¹ The Nuremberg Code, in 2 U.S. GOV't PRINTING OFFICE, TRIALS OF WAR CRIMINALS BEFORE THE NUERNBERG MILITARY TRIBUNALS UNDER CONTROL COUNCIL NO. 10 (1946-1949), reprinted in 276 JAMA 1691, 1691 (1996).

² Robert A. Burt, The Suppressed Legacy of Nuremberg, HASTINGS CENTER REP., Sept.-Oct. 1996, at 30, 33 (suggesting that the self-determination principle which emerged from the Nazi doctors’ trials masks the fact that the Nuremberg judges could not provide a reassuring answer to the question, “whether physicians and/or state officials can be trusted to protect rather than abuse vulnerable people“).

³ See Katz, Jay, The Consent Principle of the Nuremberg Code: Its Significance Then and Now, in THE NAZI DOCTORS AND THE NUREMBERG CODE: HUMAN RIGHTS IN HUMAN EXPERIMENTATION 227, 227-31 (Annas, George J. & Grodin, Michael A eds., 1992)Google Scholar [hereinafter THE NAZI DOCTORS] (discussing the first principle of the Nuremberg Code).

⁴ This observation, of course, will evoke the response that consent under the conditions of incarceration in a concentration camp would unavoidably be coercive; therefore it could never be voluntary and would not be morally valid consent. A full consideration of this claim would require, inter alia, a discussion of the meaning of coercion and challenges to the claim that prisoners under a death threat are incapable of making morally valid choices presented by the state. Under existing federal regulations, prisoners are allowed to make choices regarding their involvement as subjects in certain kinds of experimentation. See Additional Protections Pertaining to Biomedical and Behavioral Research Involving Prisoners As Subjects, 45 C.F.R. §§ 46.301-.306 (1997).

⁵ Examples include experiments that are so poorly designed as to make it unlikely that any useful information will emerge; nontherapeutic studies involving risks which, in the opinion of the institutional review board (IRB), are excessive; or studies in which the investigator has conflicts of interest that raise concerns about his ability to recruit subjects fairly.

⁶ World Med. Ass'n, Declaration of Helsinki: Recommendations Guiding Physicians in Biomedical Research Involving Human Subjects, reprinted in 277 JAMA 925, 925-26 (1997)CrossRefGoogle Scholar [hereinafter Declaration of Helsinki] (as amended by the 48th General Assembly, Somerset West, Republic of South Africa, 1996).

⁷ See 45 C.F.R. §46.116(1997).

⁸ See id. § 46.116(c) (describing conditions under which an IRB may waive some or all of the elements of informed consent); see also id. § 46.117(c) (describing waiver of the requirement that a subject sign a consent form).

⁹ See 21 C.F.R. § 50.23(a)(1) (1997).

¹⁰ See 45 C.F.R. §§ 46.116(d)(1), 46.117(c)(2).

¹¹ See 21 C.F.R. § 50.24(a)(3).

¹² See id. § 314.126(b)(2)(i) (describing placebo concurrent controlled trials).

¹³ See 45 C.F.R. § 46.116(d)(1) (stipulating that the research must present “no more than minimal risk to the subjects“).

¹⁴ See generally ROBERT J. LEVINE, ETHICS AND REGULATION OF CLINICAL RESEARCH 202-07 (2d ed. 1986) (critiquing placebo-controlled clinical trials).

¹⁵ See Biros, Michelle H. et al., Informed Consent in Emergency Research: Consensus Statement from the Coalition Conference of Acute Resuscitation and Critical Care Researchers, 273 JAMA 1283, 1286(1995)CrossRefGoogle Scholar.

¹⁶ See Marwick, Charles, Research in Emergency Circumstances, 273 JAMA 687, 687-88 (1995)CrossRefGoogle Scholar.

¹⁷ Protection of Human Subjects; Informed Consent, 60 Fed. Reg. 49,086 (1995) (to be harmonized with 45 C.F.R. pt. 46 and 21 C.F.R. pt. 50) (proposed Sept. 21, 1995).

