The proposed EU-regulation on clinical trials on medicinal products: An unethical proposal?

European Journal of Health Law

Volumn 20, Issue 4, 2013, Pages 347-362

  Heringa, Jilles ^a   Dute, Joseph ^a,b  

^a Central Committee on Research Involving Human Subjects (CCMO)   (Netherlands)

^b RADBOUD UNIVERSITY NIJMEGEN   (Netherlands)

Author keywords

clinical trials; competence of the EU; ethics; medicinal products; protection; quality; research

Indexed keywords

ARTICLE; CLINICAL TRIAL (TOPIC); EUROPEAN UNION; HUMAN; HUMAN EXPERIMENT; LEGAL ASPECT; LEGISLATION AND JURISPRUDENCE;

CLINICAL TRIALS AS TOPIC; EUROPEAN UNION; HUMAN EXPERIMENTATION; HUMANS;

EID: 84891641008     PISSN: 09290273     EISSN: 15718093     Source Type: Journal    
DOI: 10.1163/15718093-12341284     Document Type: Article

References (156)

1. Directive 2001/20/EC of 4 April 2001 of the European Parliament and of the Council 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 [2001] OJ L 121/34.
2. This directive was further concretised by directive 2005/28/EC of 8 April 2005 laying down principles and detailed guidelines for good clinical practice as regards investigational medicinal products for human use, as well as the requirements for authorisation of the manufacturing or importation of such products [2005] OJ L 91/13.
3. 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, COM(2012) 369 final, Explanatory Memorandum, pp. 2-3.
4. Assessment of the functioning of the "Clinical Trials Directive" 2001/20/EC, Public Consultation Paper of 9 October 2009 (ENTR/F/2/SF D(2009) 32674 and Revision of the "Clinical Trials Directive" 2001/20/EC, Concept paper submitted for public consultation of 9 February 2011 (SANCO/C/8/PB/SF D(2011) 143488.
5. See supra note 2.
6. Explanatory Memorandum, p. 11.
7. The ordinary legislative procedure consists in the joint adoption by the European Parliament and the Council of a regulation, directive or decision on a proposal from the Commission, Article 289 of the Treaty on the Functioning of the European Union (hereinafter: TFEU).
8. The procedure itself is described in Article 294 TFEU.
9. Opinion of the European Economic and Social Committee-with a few substantial recommendations-on the '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', COM(2012) 369 final-2012/0192 (COD) [2013] OJ C 44/99.
10. The procedure file with the state of the proceedings can be consulted at the European Parliament website: http://www.europarl.europa.eu/oeil/popups/ ficheprocedure.do?reference=2012/0192(COD)&l=EN.
11. Article 3(1) of directive 2001/20/EC states that the directive shall apply "without prejudice to the national provisions on the protection of clinical trial subjects if they are more comprehensive than the provisions of the Directive and consistent with the procedures and time-scales specified therein."
12. According to the Commission 24% of the clinical trials in Europe is multinational.
13. However, 67% of the human subjects involved in a clinical trial are involved in a multinational trial.
14. See supra note 2, Explanatory Memorandum, p. 2.
15. Art. 1.
16. Art. 2(4).
17. Art. 2(2)(e).
18. Art. 5(1).
19. Arts. 6 and 7.
20. According to recital 13 of the proposed regulation permission (or refusal) should be "contained in one single administrative decision by the Member State concerned."
21. The regulation does not contain any provisions regarding legal remedies against this administrative decision, so apparently-and logically-the availability of such remedies will depend on the legal administrative systems of the Member States concerned.
22. It is, however, intriguing what would happen if a sponsor were to appeal the decision in a Member Stated concerned and/or in a reporting Member State, in particular if the appeal relates to the conclusion regarding the centralized part I.
23. The regulation lacks any provisions coordinating such procedures.
24. Art. 6.
25. Directive 95/46/EC.
26. In this respect Article 7(1)(b) of the proposed regulation refers to Chapter V.
27. However, that chapter does not contain any provisions regarding the rewards and compensation of investigators and subjects, except for the specific provisions relating to compensation for incapacitated subjects and minors.
28. Art. 7(1)(c).
29. Art. 7(1)(e) and Art. 7(1)(f ).
30. Art. 7(1)(g).
31. Art. 7(1)(h).
32. Art. 5(2).
33. Art. 6(4)(b).
34. Art. 7(2).
35. Art. 8(1).
36. Art. 5(3).
37. Art. 8(4).
38. The date on which the assessment report is submitted to the sponsor and to the other Member States concerned
39. see Article 6(4), final paragraph.
40. Art. 8(2).
41. Art. 31(1)(h).
42. Art. 31(1)(f ).
43. Art. 31(1)(g).
44. Art. 10(1).
45. Art. 30(1)(f ).
46. Art. 30(1)(h).
47. Art. 10(2).
48. Art. 32.
49. This requirement is surprising because in clinical situations where a patient has a life threatening disease often invasive procedures need to be carried out to improve the condition of the patient.
