The clinical investigator as fiduciary: Discarding a misguided idea

Journal of Law, Medicine and Ethics

Volumn 33, Issue 3, 2005, Pages 586-598

  Morreim, E Haavi ^a  

^a UNIVERSITY OF TENNESSEE COLLEGE OF MEDICINE   (United States)

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[No Author keywords available]

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EID: 27544479119     PISSN: 10731105     EISSN: None     Source Type: Journal    
DOI: 10.1111/j.1748-720X.2005.tb00521.x     Document Type: Review

References (104)

1. A variety of terms can designate those who enroll in research trials, and each has its problems. "Subject" may seem mechanistic and cold; "patient" too easily loses the distinction between treatment and research; "participant" can equally refer to investigators and others who take one or another role in the project. This essay will use "volunteer" to emphasize that a research trial is not part of routine treatment, and that it is a means by which someone can choose to make a contribution, even where he may also hope for benefit to himself.
2. "Patients are not typically recruited for clinical trials by unrelated third parties but are recruited within the context of an established patient-physician relationship." H. Mann, "Therapeutic Beneficence and Patient Recruitment in Randomized Controlled Clinical Trials," American Journal of Bioethics 2, no. 2 (2002): 35-36, at 36.
3. See also H. Mann and B. Djulbegovic, "Clinical Equipoise and the Therapeutic Misconception," (letter) Hastings Center Report 33, no. 5 (2003): 4-5, at 4;
4. P. B. Miller and C. Weijer, "Rehabilitating Equipoise," Kennedy Institute of Ethics Journal 12 (2003): 94-118, at 93.
5. C. Weijer and P. B. Miller, "When Are Research Risks Reasonable in Relation to Anticipated Benefits?" Nature Medicine 10 (2004): 570-73, at 571.
6. See also Mann, supra note 2, at 35; K. Kovach, "Distinguishing Dilemmas in the Ethics of Placebo-controlled Trials," American Journal of Bioethics 2, no. 2 (2002): 32-33, at 32;
7. C. Weijer, S. H. Shapiro, K. C. Glass, and M. Enkin, "For and Against: Clinical Equipoise and Not the Uncertainty Principle is the Moral Underpinning of the Randomised Controlled Trial," British Medical Journal 321 (2000): 756-58, at 756
8. ; K. C. Glass, "Clinical Equipoise and the Therapeutic Misconception," (letter and reply) Hastings Center Report 33, no. 5 (2003): 5-6, at 5; Miller and Weijer, supra note 2, at 93.
9. National Placebo Working Committee, National Placebo Initiative, Draft Report, October 2003, available at 〈http://www.cihr-irsc.gc.ca/e/services/ pdf_19320.htm〉 (last visited June 28, 2005) at 37.
10. National Placebo Initiative, Draft Report, 2003, Id.;
11. K. J. Rothman and K. B. Michels, "The Continuing Unethical Use of Placebo Controls," N. Engl. J. Med. 331 (1994): 394-98, at 394;
12. M. Angell, "The Ethics of Clinical Research in the Third World," N. Engl. J. Med. 337 (1997): 847-49, at 847.
13. B. Freedman, C. Weijer and K. C. Glass, "Placebo Orthodoxy in Clinical Research II: Ethical, Legal, and Regulatory Myths," Journal of Law, Medicine & Ethics 24 (1996): 252-59, at 252.
14. B. Freedman, "Equipoise and the Ethics of Clinical Research," New England Journal of Medicine 317 (1987): 141-145; Weijer, Shapiro, Glass, and Enkin, supra note 3; Miller and Weijer, supra note 2.
