Opinion of the Economic and Social Committee on the 'Proposal for a European Parliament and Council Directive on the approximation of provisions laid down by law, regulation or administrative action relating to the implementation of Good Clinical Practice in the conduct of clinical trials on medicinal products for human use` () (98/C 95/01)

On 4 December 1997 the Council decided to consult the Economic and Social Committee, under Article 100a of the Treaty establishing the European Community, on the above-mentioned proposal.

The Section for Protection of the Environment, Public Health and Consumer Affairs, which was responsible for preparing the Committee's work on the subject, adopted its opinion on 6 January 1998. The rapporteur was Mr Colombo.

At its 351st plenary session (meeting of 28 January 1998), the Economic and Social Committee adopted the following opinion by 82 votes to four, with one abstention.

1. Introduction

1.1. The proposal is based on Article 100a. It is designed to align the principles and guidelines concerning clinical trials of medicinal products for human use. The aim is to reinforce existing practice and align procedures for the commencement of clinical trials on human subjects, through consistent application of the guidelines of the International Conference on Harmonization (ICH) ().

1.2. The matter has been codified at Community level since 1990 in the European Union guideline on Good Clinical Practice (GCP), and was harmonized internationally in January 1997 by the ICH.

1.3. The GCP standards are used by the pharmaceutical industry when it undertakes clinical trials with a view to obtaining authorization to market a proprietary medicinal product, or with a view to confirming the therapeutic effect of proprietary products that have already been authorized.

1.4. The codified GCP guidelines only provide a yardstick at present and are not applied uniformly in the Member States, which have hitherto been responsible for legislation in this area.

1.5. This situation often causes serious delays in the start of clinical trials, both because of the red tape generated by differing procedures and the differences between Member States' requirements and practices.

1.6. A uniform procedure is becoming increasingly necessary in multi-centre clinical trials, so as to attain a sufficient number of cases for the statistical validation of the data collected.

1.7. These are the main reasons why it is desirable to convert the principles and guidelines into a binding piece of EU legislation, so as to regulate an activity which now involves a large number of trials centres, often in various Member States. This procedure will become much more important from 1 January 1998, when the national procedure will be supplemented by the decentralized procedure for most marketing authorizations.

1.8. The main objectives of the proposal are as follows:

- protection of persons taking part in trials, based on the revised text of the Helsinki declaration and with reference to the Council of Europe Convention on the protection of human rights and dignity of the human being ();

- maximum safety throughout the procedure, to be obtained inter alia by introducing an inspection system;

- a more rigorous role for ethics committees by making a proper distinction between the 'lead` ethics committee which issues the opinion on whether to authorize the trial, and the ethics committees of each site, which are responsible for the launch of the trial at their site;

- speeding-up of the administrative procedures needed to begin a trial, which must always be referred to an ethics committee for its opinion and notified to the competent authority of the Member State; this authority has 30 days to provide the sponsor with reasoned grounds for non-acceptance of an application;

- more thorough exchange of information between the Member States involved in the trial.

2. General comments

2.1. In its own-initiative opinion on the free movement of medicines in the European Union (), the Committee emphasized the importance of having a pharmaceutical sector which draws its strength from the existence of a competitive, highly innovative industry within the EU.

2.1.1. The opinion pointed out that the availability of innovative, safe and effective medicines plays an important role in protecting public health and extending average life expectancy.

2.1.2. Trials on human subjects are essential for assessing whether new products are effective and safe. Such trials must be conducted according to scientific and ethical principles, while at the same time avoiding pointless and expensive studies which cover no new ground.

2.2. In assessing the proposal, the Committee feels it desirable to seek to strike a balance between the need to:

- simplify red tape;

- respect the deadlines for commencement of the clinical trial;

and the need to

- provide the utmost guarantees for trial subjects;

- coordinate findings so that the efficacy and safety of a new medicinal product can be rigorously assessed.

2.3. Article 1(3) of the proposal states that 'the principles and guidelines of Good Clinical Practice shall be adopted in the form of a directive`. The Committee sees this as a positive step forward, as it means that these principles and guidelines will be binding in all Member States. The proposal will approximate the national legislative provisions adopted recently in various Member States. Failure to harmonize these provisions would result in existing discrepancies remaining unaltered.

2.4. The Committee endorses the approximation of provisions, on condition that this does not in practice create further bureaucratic or administrative obstacles but promotes high-quality pharmacological research in the EU. The EU must remain a magnet for trials and innovation, as this will help to improve health protection.

2.5. In order to ensure that the principles and guidelines governing clinical trials are followed consistently, the provisions of the directive should also apply to independent research on new drugs conducted outside the industry (at universities, hospitals and research centres).

