Background: The Directive 2001/20/EC was an important first step towards consistency in the requirements and processes for clinical trials across Europe. However, by applying the same rules to all types of drug trials and transposing the Directive’s principles into pre-existing national legislations, the Directive somewhat failed to meet its facilitation and harmonisation targets. In the field of ethics, the Directive 2001/20/EC conditioned the way of understanding and transposing the “single opinion” process in each country. This led to a situation in which two models of research ethics committees organisation systems exist, being the model in which the “single opinion” is considered to be the decision made by a single ethics committee more effective and simpler in terms of administrative and logistic workload.
Method: A survey was conducted in 10 European countries. Members of the European Clinical Research Infrastructures Network working party number 1, with expertise in the field of ethics, responded.
Results: There is a major heterogeneity in the composition of ethics committees among the surveyed countries based on the number of members, proportion of experts versus lay members and expertise of the scientific members. A harmonised education of the ethics committees’ membership based in common curricula is recommended by the majority of countries.
Conclusions: Despite the efforts for harmonisation of the European Clinical Trial Directive, from an ethical point of view, there remains a plurality of ethics committees' systems in Europe. It is important to comprehend the individual national systems to understand the problems they are facing.
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Ethical evaluation has a multiplicity of considerations during the conduct of clinical trials.1 These ethical considerations span from matters related to the design of a study, to the conduct and even to the reporting of the results obtained. Each of these aspects needs to be carefully considered and explained in the shape of international and national legislation.
The Directive 2001/20/EC2 came to ensure legally the implementation of the principles of good clinical practice in clinical trials on medicinal products in Europe. It is very important to note that each country had different jurisdictions and an established governance of ethics committees in place before the Directive came into force.
Therefore, in order to comply with the Directive, and follow the same guidance and processes in all member states, there had to be an adaptation in the form of a national transposition. This has resulted in a wide variety of situations, some of which resulted in redundancy of tasks, role overlapping and other unnecessary day-to-day tasks (N Sanz, M Cooney, C Dualé, et al, 2009, in preparation).
This article provides a picture of the differences in the composition and practice of ethics committees, highlights current problems and bottlenecks faced when interacting with ethics committees in 10 European countries as well as trying to suggest recommendations to improve the current situation.
The European Clinical Research Infrastructures Network (ECRIN)3 was created to integrate clinical research in Europe through the interconnection of national networks of academic clinical research centres and clinical trials units.
The task of ECRIN working party 1 (WP1) on ethics was to describe how to interact with ethics committees in different European countries when performing a clinical trial on medicinal products. People with experience in clinical research ethics took part in ECRIN WP1.
In order to collect information concerning the composition of ethics committees in Europe and better understand the current situation when interacting with them (problems and recommendations) a survey was conducted in 10 European countries.
The countries surveyed were: Austria, Denmark, France, Germany, Hungary, Ireland, Italy, Spain, Sweden and the UK.
Members of the WP1 were requested to answer the following questions:
Composition of the ethics committees in their country.
Type of evaluation carried out by their ethics committees.
Involvement and role of patient associations.
Main bottlenecks when performing tasks.
Answers were discussed and extended during regular scheduled teleconferences.
All countries responded to the survey.
Composition of ethics committees
All countries report considering ethical, methodological and legal aspects in their ethical evaluation.
Although the composition of ethics committees varies substantially from country to country, they all comply with the minimal requirements described in good clinical practice.4 The proportion of members with a background in research (experts) and lay members can be seen in fig 1.
We have grouped the academic background of the ethics committee members into two categories, experts and lay members. Experts include two types of professionals: those with clinical practice experience (physicians and nurses) and those with experience in a health science discipline such as epidemiologists, pharmacists, clinical pharmacologists and biostatisticians.
Lay members include patient representatives, ethicists, social workers, psychologists, priests and lawyers.
Country-specific aspects reported
In Austria, ethics committees have at least nine members and nine substitutes. There needs to be one of all the following: a clinician; a pharmacologist; a nurse; a lawyer; a pharmacist; a patient representative; a representative of a disabled organisation, a biometrician and a person with ethical expertise (eg, priest or minister). In addition, depending on the medical field of the individual studies, a clinician with special expertise is required. Patient associations are involved in the ethics committee’s activities as members.