15. Freedman, Weijer, and Glass, supra note 6, at 253. The concept of clinical equipoise has become increasingly controversial. See F. G. Miller and H. Brody, "What Makes Placebo-controlled Trials Unethical?" American Journal of Bioethics 2, no. 2 (2002): 3-9, plus accompanying commentaries;
16. Weijer, Shapiro, Glass, and Enkin, supra note 3; Miller and Weijer, supra note 2; R. Temple and S. S Ellenberg, "Placebo-controlled Trials and Active-control Trials in the Evaluation of New Treatments: Part I: Ethical and Scientific Issues," Annals of Internal Medicine 133 (2002): 455-63;
17. R. Temple and S. S. Ellenberg, "Placebo-controlled Trials and Active-control Trials in the Evaluation of New Treatments: Part 2: Practical Issues and Specific Cases," Annals of Internal Medicine 133 (2000): 464-70;
18. F. G. Miller and H. Brody, "A Critique of Clinical Equipoise: Therapeutic Misconception in the Ethics of Clinical Trials," Hastings Center Report 33, no. 3 (2003): 19-28;
19. Miller and Weijer, supra note 2; F. G. Miller, "Research Ethics and Misguided Moral Intuition," Journal of Law, Medicine & Ethics 32 (2004): 111-16.
20. Miller and Weijer, supra note 2, at 95, 110-112; R. S. Saver, "Critical Care Research and Informed Consent," North Carolina Law Review 75 (1996): 205-71, at 221;
21. A. R Holder, "Do Researchers and Subjects Have a Fiduciary Relationship?" IRB 4, no. 1 (1982): 6-7; National Placebo Working Committee, supra note 4.
22. Glass, supra note 3, at 5.
23. D. Steinberg, "Clinical Research Should Not be Permitted to Escape the Ethical Orbit of Clinical Care," American Journal of Bioethics 2, no. 2 (2002): 27-28, at 27.
24. Several courts have discussed cases featuring interventions that were purely research, with no physician-patient relationship involved even though medical doctors and medical procedures were involved. In Payette v. Rockefeller University, 643 N.Y.S.2d 79 (App. Div. 1 Dept. 1996), for instance, a student volunteered for three studies about diet. After taking iodine injections and oral potassium iodide the student developed enlarged thyroid and hypothyroidism. The court found that because this study was not medical practice, it could not be medical malpractice. Therefore, the applicable statute of limitations was the three-year limit of ordinary negligence, not the two-and-a-half-year term applicable to medical malpractice. To emphasize the difference, the court noted that the student was not seeking medical assistance by enrolling in the study, her relationship with the investigators was not physician-patient, and the interventions she received were not undertaken to diagnose and treat her. Hence, the court found, even though doctors were involved and performed medical procedures requiring professional skill, this was not medical practice, hence could not be medical malpractice. In Craft v. Vanderbilt Univ., 18 F.Supp.2d 786 (M.D. TN, 1998), a mid-1940s study gave pregnant women a "vitamin drink" that, unbeknownst to them, contained radioactive iron isotopes. Although the objective was to learn more about how iron is absorbed during pregnancy, it was allegedly known at the time that radiation posed health risks. As with the radiation cases above, a central focus in litigation was on whether the statute of limitations had expired. A federal district court found first that the Tennessee statute of repose for medical malpractice "does not apply to conduct that does not involve medical care," id. at 796, which it defined as "actions...taken in an effort to benefit or cure the patient," id. Since this study clearly did not aim to benefit the pregnant women, the rules of ordinary negligence applied rather than the (shorter) statute of repose for medical malpractice. Vodopest v. MacGregor, 913 P.2d 779 (WA, 1996), combined a sporting activity with medical research, as investigators attempted to implement specialized breathing techniques to cope with high altitude during a mountain-climbing expedition. The plaintiff developed increasing signs of altitude sickness that were not recognized by the nurse-investigator, who encouraged the plaintiff to continue using the special breathing technique. The plaintiff developed cerebral edema leading to brain damage. The court found that, although the project's exculpatory clause could apply legitimately to the purely sporting aspects of the expedition, it could not apply to the study of the breathing technique, which constituted medical research. Another study was determined to be quality review, not research in Ancheff v. Hartford Hospital, 799 A2d 1067 (CT, 2002). A hospital had instituted a protocol for aggressively treating a particularly difficult bone infection. The plaintiff, who developed hearing and balance problems from antibiotics, claimed that the hospital had engaged in research without appropriate informed consent, on the ground that a protocol was used, that it was "radical," that the hospital gathered data on how patients did, and shared information with other healthcare providers. The hospital responded that this was simply a systematic implementation of the best available information, that there was no attempt to use control groups or to compare two research "arms" to see which approach might be better, nor other key features of research. The plaintiff tried repeatedly to enter the Belmont Report in its entirety into the record, a move the judge consistently denied as prejudicial because of its references to Nazi research horrors and other abuses. By the time the plaintiff finally sought only to admit the Report's definition of "research" the court had had enough and permitted no further discussion of the matter. The state supreme court found no obvious error in this response.