¹⁸ Protection of Human Subjects; Informed Consent, 61 Fed. Reg. 51,498 (1996) (to be codified at 21 C.F.R. pts. 50, 56, 312, 601, 812, 814) (effective Nov. 1, 1996).

¹⁹ Basic Principle number 9 states: “In any research on human beings, … [t]he physician should … obtain the subject's freely-given informed consent, preferably in writing.” Declaration of Helsinki, supra note 6, at 926.

²⁰ Id. Paul Ramsey, William Bartholome and others have noted that this so-called “proxy consent” may constitute legally and perhaps ethically sufficient permission to use an incompetent patient as a subject, but is not the moral equivalent of true consent. See, e.g., Bartholome, William G., A New Understanding of Consent in Pediatric Practice: Consent, Parental Permission, and Child Assent, 18 PEDIATRIC ANNALS 262, 262 (1989)CrossRefGoogle Scholar. The primary purpose of true consent is to respect the autonomy of the subject. See id.; see also Paul Ramsey, The Enforcement of Morals: Nontherapeutic Research on Children, HASTINGS CENTER REP., Aug. 1976, at 21, 21 (stating that even though medical codes since the Nuremberg Code have allowed surrogates to give consent for children and other incompetent persons, “[n]o attempt was made to argue that the validity of the proxy consent could be grounded in the subject's presumable consent“). Because the patient is often not participating in this decision, and his willingness to do so is unknown at best, we should not use the term consent in such situations.

²¹ Declaration of Helsinki, supra note 6, at 926.

²² 45 C.F.R. § 46.116(d) (1997).

²³ See 21 C.F.R. § 314.126(a), (b)(1)-(2)(i) (1997) (describing characteristics of an “adequate and well-controlled” study, which is the primary basis on which to determine “substantial evidence” of effectiveness for new drugs; characteristics include a clear statement of a study's objectives and intended methods of analysis, as well as use of a placebo concurrent control group, one of five recognized types of controls).

²⁴ See generally Protection of Human Subjects; Informed Consent, 61 Fed. Reg. 51,498, 51,507 (1996) (discussing the definition of the “therapeutic window” relative to obtaining consent and relative to the likelihood of survival after head injury).

²⁵ The major problem with such an approach is that failure to demonstrate a benefit would leave unanswered the question of whether earlier institution of treatment would have shown a benefit. Animal studies of treatment of brain injury generally showed that earlier institution of treatment had a greater likelihood of showing benefit.

²⁶ See id. at 51,120 (discussing prospective consent).

²⁷ 45 C.F.R. § 46.102(i).

²⁸ Compare 45 C.F.R. § 46.404 (describing “no greater than minimal risk” research with children), with id. § 46.406(a) (describing “minor increase over minimal risk” in nontherapeutic research under certain conditions).

²⁹ Janofsky, Jeffrey & Starfield, Barbara, Assessment of Risk in Research on Children, 98 J. PEDIATRICS 842,844-45 (1981)CrossRefGoogle Scholar.

³⁰ Ernest D. Prentice et al., Can Children Be Enrolled in a Placebo-Controlled Randomized Clinical Trial of Synthetic Growth Hormone?, IRB: REV. HUMAN SUBJECTS RES., Jan./Feb. 1989, at 6, 6 (reviewing the safety and efficacy of hormone therapy in connection with Turner's syndrome).

³¹ See Norman Fost & John Robertson, Deferring Consent with Incompetent Patients in an Intensive Care Unit, IRB: REV. HUMAN SUBJECTS RES., Aug./Sept. 1980, at 5, 5.

³² See id.

³³ See id.

³⁴ See id. (describing how consent must be obtained within 48 hours).

