Seen but not heard? Children in clinical trials

Medical Law Review

Volumn 18, Issue 1, 2010, Pages 1-27

  Cave, Emma ^a  

^a UNIVERSITY OF LEEDS   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

ADVISORY COMMITTEE; ARTICLE; HUMAN; INFORMED CONSENT; INTERNATIONAL COOPERATION; LEGAL ASPECT; PATIENT RIGHT; PHASE 1 CLINICAL TRIAL; PRACTICE GUIDELINE; PRESCHOOL CHILD; RISK ASSESSMENT; UNITED KINGDOM;

ADVISORY COMMITTEES; CHILD, PRESCHOOL; CLINICAL TRIALS, PHASE I AS TOPIC; GREAT BRITAIN; GUIDELINES AS TOPIC; HUMANS; INFORMED CONSENT; INTERNATIONALITY; PATIENT RIGHTS; RISK ASSESSMENT;

EID: 77952531420     PISSN: 09670742     EISSN: 14643790     Source Type: Journal    
DOI: 10.1093/medlaw/fwp024     Document Type: Article

References (113)

1. SD Edwards and MJ McNamee, 'Ethical Concerns Regarding Guidelines for the Conduct of Clinical Research on Children' (2005) 31 JME 351
2. E.C. 2001/20.
3. Medicines for Human Use (Clinical Trials) Amendment Regulations (S.I. 2006/1928). They were further amended by the Medicines for Human Use (Clinical Trials Fees Amendments) Regulations 2004 (S.I. 2004/1157); the Medicines for Human Use (Clinical Trials) Amendment (No. 2) Regulations 2006 (S.I. 2006/2984); and the Medicines for Human Use (Clinical Trials) and Blood Safety and Quality (Amendment) Regulations 2008 (S.I. 2008/941).
4. E.C. Directive 2005/28/EC.
5. Regulation 15(6)
6. Regulation 49(1)(d). The offence is punishable by fine or imprisonment: Regulation 52.
7. Regulation 50
8. See (2008) 15(2) European Journal of Health Law: a special issue devoted to medical research involving children across Europe
9. A term which poses its own definitional quandaries. See http://www.mhra.gov.uk/home/groups/l-unit1/documents/websiteresources/con009394.pdf accessed 12 November 2009.
10. 11 on adults lacking mental capacity.
11. See A Pierro and L Spitx, 'Informed Consent in Clinical Research: The Crisis in Paediatric Research' (1997) 349 The Lancet 1703
12. See Editorial, 'Paediatric Research Should Take Centre Stage' (2004) 364 The Lancet 732
13. See, for example, the recent trial which demonstrated the unnecessary use of antibiotic ointment in some childhood eye infections. P Rose and others, 'Chloramphenicol Treatment for Acute Infective Conjunctivitis in Children in Primary Care: a Randomised Double-blind Placebo-controlled Trial' (2005) 366 The Lancet 37.
14. see Editorial, 'Let Kids be Kids' (2004) 5 Lancet Oncology 641
15. See, for example, P Paolucci and others, 'Challenges in Prescribing Drugs for Children with Cancer' (2008) 9 The Lancet 176
16. World Medical Association, Declaration of Helsinki on Ethical Principles for Medical Research Involving Human Subjects (1964, as amended in 2008)
17. EU Regulation on Medicinal Products for Paediatric Use Regulation (E.C.) No. 1901/2006. See also European Commission, Communication from the Commission-Guidance on the Information Concerning Paediatric Clinical Trials to be Entered into the EU Database on Clinical Trials (EudraCT) and on the Information to be Made Public by the European Medicines Agency (EMEA), in Accordance with Article 41 of Regulation (EC) No 1901/2006, (E.C.) 2009/C 28/01.
18. European Paediatric Committee, http://www.emea.europa.eu/htms/human/paediatrics/pdco.htm accessed 12 November 2009.
19. Pediatric Research Equity Act 2003. Previous attempts by the US Food and Drug Administration to encourage paediatric research were of limited success. The 'Pediatric Rule' was struck down in 2002.
20. See Editorial, 'Paediatric Research Should Take Central Stage', above n 12
21. See PR Ferguson, 'Clinical Trials and Healthy Volunteers' (2008) 16 Med L Rev 23
22. Schedule 1, Part 4, demands that minors are included in the trial only where: '9. The clinical trial relates directly to a clinical condition from which the minor suffers or is of such a nature that it can only be carried out on minors'; and '11. The clinical trial is necessary to validate data obtained (a) in other clinical trials involving persons able to give informed consent, or (b) by other research methods'.
23. Medicines for Human Use (Clinical Trials) Regulations 2004, Sched 1, Part 4, Para 10