2.6. The Committee understands and endorses the cautious way in which the Commission intends to proceed towards the aim of a single procedure for the commencement of clinical trials, valid throughout the EU. It notes the Commission's statement (point 5 of the explanatory memorandum) regarding the inadequate cooperation at present between Member States and the difficulty of submitting a single application to the European Agency for the Evaluation of Medicinal Products (EMEA), as the agency is not yet properly equipped for this.

2.7. However, the Committee thinks that forms of cooperation should be encouraged for the purpose of gradually moving towards a single EU procedure. Use should be made here of the scientific skills and knowhow available at the EMEA, especially as regards 'orphan` medicinal products and gene and cell therapy. The following opportunities could, for example, be explored:

- at some future stage, the EMEA could be made responsible for authorizing trials on products which have to be registered under the centralized procedure;

- the Committee for Proprietary Medicinal Products (CPMP) could act as the technical body for arbitration in the event of disagreement and/or differing interpretations between Member States.

2.8. In order to boost cooperation, it is essential that an EU database be provided as part of EudraNet (a telematic network linking the relevant national authorities, the EMEA and the Commission). This would be used to coordinate and circulate information between the Member States involved in a multi-centre international trial, with an access key to guarantee the utmost confidentiality and the safeguarding of industrial protection.

2.9. The goal must be a clear and simple legal framework which allows trials to be launched simultaneously in different countries. This presupposes respect for the deadlines laid down for the favourable opinion from the ethics committees and for the acceptance of any requests from the relevant authorities for modifications (these authorities have 30 days to notify their opinion to the sponsor). It is also essential that persons undergoing trials are guaranteed the best possible risks-benefits ratio.

2.10. A harmonized EU framework which is consistent with the documents of the International Conference on Harmonization, Good Clinical Practice, pharmacovigilance standards and Good Manufacturing Practice can ensure that studies carried out in the EU are fully consistent, making it easier to check and compare the data obtained.

2.11. To this end, the Commission must obtain greater guarantees regarding the participation of third countries in multi-centre trials. The sponsor should be asked to ascertain that third countries involved in trails on a particular medicinal product are familiar with the Community guidelines and are therefore able to apply them properly.

3. Specific comments

3.1. The Committee notes that various articles of the directive contain incorrect or incorrectly used terminology. It asks the Commission to align the terminology on that of the ICH, which has become a reference point for the international scientific community and to which the Commission has also actively contributed. In particular, it asks the Commission to check on the various translations of the term 'non-interventional clinical trials`, as the present translations could give rise to misunderstandings.

3.2. Article 2

3.2.1. The definition of a 'serious adverse event or serious adverse reaction` should also mention the ICH provision on the advisability of seeking a medical opinion on other possible risks.

3.2.2. It would be helpful to include a definition of 'research coordinator`, this being the person in charge of the clinicians involved in a multi-centre trial.

3.3. Article 4

3.3.1. The current wording does not make it clear that the opinion of the ethics committee is mandatory. This weakens the position of trial subjects. The Committee therefore suggests that Article 4(2) be amended to read '... must be delivered ...`.

3.4. Article 7

3.4.1. This is the central article of the proposal. The Committee feels that respect for GCP, the mandatory nature of the favourable opinion from the ethics committee, and the possibility for Member States to intervene, together provide sufficient guarantees for trial subjects and ensure a standard procedure in all Member States.

3.4.2. A special exemption from this procedure could be allowed for gene and cell therapy products, given the recognized sensitivity of these sectors. Since centralized registration is mandatory for such products, the Commission could, as of now, make the start of trials contingent on the opinion of the EMEA as the body in charge of the centralized authorization procedure for high-tech products.

3.4.3. In order to avoid unnecessary red tape, it should be made clear that the scientific data to be presented to the Member State and to the ethics committee are to be the same.

3.5. Article 8

3.5.1. Explicit provision should be made for rigorous respect for the confidentiality of data and the utmost discretion regarding research under way.

3.6. Article 9

3.6.1. In cases where a trial is suspended or prohibited, the Member State should inform not only the Commission and the other Member States, but also the sponsor, before taking any decision.

3.7. Article 10

3.7.1. For investigational medicinal products, it would seem best to use the provisions on Good Manufacturing Practice (Directive 91/356/EEC) ().

3.8. Article 13

3.8.1. The Committee recommends that procedures and definitions be made consistent with the ICH text.

Brussels, 28 January 1998.

The President of the Economic and Social Committee

Tom JENKINS

() OJ C 306, 8.10.1997, p. 9.

() International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use.

() Council of Europe, European Treaty Series No 164, Oviedo 4.4.1997.

() OJ C 97, 1.4.1996.

() OJ L 193, 17.7.1991.