SmPC 'carve out' limits marketing authorisation

What effect does a carve-out to an SmPC, made after authorisation but prior to launch of a medicinal product, have on the scope of a Marketing Authorisation? This question was addressed by the Opinion of the Advocate General (AG) in Staat der Nederlander v Warner-Lambert Co LLC on 4 October 2018

The AG's Opinion in summary

Following a reference from the Hague Court of Appeal, the AG has opined that the 'carve out' of patented indications or dosage forms from a Summary of Product Characteristics (SmPC) of a generic medicinal product, whether made before or after a marketing authority (MA) has been granted for the generic product, results in the MA also being limited to the remaining indications or dosing forms.

What EU law says and what is unclear

Under EU law, generic medicinal products can rely on and refer to the clinical tests and trials carried out on a reference medicinal product in their MA application. However, marketing of such generic products can only occur after the 10 year exclusivity period afforded to the reference product's trial data has expired.

Even after the expiry of this data exclusivity, the reference medicinal product, or particular indications or dosage forms of it, may still be protected by patent rights, precluding the marketing of the generic medicinal products.

Article 11 of Directive 2001/83 (Article 11) therefore permits a 'carve-out', where still patent-protected indications or dosage forms of a reference medicinal product are removed from the SmPC of the generic medicinal product's MA application. This allows the generic product to be authorised and marketed for the patent-free indications or dosage forms.

However, the status of Article 11 is unclear in the situation where an MA holder becomes aware only after authorisation that it is necessary to introduce a carve-out.

The background to this case

Warner-Lambert (WL) manufactures a pregabalin product (Lyrica), which is authorised and marketed for the indications epilepsy, generalised anxiety disorder and neuropathic pain. Patent protection and data exclusivity for each of these indications had expired, with the exception of patent protection in the Netherlands for the 'second medical indication' of neuropathic pain.

Aurobindo (A) manufactures a generic pregabalin product. Following the expiry of Lyrica's data exclusivity period, A applied to the CBG (the Netherlands authority responsible for authorising medicinal products) for an MA for its generic pregabalin product. This was applied for through the decentralised procedure, with Portugal as the reference member state. A's original MA application contained a full label version of the SmPC, which included the neuropathic pain indication.

After the MA had been granted, but before A's generic pregabalin product was placed on the market, A became aware of the patent protection in the Netherlands for neuropathic pain. Therefore A notified the CBG that it was carving out neuropathic pain from the SmPC for their generic pregabalin product, and asked CBG to publish the version of SmPC with this indication carved out. However CBG did not, and instead published the full version of the SmPc.

In proceedings initiated by WL against CBG, the Hague Court of Appeal made a reference to the Court of Justice for a preliminary ruling on what effect the subsequent carve-out has on the scope of the MA.

The AG's Opinion in more detail

In the system of authorisation of medicinal products, the AG opined that an ability to make subsequent carve-outs is essential, for example in situations where an MA holder only becomes aware after authorisation that it is necessary to introduce a carve-out. This is because patent protection may differ in the various Member States, but the law provides for parallel application or recognition of an MA for a medicinal product in all or several Member States.

Further, the AG noted that it is a fundamental principle of EU law that the authorised version of a medicinal product and the version placed on the market are identical. Regardless of the time when a carve-out is introduced, any discrepancy between the scope of the MA and the SmPC must be avoided.

Therefore, the AG opined that it seemed logical to interpret Article 11 to mean that it is also possible to introduce a carve-out after an MA has been granted, and a subsequently introduced carve-out to the SmPC must also result in the limitation of the authorisation granted.

The AG reasoned that the carve-out arrangement provided for in Article 11 is the only way, after the expiry of the data exclusivity period for a reference medicinal product which is uniformly regulated in EU law, to have a generic product authorised in all or several Member States yet also take account of the potentially different patent protection in those Member States.

The AG further concluded that, as a subsequent carve-out will not automatically vary a previously granted authorisation and requires an official act of variation, a notification of a subsequent carve-out by the MA holder must be regarded as an application to limit the previously granted MA.

Conclusion

If the AG's opinion is followed, the law in relation to carve-outs under Article 11, and their effect on a MA of a generic medicinal product, will be much clearer. However, it will mean that manufacturers of generic medicinal products which have an indication or dosage form 'carved out' of their SmPC will have to apply to supplement their MA with any indication or dosage form which subsequently loses patent protection. This application would have to be made to every relevant member state in which the MA will need to be amended, which could cause the manufacturers a great amount of time and cost.