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On April 2nd, 2014, the European Parliament approved the new EU Clinical Trial Regulation.(1, 2) This Regulation will repeal the Clinical Trial Directive, which has failed to achieve its goal of simplifying the scientific and ethical review of clinical trials in the EU.(3, 4) Contrary to the Directive, the Regulation has binding legal force throughout every EU Member State. Substantive novelties include a single portal, a central database and a partly coordinated review system. All of these steps seem promising, not only for simplifying the review system, but also for improving the quality of the assessments. However, when drafting the Regulation, quality improvement did not seem to be the European Commission’s main focus. And despite serious criticisms and several adjustments, the approved document still may impair rather than improve the quality of the ethical review of proposed trial protocols. (5-10) This puts the protection of European research subjects at risk.
Before discussing our two main concerns, let us shortly explain the new review system. Currently, all Member States assess the request for authorisation of a multinational clinical trial independent from one another. To simplify and speed up this system, the European Commission has decided to have the risk-benefit assessment (and the preceding scientific assessment) performed in a coordinated matter.(6, 10) For this coordinated part, sponsors assign one of the Member States as the so called “reporting Member State”. This Member State has to make the final decision on the risk-benefit assessment. The other Member States are invited to submit their input, but within a very tight time frame. Their main task is to assess the application for their own territory, with respect to the ethical and local aspects. Thus, two types of assessment run in parallel: the coordinated risk-benefit assessment (by the reporting Member State, binding on all Member States concerned), and the assessment of the ethical and local aspects (by all Member States concerned individually).
We approve the idea to coordinate the assessment of multinational clinical trials. However, in case of such centralised judgments, the quality of these judgments should be guaranteed. This is not the case.
We are concerned mostly about the fact that the risk-benefit assessment has been taken out of the ethical domain. The European Commission fails to acknowledge that this assessment is widely regarded as a crucial part of the ethical review process.(6, 10, 11) As a result, the Regulation does not require input from an Ethics Committee.(10) This is very worrisome, because only Ethics Committees are used to focus primarily on the protection of the potential research subjects. During the risk-benefit assessment, this perspective is indispensable. It is worth noting that studies may be ethically unacceptable despite having a scientifically favourable risk-benefit ratio when the research question at stake can be answered with less risks or burdens for the research subjects. Furthermore, some studies have a favourable risk-benefit ratio due to the expected benefits for society, but are not expected to benefit the research subjects themselves. Such studies should be evaluated with more care, in particular when they involve children or other subjects who cannot provide informed consent.(11) Chapter 5 of the Regulation provides guidelines for research in these groups, but applying these guidelines appropriately requires specific ethical expertise.(10) Ideally, a multidisciplinary committee with wide ethical expertise assesses and balances the risks and potential benefits critically, and does not hesitate to demand changes in the design.
A complicating factor in this matter is that sponsors are free to choose the reporting Member State. It is not improbable that sponsors will choose the Member State that is known for the easiest risk-benefit assessment. Thus, when aiming for high quality review of clinical trials, the question which body or bodies should perform the coordinated risk-benefit assessment cannot be left to the Member States’ own discretion.
Our second concern relates to the quality of the Ethics Committees. During the first public consultation round many respondents expressed their concerns regarding the quality of the many Ethics Committees all over the EU.(5) They are worried about the fact that there is little assurance about the expertise of the members of these committees. Many respondents argued that pan-European training, quality standards, and an accreditation system were needed.(5) In addition, both the European Commission itself and many of the respondents expressed the need for more cooperation and exchange amongst the committees.(4, 5)
Unfortunately, the European Commission has failed to address these appeals. This is truly a missed opportunity. Because even when ethical issues are regarded as a national affair, the new Regulation would provide a great opportunity to improve the wide diversity in quality of the many Ethics Committees. Leaving these committees just as diverse as before means that European citizens of different Member States cannot rely upon getting the same level of protection. Especially if Ethics Committees are also involved in the coordinated risk-benefit assessment, which we just argued they should, every opportunity to improve their quality should be taken. The judgment of the Ethics Committee of the reporting Member State will then concern the protection of the research subjects in all Member States concerned.