In Denmark, each ethics committee must be composed of at least seven members, with three medical members and four lay members. The maximum is 15 members and there must always be one more lay member than expert member; in reality, however, seven out of nine ethics committees have a total of 11 members. The members with a medical background are appointed upon recommendation of medical research organisations and the lay members are members of the county council. All ethics committee members are elected every 4 years (this corresponds to the election period for county councils) and can only be re-elected once. There is no involvement of patient associations in the ethics committees.
In France, ethics committees are made up of two colleges. The first college or “scientific college” consists of seven members, of which four should have extensive experience within biomedical research. Of these four, two or more must be medical doctors and one must be well versed in biostatistics or epidemiology. In addition, one should be a general practitioner, one a hospital pharmacist and one a nurse. The second college consists of lay members, with one or more of the following: an ethicist; a psychologist; a social worker; two lawyers; and two representatives of patient associations/users of the health system. Quorum is achieved when at least seven members or more reach an agreement. Three of which must be from the first college, of which at least one should be competent in biostatistics or epidemiology. Three others should be from the second college, of which at least one should be representing associations. The French law states that patient associations must have local representatives in the ethics committees. Such associations are conditioned by a legal agreement. Local representatives are involved in the evaluation of the informed consent form and the global philosophy of the project. Their advice is supported by the information given by the ethics committee expert members. Patient associations are part of the federation of French research ethics committee, the Conférence Nationale des Comités de Protection des Personnes.
In Germany, ethics committee composition is regulated according to the different federal state laws. Composition of experts and lay members varies substantially. There is involvement of patient associations as ethics committee members, which is required by law in several federal states.
In Hungary, there are three central ethics committees for the whole country, of which only one, the Clinical Pharmacological and Ethics Committee deals with medicinal products. It has 27 members, six of which are clinical pharmacologists and seven are lay members (two lawyers, one head of a patient’s association and the rest paramedical professionals). Patient associations are involved in the ethics committee activities reviewing ethical and legal issues.
In Ireland, ethics committees have a maximum of 18 members of which a third must be lay persons. The minimum quorum for a valid committee is seven members. There is no involvement of patient associations.
In Italy, ethics committees have at least 12 members, the majority of which and the chairman must be independent of the institution by law. In some instances this proportion might be inferior but in any case less than one third. They have to include two clinicians, one general practitioner, one paediatrician, one nurse, one pharmacologist, one bioethicist, one statistician, one pharmacist, one hospital general director or regional health department director, one lawyer or insurance expert or legal medicine expert and one patient’s organisation representative.
In Spain, ethics committees should be composed of at least nine members. They should include physicians, one of whom should be a clinical pharmacologist, a hospital pharmacist and a registered nurse. At least one member must be independent of the sites where research projects requiring ethical evaluation by the committee are to be conducted and at least two members must be outside the field of health care, one of whom should have a degree in law.
In Sweden, there is one national body of ethics committees consisting of 12 regional ethics committees (located at six medical universities/faculties) and one central ethics committee (Stockholm). The regional ethics committees consist of one chairman (a lawyer), 10 senior scientists elected by the medical university/faculty and five lay members elected by the county council. The central ethics committee also has a chairman who is a lawyer, four senior scientists and two lay members. All members are appointed by the government. There is no involvement of patient associations.
In the UK, ethics committees should have no more than 18 members. They should be constituted by expert and lay members. At least half of the total memberships must be lay members and at least half of the lay members must be “lay+” members.
A “lay+” member is a person who is not and never has been a healthcare professional, a person involved in the conduct of clinical research other than as a research subject, and a chairman, member or director of a health service body or any other body providing health care.
Although there is no exact statutory requirement or guideline for the exact composition of investigational ethics committee expert members in the UK, most will consider it essential to have a statistician, a pharmacist or pharmacologist and a relevant medical doctor. There is no involvement of patient associations.
Six out of 10 countries that responded to the survey (Austria, Germany, Hungary, Ireland, Spain and the UK) described the administrative burden as one main bottleneck in the process of seeking ethics approval. This finding is consistent with another that considered this increase more relevant in those countries where the “single opinion” is made in cooperation with local ethics committees (Germany and Spain).5
Another common problem, reported by Austria, France, Italy, Spain and the UK, is the lack of specific expertise in ethics committees concerning new fields of research, such as advanced therapies (somatic cell therapies, gene therapies and tissues bio-engineering) or in relation to ethical considerations that should be applied in research on vulnerable populations. Austria, France and Germany argued as a possible reason for this lack of specific expertise the lack of regulation from the Directive 2001/20/EC regarding research other than on medicinal products. This situation is of relevance because ethics committees must assess other categories of research (radiotherapy, surgery, etc) without specific regulations to guide them.