³⁵ The term deferred consent was appropriately criticized by Tom Beauchamp for reasons which, in retrospect, seem correct. See Tom L. Beauchamp, The Ambiguities of ‘Deferred Consent,’ IRB: REVIEW HUMAN SUBJECTS RES., Aug./Sept. 1980, at 6, 7. It would have been better to acknowledge that no consent was obtained for the initial dose and that this should have been called waived consent. See supra note 8 and accompanying text (describing waiver of informed consent). The waiver could have been justified under the existing regulations, in ways that are explicated more fully by Norman Abramson and others. See Abramson, Norman S. et al., Deferred Consent: A New Approach for Resuscitation Research on Comatose Patients, 255 JAMA 2466, 2467-70 (1986)CrossRefGoogle Scholar. The problematic nature of this term emerged again in a Food and Drug Administration (FDA) challenge of a study involving head injury. See Ernest D. Prentice et al., IRB Review of a Phase II Randomized Clinical Trial Involving Incompetent Patients Suffering from Severe Closed Head Injury, IRB: REV. HUMAN SUBJECTS RES., Sept.-Oct. 1993, at 1, 1.

³⁶ See Abramson et al., supra note 35, at 2466.

³⁷ See id. at 2467.

³⁸ See id. at 2468. This position is supported by Charles McCarthy, director of Office of Protection from Research Risks (OPRR), who reported that the Drafting Committee of the Department of Health and Human Services (DHHS) regulations intended for “minimal risk” to be interpreted in this way. See McCarthy, Charles R., To Be or Not To Be: Waiving Informed Consent in Emergency Research, 5 KENNEDY INST. ETHICS J. 155, 158 (1995)CrossRefGoogle ScholarPubMed (stating that “a waiver of informed consent… was justified provided that the increment of risk associated with the subject's participation in a clinical trial was minimal and that the research offered the prospect of significant benefits to the subjects“).

³⁹ 45 C.F.R. § 46.111(a)(2) (1997).

⁴⁰ See Abramson et al., supra note 35, at 2468.

⁴¹ See id. at 2468 (distinguishing “'research’ on the one hand and ‘experimental’ or ‘innovative’ therapy on the other“).

⁴² One of the ironies of this position is that Abramson was unusual among emergency physicians in his commitment to studying innovative therapies as part of rigorously designed prospective clinical trials. Patients in the author's hands, therefore, were less likely to receive thiopental than at some other institutions, because there was a placebo arm in the study. See id. at 2466. The other irony is that the physicians in the study could legally have given thiopental to all the patients without having to consider any of the constraints of the research regulations. See R.W. Smithells, Iatrogenic Hazards and Their Effects, POSTGRADUATE MED. J., 1975 Supp. 2, at 39, 41 (“I need permission to give a new drug to half my patients but not to give it to all of them.“).

I will return to this problem—innovative therapy outside of a research trial. See infra notes 98-114 and accompanying text (describing innovative therapy and discussing an example).

⁴³ See Ernest D. Prentice et al., An Update on the PEG-SOD Study Involving Incompetent Subjects: FDA Permits an Exception to Informed Consent Requirements, IRB: REV. HUMAN SUBJECTS RES., Jan.-Apr. 1994, at 16, 16 [hereinafter Prentice et al., Update on the PEG-SOD Study]; Prentice et al., supra note 35, at 1 (describing a Phase II safety and efficacy study of PEG-SOD as a treatment for severe closed head injury).

⁴⁴ 21 C.F.R. § 50.23(a)(1)-(4) (1997).

⁴⁵ They did raise other questions, however. First, the requirement that the intervention be aimed at saving the patient's life caused problems for those who were candid enough to realize that death was not always the major concern in patients with severe head injuries. Particularly when relatives were the source of consent, the major concern was not that the patient would die, but that he would survive with severe impairment. See Prentice et al., supra note 35, at 4 (describing the possibility of post-traumatic vegetative state). The primary purpose of the treatment, therefore, was not to save the life, but to improve the prospects for quality of life. There are some emergencies in which consent is not feasible, life is not in jeopardy and the goal of experimental treatment is to save a limb, an eye or some other important but not vital structure. Second, the reference to a “legal representative” raised questions about whether spouses or adult children, generally not legal guardians, had legal authority to consent for research. State law is often murky on this subject. See id. (discussing the availability of a legal representative or next of kin).

⁴⁶ There are cases in which a placebo could be life-saving; namely, studies in which therapies that had become standard practice without scientific evidence, come under question. The progression from innovation to standard practice is common, particularly in critical care settings; when careful studies are done, long-established practices have often been shown to cause more harm than benefit, so that assignment to the placebo arm of a study can be life-saving. See Norman Fost, Distinguishing Experimentation from Practice, SEMINARS PERINATOLOGY (forthcoming 1998).

