TDAH en France : les initiatives récentes pour développer l’accès aux traitements pharmacologiques

Abstract

Pharmacological treatments for ADHD are among the most effective drugs used in psychiatry. The majority of these treatments are psychostimulants, which act by blocking the reuptake of dopamine and noradrenaline. These drugs are as follows: (i) amphetamine-derivative psychostimulants, such as methamphetamine, dexamfetamine (which is an amphetamine enantiomer), and its prodrug, lisdexamfetamine; (ii) non-amphetamine-derivative psychostimulants, that is, essentially methylphenidate, which is the oldest drug used in ADHD, and generally recommended as first-line medication, and (iii) non-psychostimulant treatments, the best known of which is atomoxetine. For a long time, France stood out from most other countries in Western Europe and North America. Immediate-release methylphenidate was approved for children in France as early as 1995, while extended-release forms have been gradually developed since the 2000s. The initial prescription had to be made by a hospital physician, either a pediatrician, a psychiatrist or a neurologist, which should officially reconduct the treatment annually. Adults were excluded from the marketing authorization (MA), with the only exception being Concerta®, a form of delayed-release methylphenidate, for which continuing treatment after the age of 18, in the case of initiation in childhood, remained within the scope of the MA and was thus reimbursed. In other situations, the use of methylphenidate in adults was off-label, and therefore not reimbursed, which was a quasi-exception in Western Europe. Pushed by the French Society for ADHD (SF-TDAH), but also by patient and family associations, including the official national association TDAH-France, who deemed that this situation was severely hampering the access to ADHD medications for both children and adults, these rules and authorizations were gradually modified from 2020 onwards. With regard to other pharmacological treatments of ADHD, France has been virtually excluded from them, since their marketing in other European and North American countries. Attempts to obtain marketing authorization for dexamfetamine and lisdexamfetamine arrived around the beginning of the 2010s, when France was in the midst of the Mediator affair, a health scandal in which the prescription of an amphetamine derivative had caused thousands of deaths by inducing cardiac valvulopathy. At that time, the French drug agency imposed such stringent requirements for the marketing authorization, especially in terms of cardiac monitoring, that the laboratory holding the lisdexamfetamine license withdrew its initiative to get access to the French market. Since then, dexamfetamine and lisdexamfetamine, as well as atomoxetine, have been available under an exception condition, which is the "Autorisation d’Accès Compassionnel" (AAC), formerly the "Autorisation Temporaire d’Utilisation (ATU) nominative", that is, under very restrictive conditions. For example, lisdexamfetamine has to be initiated abroad, which has led some patients to seek treatment in neighboring countries, e.g. the UK or Switzerland, just to obtain a first prescription. For the reasons outlined above, the lack of availability of these alternative treatments raises practical and ethical questions, as methylphenidate is not effective in some patients, whereas patients in many other European countries have access to these different treatments. Between January and November 2023, as part of the ADHD working groups set up by the Ministerial Delegation for Mental Health, and the Interministerial Delegation for Neurodevelopmental Disorders, one of the working groups was tasked with taking stock of needs in terms of access to drug treatments in ADHD, identifying and meeting with the various public players, i.e., Agence de Sécurité du Médicament et des Produits de Santé (ANSM), Haute Autorité de santé (HAS), Caisse Primaire d’Assurance Maladie (CPAM), as well as the private sector, in particular the laboratories involved. The ANSM and HAS have taken note of the need for access to a wider range of molecules, and of the support given by the relevant ministries to requests from patient associations (in particular the TDAH-France association), and the SF-TDAH. By 2023, most of the useful drugs not available in France had fallen into the public domain, or were in the process of doing so. For example, Takeda, which held the license for lisdexamfetamine, declared that it was not interested in re-applying for marketing authorization, for this reason (future loss of license), but also because of the constraints imposed by France during past negotiations to obtain marketing authorization in the early 2010s (the license was then held by another laboratory). Other laboratories have shown interest in seizing the opportunity to file an MA for a generic lisdexamfetamine in France. Although no dossier has yet been submitted to the ANSM, it is possible that this could happen soon. Similarly, the license for dexamfetamine in France is held by a laboratory which holds the license for a methylphenidate-based product, and which may seize the opportunity offered by a possible opening by the public authorities to the authorization of new molecules already labeled in other European Union countries. Finally, the working group questioned the ANSM about the problem of methylphenidate stock-outs, after recurrent phenomena of this type were repeatedly observed in the country. The ANSM has announced a number of possible solutions currently under study. In the meantime, at the request of SFTDAH and TDAH France, ANSM has published an equivalence guide for pharmacists, enabling them to switch from one methylphenidate specialty to another in the event of a stock shortage.