Clinical trials and healthy volunteers

Medical Law Review

Volumn 16, Issue 1, 2008, Pages 23-51

  Ferguson, Pamela R ^a  

^a UNIVERSITY OF DUNDEE   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

ARTICLE; CLINICAL TRIAL; HEALTH STATUS; HUMAN; HUMAN EXPERIMENT; LEGAL ASPECT; MALE; MOTIVATION; QUESTIONNAIRE; UNITED KINGDOM;

CLINICAL TRIALS AS TOPIC; ENGLAND; HEALTH STATUS; HUMAN EXPERIMENTATION; HUMANS; MALE; MOTIVATION; QUESTIONNAIRES;

EID: 40349091542     PISSN: 09670742     EISSN: 14643790     Source Type: Journal    
DOI: 10.1093/medlaw/fwm020     Document Type: Article

References (157)

1. For a description see M.D. Goodyear, 'Further Lessons from the TGN1412 Tragedy' (2006) British Medical Journal 270-271
2. N. Hawkes,'The Drug Trial That Went Horribly Wrong' The Times, 16 March 2006.
3. The distinction between 'therapeutic' and 'non-therapeutic' research has been much criticised - see, for example, K. Liddell, J. Bion, D. Chamberlain, et al., 'Medical Research Involving Incapacitated Adults: Implications of the EU Clinical Trials Directive 2001/20/EC' (2006)
4. 14 Medical Law Review, 367 at 379-384, and also Medical Ethics Today: Its Practice and Philosophy, (BMJ Publishing Group, 2004) at 489-534, 490. In the present context, however, there is no intention that the research participant will receive any health benefit from the test drug, hence the term 'non-therapeutic' remains an appropriate one.
5. M. Goodyear, 'Learning from the TGN1412 Trial' (2006) 332 British Medical Journal 677-678.
6. See also L. Rogers, R. Woods and B. Deer, 'Focus: Poison Chalice' The Sunday Times, 19 March 2006. Whether the UK regulatory body [the Medicines and Healthcare products Regulatory Agency (MHRA)] has the necessary expertise to property to assess applications to test this type of drug has been questioned:
7. P. Ghosh, 'Doubt Cast Over Drug Trial Safety' BBC News, 17 May 2006, available at http://www.news.bbc.co.uk/1/hi/health/498981O.stm.
8. An analysis of the media's response to the tragedy is L. Stobbart, MJ. Murtagh, T. Rapley, et al. 'We Saw Human Guinea Pigs Explode' (2007) 334 British Medical Journal 566-567.
9. For a recent study that explored ways in which to improve volunteers' understanding of information, see A. Paris et al., 'Improvement of the Comprehension of Written Information Given to Healthy Volunteers in Biomedical Research: A Single-blind Randomized Controlled Study' (2007) 21 Fundamentals of Clinical Pharmacology, 207-214.
10. According to M. Goodyear (supra n. 3): 'Interviews with the victims of the TGN1412 trial and their families have yielded the expected myriad of motives, including altruism, but monetary reward played an equally important role'.
11. In the animal studies, the potential drug is tested for acute toxicity using a single dose, sub-chronic toxicity by means of a 10-day dose, and chronic toxicity, involving administration of the drug for 6 months. Tests for teratogenicity may also be carried out, as well as for carcinogenicity. Data from the animal tests must be submitted with the licence application.
12. In the UK, the licensing authority is the Medicines and Healthcare products Regulatory Agency (MHRA). Clinical trial authorisations replace the previous regime of clinical trial certificate (CTC) or clinical trial exemption certificate (CTX). Applications for clinical trial authorisations are assessed by the Clinical Trials Unit, which is part of the Licensing Division of the MHRA.
13. The body responsible for establishing, recognising and monitoring ethics committees is the UK Ethics Committees Authority, established by reg. 5 of the Medicines for Human Use (Clinical Trials) Regulations 2004 (S.I. 2004 No. 1031, referred to hereafter as the '2004 Regulations'). A National Research Ethics Service was established on 27 March 2007 in response to the Department of Health's' Report of the Ad-Hoc Advisory Group on the Operation of NHS Research Ethics Committees'.