⁴⁷ See Olson, Carin M., The Letter or the Spirit: Consent for Research in CPR, 271 JAMA 1445, 1445 (1994)CrossRefGoogle ScholarPubMed (comparing “compassionate use” and “emergency use” and stating how in both, an “article is employed in a life-threatening situation for which no standard treatment is available“).

⁴⁸ See Marwick, supra note 16, at 687 (quoting Ernest Prentice, Associate Dean for Research, University of Nebraska Medical Center), which states:

Prentice wrote a very thoughtful analysis of his own IRB's approval of the much-discussed PEG-SOD study, in which the IRB relied on a flexible interpretation of the regulation. See Prentice et al., supra note 35, at 1. Prentice and his colleagues interpreted the “minimal risk” rule to refer to the incremental risk of being in the study, as compared with standard treatment. See id. at 2 (describing “minimal differential [incremental] risk“). This approach is similar to the “flexible” interpretation of Abramson and his colleagues. See Abramson et al., supra note 35, at 2468 (describing “minimal differential risk“); see also McCarthy, supra note 38, at 161 (observing “the research community's confusion about the permissibility of waiving consent in emergency research“).

⁴⁹ The Stanford University institutional review board was suspended in 1994 by the FDA for various procedural violations, such as lack of written procedures for determining which projects require review more often than annually, and lack of written procedures for ensuring prompt reporting of problems to the FDA. See Food and Drug Admin., Department of Health and Human Servs., FDA Form 483 (FDA inspectional observations made of the Administrative Panel on Human Subjects in Medical Research at Stanford University, May 3, 1994) (on file with author) [hereinafter FDA Form 483]; see also Letter from Paul W. Goebel, Jr., Chief, Institutional Review Board, Center for Drug Evaluation and Research, to Charles H. Kruger, Vice Provost and Dean, Stanford University (Sept. 28, 1994) (on file with author) (lifting the FDA sanction on the Stanford University IRB, empowering it once again to approve studies regulated by the FDA). There were no claims of violations of subjects'rights or harm to subjects. See FDA Form 438, supra.

⁵⁰ Gary B. Ellis, Informed Consent—Legally Effective and Prospectively Obtained, in OPRR REP. (Office for Protection from Research Risks, National Institutes of Health No. 93-3, Aug. 12, 1993).

⁵¹ See Olson, supra note 47, at 1446 (citing written communication from Gary B. Ellis, director of OPRR to institutional officials and IRB chairs (Aug. 12, 1993)). Former OPRR Director Gary B. Ellis acknowledged that such research would be acceptable if it involved “no more than minimal risk,” but the interpretation of minimal risk varied widely. See id. (citing written communications from Gary B. Ellis (Aug. 12, 1993 and Oct. 21, 1993)). The effect of these warnings was to make at least some IRBs very uneasy about the risk of legal sanctions if they interpreted the rules in the wrong way. See id. (noting that “current regulations do not relate to resuscitation research in humans“; “IRBs are confused“; and “the FDA and DHHS regulations are inconsistent“).

Charles McCarthy, director of OPRR, questioned OPRR's authority: “OPRR, however, seems determined to uphold a strict interpretation of the HHS regulations that, despite the intent of the Drafting Committee, rules out waivers of informed consent in virtually all cases of emergency research. OPRR has provided little justification for its position ….” McCarthy, supra note 38, at 160.

⁵² See Olson, supra note 47, at 1446 (citing oral communication with Susan Alpert, M.D., Mar. 29, 1994 and written communication with Robert Temple, M.D., Mar. 31, 1994).

⁵³ See Keith G., Lurie et al., Evaluation of Active Compression-Decompression CPR in Victims of Out-of-Hospital Cardiac Arrest, 271 JAMA 1405, 1407 (1994)Google Scholar; Olson, supra note 47, at 1445 (discussing Lurie's study).

⁵⁴ See Lurie et al., supra note 53, at 1405.