Country-specific bottlenecks reported
In Austria, the need for a “single opinion” by the ethics committee before the start of a trial applies only to trials with medicinal products. This situation becomes problematical for other types of clinical research, eg, medical devices, applied methods or combinations of a medicinal product and a medical device. There is no mandatory expertise within ethics committees for advanced therapies and no appeal mechanism for a negative opinion.
In Denmark, the committee shall decide on the approval of a project within 60 days of receiving a valid application; however, there is no time limit for a decision with respect to projects using xenogenic cell therapy, and the time limit is temporarily suspended if the committee requests supplementary information from the investigator.
In France, the time limit, specifically the time to deliver the final decision, is rather long especially when a revision is requested or questions are posed by the ethics committee. Also, there is a lack of expertise in ethics committees regarding specialised fields of research.
In addition, the specific field of “evaluation of usual care” that is proposed in France for research in which the usual care (except drugs) is assessed with an additional follow-up, make those projects hard to classify.
In Germany, there are different requirements for applications in the different federal states (eg, the number of copies per application and the amount of fees). For trials that do not involve medicinal products (eg, medical devices or surgical procedures) there is no harmonisation and a wide range of local requirements for the application process exists.
In Hungary, there is only one ethics committee that meets once every 3 weeks, which results in a very heavy workload per meeting. The sponsor only has contact with the competent authority; there is no direct link between the sponsor and the ethics committee. The competent authority thus relays all information from the sponsor to the ethics committee, this is time consuming and ineffective. Furthermore, there are many problems with the layout and content of the informed consent form (length, formulation, local legal and insurance discrepancies).
In Ireland, the ethics committee approval of trial sites is a heterogeneous process. In some cases the local ethics committee approves the site-specific assessment, whereas in other cases the hospital’s Chief Executive Officer’s approval is sufficient. The site-specific assessment is a form that each local ethics committee should sign in order to confirm that local staff is suitably qualified and that there are sufficient resources to carry out the trial locally.
In Italy, there is lack of expertise in some ethics committees to assess applications on specific fields. There is also a major problem with multi-site trials because not all ethics committees have proper appointed competence. There are too many ethics committees, lack of harmonisation and absence of internal procedures guidelines.
In Spain, the local ethics committee’s involvement in the evaluation of a clinical research proposal produces discrepancies in the interpretation of the “single opinion” concept. There is heterogeneity in the requirements and the obligation of submitting the clinical trial application to ethics committees between the first and the fifth day of every month, increasing the administrative burden. Also, ethics committees have the right to stop the clock during their evaluation period while the competent authority does not. The parallel submission to both the ethics committee and competent authority may lead to competent authorities’ non-authorisations due to absence of an ethical opinion by the time the competent authorities’ evaluation time runs out.
In addition, an ethics committee specialised in advanced therapy does not exist, which may lead to inaccurate protocol evaluation.
Finally, co-sponsorship is not allowed in Spain; as a result a sponsor with different legal entity depending on the country may face problems when submitting documentation to the ethics committees and to the competent authorities.
In Sweden, no obvious bottlenecks were identified.
In the UK, bottlenecks from the past have now been streamlined and there are no major problems at present. However, small capacity problems still exist. One is the workload, eg, in some circumstances there may be a delay of 1–2 months for an assessment of an application, and another is the lack of expertise of some ethics committees to assess applications on specific fields of research, or involving vulnerable populations.
There can also be uncertainty as to whether a project requires ethical approval or not. Research that is considered to be an audit, service development or service evaluation does not require ethical approval. Nevertheless, researchers may believe that their research will be more easily published if it is approved by an ethics committee and therefore still apply for ethics approval.
Common proposals and recommendations
The survey allowed the responders to propose recommendations to improve the current situation of ethics committees in Europe. Several recommendations focused on the need to reach a similar level of ethical awareness throughout Europe based on a common education for all European ethics committees members.
France, Italy and Spain suggested standardised training for the members of ethics committees, and Denmark and Spain proposed the introduction of an expert ethics committee on advanced therapy and other related therapies.
Also, the need for guidance on other types of research different to that covered by the Directive 2001/20/EC expressed by several countries, leads to the suggestion that a common regulatory framework on other categories of research should be set up.
