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Legislative regulation and ethical governance of medical research in different European Union countries
  1. Piret Veerus1,
  2. Joel Lexchin2,
  3. Elina Hemminki3
  1. 1Department of Epidemiology and Biostatistics, National Institute for Health Development, Tallinn, Estonia
  2. 2Faculty of Health, York University, Toronto, Canada
  3. 3Health and Social Services, THL, Helsinki, Finland
  1. Correspondence to Dr Piret Veerus, Department of Epidemiology and Biostatistics, National Institute for Health Development, Hiiu 42, Tallinn 11619, Estonia; piret.veerus{at}tai.ee

Abstract

Objective To obtain information about the similarities and differences in regulating different types of medical research in the European Union (EU).

Methods Web searches were performed from September 2009 to January 2011. Notes on pre-determined topics were systematically taken down from the web pages. The analysis relied only on documents and reports available on the web, reflecting the situation at the end of 2010.

Results In several countries, regulatory legislation applied only to clinical trials on drugs and medical devices, in other states various types of research were also regulated but by laws different from those concerning trials, and in many countries, some research areas were not controlled by legislation at all. In very few countries was all medical research handled similarly from a legal point of view. The number of research ethics committees (RECs) in a single country varied from one to 264. Their areas of responsibility, working principles and length of time to grant research permission varied as well as the rules for obtaining informed consent from vulnerable groups. In 10 EU countries, there was no appeal mechanism after a negative decision by an REC. The RECs were not accountable to any organisation in five EU countries.

Conclusions There is a need for a fundamental debate regarding whether and which kinds of changes are needed for the further harmonisation of medical research governance in the EU and how cross-country medical research could be facilitated in the future.

  • Scientific Research
  • Ethics Committees/Consultation
  • Legal Aspects

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Introduction

Although the guidelines for medical ethics can be traced back to antiquity,1 modern regulation of medical research began with the Nuremberg Code in 1947.2 The most important ethical cornerstones regulating medical research in Europe at present are the Declaration of Helsinki (1964, amended in 1975, 1983, 1989, 1996, 2000 and 2008),3 the Universal Declaration on Bioethics and Human Rights,4 drawn up within the United Nations Educational, Scientific and Cultural Organisation (UNESCO), the International Ethical Guidelines for Biomedical Research Involving Human Subjects,5 adopted in 1993 by the Council for the International Organizations of Medical Sciences (CIOMS) together with the WHO, and the Good Clinical Practice guidelines,6 drawn up by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) in 2002. In addition to these non-legally binding instruments, biomedical research at the European level is governed by three binding instruments: (1) the Clinical Trials Directive 2001/20/EC7 (which covers clinical drug trials but not non-interventional drug studies); (2) the Convention on Human Rights and Biomedicine (Oviedo Convention)8; and (3) its Additional Protocol concerning Biomedical Research9 (the latter two in countries which have ratified them).

In addition, all countries have their own country-specific legislation. A total of 16 590 clinical drug trials were recorded in the European Union (EU) Clinical Trials Register10 on 14 February 2012. However, medical research includes a much wider range of studies in addition to clinical drug trials. Various other types of research, such as nursing studies, health economics and health technology assessment studies, radiological, stem cell and gene technology studies, registry-based studies, etc, may be regulated by additional legislation.

In order to obtain information on the similarities and differences in regulating different types of medical research across Europe, a cross-country mapping exercise was carried out using web resources and published reports.11–14 Such information could be useful for sharing resources and facilitating cross-country research, as well as for defining and suggesting possible solutions to shared medical research problems.

This overview covers legislation on medical research in different EU member states, including other types of research in addition to clinical drug trials. We discuss the number of research ethics committees (RECs) in each country, their legal positions and mandates, and the length of time they require before granting research permission, and describe general rules for obtaining informed consent from vulnerable groups. The latter topic was chosen so as to analyse how RECs are coping with the demand to harmonise their practices, as set by Directive 2001/20/EC.7

Methods

Several web searches were performed from September 2009 to January 2011 by one researcher familiar with English, Estonian, Finnish, French, Italian and Russian, and relevant published reports were identified. For formulating the research questions, Medline and Applied Social Sciences Index and Abstracts (ASSIA) databases were consulted.