⁵⁵ See id. at 1407 (noting that the FDA, in light of no adverse outcomes, granted permission for the study to continue to the end of the second completed crossover period).

⁵⁶ See Prentice et al., Update on the PEG-SOD Study, supra note 43, at 16. The FDA allowed the study to resume provided the protocol was revised in accordance with ad hoc guidelines approved by the FDA. See id.

⁵⁷ See Problems in Securing Informed Consent of Subjects in Experimental Trials of Unapproved Drugs and Devices: Hearings Before the Subcomm. on Regulation, Business Opportunities, and Technology of the House Committee on Small Business, 103d Cong. 49 (1994) (testimony of Dr. Norman Fost) (describing three such safeguards: (1) review by focus groups comprised of nonsubject patients and relatives; (2) debriefing of subjects after they have been informed of the initial experimental treatments; and (3) independent review by the NIH or DHHS of study designs before the study begins).

⁵⁸ See Marwick, supra note 16, at 687.

⁵⁹ “By the end of the forum, it had become clear that there was widespread agreement that the existing regulations regarding the conduct of research under emergency circumstances need to be revised and the NIH and FDA rules harmonized.” Id. at 688.

⁶⁰ Protection of Human Subjects; Informed Consent, 60 Fed. Reg. 49,086 (1995).

⁶¹ Protection of Human Subjects; Informed Consent, 61 Fed. Reg. 51,498 (1996).

⁶² See 21 C.F.R. § 50.24(a)(1) (1997).

⁶³ See id.

⁶⁴ See id. § 50.24(a)(2).

⁶⁵ See id. § 50.24(a)(4).

⁶⁶ See id. § 50.24(a)(3)(iii).

⁶⁷ See id. § 50.24(a)(3).

⁶⁸ See id. § 50.24(a)(7)(i).

⁶⁹ See id. § 50.24(a)(7)(ii).

⁷⁰ See id. § 50.24(a)(7)(iii).

⁷¹ See id. § 50.24(a)(7)(iv).

⁷² See id. § 50.24(d)-(e). Existing rules do not require FDA oversight of studies involving new applications of a previously approved drug or device. See 21 C.F.R. § 312.2(b)(1); see also Kessler, David A., Regulating the Prescribing of Human Drugs for Nonapproved Uses Under the Food, Drug, and Cosmetic Act, 15 HARV. J. ON LEGIS. 693, 707-08 (1978)Google Scholar (describing nonapproved uses of FDA-approved drugs). In industry-sponsored trials, there would generally be an interest in obtaining prospective FDA approval for the research design, because marketing of a drug for the new indication would require FDA approval. See 21 U.S.C.A. § 355(a), (d) (West Supp. 1998) (requiring FDA approval before a new drug can be introduced into interstate commerce and setting forth the grounds for refusing an application). Some studies, however, could be funded by hospitals, medical schools, private foundations and others who would not necessarily be interested in or need FDA approval. See id. (describing substantial evidence from clinical investigations).

⁷³ JAY KATZ, EXPERIMENTATION WITH HUMAN BEINGS (1972).

⁷⁴ See Gina Kolata, Ban on Medical Experiments Without Consent Is Relaxed, N.Y. TIMES, Nov. 5, 1996, at Al (quoting ethicist and attorney Jay Katz while he was at a conference in Nuremberg, marking the 50th anniversary of the Code). “'It's a fateful step,’ said Jay Katz, lamenting the fact that ‘we are making exceptions’ to the first principle of the Code.” Id.; see also Katz, supra note 3, at 235 (praising the Nuremberg Code because it “stands alone in its unequivocal declaration of rights, perhaps even inalienable rights, of subjects to consent to participation in research“).

