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Avusturya 26.11.2002 EN

EUR-Lex - 62000TJ0074 - EN - Judgment of the Court of First Instance (Second Chamber, extended composition) of 26 November 2002

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Summary
Parties
Grounds
Decision on costs
Operative part
Keywords

1. Approximation of laws - Proprietary medicinal products - Marketing authorisation - Withdrawal of authorisation - Authorisations granted in accordance with the provisions of Chapter III' of Directive 75/319 - Definition - National authorisations harmonised under a procedure based on Article 12 of the directive - Not included

(Council Directive 75/319, Arts 12 and 15a)

2. Approximation of laws - Proprietary medicinal products - Marketing authorisation - Withdrawal of authorisation - Criteria laid down by Directive 65/65 - Exhaustive - Interpretation in accordance with the general principle that protection of public health takes precedence over other considerations

(Council Directive 65/65, Arts 11 and 21)

3. Approximation of laws - Proprietary medicinal products - Marketing authorisation - Withdrawal of authorisation - Criteria laid down by Directive 65/65 - Need for new scientific data or information - Scope - Changes in an assessment criterion - Not included

(Council Directive 65/65, Art. 11)

Summary

$$1. Article 15a(1) of Directive 75/319 relating to medicinal products provides that the variation, suspension or withdrawal of marketing authorisations granted in accordance with the provisions of [Chapter III]' of that directive, on the initiative of a Member State with a view to the protection of public health, falls within the exclusive competence of the Commission, when adopting a decision following an opinion of the Committee for Proprietary Medicinal Products in accordance with the procedures laid down in Articles 13 and 14 of that directive. Conversely, the variation, suspension and withdrawal of marketing authorisations which do not fall within the ambit of Article 15a remain, in principle, subject to the exclusive competence of the Member States.

The concept of a marketing authorisation granted in accordance with the provisions of Chapter III cannot be interpreted as also including authorisations harmonised following consultation of the Committee for Proprietary Medicinal Products under Article 12 of that directive.

Article 12 sets up, in the field of competence of the Member States, a purely consultative procedure, which is also optional and can, moreover, be initiated not only by the Member States concerned, but also by the Commission, or the applicant or holder of a marketing authorisation. In those circumstances, the principle that the Community is to act within the limits of the powers conferred upon it, precludes an interpretation of Article 15a to the effect that the harmonisation of certain marketing authorisations under a procedure based on Article 12, can have the effect of depriving the Member States concerned of their powers, by triggering the application of the arbitration procedure provided for in Article 15a in respect of the adoption of any subsequent decision regarding the suspension or withdrawal of such authorisations.

( see paras 121, 150, 155 )

2. The substantive criteria for withdrawal of a marketing authorisation are exclusively governed by Article 11 of Directive 65/65 relating to medicinal products, in accordance with Article 21 of that directive, which provides that an authorisation may not be refused, suspended or revoked except on the grounds set out in that directive. Those criteria must be interpreted in accordance with the general principle that protection of public health must unquestionably take precedence over economic considerations.

( see paras 171, 173 )

3. The withdrawal of a marketing authorisation pursuant to Article 11 of Directive 65/65 relating to medicinal products is in principle justified only where a new potential risk or the lack of efficacy is substantiated by new, objective, scientific and/or medical data or information. Mere changes in an assessment criterion, even if based on a consensus' in the medical community, cannot on their own justify the withdrawal of an authorisation where those changes are not based on new scientific data or information.

( see paras 194, 211 )

Parties

In Joined Cases T-74/00, T-76/00, T-83/00 to T-85/00, T-132/00, T-137/00 and T-141/00,

Artegodan GmbH, established in Lüchow (Germany), represented by U. Doepner, lawyer, with an address for service in Luxembourg,

applicant in Case T-74/00,

Bruno Farmaceutici SpA, established in Rome (Italy),

Essential Nutrition Ltd, established in Brough (United Kingdom),

Hoechst Marion Roussel Ltd, established in Denham (United Kingdom),

Hoechst Marion Roussel SA, established in Brussels (Belgium),

Marion Merell SA, established in Puteaux (France),

Marion Merell SA, established in Barcelona (Spain),

Sanova Pharma GmbH, established in Vienna (Austria),

Temmler Pharma GmbH & Co. KG, established in Marburg (Germany),

represented by B. Sträter and M. Ambrosius, lawyers, with an address for service in Luxembourg,

applicants in Case T-76/00,

Schuck GmbH, established in Schwaig (Germany), represented by B. Sträter and M. Ambrosius, lawyers, with an address for service in Luxembourg,

applicant in Case T-83/00,

Laboratórios Roussel Lda, established in Mem Martins (Portugal), represented by B. Sträter and M. Ambrosius, lawyers, with an address for service in Luxembourg,

applicant in Cases T-84/00 and T-85/00,

Laboratoires Roussel Diamant SARL, established in Puteaux (France), represented by B. Sträter and M. Ambrosius, lawyers, with an address for service in Luxembourg,

applicant in Case T-84/00,

Roussel Iberica SA, established in Barcelona (Spain), represented by B. Sträter and M. Ambrosius, lawyers, with an address for service in Luxembourg,

applicant in Case T-85/00,

Gerot Pharmazeutika GmbH, established in Vienna (Austria), represented by K. Grigkar, lawyer, with an address for service in Luxembourg,

applicant in Case T-132/00,

Cambridge Healthcare Supplies Ltd, established in Norfolk (United Kingdom), represented by D. Vaughan, K. Bacon, barristers, and S. Davis, solicitor, with an address for service in Luxembourg,

applicant in Case T-137/00,

Laboratoires pharmaceutiques Trenker SA, established in Brussels, represented by L. Defalque and X. Leurquin, lawyers, with an address for service in Luxembourg,

applicant in Case T-141/00,

Commission of the European Communities, represented by H. Støvlbæk and R. Wainwright, acting as Agents, and B. Wägenbaur, lawyer, with an address for service in Luxembourg,

defendant,

APPLICATION for annulment of the Commission decisions of 9 March 2000 concerning the withdrawal of marketing authorisations of medicinal products for human use containing respectively amfepramone' (C(2000) 453), as regards Cases T-74/00, T-76/00 and T-141/00, inter alia norpseudoephedrine', clobenzorex' and fenproporex' (C(2000) 608), as regards Cases T-83/00 to T-85/00, and phentermine' (C(2000) 452), as regards Cases T-132/00 and T-137/00,

