The CJEU brings clarity, on the concepts of “Significant Benefit” and “Clinical Superiority” with respect to Orphan Medicinal Products (“OMP”) in the long awaited judgement C 237/22 of 4 October 2024. 

Introduction: concepts of “Significant Benefit” and “Clinical Superiority”

The questions raised related to the interpretation of and differences between the concepts of “Significant Benefit” on the one hand, and “Clinical Superiority” on the other hand.

Significant Benefit is a criterion for obtaining orphan designation (next to other possible criteria mentioned in Article 3 of Regulation 141/2000). If the sponsor can demonstrate the significant benefit of a medicinal product compared to all authorised products and methods, a medicinal product can be designated as an orphan medicinal product.

Significant benefit may be based on:

• ‘improved efficacy’ for the entire population or a particular population subset,
• ‘improved safety’ or a ‘better tolerability’ for the entire population or for a particular subset, or
• ‘major contribution to patient care’ e.g. more convenient method of administration,

Clinical Superiority on the other hand, is a condition to obtain a derogation from the market exclusivity attributed to an orphan medicinal product (it is one of multiple possible conditions described in article 8 (3) Regulation 141/2000). If an applicant for a marketing authorisation in respect of a similar medicinal product to an authorised orphan medicinal product, for the same therapeutic indication, demonstrates that the product for which the marketing authorisation is being sought is clinically superior to the existing orphan medicinal product, the marketing authorisation for the similar medicinal product can be granted.

"Clinical superiority" is defined as:

• ‘greater efficacy’ than an authorised orphan medicinal product,
• ‘greater safety’ in a substantial portion of the target population(s),
• in exceptional cases, ‘major contribution to diagnosis or to patient care’.

The facts underlying the judgement

In the case at hand, Novartis Pharmaceuticals UK obtained in 1999 a marketing authorisation for “Tobi”, a medicinal product containing the active substance tobramycin for inhalation by nebuliser, indicated for the treatment of pulmonary infection in cystic fibrosis patients.

In 2003, Chiron was granted the designation as an ‘OMP’ for the medicinal product “Tobi Podhaler” an inhalation powder, also with active substance Tobramycin, intended, like Tobi, for the treatment of the abovementioned pulmonary infection in cystic fibrosis patients.

Tobi Podhaler was recognised to have a “significant benefit” compared to Tobi (nebuliser) as it significantly reduced delivery time of the medicinal product by comparison and it could be administered with a portable delivery system, which was an added convenience for those patients and was potentially an improvement in compliance with the treatment regime.

In 2006, Novartis acquired Chiron and Tobi Podhaler was transferred subsequently. Tobi Podhaler obtained a marketing authorisation in 2011 with maintenance of its orphan designation.

In 2016, VVB UAB obtained a marketing authorisation for its product “Tobramycin VVB” (for inhalation by nebuliser), a product that is similar to Tobi Podhaler, in derogation from the market exclusivity of Tobi Podhaler based on Article 8(3)(c) of Regulation 141/2000. In addition, Tobramycin VVB (nebuliser) is a (hybrid) generic medicinal product of Tobi (nebuliser) which is a rather exceptional situation.

The derogation of the market exclusivity was based on the fact that Tobramycin VVB was found to be clinically superior to Tobi Podhaler, given its greater safety in a substantial part of the target population (a substantial portion of the population suffering from cystic fibrosis and taking Tobi Podhaler suffered from a cough). 

The decision to grant a marketing authorisation was challenged by Novartis first in the General Court and later, after the transfer of the marketing authorisation for Tobi Podhaler from Novartis to Mylan, by the latter in the Court of Justice of the European Union.

Novartis, and later on, Mylan claimed that Tobramycin VVB (nebuliser) cannot be considered "clinically superior" to Tobi Podhaler (inhalation powder), since the latter has been granted orphan designation based on its "significant benefit" towards all other existing authorised products and methods, including the original product Tobi (nebuliser). 

The Court of Justice of the European Union dismissed the appeal and ruled in favour of the European Commission.

Key take-aways from the judgement

The judgement is interesting on multiple points. Here are some key take-aways from the judgement.

• The CJEU recognises that the concepts of clinical superiority and significant benefit are based on the same criteria (greater safety, greater efficacy and major contribution of patient care). It also confirms the criteria of both concepts should not be applied cumulatively when assessing the applications for either orphan designation (significant benefit) or obtaining a derogation from the market exclusivity (clinical superiority).
• However, the CJEU clarifies that the two concepts are not interchangeable. Both concepts appear in different contexts and have different purposes (obtaining market exclusivity v. obtaining a derogation from the market exclusivity). 
• The CJEU confirms that in case significant benefit is claimed on the basis of major contribution to patient care for the entire target population, an ‘overall evaluation of the benefit/risk balance’ needs to be done. This means that in the process leading to the designation as an orphan medicinal product, its safety and efficacy must be at least equivalent to similar products already authorised. 
• The CJEU confirms that the criterion for clinical superiority at issue (‘greater safety in a substantial portion of the target population(s)’) must be assessed with regard to a substantial part of the target population, contrary to significant benefit which was claimed on the basis of major contribution to patient care for the entire target population. 

This was exactly the reason why it was possible to conclude that a medicinal product is clinically superior (for a subset of the patient population) to an orphan medicinal product authorised on the basis of significant benefit (for the entire patient population). 

• Finally, the CJEU confirms that Article 8(3) of Regulation No 141/2000, which introduces a possibility to obtain a derogation from the market exclusivity of an orphan medicinal product, is intended by the EU legislation  to safeguard patients’ interest in having several therapeutic options where the medicinal product enjoying market exclusivity cannot be placed on the market in sufficient quantities or where there is a clinically superior medicinal product within the meaning of Article 8 (3)(c) Regulation 141/2000.