14. Regs. 12 and 49 of the 2004 Regulations.
15. A clinical trial is defined as 'any investigation in human subjects... intended (a) to discover or verify the clinical, pharmacological or other pharmacodynamic effects of one or more medicinal products, (b) to identify any adverse reactions to one or more such products, or (c) to study absorption, distribution, metabolism and excretion of one or more such products, with the object of ascertaining the safety or efficacy of those products.' (Reg. 2 of the 2004 Regulations). Approximately 90% of clinical trials are carried out by, or on behalf of, the pharmaceutical industry, see House of Commons Select Committee on Health, 4th Report, 2005, para. 160.
16. Reg. 2 of the 2004 Regulations.
17. Phases II and III involve increasing numbers of patients. In Phase II trials, selected groups of about 40-50 patients are given the drug and closely monitored. The dose range and the short term safety of the drug are explored in order to refine the most appropriate therapeutic dosage. Phase III studies involve the administration of the drug to persons for whom such a drug might be prescribed once it is marketed and test the long-term safety of the drug. Once a drug is on the market, a pharmaceutical company may sponsor Phase IV trials; the safety of a new drug can only be properly determined once large numbers of people have taken it, see European Medicines Agency, General Considerations for Clinical Trials (2006), pp. 6-10.
18. According to Hawkes (supra n. 1): 'Parexel employs more than 5,000 people in a range of services to the drug industry, including the conduct of clinical trials'. Te Genero has since become insolvent, see O. Dyer, 'Firm Involved in Drug Trial Fiasco Files for Bankrupcy' (2006) 333 British Medical Journal 114.
19. Reg. 2(1) of the 2004 Regulations.
20. Ibid.
21. Ibid.
22. See http://www.news.bbc.co.uk/1/hi/health/4815430.stm
23. See reg. 17 of the 2004 Regulations.
24. Medicines and Healthcare products Regulatory Agency, Investigations into Adverse Incidents During Clinical Trials of TGN1412 (25 May 2006), available at: http://www.mhra.gov.uk/home/
25. Report of the Expert Scientific Group, chaired by Professor G.W. Duff, 7 December 2006, Recommendation 15 (hereafter, the Duff Report) available at: http://www.dh.gov.uk/en/Publicationsandstatistics/ Publications/PublicationsPolicyAndGuidance/DH_063117
26. Reported at http://www.nmlh.nhs.uk/news/item.cfm?id-97.
27. The Duff Report, supra n. 20, at 36.
28. See also 'Drug Trial Man "May Lose Fingers"' 16 April 2006, BBC News, available at http://www.news.bbc.co.uk/1/hi/health/4914546.stm
29. M. Day, 'Duff's Report Calls for Changes in Way Drugs Are Tested' (2006) 333 British Medical Journal, 1240.
30. Explanatory Memorandum to the Medicines for Human Use (Clinical Trials) Amendment Regulations 2006, produced by the MHRA, at p. 9. (Available at: htp://www.opsi.gov.uk/si/em2006/uksiem_20061928_en.pdf)
31. Ibid.
32. Ibid.
33. J. Collier, The Health Conspiracy (Century, 1989) at 55.
34. Ibid.
35. S. Lehrman, 'Virus Treatment Questioned After Gene Therapy Death' (1999) 401 Lancet 517-518
36. Editorial, 'Learning from the TGN1412 Trial' (2006) 332 British Medical Journal 677-678 at 677.
37. See J. McHale and M. Fox, Health Care Law (Sweet & Maxwell, 2007) at 667.
38. A.C. Mastroianni, R. Faden and D. Federman (eds.) Women and Health Research: Ethical and Legal Issues of Including Women in Clinical Studies, Chap. 6, Vol. 1 (National Academy Press, 1994) 128-174, at 151.
39. 7175 volunteers were studied. See Collier, supra n. 27.
40. My thanks are due to Dr Trevor Smith of Tayside Medical Research Ethics Committee, in particular, for his assistance in this.
