The Medicinal Products Directive
The Medicinal Products Directive requires a marketing authorisation for every medicinal product placed on the market and provides for different application routes: a full procedure and a simplified procedure.
Article 10b of the Medicinal Products Directive regulates a simplified application procedure for combination medicines: products in which two or more active substances are combined in a single dosage form. This route is intended for situations where the individual active substances have already been in the European market, but have not previously been combined for therapeutic purposes. In such cases, the applicant does not need to resubmit all data on the individual substances, but may refer to existing dossiers. However, new data must be submitted on the combination itself, particularly regarding safety and efficacy.
Central to this order for reference is the question whether the simplified application procedure can be used multiple times for the same combination of active substances. Can multiple marketing authorisations be granted for medicines with the same combination of active substances while the data protection period for the first authorisation is still running? The ABRvS asks the CJEU to clarify whether article 10b can be used again in such cases, or whether this route is only available once per combination.
Background to the case
In 2019, the Medicines Evaluation Board (het College ter Beoordeling van Geneesmiddelen, CBG) granted marketing authorisations to five pharmaceutical companies (Laboratorios Cinfa S.A., Laboratorios Normon S.A., Zentiva k.s., Win Medica S.A., and Refarm S.A., collectively referred to as Laboratorios Cinfa in the judgment) for medicines containing a fixed combination of ezetimibe and atorvastatin. Laboratorios Cinfa used the simplified procedure under article 10b for their applications. For the same combination, the Dutch company Organon had previously obtained a marketing authorisation for its product Atozet, also via article 10b.
Organon was thus the first holder of a marketing authorisation for this combination with its product Atozet. When the CBG later granted authorisations to Laboratorios Cinfa, Organon objected. According to Organon, article 10b can only be used once per combination of active substances. Once a marketing authorisation has been granted for that combination via the simplified procedure (as with Atozet), the condition that the substances “have not previously been combined for therapeutic purposes” is no longer met. Therefore, a second applicant, in this case Laboratorios Cinfa, should not be allowed to use this route.
The CBG rejected Organon’s objections by decision of 29 October 2020, after which Organon appealed to the court of the district of North-Holland.
The court sided with Organon and ruled on 26 July 2022 that article 10b does not allow a new marketing authorisation for the same combination via the simplified procedure. Since ezetimibe and atorvastatin had already been combined in Organon’s Atozet, the court upheld Organon’s appeal and annulled the CBG’s decision of 20 October 2020. The court revoked Laboratorios Cinfa’s authorisations, meaning they currently do not hold these marketing authorisations.
The CBG and Laboratorios Cinfa appealed to the ABRvS. They argue that article 10b does not exclude multiple applicants from obtaining a marketing authorisation for the same combination through this procedure, provided each submits their own dossier and does not use data still under data protection. In their view, this interpretation follows from the purpose of article 10b, practice in other Member States, and positions of the European Commission and the Coordination Group for Mutual Recognition and Decentralised Procedures - Human (CMDh).
Different interpretations of article 10b
The wording of article 10b leaves scope for different interpretations.
Therapeutic purpose
This scope for interpretation lies mainly in the phrase “but which have not previously been combined for therapeutic purposes.” A strict reading would mean the simplified procedure can only be used once per combination of active substances. A broader interpretation is also defensible: that the condition only applies at the time of the first combination, and that subsequent applications are possible, provided each applicant submits their own dossier and does not use protected data.
Therapeutic indication
It is also relevant that the therapeutic indications of the medicines differ. Organon’s Atozet is authorised for the prevention of cardiovascular events in patients with coronary heart disease and a history of acute coronary syndrome, while Laboratorios Cinfa’s medicines are indicated solely as substitution therapy for various forms of (familial and non-familial) hypercholesterolemia. This raises the question whether “combined for therapeutic purposes” should be interpreted based on the requested indication, or solely on the combination of substances in a single dosage form.
Textual versus contextual Interpretation
The ARBvS applied the usual EU interpretative methods – textual, contextual, and teleological – but these lead to different conclusions. Textually, the provision seems to point to one-time use, whereas the context and purpose of Article 10b of the Medicinal Products Directive (promoting public health and avoiding unnecessary repetition of tests on humans and animals) support repeated use.
Practice in other Member States and interpretation by the European Commission
In addition, practices differ among Member States. Within the CMDh (a European coordination body with representatives from the Member States), there is no full consensus: a large majority of Member States allow multiple use of Article 10b, but some apply a strict interpretation and refuse a second authorization for the same combination. This divergence increases the risk of inconsistent case law.
The European Commission has repeatedly advocated for a broad interpretation. In 2008 and 2012, it confirmed that Article 10b does not exclude multiple applications for the same combination. In a recent clarification from November 2022, it reiterated this position: applications under Article 10b may be submitted for a combination that already has a marketing authorization, provided the applicant does not refer to data still under protection and submits a complete independent dossier.
National case law aligns with this view. In Spain, the Supreme Administrative Court (Tribunal Supremo) ruled on May 14, 2024, that EU law does not preclude multiple use of Article 10b. A similar procedure is pending in France, which has been suspended awaiting the outcome of this case before the CJEU.
Preliminary questions
In light of the above, the ARBvS submits two questions to the CJEU:
- Should Article 10b of Directive 2001/83/EC be interpreted to mean that, once a marketing authorization has been granted for a certain combination of active substances, a subsequent authorization for that same combination of active substances can also be granted under that article?
- Is the requested therapeutic indication requested relevant to that assessment? In other words, does a difference in therapeutic purpose make the combination “new”?
The ARBvS is withholding further consideration of the appeal until the CJEU has issued its ruling.
Loyens & Loeff’s view
The preliminary questions intersect with a broader policy discussion about the structure of the authorization system for combination medicines. The CJEU will have to balance innovation protection against effective market access.
If the CJEU rules that Article 10b can be applied multiple times, subsequent applicants may refer to existing dossiers on individual substances for which authorization has already been granted. This means they do not need to generate new preclinical or clinical data for those substances. It avoids unnecessary repetition of animal and human testing, which aligns with the broader EU objective to repeat tests only when strictly necessary. Moreover, a broad interpretation accelerates market entry for new combination medicines and fosters competition in the pharmaceutical market.
However, if the Court concludes that article 10b can only be used once for a given combination, this would create significant exclusivity for the first applicant. That party would then enjoy not only the usual data exclusivity but also de facto “procedural exclusivity.” Subsequent parties could only: submit a full dossier under article 8 of the Directive (including complete preclinical and clinical data for both the individual substances and the combination) or file a generic application only after the data protection period has expired.
The Court’s answer to the second question is also crucial. If the Court determines that the therapeutic indication is irrelevant to whether substances are combined “with therapeutic intent,” article 10b will have broad application: regardless of indication, the combination remains the same. If the indication is deemed relevant by the Court, a different therapeutic purpose could make it a “new” combination under article 10b.
Whichever direction the Court takes, the ruling will most likely have significant impact on national authorities’ authorization practices and pharmaceutical companies’ strategies for developing and positioning combination medicines.
Contact
If you have any questions about the content of this blog, the preliminary questions referred by the ABRvS, the application of Article 10b of the Medicinal Products Directive or, more generally, about the Medicinal Products Directive, please feel free to contact your regular contact person within our Life Sciences & Healthcare Team or the undersigned.
