The EU Directive: Practical Implications for Clinical Research Teams

New requirements for clinical research teams, and administrative responsibilities and constraints for investigators conducting noncommercial trials.

On the 1st of May, the Directive 2001/20/EC on clinical research became law across the 25 member states of the European Union.

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This directive covers a wide sweep of issues on interventional trials which have implications for clinical research teams, including the suitability of investigators and the quality of facilities, informed consent, ethics committees, noncommercial trials, and the European clinical trials database (EUDRACT).

In this article, we will concentrate on the practical implications of new issues that this directive will bring to clinical research practice at investigative sites. We will also discuss noncommercial studies where investigators will be obliged to fulfill the responsibilities of sponsors.

Suitability and quality guidelines
The directive has introduced the dimension of the suitability of investigators, their supporting staff, and the quality of facilities into the practice of clinical trials across Europe. This is a welcome initiative giving new importance and consciousness to the conditions in which clinical trials will be carried out and managed at investigative sites. It is well known that there are great differences in standards of facilities, which vary in size, expertise, and organization.

Training of investigators and clinical research teams. Principal Investigators will be legally required to send their qualifications and any GCP training or experience obtained from work with clinical trials to the local ethics committees for opinion on their suitability to conduct clinical trials.

Such individual and group training is a major factor. Emphasis is being placed on theory and clinical trial practice. Investigators may have clinical knowledge, experience, and renown in the pathology under study, but too few have training in the theory of good clinical research practice. This is relevant because as of 1 May some investigators will be undertaking the responsibilities of sponsors for noncommercial academic trials.Investigators and their supporting staff will need adequate protected time for training. Details of training sessions must be recorded by the investigator and the members of the research team.

Facilities. Clinical investigative sites will be required to submit to the local ethics committee an evaluation of the quality of the facilities (including the availability of adequate resources, personnel, and laboratory facilities) in which they plan to conduct a clinical trial. At present, many clinical investigative teams perform clinical trials in clinics and inpatient facilities that do not meet the adequate privacy environment standards required by the directive.

Informed consent and protection of subjects
The directive has reiterated the basic requirements of informed consent, which are already detailed in the Guidelines of GCP CPMP/ICH135/952 and the Declaration of Helsinki.²

There are two new areas that will have practical implications for investigative teams. First, the increase in the amount of information to be given to clinical trial subjects; and second, the protection to be accorded to children and adults incapable of giving legal informed consent.

Additional information to be given to clinical trial subjects.General information: Subjects will have the right to know the name and address of the sponsor, the institutional affiliation of the investigator, the financial ties between the investigator and the sponsor, the source of finance for the study, and contact details of all personnel involved in the trial.

Privacy rights: The Directive 95/46/EEC already deals with general safeguards to subjects privacy and protection of personal data.3 The new directive, however, is clear on matters affecting subjects in clinical trials; for example, that they should be informed who will access their clinical trial data, the procedure for handling any retained identifiable biological samples, and plans to anonymize or destroy samples after analysis.

The practical implications for clinical research teams will be that the documents of information for subjects/patients will be long(er) and (even more) detailed. It is likely that there will be need for more than one consultation with a potential participant, parent, or legal representative to allow for the giving of information, discussion, and reflection. If there is a pharmacogenetic component to the clinical trial, investigative site teams will need adequate time to explain clearly to the participants the background and purpose of any genetic tests, the planned analyses, whether the samples will be kept for future analyses, and the fact that he/she may abstain from the genetic testing but still participate in the main part of the trial. This will take time, which will surely be a source of difficulty for investigators who seek to enroll patients in clinical trials in emergency departments or the intensive care setting.

Advertising for trial subjects: Clinical research teams will need to have written procedures for the management of persons responding to advertisements. Advertisements must contain information, which may include, for example, the nature of the project, type/group of subjects who might be included, and the fact that the subject will be placed on a volunteer register. Investigative site teams will need to follow formal advertising regulations, which will require more complete information in advertising notices. This will require more resources being available for that purpose.

Person incapable of giving legal consent. Formerly, investigators were not obligated to describe the procedure for obtaining informed consent from a patient or his legal representative, the process being an informal voluntary code of (ethical) practice by a physician/investigator wishing to offer treatment to his/her sick patient in a clinical trial. This has now been formalized into a more standardized procedural approach, which will make investigators and clinical research teams more conscious of their responsibilities towards persons incapable of giving legal informed consent.

