The European Clinical Trials Directive will be fully implemented on 1 May 2004 - we have seen these words many times since April 2001 when the European Union Directive stated its concern with: "the laws, regulations and administrative provisions of the member states relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use".

The Directive was published 1 May 2001 with its main objective being to simplify and harmonise the administrative provisions governing clinical trials by establishing a clear, transparent procedure and creating conditions conducive to the effective co-ordination of such clinical trials in the European Community by the authorities concerned.

Three years later, acknowledged by the Medicines and Healthcare Products Regulatory Agency (MHRA) as being "quite short", how are these regulations being implemented by the member states?

Each one was given until 1 May 2004 to transpose the Directive into national legislation. The effect of implementation will be different for each member as they bring the new rules into the vaious regulatory systems that exist across the 25 countries that will make up the EU following accession. As of December 2003, only three of the 15 current members have transposed the Directive into their national laws: Denmark, Italy and Sweden.

Transposition was noted as "in progress" in the other countries. In the UK the regulations are awaiting finalisation, while in France the law on public health policy is before the Senate. In Portugal a law is expected to be published soon, while Germany and Austria are to amend their medicines laws. In the Netherlands the Directive will be transposed within the law on medicinal-scientific research. The countries that appear to be furthest behind, with little or no progress reported, include Belgium, Finland and Luxembourg.

Implementing the Directive

The practicalities of implementing the Directive has been the subject of much debate, as the scope of the Directive is wide and sets standards for good clinical practice (GCP) when designing, conducting, recording and reporting every clinical trial on medicinal products whether sponsored by industry, government, research organisation, charity or university. It also sets a common system of authorisation and control for clinical trials and the manufacture or importing of investigational medicinal products (IMPs), to ensure that they are in line with good manufacturing practice (GMP).

The only trials to be excluded from the regulations are non-interventional trials, which are studies that involve products with a marketing authorisation that are prescribed in the usual manner and used in accordance with the authorisation.

The common system for clinical trial approval is by means of a clinical trials authorisation (CTA) application, which is designed to ensure that the same standardised information is reviewed and approved by the competent authority (CA) in a member state prior to initiation of the trial.

Trials must be approved by one ethics committee in each member state in which the trial is to be conducted. Specific time frames are set for review, such that each review must be completed within 60 days, although a member may set shorter time limits for the CA review where it is in compliance with current practice.

Exceptions exist for gene or somatic cell therapy trials, or trials of products containing genetically modified organisms. Here the limit may be extended for 30 days and a further 90 if a consultation with a group or committee is required. The sponsor must notify the licensing authority and the relevant ethics committee in writing that the trial has ended. This must be done within 90 days of the conclusion of the clinical trial or 15 days if the trial is terminated prematurely.

Prior to the implementation of the Directive the process and time involved in initiating a trial varied across member states; some requiring ethics committee approval with or without notification to the board of health (or equivalent). In the UK, clinical trials certificates (CTC), clinical trials exemption (CTX), clinical trials in marketed products (CTMP) and doctors and dentists exemption (DTX) will all go, and for the first time in the UK phase I studies will be included in the MHRA review and require CA authorisation. This is a significant change for phase I healthy volunteer studies and will have a big impact on the business of dedicated phase I contract research organisations (CROs).

Manufacturing and importing

The manufacturing and importing of IMPs will now also require authorisation and all IMPs must be certified by a qualified person (QP) that it has been manufactured in accordance with GMP, the product specification file and the clinical trial application.

An IMP is defined as a pharmaceutical form of an active substance or placebo being tested, or to be tested or used as a reference in a clinical trial. It also includes a medicinal product that has a marketing authorisation (MA) but is, for the purposes of the trial, used in some other way than that for which the product received an MA.

This could potentially make every pharmaceutical product used in clinical trials an IMP. In the case of comparator products with MAs not manufactured in the EU, if documentary compliance cannot be obtained, the batch must undergo analyses to confirm its quality. Many researchers feel that these requirements will increase the indirect costs of GMP and GCP inspections, and will add bureaucracy and expense to the process and have voiced concern as to whether the MHRA has sufficient resources for the inspections.

Another new concept is the European clinical trials database (EUDRACT), which will capture details of all clinical studies in the EU.

This will allow CAs, the EMEA and the European Commission access to information on all trials being conducted within the EU. It will include details from trial approval applications and any subsequent amendments, the ethics committee review, GCP/GMP inspection results to the end of trial declaration. A further European database (Eudravigilance) linked to EUDRACT, will record all suspected unexpected serious adverse reactions (SUSARs).

Mark Vermette, director, clinical solutions, First Consulting Group Life Sciences and a keen observer of the clinical trials legislative process said:  "I have followed the EU directives and associated comment with great interest. Much of it has been negative, but in truth I see this Directive as being really timely, certainly in light of the expansion of the EU and the increase in clinical trials we are experiencing in Europe. All the increased vigilance in safety, information, credentials, etc, contributes to the proper conduct of trials, but there is a potential downside.ember states lacking the infrastructure or facilities to meet the directives will be at a considerable disadvantage and unable to effectively compete. To catch up with current best practice and achieve compliance will be costly, lengthy and for many of the less wealthy states to recently join the EU, a step too far.The research and development of new medicines in the UK is big business: the cost of developing a new medicine is about £500 million, 60% of which is spent in clinical trials; and the full development process takes about 10 to 12 years. Fewer than one or two compounds in 10,000 tested actually make it through the process and are eventually authorised for use in patients.

