Judgments nº T-783/17 of Tribunal General de la Unión Europea, September 19, 2019

• Resolution Date: September 19, 2019
• Issuing Organization: Tribunal General de la Unión Europea
• Decision Number: T-783/17

(Medicinal products for human use - Suspension of the marketing authorisation for gadolinium-containing contrast agents - Articles 31 and 116 of Directive 2001/83/EC - Precautionary principle - Equal treatment - Proportionality - Impartiality)

In Case T-783/17,

GE Healthcare A/S, established in Oslo (Norway), represented by D. Scannell, Barrister, G. Castle and S. Oryszczuk, Solicitors,

applicant,

v

European Commission, represented by M. Wilderspin and A. Sipos, acting as Agents,

defendant,

ACTION based on Article 263 TFEU seeking annulment of Commission Implementing Decision C(2017) 7941 final of 23 November 2017, concerning, in the framework of Article 31 of Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use (OJ 2001 L 311, p. 67), the marketing authorisations for gadolinium-containing contrast agents for human use which contain one or more of the active substances ‘gadobenic acid, gadobutrol, gadodiamide, gadopentetic acid, gadoteric acid, gadoteridol, gadoversetamide and gadoxetic acid’, in so far as that decision concerns Omniscan,

THE GENERAL COURT (Fourth Chamber),

composed of H. Kanninen, President, L. Calvo-Sotelo Ibáñez-Martín (Rapporteur) and I. Reine, Judges,

Registrar: P. Cullen, Administrator,

having regard to the written part of the procedure and further to the hearing on 29 January 2019,

gives the following

Judgment

1. Background to the dispute

   1 The applicant, GE Healthcare A/S, is a Norwegian wholly owned subsidiary of GE Healthcare Inc. The applicant is a member of the GE Healthcare group of companies, engaged in various medical and pharmaceutical activities worldwide.

   2 The applicant is the manufacturer of Omniscan (gadodiamide) and the marketing authorisation (‘MA’) holder for that product in fifteen Member States.

   3 Omniscan is a contrast agent with a linear structure based on gadolinium (‘linear gadolinium’), as opposed to contrast agents also based on gadolinium but with a macrocyclic structure (‘macrocyclic gadolinium’). It is administered intravenously and is used to provide contrast image enhancement, in order to improve images obtained in magnetic resonance imaging (‘MRI’) and in magnetic resonance angiography imaging. Gadolinium-containing contrast agents improve the visualisation of tumours and lesions in patients and optimise the accurate diagnosis of chronic conditions such as cancer and heart disease. They are classed as medicinal products.

   4 In the course of 2010, the Committee for Medicinal Products for Human Use (‘CHMP’) found a link between gadolinium-containing contrast agents and nephrogenic systemic fibrosis in patients with severe renal impairment. That finding led to the adoption of risk-management measures. Those measures include warnings in the product information, restrictions on use in patients with impaired renal function and contraindication in patients with severe or acute renal impairment.

   5 On 14 January 2016, a common assessment was made of documents analysing the adverse effects caused by medicinal products, in other words periodic safety update reports (‘PSUR’). During that assessment of the PSUR on gadolinium-containing contrast agents, the Pharmacovigilance Risk Assessment Committee (‘PRAC’) observed that studies had shown that gadolinium is retained in the human body, including in the brain, but that no clinical consequences of that retention had been identified to date. At that stage, the PRAC considered that the risk-benefit balance of Omniscan remained positive. Nevertheless, the PRAC recommended adding the accumulation and retention of gadolinium in the brain to the risk management plan and to state in that plan that there was no information on the clinical implications of that retention. Finally, the PRAC suggested that there should be an in-depth review of that accumulation and its clinical consequences.

   6 On 9 March 2016, the European Commission triggered a referral as provided under Article 31 of Directive 2001/83 on the ground that a review of gadolinium-containing contrast agents would allow a more in-depth assessment of the evidence of their accumulation in the brain. The Commission added that such a review would also enable a re-evaluation of the risk-benefit balance of those products in order to determine whether the MA should be maintained, varied, suspended or revoked.

