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The Globalization of Health Law: The Case of Permissibility of Placebo-based Research

Published online by Cambridge University Press:  24 February 2021

Timothy S. Jost
Timothy S. Jost*
Affiliation:
Ohio State University, University of California at Santa Cruz, University of Chicago, Washington & Lee University, Spring 2000
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Extract

If any trend can be confidently predicted for the next millennium (or, more modestly, for our lifetimes) it is the globalization of health law. We live in an age of global markets and global communications. While care of the individual patient has remained largely local, national borders are quite porous to health care professionals. The cross-border flow of patients is a significant factor in some regions, and the development of telemedicine and internet pharmacies is radically expanding the possibility of cross-border medical practice.

Type
Articles
Information
American Journal of Law & Medicine , Volume 26 , Issue 2-3: The Changing Face of Law and Medicine in the New Millennium , 2000 , pp. 175 - 186
Copyright
Copyright © American Society of Law, Medicine and Ethics and Boston University 2020

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References

1 See Zbigniew Bankowski, International Ethical Considerations for Research on Human Subjects, in Ethical Issues in Research 177 (Darwin Cheney ed., 1993).

2 See VaxGen Joins Public and Private Sector Commitment to Develop HIV/AIDS Vaccines, Press Release (Chem. Bus. Newsbase) (Mar. 13, 2000), available in 2000 WL 17078840 (discussing the globalization of anti-AIDS efforts and the widespread international Phase HI clinical trials of AIDSVAX, a potential AIDS vaccine).

3 World Med. Ass'n, Declaration of Helsinki: Recommendations Guiding Physicians in Biomedical Research Involving Human Subjects (Helsinki, Finland, 1964), as revised in Tokyo, Japan 1974; Venice, Italy, 1983; Hong Kong, 1989 [hereinafter Revised Declaration].

4 See Protection of Human Subjects, 21 C.F.R. pt. 50 (1999) (food and drugs); 22 C.F.R. pt. 225 (foreign relations); 45 C.F.R. pt. 46 (1999) (public welfare).

5 Howard M. Spiro, Doctors, Patients and Placebos 10 (1986). 6 Id. at 11 (quoting Arthur K. Shapiro, The Placebo Response, in 2 Modern Perspectives in World Psychiatry 596 (John G. Howells ed., 1971).

7 See id. at 10-11.

8 See Louis Lasagna, The Helsinki Declaration: Timeless Guide or Irrelevant Anachronism?, 15 J. Clinical Psychopharmacology 96, 96 (1995).

9 See id. at 97.

10 See National Comm'n. for the Protection of Human Subjects of Biomedical & Behavioral Research, The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research, 44 Fed. Reg. 23192 (1979) (notice of report).

11 See Christine C. Grady, Science in the Service of Healing, Hastings CTR. REP., Nov.-Dec. 1998, at 34, 36.

12 See id.

13 See Pamela J. Clark & Paul E. Leaverton, Scientific and Ethical Issues in the Use of Placebo Controls in Clinical Trials, Ann. Rev. Pub. Health, 1994, at 19, 32.

14 See Barbara Stanley, An Integration of Ethical and Clinical Considerations in the Use of Placebos, 24 Psychopharmacology Bull. 18, 18 (1988).

15 See Hearing on Clinical Trials and Patient Safety Before the House Comm. on Gov't Reform, 105th Cong. 171, 173 (1998) (statement of Adil E. Shamoo, Ph.D., Citizens for Responsible Care in Psychiatry and Research); Benjamin Freedman et al., Placebo Orthodoxy in Clinical Research II: Ethical, Legal and Regulatory Myths, 24 J.L. Med. & Ethics 252, 253-54 (1996); Kenneth J. Rothman & Karin B. Michels, The Continuing Unethical Use of Placebo Controls, 331 New Eng. J. Med. 394, 395 (1994).

16 See Hearing on Clinical Trials and Patient Safety Before the House Comm. on Gov't Reform, 105th Cong. 193 (1998) (testimony of Peter Lurie, M.D., M.P.H., University of Michigan Institute for Social Research and Public Citizen's Health Research Group) [hereinafter Lurie Testimony].

17 See Freedman et al., supra note 15, at 255.

18 See Robert J. Levine, The Use of Placebos in Randomized Clinical Trials, Institutional Rev. BD., Mar.-Apr. 1995, at 1, 1.