50. When only minimal risk and burden is acceptable then such research-for instance on intensive care units-will be nearly impossible.
51. Art. 73.
52. Art. 76.
53. Directive 2001/20/EC is based on Article 95 EC (the predecessor of Article 114 TFEU).
54. E.g. Directive 2011/24/EU of the European Parliament and of the Council of 9 March 2011 on the application of patients' rights in cross-border healthcare [2011] L 88/45.
55. This directive is solely based on Article 114 TFEU.
56. Recital 2 states: "Given that the conditions for recourse to Article 114 TFEU as a legal basis are fulfilled, Union legislation has to rely on this legal basis even when public health protection is a decisive factor in the choices made."
57. See Case C-376/98, Federal Republic of Germany v. European Parliament and Council of the European Union (Tobacco Advertising 1), [2000], ECR I-8498, recitals 77-78;
58. C-380/03, Federal Republic of Germany v. European Parliament and Council of the European Union (Tobacco Advertising 2), [2006] ECR I-11631, recital 95.
59. See the critical article of H.W. Liu, "Harmonizing the internal market, or public health?-Revisiting case C-491/01 (British American Tabacco)
60. case C-380/03 (Tobacco Advertising II), The Columbia Journal of European Law Online (2009), see website: http://www.cjel.net/online/15-2-liu/.
61. Ulla Neergaard, "EU Health Care Law in a Constitutional Light: Distribution of Competences, Notions of 'Solidarity', and 'Social Europe' ", in: J.W. van de Gronden, E. Szyszcak, U. Neergaard and M. Krajewski (Eds.), Health Care and EU Law (Asser Press, The Hague, 2011), p. 24.
62. Neergaard refers to T.K. Hervey and J.V. McHale, Health Law and the European Union, (Cambridge University Press, 2004), Chapter 3.
63. The objective of the proposed regulation according to recital 66 is "to ensure that, throughout the Union, clinical data are reliable and robust while ensuring the safety and rights of subjects."
64. Art. 5 Treaty on European Union and Protocol No. 2 on the application of the principles of subsidiarity and proportionality.
65. Cf. H. Busy, T. Hervey and A. Mohr, "Ethical EU law? The influence of the European Group on Ethics in Science and New Technologies", European Law Review 33 (2008) 820.
66. P. 13.
67. Moreover, recital 12 of the proposed regulation reads: "Some aspects in a clinical trial application relate to issues of an intrinsic national nature or to ethical aspects of a clinical trial.
68. Those issues should not be assessed in cooperation among all Member States."
69. The European Group on Ethics in Science and New Technologies (EGE) has made a critical statement as to the ethics in the proposed regulation.
70. This critical view may play an important role in the ethical assessment and thus the political support for the proposed regulation.
71. References:-Statement of the European Group on Ethics in Science and New Technologies (EGE) on the Proposal for a Regulation of the European Parliament and the Council on Clinical Trials on Medicinal Products for Human Use, and repealing Directive 2001/20/EC (COM 2012) 369 final.
72. See the EGE website: http://ec.europa.eu/bepa/european-group-ethics/docs/ pdf/proposal-for-a-regulation-of-the-european-parliament-and-the-council-on- clinical-trials-on-medicinal-products-for-human-use.pdf.
73. The mission of the EGE is stated in article 2 of its Mandate 2011-2016: "The task of the EGE shall be to advise the Commission on ethical questions relating to sciences and new technologies, either at the request of the Commission or on its own initiative.
74. The Parliament and the Council may draw the Commission's attention to questions which they consider to be of major ethical importance."
75. See the EGE website: http://ec.europa.eu/bepa/european-group-ethics/ welcome/mandate-2011-2016/index-en.htm.
76. See also: H. Busy, T. Hervey and A. Mohr, "Ethical EU law? The influence of the European Group on Ethics in Science and New Technologies", European Law Review 33 (2008) 803-842.
77. The writers conclude in their article that the EGE increasingly "is playing the role of broker between those parts of the EU legislature and executive, and stakeholders, such as industry
78. that seek to enhance the regulatory environment for the development of new biotechnologies within the European Union, and those parts of the legislature and European citizenry who are suspicious of the ethical adequacy of such a regulatory environment." p. 835.
79. The Commission might seem somewhat inconsistent when it acknowledges that "science and ethics cannot be separated.
80. See supra note 2, Explanatory Memorandum, p. 5.
81. Cf. the remark of the EGE in its statement that "Aspects covered by Part I contain information essential to an ethically sound evaluation of the proposed clinical trial.
82. e.g. sample size, randomisation, comparator, its clinical and statistical relevance.