No special software was used to perform the search. The web pages of national ethics committees, the European Forum for Good Clinical Practice (EFGCP) report11 and the Privacy in Research Ethics and Law (PRIVIREAL) report15 were used as sources of information. As the EFGCP report was last updated in April 2011, whereas the PRIVIREAL report dates from 2005, the former was used preferentially when disagreements occurred. The web pages of the national ethics committees were identified from European databases.16 ,17 Many of the pages contained information only in the local language: pages in English, Estonian, Finnish, French, Italian and Russian were read in the original language, but otherwise English summaries or data from international publications were used. Different data sources were used to acquire different types of information, for example, the number of RECs in a single country was obtained from the EFGCP report, and the mandate of RECs from the web pages of the national ethics committees, etc. Notes on pre-determined topics were systematically taken down. Specific terms were copied directly from the original source as far as possible to avoid misunderstandings during translation.

All documents and web resources used for this research were publicly available. The entire project (Ethical Review and Administrative Governance of Clinical Research, MERGO) was approved by the ethics committee of the National Institute for Health and Welfare (THL), Finland (17 June 2010, amendment 27 January 2011).

Results

Legislation on medical research in different EU member states

The European Clinical Trials Directive had been adopted in most of the present member states by 2004. In various countries national legislation based on European Directives was enacted to regulate different areas of medical research. These laws varied across the EU: some countries had very detailed legislation, while others had only a few framework laws. Countries could be roughly divided into three categories according to how they regulated medical research: (1) those only regulating trials on medicinal products and medical devices; (2) those with legislation regulating trials on medical products and medical devices in addition to different legislation regulating other types of medical research; and (3) those where all medical research was handled in the same way (table 1).

Table 1

Classification of European Union countries according to their method of regulating medical research and the mandate of research ethics committees (RECs), 2010

In 2010, the Oviedo Convention regulating biomedical research had been ratified by 15 member states (Bulgaria, Cyprus, Czech Republic, Denmark, Estonia, Finland, Greece, Hungary, Latvia, Lithuania, Portugal, Romania, Slovakia, Slovenia and Spain) and signed by six (France, Italy, Luxembourg, Netherlands, Poland and Sweden).

According to our findings, the majority of countries regulated medical research on the basis of the scope and content of the research. Clinical drug trials (or drug and device trials, subsequently called drug trials) were legally regulated in all EU countries, and most countries also regulated other types of research, but under different legislation, generally biomedical research and genetic studies. In many countries, there were no specific laws for trials using products other than drugs, genetic studies or registry-based studies. Only two countries (Denmark, Netherlands) regulated all medical research in the same way.

REC details

The number of RECs varied from one in Luxembourg and Romania to 215 in Belgium and 264 in Italy (table 2). In Cyprus, Denmark, Finland, France, Germany, Greece, Hungary, Latvia, Lithuania, Malta, Netherlands, Poland, Portugal, Slovakia, Slovenia and Sweden, there was one national ethics committee and several local or regional RECs. In most of these countries, the central ethics committee handled applications for clinical drug trials, while local RECs handled applications for other types of medical research. In some countries, the central committee also functioned as a coordinator for medical research and as an advisory institution for difficult cases.

Table 2

Number of research ethics committees (RECs) and accountability of RECs at different levels in European Union countries, 2010

In the countries with one central or national REC, its members were appointed by the ministry of health (or the health minister). The members of regional, local and institutional RECs were appointed by various bodies in different countries: research or healthcare institutions, universities, ministries of health, regional authorities or other appointing bodies.

Based on the mandate of RECs, countries can be divided as follows: (1) countries where RECs are responsible only for clinical drug trials; (2) countries where medical research has to be approved by RECs; and (3) countries where all research on human subjects is reviewed by RECs (table 1).

In the majority of countries, the mandates of RECs coincided with the areas covered by national legislation (table 1), although there were exceptions. In Belgium, Malta, Poland and Portugal, specific legislation existed only for clinical drug trials, whereas all medical research had to be approved by RECs (and in Poland, all research on human subjects). In Greece, Latvia, Lithuania and Luxembourg, legislation also covered other types of research except clinical drug trials, but only applications for clinical drug trials had to be submitted to RECs.