24. For a general appraisal of consent requirements in research on children
25. see M Brazier and E Cave, Medicine, Patients and the Law (Lexis-Nexis/Penguin, London 2007) para 16.10.
26. Family Law Reform Act 1969, s8(1) The consent of a minor who has attained the age of 16 years to any surgical, medical or dental treatment which, in the absence of consent, would constitute a trespass to his person, shall be as effective as it would be if he were of full age; and where a minor has by virtue of this section given an effective consent to any treatment it shall not be necessary to obtain any consent for it from his parent or guardian.
27. Family Law Reform Act 1969, s8(3) 'Nothing in this section shall be construed as making ineffective any consent which would have been effective if this section had not been enacted'.
28. [1985] 3 All ER 402, HL
29. Confirmed post Human Rights Act 1998 in R (Axon) v Secretary of State for Health [1006] EWHC 37 (Admin)
30. Re R (A Minor) (Wardship: Consent to Treatment) [1992] Fam. 11
31. Re W (A Minor) (Medical Treatment: Court's Jurisdiction) [1993] Fam. 64 discussed in E Cave, 'Adolescent Consent and Confidentiality in the UK' (2009) 16 European Journal of Health Law 309.
32. M Freeman, 'Taking Children's Rights More Seriously' (1992) 6 International Journal of Law, Policy and the Family 52
33. J Eekelaar, 'The Emergence of Children's Rights' (1986) 6 OJLS 161
34. For a contrasting view see M Brazier, C Bridge, 'Coercion or Caring: Analysing Adolescent Autonomy' (1996) 16 Legal Studies 84
35. Children Act 1989, s3(1) 'In this Act " parental responsibility" means all the rights, duties, powers, responsibilities and authority which by law a parent of a child has in relation to the child and his property'
36. See, for example, Gillick v West Norfolk and Wisbech Area Health Authority [1985] 3 All ER 402, HL; Re R [1991] 3 WLR. 592; Re W [1992] 3 WLR. 758; R (on the application of Axon) v Secretary of State for Health & Another [2006] EWHC. 37 (Admin).
37. For example, Re B [1981] 1 WLR 1421 involving the authorisation of a life saving operation on an infant against the wishes of the parents
38. WMA, Declaration of Helsinki (1996) para 5
39. Medical Research Council, Medical Research Involving Children (2004) para 5.3.1.a.
40. The General Medical Council, 0-18 Years: Guidance to All Doctors (2007) para 38 advices that: 'If [children under the age of 18] are able to consent for themselves, [the doctor] should still consider involving their parents, depending on the nature of the research'
41. GMC, 0-18 Years: Guidance to All Doctors (2007), para 38
42. D Hunter and BK Pierscionek, 'Children, Gillick Competency and Consent for Involvement in Research' (2007) 33 Journal of Medical Ethics 659
43. Re W (A Minor) (Medical Treatment) [1992] 4 All ER 627, [635] per Lord Donaldson
44. An exception is created for trials of emergency medicines in The Medicines for Human Use (Clinical Trials) and Blood Safety and Quality (Amendment) Regulations 2008 (S.I. 2008/941), Regulation 4.
45. F Baylis and J Downie, 'The Limits of Altruism and Arbitrary Age Limits' (2003) 3 The American Journal of Bioethics 19
46. Arguing that children of 14 and above could provide such assent
47. T M Burke, R Abramovitch and S Zlotkin, 'Children's Understanding of the Risks and Benefits Associated with Research' (2005) 31 Journal of Medical Ethics 715
48. suggesting that children as young and six can understand the necessary concepts involved in research if age-appropriate modules of information are used
49. Medicines for Human Use (Clinical Trials) Regulations 2004, Sched 1, Part 4, Para 6
50. Medicines for Human Use (Clinical Trials) Regulations 2004, Sched 1, Part 4, Para 7
51. Council of Europe, 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 (ETS No 164, 1997)
52. A Plomer, 'Medical Research, Consent and the European Convention on Human Rights and Biomedicine' in A Garwood-Gowers, J Tingle and T Lewis (eds), Healthcare Law: The Impact of the Human Rights Act 1998 (Cavendish Publishing, London 2001) 313-30
53. A Plomer, The Law and Ethics of Medical Research: International Bioethics and Human Rights (Cavendish Publishing, London 2005) Ch 1