83. Evaluation of these aspects is crucial for the protection of research participants from harm and unnecessary risk, aspects that are at the core of ethical evaluation of medical research." See supra note 52, p. 1.
84. The EGE also notes that a Member State may have ethically valid reasons to object to a trial: "For example differences in e.g. antibiotic resistance of bacteria might make a study ethically relevant in one country but might do more harm than benefit in another."
85. See supra note 52, p. 3.
86. Art. 9.
87. The requirement of a multi-disciplinary evaluation of clinical research was established in the second version of the Helsinki Declaration in 1975.
88. This is mentioned in the Statement of the EGE, see supra note 52, p. 2.
89. The European Economic and Social Committee also calls for "explicit inclusion in the regulation of assessments by an independent ethics committee (in line with the requirements of the Paragraph 15 of the Declaration of Helsinki, Chapter II of the Proposal and Directive 2001/20/EC).
90. The ethical assessment is a critical part in the authorisation process of clinical trials to ensure patients' rights are respected.
91. An approval of a clinical trial should not be granted until an independent ethics committee has issued a favourable opinion."
92. See supra note 7, par. 1.7.
93. Convention for the Protection of Human Rights and Dignity of the Human Being with regard to the Application of Biology and Medicine: Convention on Human Rights and Biomedicine, Oviedo, 4 April 1997, ETS no. 164.
94. Article 16(iii) includes as a condition for undertaking research on a person that "the research project has been approved by the competent body after independent examination of its scientific merit, including assessment of the importance of the aim of the research, and multidisciplinary review of its ethical acceptability."
95. In par. 100 of the Explanatory Report to the Convention this body is referred to as an "independent multi-disciplinary ethics committee."
96. Additional Protocol to the Convention on Human Rights and Biomedicine, concerning Biomedical Research, Strasbourg, 25 January 2005.
97. Article 9(1) states that "every research project shall be submitted for independent examination of its ethical acceptability to an ethics committee."
98. Article 3.2 of the ICH Topic E 6 (R1) Guideline for Good Clinical Practice: Step 5: Note for guidance on Good Clinical Practice. (July 2002 CPMP/ICH/135/95).
99. Directive 2005/28/EC states that the approach for Good Clinical Practice of the International Conference on Harmonisation (ICH), as published by the European Medicines Agency should be taken into account (recital 8).
100. The EGE recommends: "Set realistic timelines which should serve to expedite the process while allowing a robust consideration of the issues.
101. See supra note 52 p. 4.
102. The EESC mentions that the timelines "are clearly to be regarded as too short and therefore they should be extended."
103. See supra note 7, par. 3.8
104. see par. 4.6 for specific proposed extensions of time limits.
105. See for instance, Art. 5(3) in the validation phase, Art. 8(4) in the decision making phase.
106. The European Journal of Health Law published a number of articles about clinical trials on minors and incapacitated subjects over the years.
107. See for instance: H.D.C. Roscam Abbing, 'Medical Research Involving incapacitated persons: what are the standards?,' European Journal of Health Law 2 (1994)147-158;
108. A. Bayens, 'Implementation of the clinical trials directive, pitfalls and benefits,' European Journal of Health Law 1 (2002) 31-47;
109. J.K.M Gevers, 'Medical research involving children,' European Journal of Health Law 2 (2008) 103-108.
110. Moreover, this issue (2008, nr. 2) is wholly dedicated to clinical trials on minors;
111. H.D.C. Roscam Abbing, 'Patients in a technology and market driven Europe,' European Journal of Health Law 1 (2010) 16-18;
112. C.M. de Klerk, 'Protection of incapacitated elderly in medical research,' European Journal of Health Law 4 (2012) 367-378.
113. Art. 3(1) of directive 2001/20/EC states that the directive shall apply "without prejudice to the national provisions on the protection of clinical trial subjects if they are more comprehensive than the provisions of the Directive and consistent with the procedures and time-scales specified therein."
114. See the EFGCP Report on The Procedure for the Ethical Review of Protocols for Clinical Research Projects in Europe, updated report of April 2012.
115. Question 36 relates to research on healthy volunteer children. See the EFGCP website: http://www.efgcp.be/efgcpreports.asp?l1=5&l2=1.
116. Art 31(1)(f ) of the proposed regulation states as a condition for research on minors: "such research either relates directly to a medical condition from which the minor suffers or is of such a nature that it can only be carried out on minors."
117. See supra note 58.
118. See supra note 59.