25. E. H. Morreim, "Medical Research Litigation and Malpractice Tort Doctrines: Courts on a Learning Curve," Houston Journal of Health Law and Policy 4, no. 1 (2003): 1-86.
26. Miller and Brody, "A Critique of Clinical Equipose," supra note 8, at 22.
27. See also F. G. Miller and D. L. Rosenstein, "The Therapeutic Orientation to Clinical Trials," N. Engl. J. Med. 348 (2003): 1383-86, at 1383.
28. D. A. DeMott, "Beyond Metaphor: An Analysis of Fiduciary Obligation," Duke Law Journal 819 (1988): 879-924, at 879.
29. T. Frankel, "Fiduciary Law," California Law Review 71 (1983): 795-836, at 795;
30. A. W. Scott, "The Fiduciary Principle," California Law Review 4 (1949): 539-55, at 541; Cooter and Freedman, supra note 21, at 1045. See, e.g., Scott v. Dime Savings Bank of New York, FSB, 886 F.Supp. 1073, 1078 (S.D.N.Y 1995), affd w/o opin., 101 F.3d 107 (2d Cir. 1996), cert. denied, 520 U.S. 1122 (1997). See also Doe v. Roe, 681 N.E.2d 640, 646 (Ill.App.1 Dist. 1997); Calhoun v. Rane, 599 N.E.2d 1318 (Ill.App. 1 Dist. 1992); Coughlin v SeRine, 507 N.E.2d 505 (Ill.App.1Dist. 1987); Moore v. Regents of the Univ. Of Caifornia., 793 P.2d 479, 483 (CA, 1990); Lockett v. Goodill, 430 P.2d 589, 591 (WA, 1967); Miller v. Kennedy, 522 P.2d 852, 860-61 (Wash. Ct. App. 1974), aff'd, 530 P.2d 334 (WA, 1975); Shadrick .v Coker, 963 S.W.2d 726, 735 (TN, 1998); Collins v. Nugent, 443 NE2d 277 (111. App. 1 Dist. 1982); Lownsbury v. VanBuren, 762 N.E.2d 354 (Ohio 2002).
31. J. C. Shepherd, The Law of Fiduciaries (Toronto: The Carswell Company Limited, 1981): at 21.
32. M. A. Rodwin, "Strains in the Fiduciary Metaphor: Divided Physician Loyalties and Obligations in a Changing Health Care System," American Journal of Law & Medicine 21 (1995): 241-57.
33. Shepherd, supra note 17, at 29.
34. K. B. Davis, Jr., "Judicial Review of Fiduciary Decisionmaking - Some Theoretical Perspectives," Northwestern University Law Review 80 (1986): 1-99, at 4, 6.
35. DeMott, supra note 15, at 901. As noted by Rodwin, fiduciaries usually "have specialized knowledge or expertise. Their work requires judgment and discretion." Rodwin, supra note 18, at 243. See also Cooter and Freedman, supra note 21, at 1046, 1048-49; Frankel, supra note 16, at 810.