41. The questionnaires sent to the volunteers contained the same questions as those used in the structured interviews. The responses people give to an anonymous postal questionnaire may differ from those that they would give in a face-to-face interview. In fact, the only significant difference between the two groups was in relation to the financial motivation, op. cit n. 50.
42. It is important that such participants appreciate that their condition will not be improved by the test drug. For a discussion of the ethical issues raised by participation in Phase I trials of those who actually suffer from the disease the test drug is designed to treat, see J. Savulescu, 'Harm, Ethics Committees and the Gene Therapy Death' (2001) 27 Journal of Medical Ethics, 148-150.
43. 'Research on Healthy Volunteers' (1986) 20 Journal of the Royal College of Physicians, 3-17 at 5.
44. See also Medical Ethics Today, supra n. 2 at 503.
45. Healthy volunteers are 'the human pharmacological baseline, against which therapeutic and pharmaceutical variability can be qualified'. S. Toon, 'Pharmacokinetic and Pharmacodynamic Assessment in Early Drug Development - Current Approaches and Future Developments' in B. Close, R. Combes, A. Hubbard and J. Illingworth (eds), Volunteers in Research and Testing (Taylor & Francis, 1997) 161-168 at 164.
46. For the legal implications of excluding women and the elderly from clinical trials, see O.P. Corrigan, '"First in Man": The Politics and Ethics of Women in Clinical Drug Trials' (2002) 72 Feminist Review 40-52,
47. and P.R. Ferguson, 'Selecting Participants When Testing New Drugs: The Implications of Age and Gender Discrimination' (2002) 70 Medico-Legal Journal, 130-134.
48. The RCP has suggested that the use of women of childbearing age requires particularly careful consideration by an Ethics Committee - supra n. 36 at 6.
49. Correspondence to author from Future Medical Services, Birmingham.
50. See Rogers, Wood and Deer, supra n. 3. The authors criticised the advertisement, saying 'The sales pitch could have been written by a time-share spiv'. They later accuse Parexel of 'placing advertisements online or in local papers, where they catch the attention of the young and the poor'.
51. Hawkes, supra n. 1.
52. G. Suntharalingam et al., 'Cytokine Storm in a Phase I Trial of the Anti-CD28 Monoclonal Antibody TGN1412' (2006) 355 New England Journal of Medicine 1018-1028.
53. K. Mandeville, 'My life as a Guinea Pig' (2006) 332 British Medical Journal 735.
54. C. Trivedi, 'Making a Career Out of Drug Tests' BBC News, 15 March 2006, available at http://www.news.bbc.co.uk/1/hi/england/london/4809322.stm
55. See McHale and Fox, supra n. 30 at 680.
56. For example, 'Research on Healthy Volunteers', supra n. 36
57. D.W. Vere, 'Testing new Drugs - the Human Volunteer' (1978) 4 Journal of Medical Ethics 81-83
58. Medical Ethics Today, supra n. 2.
59. Supra n. 36 at 5.
60. See, for example, D. Leppard, 'Elephant Man Drug Victims Told to Expect Early Death' The Times, 30 July 2006. Rogers, Woods and Deer ( supra n. 3) refer to '...those lured by the prospect of £2,000 for lazing in a private clinic...'. The authors later note 'Official guidelines state that payments to volunteers should only be for "expense, time and inconvenience", and should not "induce people to take part in studies against their better judgment". Yet the two men hovering between life and death this weekend are ... a trainee plumber who had hoped to make enough cash to take his mother on holiday, and another man referred to as "a serial human guinea pig". In four years he is said to have earned £60,000 from drug trials'.
61. Trivedi, supra n. 43.
62. T.F. Murphy, Case Studies in Biomedical Research Ethics (MIT, 2004) at 54.
63. There was a difference in the responses of those interviewed from those sent questionnaires in relation to this motivation, with the latter being more likely to rate the money they would earn from participation as being a relevant or highly relevant factor (interviewees: 71%; questionnaire respondents: 90%). Although this may be as a result of the interview process making respondents less candid (for fear of appearing less than altruistic), it may equally have been due to a range of other factors, such as the nature of the studies in which they were participating, the variable rates of remuneration paid in the different studies, etc.
