Teva B.V., R (on the application of) v The Secretary of State for Health acting as the Licensing Authority & Anor

Under the EU pharmaceutical regime, the concept of a global marketing authorisation derives from the initial marketing authorisation and the continuity of its active substance. A competent authority may determine under Article 6(1) of the Directive 2001/83/EC whether a product belongs to an existing global marketing authorisation. A determination made in the centralised procedure is binding when a later generic application relies on that product as its reference medicinal product.

Whether a substance is an active substance requires assessment in the particular medicinal product. The substance must be capable of exerting a pharmacological, immunological or metabolic action intended to have a therapeutic effect. Clinical relevance, therapeutic indication and dose are not requirements at this stage. Clinical relevance is principally relevant to later assessment of safety, efficacy and the overall risk-benefit balance.

Teva sought judicial review of the MHRA’s refusal to validate its decentralised Article 10(1) application for a generic dimethyl fumarate product. The proposed reference medicinal product was Biogen’s Tecfidera.

The MHRA relied on the European Commission’s 2014 decision granting Tecfidera a marketing authorisation. The decision stated that dimethyl fumarate and the monoethyl fumarate salts in Fumaderm were different active substances and that Tecfidera and Fumaderm therefore belonged to different global marketing authorisations.

Teva argued that the Commission’s recital was non-binding and that the MHRA should determine afresh whether the monoethyl fumarate salts made a clinically relevant therapeutic contribution to Fumaderm. The issues were whether the Commission’s determination bound the MHRA and whether the MHRA applied the correct test.

1. The claim was dismissed. Teva failed on both grounds of challenge.
2. Articles 6 and 10 of the Directive 2001/83/EC form a unitary code. The global marketing authorisation flows from the initial marketing authorisation and inheres in the innovative active substance. It supplies the bundle of rights governing reliance on the reference product’s dossier.
3. The phrase in Article 6(1), referring to the application of Article 10(1), identifies the principal function of the global marketing authorisation. It does not confine decisions about active substance identity or global marketing authorisation to the later generic application. Article 6(1) permits a determination, during the application process, that a product does or does not belong to an existing global marketing authorisation.
4. The Commission had power to make that determination in the centralised procedure. The fact that it appeared in recital (3), rather than the operative article, was not decisive. The material question was whether the determination formed an essential basis for the operative decision and produced legal effects. It did. The MHRA was therefore bound to respect the Commission’s conclusion and had no duty to reconsider it afresh under Article 10(1).
5. The proper interpretation of Article 1(3a) requires a composite, two-limb inquiry. The substance must be intended to exert a pharmacological, immunological or metabolic action, and that action must be directed towards restoring, correcting or modifying physiological functions or making a diagnosis. The relevant action must be assessed in the medicinal product under consideration and must be capable of scientific ascertainment. There is no separate threshold of clinical importance at this stage.
6. Therapeutic indication and dose do not define the active substance. Clinical relevance belongs principally to the later assessment of safety, efficacy and the overall risk-benefit balance. If the substance is active, further stages may require comparison of therapeutic moiety and, where appropriate, safety and efficacy profiles.
7. The MHRA applied the correct test. It was entitled to consider the existing scientific assessment and whether the evidence continued to show that monoethyl fumarate exerted pharmacological action in Fumaderm. It was not required to decide whether that action was clinically important in the particular sense advanced by Teva.