THE COURT OF FIRST INSTANCE

OF THE EUROPEAN COMMUNITIES (Second Chamber, Extended Composition),

composed of: R.M. Moura Ramos, President, V. Tiili, J. Pirrung, P. Mengozzi and A.W.H. Meij, Judges,

Registrar: D. Christensen, Administrator,

having regard to the written procedure and further to the hearing on 7 and 8 May 2002

gives the following

Judgment

Grounds

Legal context

Directive 65/65/EEC

1 On 26 January 1965, the Council adopted Directive 65/65/EEC on the approximation of provisions laid down by law, regulation or administrative action relating to medicinal products (OJ, English Special Edition 1965-1966, p. 20). That directive has been amended on several occasions, in particular by Council Directive 83/570/EEC of 26 October 1983 (OJ 1983 L 332, p. 1) and Council Directive 93/39/EEC of 14 June 1993 (OJ 1993 L 214, p. 22) (hereinafter, as amended, Directive 65/65'). Article 3 of that directive lays down the principle that no medicinal product may be placed on the market of a Member State unless an authorisation has first been issued by the competent authorities of that Member State in accordance with that directive or an authorisation has been granted in accordance with Council Regulation (EEC) No 2309/93 of 22 July 1993 laying down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Agency for the Evaluation of Medicinal Products (OJ 1993 L 214, p. 1).

2 Article 4 of Directive 65/65 provides, inter alia, that, in order to obtain a marketing authorisation as provided for in Article 3, the person responsible for placing the product on the market is to apply to the competent authority of the Member State concerned. Under Article 5, that authorisation is to be refused if it proves that the medicinal product is harmful in the normal conditions of use, or that its therapeutic efficacy is lacking or is insufficiently substantiated by the applicant, or that its qualitative and quantitative composition is not as declared, or if the particulars and documents submitted in support of the application do not comply with Article 4. Under Article 4b of Directive 65/65, when the marketing authorisation referred to in Article 3 is issued, the person responsible for placing that product on the market is to be informed, by the competent authorities of the Member State concerned, that they approve the summary of the product characteristics referred to in point 9 of the second paragraph of Article 4, the content of which is defined in Article 4a.

3 Article 10(1) of Directive 65/65 states that the authorisation is to be valid for five years and is to be renewable for five-year periods after consideration by the competent authority of a dossier containing, in particular, details of the data on pharmacovigilance and other information relevant to the monitoring of the medicinal product.

4 The first paragraph of Article 11 of Directive 65/65 provides:

The competent authorities of the Member States shall suspend or revoke an authorisation to place a medicinal product on the market where that product proves to be harmful in the normal conditions of use, or where its therapeutic efficacy is lacking, or where its qualitative and quantitative composition is not as declared. Therapeutic efficacy is lacking when it is established that therapeutic results cannot be obtained with the medicinal product.'

5 Under Article 21 of Directive 65/65, a marketing authorisation for a medicinal product is not to be refused, suspended or revoked except on the grounds set out in that directive.

Directive 75/318/EEC

6 Council Directive 75/318/EEC of 20 May 1975 on the approximation of the laws of Member States relating to analytical, pharmaco-toxicological and clinical standards and protocols in respect of the testing of medicinal products (OJ 1975 L 147, p. 1), which has been amended on several occasions, in particular by Directives 83/570 and 93/39 (hereinafter, as amended, Directive 75/318'), lays down uniform rules for the conduct of the tests and trials referred to in point 8 of the second paragraph of Article 4 of Directive 65/65 and specifies the particulars which must accompany an application for marketing authorisation for a medicinal product pursuant to points 3, 4, 6 and 7 of that paragraph.

7 The seventh and eighth recitals in the preamble to that directive read as follows:

[w]hereas the concepts of "harmfulness" and "therapeutic efficacy" referred to in Article 5 of Directive 65/65/EEC can only be examined in relation to each other and have only a relative significance depending on the progress of scientific knowledge and the use for which the medicinal product is intended; whereas the particulars and documents which must accompany an application for authorisation to place a medicinal product on the market [must] demonstrate that potential risks are outweighed by the therapeutic efficacy of the product; whereas failing such demonstration, the application must be rejected;

[w]hereas the evaluation of "harmfulness" and "therapeutic efficacy" may be modified in the light of new discoveries and standards and protocols must be amended periodically to take account of scientific progress'.

Directive 75/319/EEC

8 Second Council Directive 75/319/EEC of 20 May 1975 on the approximation of provisions laid down by law, regulation or administrative action relating to proprietary medicinal products (OJ 1975 L 147, p. 13), amended on several occasions, in particular by Directives 83/570 and 93/39 (hereinafter, as amended, Directive 75/319'), establishes, in Chapter III (Articles 8 to 15c) a procedure for the mutual recognition of national marketing authorisations (Article 9), together with Community arbitration procedures.

9 That directive expressly provides for referrals to the Committee for Proprietary Medicinal Products (hereinafter the CPMP') of the European Agency for the Evaluation of Medicinal Products, for application of the procedure governed by Article 13, where, in the context of the procedure for mutual recognition established by Article 9, a Member State considers that there are grounds for supposing that the authorisation of the medicinal product concerned may present a risk to public health and the Member States do not reach agreement within the prescribed time-limit (Article 10 of that directive), where Member States have adopted divergent decisions concerning the grant, suspension or withdrawal of national authorisations (Article 11), and in specific cases where the interests of the Community are involved (Article 12). In addition, the directive expressly provides that the variation, suspension and withdrawal of marketing authorisations granted in accordance with the provisions of Chapter III thereof are subject to the procedures laid down in Articles 13 and 14 (Articles 15 and 15a). Finally, Article 15b provides that Articles 15 and 15a are to apply by analogy to medicinal products authorised by the Member States following an opinion of the CPMP issued prior to 1 January 1995, in accordance with Article 4 of Council Directive 87/22/EEC of 22 December 1986 on the approximation of national measures relating to the placing on the market of high-technology medicinal products, particularly those derived from biotechnology (OJ 1987 L 15, p. 38). The procedures established by Articles 12 and 15a of Directive 75/319 are of particular relevance in the present case.