We realise that now the new Regulation is approved, major changes are difficult. However, to rush through a system that is clearly inadequate appears to be unnecessary. European research subjects deserve a Clinical Trial Regulation that is built upon a sound ethical basis. Therefore, we recommend that this new legislature will be adjusted before coming into force. In practical terms, we recommend: 1) To assign the Ethics Committee of the reporting Member State as the key figure in an integrated risk-benefit assessment system; 2) To provide this committee with enough time to take scientific advice from experts and to cooperate effectively with the Ethics Committees of the other Member States concerned; and 3) To establish a quality and accreditation system for all Ethics Committees so that all trials are reviewed by competent committees using the expertise of the full academic medical community.
REFERENCES
1. Watson R. EU nations approve law to overhaul clinical trials. BMJ 2013;347:f7682
3. 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". Official Journal of the European Communities 1.5.2001: L121/34-L121/44.
4. European Commission. Assessment of the functioning of the “Clinical Trials Directive” 2001/20/EC. Public consultation paper. Brussels: European Commission, 2009.
5. European Commission. Assessment of the functioning of the “Clinical Trials Directive” 2001/20/EC. Summary of responses to the public consultation paper. Brussels: European Commission, 2010.
6. European Commission. Revision of the “Clinical Trials Directive”. Concept paper submitted for public consultation. Brussels: European Commission, 2011.
7. European Commission. Revision of the “Clinical Trials Directive”. Summary of the replies to the public consultation on the “Concept paper”. Brussels: European Commission, 2011.
8. Tuffs A. Germany opposes EU plans for regulating clinical trials owing to lack of ethical standards. BMJ 2012;345:e6640.
9. Hasford J. New European Union regulation of clinical trials puts trial participants at risk. BMJ 2013;346:f665.
10. Council of the European Union. Proposal for a Regulation of the European Parliament and of the Council on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC. Brussels: Council of the European Union, 2013.
11. Emanuel EJ, Wendler D, Grady C. What makes clinical research ethical? JAMA 2000;283:2701-11.
Competing interests:
No competing interests
04 April 2014
Anna E Westra
Paediatric Resident and Postdoctoral Researcher in Medical Ethics
Wendy Bos, Adam F Cohen
Erasmus MC - Department of Medical Ethics and Philosophy of Medicine
Re: EU nations approve law to overhaul clinical trials
On April 2nd, 2014, the European Parliament approved the new EU Clinical Trial Regulation.(1, 2) This Regulation will repeal the Clinical Trial Directive, which has failed to achieve its goal of simplifying the scientific and ethical review of clinical trials in the EU.(3, 4) Contrary to the Directive, the Regulation has binding legal force throughout every EU Member State. Substantive novelties include a single portal, a central database and a partly coordinated review system. All of these steps seem promising, not only for simplifying the review system, but also for improving the quality of the assessments. However, when drafting the Regulation, quality improvement did not seem to be the European Commission’s main focus. And despite serious criticisms and several adjustments, the approved document still may impair rather than improve the quality of the ethical review of proposed trial protocols. (5-10) This puts the protection of European research subjects at risk.
Before discussing our two main concerns, let us shortly explain the new review system. Currently, all Member States assess the request for authorisation of a multinational clinical trial independent from one another. To simplify and speed up this system, the European Commission has decided to have the risk-benefit assessment (and the preceding scientific assessment) performed in a coordinated matter.(6, 10) For this coordinated part, sponsors assign one of the Member States as the so called “reporting Member State”. This Member State has to make the final decision on the risk-benefit assessment. The other Member States are invited to submit their input, but within a very tight time frame. Their main task is to assess the application for their own territory, with respect to the ethical and local aspects. Thus, two types of assessment run in parallel: the coordinated risk-benefit assessment (by the reporting Member State, binding on all Member States concerned), and the assessment of the ethical and local aspects (by all Member States concerned individually).
We approve the idea to coordinate the assessment of multinational clinical trials. However, in case of such centralised judgments, the quality of these judgments should be guaranteed. This is not the case.