36. P. D. Jacobson and M. T. Cahill, "Applying Fiduciary Responsibilities in the Managed Care Context," American Journal of Law & Medicine 26 (2000): 155-73, at 160.
37. "Often the party that the fiduciary serves cannot effectively monitor the fiduciary's performance. The fiduciary relationship is based on dependence, reliance, and trust." Rodwin, supra note 18, at 243.
38. Id. at 243.
39. Meinhard v. Salmon, 164 N.E. 545 (N.Y. 1928). See also Davis, Jr., supra note 20, at 3.
40. Id. at 25.
41. Shepherd, supra note 17, at 35, 93.
42. Scott, supra note 16, at 39.
43. Frankel, supra note 16, at 823.
44. Scott, supra note 16, at 540.
45. DeMott, supra note 15, at 906. See also Davis, Jr., supra note 20, at 19; Shepherd, supra note 17, at 35; P. D. Finn, Fiduciary Obligations (Sydney: The Law Book Company Limited, 1977): at 3. "Anything that compromises the fiduciary's loyalty to the fiducie or the fiduciary's exercise of independent judgment on the fiducie's behalf creates a conflict of interest." Rodwin, supra note 18, at 244.
46. "Fiduciary law creates a cluster of presumptive rules of conduct compendiously described as the duty of loyalty. The obligations comprising this duty restrict the permissible scope of a fiduciary's behavior whenever possible conflicts of interest arise between the principal and the fiduciary." Cooter and Freedman, supra note 21, at 1053-54. "Other rules of fiduciary conduct include, for example, the rule against conflicts of duty, the rule against self-interested transactions, the rule against bribes and secret commissions, the rule against purchasing trust property, and the rule regarding fiduciary opportunities." Id. at 1053 n.19. See also Rodwin, supra note 18, at 244; Frankel, supra note 16, at 824; Shepherd, supra note 17, at 41.
47. Cooter and Freedman, supra note 21, at 1048; DeMott, supra note 15, at 900; Holder, supra note 9, at 6; Scott, supra note 16, at 40.
48. Finn, supra note 31, at 15.
49. It is useful to distinguish between conflicts of interest, in which the fiduciary's duty is pitted against his own personal benefit, and conflicts of obligation, in which his duty to the entrustor is pitted against his duty to some other party. See E. H. Morreim, "Conflict of Interest," in S.G. Post, ed., Encyclopedia of Bioethics, 3d ed. (New York: Macmillan Reference USA, 2004): 503-08.
50. They are voluntary undertakings, for instance. Fiduciary relations may not be imposed on anyone unwilling to assume them even if, once assumed, the duties binding the fiduciary are not optional. See, e.g., Frankel, supra note 16, at 820; Scott, supra note 16, at 540.
51. Moreover, the law looks with a rather dim view on the advice that is given by a fiduciary laboring under a conflict of interest. In the face of such a conflict the law actually presumes "that the fiduciary has misused his advice-giving powers to the detriment of his beneficiary." Shepherd, supra note 17, at 39. See also Cooter and Freedman, supra note 21.
52. Interestingly, this point was expressly noted in the proceedings surrounding the case of Hyman v. Jewish Chronic Disease Hospital, in which live cancer cells were injected subcutaneously into elderly, debilitated nursing home patients. As noted by the Board of Regents, University of the State of New York, "the investigators' claim that they had acted as compassionate physicians was irrelevant. The experiment had not been part of 'the usual doctor-patient relationship,' so there was 'no basis for the exercise of their usual professional judgment.' Thus, even though Sougham and Mandel wore white coats, they were researchers, not clinicians." B. H. Lerner, "Sins of Omission - Cancer Research Without Informed Consent," N. Eng. J. Med. 351 (2004): 628-30, at 629.
