Medical research involving incapacitated adults: Implications of the EU clinical trials directive 2001/20/EC

Medical Law Review

Volumn 14, Issue 3, 2006, Pages 367-417

  Liddell, Kathleen ^a   Bion, Julian ^b   Chamberlain, Douglas ^c   Druml, Christiane ^d   Kompanje, Erwin ^e   Lemaire, Francois ^f   Menon, David ^a   Vrhovac, Bozidar ^g   Wiedermann, Christian J ^h  

^a UNIVERSITY OF CAMBRIDGE   (United Kingdom)

^b UNIVERSITY OF BIRMINGHAM   (United Kingdom)

^c CARDIFF UNIVERSITY SCHOOL OF MEDICINE   (United Kingdom)

^d MEDICAL UNIVERSITY OF VIENNA   (Austria)

^e ERASMUS MEDICAL CENTER   (Netherlands)

^f HENRI MONDOR HOSPITAL   (France)

^g UNIVERSITY OF ZAGREB   (Croatia)

^h INNSBRUCK MEDICAL UNIVERSITY   (Austria)

Author keywords

[No Author keywords available]

Indexed keywords

ARTICLE; CLINICAL TRIAL; CONFLICT OF INTEREST; CUSTODY; DISABLED PERSON; ETHICAL THEORY; EUROPEAN UNION; FINANCIAL MANAGEMENT; HUMAN; HUMAN EXPERIMENT; INFORMED CONSENT; LEGAL ASPECT; MENTAL CAPACITY; RESEARCH ETHICS; RISK ASSESSMENT; UNITED KINGDOM;

CLINICAL TRIALS; CONFLICT OF INTEREST; DISABLED PERSONS; ETHICAL THEORY; ETHICS, RESEARCH; EUROPEAN UNION; GREAT BRITAIN; HUMANS; INFORMED CONSENT; MENTAL COMPETENCY; PROXY; RESEARCH SUPPORT; RISK ASSESSMENT; THERAPEUTIC HUMAN EXPERIMENTATION;

EID: 33750529955     PISSN: 09670742     EISSN: 14643790     Source Type: Journal    
DOI: 10.1093/medlaw/fwl011     Document Type: Article

References (270)

