A laborious creation of the register of hybrid groups
The purpose of the hybrid group registry is to enable substitution in certain medical situations, taking into account the variety of “hybrid” situations.
Thus, the creation of the hybrid group registry is the result of a long legislative process in France that led to the creation of hybrid groups and the hybrid group registry to address the potential risks associated with substitution:
1- The first steps were introduced with the 2019 law related to finance of the French public health system (so-called LFSS*) and its decree no. 2019-1192 of November 19, 2019: these texts laid the foundations with the definition of the hybrid register and an initial framework for substitution;
2- Next came the decree of April 12, 2022: this is the first list of ATC classes R03A & R03B of drugs that can be included in groups included in the hybrid register, i.e., drugs for obstructive airway diseases administered by inhalation. Since then, new ATC classes have been added;
3- New details were provided in the decrees of January 31, 2023, with the medical situations:
– in which substitution is possible;
– in which the physician can exclude substitution;
4- finally, everything actually has started with the ANSM decision of April 22, 2024: the creation of the register of hybrid groups and the registration of products in this register allowing the first substitutions on the pharmacy field.
A variety of hybrid products
Hybrid medicinal products are defined in the French Public Health Code (Articles L5121-1 5°c) and R5121-28)) and in Article 10(3) of Directive 2001/83/EC as medicinal products that do not meet the definition of generic medicinal products:
– due to differences in the active substance, therapeutic indications, dosage, pharmaceutical form, or route of administration,
– or when bioequivalence with the reference medicinal product could not be demonstrated by bioavailability studies.
This definition therefore covers a wide variety of situations: let us cite topical drugs for which bioavailability is not achievable due to a local mode of action (e.g. dermatological, ophthalmic or pulmonary), parenteral drugs with a variety of pharmaceutical presentations, or even drugs which, for historical reasons, have heterogeneous therapeutic indications.
The content of the dossier depends on the reason for the hybrid drug. In many situations, substitution in pharmacies is not trivial.
However, it should be noted that, as with generic drugs, marketing authorizations for hybrid drugs refer in part to the non-clinical and/or clinical data of a reference drug that has had a marketing authorization for more than 8 years in France or the European Union.
In addition to this definition, the French Public Health Code defines:
– A hybrid group as the grouping of a reference drug and its hybrid drugs that can be substituted for it (Article L5121-1 5°d)).
– The register of hybrid groups, including substitutable hybrid groups (Article L5121-10).
*Loi de Financement de la Sécurité Sociale
In practice
Unlike generic medicinal products, inclusion in the hybrid group register is not automatic. However, the Marketing Authorisation Holder is not required to submit a request: it is the ANSM (French National Agency for the Safety and Health) that assesses the legitimacy of the product’s inclusion.
Hybrid groups are classified by active substance designated by its common name.
As with the generics register, the specialties listed in the register are classified by hybrid group. Each group includes the reference specialty (identified by the letter “R”) and its hybrids (identified by the letter “H”).
The hybrid group register indicates, for each product, its name, dosage, pharmaceutical form, and the name of the marketing authorisation holder and, if different, the name of the “Exploitant”. This register also includes the nature of any differences observed between a hybrid product and the reference product. Excipients with known effects are also included. Finally, the medical conditions for which substitution may be made are also specified, where applicable.
The decision to register is made on a case-by-case basis and is the responsibility of the Director General of the ANSM.
To date, only medicinal products belonging to therapeutic classes R03A and R03B used for obstructive pulmonary diseases have been included in the hybrid group register. We are awaiting new registrations for the following ATC classes:
• A01AB – Stomatological preparations – Antiinfectives and antiseptics for local oral treatment
• D01A – Dermatological medicinal products – Antifungals for topical use
• D05A – Antipsoriatics – Antipsoriatics for topical use
• D08A – Antiseptics and disinfectants – Antiseptics and disinfectants
• D11A – Other dermatological preparations – Other dermatological preparations
• R02A – Throat preparations – Throat preparations
• S01A – Ophthalmogicals– Antiinfectives
• S01E – Ophthalmogicals – Antiglaucoma preparations and miotics
• S02A – Otologicals– Antiinfectives
The hybrid registry began with a sample of respiratory drugs, but is expected to expand significantly in the coming years.
Atessia supports its clients in their registration strategy for hybrid drugs in Europe.
Article written by Agathe DAUBISSE, Senior Regulatory Affairs Consultant