According to results from the PRIVIREAL study, RECs in most countries had approval power. However, RECs had advisory power in Austria, Finland, France and Slovakia, and in the Czech Republic, Latvia, Malta and Portugal the type of power they had was determined by the type of research.15 However, the difference between approval power (expressly giving permission to conduct the research) and advisory power (voicing no objection to the research) is largely academic as it is not possible to carry out research if an REC opposes it. Still, it is easier to appeal against a decision than against advice.

The length of time for obtaining research permission varied from 15 to 90 days. In some countries, the same rules were applied for all types of research (France, Greece, Malta, Poland, Slovakia, Slovenia, Swedenand UK). However, in others, the length of time also depended on the type of research (Austria, Belgium, Cyprus, Denmark, Estonia, Germany, Hungary, Italy, Netherlands and Spain), while in some countries, the length of time was specified only for drug trials but not for other types of research (Bulgaria, Czech Republic, Finland, Ireland, Latvia, Lithuania, Luxembourg, Portugal, Romania and Spain).

In most countries, there was no procedural interaction between the national competent authority (in most cases the national medicines agency) and the REC concerning the authorisation of a trial with a medicinal product: exceptions were Austria, Hungary, Lithuania and Netherlands. In some countries, despite the lack of legislated interaction, information was exchanged between the competent authority and RECs: Belgium, Denmark, Finland, France, Greece, Latvia, Luxembourg, Malta, Poland, Spain and UK.

Rules for obtaining informed consent from vulnerable persons in clinical drug trials differed depending on the country (table 3). The countries can be divided into four general categories: (1) those where more or less the same rules were applied to all vulnerable groups with no exceptions; (2) those where different rules were applied to different vulnerable groups, for example, minors, mentally ill patients, unconscious patients, etc, with no exemptions in specific cases; (3) those where informed consent was not required in certain specific cases (otherwise, either the same or different rules were applied to different vulnerable groups); and (4) direct involvement of the REC was needed for obtaining consent from vulnerable groups or for regulating the procedure.

Table 3

Classification of European Union countries according to principles for obtaining informed consent from vulnerable groups, 2010

After a negative decision from the REC, there was no appeal mechanism in 10 EU countries (Belgium, Czech Republic, Germany, Greece, Ireland, Italy, Malta, Romania, Slovakia and Spain), and the appeal mechanisms in the countries where it was available differed (table 4). In many countries, an appeal could be sent to the central ethics committee (Bulgaria, Cyprus, Denmark, Finland, Latvia, Lithuania, Netherlands and Sweden), in some it could be sent to another REC (France, Slovenia and UK) and in some countries, to the ministry of health (Luxembourg, Poland and Portugal). In Austria, the appeal had to be filed with the competent authority, in Estonia with the court, and in Hungary different rules were applied for different types of research. If the appeal body was the central ethics committee, the possibilities for appealing decisions varied. The nature of the appeal also varied; for example, in Finland, on request the central committee only issued opinions, not decisions, concerning rejected proposals or their handling.

Table 4

Institution hearing the appeal after a negative decision by a local research ethics committee (REC), 2010

The RECs were not accountable to any organisation in five countries (Czech Republic, Estonia, France, Spain and Sweden); in the rest, the body to whom they were accountable varied (table 2). In many countries, the central REC was accountable to the government or the ministry of health, and the local RECs to the central REC or to the institution that appointed its members. In Denmark, Latvia, Poland and Slovenia, the central REC was independent, and the local RECs were accountable to the central committee.

Discussion

Our study aimed to provide an overview of the situation in EU member states in 2010 regarding medical research legislation and its implementation from the viewpoint of the working principles of the RECs. Any changes after 2010 are not included in the present analysis.

In addition to variations in adopting international legislation on clinical drug trials and biomedical research, implementation varied significantly from country to country. In some states, a single law covered all areas of medical research, in others medical research was regulated by various separate acts and decrees, and in many some research areas were not covered by any legislation.

Besides large variations in the legal regulation of medical research in the EU, our study found notable differences between countries concerning the type of research handled by RECs, which sometimes differed from that specified by national laws. Indeed, some countries had no appeal mechanism after a negative decision by the REC, and the RECs were not accountable to any organisation. Variation between countries may be due to different historical and cultural contexts, but also to the fact that some countries focus only on regulating drug trials, while the others aim to regulate all medical research.

