Masterstudiengang "Drug Regulatory Affairs"

Master-Thesis

The regulatory requirements of EU-Directive 2001/20/EC and transposition into national legislation of the Member States

Heike Strutzenberger (Abschlußjahr: 2004)

The purpose of the present work is to analyse the transposition of the EU-Directive 2001/20/EC on the procedures for commencement and conduction of clinical trials. Based on an overview on the regulatory requirements, aims, scope and most important elements of the Directive, the interim situation regarding transposition into national legislation of Member States and impact for the application and performance of clinical trials is investigated. The transposition of the regulatory requirements of the Directive into national legislation of Czech Republic, Germany and Italy are introduced.

The evaluation of transposition into national legislation demonstrates: four Member states have completed the implementation; seven Member States have published the draft legislation, some of them will not keep to the date of 1st May 2004; four Member States and two of accession countries are in process of transposition; seven accession countries implemented a lot of elements in pharmaceutical law; for Member State Luxembourg it is unknown when Directive will be implemented.

The performance of clinical trials is both the bases of medical development and an indispensable component of medicinal product safety. The legal bases of clinical trials are set out in national laws, decrees and regulations. By 15 and at least 25 Member States, each which its own clinical practices and procedures, the current practices diverge in individual Member States considerably on the rules on commencement and conduct of the clinical trials.

The Directive 2001/20/EC was released in April 2001 in February 2001. This required the EU Member States to have adopted legislation by May 2003 and to have applied provisions by May 2004, at the latest. With the first wave of EU enlargement starting in May 2004, ten additional countries will require implementation of the Directive 2001/20/EC by the time of accession.

The main purpose of the Directive is to transfer GCP requirements from guidance into law and guaranteeing the protection of the patients involved in clinical trials. The Directive is intended to simplify, accelerate and harmonise the administrative provisions governing such clinical trials by establishing a clear, transparent procedure. On the whole, it can be stated that there is a great improvement with regard to the harmonisation of the legislative conditions for clinical trials. However, it is clear from the national legislation that requirements are not fully harmonised.

The regulations have been designed to be broad in scope and cover all types of trials. Standards set out for protecting clinical trials subjects and for commencement and conducting clinical trials within Member States. Some regulations in the Directive oblige the Member States to adapt the national legislation accordingly. Some of the provisions in the Directive offer the Member States some regulatory leeway, associated with the opening of these national leeway's in handling is the possibility that the legal regulations of the Member States differ in details.

Compared with the authorisation of new medicinal products, in the case of clinical trials the simplification in the EU is limited: in the centralised procedure the authorisation in one country becomes valid at the same time for the other countries in the Community. The mutual recognition of an approval of a clinical trial already granted in a Member State was not included in the Directive. As it is the aim of the Directive to harmonise the legislative conditions of the Member States, the step of mutual recognition would be logical.

Procedures on commencement of clinical trials are not really simplified. For multi-centre clinical tials a single Ethics Committee opinion is required, notwithstanding the number of Ethics Committees. However, due to the different procedures in the Member States it is necessary, that separate Ethics Committee opinion should be obtained. As it is the aim of the Directive to simplify procedures of the Member States, establishment of one master Ethics Committee per Member State would be logical.

In the event of a negative decision or non-adherence by the Ethics Committee to the set periods time, the Directive does not offer the sponsor a means of a legal address.

No transition period is mentioned this might cause some additional problems. After the implementation, for ongoing clinical trials that were started before 1 May 2004, the regulations in force until 30 April 2004 must be followed until these trials are completed. For clinical trials starting after 1 May 2004, the new regulations resulting from the Directive, and thus the 25 national regulations apply. All new trials conducted after that date will require authorisation from the regulatory agency. The regulations of the Directive are not applicable to clinical trials for which an application to the appropriate authority was made before implementation of the Directive.

With the implementation of Directive 2001/20/EC, the application and approval procedure for clinical trials should be accelerated. The clinical trial initiation timelines are affected by the Directive, fixing the timeline to 60 days. Not all authorities are implementing the review timeline exactly, the periods of the approval procedure for a clinical trial differ between the Member States. This means that it will still result in different starting dates within the EU for the practical implementation of the trial.

After the implementation longer times for the implementation of clinical trials are to be expected as a result of more time being required for applications/approval procedures. This will also lead to increased trial costs for applications, insurance, monitoring, personnel (estimated at 5-10 %).

After the implementation an increased amount of work for clinical trials is to be expected, e.g. Investigational medicinal Product Dossier IMPD; reports of SUSARs. There will also be an increase in the organisational effort required. The information to be supplied with an application, the time required for making the application, and the resultant costs per clinical trial will increase to a level corresponding to that of the USA/FDA.

The Directive support a database of information on clinical trials. It can be stated that this is a benefit. Transparency and information about clinical trials within Member States will considerably increase and well-founded statements on efficacy of, and adverse reactions to, medicinal products may be expected. However, the European Commission will not be ready with the set-up of databases by the time of implementation target.

In each country different interests compared to the current system force the regulators to slightly adjust the legislation. The Member States (25 as of May 2004) are allowed to implement this requirement slightly differently. In summary there is still a piece of way to go until the harmonised and well working system will be available in the European Union.

Pages: 89