Country-specific proposals reported
In Austria they propose the harmonisation of laws and ethical procedures for all categories of clinical research including investigational medicinal products, medical devices, surgery, etc.
In Denmark they propose to have open access databases, a consolidation of the committees’ specialist expertise and the introduction of controls on approved trials.
In France, they advocate the provision of specific resources to compensate for the time spent by ethics committee members and suggest providing training to ethics committee members, as there is a lack of support from the government in terms of education.
In Germany they suggest standardisation regarding documents to be submitted, fees to be paid and a harmonised application process for all types of clinical research including medicinal products, medical devices, surgical procedures, etc.
In Ireland they propose a harmonised electronic application form and a harmonised process for ethical review of all interventional clinical trials, as at the moment only clinical trials using a medicinal product use the “single opinion” process. They also advocate a timeline for site-specific assessment approval at each trial site.
In Italy they propose having more specific guidelines on ethical sensitive aspects such as vulnerable populations, altogether with the introduction of specific continuous training.
In Spain they suggest placing into the reference ethics committee the main scientific evaluation, leaving local aspects to local ethic committees, and the creation of a coordination centre for reference ethics committees in Spain or Europe to standardise evaluation methodology and have updates on new and advanced therapies through a similar training.
In UK they suggest that the quality of ethical review is paramount. They propose standardising the review process for all research areas and improving the quality of the ethical review by focusing on continuous training.
All of the countries surveyed have a functioning ethics committee system evaluating research on human beings. All of them comply with the minimal requirements stated in good clinical practice. The major task of the ethics committees is the protection of humans. Our results indicate that in their review process the ethics committees balance ethical, methodological and legal aspects.
An adequate judgement, concerning the risks and burdens to the research participants requires expertise from many scientific and medical disciplines. In addition, competence in moral assessment as well as knowledge of law and ethics is important. Our findings indicate that members with clinical practice experience (physicians and nurses) are mandatory for all surveyed ethics committees, together with specialists in activities related to medical research (epidemiologists, pharmacists, pharmacologists and/or biostatisticians). This is a legal requirement in Austria, Germany, Italy and Spain.6 Lawyers and other lay members (ethicists, social workers and priests) are the second group of mandated representatives.
One of the biggest differences among the target countries is the representation number of those experts. The same is true for the participation of lay persons. In Denmark they represent the majority of all committees members, with four out of seven. In Austria, France, Sweden and the UK they represent half of the membership, whereas in Hungary, Ireland, Italy and Spain, they are minority represented with seven out of 27, one third, one fourth and two out of nine, respectively. In the same line, the representation of patients or patient groups is unevenly perceived as an ethical requirement, only five out of 10 countries includes representatives of patient associations in their committees (Austria, France, Germany, Hungary and Italy).
From an ethical point of view, the Directive 2001/20/EC has introduced a considerable degree of harmonisation into national ethics committee systems, although the form this has taken depends on contextual and social features in each country. These differences have resulted in immense variations regarding ethics committee working practices and workload. The results of our survey indicate that an increase in the administrative burden could be considered as sequelae of the transposition of the Directive into national legislations.
Our survey did not analyse which processes are the origin of the administrative burden, but it can be stated that an increase in administrative burden has been noted in the majority of the countries surveyed.
The efficiency of a review system depends on a clear regulatory framework. The Directive came into being reinforce participants’ protection throughout the standardisation of certain processes and timelines, but it is obvious that further efforts are needed to promote more consistent and effective ethical evaluation of research at the local, national and European level.
First, there is a need for a common regulatory framework on other categories of research not involving medicinal products. Ethics committees that are competent bodies for all areas of clinical research feel unable to evaluate other categories of research other than that on medicinal products. Legislation on these areas will be an urgent need.
Second, the need for formal training of ethics committee members makes education an important tool for achieving ethical cohesion throughout Europe. The need for specific training on innovative research and on highly specialised fields of research (somatic cell therapy, gene therapy, tissue bio-engineering) supports the recommendation for introducing an expert ethics committee on advanced therapies at a national level. A common legislation and an educational programme regarding vulnerable populations participating in clinical research is also a matter of concern.
ECRIN is in a unique position to foster harmonisation of ethics committee practice in Europe to facilitate multinational European clinical research. The current analysis is the first step in this direction.
Funding ECRIN is a project funded by the EU Sixth and Seventh Framework Programmes.
Competing interests None.
Provenance and peer review Not commissioned; externally peer reviewed.
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