Two sets of information sheets may be required. In addition, information must be given to the subjects parent(s) or legal representative, and the subject will be given information according to his/her capacity to understand. The procedures to obtain assent/consent from the patient as well as from the parent or legal representative should be described in the protocol. In addition, during the clinical trial there will be a need for constant surveillance to assess the ability of these patients, to confirm or withdraw their participation in the study.

Ethics committees
Ethics committees received particular attention in the directive in a bid to standardize their administrative functioning across the European Union. From the practical perspective of investigative sites there will be the introduction of the single opinion and clear timelines within which sponsors and the ethics committees must operate.

Single opinion. There will be a single national ethics committee opinion in each Member State for proposed multicenter trials. The concept of Single Opinion already functions in some European countries. However, in other countries, such as Belgium, where the Single Opinion system will be newly established, there will be both local and the new national ethics committees. Investigators or sponsors (the directive does not specify who) will be obliged to submit documentation to both committees. This will increase the administrative burden for clinical trial sites. In addition, where both the national and local committees exist, there will of course be the possibility that local ethics committees reject the study or amendment, etc., at specific sites. This situation might delay the start of a study or the implementation of an amendment by a site or a country during discussions to reach agreement.

For single-center trials, the principal investigator will submit the appropriate documentation to the local ethics committee. For multicenter trials the coordinating investigator will be responsible for the submission of documents to the national ethics committees, and investigators at site level may submit these to their local ethics committees.

Response times from ethics committees (and competent authorities).Protocol: 60 days, with an extension of 30 days if there is a request for further information. Amendments: 35 days for the EC; the CA may extend this if it wishes further information.

The advantage of such centralized national systems is that, with the timelines set down for the responses by ethics committees, there will be less delay in the commencement of clinical trials across Europe. At present, some countries have to wait many months for approval from their ethics committees, while their neighbors have approval within weeks and very obligingly go ahead and polish off the recruitment. This leads to a sense of frustration at investigative sites waiting for approval and delays the overall recruitment for the sponsors.

Many investigative sites (including our own here in Belgium) have benefited from ethics committee rapid response, thus having an advantage over others dependant on slower response approval systems.

Information to be notified to ethics committees. The application form has two modules (the first is the same as that for submission to the competent authority). There will be a considerable increase and detailing in the information to be submitted, though this may vary between countries. In commercial trials, sponsors will collate all this information.

When an academic noncommercial study is involved, the principal/coordinating investigator acting as sponsor has these responsibilities (see list of administrative responsibilities).

Noncommercial trialsAt this time, there are many clinical investigative sites (like ourselves) that perform both commercial trials with the pharmaceutical industry and noncommercial (academic) studies alone or in collaboration with other investigators.

The directive recognizes that noncommercial clinical trials conducted by researchers (without the participation of the pharmaceutical industry) may be of great benefit to patients. However, after May 2004 no intervention research may be initiated without a sponsor, defined in the directive as an individual, company, institution or organization which takes responsibility for the initiation, management and/or financing of a clinical trial. This means that investigators who wish to perform clinical trials without commercial backing must themselves become the study sponsors. The administrative responsibilities will be exactly the same as those of the pharmaceutical industry for commercial trials.

There has been much commentary on this issue over recent months, and it is indeed a very new area for the investigative site teams involving administrative and legal constrains and responsibilities.^4-6

The coordinating investigator with new sponsor responsibilities. A new function, the coordinating investigator, has emerged from the directive. From the perspective of the clinical research team, the practical implications of the above are:

• In the case where ones center is involved in a multicenter, noncommercial study as an investigative site, then there is no additional responsibility.
  
• In the case where a single center is conducting a noncommercial study, the principal investigator of the study will fulfill all the responsibilities of sponsor.
  
• In the case of a single-country, multicenter, noncommercial study, a coordinator will be chosen from among the participating investigators. This coordinating investigator (who will most likely also be the principal investigator) will have the responsibilities as sponsor of the study and the coordination of the principal investigators at different sites.
  