64. Goodyear, supra, n. 3.
65. The Declaration of Helsinki was adopted by the World Medical Association in June 1964, amended by the General Assembly of the Association in 1975, 1983, 1989, 1996 and 2000, and notes of clarification added in 2002 and 2004.
66. The Nuremberg War Crimes Tribunal was established at the end of the Second World War to prosecute Nazi doctors, among others, who had conducted unethical experiments.
67. The 2004 Regulations implemented the European Union's Clinical Trials Directive 2001/20/EC. The Directive has since been amended by Directives 2002/98/EC, 2003/63/EC and 2005/28/EC (discussed further, below).
68. By the Medicines for Human Use (Clinical Trials) Amendment Regulations (S.I. 2006 No. 1928). These Regulations came into force on 29 August 2006, hence were not operative at the time of the TGN1412 trial. The 2004 regulations have also been amended by the Medicines for Human Use (Clinical Trials) Amendment (No. 2) Regulations 2006 (S.I. 2006 No. 2984). These relate to the use of incapacitated subjects in clinical trials and are not germane to the present paper.
69. According to Article 1 of Directive 2005/28, the principles of Good Clinical Practice, as referred to in Directive 2001/20/EC, must be applied to clinical trials.
70. By reg. 49.
71. Schedule 1, Part 2, para. 1 of the 2004 Regulations, as amended by the 2006 Regulations.
72. Principle 3 of the 2004 Regulations, as amended. The original version required trials to 'be scientifically sound, and described in a clear, detailed protocol' (principle 5).
73. Supra, n. 52, principle 6.
74. Supra, principle 22.
75. The Nuremberg Code (1947). See (1996) 313 British Medical Journal 1448.
76. The Code is cited in I. Kennedy and A. Grubb, Medical Law: Text with Materials, 3rd edn. (Butterworths, 2000) at 1677-1678.
77. Ibid.
78. Supra, n. 52, principle 22.
79. Schedule 1, Part 3, para. 3 of the 2004 Regulations.
80. Ibid, Schedule 1, Part 1, para. 3.
81. L. Rogers, R. Woods and B. Deer, supra n. 3.
82. Ibid.
83. Schedule 1, Part 2, para. 14 of the 2004 Regulations, as amended by the 2006 Regulations.
84. Para. 4.8.10 of the Guidelines for Good Clinical Practice. In addition, the 2004 Regulations stress that the volunteers must be given 'the opportunity to understand the objectives, risks and inconveniences of the trial and the conditions under which it is to be conducted.' (Schedule 1, Part 3, para 1). One of the conditions under which a trial is conducted relates to whether or not the investigators and sponsors have adequate insurance. See also the Central Office for Research Ethics Committees (COREC): 'Information sheets and consent forms: Guidelines for Researchers and reviewers' (December 2006), available at: http://www.corec.org.uk/recs/guidance/docs/ Info_sheet-and_consent_form_guidance.pdf
85. 'Drug Trial Victims Offered £5,000' BBC News, 19 April 2005, available at http://www.news.bbc.co.uk/1/hi/england/london/4921672.stm. This is also reflected in paragraph of the TGN1412 Consent Form (available at http://www.circare.org/foia5/tgn1412consentform.pdf). TeGenero has, however, been criticised for having only £2 m insurance for the trial.
86. Supra n. 36 at 5.
87. Ibid.
88. Ibid.
89. C. Bendall, 'Clinical Research - The Relationship between Law and Guidelines', in B. Close, et al., supra n. 36.
90. Ibid.
91. Vere, supra n. 36, at 81, emphasis in original. For a criticism of the EC Directive's use of the term 'no risk', see Liddell et al., supra n. 2 at 391-392.
