Out-Law Analysis Lesedauer: 3 Min.

Court to rule on concept of new active substance in Mylan v EMA

EU judges are expected to provide some clarity on the concept of a ‘new active substance’ in a ruling set to be published on Wednesday 7 December.

The judgment of the EU General Court will be of importance to pharmaceuticals businesses because a finding of ‘new active substance’ takes a product outside the global marketing authorisation of an earlier product and means that the later product benefits from its own period of data and market exclusivity, which impacts entry onto the market of rival generic products.

Mylan v the European Medicines Agency (EMA)

The case before the EU General Court concerns a dispute between generic medicines manufacturer Mylan and the European Medicines Agency (EMA).

The dispute relates to a marketing authorisation (MA)he EMA granted to Sanofi for a product called teriflunomide and Mylan’s MA application for a generic teriflunomide product.

Teriflunomide, leflunomide and the concept of new active substance

Sanofi sells teriflunomide under the brand name Aubagio. It was granted an MA for the product in 2013. Teriflunomide is indicated for use in the treatment of relapsing multiple sclerosis in patients aged 10 and older.

Teriflunomide is the active metabolite of another product, leflunomide.

In 1999, Sanofi obtained an MAfor leflunomide, which it sells under the brand name Arava. Arava is indicated for use in the treatment of certain arthritic conditions in adults.

During the MA approval process for teriflunomide, the CHMP considered whether teriflunomide was a new active substance – an active substance being a chemical component of a medical product that has a therapeutic effect on patients.

EU legislation provides that the different salts, esters, isomers, mixtures of isomers, complexes or derivatives of an active substance shall be considered to be the same active substance, unless they differ significantly in properties with regard to safety and/or efficacy. Guidance on what might constitute a significant difference in safety and/or efficacy is provided in an EMA reflection paper.

The CHMP considered whether teriflunomide should be considered a derivative of leflunomide. It concluded it should. It then considered whether the two substances differ significantly with regards to safety and/or efficacy.

On 21 March 2013, the CHMP adopted a positive opinion recommending the grant of the Aubagio MA. However, it initially said teriflunomide could not be considered a new active substance, stating that the evidence Sanofi provided in a bid to demonstrate significant differences in properties with regards to safety and efficacy “indicated rather minor differences between teriflunomide and leflunomide with unknown or questionable clinical relevance".

Sanofi requested a re-examination of the CHMP opinion on the new active substance status and in June 2013 the CHMP adopted a revised opinion in which it concluded that teriflunomide could in fact be considered a new active substance. It reached this revised position after essentially determining that there was scope for “a significant difference” in the safety profile of leflunomide and teriflunomide.

The CHMP’s opinion was not unanimous, however. Nine members of the committee did not agree with the conclusion that teriflunomide should be considered a new active substance. In their view the evidence provided by Sanofi did not meet the standard required by either EU legislation of the guidance provided in the EMA’s reflection paper – that a significant difference in safety and/or efficacy had not been demonstrated.

The impact on Mylan

The effect of the CHMP’s revised decision is that teriflunomide is not within the global marketing authorisation of leflunomide. It means teriflunomide has its own data and market exclusivity.

Sanofi therefore benefited from eight years data exclusivity and obtained an additional year’s market exclusivity for teriflunomide, resulting in three years market exclusivity, on the basis that there is significant clinical benefit derived from the finding that the product could be used in the treatment of children as well as adults. It means generic teriflunomide products are prohibited from entering the European market until 2024.

Mylan, however, applied to the EMA for an MA for a generic version of Aubagio. In August 2020, the EMA refused to validate that application citing the fact that Aubagio was still within its data exclusivity period.

On 28 October 2020, Mylan issued proceedings against the EMA before the General Court to annul the EMA’s decision not to validate its application. Mylan is seeking a declaration that Aubagio does not have new active substance status and that Aubagio therefore falls within the same global marketing authorisation as leflunomide.

The EU General Court heard arguments in the case on 11 May this year. Its decision in the case is expected to be published on 7 December.

Written by Natalie Coan of Pinsent Masons.

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