⁷⁵ “Many [African Americans] will wonder what's different about this latest abrogation of informed consent. Is this yet another opportunity to force African Americans to be guinea pigs for ‘white’ science? … [T]he Tuskegee experiment is the emblem of experimentation without consent.…” Annette Dula, Bearing the Brunt of the New Regulations: Minority Populations, HASTINGS CENTER REP., Jan.-Feb. 1997, at 11, 12. Annette Dula goes on to describe other atrocities in the history of human experimentation on minorities, see id., none of which would be permissible under the new rule. See generally JONES, JAMES H., BAD BLOOD: THE TUSKEGEE SYPHILIS EXPERIMENT 2 (1993)Google Scholar (describing the Tuskegee Study, which in no way involved treatment, but was instead “a nontherapeutic experiment, aimed at compiling data on the effects of the spontaneous evolution of syphilis on black males“); Gamble, Vanessa N., Under the Shadow of Tuskegee: African Americans and Health Care, 87 AM. J. PUB. HEALTH 1773 (1997)CrossRefGoogle Scholar (discussing the legacy of Tuskegee).

⁷⁶ In the words of George Annas, ethicist and health lawyer at Boston University:

Kolata, supra note 74, at Al.

⁷⁷ Jack Kevorkian, At Least My Patients Gave Consent, L.A. TIMES, Feb. 12, 1997, at B9.

⁷⁸ See Burt, supra note 2, at 30; Katz, Jay, Informed Consent—Must It Remain a Fairy Tale?, 10 J. CONTEMP. HEALTH L. & POL'Y 69, 71 (1994)Google Scholar.

⁷⁹ See Committee on Bioethics, American Academy of Pediatrics, Informed Consent, Parental Permission, and Assent in Pediatric Practice, 95 PEDIATRICS 314, 315 (1995)Google Scholar; Bartholome, supra note 20, at 262.

⁸⁰ See Protection of Human Subjects; Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research, Report of the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, 44 Fed. Reg. 23,192, 23,193 (1979) (stating that subjects with diminished autonomy may “require protect[ion],” the extent of which “should depend upon the risk of harm and the likelihood of benefit” to the subject).

⁸¹ See Bartholome, supra note 20, at 262-64 (discussing assent, consent and dissent by the child); Committee on Bioethics, supra note 79, at 315-16 (same).

⁸² See supra note 8 and accompanying text (discussing federal regulations regarding waiver of informed consent).

⁸³ See RUTH R. FADEN & TOM L. BEAUCHAMP, A HISTORY AND THEORY OF INFORMED CONSENT 38-39 (1986).

⁸⁴ See generally Katz, supra note 78, at 72-81 (describing the physician's role in medical decision- making).

⁸⁵ See Levine, Robert J., International Codes and Guidelines for Research Ethics: A Critical Appraisal, in THE ETHICS OF RESEARCH INVOLVING HUMAN SUBJECTS: FACING THE 21ST CENTURY 235, 239 (Vanderpool, Harold Y. ed., 1996)Google Scholar [hereinafter ETHICS OF RESEARCH].

⁸⁶ “Consent … is a means to an end…. [The goal] is to do what the patient would want.” Kolata, supra note 74, at Al (quoting Dr. Norman Fost).

⁸⁷ “[I]t seems to me that a reasonable person [with severe head injury] would very much want to be in [an emergency research] study,” especially if standard treatment would provide little help. Kolata, supra note 74, at Al (quoting Dr. Norman Fost).

⁸⁸ See Katz, supra note 78, at 69.

⁸⁹ See Ingelfinger, F.J., Informed (but Uneducated) Consent, 287 NEW ENG. J. MED. 465, 465 (1972)CrossRefGoogle Scholar (“The trouble with informed consent is that it is not educated consent.“).

⁹⁰ See id. at 466.

⁹¹ See id. at 465; see also JAY KATZ, THE SILENT WORLD OF DOCTOR AND PATIENT 48-84 (1984) (describing the history and evolution of the legal doctrine of informed consent).

⁹² See 45 C.F.R. § 46.116 (1997).

⁹³ See supra note 20 (discussing how proxy consent, although perhaps ethically sufficient, is nonetheless not equivalent to true consent).

⁹⁴ See 45 C.F.R. §46.116(d).

⁹⁵ “[T]he doctrine of informed consent, as currently articulated, imposes similar disclosure and consent obligations for therapy and research, with the only difference being that for research the informed consent process is subjected to review by IRBs.” Katz, Jay, Human Experimentation and Human Rights, 38 ST. LOUIS L.J. 7, 13-14 (1993)Google Scholar.