1. This article arises out of: 'Report of the 1st Meeting of the Vienna Initiative to Save European Academic Research' (2006) 118 Wiener Klinische Wochenschrift Supplementum 1.
2. E.g. Directive 2001/20/EC (Clinical Trials Directive); Directive 95/46/ EC (Data Protection Directive); Human Tissue Act 2004; Mental Capacity Act 2005; Data Protection Act 1998; Health and Social Care Act 2001 (s. 60); The Medicines for Human Use (Clinical Trials) Regulations 2004; P. Klepstad, A. Dale, 'Further Restrictions for ICU Research' (2006) 32 Intensive Care Medicine 175 (on Norwegian biobanks).
3. E.g. Academy of Medical Sciences, European Clinical Trials Directive - A Summary of Papers Presented at the Symposium Organised by the Academy Forum on 3 June 2003 (London, 2003)
4. Anon, 'Red Tape Poses Threat to Research' BBC News (20/01/2004)
5. B. Gennery, 'Academic Clinical Research in the New Regulatory Environment' (2005) 5(1) Clinical Medicine 39-41
6. E. Munro et al., 'Researching Vulnerable Groups: Ethical Issues and the Effective Conduct of Research in Local Authorities (2005) 35 British Journal of Social Work 1023-1038
7. A. Abbott, 'Europe's Researchers Up in Arms Over Clinical-Trial Rules (2004) 427 Nature 276.
8. Earl Howe, Hansard (House of Lords) 11 May 2006 col. 1136.
9. A. Grienenberger, 'Establishing pan-European Clinical Trials: Regulatory Compliance and Other Practical Considerations' (2004) 7(4) Journal of Biolaw and Business 58-63
10. X. Bosch, 'Europe's Restrictive Rules Strangling Clinical Research' (2005) 11 Nature Medicine 1260
11. O. O'Neill, 'Some Limits of Informed Consent' (2003) 29 J.M.E. 4-7
12. K. Liddell and A. Hall, 'Beyond Bristol and Alder Hey: The Future Regulation of Human Tissue' (2005) 13 Med.L.Rev. 170, 194-201, 220-223
13. Academy of Medical Sciences, Personal Data for Public Good: Using Health Information in Medical Research (2006)
14. A. Iversen et al., 'Consent, Confidentiality, and the Data Protection Act' (2006) 332 B.M.J. 165-169
15. S. Kerrison et al., 'United Kingdom Research Governance Strategy' (2003) 327 B.M.J. 553, 556
16. D. Torgerson, J. Dumville, 'Rapid Response-Research Governance also Delays Research' (2004) 328 B.M.J. 710.
17. R. Rhodes, 'Rethinking Research Ethics' (2005) 5(1) AJOB 7, 7-28
18. K. Maschke, 'Reconciling Protection with Scientific Progress' (2005) 35(5) Hastings Center Report 3
19. J. O'Herrin et al., 'Health Insurance Accountability Act (HIPAA) Regulations: Effect on Medical Record Research' (2004) 239 Annals of Surgery 772.
20. Baroness Hayman, Hansard (House of Lords) 5 May 2006, col. 1104
21. Department of Trade and Industry, Science and Innovation Investment Framework 2004-2014: Next Steps (2006) 4, 6.
22. E.g. D. Evans et al., 'Human Guinea Pigs Pay for Lax FDA Rules' Seattle Times (21 November 2005) http://seattletimes.nwsource.com/html/health/ 2002606640_drugtesting06.html (last visited 31/05/06).
23. J. Hoffman, 'Rapid Response to - Regulations are Stifling Development of New Drugs' (2004) 328 B.M.J. 600-a.
24. E.g. The healthy volunteer trial at Northwick Park Hospital London in which six participants suffered life-threatening adverse reactions: A. Lansley and J. Kennedy, Hansard (House of Commons) 27 March 2006, col 810W (also 19 April 2006)
25. MHRA, Investigations into Adverse Incidents during Clinical Trials of TGN1412 (25 May 2006).
26. See also BBC 2, Trial and Error - Horizon Programme Script (2003) http://www.bbc.co.uk/science/horizon/2003/trialerrortrans.shtml (gene therapy trials)
27. R. Nicholson, 'Paternalism No Problem' (1992) 22(4) Hastings Center Report 4-5 (UK breast cancer trials)
28. A. Plomer, The Law and Ethics of Medical Research (London 2005) 45-46 (sarin experiments)
29. R. Steinbrook, 'Protecting Research Subjects - the Crisis at John Hopkins, (2002) 346 N.E.J.M. 716
30. R. Macklin, Double Standards in Medical Research in Developing Countries (2004).
31. E.g. H. Beecher, 'Ethics and Clinical Research' (1966) 274 N.E.J.M. 1354-1360.
32. Directive 2001/20/EC 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 (OJ L 121/34; 1 May 2001).
33. F. Lemaire et al., 'The European Union Directive on Clinical Research: Present Status of Implementation in EU Member States' Legislation with Regard to the Incompetent Patient' (2005) 31 Intensive Care Medicine 476-479.
34. The Council of Europe agreed a Convention on Human Rights and Biomedicine in Oviedo in 1997 ('Oviedo Convention'). Article 17 relates specifically to research with IAs. The Council subsequently worked on an Additional Protocol ('Additional Protocol to the Oviedo Convention') that addresses research involving IAs in more detail. It was finally agreed in 2005. Given that the majority of European Member States have ratified the Convention and the Additional Protocol bears a close resemblance to the Declaration of Helsinki, it is remarkable that Article 5 of CTD differs in striking ways: See below Section II-B and III-A (on clinical equipoise), Section III-B (on permitted investigations) and Section III-D (on emergency research).
35. In practice, it can be difficult to establish whether an adult is capable of giving legal consent. For reasons of space this issue is not discussed in this article. See generally: M. Gunn, 'Decision-making Capacity' (1999) 7 Med.L.Rev 269-306
36. British Medical Association and Law Society, Assessment of Mental Capacity: Guidance for Doctors and Lawyers (2004).
37. In fact, some of our recommendations would strengthen the protection of patient-subjects: See Sections II, III-A, III-C, III-E.
38. See references op.cit., n.15.
39. Background literature: Plomer, op.cit., n.10, 43-65
40. J. McHale, 'Clinical Research' in A. Grubb (ed.), Principles of Medical Law (2004) 853, 869-889
41. BMA, op.cit., n.15
42. P. Lewis, 'Procedures that are Against the Medical Interests of Incompetent Adults' (2002) 22 Oxford Journal of Legal Studies 575-618
43. J.K. Mason et al., Law and Medical Ethics (2002) 571-593
44. P. Moodie, M.Wright, 'Medical Research and Alzheimer's Disease: A Study of the Hazards of Conducting Research on the Incompetent Patient' (1997) 2 Medical Law International 291-313
45. D. Giesen, 'Civil Liability of Physicians for New Methods of Treatment and Experimentation: A Comparative Examination' (1995) 3 Med.L.R. 22-52.