10 Article 12 of Directive 73/319 provides:

The Member States or the Commission or the applicant or holder of the marketing authorisation may, in specific cases where the interests of the Community are involved, refer the matter to the [CPMP] for the application of the procedure laid down in Article 13 before reaching a decision on a request for a marketing authorisation or on the suspension or withdrawal of an authorisation, or on any other variation to the terms of a marketing authorisation which appears necessary, in particular to take account of the information collected under the pharmacovigilance system provided for in Chapter Va.

The Member State concerned or the Commission shall clearly identify the question which is referred to the [CPMP] for consideration and shall inform the person responsible for placing the medicinal product on the market.

The Member States and the aforementioned person shall forward to the [CPMP] all available information relating to the matter in question.'

11 Article 15a of Directive 75/319 states:

1. Where a Member State considers that the variation of the terms of a marketing authorisation which has been granted in accordance with the provisions of this chapter or its suspension or withdrawal is necessary for the protection of public health, the Member State concerned shall forthwith refer the matter to the [CPMP] for the application of the [procedures] laid down in Articles 13 and 14.

2. Without prejudice to the provisions of Article 12, in exceptional cases, where urgent action is essential to protect public health, until a definitive decision is adopted a Member State may suspend the marketing and the use of the medicinal product concerned on its territory. It shall inform the Commission and the other Member States no later than the following working day of the reasons for its action.'

12 Article 13 of Directive 75/319 governs the procedure before the CPMP, which issues a reasoned opinion. Paragraph 5 of that article provides that the European Agency for the Evaluation of Medicinal Products is to forward the final opinion of the CPMP to the Member States, the Commission and the person responsible for placing the medicinal product on the market, together with a report describing the assessment of the medicinal product and stating the reasons for its conclusions. Article 14 of that directive governs the Community decision-making procedure. The first subparagraph of Article 14(1) provides that within 30 days of the receipt of the CPMP opinion, the Commission is to prepare a draft of the decision to be taken in respect of the application, taking into account Community law. Under the third subparagraph of Article 14(1), [w]here, exceptionally, the draft decision is not in accordance with the opinion of the [European] Agency [for the Evaluation of Medicinal Products], the Commission shall also annex a detailed explanation of the reasons for the differences'. The final decision is adopted in accordance with the regulatory procedure governed by Articles 5 and 7 of Council Decision 1999/468/EC of 28 June 1999 laying down the procedures for the exercise of implementing powers conferred on the Commission (OJ 1999 L 184, p. 23). The Commission is assisted in that procedure by the Standing Committee on Medicinal Products for Human Use, set up by Article 2b of Directive 75/318.

Community code on medicinal products for human use

13 All the directives relating to medicinal products for human use which govern the decentralised Community procedure', in particular Directives 65/65, 75/318 and 75/319, have been recast in 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; hereinafter, the Code'). Even though the Code was not in force when the contested decisions were adopted, it should be taken into account where appropriate. In so far as the Code restates in a more structured corpus, without amending them, the provisions of Directives 65/65 and 75/319, a systematic analysis of the provisions of Chapter III of Directive 75/319 is part of the scheme of that code.

Facts

14 The applicants are holders of marketing authorisations, initially issued by the competent national authorities, for medicinal products containing amphetamine-like' anorectic agents. Those centrally-acting anorectics, so-called because they act at the level of the central nervous system, accelerate the feeling of satiety and have been used for many years in a number of Member States in the treatment of obesity.

15 The applicants in Cases T-74/00, T-76/00 and T-141/00 are holders of marketing authorisations of medicinal products containing amfepramone. The applicants in Cases T-83/00, T-84/00 and T-85/00 hold marketing authorisations for medicinal products containing norpseudoephedrine, clobenzorex and fenproporex respectively. The applicants in Cases T-132/00 and T-137/00 hold marketing authorisations for medicinal products containing phentermine.

16 On 9 March 2000, the Commission adopted, on the basis of Article 15a of Directive 75/319, three decisions (hereinafter the contested decisions') concerning the withdrawal of marketing authorisations of medicinal products for human use which contain phentermine' (C(2000) 452), amfepramone' (C(2000) 453) and the substances clobenzorex', fenbutrazate', fenproporex', mazindol', mefenorex', norpseudoephedrine', phenmetrazine', phendimetrazine' or propylhexedrine' (C(2000) 608). In Article 1 of the operative part of each of those decisions, the Commission ordered the Member States to withdraw the national marketing authorisations provided for in the first paragraph of Article 3 of Directive 65/65 ... concerning the medicinal products listed in Annex I [to the decision] which contain the [substance or substances assessed]'. Article 2 of each of the contested decisions justified that withdrawal by referring to the scientific conclusions which were appended to the CPMP final opinion of 31 August 1999 on the substance or substances concerned and annexed to the respective decision (Annex II). Article 3 of each of those decisions required the Member States concerned to comply with the decision within 30 days of its notification.

17 The anorectic agents referred to in those decisions had already been the subject of Commission Decision C(96) 3608 final/1 of 9 December 1996 concerning the placing on the market of the medicinal products for human use which contain the following substances: clobenzorex, norpseudoephedrine, phentermine, fenproporex, mazindol, amfepramone, phendimetrazine, phenmetrazine, mefenorex (hereinafter the decision of 9 December 1996'), subsequent to an opinion of the CPMP to which the matter had been referred under Article 12 of Directive 75/319 (see below, paragraphs 20 to 25). The contested decisions were adopted following a reassessment of those substances, under Article 15a of that directive, at the request of several Member States.

