HASfter four years of investigation by the Marseilles court, the National Medicines Safety Agency (ANSM) has just been indicted for “deception” in the Levothyrox case. In the spring of 2017, upon the introduction of Merck’s new Levothyrox formula (a drug at the time in a quasi-monopoly situation and taken by nearly three million patients), many patients complained of adverse effects sometimes very handicapping.
About 36,000 of them made a pharmacovigilance report and more than 10,000 filed a complaint, which triggered the opening of an investigation against X by the Marseille public prosecutor’s office in March 2018, for “aggravated deception”, “unintentional injuries” and “endangering the lives of others”. In this case, the errors of the agency were numerous. She accepted the study provided by Merck claiming to demonstrate the bioequivalence of the two formulations. This acceptance is based on two errors.
The agency did not understand that the organization of the Merck study, in which each subject received the old formulation once and the new one once, did not allow attribution of the observed effect of the difference of wording. This inadequate study organization is still accepted today by the French agency and by the European agency. The American agency, the Food and Drug Administration, for its part, requires that each subject receive each of the two formulations twice.
A non-binding guideline
The Merck laboratory and the ANSM will not fail to point out that the study which was carried out complied with the guideline (LD) of the European Medicines Agency (EMA) which defines average bioequivalence as a condition for verifying whether a new formula is prescribeable. Unlike a European directive, a guideline is not binding, and it absolutely does not guarantee that the new formula is “substitutable”, that is to say can replace a treatment already in progress!
On this non-binding nature of a LD, you should read the text of the EMA which clearly explains that you must be free from it when science suggests it. The analysis of the Merck study, published in February 2017, did not make it possible to document the bioequivalence in each patient, yet essential insofar as three million people were going to be forced to change treatment, Merck’s levothyroxine being the alone on the French market.
The agency did not request analysis of individual variations in response to the two formulations. Yet it is well known that levothyroxine has a narrow therapeutic range, which means that some patients may be thrown off balance by a small dose change. The analysis carried out by Merck consisted in comparing the biological availability of the two formulations in 204 healthy volunteers who successively received one and the other of the two formulations.
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