46. The drugs produce atypical responses due to differences in brain development and maturity. For instance people with Down's syndrome have a high risk for developing Alzheimer's disease with prevalence rates reaching 50% as early as 50-60 years of age. Small trials of anti-dementia medication have shown some benefit but also the possibility of some increase in confusion. It is increasingly important to establish whether these medications are beneficial in this client group and whether side-effects are similar or different. It also seems that the progression of dementia may be different in the general population compared with those with Down's syndrome who have Alzheimer's disease, which itself warrants further study: Correspondence A. Holland, Professor in Developmental Psychiatry, University of Cambridge (11/05/ 2006).
47. Anti-psychotics may offer neurological and cognitive benefits to schizophrenic patients but evidence is accumulating of problems with diabetes, lipid dysregulation, metabolic syndromes and sexual side effects: A. Mitchell and D. Malone, 'Physical Health and Schizophrenia' (2006) 19 Current Opinion Psychiatry 432-437.
48. Only 3% receive tissue plasminogen activator. The remaining 97% receive no specific therapy because t-PA must be administered within a few hours and is currently associated with dangerous side effects. Research is needed to find safe and practical therapies for these patients: A. Rogalewski et al., 'Toward a Multinodal Neuroprotective Treatment of Stroke' (2006) 37 Stroke 1129-1136.
49. P. Edwards et al., 'Final Results of MRC CRASH: A Randomised Placebo-controlled Trial of Intravenous Corticosteroid in Adults with Head Injury Outcomes at 6 Months' (2005) 365 Lancet 1957-1959.
50. J. Herlitz et al., 'Factors Associated with Survival to Hospital-Discharge Among Patients Hospitalised Alive After Out-of-Hospital Cardiac Arrest' (2003) 89 Heart 25-30.
51. E. Kompanje et al., 'Ethical Considerations on Consent Procedures for Emergency Research in Severe and Moderate Traumatic Brain Injury' (2005) 147 Acta Neuochir 633.
52. G. Bernard et al., 'Recombinant Human Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) Study Group. Efficacy and Safety of Recombinant Human Activated Protein C for Severe Sepsis' (2001) 344 N.E.J.M. 699-709.
53. The Acute Respiratory Distress Syndrome Network, 'Ventilation with Lower Tidal Volumes as Compared with Traditional Tidal Volumes for Acute Lung Injury and the Acute Respiratory Distress Syndrome' (2000) 342 N.E.J.M. 1301-1308.
54. G. van den Berghe et al., 'Intensive Insulin Therapy in the Critically Ill Patients' (2001) 345 N.E.J.M. 1359-1367.
55. S. Bernard et al., 'Treatment of Comatose Survivors of Out-of-hospital Cardiac arrest with Induced Hypothermia' (2002) 346 N.E.J.M. 557-563
56. Hypothermia after Cardiac Arrest Study Group, 'Mild Therapeutic Hypothermia to Improve the Neurologic Outcome After Cardiac Arrest' (2002) 346 N.E.J.M. 549-556.
57. CRASH Trial Management Group, 'Research in Emergency situations: With or Without relatives Consent' (2004) 21 Emergency Medicine Journal 703.
58. For a general review see: A. Baeyens, 'Implementation of the Clinical Trials Directive: Pitfalls and Benefits' (2002) 9 European Journal of Health Law 31-47
59. Special Report, op.cit., n.1.
60. E.g. CTD Articles 9, 10.
61. CTD Articles 16, 17, 18.
62. CTD Article 13.
63. CTD Article 9.
64. CTD Article 14.
65. CTD Article 15.
66. CTD Article 12.
67. CTD Article 11.
68. CTD Article 10.
69. CTD Article 3.
70. CTD Article 3.
71. CTD Article 6.
72. E.g. Ethics committees and competent authorities have a maximum of 60 days to make a decision on the acceptability of a clinical trial protocol: Articles 6, 9.
73. CTD Articles 3, 5.
74. CTD Articles 3, 4, 5.
75. CTD Article 2(a), 2(c) and 2(d).
76. One of the initial steps was to agree a set of guidelines on Good Clinical Practice for Trials on Medicinal Products in the European Community (GCP) in July 1990. However, this was considered inadequate because the guidelines themselves had no legally binding effect, Member State laws could displace the standards, the standards were not democratically accountable, the power to carry out inspections to ensure compliance with GCP was unclear, and there were no penalties for breaches. An article proposing a binding Directive was circulated in 1991 even before the GCP guidelines had been implemented: D. Sprumont, 'Legal Protection of Human Research Subjects in Europe' (1999) 6 European Journal of Health Law 25, 33. The CTD echoed this history. Once agreed, and even before Member States had transposed it, the Council and Parliament were at work preparing further Directives to expand on the meaning of 'good clinical practice' and 'good manufacturing practice'. These were agreed in 2003 ('the Good Manufacturing Directive' 2003/94/ EC) and 2005 ('the Good Clinical Practice Directive' 2005/28/EC). Another example is that UK government implemented the CTD in 2004, but recognised the need to amend aspects of the Regulations which restricted emergency research within a year: See Section III-D and the Medicines for Human Use (Clinical Trials) Amendment Regulations 2006.
77. World Medical Association, Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects (1964). The Declaration was first published in 1964 in an attempt to extend and remedy the problems of the Nuremberg Code 1949 (e.g. the Code, prepared by lawyers, inadvertently prohibited all research with incompetent adults). Over the years, the Declaration has been amended several times most recently in 2000 and in Notes of Clarification in 2002 and 2004. It has been described as 'the most widely accepted guidance worldwide on medical research involving human subjects': See generally D. Human and S. Fluss, 'The World Medical Association's Declaration of Helsinki: Historical and Contemporary Perspectives' (2001, fifth draft) http://www.wma.net/e/ ethicsunit/pdf/draft_historical_contemporary_perspectives.pdf.
78. European Medicines Agency, ICH Topic E6 Note for Guidance on Good Clinical Practice CPMP/ICH/135/95 (2002).
79. More fully, the 'International Conference on Harmonisation of Technical Requirements for the Registration of Pharmaceuticals for Human Use'.