18 According to the applicants' replies to a written question from the Court, the five-year validity period - specified in Article 10(1) of Directive 65/65 - of the marketing authorisations of some of the medicinal products which are marketed by the applicants and covered by the contested decisions, had expired before those decisions were adopted. However, the applicants explained at the hearing that when those decisions were adopted those authorisations were the subject of renewal procedures before the competent authorities of the Member States concerned. Those procedures were suspended following the contested decisions. The marketing authorisations therefore remained in force, in accordance with the applicable national rules, pending the adoption of decisions on the applications for renewal. The Commission has not contested the applicants' submissions in that regard.

19 At the hearing, the applicants did however add that, in the meantime, the competent authorities of the Member States concerned have either suspended the marketing authorisations of the medicinal products in question or withdrawn them in compliance with the contested decisions. In reply to a question put by the Court, the applicants confirmed that if the contested decisions were annulled on the ground of the Commission's lack of competence, the resumption, if any, of the marketing of the medicinal products in question would be conditional upon the adoption of positive decisions by the competent national authorities.

Commission Decision C(96) 3608 final/1 of 9 December 1996

20 On 17 May 1995, the Federal Republic of Germany made a referral to the CPMP under Article 12 of Directive 75/319, expressing its concerns in respect of the risks presented by certain centrally-acting anorectics. That referral covered both amphetamine-like' anorectics - marketed by the applicants -, which enhance neurotransmission at the level of the neurotransmitters (catecholamine) and usually have a stimulant effect, and serotonergic anorectics, which act by increasing the release and reducing the re-uptake of serotonin and have no stimulant or euphoriant effect. The competent national authority suspected those medicinal products of inducing primary pulmonary hypertension (PPH').

21 The CPMP initiated the procedure provided for in Article 13 of Directive 75/319 for the purpose of investigating those two classes of anorectics.

22 In his scientific assessment report of 5 February 1996, the rapporteur, Dr Le Courtois, assessed the benefit/risk balance of anorectics. In that connection, he found, first, that there was a risk of PPH, which was most of the time fatal', and that anorectics in combination with diet induced a weight-loss of 3 to 4 kg and were often prescribed in an aesthetic aim to young women who are not really obese'. He inferred that measures restricting the use of anorectics were justified because, in the absence of such measures, the risks linked with the use of anorectics obviously outweigh the therapeutic benefit'. Second, he pointed out that when obesity is [so] marked that it decreases the patient's life expectancy, there is a need for a pharmacological treatment as adjunctive therapy, in the context of a global approach including diet, psychotherapy, exercise. Only anorectics are today available as pharmacological treatment, thus they have a place in the treatment of obesity'. He concluded by recommending the harmonisation of certain information contained in the summaries of product characteristics of the medicinal products in question.

23 On 17 July 1996, the CPMP issued three final opinions on amfepramone, phentermine and the third group of amphetamine-like' substances under consideration, which included clobenzorex, fenproporex and norpseudoephedrine. It recommended maintaining the marketing authorisations subject to a certain number of amendments to the summaries of product characteristics for the medicinal products containing those substances.

24 In its assessment report of 18 July 1996 on all anorectic agents, the CPMP essentially explained inter alia that the International Primary Pulmonary Hypertension Study (hereinafter the IPPH Study)', which had been the subject of a report of 7 March 1995, had proven a causal link between the use of anorectics and the occurrence of PPH. The risk of PPH was higher when the treatment duration exceeded three months. The CPMP noted that the reported cases showed that this was a class effect' common to all anorectics. As regards the efficacy of those substances, the CPMP found that the weight-loss obtained after short-term treatment was 2 to 5 kg on average, that long-term efficacy had not been established, and that weight-regain occurred immediately after the pharmacological treatment was discontinued. In those circumstances, it considered the benefit/risk balance for the anorectic compounds to be favourable, subject to amendment of the summaries of product characteristics for the medicinal products in question.

25 That procedure led to the adoption of the decision of 9 December 1996 which is expressly based on Article 14 of Directive 75/319. In line with the CPMP opinions of 17 July 1996, the Commission instructed the Member States concerned to amend certain clinical particulars in the summaries of product characteristics approved when the marketing authorisations of the medicinal products in question were granted. It stipulated that the following clinical particulars be included:

Therapeutic indications

Adjunctive therapy to diet, in patients with obesity and a body mass index (BMI) of 30 kg/m2 or higher who have not responded to an appropriate weight-reducing regimen alone.

Note: short-term efficacy only has been demonstrated with regard to weight-reduction. No significant data on changes in morbidity or mortality are yet available.'

Posology and method of administration

It is recommended that treatment should be conducted under the care of physicians experienced in the treatment of obesity. ...

The management of obesity should be undertaken using a global approach which should include dietary, medical and psychotherapeutic methods. ...

The duration of treatment is 4-6 weeks and should not exceed three months.'

Contraindications

- Pulmonary artery hypertension

- Severe arterial hypertension

- Current or past history of cardio-vascular or cerebro-vascular disease

- Current or past medical history of psychiatric disorders including anorexia nervosa and depression

- Propensity towards drug abuse, known alcoholism

- Children below 12 years

Combination drug therapy with any other centrally-acting anorectic agent is contraindicated due to the increased risk of potentially fatal pulmonary artery hypertension.'

Special warnings and precautions for use

Cases of severe, often fatal, pulmonary artery hypertension have been reported in patients who have received anorectics [of this type]. An epidemiological study has shown that anorectic intake is ... strongly associated with an increased risk for this adverse drug reaction. In view of this rare but serious risk ... careful compliance with the indication and the duration of treatment is required ... .'

Undesirable effects

... pulmonary arterial hypertension ... The occurrence or aggravation of exertional dyspnea is usually the first clinical sign and requires treatment discontinuation and investigation in a specialised unit ... .

[E]ffects [on the central nervous system]

- the prolonged use of [these substances] is associated with a risk of pharmacological tolerance [reduction in efficacy], dependence and withdrawal syndrome

- the most common adverse reactions which have been described are: psychotic reactions or psychosis, depression, nervousness, agitation, sleep disorders and vertigo

- convulsions have been reported

Cardio-vascular effects

- the most common reported reactions are tachycardia, palpitations, hypertension, precordial pain

- rarely cases of cardiovascular or cerebro-vascular accidents have been described in patients treated with anorectic agents. In particular stroke, angina, myocardial infarction, cardiac failure and cardiac arrest have been reported.'