⁹⁶ See id. at 14 (noting that research is subject to IRB scrutiny).

⁹⁷ See Burt, supra note 2, at 30; Katz, supra note 3, at 227.

⁹⁸ See Protection of Human Subjects; Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research, Report of the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, 44 Fed. Reg. 23,192, 23,193 (1979) (noting that when a clinician makes a significant departure from standard practice in an often “new, untested or different” way, it does not automatically constitute “research,” and is therefore subject to formal protocols setting forth specific objectives and procedures).

⁹⁹ See id. at 4 (defining “innovative therapy” as a type of “nonvalidated practice“). “Therapy” here is intended to encompass innovative diagnostic and monitoring techniques, intended primarily for the benefit of the patient with no intent to advance knowledge for the general welfare. See, e.g., Levine, Robert J., Informed Consent in Research and Practice: Similarities and Differences, 143 ARCHIVES INTERNAL MED. 1229, 1231 (1982)CrossRefGoogle Scholar, cited in Katz, supra note 95, at 25.

¹⁰⁰ See Katz, supra note 95, at 12 (stating that “every medical intervention, therapeutic or investigative in intent, constitutes an experiment“).

¹⁰¹ Personal communication with Paul Lietman, M.D., Ph.D. (1971).

¹⁰² Much of this discussion is drawn from Fost, supra note 46.

¹⁰³ See, e.g., Olson, supra note 47, at 1447 (observing that the “only honest approach is to recognize that truly informed prospective consent is not possible for some research“); see also Biros et al., supra note 15, at 1284-85 (discussing regulatory issues applicable to emergency research).

¹⁰⁴ These misadventures include the inappropriate use of exogenous oxygen to minimize hypoxic brain damage, infant mortality due to sulfisoxazole use, excessive administration of Vitamin K, overdosages of chloramphenicol, bicarbonate therapy for the acidemia of “respiratory distress syndrome” and the use of gentamicin for gram negative infections. See Odell, Gerard B., Therapeutic Misadventures in Neonatal Care, in MODERN PERINATAL MEDICINE 323, 323-31 (Gluck, Louis ed., 1974)Google Scholar; Fost, supra note 46.

¹⁰⁵ See generally Charles R. McCarthy, Challenges to IRBs in the Coming Decades, in ETHICS OF RESEARCH, supra note 85, at 127, 142 (discussing a variety of ethical issues in research and noting that the resolution of which is necessary to preserve the integrity of the research community).

¹⁰⁶ See supra notes 68-72 and accompanying text.

¹⁰⁷ See Baxter Healthcare Corp., Hemoglobin Therapies (May 8, 1998) http://www.baxter.com/www/Biotech/hemoglobin_ther.html.

¹⁰⁸ See id.

¹⁰⁹ See id.

¹¹⁰ See id.

¹¹¹ See id.

¹¹² It is important to keep in mind that a difference between the treatment and control groups could be due to factors besides a difference in drug effect, including nonrandom assignment; chance; and other nondrug factors. A European trial with the same drug is still in progress, see id., suggesting that serious toxicity has not been seen in that study.

¹¹³ See Beecher, Henry K., Ethics and Clinical Research, 274 NEW ENG. J. MED. 1354 (1966)CrossRefGoogle Scholar (describing unethical medical research).

¹¹⁴ See supra notes 62-72 and accompanying text (describing DHHS and FDA oversight).

¹¹⁵ See Abramson, Norman S. & Safar, Peter, Deferred Consent: Use in Clinical Resuscitation Research, 19 ANNALS EMERGENCY MED. 781, 782 (1990)CrossRefGoogle Scholar.

¹¹⁶ See id.

¹¹⁷ See id. at 781-82.

¹¹⁸ See id.

¹¹⁹ See id. at 782.

¹²⁰ See id.

¹²¹ See id.

¹²² See id.

¹²³ See id.

¹²⁴ See id. at 783.

¹²⁵ See id.