19 See Stanley, supra note 14, at 18.

20 See Freedman et al., supra note 15, at 255-56.

21 See Paul S. Appelbaum et al., False Hopes and Best Data: Consent to Research and Therapeutic Misconception, Hastings Ctr. Rep., Apr. 1987, at 20, 20-24; see also Stanley, supra note 14, at 19-20 (suggesting that “having patients understand what a placebo is and under what conditions they will receive it, is probably much more important than making sure they are informed of every possible minor risk of a procedure.”).

22 See Udo Schiiklenk, Unethical Perinatal HIV Transmission Trials Establish Bad Precedent, Bioethics 312, 315(1998).

23 A particularly troublesome issue under consideration in the United States is the use of placebo-controlled studies in emergency care research, where the patient is often in extremis and lacking capacity. Recent regulations of the Food and Drug Administration seem to permit such research where existing treatments are unproven or unsatisfactory. See 21 C.F.R. § 50.24(a)(1) (1999).

24 See Rothman & Michels, supra note 15, at 397.

25 See Robert J. Levine, The Need to Revise the Declaration of Helsinki, 341 New Eng. J. Med. 531, 532 (1999); David B. Resnik, The Ethics of HIV Research in Developing Nations, 12 Bioethics 286,297-98,300(1998).

26 See Council on Ethical & Judicial aff., American Med. Ass'n, Rep. no. 2-A-96, Ethical Use of Placebo Controls in Clinical Trials 3 (1996) [hereinafter Ceja Rep. no. 2-A-96]. In active controlled studies the control group is given the current standard treatment. See id.

27 See id. at 3; Robert Temple, Government Viewpoint of Clinical Trials, 16 Drug Info. J. 10, 12 (1982). Another asserted, though contested, disadvantage of equivalency trials is that they create incentives for poor research techniques, which would have the effect of concealing differences rather than disclosing them. See id. at 11-12; Ceja Rep. no. 2-A-96, supra note 26, at 3. On the other hand, to the extent that placebo-controlled trials simply demonstrate that a new treatment is “better than nothing,” but not better than existing treatments, they do not clearly justify the release of the new product. See Lurie Testimony, supra note 16, at 196.

28 See D.A. Curson et al., Does Short Term Placebo Treatment of Chronic Schizophrenia Produce Long Term Harm?, 293 Brit. Med. J. 726, 726 (1986).

29 See Temple, supra note 27, at 11. For a refutation of this position, see Benjamin Freedman et al., Placebo Orthodoxy in Clinical Research I: Empirical and Methodological Myths, 24 J.L. Med. Ethics 243, 248-50 (1996) (stating “active control equivalence study (ACES) represents an alternative trial design that, in fact, avoids nearly all of the pitfalls to which Temple alludes. .. . In an ACES, two treatments are compared, not to test if one is superior, but to test whether they are equivalent.”).

30 See Joe Collier, Confusion Over Use of Placebos in Clinical Trials, 311 Brit. Med. J. 821, 821 (1995).

31 See Ceja Rep. No. 2-A-96, supra note 26, at 5-6.

32 See generally Clark & Leaverton, supra note 13, at 33-34 (discussing a study finding no difference between the drug and placebo groups in their respective risks of experiencing “adverse events").

33 See id. at 32 (quoting Louis Lasagna: “too often the placebo-treated patients turn out to be the lucky ones in a drug trial, deprived only of a toxic and ineffective chemical.”).

34 See Collier, supra note 30, at 821.

35 See Ceja Rep. No. 2-A-96, supra note 26, at 6.

36 See id. at 7 (noting that because research involves patients who voluntarily assume risk, researchers must make their understanding of the potential harms a “top priority”); Levine, supra note 25, at 532.

37 See Clark & Leaverton, supra note 13, at 32.

38 See id.

39 See id. at 4.

40 Revised Declaration, art. II § 3. Article III, section 4 of the Declaration, which provides that “[i]n research on man, the interest of science and society should never take precedence over considerations related to the well-being of the subject” also seems to reject the utilitarian justifications of placebo-based research discussed below. See id. art. Ill § 4.

41 Id. art. II § 3.

42 See Lurie Testimony, supra note 16, at 189.

43 Council for Int'l Org. of Med. Sci., World Health Org., International Ethical Guidelines for Biomedical Research Involving Human Subjects 39 (1993).

