Dutch CJEU referral to clarify EU law on ‘combination’ medicines

EU pharma legislation generally requires medicines manufacturers to provide the results of pre-clinical tests and of clinical trials to regulators when applying for a marketing authorisation. However, there are some exceptions to those requirements, including where the product is essentially similar to a medicinal product that received marketing authorisation in the EU at least eight years earlier. Until that moment, the first product enjoys data protection, which means that manufacturers of generics have to wait until the eight years of data protection have expired before they can apply for marketing authorisation for their rival products. These rules are set out in article 10 of the Medicines Directive.

Article 10(b) specifically addresses combination products. It provides that if previously approved products are for the first time combined therapeutically in a combination product, only the results of the clinical research regarding the combination need to be provided. The applicant is not required to provide the documentation for each individual previously separately known and approved active substance.

Questions relating to article 10(b) have now arisen in a case before the Administrative Law Division of the Council of State, which is the highest Dutch administrative court. It decided that it needs help interpreting EU law in order to resolve a dispute before it and has referred questions to the Court of Justice of the EU (CJEU).

In the case before the Dutch court, a dispute has arisen over marketing authorisations granted by the Dutch Medicines Evaluation Board (MEB) to Laboratorios Cinfa for fixed-dose combinations of ezetimibe and atorvastatin. In the Netherlands, Laboratorios Cinfa seeks to obtain marketing authorisation for its combination of ezetimibe and atorvastatin for treating specific cardiovascular conditions. Organon challenged the grant on the basis that it has an earlier fixed-dosed authorisation for the same combination under article 10(b), Atozet, for the prevention of cardiovascular conditions and treatment of high cholesterol levels in patients.

The core legal question that the Council of State has posed to the CJEU is whether multiple marketing authorisations can be granted under article 10(b) for the same combination of active substances while the protection period for the first dossier is still running.

A district court in the Netherlands had previously annulled Laboratorios Cinfa’s authorisations, holding that article 10(b) cannot be used more than once for the same combination of ingredients. Laboratorios Cinfa and the MEB appealed, arguing that the purpose of those provisions – avoiding unnecessary repetition of trials and promoting public health – supports multiple use of article 10(b), provided each applicant submits its own data package.

The Council of State noted divergent practices among EU member states on the issue. It also acknowledged the European Commission’s position – that, for reasons of procedural economy, article 10(b) should not preclude multiple authorisations providing regulatory data protection rules are respected. Given the lack of clarity and risk of inconsistency, it has asked the CJEU whether article 10(b) can be applied more than once for the same combination of active substances and whether a difference in therapeutic indication affects the interpretation.

The case before the Council of State has been suspended pending the CJEU’s ruling.

Amsterdam-based Arjan Reijns of Pinsent Masons, who often handles regulatory matters for pharmaceutical companies, said: “The legal landscape in the member states is understandably divided; a rationale against a strict interpretation would be that it is unreasonable to grant additional exclusivity for a ‘simple’ combination, especially if such treatment was already prescribed via the separate components.”

Carly Van der Beek, who works alongside Reijns for Pinsent Masons in Amsterdam, added: “Under a narrow interpretation of article 10(b), any subsequent applicants would be required to submit full dossiers or wait until the regulatory data protection for the first product expires. However, as Laboratorios Cinfa argued, submitting a full dossier would require duplicative clinical trials, which not only goes against the purpose of EU medicines law, but could also conflict with ethical principles set out in the Declaration of Helsinki. By contrast, a broad interpretation would allow competitors to rely on simplified applications, thereby fostering competition while avoiding unnecessary repeat trials.”

“The case can be viewed in the context of the EU’s pharma law revamp, which is expected to be finalised later this year. Notably, the proposed updated legislation does not appear to include a specific provision mirroring the existing article 10(b), which explicitly provides for abridged applications for an active substance combination,” van der Beek added.