53. Morreim, supra note 13, at 16-17.
54. It is sometimes said that people participating in research may fare better simply from the extra attention of being in a trial. See, e.g., ECRI, "Should I enter a Clinical Trial? A Patient Reference Guide for Adults with a Serious or Life-threatening Illness," ERCI (February 2002): at 33;
55. F. G. Miller, D. L. Rosenstein, "TheTherapeutic Orientation to Clinical Trials," N. Eng. J. Med. 348 (2003): 1383-86, at 1383;
56. F. G. Miller and H. Brody, "A Critique of Clinical Equipoise: Therapeutic Misconception in the Ethics of Clinical Trials," Hastings Center Report 3, no. 33 (2003): 19-28, at 21-22;
57. L. R. Churchill, D. K. Nelson, G. E. Henderson, N. M. P. King, A. M. Davis, E. Leahey, B. S. Wilfond, "Assessing Benefits in Clinical Research: Why Diversity in Benefit Assessment can be Risky," IRB: Ethics & Human Research 25 (2003): 1-8, at 3.
58. But see: J. M. Peppercorn, J. C. Weeks, E. F. Cook and S. Joffe, "Comparison of Outcomes in Cancer Patients Treated within and outside Clinical Trials: Conceptual Framework and Structured Review," Lancet 363 (2004): 263-70, at 263: "Despite widespread belief that enrolment in clinical trials leads to improved outcomes in patients with cancer, there are insufficient data to conclude that such a trial effect exists. Until such data are available, patients with cancer should be encouraged to enroll in clinical trials on the basis of trials' unquestioned role in improving treatment for future patients."
59. C. Weijer, "When Argument Fails," American Journal of Bioethics 2, no. 2 (2002): 10-11;
60. C. Weijer, "The Ethical Analysis of Risk," Journal of Law, Medicine and Ethics 28 (2000): 344-61.
61. Steinberg, supra note 11, at 27.
62. P. S. Appelbaum, "Clarifying the Ethics of Clinical Research: A Path Toward Avoiding the Therapeutic Misconception," American Journal of Bioethics 2, no. 2 (2002): 22-23;
63. P. S Appelbaum, C. W. Lidz and T. Grisso, "Therapeutic Misconception in Clinical Research: Frequency and Risk Factors," IRB 26, no. 2 (2004): 1-8;
64. Miller and Brody, "A Critique of Clinical Equipose," supra note 8; Miller and Rosenstein, supra note 8, at 348:1383-86, at 1384; Miller, supra note 8, at 111.
65. Holder, supra note 9, at 6. Karin Morin also suggests that traditionally the physician-patient relationship and the investigator-subject relationship have both been described as fiduciary. K. Morin, "The Standard of Disclosure in Human Subject Experimentation," The Journal of Legal Medicine 19 (1998): 157-221, at 216. See also Vodopest v. MacGregor, 913 P.2d 779, 788 (WA, 1996).
66. It is interesting to note that even the leading case emphasizing investigators' duties toward subjects does not deem the relationship fiduciary, but rather a "special relationship." Grimes v. Kennedy Krieger, 782 A.2d 834, 843 (MD, 2001).
67. Moore v. Regents of the University of California, 793 P.2d 479 (CA, 1990), cert, denied 112 S. Ct. 2967 (1992).
68. Id., at 481. See also Moore v. Regents of the University of California, 249 Cal. Rptr. 494, 500 (Cal.App. 2 Dist. 1988).
69. For further discussion of Moore see E. H. Morreim, "Medical Research Litigation and Malpractice Tort Doctrines: Courts on a Learning Curve," Houston Journal of Health Law and Policy 4 (2003): 1-86, at 22 ff.
70. Moore, 793 P.2d 485.
71. E. H. Morreim, "Medical Research Litigation and Malpractice Tort Doctrines: Courts on a Learning Curve," 4 Houston Journal of Health Law and Policy 1(2003): 1-86, at 22 ff.