Decision C(2000) 453 concerning the withdrawal of marketing authorisations of medicinal products which contain amfepramone, contested in Cases T-74/00, T-76/00 and T-141/00

26 By letter of 7 November 1997, the Belgian Ministry for Social Affairs, Public Health and the Environment informed the CPMP of several cases of cardiac valve disorders observed in patients treated with medicinal products containing fenfluramine, either in monotherapy or in combination with medicinal products containing phentermine and amfepramone. The procedure under Article 15a of Directive 75/319 had already been initiated, on 22 October 1997, in respect of fenfluramine and dexfenfluramine. The Belgian Government therefore requested that such a procedure be initiated in respect of amfepramone and phentermine.

27 On 19 November 1997, the CPMP initiated the procedure under Article 13 of Directive 75/319 in respect of amfepramone used in monotherapy.

28 From 12 to 14 May 1998, the draft first scientific report on amfepramone (the Picon/Abadie Report) was discussed by the pharmacovigilance' working party, which is composed of national experts in the field of pharmacovigilance and is responsible for advising the CPMP on matters relating to the safety of medicinal products (pharmacological vigilance). In its report to the CPMP, that working party concluded:

... a causal relationship between the occurrence of valve heart disorders and the use of amfepramone could not [be] established. The benefit is considered unchanged compared to the previous CPMP opinion. [T]he benefit/risk balance of amfepramone-containing medicinal products remains unchanged'.

29 The Picon/Abadie Report, drawn up on 4 June 1998, states:

There is no clinical, epidemiological or experimental argument to evidence an association between amfepramone and the occurrence of heart valvular disease ... The benefit of amfepramone in the treatment of obesity is not modified ...'.

30 By letters of 27 July 1998, the CPMP requested the holders of marketing authorisations of medicinal products containing amfepramone and phentermine to submit their observations on inter alia the benefit/risk balance of those medicinal products in the light of the Note for guidance on clinical investigation of drugs used in weight control', which was approved by the CPMP in December 1997 and came into effect in June 1998 (hereinafter the CPMP Note for Guidance').

31 At its meeting of 17 September 1998, the CPMP decided to conduct the two procedures for amfepramone and phentermine separately from, but at the same time as, the procedure initiated on the same day concerning inter alia clobenzorex, fenproporex and norpseudoephedrine (see below, paragraph 62). In its report of 31 August 1999 on phentermine (see below, paragraph 55), the CPMP justified that decision on the grounds that medicinal products constituted only one of the factors in the treatment of obesity and that all the substances under consideration had the same pharmacological characteristics and the same indications.

32 A new report supplementing the Picon/Abadie Report was drawn up in April 1999 (the Castot/Fosset Martinetti/Saint-Raymond Report). That report concluded:

[a]mfepramone does not fulfil the criteria of an effective therapy in obesity-treatment. Due to its potentials for tolerance and psychological dependence, amfepramone can only be used for less than three months, [which] contradicts current guidelines recommending long-term treatment. Considering the lack of therapeutic efficacy and the negative safety profile for long-term treatment (more than three months), the benefit/risk ratio of amfepramone is negative'.

33 On 12 April 1999, Professor Winkler sent to the members of the CPMP a discussion paper which drew attention to the negative evaluation of the benefit/risk balance of the substances under consideration, which had been made in the assessment reports on amfepramone (referred to above), on phentermine (see below, paragraph 47 et seq.), and also on clobenzorex, fenproporex and norpseudoephedrine (see below, paragraph 61 et seq.), and summarised the oral observations made by the holders of the marketing authorisations concerned. As regards, in particular, the efficacy of those substances, it is apparent from that discussion paper that, in one oral question, the marketing authorisation holders had been requested to provide data showing that the substances evaluated made it possible to achieve either a long-term reduction in body weight, and thus had a therapeutic benefit (namely, a decrease in morbidity or mortality or an improvement in quality of life), or a short-term reduction in body weight carrying long-term advantages within an anti-obesity programme. In addition, in his discussion paper, Professor Winkler refuted the argument put forward by the marketing authorisation holders that there had been no new developments concerning the safety and efficacy of the substances under consideration. On the basis of the CPMP Note for Guidance and new national guidelines, he relied on the developments in the evaluation criteria in order to assert that there was now a general consensus' that the treatment of obesity requires a significant and long-term loss of weight (over more than one year). Medicinal products containing anorectic substances were therefore effective only if they were suitable for long-term use or if their short-term use resulted in a significant and lasting weight-loss. Furthermore, Professor Winkler stated that the introduction of new drugs to the market, namely orlistat' and sibutramine', apparently suitable for such long-term treatment, further demonstrated how the anorectic field had changed within a few years. Finally, he disputed the relevance of two new studies, the Trenker Study' on amfepramone, carried out by Professor Rottiers (1999), and the study on phentermine carried out by Professor Caterson and others, designed to show the long-term efficacy of those substances.

34 On 22 April 1999, the CPMP issued its opinion (CPMP/969/99) on the scientific assessment of medicinal products containing amfepramone and recommended withdrawing the marketing authorisations of those products.

35 The applicants appealed to the CPMP against that opinion, pursuant to the second sentence of Article 13(4) of Directive 75/319.

36 In their report of 17 August 1999 on amfepramone, the rapporteur and co-rapporteur in the appeal procedure, Professors Garattini and de Andres-Trelles, recommended that medicinal products containing amfepramone be withdrawn from the market. In particular, they pointed out that very high risks were acceptable when compensated for by benefits. If the expected benefit were near trivial, no level of potentially important risk could be accepted.

37 On 27 August 1999, the applicants proposed carrying out further clinical trials of amfepramone.

38 In its final opinion of 31 August 1999 (CPMP/2163/99), the CPMP rejected the applicants' appeals and, on the basis of an assessment of the benefit/risk balance, recommended withdrawing the marketing authorisations of medicinal products containing amfepramone.