We are concerned mostly about the fact that the risk-benefit assessment has been taken out of the ethical domain. The European Commission fails to acknowledge that this assessment is widely regarded as a crucial part of the ethical review process.(6, 10, 11) As a result, the Regulation does not require input from an Ethics Committee.(10) This is very worrisome, because only Ethics Committees are used to focus primarily on the protection of the potential research subjects. During the risk-benefit assessment, this perspective is indispensable. It is worth noting that studies may be ethically unacceptable despite having a scientifically favourable risk-benefit ratio when the research question at stake can be answered with less risks or burdens for the research subjects. Furthermore, some studies have a favourable risk-benefit ratio due to the expected benefits for society, but are not expected to benefit the research subjects themselves. Such studies should be evaluated with more care, in particular when they involve children or other subjects who cannot provide informed consent.(11) Chapter 5 of the Regulation provides guidelines for research in these groups, but applying these guidelines appropriately requires specific ethical expertise.(10) Ideally, a multidisciplinary committee with wide ethical expertise assesses and balances the risks and potential benefits critically, and does not hesitate to demand changes in the design.
A complicating factor in this matter is that sponsors are free to choose the reporting Member State. It is not improbable that sponsors will choose the Member State that is known for the easiest risk-benefit assessment. Thus, when aiming for high quality review of clinical trials, the question which body or bodies should perform the coordinated risk-benefit assessment cannot be left to the Member States’ own discretion.
Our second concern relates to the quality of the Ethics Committees. During the first public consultation round many respondents expressed their concerns regarding the quality of the many Ethics Committees all over the EU.(5) They are worried about the fact that there is little assurance about the expertise of the members of these committees. Many respondents argued that pan-European training, quality standards, and an accreditation system were needed.(5) In addition, both the European Commission itself and many of the respondents expressed the need for more cooperation and exchange amongst the committees.(4, 5)
Unfortunately, the European Commission has failed to address these appeals. This is truly a missed opportunity. Because even when ethical issues are regarded as a national affair, the new Regulation would provide a great opportunity to improve the wide diversity in quality of the many Ethics Committees. Leaving these committees just as diverse as before means that European citizens of different Member States cannot rely upon getting the same level of protection. Especially if Ethics Committees are also involved in the coordinated risk-benefit assessment, which we just argued they should, every opportunity to improve their quality should be taken. The judgment of the Ethics Committee of the reporting Member State will then concern the protection of the research subjects in all Member States concerned.
We realise that now the new Regulation is approved, major changes are difficult. However, to rush through a system that is clearly inadequate appears to be unnecessary. European research subjects deserve a Clinical Trial Regulation that is built upon a sound ethical basis. Therefore, we recommend that this new legislature will be adjusted before coming into force. In practical terms, we recommend: 1) To assign the Ethics Committee of the reporting Member State as the key figure in an integrated risk-benefit assessment system; 2) To provide this committee with enough time to take scientific advice from experts and to cooperate effectively with the Ethics Committees of the other Member States concerned; and 3) To establish a quality and accreditation system for all Ethics Committees so that all trials are reviewed by competent committees using the expertise of the full academic medical community.
REFERENCES
1. Watson R. EU nations approve law to overhaul clinical trials. BMJ 2013;347:f7682
2. European Parliament / News. Brussels: European Parliament. Clinical trials: clearer rules, better protection for patients; 2014 Apr 2 [cited 2014 Apr 3]. Available from: http://www.europarl.europa.eu/news/en/news-room/content/20140331IPR41186....
3. 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". Official Journal of the European Communities 1.5.2001: L121/34-L121/44.
4. European Commission. Assessment of the functioning of the “Clinical Trials Directive” 2001/20/EC. Public consultation paper. Brussels: European Commission, 2009.
5. European Commission. Assessment of the functioning of the “Clinical Trials Directive” 2001/20/EC. Summary of responses to the public consultation paper. Brussels: European Commission, 2010.
6. European Commission. Revision of the “Clinical Trials Directive”. Concept paper submitted for public consultation. Brussels: European Commission, 2011.
7. European Commission. Revision of the “Clinical Trials Directive”. Summary of the replies to the public consultation on the “Concept paper”. Brussels: European Commission, 2011.
8. Tuffs A. Germany opposes EU plans for regulating clinical trials owing to lack of ethical standards. BMJ 2012;345:e6640.
9. Hasford J. New European Union regulation of clinical trials puts trial participants at risk. BMJ 2013;346:f665.
10. Council of the European Union. Proposal for a Regulation of the European Parliament and of the Council on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC. Brussels: Council of the European Union, 2013.
11. Emanuel EJ, Wendler D, Grady C. What makes clinical research ethical? JAMA 2000;283:2701-11.
Competing interests: No competing interests