In contrast to the intention of the Directive to centralise and harmonise the work of RECs, the number of RECs, the appointment of members to RECs, the timelines for obtaining research permission from them, and the procedures for obtaining informed consent from vulnerable persons all varied across Europe. There was no uniform method of implementing European legislation in the different countries. This situation raises doubts about the feasibility of international multicentre studies in the EU. The Clinical Trials Directive requires ethics committees to reach their decision on a research proposal within 60 days; however, the practice in different states often did not meet this requirement. We realise that real-life practice may differ from that required by legislation, and the existence of timelines only for clinical drug trials may influence the timelines for handling applications for other types of research.

Therefore, harmonisation should be considered as regards legislation on clinical drug trials and also on other types of research, and should cover the working principles of RECs. Different types of research require different legislation, and the work of RECs has to be based on clear laws. The existence of many ethics committees with one central committee seems to provide a more transparent procedure for researchers in comparison with other current practices across the EU.

Research concerning vulnerable persons deserves special attention. More discussion among researchers and stakeholders is needed on the requirements concerning informed consent from different groups of vulnerable persons and the use of the same rules for all such groups is questionable.

As far as we know, no previous studies have coherently covered the topics included in this study. The problems which may arise in international research due to differences in REC functions,18 the heterogeneity in the composition of RECs,19 the requirement to broaden the range of REC tasks20 and the need to harmonise research terminology21 have been discussed earlier. Previous studies on conflicts between ethical and scientific standards for international drug trials demonstrated lack of clarity on interpretational issues.22

In most countries, legislation was available only in the national language. The information available on the web was very fragmented and often only short summaries in English were provided. Even if translated into English, the meanings of several key terms varied (eg, the definition of medical research). In general, three broad categories for medical research were used (clinical trials, medical research and research involving human subjects), but their definitions were not always clearly consistent. We relied only on documents and reports available on the web, and did not have the opportunity to check the correctness of our interpretation of this information with national stakeholders. Due to these problems, our study may contain mistakes in the details and some countries may have been incorrectly classified in some tables. However, these inaccuracies do not change our main conclusion that there is enormous intercountry variation in all aspects of medical research governance across the EU.

A fundamental debate in the research community is required about the necessity of further harmonisation, what principles should underpin harmonisation and how it could be achieved, if it is actually desirable. Key members of the medical research community have expressed the opinion that changes should be made at the European level and not by national governments (personal communications with national stakeholders from different EU countries). The content of changes is still in dispute; more pragmatic standards proportionate to the incremental risk entailed in clinical research might be needed.23

The Clinical Trials Directive underwent public consultation from 2009 to 2011 to explore possible solutions to problems in conducting clinical drug trials.24 In March 2010 EFGCP organised a final meeting to summarise and discuss the proposals regarding Directive 2001/20/EC25 and several solutions were proposed to deal with various obstacles.26 In 2011, a second public consultation was launched, and in July 2012, the European Commission adopted a proposal for a Regulation on Clinical Trials to resolve a number of problems identified with the current legislation. The scope of the Regulation is limited to clinical research on medicinal products and includes simplified authorisation and reporting procedures as well as the possibility that the Commission could conduct follow-up investigations of trials. However, the new Regulation does not regulate or harmonise the functioning of RECs.27 The European Network of Research Ethics Committees (EUREC) has stated that failing to deal with the role of RECs in clinical trial assessment is not acceptable, and has expressed its willingness to contribute to the harmonisation of the work of RECs in the EU.28

Simultaneously with the EU Clinical Trials Directive, the EU Data Protection Regulation, the CIOMS guidelines for biomedical research involving human subjects and the Declaration of Helsinki are all undergoing amendments. Unfortunately, the groups amending these documents are all acting separately. The EU legislation focuses mainly on clinical drug trials, and there is no European initiative on other types of medical research and often no national legislation. The governance of medical research should be based on the scope and related risks of the research, and should certainly take into account differences in cultural context between societies. Finally, there continues to be a need for a mechanism to facilitate cross-border research and research in general.

References

Footnotes

  • Funding The study was funded by the Academy of Finland (grant 28356) and by the Estonian Research Council (IUT5-1).

  • Competing interests None.

  • Provenance and peer review None.

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