Abstract
Chapter 12 addresses the level of acceptable risk in research on vulnerable participants, such as children and adult persons not able to consent. This is a highly controversial issue, and the chapter starts with a discussion of when, if ever, can it be justified to expose vulnerable persons who are not able to consent to risks and burdens for the sake of others. The legal framework identifies several additional safeguards that aim to afford vulnerable persons better protection. Research on the following groups of people are discussed separately: Persons not able to consent, children, patients in a clinical emergency situation, pregnant and breastfeeding women, prisoners and others deprived of liberty, and similarly vulnerable persons. These safeguards restrict the level of acceptable risk, and, for some groups, include the precondition of the significant potential benefits to others and the controversial precondition of only minimal risks and burdens to the participant. The precondition of only minimal risks and burdens is discussed in great detail with references to both European and American standards, literature, and practice. The minimal risks standard is also quantified and exemplified, and the consequences of this precondition is discussed.
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Notes
- 1.
The term “acceptable” is here used in accordance with is ordinary meaning, cf. Section 9.3.
- 2.
Therapeutic and nontherapeutic research is defined in Section 3.7.
- 3.
The UN Convention on the rights of the child.
- 4.
Paragraph 87.
- 5.
See, for example, Westra et al. (2009).
- 6.
Ross (2006).
- 7.
Ross (2006, p. 67).
- 8.
Regulation (EC) No 1901/2006 of the European Parliament and of the Council of 12 December 2006 on medical products for paediatric use; See also: The EU Paediatric Guidelines (2008).
- 9.
Maar (2007).
- 10.
See Sections 10.3.5 and 11.4.5.
- 11.
Article 15 of the Additional Protocol is as mentioned equivalent to Article 17 in the Oviedo Convention. References are therefore primarily given to the former provision.
- 12.
See Section 5.4.6.
- 13.
See also Oviedo Convention Article 6.
- 14.
Paragraph 91.
- 15.
“Child” and “minor” are here understood as synonyms referring to born persons below 18 years of age, cf. the Child Convention Article 1.
- 16.
See Section 9.5 on the requirements of necessity and lesser mean. This view is also taken in the Community Paediatric Guidelines of 2008.
- 17.
Accounted for in Chapter 2.
- 18.
US Federal law “Common rule” 45 CFR 46.
- 19.
Cf. Section 12.5.
- 20.
See US Federal law CFR 45 §46.406 and §46.407.
- 21.
Note that CIOMS Guideline 9 apparently recognise a “relative” minimal risk standard that is not acceptable in European law, see Section 12.5.9.
- 22.
The Royal College of Physicians of London (2007, pp. 36–38).
- 23.
“Forum shopping” is a common term used about the dubious practice (in this context) where one chooses the subjectively preferable legal solution (framework, jurisdiction, research ethics committee, and so on).
- 24.
Cf. Section 4.3 and Article 34 of the Additional Protocol: “None of the provisions of this Protocol shall be interpreted as limiting or otherwise affecting the possibility for a Party to grant research participants a wider measure of protection than is stipulated in this Protocol.”
- 25.
It may be noted if one opt for the more liberal interpretational alternative which may seem to tolerate a minor increase over minimal risk, it is clear that a “minor increase”, nevertheless must be understood as just that: a minor increase. In practice where the assessments often are rough and approximate assessments, such a “more liberal” solution should not amount to much difference. It is clear that a risks which is double as risky as a minimal risk is not a minor increase. Hence, the minor increase terminology cannot be used to pave way for a slippery slope in the practice of researchers or research ethics committees.
- 26.
See Simonsen (2011) on the relationship and need for harmonisation between Convention law and Community law.
- 27.
See Section 9.5 on the requirements of necessity and lesser mean.
- 28.
Norwegian Medicine Agency Guidelines concerning clinical trials (2009).
- 29.
Cf. Section 12.5.
- 30.
Paragraph 87.
- 31.
Cf. Chapter 12.
- 32.
See “Common rule” 45 CFR §46.111 (adults) and §46.404 – §46.406.
- 33.
See Chapter 14, which more specifically addresses the use of placebo in clinical trials.
- 34.
See Section 2.2 and Simonsen (2011) on the relationship and need for harmonisation between Convention law and Community law.
- 35.
This means that in most projects that involved modest to high risks, this was done. Approximately half of the studies were noninterventional.
- 36.
Paragraph 105.
- 37.
See Lötjönen (2002, p. 183).
- 38.
See, for example, the case of Shtukaturov v. Russia, Judgment by the ECtHR of 27 March 2008.
- 39.
This follows from the general requirements of necessity and lesser means, see Section 9.5, and Article 19 (2) (i).
- 40.
Likewise Lötjönen (2002, p. 183).
- 41.
CFR 21 §50.24.
- 42.
Plomer (2001).
- 43.