54. Council of Europe, Additional Protocol Concerning Biomedical Research, (Strasbourg, 2005), Article 15(1)(iv)
55. Medicines for Human Use (Clinical Trials) Regulations 2004, Sched 1, Part 4, Para 7
56. CIOMS, International Ethical Guidelines for Biomedical Research Involving Human Subjects Guideline (2002), guideline 14. Though see below for an exception to this rule.
57. European Commission, Recommendations of the Ad Hoc Group for the Development of Implementing Guidelines for Directive 2001/20/EC Relating to Good Clinical Practice in the Conduct of Clinical Trials on Medicinal Products for Human Use, Ethical Considerations for Clinical Trials on Medicinal Products Conducted with the Paediatric Population (2008). http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol-10/ethical_considerations.pdf accessed 12 November 2009.
58. World Medical Association, Declaration of Helsinki on Ethical Principles for Medical Research Involving Human Subjects, (1964, as amended in 1996) Para I.11.
59. A summary of the reactions to the controversial 2000 revisions can be found at 'The International Response to Helsinki VI' http://www.wma.net/e/ethicsunit/pdf/intl_response_helsinki.pdf accessed 12 November 2009.
60. EC Directive 2005/28/EC
61. World Medical Association, http://www.wma.net/e/ethicsunit/helsinki.htm accessed 12 November 2009.
62. World Medical Association, Declaration of Helsinki on Ethical Principles for Medical Research Involving Human Subjects, (1964, as amended in 2008) Para 24: 'After ensuring that the potential subject has understood the information, the physician...must seek the potential subject's freely-given informed consent, preferably in writing'.
63. World Medical Association, Declaration of Helsinki (1964, as amended in 2008) Para 28
64. European Commission n 47, above para 7
65. J Fortin, 'Accommodating Children's Rights in a Post Human Rights Act Era' (2006) 69 Med Law Rev 299
66. At 316 referring to Herczegalvy v Austria (1992) 15 EHRR 437, at [82]
67. Human Rights Act 1998, Article 8(1): 'Everyone has the right to respect for his private and family life, his home and his correspondence'
68. Parental and child privacy rights under Article 8 are discussed by J Loughrey, 'Medical Information, Confidentiality and a Child's Right to Privacy' (2003) 23 LS 510
69. J Loughrey, 'Can you Keep a Secret?' [2008] CFLQ 312
70. See for example, S Choudhry and H Fenwick, 'Taking the Rights of Parents and Children Seriously: Confronting the Welfare Principle under the Human Rights Act' (2005) 25 OJLS 253
71. A Hall 'Children's Rights, Parents' Wishes and the State: The Medical Treatment of Children' [2006] Fam Law 317
72. J Fortin, 'Children's Rights - Substance or Spin?' [2006] Fam Law 757;
73. R Taylor, 'Reversing the Retreat from Gillick? R (Axon) v Secretary of State for Health' [2007] CFLQ 81
74. J Fortin, above n 57, 311
75. Article 8(2): There shall be no interference by a public authority with the exercise of this right except such as is in accordance with the law and is necessary in a democratic society in the interests of national security, public safety or the economic well-being of the country, for the prevention of disorder or crime, for the protection of health or morals, or for the protection of the rights and freedoms of others
76. In the USA, for example, the legal requirement in clinical trials that capable children give assent is subject to two exceptions: (1) The child is incapable of giving assent. (2) There is 'a prospect of direct benefit that is important to the health or well-being of the children and is available only in the context of the research'. Department of Health and Human Services, Regulations for the Protection of Human Subjects 45 CFR 46.408. See also CIOMS, above n 46, Commentary to Guideline 14: Guideline 14 requires that, in addition to parental permission, the assent of the child is obtained where the child is in fact capable of giving it.
77. Medicines for Human Use (Clinical Trials) Regulations 2004, Sched 1, Part 4, Para 9
78. Medicines for Human Use (Clinical Trials) Regulations 2004, Sched 1, Part 4, Para 10
79. This point was made by Brazier and Cave, above n 22, p 425
80. CIOMS, above n 46, para 9
