Despite the recent publication of the list of relevant classes listed in the hybrid group register, the legal framework for hybrid medicinal products remains incomplete in France
The revision of the Community code for medicinal products in 2004 gave rise to a new category of hybrid medicinal products. A decade later, France decided to create a specific regimen of substitution attached to this category. Initiated by the Social Security Financing Act for 2019 (“LFSS”), the regime is however still not active.
This new category was created for products not filling the criteria of generic medicinal products, in order to nonetheless foster substitution and create additional savings. However, the subsequent decrees and orders implementing these measures have been published piecemeal since then – the latest being the order stating the first groups eligible for registration in the hybrid register.The system remains, even today, incomplete pending the publication of the implementing text regulating the substitution of hybrids, as the substitution seems to prove much more complex than expected with hybrids as compared to generics.
A new category built on the basis of a differentiation with generics
Hybrids are medicinal products that do not meet the definition of generics, forming a category borrowing both from the generic regime and standard requirements applicable to medicinal products.
Pursuant to article L.5121-1 5° c) of the French public health code, which partly reproduces the definition of the Community code, it is either because (i) they contain differences in relation to their reference product (or princeps) in terms of therapeutic indications, dosage, pharmaceutical form or route of administration or because (ii) their bioequivalence with the reference product has not been demonstrated by bioavailability studies, that hybrids do not meet the definition of generics.
Hybrids can therefore contain variations in terms of formulations compared to their princeps, which may be related to a new galenic form (e.g. an oral form instead of a tablet) or a new packaging or may present a different dosage or route of administration (which can allow for instance a reduction in the number of daily doses) or include broader or narrower therapeutic indications.
The nature of the active ingredient itself shall not vary however, enabling the applicant to rely partly on the results of pre-clinical and clinical trials of the princeps and partly on new data. Hybrids therefore benefit from lower production costs and have a lower price than their princeps.
The slow process of adoption of the implementing texts
Based on the finding that there were barriers to the substitution of generics, the French lawmaker created in the LFSS for 2019 the new category of hybrid medicinal products, whose substitution conditions were supposed to be as aligned as possible with those of generic medicinal products.
This measure was widely discussed as part of the parliamentary debate of the 2019 LFSS. It was even proposed to drop the provisions for lack of therapeutic consideration, in light of the financial impact for patients refusing the substitution of hybrid medicinal products and, above all, the risks linked to the very nature of hybrids which, unlike generics, are not identical to their princeps. Any change of dosage or galenic form was presented as “far from trivial” and it was noted that this could impact the efficacy or tolerance of the product, taking as an example the change of formula of Levothyrox.
This new category of products was ultimately created but details remained to be specified by means of several implementing texts . A decree adopted in November 2019 , which entered into force on 1 January 2020, first specified the features of the future register of hybrid groups, in particular the procedures for registration and withdrawal from the group of hybrids and princeps in this register.
Pending the adoption of the implementing texts, the ANSM's decision-making practice was to include hybrid medicinal products in the repertoire of generic groups in the absence of hybrid register. The French administrative Supreme Court considered this to be illegal and annulled the ANSM’s decision granting the generic status for hybrid products, in a ruling issued on 7 July 2021.
It then took close to one year to specify the list of classes of medicinal products eligible in the register of hybrid groups. An order issued in April 2022 lists for now only two groups (i.e. medicinal products for obstructive airway diseases - inhaled adrenergic and (2) medicinal products for obstructive airway diseases - other inhaled medications for obstructive airway diseases, which were concerned by the ruling issued by the administrative Supreme Court).
A remaining missing piece to the puzzle
Despite the creation of hybrid groups, the framework remains incomplete and the dedicated hybrid register has not been created to date.
An implementing order aiming at specifying the modalities of application of the right of pharmacists to substitute hybrids to princeps indeed still remains to be adopted. In the absence of details on the medical situations in which pharmacists can substitute within a hybrid group, the right of substitution remains only theoretical.
The regulatory saga will thus continue.