72. Moore v. Webb, 345 SW2d 239 (Mo App '61); McCloud v. Seier, 567 SW2d 127 (Mo. 1978); Woytus v. Ryan, 776 SW2d 389 (Mo. 1989); Brandt v. Med Def. Assoc., 856 SW2d 667 (Mo App. 1992); Garcia v. Coffman, 946 P.2d 216 (N.M. App. 1997); Lockett v. Goodill, 430 P.2d 587 (Wash. 1967); Miller v. Kennedy, 522 P.2d 852, 860-61 (Wash. Ct. App. 1974), aff'd, 530 P.2d 334 (Wash. 1975); Hammonds v. Aetna Cas. & Sur. Co., 243 F.Supp. 793, 801-01 (N.D. Ohio 1965); Murphy v. Godwin, 303 A.2d 668 (Del. Super., 1973); Shadrick v. Coker, 963 S.W.2d 726 (TN, 1998); Benton v. Snyder, 825 S.W.2d 409, 414 (TN, 1992); Craft v. Vanderbilt University, 18 F.Supp.2d 786 (M.D. TN, 1998); Sard v. Hardy, 379 A.2d 1014 (Md. App. 1977); Keogan v. Holy Family Hospital, 622 P.2d 1246 (Wash. 1980); Roy v. Hartogs, 366 N.Y.S.2d 297 (NY, 1975); Hunter v. Brown, 484 P.2d 1162 (Wash. App., 1971), aff'd, 502 P.2d 1194 (Wash. 1972); Mason v. Ellsworth, 474 P.2d 909, 917-18 (Wash. App., 1970); Gates v. Jensen, 595 P.2d 919 (WA, 1979); Bowman v. McPheeters, 176 P.2d 745, 748 (Cal. 1947); Natanson v. Kline, 350 P.2d 1093, 1101, 1103 (KS, 1960); Berkey v. Anderson, 82 Cal. Rptr. 67, 77-78 (Cal. App. 2 Dist. 1969); Tighe v. Ginsberg, 540 NYS 2d 99 (1989); MacDonald v. Clinger, 446 NYS 2d 801 (1982); Wohlgemuth v. Meyer, 293 P.2d 816 (Cal. App. 1 Dist. 1956); Moore v. Regents of the University of California, 793 P.2d 479, 483 (Cal. 1990); Petrillo v. Syntex Laboratories, Inc., 499 N.E.2d 952 (Ill. App. 1 Dist. 1986); Witherell v Weimer, 118 Ill App 2d 321; Lownsbury v. VanBuren, 762 N.E.2d 354 (Ohio 2002); Brandt v. Medical Defense Associates, 856 SW2d 667 (Mo.Banc 1992).
73. Grimes v. Kennedy Krieger, 782 A.2d 807 (MD, 2001).
74. Grimes, 782 A.2d 834.
75. Id., at 843.
76. Greenberg v. Miami Children's Hospital Research Institute, 264 F.Supp.2d 1064 (S.D., FL, 2003).
77. Greenberg, 264 F. Supp.2d 1071-72.
78. Hamlet v. Genentech, Inc., et al, No. 03 CvS 1161 (No. Car. Super. Ct., 2004).
79. Id.
80. Suthers v. Amgen, 2005 WL 1349450 (S.D., NY, 2005) (denying preliminary injunction).
81. Id. at 7.
82. Id., n. 9, citing E. H. Morreim, "Litigation in Clinical Research: Malpractice Doctrines versus Research Realities," Journal of Law, Medicine and Ethics 32, no. 3 (2004): 474-484.
83. Id. at 8.
84. Frankel, supra note 16.
85. Id. at 829-30.
86. Id. at 830.
87. DeMott, supra note 15.
88. Id. at 891-92. See also Shepherd, supra note 17, at 60 ("Whatever our criticisms of applying moral rules to legal fact situations, we cannot lose sight of the moral foundation upon which many of our legal rules have been erected, including those in the area of fiduciaries.").