Accounted for in Sections 10.3.6 and 10.3.7.
- 44.
Norwegian Medicine Agency Guidelines concerning clinical trials (2009).
- 45.
Plomer (2001).
- 46.
According to Article 15 of the Additional Protocol. See, however, US regulations CFR 45 Section 46 subpart B where this is regulated.
- 47.
Paragraph 103.
- 48.
Paragraph 103.
- 49.
If she does not have the capacity to give a legally valid consent the stricter additional safeguards in Article 15 (2) of the Additional Protocol applies.
- 50.
US law 21 CFR Subpart B §46.204 (b): “The risk to the fetus is caused solely by interventions or procedures that hold out the prospect of direct benefit for the woman or the fetus; or, if there is no such prospect of benefit, the risk to the fetus is not greater than minimal and the purpose of the research is the development of important biomedical knowledge which cannot be obtained by any other means; (c) Any risk is the least possible for achieving the objectives of the research.” [Italics added]
- 51.
See Article 15 (2) (ii), as well as Articles 19 and 20.
- 52.
See US Federal law 45CFR46 §46.204 (d): “If the research holds out the prospect of direct benefit to the pregnant woman, the prospect of a direct benefit both to the pregnant woman and the fetus, or no prospect of benefit for the woman nor the fetus when risk to the fetus is not greater than minimal and the purpose of the research is the development of important biomedical knowledge that cannot be obtained by any other means, her consent is obtained in accord with the informed consent provisions of subpart A of this part.”
- 53.
See Chapter 2 on the relationship between Convention law and Community law.
- 54.
Explanatory Report Paragraph 114.
- 55.
US Federal law 45CFR46 §46.306.
- 56.
See Sections 10.3.5 and 11.4.5.
- 57.
The issue of “single standard” or “multiple standards” is addressed in Section 12.5.9 in relation to the definition of “minimal risk”.
- 58.
See section above on the estimation of potential benefits and the relevant factors therein.
- 59.
Article 3 of the Additional Protocol; and Article 2 (1) of the GCP Directive; see Section 5.2 where the principle, and this issue, is investigated at a more principal level.
- 60.
See Section 10.3.5 where some of these factors are noted.
- 61.
All citations from Article 15 (2) (i) of the Additional Protocol.
- 62.
See Section 9.5 for an account of these two norms.
- 63.
Paragraph 89.
- 64.
Paragraph 90.
- 65.
Article 15 (2) (ii) of the Additional Protocol.
- 66.
See US Federal law 45CFR46 Subpart B, C, and D.
- 67.
- 68.
Paragraph 91.
- 69.
See the Explanatory Report to Article 15 (2) Paragraph 87, cited above.
- 70.
See Section 3.2 on the definition of “risk”.
- 71.
In the Oxford dictionary (1989) “expect” is explained by “If you expect something to happen, you believe that it will happen.” p. 421.
- 72.
See the definition of “burden” in Section 3.3 and the discussion of the relationship to risks in Section 3.4.
- 73.
Accounted for in Section 11.4.5.
- 74.
See Section 3.3 on the definition of “burden”.
- 75.
Personal communication with the plaintiff’s lawyer June 2007.
- 76.
Paragraph 96.
- 77.
Personal communication with REC Middle Norway June 2007.
- 78.
See Preamble and paragraph 87 and 92 of the Explanatory Report.
- 79.
Wendler (2005), reaches the same conclusion; In a publication four years later David Wendler (2009b) leaves his original position and argues for a double standard for children, in so far that he argued that there should be one standard for children below 14 years of age, and one for those above. Again, the argumentation is convincing, but the result is not practically or sustainable.
- 80.
VG 22. February 2008.
- 81.
Extra Bladet 21 February 2008.
- 82.
Goldenberg and Matetzky (2005).
- 83.
See Field and Behrman (2004).
- 84.
Shah et al. (2004).
- 85.
Shah et al. (2004).
- 86.
Shiel (2009).
- 87.
Paragraph 100 of the Explanatory Report.
- 88.
Paragraph 97 of the Explanatory Report.
- 89.
See Section 12.5.6 below on research in clinical emergency situations where even these procedures occasionally will be above minimal risk because of the nature and context.
- 90.
Lentnek (2007).
- 91.
Explanatory Report to Article 17 of the Additional Protocol, Paragraph 99.
- 92.
Accounted for in Section 12.5.8.
- 93.
This position is also taken by an American committee of scholars, see Field and Behrman (2004, p. 123).
- 94.
See Kjelland (2008).
- 95.
- 96.
Accounted for in Section 11.4.5.
- 97.
Wendler (2005).
- 98.
Ross (2006).
- 99.
Cf. Section 8.3.
- 100.
Slovic (2000).
- 101.
See Section 7.3.
- 102.
Slovic (2000); the risk of dying in any one year from the release of radiation from nearby nuclear power station is approximately 1 in 10 000 000 (BMJ Living with risk (1987, p. 23)).