• In the case of a multinational, multicenter, noncommercial study, a national coordinating investigator will be chosen in each country from among the participating investigators. This national coordinating investigator will have the responsibilities of the sponsor of the study in his/her country and will be responsible for the coordination of the principal investigators at different sites in that member state. In addition, he/she will be the national contact person for the study. If ones center is also that of the coordinating investigator (single country, multicenter trials), or national coordinating investigator (multinational, multicenter trial) then quite apart from the clinical and administrative conduct of the study (as a site), there are additional administrative responsibilities of a sponsor and the coordination of the work of the principal investigators of the other sites.

Study medication. Noncommercial trials will be carried out using either marketed or investigational medicinal products. For trials using marketed products, things will not essentially change from the current practice of using commercially packaged and labelled medication if they are used within the guidelines of the 65/65/EEC directive on authorized medication (this is a favor by the directive to the sponsors of noncommercial trials).7 Investigators using investigational medical products will be taking on major responsibilities and costs. These drugs will have to be produced by a manufacturer certified to good manufacturing practice (GMP) standards that must respect the legal obligations on manufacture, packaging, and labelling.

Monitoring of investigative sites in noncommercial trials. This is not specifically mentioned in the directive, but as the validity of data or the clinical research practice must not be doubted in these studies, systems must be put in place by the principal/coordinating investigators for the monitoring of the clinical, logistical, and administrative data at investigative sites. There is also the issue of recording and reporting adverse events during the clinical trial. Suspected Unexpected Serious Adverse Reactions (SUSARs) for both commercial and investigational medicinal products must be reported within strict timelines to other investigators, ethics committees, and competent authorities, so systems must be in place for verification that these obligations are being respected. As with commercial studies, the principal investigator/sponsor will need to produce yearly/final reports for the ethics committees and competent authorities on their noncommercial trials. They will require up-to-date reliable data.

How are investigative sites to find appropriate financing? After 1 May, there were major changes when the administrative and legal obligations became exactly the same for commercial and noncommercial studies. How are investigative sites that rely on public funding to find the money? Until now, investigative sites (like ourselves) have had relatively little difficulty in setting up and performing noncommercial trials, especially when they were done within structures that were already staffed and equipped for clinical trials.

There will be need for trained personnel and suitable facilities. There will be high costs for the insurance necessary to cover participants in these studies. If investigative drugs are being tested, there will be the expenses related to its manufacture, labelling, and packaging. Studies will need monitoring to ensure the integrity of the data and the conduct of the study. Finally, there will be need for an accountant to keep track of the finances in such an enterprise. Cash flow and solvency will be matters of earnest interest to the investigator thinking of undertaking a noncommercial trial in the future.

Administrative obligations of sponsors
This section deals with the responsibilities of sponsors, which will be identical in both commercial and noncommercial studies. Principal/coordinating investigators (and their clinical research teams) who will fulfill the responsibilities of sponsors of noncommercial academic studies need to be aware of their administrative and legal obligations in order to comply with the new accountability at the national and European level. This indeed is the point where the academic research community will find itself seriously challenged.

(Principal/coordinating investigators who undertake the responsibilities of sponsors in noncommercial trials will be noted as sponsors in the following sections.)

Practical applications of sponsors administrative obligations. Administrative responsibilities: In practice, the sponsor will be responsible for the following (nonexclusive):

• Writing the protocol incorporating the new requirements of the directive
• Writing the subject information and informed consent documents incorporating the new requirements of the directive
• Submission of the study and documentation to the national ethics committees
• Submission of the study and documentation to the competent authorities of the member state
• Submission of substantial amendments to the national ethics committees and the competent authorities
• Reporting of SUSARs to the ethics committees, the competent authorities, and other investigators (if multicenter trial). This is the case for both investigative products and medication with marketing authorization
• Submission of annual reports to ethics committees and the competent authorities
• Submission of End of Study notification to the ethics committees and the competent authorities
• Submission of End of Study reports to the ethics committees and the competent authorities
• Response to the ethics committees and the competent authorities of any clarifications that may be requested.

Steps in the notification of a clinical trials.