   7 The first subparagraph of Article 31(1) of Directive 2001/83 sets out a procedure whereby ‘the Member States, the Commission, the applicant or the marketing authorisation holder shall, in specific cases where the interests of the Union are involved, refer the matter to the [CHMP] for application of the procedure laid down in Articles 32, 33 and 34 before any decision is reached on an application for an [MA] or on the suspension or revocation of an [MA], or on any other variation of the [MA] which appears necessary’. Furthermore, the second subparagraph of Article 31(1) of Directive 2001/83 provides that ‘where the referral results from the evaluation of data relating to pharmacovigilance of an authorised medicinal product, the matter shall be referred to the [PRAC] … . The [PRAC] shall issue a recommendation … . The final recommendation shall be forwarded to the [CHMP]’.

   8 At the end of the first recommendation of 9 March 2017, the PRAC recommended, inter alia, the suspension of the MA for Omniscan.

   9 On 20 March 2017, the applicant requested a re-examination of the first PRAC recommendation. In that request for re-examination, the applicant claimed that that first recommendation was based on errors and omissions, that a fair assessment of the risk-benefit balance of Omniscan had not been carried out and that the precautionary principle had not been applied correctly. Moreover, the applicant took issue with the composition of the expert group consulted by the PRAC. Lastly, the applicant took the view that the suspension of the MA for Omniscan was disproportionate given that it was possible to adopt other measures to minimise the risks.

   10 The PRAC issued its second recommendation on 6 July 2017. It was very similar to the first.

   11 The PRAC thus acknowledged that gadolinium could be detected in the brain after being administered. It also observed that the long-term clinical consequences of gadolinium retention in the brain remained unknown and that, although no adverse neurological effects had yet been demonstrated to be caused by that accumulation, long-term safety data was limited. The PRAC considered, nevertheless, that absent or limited information in case studies on the effects of gadolinium could not be regarded as evidence of the absence of gadolinium toxicity in the brain. In view, in particular, of data supporting dechelation of linear agents in vivo and of the affected regions of the brain, the PRAC considered that harmful effects, such as impairment of fine motor skills or cognitive impairment, as well as potential interaction with disease processes, were plausible. The PRAC therefore considered that there were reasonable and serious concerns raised as to the potential of neurological harm associated with the accumulation of gadolinium in the brain. Nonetheless, the PRAC issued the opinion that, although both linear and macrocyclic gadolinium-containing agents had the ability to distribute to the brain, linear agents are retained and persist in the brain for up to 1 year or longer, whereas macrocyclic agents show only a transient increase in the concentration of gadolinium in the brain and undergo early washout.

   12 Moreover, and while the applicant claimed that Omniscan had a unique indication in myocardial perfusion imaging in four Member States as it was of special benefit to that type of imaging, the PRAC called into question that special benefit. The PRAC observed that Omniscan was also indicated for whole-body MRI, which encompassed imaging of the heart, including myocardial perfusion imaging. The PRAC also recalled that Omniscan was contraindicated for use in patients with severe or acute renal impairment, but noted that, following the introduction of risk minimisation measures in 2010, there had been no new confirmed cases of nephrogenic systemic fibrosis. The PRAC also described the appearance of skin plaques following injection of linear gadolinium. Finally, as regards hypersensitivity reactions, the PRAC acknowledged that the summary of product characteristics for Omniscan already included appropriate warnings and risk minimisation measures, and that the claimed differences between Omniscan and other gadolinium-containing contrast agents were, in that respect, too subtle to influence the risk-benefit balance.

   13 In the light of the foregoing, and taking into account the existence of alternative products and the serious concerns regarding potential neurological harm, as well as the risks already associated with the use of linear gadolinium-containing contrast agents, including the significant risk of nephrogenic systemic fibrosis and skin plaques, the PRAC considered that patients could not bear those risks until conclusive scientific evidence on the long term neurotoxic effects of Omniscan became available, and that the benefit of that product in terms of contrast enhancement in MRI did not outweigh those risks.

   14 Ultimately, in its second recommendation, the PRAC reiterated its conclusion that the risk-benefit balance of linear gadolinium-containing contrast agents was no longer favourable, and that, with exceptions, the MA for those products should be suspended, while the MA for other macrocyclic products should be merely varied. As in its first recommendation, the PRAC recommended that that suspension could be lifted only if MA holders were able to provide data indicating either that there were clinically important benefits which were not established at that time, and which would outweigh the risks related to the product, or...