39 In its scientific conclusions annexed to that opinion, the CPMP stated:

Therapeutic efficacy for treating obesity requires a significant and long-term lowering of body weight (at least one year). This is based on accumulated scientific knowledge acquired over the years and is laid down in current medical recommendations; this is reflected in the [CPMP Note for Guidance]. This is also expressed in current guidelines, e.g. the Scottish guideline (November 1996), a guideline from the Royal College of Physicians (1998) and in a guideline from the American Society for Clinical Nutrition (1998).'

40 The CPMP found that, according to most of the available studies on amfepramone, when associated with a low-calorie diet that substance induced a weight-loss greater than a placebo. However, the mean effect was modest, never exceeding 5.1 kg whatever the duration of treatment. Moreover, no specific effect on recognised risk factors of obesity had been demonstrated. In addition, rapid weight-regain occurred once treatment was discontinued and there were no controlled studies demonstrating that a limited short-term effect provided any clinical benefit within a programme for the treatment of obesity. The Trenker Study on amfepramone failed to demonstrate the efficacy of treatment with amfepramone over a 12-month period given, first, the small number of patients included in the study (29 in the amfepramone group), the high drop-out rate (25%) and the unbalanced groups and, second, the modest loss of weight. On the subject of efficacy, the CPMP concluded that:

in spite of the fact that nowadays obesity is considered a chronic disorder and that its management should be envisaged as a long-term strategy, amfepramone has only been shown to produce modest short-term weight-reductions of dubious and unproven relevance for the outcome of the disorder. Its long-term effects remain unproven'.

41 As regards the safety of amfepramone, the CPMP essentially reiterated the undesirable effects already taken into consideration in the decision of 9 December 1996.

42 With particular regard to the risk of PPH, it recalled that, in its opinions of 17 July 1996 (see above, paragraphs 23 and 24), it had relied on the IPPH Study to conclude that the risk of inducing PPH might be a class effect of amphetamine-like agents. However, data published subsequently had shown that study to be inconclusive on that matter. Noting that, in the data from spontaneous reporting, several cases of [PPH] with amfepramone have been reported', the CPMP found that:

in the absence of more formal epidemiological evidence, the possibility of an increased risk of [PPH] associated with amfepramone cannot currently be supported [or] refuted'.

43 Finally, after stating that 25 cases of cardiac valve disorders associated with amfepramone use, mostly in combination with fenfluramine or dexfenfluramine, had been spontaneously reported, it concluded:

[i]t would appear that amfepramone monotherapy does not increase the risk of cardiac valve disorders but, as ... is often the case in the absence of specifically-designed epidemiological studies, the possibility cannot be categorically excluded'.

44 As regards the benefit/risk balance, the CPMP considered that [o]n the basis of the available evidence on [amfepramone's] efficacy, it is no longer possible to consider that amfepramone has therapeutic efficacy in the treatment of obesity or (as a consequence) that its benefit/risk balance is positive.'

45 In a dissenting opinion appended to the CPMP final opinion of 31 August 1999, four members of that committee, Professor Hildebrandt, Dr Haase, Professor Odlind and Dr Sjöberg, declared themselves in favour of suspending, rather than withdrawing, the marketing authorisations of medicinal products containing amfepramone, given the fact that obesity was a significant health problem'. After pointing out, first, the absence of any significant new safety concerns since the CPMP opinion of 17 July 1996 and, second, the lack of data on the long-term efficacy of amfepramone, they referred to the particular need, in the light of recent guidelines in the treatment of obesitas', to carry out clinical trials in order to collect data long-term (over a period of more than one year) on the efficacy and safety of the substance in question.

46 On 9 March 2000, the Commission adopted the contested decision, C(2000) 453.

Decision C(2000) 452 concerning the withdrawal of marketing authorisations of medicinal products which contain phentermine, contested in Cases T-132/00 and T-137/00

47 On 19 November 1997, following a referral by the Belgian Ministry for Social Affairs, Public Health and the Environment (see above, paragraph 26), the CPMP initiated the procedure under Article 13 of Directive 75/319 in respect of phentermine used in monotherapy.

48 The pharmacovigilance working party concluded in its report on phentermine, drawn up at its meeting of 12 to 14 May 1998, at which the co-rapporteur, Professor Hildebrandt, submitted his draft scientific report, that, as was the case for amfepramone (see above, paragraph 28), the evaluation of the efficacy of phentermine had not changed since the CPMP opinion of 17 July 1996.

49 In his final scientific report on phentermine of 12 April 1999, the co-rapporteur concluded that that substance had a benefit/risk balance which was not satisfactory'. As regards the benefits, he found that the efficacy of phentermine as an adjunctive treatment for obesity had been demonstrated in a small number of studies which included relatively few patients and did not conform to current standards. The weight-loss achieved was modest and there was no data on the long-term effects of phentermine and a fortiori on the maintenance of weight-loss. Consequently, most of the basic requirements laid down in the CPMP Note for Guidance were not met.

50 On the same date, the aforementioned discussion paper drawn up by Professor Winkler (paragraph 33) was sent to the members of the CPMP.

51 In its opinion of 22 April 1999 on phentermine (CPMP/968/99), the CPMP recommended withdrawing the marketing authorisations of medicinal products containing that substance. The applicants appealed to the CPMP against that opinion.

52 By letter of 13 August 1999, the holders of marketing authorisations of medicinal products containing phentermine also proposed carrying out clinical trials to investigate its long-term efficacy.

53 In their report of 17 August 1999 on phentermine, the rapporteur and co-rapporteur in the appeal procedure, Professors Garattini and de Andres-Trelles, proposed recommending the withdrawal of those marketing authorisations. They pointed out, inter alia, that the best available evidence for efficacy in longer-term use (but still over only 36 weeks) came from the 1968 report by Dr Munro and others. However, according to that study, the weight-loss was less than 10% of the original weight, applied only to a small percentage of patients and tended to diminish with the duration of the treatment. In addition, the weight-regain at the end of the treatment could result in the post-treatment weight exceeding the original weight. There were no studies of longer than 36 weeks. The available results did not constitute sufficient proof of the long-term efficacy of phentermine.