89. Steinberg, supra note 11, at 27.
90. Glass, supra note 3, at 5.
91. Miller and Brody, "What Makes Placebo-controlled Trials Unethical?" supra note 8;
92. Miller and Brody, "A Critique of Clinical Equipose," supra note 8; Miller and Rosenstein, supra note 8; Miller, supra note 8;
93. E. J. Emanuel and F. G. Miller, "The Ethics of Placebo-controlled trials - A Middle Ground," N. Engl. J. Med. 345 (2001): 915-19.
94. It is interesting that proponents of the Common View - who emphasize that the investigator-volunteer relationship is surely fiduciary - harshly criticize this emphasis on refraining from exploitation. See T. Lemmens and P. B. Miller, "Avoiding a Jekyll-and-Hyde Approach to the Ethics of Clinical Research and Practice," American Journal of Bioethics 2, no.2 (2002): 14-17, at 14; Steinberg, supra note 11, at 27; Miller and Weijer, supra note 2, at 95. It is far too weak, they argue, to characterize the true obligations of the physician-investigator toward his patient-volunteer. Closer study of fiduciary law, however, reveals that in fact a fiduciary's leading duty is to refrain from exploiting the entrustor. As noted above, fiduciaries have discretion that empowers them to use their advantaged position to promote their own rather than the entrustor's benefit. For this reason, the most central challenge of fiduciary law is to determine how to prevent such abuse without unduly attenuating the very power and discretion that permits the fiduciary to do his job. It would appear that the Common View should enthusiastically embrace, not abjure, the non-exploitation theme. See Frankel, supra note 16, at 809; Shepherd, supra note 17, at 84-85; Cooter and Freedman, supra note 21, at 1048-49; Davis, Jr., supra note 20, at 1; DeMott, supra note 15, at 902, 914.
95. R. Nozick, Anarchy, State, and Utopia (New York: Basic Books, Inc., 1974): at 29-33.
96. Id. at 32-33.
97. See, e.g., P. S. Appelbaum, L. H. Roth, C. W. Lidz, P. Benson, and W. Winslade, "False Hopes and Best Data: Consent to Research and the Therapeutic Misconception," Hastings Center Report 117, no. 2 (1987): 20-24;
98. P.S. Appelbaum, L. H. Roth, and C. Lidz, "The Therapeutic Misconception: Informed Consent in Psychiatric Research," International Journal of Law & Psychiatry 5, no. 3-4 (1982): 319-29;
99. see also E. H. Morreim, "By Any Other Name: The Many Iterations of 'Patient Advocate' in Clinical Research," IRB: Ethics & Human Research 26, no. 6 (2004): 1-8.
100. For further discussion of the basic criteria of ethical research, see E. J. Emanuel, D. Wendler, and C. Grady, "What Makes Clinical Research Ethical?" JAMA 283 (2000): 2701-11.
101. R. J. Levine, "Placebo Controls in Clinical Trials of New Therapies for Conditions for Which There are Known Effective Treatments," in H. A. Guess, A. Lkeinman, J. W. Kusek, and L. W. Engel, eds., The Science of the Placebo: Toward an Interdisciplinary Research Agenda (London: BMJ Books, 2002): 264-80.
102. Appelbaum, Roth, Lidz, Benson, and Winslade, supra note 74; Appelbaum, Roth, and Lidz, supra note 74; Appelbaum, supra note 43; Appelbaum, Lidz, and Grisso, supra note 43.
103. For further discussion of the tensions inherent when one physician provides both treatment and research, see H. Brody and F. G. Miller, "The Clinician-investigator: Unavoidable but Manageable Tension," Kennedy Institute of Ethics Journal 13 (2003): 329-46.
104. S. M. Grunberg and W. T. Cefalu, "The Integral Role of Clinical Research in Clinical Care," N. Engl. J. Med. 348 (2003): 1386-88, at 1388; Miller and Rosenstein, supra note 8, at 1385