• The sponsor must register with the EUDRACT database (via the Internet).
• The sponsor then obtains a EUDRACT number.
• The competent authorities (by the coordinator investigator/sponsor) and the ethics committee (by the coordinator sponsor or investigator) will be notified of the studythis can be done in parallel or sequentially. (After receiving approval of the study by the ethics committee, the competent authority will complete this information in EUDRACT at the beginning of the trial.)

Amendments: The sponsor has the obligation to assess if an amendment is substantial, meaning that it could have a significant impact on the safety or the physical or mental integrity of the subjects, the scientific value of the trial, the conduct or management of the trial, the quality, or the safety of any investigational medicinal product used in the trial. Substantial amendments must be submitted to the competent authority, the ethics committee, and the other investigators. The application form, which should be used, is common to both.

The principal investigator in single-center trials or co-coordinating investigator in multicenter trials should sign the substantial amendment. Amendments may not be implemented without a favorable opinion of the ethics committee and the competent authorities. In cases of changes consisting of urgent safety measures to protect the trial subjects, however, the sponsor should inform the ethics committee and the competent authority as soon as possible after these measures have been implemented.

The sponsor need not notify nonsubstantial amendments to the ethics committees or the competent authorities. These should be recorded and be available on request for inspections at investigative sites and at the sponsors offices. This is surely the only example in the directive where, compared with current practice, there will be a lessening of the administrative load at investigative sites.

It is clear that clinical investigative teams will need to adapt to the new status of noncommercial studiesall studies are the same in the eyes of the law in Europe after 1 May 2004.

Inspections
It is an objective of the Directive 2001/20/EC that inspections will be carried out to determine compliance to the laws on clinical trial practice. Most clinical investigative teams have at some time had an inspection for ongoing studies, or those that have been completed. Soon these inspectors will be from Europe too. We had no further information at press time.

Investigator site file. At this time, the signal from the European Medicinal Evaluation Agency is that the investigator site file is under evaluation, and a document is expected in future months.

Conclusions
What are the conclusions on the practical implications of such a directive for clinical research teams? The first is that there is now a long overdue legal framework for participants and personnel on the practice of clinical trials in Europe. There is also new accountability and control of the practice of clinical research at investigative sites.Participant protection is a clear winner, as evidenced by the increased information that must now be provided to participants of clinical trials, and the necessity for detailing administrative and study management procedures in the protocol.

The directive will raise and standardize the practice of clinical trials between investigative sites across Europe, making it a safe and sure place for practice of commercial and noncommercial studies.

Noncommercial academic studies will now be on the same legal and administrative level as those sponsored by the pharmaceutical industry. The funding of these studies is uncertain. Only highly organized, specialized centers of excellence with a highly professional sponsor mindset will be able to obtain funds for the most scientifically original and relevant studies.

All of this signals big changes for clinical research teams.

References
1. Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001 on the approximation of 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. URL for Guidance Papers: http:/pharmacos.eudra.org./F2/pharmacos/docs.htm#news.

2. World Medical Association Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects.

3. Directive 95-46-EC of the European Parliament and of the Council on the protection of individuals with regard to the processing of personal data and on the free movement of such data.

4. Editorial: Whos afraid of the European Clinical Trials Directive? Lancet, 361 (28 June 2003).

5. F. Meunier and D. Lacombe, European Organisation for Research and Treatment of Cancers point of view, The Lancet, 362 (23 August 2003).

6. N. Clumeck and C. Katlama, A Call for a Network of Centres of Excellence in Clinical Research in Europe, The Lancet, 363 (9412) (13 March 2004).

7. 65/65/EEC on the approximation of provisions laid down by law regulation or administrative action relating to medicinal products.

Elizabeth ODoherty,* RN, is research nurse and site coordinator with the Department of Infectious Diseases, St. Pierre University Hospital, 322 Rue Haute, B-1000 Brussels, Belgium, +(32) 2 535 41 31, fax +(32) 2 539 36 14, email: Elizabeth_ODOHERTY@stpierre-bru.be.Nathan Clumeck,, MD, PhD, is head of the Department of Infectious Diseases, St. Pierre University Hospital, 322 Rue Haute, B-1000 Brussels, Belgium, +(32) 2 535 41 72, fax +(32) 2 539 36 14, email: Nathan_CLUMECK@stpierre-bru.be.

*To whom correspondence should be addressed.