Case T‑416/22
Fresenius Kabi Austria GmbH and Others
v
European Commission
Judgment of the General Court (Fifth Chamber, Extended Composition) of 15 May 2024
(Medicinal products for human use – Suspension of national marketing authorisations for medicinal products for human use containing the active substance hydroxyethyl starch (HES), solutions for infusion – Action for annulment – Direct concern – Partial inadmissibility – Obligation to state reasons – Error of law – Manifest error of assessment – Precautionary principle – Proportionality – Article 116 of Directive 2001/83/EC)
1. Action for annulment – Natural or legal persons – Measures of direct and individual concern to them – Direct concern – Criteria – Commission decision requiring Member States to suspend marketing authorisations for a medicinal product – Decision directly affecting the legal position of the holders of those authorisations – No discretion on the part of the Member States as to the implementation of the decision in respect of those holders
(Art. 263, fourth para., TFEU; European Parliament and Council Directive 2001/83, as amended by Directive 2010/84)
(see paragraphs 22-26, 28-32)
2. Action for annulment – Natural or legal persons – Legal standing – Action brought against the Commission decision requiring Member States to suspend marketing authorisations for a medicinal product – Action brought by certain holders of those authorisations affecting, in part, the rights of other holders – Partial inadmissibility
(Art. 263, fourth para., TFEU; European Parliament and Council Directive 2001/83, as amended by Directive 2010/84)
(see paragraphs 34, 36)
3. Approximation of laws – Medicinal products for human use – Marketing authorisation – Variation, suspension or withdrawal of authorisation – Conditions – Alternative nature – Interpretation of these conditions in accordance with the general principle of primacy of public health protection
(European Parliament and Council Directive 2001/83, as amended by Directive 2010/84, Art. 116)
(see paragraph 76)
4. EU law – Interpretation – Methods – Literal, systematic and teleological interpretation – Consideration of origins of a provision – Whether permissible
(see paragraph 78)
5. Approximation of laws – Medicinal products for human use – Marketing authorisation – Variation, suspension or withdrawal of authorisation – Conditions – Assessment of the risk-benefit balance of the medicinal product concerned – Concept of risk-benefit balance – Taking into account of the risks posed by the unauthorised use of the medicinal product – Included
(European Parliament and Council Directive 2001/83, as amended by Directive 2010/84, recital 2, Arts 1(28) and (28a), 22, second para., 23(2), 101(1) and (2), 116)
(see paragraphs 79-100)
6. Approximation of laws – Medicinal products for human use – Marketing authorisation – Variation, suspension or withdrawal of authorisation – Conditions – Requirements of proof – Need for scientific data or new information – Scope – Compliance with the precautionary principle
(European Parliament and Council Directive 2001/83, as amended by Directive 2010/84, Art. 116)
(see paragraphs 110-115, 159)
7. Approximation of laws – Medicinal products for human use – Marketing authorisation – Variation, suspension or withdrawal of authorisation – Commission decision requiring Member States to suspend marketing authorisations for a medicinal product – Judicial review – Limits
(European Parliament and Council Directive 2001/83, as amended by Directive 2010/84, Art. 116)
(see paragraphs 117-119, 206)
8. Approximation of laws – Medicinal products for human use – Marketing authorisation – Variation, suspension or withdrawal of authorisation – Commission decision requiring Member States to suspend marketing authorisations for a medicinal product – Breach of the principle of proportionality – None
(European Parliament and Council Directive 2001/83, as amended by Directive 2010/84, Art. 116)
(see paragraphs 205, 207, 208, 213-215)
Résumé
The General Court, sitting in an enlarged formation of five judges, dismisses the action brought by Fresenius Kabi Austria GmbH and other legal persons (‘the applicants’) for annulment of the decision of the European Commission requiring the Member States concerned to suspend the marketing authorisations (‘MAs’) of medicinal products containing hydroxyethyl starch (‘HES’). (1)
The applicants are part of the worldwide Fresenius group. The latter manufactures and distributes, inter alia, medicinal products containing HES as an active substance which, in the form of solutions for infusion, are mainly used for the treatment of hypovolaemia (low blood volume) caused by acute (sudden) blood loss, when treatment with alternative solutions is considered insufficient. The applicants hold MAs for some of those medicines.
Following several assessments, carried out since 2013, and successive attempts to establish risk minimisation measures (‘the RMMs’), the Commission found, by the contested decision, that the risk-benefit balance of those medicinal products could not be considered to be favourable, in particular because of the risks associated with their off-label use. It ordered the suspension of the MAs for those medicinal products.