44 See American Med. Ass'n, World Med. Ass'n, Doc. no. l7.CRev/97/A, Proposed Revision of the Wma Declaration of Helsinki 6 (1997).

45 See id.

46 World Med. Ass'n, Background Document for the American Medical Association Proposed Revision of the WMA Declaration of Helsinki 6 (unpublished report) (1998).

47 See American Med. Ass'n, World Med. Ass'n, Doc. No. 17.C/Revl/99, Proposed Revision of the WMA Declaration of Helsinki (1999).

48 See id. § 18.

49 See id. § 19.

50 See Stellungnahme zum Vorschlag der American Medical Association zur Revision der Revidierten Deklaration von Helsinki at V. (unpublished report) (on file with author) (translation by author).

51 See id.

52 See id.

53 See Sarah Ramsay, WMA Postpones Decision to Revise Declaration of Helsinki, 354 LANCET 928 (1999).

54 See Paul R. McGinn, Helsinki Revisited, AMA News, Feb 21, 2000, at 20.

55 Council on Ethical & Judicial aff., American Med. Ass'n, Ethical Opinion NO. E-2.075,The Use of Placebo Controls in Clinical Trials (June 1997) [hereinafter CEJA OPINION NO. E-2.075].

56 See id.; CEJA REP. No. 2-A-96, supra note 26.

57 See CEJA OPINION No. E-2.075, supra note 55.

58 See CEJA REP. No. 2-A-96, supra note 26, at 8.

59 See, e.g., Baruch A. Brody, the Ethics of Biomedical Research: an International Perspective 150-51 (1998); Benjamin Freedman, Placebo-Controlled Trials and the Logic of Clinical Purpose, Institutional Rev. BD., Nov.-Dec. 1990, at 1, 2-3, 5; Carol Levine et al., Building a New Consensus: Ethical Principles and Policies for Clinical Research on HIV/AIDS, Institutional Rev. BD., Jan.-Apr. 1991, at 1, 8; Levine, supra note 18, at 3-4.

60 Erwin Deutsch, Medizinrecht 1542 (Springer-Verlag, 1997) (translation by author).

61 Id. 1 792 (translation by author).

62 Country Report of Germany 12 (Apr. 7, 1999) (unpublished report for Symposium on Research Freedom and Research Control by Ethics Committees, Goettingen, Germany, Apr. 7-12, 1999) (on file with author) (translation by author).

63 Country Report of New Zealand 17 (Apr. 7, 1999) (unpublished report for Symposium on Research Freedom and Research Control by Ethics Committees, Goettingen, Germany, Apr. 7-12, 1999) (on file with author).

64 See Country Report of Switzerland (Apr. 7, 1999) (unpublished report for Symposium on Research Freedom and Research Control by Ethics Committees, Goettingen, Germany, Apr. 7-12, 1999).

65 Country Report of Portugal (Apr. 7, 1999) (unpublished report for Symposium on Research Freedom and Research Control by Ethics Committees, Goettingen, Germany, Apr. 7-12, 1999).

66 Country Report of Spain (Apr. 7, 1999) (unpublished report for Symposium on Research Freedom and Research Control by Ethics Committees, Goettingen, Germany, Apr. 7-12, 1999).

67 See Country Report of France (Apr. 7, 1999) (unpublished report for Symposium on Research Freedom and Research Control by Ethics Committees, Goettingen, Germany, Apr. 7-12, 1999).

68 Country Report of the United Kingdom 10-11 (Apr. 7, 1999) (unpublished report for Symposium on Research Freedom and Research Control by Ethics Committees, Goettingen, Germany, Apr. 7-12, 1999) (on file with author).

69 See Country Report of Japan (Apr. 7, 1999) (unpublished report for Symposium on Research Freedom and Research Control by Ethics Committees, Goettingen, Germany, Apr. 7-12, 1999).

70 See id.

71 See 21 U.S.C. § 355(a) (1994).

72 Id. § 355(d).

73 21 C.F.R. § 314.126(b)(2) (1999).

74 Id.

75 Gary Taubes, Use of Placebo Controls in Clinical Trials Disputed, 267 Science 25 (1995); see Temple, supra note 27, at 10-17.

