The new EU “Pharma Package”: Global (Orphan) Marketing Authorization

In this fifth alert in our weekly series on the EU Pharma Package, we will delve into the global marketing authorization (GMA) concept which has largely remained untouched in the legislative proposal – aside from an important introduction of the notion of a GMA for orphan medicinal products. We will discuss the missed opportunity to codify existing case law and provide further clarification in this respect.

Background

While the GMA concept was first introduced with the adoption of Directive 2004/27/EC, amending Directive 2001/83/EC, this was a codification of the case law of the Court of Justice of the European Union (CJEU). The CJEU had already stated that the regulatory data protection provisions of Directive 2001/83/EC do not afford a new period of protection for the development of an original medicinal product, even where for instance such development is authorized through a separate procedure and under a different name (see for instance the CJEU 3 December 1998, in Case C-368/96, Generics and others and CJEU 9 of April 2004, in Case C-106/01, Novartis).

The GMA concept is important for the abridged procedure and the question of whether the applicant of a generic medicinal product may refer to the results of the pre-clinical tests and of clinical trials (i.e. pharmacological, toxicological and clinical documentation) contained in the file of the reference medicinal product. It has been constructed in a way to ensure a balance between incentivizing pharmaceutical innovation, while at the same time avoiding repetition of tests and trials on humans and animals where not absolutely necessary (CJEU 3 December 1998, Case C-368/96, Generics and others, paras. 83 to 85) and ensuring access to affordable medicinal products (CJEU 16 March 2023, Case C-438/21 P to C-440/21 P, Pharmaceutical Works Polpharma, para. 92).

GMA concept

Under the current regulatory framework, it is provided in Article 6(1) in the second subparagraph of Directive 2001/83/EC that “when a medicinal product has been granted an initial marketing authorisation, any additional strengths, pharmaceutical forms, administration routes, presentations as well as any variations and extensions must also be granted an authorisation or be included in the initial marketing authorisation. All these marketing authorisations are considered as belonging to the same GMA, in particular for the purpose of the application of Article 10(1) [of Directive 2001/83/EC]”. Article 10(1) of Directive 2001/83/EC lays down the rules on regulatory data protection.

In other words, the GMA contains the initial authorization and all subsequent developments authorized through separate procedures, including in different Member States within the EU and/or under a different name, granted to the marketing authorization holder of the initial authorization. For example, where a product is initially authorized nationally and, subsequently, an additional strength is authorized through the centralized procedure, this is also part of the same GMA.

This means that for a reference medicinal product, the start of the regulatory data protection period is the date when the first marketing authorization was granted in the EU. The aforementioned subsequent developments to the original product will not restart or prolong this period and will have the same end point for regulatory data protection purposes. An exception to this rule is a new indication of a significant clinical benefit, which can lead to a one-year prolongation of the market protection period.

Continued legal discussions

Since its introduction by Directive 2004/27/EC, the CJEU has had other opportunities to further clarify the scope of this provision (See for instance CJEU 28 June 2017, Joined Cases C-629/15 P and 630 15 P, Novartis). In the case law, it is observed that while the GMA concept is instrumental in the determination of the conditions under which applicants in the abridged procedure may rely on the data contained in the file of the reference medicinal product, the constitutive elements by which a GMA can be identified and by which a specific GMA can be distinguished from another GMA, are not specified in Article 6(1) second subparagraph of Directive 2001/83/EC.

The case law has identified two constituent elements, namely the identity of the marketing authorization holder and of the active substance(s) (see for instance Opinion of AG Bobek of 21 December 2016 in joined Cases C-629/15 P and C-630/15 P, Novartis Europharm, para. 46). If either the marketing authorization holder or the active substance changes, the same GMA no longer applies.

These two constituent elements often lead to legal discussions, which has prompted the European Commission to issue guidance through its Notice to Applicants (an explanatory document for marketing authorization applicants). Although that notice is certainly not legally binding, it may offer helpful guidance, as suggested by the AG in the Olainfarm judgment (Opinion of AG Wahl of 20 May 2014 in joined Case C-104/13, Olainfarm, para. 39).

In particular, the Notice to Applicants deals with the recurring situation of combination medicinal products and more specifically where the medicinal product being assessed only contains one active substance which was part of an already authorized combination product. It is stated that the new medicinal product will not fall within the same GMA if, “during the assessment procedure of the already authorised combination product, the marketing authorisation holder had demonstrated that each substance of the fixed combination has a documented therapeutic contribution within the combination and therefore all compounds are different active substances” (European Commission’s Notice to Applicants – Volume 2A – Procedures for marketing authorisations – Revision 11, July 2019, page 9).

Despite the European Commission’s guidance, ongoing legal proceedings involving combination products underscore the continuing need for the EU legislator to further refine and clarify the GMA concept through targeted legislative amendments. In the cases that arose after the CJEU judgment of 16 March 2023 (CJEU 16 March 2023, Case C-438/21 P to C-440/21 P, Pharmaceutical Works Polpharma), there is ongoing debate whether one should only look at the therapeutic moieties of the substances of the combination product or whether the therapeutic contribution of each substance within the combination product should also be considered and, if so, to what extent under Article 6(1) second subparagraph of Directive 2001/83/EC. In other words, the question is whether the evaluation should be based on the abstract form of the substances or on their actual functioning within the combination.

It is unfortunate that none of the EU institutions have used the opportunity of the EU Pharma Package reform to codify existing case law and improve the wording of GMA-provision in their respective proposals.

GMA for orphan medicinal products

One change in the EU Pharma Package, that is of particular note, is the introduction of the GMA concept for orphan medicinal products. All three EU institutions have proposed introducing the concept of a “global orphan marketing authorization”, which would mean that marketing authorization holders that have more than one product with the same active substance for different orphan indications would no longer be eligible for separate orphan market exclusivity.

In addition, all three EU institutions agree that, unlike under current EU law, generics and biosimilars would be able to apply for, and (under the Parliament’s and Council’s proposals) even obtain, a marketing authorization prior to expiry of the orphan market exclusivity period, where the remainder of the market exclusivity period is less than two years.

Conclusion

The GMA concept remains a cornerstone of the EU's pharmaceutical regulatory framework, balancing the need for innovative incentives with the imperative to avoid unnecessary duplication of clinical trials and ensure timely access to affordable medicines.

Despite its importance, the current EU Pharma Package leaves the existing GMA provisions largely unchanged, missing an opportunity to clarify and codify key aspects that have been subject to ongoing legal debate and case law.

The lack of legislative clarification, particularly regarding the identification of constituent elements of a GMA and the treatment of combination products, perpetuates uncertainty for stakeholders and results in continued reliance on non-binding guidance and judicial interpretation. As the pharmaceutical landscape evolves and legal questions persist, further legislative action may be necessary to provide greater legal certainty and ensure that the GMA framework continues to serve its intended purpose effectively within the EU regulatory system.

This may become all the more important now that the GMA concept is also being introduced for orphan medicinal products.