54 On 31 August 1999, the CPMP issued its final opinion on phentermine, in which it recommended that the marketing authorisations of medicinal products containing that substance be withdrawn on the ground that the benefit/risk balance was unfavourable. It relied essentially on the same arguments as those set out in its final opinion on amfepramone (see above, paragraphs 39 to 44). Those two opinions gave rise to similar dissenting opinions (see above, paragraph 45).

55 In its scientific conclusions annexed to its final opinion on phentermine, and in its report of 31 August 1999 on that substance, the CPMP first of all noted essentially that, according to the latest guidelines, therapeutic efficacy required a significant and long-term lowering of body weight (for at least one year). As regards phentermine in particular, it stated that, according to a number of short-term studies, only a slight decrease in body weight can be achieved' with phentermine. Moreover, no studies were available concerning the effects of phentermine on the risk factors of obesity. The new study relied on by certain marketing authorisation holders did not provide any additional relevant information. In addition, weight was rapidly regained after treatment was discontinued and there were no controlled studies demonstrating that a limited short-term effect had any clinical benefit within an obesity-treatment programme. The CPMP therefore concluded, in terms similar to those used in respect of amfepramone (see above, at the end of paragraph 40), that phentermine lacked therapeutic efficacy.

56 In respect of safety, the CPMP also recalled the undesirable effects of the substances under consideration, which had already been taken into consideration by the Commission in its decision of 9 December 1996.

57 However, as regards the risk of PPH, the CPMP acknowledged that phentermine had not been among the substances investigated in the IPPH Study on which it had based its opinion of 17 July 1996, and that, as a consequence, formal evidence from epidemiological studies is lacking'. After observing that several cases of PPH associated with phentermine had been reported, it suggested that, in the absence of evidence that there is an association between phentermine and that medical condition, the possibility of an increased risk of [PPH] ... cannot be excluded'.

58 In respect of the risk of cardiac valve disorders, the CPMP pointed out that, in 1997, the United States Food and Drug Administration (hereinafter the FDA') had reported numerous cases of cardiac valve disorders in patients receiving fenfluramine in combination with phentermine and more than five cases of cardiac valve disorders associated with the use of phentermine in monotherapy. In two cases the treatment duration was less than three months. In the European Union, only 10 cases (in Belgium), associated with the combined use of phentermine and other anorectic agents, had been reported to the pharmacovigilance systems. The CPMP deduced that although there is not enough evidence to assert that phentermine increases the risk of cardiac valve disorders, such [a] hypothesis cannot be ruled out for the time being'.

59 The CPMP concluded, just as in respect of amfepramone (see above, paragraph 44), that the benefit/risk balance of phentermine was unfavourable on the ground of its lack of efficacy.

60 On 9 March 2000, the Commission adopted the contested decision, C(2000) 452.

Decision C(2000) 608 concerning the withdrawal of marketing authorisations of medicinal products which contain, inter alia, clobenzorex, fenproporex and norpseudoephedrine, contested in Cases T-83/00, T-84/00 and T-85/00

61 In its letter to the CPMP of 31 August 1998, prompted by the aforementioned referral to that committee in respect of phentermine and amfepramone (paragraph 26), the Austrian Federal Ministry for Labour, Health and Social Affairs pointed out that clobenzorex, fenbutrazate, fenproporex, mazindol, mefenorex, norpseudoephedrine, phenmetrazine, phendimetrazine and propylhexedrine belonged to the same group of amphetamine-related anorectics. It added that it was likely that all those substances shared the same effects and side effects and requested the CPMP to issue a reasoned opinion, under Article 15a of Directive 75/319, on all the medicinal products containing those substances. It pointed out that recent developments concerning the efficacy of anorectics (namely, the CPMP decisions in connection with new anti-obesity medicinal products, the CPMP Note for Guidance, and the cardiac valve disorders reported by the Belgian Government) justified a re-evaluation of the benefit/risk balance of those substances.

62 On 17 September 1998, the CPMP initiated the procedure under Article 13 of Directive 75/319 in respect of the substances referred to in the Austrian request.

63 The rapporteur and co-rapporteurs submitted their scientific assessment reports on those substances. On 12 April 1999, Professor Winkler's discussion paper, referred to above (paragraph 33), was sent to the members of the CPMP.

64 On 22 April 1999, the CPMP issued an opinion on the substances under consideration, in which it recommended withdrawing the marketing authorisations for medicinal products containing those substances. The applicants appealed to the CPMP against that opinion.

65 On 27 August 1999, the applicants proposed carrying out further clinical trials, in accordance with the latest CPMP guideline'.

66 In its final opinion of 31 August 1999 (CPMP/2164/99), the CPMP rejected the applicants' appeals and, on the basis of an analysis of the benefit/risk balance, recommended withdrawing the marketing authorisations for medicinal products containing, inter alia, clobenzorex, fenproporex and norpseudoephedrine. That CPMP opinion was the subject of a dissenting opinion similar to those annexed to the CPMP opinions on amfepramone and phentermine (see above, paragraph 45).

67 In its scientific conclusions annexed to that opinion, the CPMP pointed out essentially, in the same terms as in its opinions on amfepramone and phentermine (see above, paragraphs 39 and 55), that according to the latest guidelines therapeutic efficacy in the treatment of obesity requires a significant and long-term lowering of body weight for at least one year.

68 It noted that there were a very few double-blind placebo studies which showed that amphetamine-like substances could lower body weight at least for a short period and to a limited degree. The administration of higher doses resulted in more pronounced weight-loss, but was accompanied by significant side effects. Within weeks of treatment, pharmacological tolerance developed. Moreover, rapid weight-regain occurred once treatment was discontinued and there were no controlled studies demonstrating that a limited short-term effect provided any clinical benefit within an obesity-treatment programme. In addition, due to the risk of dependence associated with the substances examined, it had not been possible to carry out any studies to investigate whether, when used for more than three months, those substances induced a long-term reduction in weight. The CPMP concluded that, given current scientific knowledge and medical recommendations' on the treatment of obesity, the substances examined lacked therapeutic efficacy when used for three months or less. Since it was not acceptable to prescribe those substances for longer than three weeks, their long-term use was of no relevance.