76 See, e.g., Rothman & Michels, supra note 15, at 395.

77 See, e.g., 21 C.F.R. § 314.126(b) (relating to characteristics of adequate and well-controlled studies of new drugs); Id. § 860.7(f)(1) (relating to determining safety and effectiveness of medical devices).

78 See Freedman et al., supra note 15, at 256; Rothman & Michels, supra note 15, at 395.

79 See. e.g., 21 C.F.R. § 314.126(b); Id. § 860.7(f)(1).

80 Council Directive 75/318/EEC of 20 May 1975 on the Approximation of the Laws of Member States Relating to Analytical, Pharmaco-Toxicological and Clinical Standards and Protocols in Respect of the Testing of Proprietary Medicinal Products, Annex pt. 3, ch. 1, § 2 1975 O.J. (L 147) 1, 10.

81 Commission Directive 91/507/EEC of 19 July 1991 Modifying the Annex to Council Directive 75/318, Annex pt. 4, § B. 1.2, 1991 O.J. (L 270) 32, 32.

82 See id. § C.3(d).

83 See generally Council Recommendation 87/176/EEC of 9 February 1987 Concerning Tests Relating to the Placing on the Market of Proprietary Medicinal Products, Annexes VII, VIII, XIII, 1987 O.J. (L. 073) 1-46.

84 See generally Council Regulation 2309/93 of 22 July 1993 Laying Down Procedures for the Authorization and Supervision of Medicinal Products for Human and Veterinary Use and Establishing a European Agency for the Evaluation of Medicinal Products, 1993 O.J. (L 214) 1-21.

85 ICH Harmonised Tripartite Guideline: Statistical Principles for Clinical Trials, § 3.3.1, International Conference on Harmonisation of Tech. Requirements for Registration of Pharm.Topic E9 (Feb. 5, 1998).

86 See International Conference on Harmonisation of Tech. Requirements for Registration of Pharm., The Choice of Control Group in Clinical Trials (last modified Apr. 13, 2000) <http://www.ifpma.org/ich5e.html>.

87 See id.

88 See Resnik, supra note 25, at 286.

89 See id. at 289. The protocol involves prolonged oral administration of Zidovudine to human immunodeficiency virus-infected pregnant women, intravenous administration administration during delivery, and oral administration to the newborn child. See Levine, supra note 25, at 533.

90 See Resnik, supra note 25, at 286.

91 See id. at 286-89.

92 See George J. Annas & Michael A. Grodin, Human Rights and Maternal-Fetal HIV Transmission Prevention Trials in Africa, 88 AM. J. Pub. Health 560, 560 (1998).

93 See Resnik, supra note 25, at 287.

94 Most notably, the trials provoked a heated editorial exchange in the most prestigious U.S. medical journal, the New England Journal of Medicine. See Marcia Angell, The Ethics of Clinical Research in the Third World, 337 New Eng. J. Med. 847, 848 (1997) (criticizing the trials); Lurie, Peter & Wolfe, Sidney M., Unethical Trials of Interventions to Reduce Perinatal Transmission of the Human Immunodeficiency Virus in Developing Countries, 337 New Eng. J. Med. 853, 853-54 (1997)Google Scholar (same). But cf Varmus, Harold & Satcher, David, Ethical Complexities of Conducting Research in Developing Countries, 337 New Eng. J. Med. 1003, 1003 (1997)Google Scholar (defending the trials). Among the many other articles discussing this controversy, see generally Symposium, HIV Research in Developing Countries, 12 Bloethics 286 (1998); Symposium, A World of Research Subjects, Hastings CTR. REP., Nov.-Dec. 1998, at 25; Annas & Grodin, supra note 92, at 560; Harold Varmus & David Satcher, The Conduct of Clinical Trials of Maternal-Infant Transmission of HIV Supported by the United States Department of Health and Human Services in Developing Countries (last modified Sept. 9, 1999) <http://www.nih.gov/news/mathiv/mathiv.htm>.

95 See Annas & Grodin, supra note 92, at 562.

96 A more relevant standard for evaluating these trials might be the Council for International Organizations of Medical Sciences International Ethical Guidelines, especially Guideline 8 on Research Involving Subjects in Underdeveloped Communities. See Council for Int'l ORG. of Med. Sci., supra note 43.

97 See Revised Declaration, supra note 3, at § II.3.

98 See Lasagna, supra note 8, at 97.