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COPYRIGHT 2008 Pro-Ed
Ethical and legal principles are provided for reviewing the ethics of recent cases of biomedical research abuse involving persons with decisional impairments or legal incapacity who were unable to understand the risks and benefits of the research to which they were subjected. Research abuse continues to occur despite guidance from the Nuremburg Code, the Declaration of Helsinki, the U.S. Belmont Report, extensive federal regulations governing human participant research, and several professional and disciplinary codes of ethics with which, the authors believe, the majority of researchers comply. Contributing to research abuse are weaknesses in the institutional review board and research ethics board review process; conflicting opinions about applicable ethical principles; mounting evidence of pervasive conflicts of interest; and dubious conflated research and marketing practices involving researchers, pharmaceutical and medical device manufacturers, and government research sponsors and regulatory agencies. Several recommendations are made to correct identifiable weaknesses and failures in the governance of biomedical research.
Keywords: research ethics; human participants abuse; decisional impairments; Nuremberg Code; institutional review boards; conflicts of interest
People with decisional impairments and legal incapacity historically have been targeted by biomedical researchers and their governmental and industrial sponsors for exposure to experiments that impose high risks without offsetting therapeutic benefits on the theory that the future good of society justifies what is done to them. The final report of the Advisory Committee on Human Radiation Experiments (ACHRE, 1995) systematically reviewed and condemned much of what was done to institutionalized persons with mental retardation in such places as Willowbrook in New York State and the Walter Fernald School in Massachusetts. Abusive biomedical research has continued to this day since the publication of the ACHRE report--although now involving different decisionally impaired populations than the persons with mental retardation whose human fights were secretly violated between 1944 and 1974 in radiation experiments conducted and sponsored by the U.S. government (Schatz, 2003).
We review the ethical and legal principles by which to judge the propriety of several recent cases, including symptom provocation experiments on schizophrenic patients, respirator tidal volume experiments on cognitively impaired and unconscious patients with acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), experiments on children with HIV under municipal or state guardianship, and lead-poisoning experiments on healthy poor children subject to parental control that caused ensuing neurological impairments. Each of the cases has provoked controversy, some have been litigated, and all have received considerable professional and general media attention and commentary.
The cases all involve use of surrogate or, in the case of children, parental consent to enroll persons who were either physically, intellectually, psychologically, or legally incapable of understanding and consenting to the risks and benefits of the research to which they were subjected; hence, they are deemed decisionally impaired, in the broad usage of the term. The decisional state or legal capacity rather than the etiology or condition causing it is our focus. Decisional impairment refers to a primary condition, such as dementia or psychosis, that is known to interfere with normal cognitive functioning; it also refers to "conditions in which patients might reasonably be expected to have cognitive impairments as a consequence of severe pain or anxiety or confusion, such as cancer or trauma or life-threatening illness" (UCSD Task Force on Decisional Capacity, 2003). Federal and state laws require parental consent for children to participate in research because their intellectual and emotional capacities are deemed so limited that they lack legal capacity to give consent (see the Researcher's Guide, UMBC, 2006).
Weaknesses in the institutional review board (IRB) and research ethics board (REB) review process (Ashcrofl, Newson, & Benn, 2005; Breckler, 2005; Wilson, 2005); conflicting opinions about applicable ethical principles (Ashcroft, 2005; Baum, 2000; Bevan, 2000; Levine, 1999; Lilford & Djulbegovic, 2001; Rothman & Michels, 2000); and mounting evidence of pervasive conflicts of interest and dubious conflated research and marketing practices involving biomedical researchers, pharmaceutical and medical device manufacturers, and government research sponsors and regulatory agencies in the United States and other countries (Ashcroft et al., 2005; "Drug Industry Human Testing," 2005; Elliott, 2005; "Prominent Medical School Professors" 2005; University of Bath, 2005; Wilson, 2005) argue for offsetting reforms in research governance to strengthen the protections afforded to people with decisional impairments and legal incapacity. Commitment to the primacy of individual human rights as recognized by the International Covenant on Civil and Political Rights (1966) and to the safeguards contained in the Fourth, Fifth, and Eighth Amendments of the U.S. Constitution (Schatz, 2003) urges adoption of policies to enhance openness, full disclosure, and public accountability in biomedical research to curtail, if not end, documented abuses.