80. See generally: Sprumont, op.cit., n.47, 29
81. D. Kidd, 'The International Conference on Harmonisation of Pharmaceutical Regulations, the European Medicines Evaluation Agency, and the FDA: Who's Zooming Who?' (1996) 4 International Journal of Global Legal Studies 183.
82. Note that the Article 5 conditions do not apply where an individual gives or refuses consent prior to the onset of their incapacity. This is assumed throughout the rest of the article.
83. Under English common law, a researcher was potentially liable in battery or negligence for acts done to an IA which normally require consent if those acts were not consistent with their 'best interests' and the Bolam principle; the assent of the IA's spouse or family member was not lawful justification. This was widely interpreted to mean that the anticipated benefits of research (direct or indirect) needed to outweigh the anticipated disbenefits. Accordingly, so-called 'non-therapeutic research' was not considered to meet the best interests test (see Law Commission, Mental Incapacity (HMSO, 1995)
84. BMA op.cit., n.15). Thus, the common law excluded a variety of research regarded as ethical by the profession including research with healthy IAs which involves no more than biometric measurements, observational studies in nursing homes, genetic studies of adults with learning disabilities and other epidemiological studies involving blood, saliva or tissue samples. That said, the standard interpretation had not been tested in a case involving medical research (as distinct from innovative therapy where the best interests test can be applied straightforwardly: Simms v. Simms [2003] Fam 83). Thus many chose to overlook or to comply creatively with prevailing legal rules. In future, the Clinical Trial Regulations 2004 which transpose the CTD will govern clinical drug trials involving IAs, and the Mental Capacity Act 2005 will cover other research where consent is normally required. Neither requires the best interests test to be applied in situations of research. Both state that the interests of the individual outweigh those of science and society and require (inter alia) consent from legal representatives.
85. Academy of Medical Sciences (2003), op.cit., n.3, 6.
86. Department of Health and MRC, Clinical Trial Tool Kit http://www.ct-toolkit.ac.uk/ (last visited 31/05/06).
87. A B.M.J. editorial in 2006 argues that the number of new academic trials for cancer studies has dropped by 63%: A. Hemminki and P. Kellokumpu-Lehtinen, 'Harmful Impact of EU Clinical Trials Directive' (2006) 332 B.M.J. 501.
88. Some Member States have applied similar strict principles to research based on human tissue, health records and pathophysiological observations despite the lower risks: Lemaire et al., (2005), op.cit., n.13.
89. R. Watson, 'Scientists Beg EU to Repeal New Rules for Clinical Trials' (2004) 328 B.M.J. 187
90. AMS (2003), op.cit., n.3, 6.
91. Lemaire et al., (2005), op.cit., n.13. Some Member States have not clearly excluded challenge agents, mechanistic studies or research on medical devices.
92. M. Daniels, 'Impact of the Clinical Trials Directive on the Research-based Pharmaceutical Industry' (2003),
93. AMS op.cit., n.3, 11-12.
94. A special regulation has been proposed to facilitate commercial sector research on medicines for children. A similar step has yet to be taken for incapacitated adults although the problems are comparable in many respects: Commission Communication regarding the Council Common Position on the paediatric regulation COM(2006) 118 (13/03/06).
95. Medicines and Health products Regulatory Agency ('MHRA'), Consultation on Implementation of the European Commission's Directive on Good Clinical Practice (2005/28/EC) MLX 328 (2005).
96. See also: European Commission, Draft Guidance on 'specific modalities' for non-commercial clinical trials (June 2006).
97. US National Bioethics Advisory Commission ('NBAC'), Research Involving Persons with Mental Disorders That May Affect Decisionmaking Capacity (1998)
98. NBAC, Ethical and Policy Issues in Research Involving Human Participants (2001). The reports came about as a result of gaps, uncertainties, heterogeneity and inconsistent rulings in US law in the 1980s and 90s. They are more detailed and persuasive than any report undertaken in Europe.
99. Where the CTD sets stricter constraints than the Convention and its Protocol, Member States must abide by the CTD.
100. National Commission, The Belmont Report: Ethical Principles and Guidelines for Protection of Human Subjects of Biomedical and Behavioural Research (1979). This report not only explained the boundaries between practice and research, but set out an ethical framework - based on respect for persons, beneficence and justice - that revolutionised medical research and clinical practice. The National Commission also wrote a report in 1978 on Research Involving Those Institutionalized as Mentally Infirm. It rejected both the complete ban in the Nuremberg Code and the restrictions in the 1964 Helsinki Declaration, and proposed a framework that allowed research even where it offered no potential direct benefit to the individual provided the burdens and risks of research did not exceed a certain level.
101. Belmont Report, op.cit., n.63.
102. For example, the patient may not have his drug dosage raised or lowered even when the change might suit him; he may be required to forgo helpful medications during a 'washout period'; he may be denied drugs that treat side effects such as decongestants or sleeping pills; or he may be required to remain in hospital for a longer period.
103. F. Lemaire, 'Patient Care Versus Research: Does Clinical Research Provide Individual Benefit to Patients Enrolled in Trials' (2004) 10 Current Opinion in Critical Care 565, 565.
104. R. Levine, 'The Need to Revise the Declaration of Helsinki' (1999) 341 Lancet 531-534.