The applicants asked the Court to annul the contested decision on the grounds, inter alia, that the Commission had incorrectly interpreted the concept of ‘risk-benefit balance’ within the meaning of Directive 2001/83 (2) in so far as, in assessing the risk-benefit balance of the medicinal products in question, it took account of the risks posed by their off-label use. They also argued that the RMMs put in place were complied with in most Member States. In their view, failure to comply with those RMMs in other Member States should not lead to the conclusion that those RMMs were not effective in preventing the risks in question.
Findings of the Court
As a preliminary point, the Court notes that the conditions for amending, suspending or withdrawing an MA referred to in Directive 2001/83, namely a finding that the medicinal product is harmful, that the therapeutic effect is lacking, that the risk-benefit balance is not favourable or that the medicinal product does not have the declared qualitative and quantitative composition, (3) are alternative and not cumulative. They must, moreover, be interpreted in accordance with the general principle that the protection of public health must unquestionably be given overriding importance in relation to economic considerations.
In that context, the Court rules on the condition relating to the risk-benefit balance of the medicinal product and, more specifically, on the concept of ‘risk-benefit balance’.
It observes, in the first place, that, as regards the literal interpretation, the provisions of Directive 2001/83 which are concerned with the definition of this concept and that of ‘risks related to use of the medicinal product’ (4) neither explicitly include nor exclude consideration of the risks resulting from the off-label use of a medicinal product in the assessment of its risk-benefit balance. By contrast, those provisions refer to ‘any risk’ to patient or public health relating to the quality, safety or efficacy of the medicinal product and do not restrict the concept of ‘safety of the medicinal product’ to specific uses. Thus, they do not exclude risks resulting from the off-label use of a medicinal product from the concept of risks relating to the safety of that medicinal product.
In the second place, as regards the contextual interpretation of that concept, the Court analyses the provisions of Directive 2001/83 which lay down certain information obligations incumbent on the holder of an MA for a medicinal product. (5) It notes that those provisions explicitly lay down an obligation to communicate to the competent national authority ‘data on the use of the medicinal product where such use is outside the terms of the [MA]’ which may constitute ‘new information which might influence the evaluation of the benefits and risks of the medicinal product concerned’.
Moreover, by referring to the provisions of Directive 2001/83 which describe the objective of the pharmacovigilance system and the scope of the information which it serves to collect, (6) the Court states that it follows, first, that the concept of ‘risks … as regards patients’ or public health’ also covers risks resulting from use ‘outside the terms of the [MA]’. Secondly, Member States may take into account all the information collected under the pharmacovigilance system, including information relating to the risks associated with the off-label use of a medicinal product, in order to examine options for preventing or reducing the risks and, if necessary, to take regulatory measures concerning the MA in question. Those provisions do not contain any indication that the suspension or revocation of an MA would be excluded as a matter of principle from the measures that Member States could take in order to address the risks related to the off-label use of a medicinal product.
Finally, the Court finds that, by the provisions of Directive 2001/83 concerning the decision to grant an MA subject to certain conditions, (7) the legislature has expressly provided for the conditions under which information on the efficacy and safety of a medicinal product relating to its use ‘under normal conditions’ may be limited. The fact that the provision of that directive providing for the suspension of an MA contains no reference to ‘normal conditions’ of use supports the interpretation that the concept of ‘risks related to use of the medicinal product’ also covers the risks related to its off-label use.
The Court therefore concludes that the contextual interpretation of the concept of ‘risk-benefit balance’ supports the conclusion that that concept covers the risks associated with the off-label use of a medicinal product.
In the third and last place, as regards the teleological interpretation of that concept, the Court emphasises that, in so far as Directive 2001/83 imposes an obligation on the competent authorities to suspend, withdraw or amend MAs where the risk-benefit balance of a medicinal product is considered to be unfavourable, it pursues its essential objective of safeguarding public health.
Therefore, in order to ensure that that objective is effectively pursued, the competent authorities must be able to take into account information relating to all the risks that a medicinal product poses to public health, including those associated with its off-label use. The off-label use of a medicinal product, which is not uncommon and is decided by a medical professional weighing up the benefits and risks and who must be informed as fully as possible, may pose risks to public health similar to those associated with the use of that medicinal product in accordance with the MA. The teleological interpretation of the concept of ‘risk-benefit balance’ therefore confirms the conclusion that that concept also covers the risks associated with the off-label use of a medicinal product.
Consequently, the Court concludes that, in taking account of the risks posed by the off-label use of the medicinal products in question when assessing their risk-benefit balance, the Commission did not misinterpret that concept.
As regards compliance with the RMMs, the Court finds that the Commission made no manifest error of assessment in concluding that the off-label use of the medicinal products concerned persisted despite the RMMs put in place.