- 103.
See Paragraph 87 of the Explanatory Report.
- 104.
This specification occurs only in Article 15 (2) (ii) of the Additional Protocol, but it is also implied in Article 17 (2) (ii) of the Oviedo Convention.
- 105.
Article 3 of the Additional Protocol and Article 2 (1) of the GCP Directive. See Section 5.2.5 on the principle of human primacy.
- 106.
The TEDDY-study.
- 107.
My account is primarily based on the statement of The Norwegian National Committee for Medical Research Ethics (2007).
- 108.
The Norwegian Institute of Public Health (2008b). http://www.fhi.no (accessed 20.06.11).
- 109.
The Norwegian National Committee for Medical Research Ethics (2007). Statement of 10 October 2007 at http://www.etikkom.no (accessed 20.06.11).
- 110.
See Section 3.6 on the concept of “direct benefit”.
- 111.
The Norwegian Biotechnology Advisory Board. Statement of 13 September 2007.
- 112.
The Norwegian Ethical Committee for Physicians (2007). Statement of 30 October 2007.
- 113.
The Norwegian Directorate of Health (2007). Decision of 10 December 2007.
- 114.
The Norwegian Ministry of Health (2008). Letter from the Ministry of Health dated 1 July 2008.
- 115.
Cf. the foregoing section.
- 116.
The US paediatrician and bioethicist, Liain Ross, came to the same conclusion in 2006 after investigating similar studies in other countries (Ross 2006). This indicates that US Federal law and the US minimal risk standard is comparable to European law and the European minimal risk standard.
- 117.
After 2009 the question is beyond doubt as the Act explicitly incorporates the provisions entailed in the Oviedo Convention and the Additional Protocol into Norwegian law.
- 118.
See, for example, Ross (2006, pp. 191–206).
- 119.
See Simonsen and Nylenna (2005, pp. 192–201).
- 120.
See, for example, Ross (2006, pp. 191–206).
- 121.
Common Rule 45CFR46 §46.204 (b): “The risk to the fetus is caused solely by interventions or procedures that hold out the prospect of direct benefit for the woman or the fetus; or, if there is no such prospect of benefit, the risk to the fetus is not greater than minimal and the purpose of the research is the development of important biomedical knowledge which cannot be obtained by any other means.”
- 122.
Common Rule 45CFR46 §46.306, see §46.303 (d) which defines minimal risk in this context as: “(d) Minimal risk is the probability and magnitude of physical or psychological harm that is normally encountered in the daily lives, or in the routine medical, dental, or psychological examination of healthy persons.”
- 123.
Common Rule 45CFR46 §46.404 et al.
- 124.
Common Rule 45CFR46 §46.205 (b) (ii): “The purpose of the research is the development of important biomedical knowledge which cannot be obtained by other means and there will be no added risk to the neonate resulting from the research.”
- 125.
Wendler (2005, p. 38).
- 126.
See, for example, London Royal College of Physicians, p. 36.
- 127.
See, for example, Rt.1960:841 The Vaccine Judgment of the Norwegian Supreme Court.
- 128.
See, for example, Wendler (2005).
- 129.
The US National Bioethics Advisory Commission, Final report (2001, p. 84).
- 130.
“When there is ethical and scientific justification to conduct research with individuals incapable of giving informed consent, the risk from research interventions that do not hold out the prospect of direct benefit for the individual subject should be no more likely and not greater than the risk attached to routine medical or psychological examination of such persons. Slight or minor increases above such risk may be permitted when there is an overriding scientific or medical rationale for such increases and when an ethical review committee has approved them.” [Italics added]
- 131.
The US National Bioethics Advisory Commission, Final report (2001, p. 83).
- 132.
See, for example, Wendler (2005).
- 133.
Field and Behrman (2004, p. 122–123).
- 134.
Field and Behrman (2004, p. 124).
- 135.
Grimes v. Kennedy Krieger 782 A.2d 807 (Md. 2001).
- 136.
Grimes v. Kennedy Krieger at p. 818.
- 137.
Grimes v. Kennedy Krieger at p. 813.
- 138.
Grimes v. Kennedy Krieger at pp. 815–817.
- 139.
P. 843.
- 140.
P. 844.
- 141.
Discussed in the foregoing section.
- 142.
P. 850.
- 143.
See Ross (2006).
- 144.
See the Additional Protocol Articles 6, 15 (2), 18 (1), 19 (2), and 20; and the Clinical Trials Directive Articles 3 (2) (a), 4 and 5.
- 145.
Paragraph 96.
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Simonsen, S. (2012). Nontherapeutic Research on “Vulnerable” Participants. In: Acceptable Risk in Biomedical Research. International Library of Ethics, Law, and the New Medicine, vol 50. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-2678-9_12
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