105. NBAC recommended that when assessing risky procedures one should separately assess those risks that present a prospect of direct medical benefit and those that do not: 'Although these categories may seem to imply a distinction between 'therapeutic' and 'non-therapeutic' [research], that is not the case and, in fact, is a serious misconception': [NBAC (1998), op.cit., n.61, 8]. It expanded on this in its 2001 report: 'In general, each component of a study should be evaluated separately, and its risks should be both reasonable in themselves as well as justified by the potential benefits to society or the participants. Potential benefits from one component of a study should not be used to justify risks posed by a separate component of a study': NBAC (2001), op.cit., n.61, recommendation 4.1.
106. C. Weijer, 'The Ethical Analysis of Risk in Intensive Care Unit Research' (2004) 8 Critical Care 85.
107. Lemaire (2004), op.cit., n.66, 567-568.
108. C. Weijer and P. Miller, 'When are Research Risks Reasonable in Relation to Anticipated Benefits?' (2004) 10(6) Nature Medicine 570-573
109. A. McRae and C. Weijer, 'Lessons from Everyday Lives: A Moral Justification for Acute Care Research' (2002) 30 Critical Care Medicine 1146-1148
110. C. Freedman et al., 'Demarcating Research and Treatment: A Systematic Approach for the Analysis of the Ethics of Clinical Research' (1992) 40(4) Clinical Research 653-660
111. C. Weijer, 'Ethical Analysis of Risk' (2000) 28 J.L.M.E. 344-361.
112. A placebo control should be regarded as a special kind of therapeutic component. (Correspondence P. Miller, 14/05/06).
113. Sometimes a procedure may appear to be geared both to therapy and research. For example, a single blood sample might be analysed for both clinical and research purposes, or a doctor might reflect upon the implications of a patient's therapy for future patients. These situations are simple enough to resolve. If the physician's conduct is constrained by the individual's well being so that his dual purpose presents no conflict of interest and there is a reasonable expectation that what he is doing may benefit the specific IA, the activity is a therapeutic component.
114. Typical examples of research components include randomisation (particular patients might prefer treatment A or B), enrolment (this takes up the subject's time and probably involves them giving over additional personal information), delivery of a set dosage (ordinarily the doctor would adjust the dosage if it seemed to suit the patient), and special monitoring (the subject might be asked to provide special blood or urine samples, to return to hospital for follow up tests or in some circumstances to be X-rayed, etc.)
115. That is, the physician-researcher must demonstrate that the risks associated with the clinical components are equivalent to the risks that doctors normally undertake in clinical care - the anticipated benefits should outweigh the risks.
116. P. Appelbaum et al., 'False Hopes and Best Data: Consent to Research and the Therapeutic Misconception' (1987) 17 Hastings Center Report 20.
117. Lemaire (2004), op.cit., n.66, 565.
118. In these scenarios, an aggregate risk analysis would find no clinical benefit to weigh against the research risk so the risk ratio would be negative.
119. For one exception: I. Kennedy, 'Consent and Randomized Controlled Trials' in I. Kennedy (ed.), Treat me Right - Essays in Medical Law and Ethics (1992) 213.
120. The principle is also mentioned obliquely in: Mason et al., op.cit., n.18, 579.
121. B. Freedman, 'Equipoise and the Ethics of Clinical Research' (1987) 317 N.E.J.M. 141
122. C. Weijer and E.J. Emmanuel, Protecting Communities in Biomedical Research (2000) 289 Science 1142
123. P. Miller and C. Weijer, 'Rehabilitating Equipoise' (2003) 13 Kennedy Institute of Ethics Journal 93.
124. For similar reasons, the duty might extend to other health professionals, but it is typically associated with the people controlling a research project and the patient's clinical care (i.e. the doctors).
125. An explanation for this obligation is given below with reference to work by T. Ackermann and O. O'Neill: See below Section IV-C and IV-D.
126. In some jurisdictions the principle might also be argued to be a fiduciary obligation of a doctor: P. Miller and C. Weijer, 'Fiduciary Obligation in Clinical Research' (2006) 34(2) J.L.M.E. 424.
127. P. Alderson, 'Equipoise as aMeans of Managing Uncertainty: Personal, Communal and Proxy' (1996) 22 J.M.E. 135.
128. This is usually determined by the doctor's intuitions, the conventions at the institution where he or she works, or the resources at the patient's disposal.
129. Weijer (2004), op.cit., n.69, 86.
130. By the individual where possible (through mechanisms of consent) and other persons expert in risk analysis and research ethics.
131. Contrast the Helsinki Declaration which requires 'best methods' save in exceptional circumstances, and the Additional Protocol to the Oviedo Convention which requires 'proven methods'.
132. This is relevant not only to the legitimacy of starting the trial, but also the criteria for when it should end.
133. F. Gifford, 'Community Equipoise and the Ethics of Randomised Clinical Trials' (1995) 9 Bioethics 127.
134. Particular patients may have personal preferences which tip the balance in favour of one treatment. For instance, some women may be opposed to therapies that affect their body image such as mastectomy or hair loss: S. Botros, 'Equipoise, Consent and the Ethics of Randomised Clinical Trials' in P. Byrne (ed.), Ethics and Law in Health Care and Research (1990) 9, 16.
135. See generally: J. Meran, 'Consent and Equipoise, the Crucial Ethical Issues in Randomised Clinical Trials' (2003) 26 Onkologie 524-527.
136. F. Miller and H. Brody, 'A Critique of Clinical Equipoise: Therapeutic Misconception in the Ethics of Clinical Trials' (2003) 33 Hastings Center Report 19-28.
137. In an effort to make their case, Miller and Brody argue that the principle of clinical equipoise fails to appreciate the distinction between treatment and research, but in doing so they overlook the system of component analysis put forward by Weijer, op. cit., n.69. He and his co-authors are clearly cognisant of the distinction between research and therapy whilst joining others to advocate the importance of equipoise.
138. It is not clear which constraints beyond consent, if any, Miller and Brody would advocate.
139. Amended Helsinki Declaration, Article 15.