A potential new medicine may be rejected at various stages in the development process on safety, efficacy or quality grounds. Twenty-five of the world top selling 100 medicines were discovered and developed in the UK, more than any other country except the US, and hundreds of potential new compounds are now undergoing research in the UK.

The non-commercial sector

Whilst pharma companies make up nearly a quarter of all UK R&D business, the non-commercial sector also plays an important part.

Indeed, attracting clinical trials to the UK is important for patients, the NHS, academia and the nation economy. No other EU member state has the volume of non-commercial funding for clinical research.

"There is the potential for sponsor companies or governments to invest in the facilities and governance in EU member states and develop centres of expertise where they did not previously exist. Such investment would bring them into compliance and share the rewards of reduced costs of clinical trials in emerging European markets. This would be a win-win for both sides.

"Investment will improve healthcare facilities, make medication available at low cost and provide a source of revenue. Such actions will also overcome the huge inherent advantage for existing CROs and facilities in member states that will undoubtedly thrive in the short-term due to the reduction in competition. For facilities operating at the more sophisticated end of the clinical trials spectrum, in reality these directives pose few extra challenges," adds Mr Vermette.

A report in November 2003's BMJ shows that there has been a marked decline in clinical trials funded by the NHS over the past few years. This has been linked to reorganisation within the health service but also to decreased support from medical research charities and the Medical Research Council.

An associated issue in Europe is the implementation of the Clinical Trial Directive, which makes little distinction between commercial and non-commercial trials for regulatory purposes. And indeed concerns have been raised that the regulations might make Europe an unattractive venue for research investment.

This has implications not only economically, but also for patients who often benefit directly and indirectly from the research, with the possibility of early access to new treatments.

In addition to the many changes and practicalities of implementing the Directive there is strong feeling on the issues surrounding its implementation, not least in the UK, where it is felt by many organisations and individuals that it is the non-commercial research that will be most adversely affected. Unlike most major pharma companies, the non-commercial sector will need to install management systems, staff training and documentation processes, which will require substantial local investment.

European healthcare researchers have launched a campaign calling on the European Parliament and Commission to repeal the Directive, which according to these investigators places enormous, and possibly insurmountable obstacles in the way of non-commercial, academically-led, patient-focused clinical research the document is available at www.saveeuropeanresearch.org.

One of the key criticisms is the Directive's definition of the 'sponsor'. Any individual or organisation in this position would have to take full legal and financial responsibility for the clinical trials. This would include covering the cost of all drugs and devices (even the cost of routine non-investigational aspects of the treatment) while patients are being studied. Thus, an academic sponsor rather than the health service would have to pay for all the drugs that a patient was receiving, including fully licensed drugs, even if one component of their treatment was 'experimental'.

Concern with the cost of research

Although the pharma industry can provide the level of funding to support this role, the non-commercial sector cannot. Thus the campaign organisers believe that those involved in publicly funded research will not be able to take on the role of the sponsor, resulting in an end to non-commercial trials.

Cancer research, for example, would be hard hit, as clinical trials are often conducted to develop a strategy for treatment rather than to approve a new drug for marketing.

Professor John Crown of the Trish Clinical Oncology Research Group, one of the founders of the campaign believes that trials which led to the cure of childhood leukaemia, and to the development of treatments for patients with breast and throat cancer, to avoid mutilating surgery, would not have been possible if the regulations had been in place at the time when they were conducted.

Many researchers remain worried and the impact of the Clinical Trials Directive remains to be seen. In a recent statement EU research commissioner Phillippe Busquin acknowledged these problems and highlighted a worrying trend in European research investment by pharma companies. According to the campaigners and organisers, the Directive can only accelerate this downward trend.  

A recent advertisement from a Canadian CRO highlights the issue using a slogan: 'Are you concerned about the implementation of the new European Clinical Trials Directive? If so...consider Canada" and boasts a six day review time for bioequivalence and phase I healthy volunteer trials.

Although a repeal of the Directive is highly unlikely, the European Commission is aware of the problem and it is possible that it will do something to alleviate it. For example, the Commissioner has suggested that institutes and research agencies should create a forum to see how better to finance and lead academic multicentre trials. In the UK, the Department of Health and Medical Research Council are jointly leading a project to clarify six key issues for non-commercial trials:

• The single sponsor model
• Excessive monitoring and pharmacovigilance
• Onerous trial and manufacturing authorisation and registration
• Transitional arrangements
• Trials in incapacitated adults
• Uncertainty about precise requirements and legal liability

The project will draw up practical guidance, taking into account any flexibility in the Directive, to allow researchers involved in publicly funded trials to comply with the regulations.

They are exploring a way in which the sponsor duties can be distributed amongst the partners. They are also considering the acceptability of different approaches to monitoring and pharmacovigilance that are less labour intensive and expensive than those used in commercial trials.

The MHRA suggest that non-commercial researchers will be able to use the flexibilities in the legislation to authorise trials and manufacture, and the possibility of differential fees. It has also stated that it will clarify the process for obtaining consent for incapacitated adults to enter a trial. The precise requirements of the legislation, for sponsors and investigators, conducting non-commercial trials for different types of product will be clarified.

To move forward the regulators, pharma companies and the non-commercial sector must work together to ensure that R&D remains a viable business in the UK and that high quality clinical trials continue to be performed within reasonable timescales.