69 In respect of safety, the CPMP pointed out the undesirable effects of the substances under consideration, which had already been reported in the decision of 9 December 1996.

70 As regards, more specifically, the risk of PPH, the CPMP noted, as in respect of amfepramone (see above, paragraph 42), that according to data published subsequently the IPPH Study, on the basis of which it had concluded in its opinion of 17 July 1996 that there was a risk of PPH, was inconclusive in that regard. As to that risk, it stated:

taking into account data from spontaneous reports and in the absence of more formal epidemiological evidence, the possibility of an increased risk of PPH associated with these active substances cannot currently be ruled out'.

71 Finally, as regards the risk of cardiac valve disorders, the CPMP stated that no cases had been reported for the substances evaluated in the opinion. It found that, at that time, there was no evidence of a link between cardiac valve disorders and the use of those substances.

72 The CPMP concluded, as in respect of amfepramone and phentermine, that the substances evaluated had an unfavourable benefit/risk balance on the ground of their lack of efficacy (see above, paragraph 44).

73 On 9 March 2000, the Commission adopted Decision C(2000) 608.

Procedure

74 By applications lodged at the Court Registry on 30 March, 3 and 6 April and 17, 22 and 25 May 2000 respectively, the applicants brought the present actions.

75 By separate documents, lodged at the Court Registry on the same day as the principal applications, they submitted eight applications for suspension of the operation of the three contested decisions.

76 By order of 28 June 2000 in Case T-74/00 R Artegodan v Commission [2000] ECR II-2583, the President of the Court of First Instance ordered suspension of the operation of Decision C(2000) 453 in respect of the applicant Artegodan. No appeal was lodged against that order.

77 By order of 19 October 2000 in Case T-141/00 R Trenker v Commission [2000] ECR II-3313 and six other orders of 31 October 2000 in Cases T-76/00 R Bruno Farmaceutici and Others v Commission [2000] ECR II-3557, T-83/00 R II Schuck v Commission [2000] ECR II-3585, T-84/00 R Roussel and Roussel Diamant v Commission [2000] ECR II-3591, T-85/00 R Roussel and Roussel Iberica v Commission [2000] ECR II-3613, T-132/00 R Gerot Pharmazeutika v Commission [2000] ECR II-3635 and T-137/00 R Cambridge Healthcare Supplies v Commission [2000] ECR II-3653, the President of the Court of First Instance also ordered suspension of the operation of the three contested decisions in respect of the applicants in those cases. The Commission appealed against those seven orders. By orders of 11 April 2001 in Cases C-459/00 P(R) Commission v Trenker [2001] ECR I-2823, C-471/00 P(R) Commission v Cambridge Healthcare Supplies [2001] ECR I-2865, C-474/00 P(R) Commission v Bruno Farmaceutici and Others [2001] ECR I-2909, C-476/00 P(R) Commission v Schuck [2001] ECR I-2995, C-477/00 P(R) Commission v Roussel and Roussel Diamant [2001] ECR I-3037, C-478/00 P(R) Commission v Roussel and Roussel Iberica [2001] ECR I-3079 and C-479/00 P(R) Commission v Gerot Pharmazeutika [2001] ECR I-3121, the President of the Court of Justice set aside the orders of the Court of First Instance and dismissed the applications for interim relief.

78 In Case T-74/00 R Artegodan v Commission, cited above, the Commission sought, by application lodged at the Court Registry on 20 April 2001, the cancellation, under Article 108 of the Rules of Procedure of the Court of First Instance, of the aforementioned order of the President of the Court of First Instance of 28 June 2000. By order of 5 September 2001 ([2001] ECR II-2367), the President of the Court of First Instance dismissed that application. On 13 November 2001, the Commission brought an appeal against that order. By order of 14 February 2002, the Court of Justice set aside the order of 5 September 2001 and cancelled the aforementioned order of 28 June 2000, thereby ending the suspension of the operation of the contested decision (C(2000) 453) as regards Artegodan (Case C-440/01 P(R) Commission v Artegodan [2001] ECR I-1489).

79 In its application, the applicant in Case T-141/00 had sought to have that case joined with Case T-76/00. By order of 23 July 2001, after hearing all the parties, the President of the Second Chamber ordered that Cases T-74/00, T-76/00, T-83/00, T-84/00, T-85/00, T-132/00, T-137/00 and T-141/00 be joined for the purposes of the oral procedure and of the final judgment.

80 By decision of 14 March 2002, the Court of First Instance referred the cases to the Second Chamber, Extended Composition, in accordance with Article 51(1) of its Rules of Procedure.

81 By order of 25 April 2002, the President of the Second Chamber, Extended Composition, after hearing all the parties, ordered that the aforementioned cases and Case T-147/00 be joined for the purposes of the oral procedure.

82 Upon hearing the report of the Judge-Rapporteur, the Court of First Instance (Second Chamber, Extended Composition) opened the oral procedure. By way of measures of organisation of procedure, the parties were requested to reply to a number of written questions from the Court and to produce certain documents. They complied with those requests.

83 The oral arguments of the parties were heard as were their replies to the questions put by the Court at the hearing on 7 and 8 May 2002. At that hearing, the experts advising the parties were also heard, inter alia at the request of the parties.

Forms of order sought

84 In Case T-74/00, the applicant claims that the Court should:

- annul Commission Decision C(2000) 453 of 9 March 2000;

- in the alternative, annul that decision in so far as Article 1 thereof, in conjunction with Annex I thereto, requires Germany to withdraw the marketing authorisation of the medicinal product Tenuate Retard', containing amfepramone, marketed by the applicant;

- order the Commission to pay the costs.

85 In Case T-76/00, the applicants claim that the Court should:

- annul Commission Decision C(2000) 453 of 9 March 2000;

- in the alternative, annul that decision in so far as Article 1 thereof, in combination with Annex I thereto, requires Belgium, Denmark, Germany, the United Kingdom, France, Italy, Luxembourg, Austria and Spain to withdraw the marketing authorisations of the medicinal products containing amfepramone which are marketed by the applicants;