¹²⁶ It cannot be inferred that the results would be the same for all trials. There are many variables, including the results of standard treatment; the expected risks of the experimental treatment; the particular population; the level of trust in the treating institution and physicians; and so on. More empiric work is needed and should be available from the trials conducted under the waiver. The Abramson study only shows that waived consent can be compatible with the informed desires of the great majority of those who would be asked to consent prospectively.

¹²⁷ Some have argued, unconvincingly in my view, that placebos are never justified, even with consent. See Rothman, Kenneth J. & Michels, Karin B., The Continuing Unethical Use of Placebo Controls, 331 NEW ENG. J. MED. 394, 397 (1994)CrossRefGoogle Scholar (claiming, inter alia, that placebo controls almost always violate the Declaration of Helsinki). But see Varmus, Harold & Satcher, David, Ethical Complexities of Conducting Research in Developing Countries, 337 NEW ENG. J. MED. 1003, 1004 (1997)CrossRefGoogle Scholar (stating that the “most compelling reason to use a placebo-controlled study is that it provides definitive answers to questions about the safety and value of an intervention … [which] are the point of the research“). For an analysis of the deficiencies of the Declaration, see Levine, supra note 85, at 250-53.

¹²⁸ See Rothman & Michels, supra note 127, at 395 (describing clinical trials in which some patients did not receive the “best proven” treatments).

¹²⁹ See id. at 397 (discussing recommendations regarding placebo controls).

¹³⁰ This discussion assumes a study in which all patients receive standard treatment, and are randomized to receive either an experimental treatment or placebo. The argument changes if standard treatment is withheld.

¹³¹ See Abramson & Safar, supra note 115, at 783 (describing generally positive reactions from families’ participation in a “deferred consent” study and concluding that “participation … was refused only when families thought, because of the patient's underlying state of health, that further lifesaving therapy should be withheld” (emphasis added)).

¹³² Recall that even concurrent so-called informed consent is commonly only a window into what the patient might want if fully informed. See, e.g., Ingelfinger, supra note 89, at 465 (discussing problems with truly informed consent). Present standards for legally valid consent fall far short of confirming that the patient's consent is truly informed and freely chosen. See. e.g., Katz, supra note 95, at 24 (“The U.S. federal regulations on informed consent … do not go far enough in emphasizing the centrality of the inviolability of the human rights of research subjects, if not as an ethical obligation than surely as a societal obligation in a democracy.“); see also Katz, supra note 78, at 84 (stating that “informed consent in today's world, is largely a charade which misleads patients into thinking that they are making decisions when indeed they are not“).

¹³³ 21 C.F.R. § 50.24(1997).

¹³⁴ See supra notes 68-70 and accompanying text; see also Protection of Human Subjects; Informed Consent, 61 Fed. Reg. 51,498, 51,513, 51,517 (1996) (discussing community consultation and public disclosure).

¹³⁵ See Gamble, supra note 75, at 1773.

¹³⁶ See id.

¹³⁷ 21 C.F.R. § 50.24(b).

¹³⁸ See Marcia Angell, Editorial Responsibility: Protecting Human Rights by Restricting Publication of Unethical Research, in THE NAZI DOCTORS, supra note 3, at 276, 276.

¹³⁹ See Katz, supra note 3, at 227, 228.

¹⁴⁰ See Protection of Human Subjects; Informed Consent, 61 Fed. Reg. at 51,498; Protection of Human Subjects; Informed Consent, 60 Fed. Reg. 49,086, 49,086 (1995).

¹⁴¹ See Merz, Jon F. & Caplan, Arthur L., Informed Consent for Emergency Research, 274 JAMA 1196, 1196 (1995)CrossRefGoogle Scholar (discussing advance directives in the context of emergency research).

¹⁴² See 21 C.F.R. § 50.24(a)(2)(iii) (allowing deferred consent if there is no reasonable way to identify patients prospectively); id. § 50.24(a)(4) (allowing deferred consent if there is no practical way to carry out the research without a waiver).

¹⁴³ See Prentice et al., supra note 35, at 4 (discussing the risk of vegetative state after severe head trauma).

¹⁴⁴ See id. (observing that the experimental treatment might “theoretically[] reduce the risk of brain damage and/or mortality“).