92. P. Ghosh, supra n. 3. TGN1412 has been described as a 'superagonist', meaning that it greatly increases the body's immune response. This may have caused over-stimulation of the immune system, 'sending ... T cells rampaging through the body destroying its own tissues'. S. Bhattacharya and A. Coghlan, 'Catastrophic Immune Response May Have Caused Drug Trial Horror' New Scientist, 17 March 2006, available at: http://www.newscientist.com/channel/health/
93. See S. Lister, 'What the Ape Can Tell Us about that Horrific Human Drug Trial' The Times, 2 May 2006.
94. Available at: http://www.circare.org/foia5/tgn1412_consentform.pdf
95. Hawkes, supra n. 1.
96. O. Dyer, 'Payment Offered to Injured Trial Participants Has Strings Attached' (2006) 332 British Medical Journal 990. See also 'Drug Trial Victims Offered £5,000' BBC News, 19 April 2005, available at http://www.news.bbc.co.uk/1/hi/england/london/4921672.stm
97. Ibid.
98. In light of the £2 million insurance, it is not surprising that the participants rejected the company's offer of an interim payment of £5,000. It has, however, been reported that interim payments of £10,000 were accepted in April 2006: F. Gibb, 'Elephant Man Drug Trials are left in Limbo' The Times, 7 October 2006.
99. I. Dodds-Smith, 'Clinical Research' in C. Dyer (ed.), Doctors, Patients and the Law, Chapter 8 (Blackwell Scientific Publications, 1992) 140-166 at 146.
100. The Duff Report, supra n. 20 at 42.
101. The findings were preliminary since the agent given to the volunteers had not been analysed for contamination (ibid. at 43).
102. Toon, supra n. 36 at 162.
103. See Rogers, Woods and Deer, supra n. 3.
104. S. Mayor, 'Severe Adverse Reactions Prompt Call for Trial Design Changes' (2006) 332 British Medical Journal 683.
105. J. Posner, Textbook of Pharmaceutical Medicine, (BMJ Books, 2002) at 205-206,
106. cited by C.C. Chan (letter) (2006) 332 British Medical Journal 1035.
107. B. Deer, 'Elephant-man Given Drug "Too Quickly": "Reckless Error" Left Men Fighting for Life' The Times, 24 September 2006.
108. Ibid.
109. Ibid. A protocol is'a document that describes the objectives, design, methodology, statistical considerations and organisation of a clinical trial' (reg. 2 of the 2004 Regulations). Reg. 29 requires adherence to the protocol relating to a trial. It is an offence to contravene this and the maximum penalty if prosecuted on indictment is two years' imprisonment [see reg. 49 (offences) and reg. 52 (penalties)]. Note that reg. 51(1) provides: 'A person does not commit an offence under these Regulations if he took all reasonable precautions and exercised all due diligence to avoid the commission of that offence'.
110. Rogers, Woods and Deer, supra n. 3. Brent Medical Ethics Committee approved the study on 14 February 2006. See http://www.mhra.gov.uk/home/ idcplg?IdcService-GET_FILE&dID-20363&noSaveAs-1&Rendition-WEB
111. Report of the Working Party on Statistical Issues in First-in-Man Studies, available at http://www.rss.org/first-in-man-report.
112. For a summary, see S. Mayor, 'UK Report Recommends Better Planning for Phase I Trials' (2007) 334 British Medical Journal 551.
113. S. 3(1) of the 1987 Act.
114. As defined, ibid. s. 1(2)(a) and (b).
115. Ibid. s. 45(1).
116. For a more detailed discussion of the operation of the 1987 Act in relation to pharmaceutical products, see P.R. Ferguson, Drug Injuries and the Pursuit of Compensation, Chap. 7 (Sweet & Maxwell, 1996).
117. 'Personal injury' includes any disease or other impairment of a person's physical or mental condition - s.45(1) of the 1987 Act.
118. Ibid. s. 3(1).
119. Ibid. s. 4(1)(b) and (c).
120. Implementation of E. C. Directive on Product Liability, DTI Consultation Document, 1985, para. 56.
121. See Guide to the Consumer Protection Act 1987 (2001), (available at http://www.berr.gov.uk/files/file22866.pdf).
122. See also McHale and Fox: 'If a research subject is injured due to defective drugs... a strict liability action may be brought under the Consumer Protection Act 1987...'. Supra n. 30, at 719.