140. Some have suggested that if Miller and Brody's argument is accepted then an alternative safeguard against exploitation would be needed. Short of this, the argument should be rejected: L. Jansen and A. Closer, Look at the Bad Deal Trial: Beyond Clinical Equipoise' (2005) 35 Hastings Center Report 29, 31-34.
141. Amended Helsinki Declaration, Note of Clarification on Paragraph 29 (2002).
142. It recognises fewer exceptions but requires only that the physician guarantee 'proven methods' rather than 'best current methods': Additional Protocol to the Oviedo Convention, Article 23(2).
143. Ethical justifications for this stance are explained in more depth in Section IV.
144. See generally H. Silverman et al., 'The European Union Directive and the Protection of Incapacitated Subjects in Research: An Ethical Analysis' (2004) 30 Intensive Care Medicine 1723-1729.
145. Amended Helsinki Declaration Article 18.
146. Oviedo Convention Article 16(ii).
147. Oviedo Convention Article 17(1)(ii).
148. Additional Protocol to the Oviedo Convention Article 15(i).
149. The problems and irrationalities of aggregate risk analysis were explained above: Section II-A.
150. The phrasing is not as problematic for a physician-researcher who is more optimistic about the test-drug than the medical community. For instance, an individual investigator could honestly claim to observe the principle of clinical equipoise (it is measured against the views of medical community) whilst simultaneously expecting that the test-drug will be beneficial. This may absolve a few investigators from legal liability, but it will not absolve the majority (since, overall, the profession is uncertain whether the test-drug is better) and it does not resolve the difficulties of legal interpretation for research ethics committees or Member State authorities. The latter should adopt the objective stance of a reasonable hypothetical physican-researcher.
151. Except in equivalence trials where both arms are expected to have the same outcome.
152. In the same way that if one plucks a card from a full deck, there are 'grounds for expecting' the card selected will be a spade.
153. The issue is more controversial where proven therapies are expensive and hence not ordinarily available to research participants. The question is whether individuals should be offered the opportunity to participate in the trial (at least they receive an unproven drug rather than unaffordable therapy), or whether this unreasonably exploits their economic vulnerability.
154. See above Section II-A.
155. The CTD refers in particular to the 1996 version which casts doubts on amendments and clarifications made in 2000, 2002 and 2004. But officials have confirmed that the EMEA supports the line taken on placebo trials in the 2000 version of the Declaration: EMEA/CPMP Position Statement on the Use of Placebo in Clinical Trials with regard to the revised Declaration of Helsinki (EMEA/17424/01, 2001); B. van Zweiten-Boot, 'Choice of Control Groups' in Academy of Medical Sciences (2003), op.cit., n.3, 79.
156. See above Section II-A.
157. S. Mayer et al., 'Recombinant Activated Factor VII Intracerebral Hemorrhage Trial Investigators: Recombinant Activated Factor VII for Acute Intracerebral Hemorrhage' (2005) 352 N.E.J.M. 777-785.
158. McRae, Weijer (2002), op.cit., n.71, 1148-1149.
159. An ethical case for 'minimal risk' is explained below (see Section IV). Weijer also argues that it is consistent with a fiduciary's duty of care and parens patriae duties: Miller,Weijer (2006), op.cit., n.83
160. McRae,Weijer (2002), op.cit., n.71, 1149-1150.
161. ICH-GCP para 4.8.14.
162. NBAC (2001), op.cit., n.61, recommendation 2.5. It proposed stricter scrutiny where the research involved risks more than minimal.
163. The US Common Rule (45 CFR 46), which was issued by the DHHS in 1981 and codified in 1991, governs research involving IAs within the category of research with persons 'vulnerable to coercion or undue influence'. See especially: 45 CFR 46.102(i).
164. Amended Helsinki Declaration Article 28.
165. J. Karlawish and J. Hall, 'The Controversy over Emergency Research: A Review of the Issues and Suggestions for a Resolution' (1996) 153 American Journal of Critical Care Medicine 499, 501.
166. Once, that is, it is understood that minimal risk applies to the risks of research and not therapeutic components of the trial. A residual criticism is that the standard is too vague: NBAC (1998), op.cit., n.61, chapter 4 citing Loretta Kopelman.
167. NBAC (2001), op.cit., n.61, recommendation 4.2
168. NBAC (1998), op.cit., n.61, chapter 4.
169. McRae, Weijer (2002), op.cit., n.71, 1150. NBAC suggests that the general population be used as a benchmark because the risks faced in their daily lives are usually lower than those confronted by patients. NBAC added a caveat that if the study nonetheless poses higher risk for any prospective participants then the ethics committee should insist on additional safeguards.
170. Additional Protocol to the Oviedo Convention Article 17.
171. D. Wendler, 'Protecting Subjects Who Cannot Give Consent: Toward a Better Standard for 'Minimal' Risk' (2005) 35 Hastings Center Report 37, 40.
172. Further discussion is needed about the importance of these procedures in research with IAs. Perhaps the European legal framework should allow research risks slightly above minimal provided such research is subject to more rigorous scrutiny. Further discussion of the ethical legitimacy of such a framework would be required.
173. In fact, empirical studies show that legal representatives tend to reject research proposals more frequently than competent individuals: S. Mason et al., 'Brief Report on the Experience of Using Proxy Consent for Incapacitated Adults' (2006) 32 J.M.E. 61-62.
174. Karlawish and Hall, op.cit., n.121, 502.
175. E.g. Amended Helsinki Declaration Article 24.
176. Ibid.
