Narrow Therapeutic Index (NTI)], a new formulation is imposed on millions of patients. Switchability is the key issue and it is neither sufficient nor indeed appropriate to refer to a third source of variability, when this is simply ‘noise’ even though this ‘noise’ is specific to drugs such as levothyroxine, for which a baseline correction is in order. The reliability issues raised by correction for a baseline T4 level have been addressed previously, placed in perspective, and even already disputed by others [3, 4]. We re-iterate that it was not our intention to reanalyze this data set, for which the experimental design was not publicly available. Moreover, we made no claim that individual bioequivalence (BE) does not exist in this case. Therefore, exploration of all possible factors underlying the observation, from the raw data, that almost 70% of subjects enrolled in this trial were outside the a priori BE acceptance range was not our goal. In short, this value was for us simply a “warning signal”. We return to and re-state our main message, namely that an analysis to determine average bioequivalence (ABE), conducted by tightening the a priori acceptance interval, cannot establish unequivocally switchability of the two Levothyrox® formulations. This fundamental message is not nullified by referring to difficulties in correcting for the baselineT4 level, required by the European Union (EU) guideline and which Merck used to demonstrate ABE. Rather, it should be understood that the 2010 EU guideline on ABE explicitly excluded the issues of substitution and switchability. The word ‘substitution’ is quoted once only as follows “Furthermore, this guideline does not cover aspects related to generic substitution as this is subject to national regulation” and the word ‘switchability’ is not mentioned in this guideline [5]. This is because there is no consensus among the various EU member states on the issues of BE acceptance criteria and switchability, as reviewed recently by Verbeeck and Musuamba [6]. For example, the Danish Health and Medicines Authority requires tighter acceptance limits of 0.90–1.11 for substances with an NTI, in respect of automatic substitution for a list of substances that are considered switchable. It is important to note that the Danish regulatory authority specifically excludes from this list three substances including thyroxine [6]. The Federal This reply refers to the article available at https ://doi.org/10.1007/ s4026 2-019-00785 -x.