123. The Directive on the Approximation of Laws, Regulations and Administrative Provisions of Member States Concerning Liability for Defective Products [1985] O.J. L210/29.
124. Implementation of E. C. Directive on Product Liability: An Explanatory and Consultative Note: Views of the Association of the British Pharmaceutical Industry (1985) at 2.
125. S. 4(1)(e) of the 1987 Act.
126. 'Research on Healthy Volunteers', supra n. 36 at 12.
127. B. Deer, supra n. 89.
128. M. Goodyear, supra n. 3.
129. Directive 2005/28/EC of 8 April 2005. See Reg. 28(1) and Schedule 1, Part 2 of the 2004 Regulations.
130. Available at http://www.ec.europa.eu/enterprise/pharmaceuticals/eudralex/ vol-10/v10_intro.pdf
131. Detailed guidance on the application format and documentation to be submitted in an application for an Ethics Committee opinion on the clinical trial on medicinal products for human use (February 2006) at 6.
132. Reg. 32 of the 2004 Regulations. Reg. 2 defines an investigator as 'the authorised health professional responsible for the conduct of that trial at a trial site, and if the trial is conducted by a team of authorised health professionals at a trial site, the investigator is the leader responsible for that team'.
133. Ibid. reg. 33. This must be with in 7 days in relation to adverse reactions which are fatal or life-threatening (reg. 33(1)) and within 15 days for all other cases (reg. 33(3)).
134. Ibid. reg. 49.
135. Ibid. reg. 35. It is also an offence to contravene this regulation (see reg. 49).
136. S. Mayor, 'Inquiry into Adverse Events in Trial Blames Drug, Not Study Design' (2006) 332 British Medical Journal 870.
137. Supra n. 20.
138. Supra n. 93.
139. MHRA, 'Applications for first time in man (FTIM) trials with higher risk compounds', at http://www.mhra.gov.uk/home/ idcplg?IdcService=SS_GET_PAGE&nodeId-986
140. Ibid.
141. MHRA, 'Investigations into Adverse Incidents During Clinical Trials of TGN1412', supra n. 19, Appendix 1.
142. Ibid.
143. Reg. 29A, inserted by the 2006 Regulations (in force from 29 August 2006). The sponsor has 7 days from the breach to do this. Failure to do so is an offence - see reg. 49 of the 2004 Regulations, as amended by reg. 26 of the 2006 Regulation.
144. Ibid, reg. 29A.
145. Available at: Http://www.mhra.gov.uk/home/ idcplg?IdcService=SS_GETPAGE&useSecondary=true&ssDocName= CON2030355&ssTargetNodeId=387
146. Regulation 31A(1) and (4) of the 2004 Regulations, (added by the 2006 regulations).
147. Ibid, reg. 31A(8).
148. House of Commons Health Committee. The Influence of the Pharmaceutical Industry. Fourth report of Session 2004-05 (Stationery Office 2005). The report is available at http://www.publications.parliament.uk/pa/cm200405/cmselect/cmhealth/42/ 4204.htm. This was the first major select committee inquiry into the pharmaceutical industry since 1914.
149. Ibid. The others were: The provision of drug information and promotion; professional and patient education; regulatory review of drug safety and efficacy; and product evaluation, including assessment of value for money.
150. Ibid.
151. 'Clinical Trials Registration' (editorial) (2007) 334 British Medical Journal, 1177-1178.
152. Ibid.
153. Supra n. 128: 'Conclusions and recommendations', no. 18, and para. 355.
154. Regulations, Schedule 1, Part 1, para. 3.
155. S. Knight, 'Surge in Drug Volunteers Despite Trial Tragedy' The Times 16 March 2006.
156. See also Stobbart et al., supra n. 3.
157. It has, however, been reported more recently that there has been a fall in the number of Phase I volunteers: J. Whelan, 'Learning the Right Lessons', New Scientist, 24 March 2007, available at http://www.newscientist.com/article/mg19325962.600-learning-the-right- lessons.html