177. It is generally unproblematic to read it more narrowly - for example that persons suffering from a stroke must not be involved in research unless it relates to treatments for stroke (or knowledge about strokes) - because physicians rarely want to involve IAs in other research. However, situations can be envisaged which demonstrate that the condition is not helpful. For example, a physician-researcher might propose a large-scale study to investigate the impact of socio-economic factors on the quality of proxy decision-making. He might propose to enrol a wide variety of IAs - some suffering stroke, cardiac arrest, sepsis, etc. The issue here is not to ensure that the patient-subjects suffer from the same condition, but that they have not been chosen because they are easy to exploit. There should be an independent, demonstrably valid reason for including them.
178. For a controversial study where insufficient preliminary studies were conducted: Huang http://www.hinduonnet.com/fline/fl1824/18241140.htm; http://www.hsph.harvard.edu/bioethics/archives/200108/msg00008.html
179. See e.g. Helsinki Declaration Article 24; ICH-GCP 4.8.14; Oviedo Convention Article 17(1)(ii); Additional Protocol Article 15(1)(ii), Mental Capacity Act 2005 s.31.
180. T. Aufderheide et al., 'Hyperventilation-induced Hypotension During Cardiopulmonary Resuscitation' (2004) 109 Circulation 1960-1965.
181. D. Menon and K. Liddell, 'Legislation and Research in Intensive Care and Emergency Medicine' (2004) 5(3) Journal of the Intensive Care Society 98-99.
182. Lemaire et al. (2005), op.cit., n.13.
183. E.g. J. Luce, 'California's New Law Allowing Surrogate Consent for Clinical Research Involving Subjects with Impaired Decision-making Capacity' (2003) 29 Intensive Care Medicine 1024, 1024-1025.
184. A personal representative is more likely to know whether the IA has special idiosyncrasies that are likely to affect theway they experience the research. For example, the magnitude of pain and anxiety may be much greater in an intellectually disabled person with a fear of needles than a 30-year-old diabetic. They may know that the IA has a duodenal ulcer, meaning an aspirin may (unusually) present more than minimal risk: Karlawish and Hall, op.cit., n.121, 502.
185. NBAC (1998), op.cit., n.61, text to recommendation 14.
186. See below Section IV-D.
187. MHRA, Draft Guidance on Consent by a Legal Representative on Behalf of a Person not Able to Consent Under the Medicines for Human Use (Clinical Trials) Regulations 2003 (2003) para 76
188. see the solution proposed: Ibid., para 77.
189. J. Tu et al., 'Impracticability of Informed Consent in the Registry of the Canadian Stroke Network' (2004) 350 N.E.J.M. 1414-1421.
190. Directive 95/46/EC Article 8(3), Recital 34. Also Articles 10, 11 (read in light of Recitals 38, 39).
191. See, for example, Directive 95/46/EC Recital 45 and Data Protection Act 1998 (UK) s.10, 33(2).
192. Oral consent in the presence of a witness is permitted if the individual is 'unable to write': CTD Article 3(2)(d). It is ambiguous whether a physician-researcher may proceed with research if he has managed only to contact an able-bodied, literate legal representative by telephone. The
193. V. De Maio et al., 'Optimal Defibrillation Response Intervals for Maximum Out-of-Hospital Cardiac Arrest Survival Rates' (2003) 42 Annals of Emergency Medicine 242-250.
194. Kompanje et al., (2005), op.cit., n.24.
195. Most severe traumatic brain injuries occur outside the domestic situation: D. Wright et al., 'Necessary Time to Achieve Next of Kin Proxy Consent for Acutely Injured Altered Status Patients' (2001) 8 Academic Emergency Medicine 419.
196. Kompanje et al., (2005), op.cit., n.24.
197. The average time to contact relatives of unconscious patients was 78 minutes: E. Kompanje and A. Maas, 'Treat First, Ask Later? Emergency Research in Acute Neurology and Neurotraumatology in the European Union' (2004) 30 Intensive Care Medicine 168-169.
198. McRae, Weijer (2002), op.cit., n.71, 1146.
199. Cardiac Arrest Study Group, op.cit., n.28.
200. Paras 3.1.7 and 4.8.15.
201. Amended Helsinki Declaration Article 26.
202. Additional Protocol to the Oviedo Convention Article 19.
203. See generally, J. Berg, 'Waiver of Informed Consent for Emergency Research' (1997) 1 Journal of Medicine and Law 1-29
204. B. Foëx, 'The Problem of Informed Consent in Emergency Medicine Research' (2001) 18 Emergency Medicine Journal 198-204.
205. McRae, Weijer (2002), op.cit., n.71, 1146-1150.
206. Ibid. 1146-1147.
207. 21 CFR 50.24; FDA Draft Guidance for Institutional Review Boards, Clinical Investigators, and Sponsors: Exception from Informed Consent Requirements for Emergency Research (2000) http://www.fda.gov/ora/ compliance_ref/bimo/err_guide.htm (last visited 25/05/06).
208. K. Kipnis et al., 'An Open Letter to IRBs Considering Northfield Laboratories' Poly-Heme Trial' (2006) 6(3) A.J.O.B. 1-4.
209. MHRA, op.cit., n.141, para 53.
210. See above Section II-A.
211. Op.cit., n.6.
212. The draft guidance is equivocal: MHRA, op.cit., n.141, para 47 ('may'); c.f. paras 65, 75.
213. It was thought that the test-drug might help break down the blood clots that begin to form during the infarction. These clots block the small blood vessels limiting recovery when resuscitation eventually takes place: F. Spohr et al., 'International Multicentre Trial Protocol to Assess the Efficacy and Safety of Tenecteplase During Cardiopulmonary Resuscitation in Patients with Out-of-hospital Cardiac Arrest: The Thrombolysis in Cardiac Arrest (TROICA) Study' (2005) 35 European Journal of Clinical Investigation 315-323.
214. A straw poll of paramedics who might have been involved in TROICA trial confirmed this issue. The situation in continental Europe differs since a doctor will usually be sent out with the ambulance.
215. Lemaire et al., (2005), op.cit., n.13.
216. §43a Arzneimittelgesetz.
217. The Medical Research Involving Human Subjects Act s.6(2)
218. A poster at the department, or a posting on the website is considered sufficient.
219. Lemaire et al. (2005), op.cit., n.13.
220. In relation to UK, Wales and Northern Ireland (not Scotland).
221. CTD Recital 5.
222. See MHRA, Consultation on Amendment to the Medicines for Human Use (Clinical Trials) Regulations 2004 (SI 2004/1031) MLX 326 (ended October 2005). It is planned that the revisions will also be implemented in Scotland.
223. Medical Research Council, Response to Consultation on the Amendment to the Medicines for Human Use (Clinical Trials) Regulations 2004. Some have suggested that 48 hours is the minimum practical time.