119. For example, in The Netherlands the restrictions on non-therapeutic medical research with minors and incapacitated subjects requires that the research is always group-related and the risks are negligible and the burden is minimal
120. see Article 4(1) of the Dutch Medical Research Involving Human Subjects Act.
121. However, recently a bill was submitted to Dutch Parliament setting this threshold lower to the extent that burden and risk are limited to a 'minor increase over minimal' (Kamerstukken II 2012/2013, 33 508, nr. 2).
122. See supra note 58.
123. EU Member States that have signed and ratified the Convention include Bulgaria, Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Greece, Hungary, Latvia, Lithuania, Portugal, Romania, Slovakia, Slovenia and Spain.
124. Luxembourg, Italy, Poland and The Netherlands have signed but not yet ratified the Convention.
125. For an up-to-date overview of all the countries that have signed the Convention see the COE website: http://conventions.coe.int/Treaty/Commun/ ChercheSig. asp?NT=164&CM=&DF=&CL=ENG.
126. See supra note 59.
127. Only a few EU Member States have signed and ratified this Protocol: Bulgaria, Hungary, Slovakia and Slovenia.
128. Cyprus, Denmark, Greece, Portugal, Romania and Sweden have signed but not yet ratified the Protocol.
129. For an up-to-date overview see the COE website: http://conventions. coe.int/Treaty/en/Treaties/Html/195.htm.
130. Art. 15 (2)(ii) of the Protocol.
131. Moreover the description of minimal risk and minimal burden in Article 17 of the Protocol further defines the threshold of acceptable risk and burden
132. for the purposed of this Protocol it is deemed that the research bears a minimal risk if, having regard to the nature and scale of the intervention
133. it is to be expected that it will result, at the most, in a very slight and temporary negative impact on the health of the person concerned.
134. It is deemed that it bears a minimal burden if it is to be expected that the discomfort will be, at the most, temporary and very slight for the person concerned.
135. In assessing the burden for an individual, a person enjoying the special confidence of the person concerned shall assess the burden where appropriate.
136. Art. 27 Declaration of Helsinki, October 2008.
137. Art. 30(1)(h).
138. European Parliament resolution of 19 January 2011 on a European initiative on Alzheimer's disease and other dementias (2010/2084(INI)).
139. Art. 30 (1)(c), 31 (1)(c).
140. These provisions are largely the same as the Articles 4(c) and 5(c) in directive 2001/20/EC.
141. Art 17(1)(v) of the Biomedicine Convention and Art. 15 (1)(v) of the Additional Protocol.
142. It is stated in the Explanatory Report to the Biomedicine Convention (ETS No. 164) that "the person concerned does not object (the wish of the person concerned prevails and is always decisive)," par. 108.
143. Art. 28 Declaration of Helsinki, October 2008.
144. Cf. L. Bergkamp, "Medical Research Involving Human Beings: Some Reflections on the Main Principles of the International Regulatory Instruments", European Journal of Health Law, 11 (2004) 64.
145. Clinical studies other than on medicinal products remain regulated on the basis of national legislation of the Member States.
146. From a principled point of view it is hard to defend why a different set of criteria should be applicable to non-medicinal and medicinal clinical trials, respectively.
147. Moreover, the Commission has proposed a regulation on medical devices and a regulation on in vitro diagnostic medical devices
148. both of which contain only very general criteria for the assessment of clinical trials: Regulation of the European Parliament and of the Council on medical devices, and amending Directive 2001/83/EC, Regulation (EC).
149. No 178/2002 and Regulation (EC) NO 1223/2009 of 26 September 2012, COM(2012) 542 final, and in the Proposal for a Regulation of the European Parliament and of the Council on in vitro diagnostic medical devices of 26 September 2012, COM(2012) 541 final.
150. Proposed regulation, see supra note 2, recital 63.
151. The World Medical Association (WMA) sent a letter to the European Parliament dated 7 February 2013 on the proposed regulation and stated-among other things-that it is "deeply concerned that the current draft regulation leads to a significant paradigm shift that risks putting economic interests before ethics."
152. See the WMA website: http://www.wma.net/en/45blogs/2013-pblog28/EU-CTR- MEPs.pdf
153. Cf. the illuminating chapter on the role of risk, ethics, rights and markets as framing devices for the EU's regulation of new health technologies.
154. G. Bache, M.L. Flear and T.K. Hervey, "The Defining Features of the European Union's Approach to Regulating New Health Technologies.
155. M.L. Flear, A. Farrell, T.K. Hervey, T. Murphy , European Law and New Technologies (Oxford: OUP, 2013).
156. Their conclusion is that "markets are key to the EU approach to regulation of new health technologies" (p. 41).