81. Section III, para 2
82. Section III, para 3
83. For a supporting stance, see Royal College of Paediatrics, 'Child Health: Ethics Advisory Committee Guidelines for the Ethical Conduct of Medical Research Involving Children' (2000) 82 Archives of Disease in Childhood 177
84. World Medical Association, Declaration of Helsinki on Ethical Principles for Medical Research Involving Human Subjects (1964, as amended in 2008) Para 27
85. Medical Research Council, Medical Research Involving Children (2004), Para 4.3.1.
86. European Commission, above n 47, para 12
87. Medicines for Human Use (Clinical Trials) Regulations 2004, Sched 1, Part 5, Para 9
88. B Freedman, 'Equipoise and the Ethics of Clinical Research' (1987) 317 The New England Journal of Medicine 141
89. Medicines for Human Use (Clinical Trials) Regulations 2004, Sched 1, Part 4, Para 10
90. B Freedman, above n 76. According to Freedman, clinical equipoise arises where there 'exists...an honest, professional disagreement among expert clinicians about the preferred treatment'. Freedman demands that '...the results of a successful trial should be convincing enough to resolve the dispute among clinicians'.
91. J Harris, 'Scientific Research Is a Moral Duty' (2005) 31 Journal of Medical Ethics 242.
92. But see I Brassington, 'John Harris' Argument for a Duty to Research' 21(3) (2007) Journal of Medical Ethics 160
93. S Shapshay and KD Pimple, 'Participation in Biomedical Research Is an Imperfect Moral Duty: A Response to John Harris' (2007) 33 Journal of Medical Ethics 414
94. Paragraph II.4. This is endorsed in the Declaration of Helsinki (2004) para 31.
95. N King, 'Defining and Describing Benefit Appropriately in Clinical Trials' (2000) 28 Journal of Law and Medical Ethics 332
96. Under the Medicines for Human Use (Clinical Trials) Regulations 2004 Sched 1, Part 4, Para 11, a trial involving minors can only proceed if it is necessary to validate data from clinical trials involving adults, or from other research
97. Medicines for Human Use (Clinical Trials) Regulations 2004, Sched 1, Part 2, Para 2
98. Medicines for Human Use (Clinical Trials) Regulations 2004, Sched 1, Part 4, Para 10
99. Department of Health and Human Services, Regulations for the Protection of Human Subjects 45 C.F.R. 4645, subpart D.
100. See, for example, S McPhee and others, 'Immune Responses to AAV in a Phase I Study for Canavan Disease' (2006) 8 Journal of Genetic Medicine 577
101. J Kimmelman and N Palmour, 'Therapeutic Optimism in the Consent Forms of Phase I Gene Transfer Trials: an Empirical Analysis' (2005) 31 Journal of Medical Ethics 209. This study relates to trials involving adult participants.
102. See UCL Institute for Child Health Gene Therapy for X-SCID
103. Additional Briefing 18 December 2007 http://www.ich.ucl.ac.uk/pressoffice/pressrelease_00592 accessed 12 November 2009.
104. Simms v Simms and an NHS Trust [2002] EWHC 2734, Fam.
105. See JA Harrington, 'Deciding Best Interests: Medical Progress, Clinical Judgment and the 'Good Family" [2003] 3 Web Journal of Current Legal Issues. http://webjcli.ncl.ac.uk/2003/issue3/harrington3.html.
106. Abigail Alliance for Better Access to Developmental Drugs v Von Eschenbach, 445 F.3d 470 C.D.C. Cir. (2006).
107. Alliance for Better Access to Developmental Drugs v Von Eschenbach, No. 04-5350, 2007 W.L. 2238914, (C.D.C. Cir. Aug 7, 2007). The Supreme Court has declined to hear an appeal.
108. See A Caplan, 'Is It Sound Public Policy to let the Terminally Ill Access Experimental Medical Innovations?' (2007) 7 American Journal of Bioethics 1
109. E Dorenzo and J Moss, Writing Clinical Research Protocols: Ethical Con- siderations (Elsevier Academic Press, Burlington 2006) 50: 'A blanket con- demnation of no-direct-benefit research is not an answer but a demonstration of lack of appreciation of the appropriate and necessary risks that are essential parts of a sound, deliberative, medical progress'
110. J Fortin, above n 57, at 320
111. European Commission, above n 47
112. For example Mabon v Mabon [2005] EWCA Civ 634 and; R (on the appli- cation of Axon) v Secretary of State for Health & Another [2006] EWHC. 37 (Admin).
113. As supported by USA statute: 45 CFR. 46.408(a).