224. The proposal was delayed first by the political climate following the TGN1214 clinical trial disaster, and then again for unspecified reasons.
225. Kompanje et al. (2005), op.cit., n.24
226. Mason et al., op.cit., n.127, 61-62.
227. See e.g. on heterogeneity of structure and composition: The webpage of the research group known as 'Privireal' (Privacy in Research Ethics and Law) http://www.privireal.org/content/rec/countries.php (last visited 01/ 06/2006).
228. On the inconsistency of decisionmaking: H. Hearnshaw, 'Comparison of Requirements of Research Ethics Committees in 11 European Countries for a Non-invasive Interventional Study' (2004) 328 B.M.J. 140-141
229. P. Glasziou and I. Chalmers, 'Ethics Review Roulette: What Can We Learn?' (2004) 328 B.M.J. 121-122.
230. CTD Article 9(1). Responsibility for seeking an opinion rests with the sponsor.
231. A single suspension of time is allowed if the REC seeks additional information from the applicant. No extensions are permitted except a 30-day period where the trial involves certain kinds of genetic technology.
232. E.g. P. Wainwright and J. Saunders, 'What are the Local Issues? The Problem of the Local Review of Research' (2004) 30 J.M.E. 313-317
233. E. Cave and S Holm, 'New Governance Arrangements for Research Ethics Committees: Is Facilitating Research Achieved at the Cost of Participants' Interest?' (2002) 28 J.M.E. 318-321.
234. For example, one multinational research project, which proposed to survey the opinions of patients and their relatives on the ideal qualities of an intensive care doctor, was approved by ethics committees in eight Member States, but rejected twice by an UK multicentre research ethics committee (MREC) before being approved on appeal by a second MREC. However, the second MREC still required the local study coordinators to obtain approval from their local research ethics committees (LRECS) in each of ten participating hospitals: Relevant papers and correspondence with authors.
235. CTD Articles 5(d); 6(3)(j).
236. NBAC recommended two in its 1998 report: NBAC (1998), op.cit., n.61, Executive Summary.
237. For example, this might be a responsibility for the MHRA.
238. One of NBAC's specific recommendations was that a Special Standing Panel (SSP) should be established to review protocols referred by IRBs for research involving IAs: NBAC (1998), op.cit., n.61.
239. Utilitarians, typically define positive value as happiness, health, well being or preferences.
240. Lewis, op.cit., n.18, 616-617.
241. K. Liddell, Biolaw and Deliberative Democracy: Regulating Genetic Technology in a Morally Pluralist Society (DPhil thesis, University of Oxford, 2003)
242. K. Liddell and A. Hall, 'Beyond Bristol and Alder Hey: The Future Regulation of Human Tissue (2005) 13 Med.L.Rev. 170, 177-180.
243. J. Rawls, Political Liberalism (1996).
244. In Rawls' idea of public reason, reasonable citizens strive to find legal standards that all citizens can mutually agree to accept and regard as compatible with their comprehensive moral beliefs, in view of the fact that they live in a free but consequently radically pluralist society. Rawls' normative imperative is based on citizens' desire to promote their moral powers and freedoms while recognising that moral neutrality is not immediately possible. Instead, they seek laws that reflect fair terms of cooperation: Liddell, op.cit., n.190, 171.
245. These forms of consensus are indifferent to the normative authority of morality and precipitate instability as groups clammer to assert their beliefs whenever they have the power to do so.
246. Amended Helsinki Declaration Article 32.
247. S. McLean and S. Elliston, 'Bioethics, the Council of Europe and the Draft Convention' (1995) 2 European Journal of Health Law 5, 8-9.
248. E.g. Belmont Report, op.cit., n.63
249. T. Beauchamp and J. Childress, Principles of Biomedical Ethics (2001) 12-14.
250. See e.g. the succinct account by Silverman et al., op.cit., n.101, 1724-1726.
251. T. Ackerman, 'Medical Research, Society and Health Care Ethics' in R. Gillon (ed.), Principles of Health Care Ethics (1994) 873-875.
252. Although it is not possible to secure the informed consent of adults lacking capacity, it is possible to follow decisions made before they lost capacity or to ask a proxy who knows them well for substituted consent.
253. Ackermann, op.cit., n.198, 875.
254. The obligation of beneficence does not mean that all risk should be avoided (this would be impossible); it means serious risk must be avoided.
255. Ackermann, op.cit., n.198, 878-879.
256. S. McLean, and S. Elliston, op.cit., n.195, 8.
257. Ibid., 10.
258. Many other public programs for health, education, housing and jury service (to name but a few) would also be inherently un-Kantian, as they are organised without the consent of all those who contribute to them.
259. O. O'Neill, 'Public Health or Clinical Ethics: Thinking Beyond Borders' (2002) 16 Ethics and International Affairs 35, 35-38.
260. O. O'Neill, Autonomy and Trust in Bioethics (2002) 84, 91, 92.
261. A rational person realises that, all things being equal, he cannot regard himself as being permitted to act in ways that are forbidden to others because other citizens would not accept this, furthermore, if others took the same attitude his interests would be curtailed.
262. Identifying these principles is the most difficult and contentious step in Kantian reasoning.
263. O'Neill, op.cit., n.207, 88
264. J. Rachels, The Elements of Moral Philosophy (1999) 125.
265. O'Neill, op.cit., n.207, 88.
266. Ibid., 88-89.
267. O. O'Neill, 'Self-Legislation, Autonomy and the Form of Law' (Vienna, 2004) 9 http://www.phil.cam.ac.uk/u_grads/Tripos/Ethics/course_material/ self_legislation_ult_05.pdf last visited 01/06/2006).
268. R. Kukla, 'Conscientious Autonomy: Displacing Decisions in Health Care' (2005) 35 Hastings Center Report 34, 35, 38-41.
269. In fact, consent procedures can be problematic where they give unconditioned priority to directionless, unreflective choices regardless of the needs of other people: O'Neill, op.cit., n.207, 85.
270. For the list of recommendations submitted to the European Commission as a result of our research: Op.cit., n.1, 7-8.