Our analytic approach follows the customary course of biomedical research ethics development by reacting to concrete examples of problematic behavior and asking "How can this particular evil be avoided?" (Weijer, 1997). Paradoxically, even clinicians, who take great pains to obtain valid consent and succeed through the consenting process to meet the needs of parents trying to decide whether to enroll their children in an oncology trial, themselves remain dissatisfied with the process and obstacles to obtaining "good informed consent" (Kodish et al., 1998). With Weijer (1997), we also recognize that questions of ethics in research are "no longer restricted to narrow aspects of the protocol (e.g., the consent form) but, rather, are seen to permeate the design, conduct and (even) reporting of research" (p. 1554). Common counterarguments to our policy change proposals are presented to highlight how difficult it will be to gain their acceptance by the biomedical research community without benefit of strong advocacy by affected consumers and the public at large.
Applicable Ethical Standards
The sources of ethical standards governing research involving human participants conducted in the United States are the Nuremberg Code (1947/1949); the Declaration of Helsinki (World Medical Assembly, 1964, as amended); the Belmont Report of the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research (1979), on which current federal law and regulations are based (45 C.ER. 46 and 21 C.ER. 50); and the Good Clinical Practice Guidelines (International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 1997; Toxicology Excellence for Risk Assessment, 2002). There are also four international human rights instruments that have immediate bearing: (a) Universal Declaration of Human Rights (1948), (b) International Covenant on Civil and Political Rights (1966), (c) Declaration on the Right and Responsibility of Individuals, Groups and Organs of Society to Promote and Protect Universally Recognized Human Rights and Fundamental Freedoms (1999), and (d) Principles for the Protection of Persons With Mental Illness and the Improvement of Mental Health Care (1991).
The Nuremberg Code was enacted by the World War II war crimes tribunal in reaction to the atrocities committed by Nazi physicians on concentration camp inmates before and during the war. The code lays down the basic conditions and limits under which experiments on human participants are permitted. First and foremost is that the human participant be legally capable of giving voluntary informed consent to take part
without the intervention of any element of force, fraud, deceit, duress, overreaching, or other ulterior form of constraint or coercion; and should have sufficient knowledge and comprehension of the elements of the subject matter involved as to enable him to make an understanding and enlightened decision. (Principle 1)
Second, the human participant "should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to him to be impossible" (Principle 9). Third, the experiment must offer the prospect of yielding "fruitful results for the good of society, unprocurable by other methods or means of study, and not random and unnecessary in nature" (Principle 2). Fourth, the risk entailed should "never exceed that determined by the humanitarian importance of the problem to be solved by the experiment" (Principle 6). Fifth, the experiment should be terminated if the scientist in charge "has probable cause to believe, in the exercise of good faith, superior skill and careful judgment required of him that a continuation of the experiment is likely to result in injury, disability, or death to the experimental subject" (Principle 10).
The Declaration of Helsinki of the World Medical Assembly (1964) builds on the Nuremberg Code and amplifies its provisions with respect to the conduct of (a) medical research combined with professional care and (b) nontherapeutic research involving human participants. Generally, Principle 6 of the Declaration of Helsinki enunciates "the fight of the research subject to safeguard his or her integrity" and the duty of the scientifically qualified persons under the supervision of a clinically competent medical person "to respect the privacy of the subject and to minimize the impact of the study on the subject's physical and mental integrity and on the personality of the subject." Principle 7 indicates that "physicians should abstain from engaging in research involving human subjects unless they are satisfied that the hazards involved are believed to be predictable" and that they "should cease any investigation if the hazards are found to outweigh the potential benefits." Principle 9 affirms that
each potential subject must be adequately informed of the aims, methods, anticipated benefits and potential hazards of the study and the discomfort it may entail; that he or she is at liberty to abstain from participation in the study and that he or she is free to withdraw his or her consent to participation at any time.
The Declaration of Helsinki addresses a number of issues on which the Nuremberg Code is silent. Principle 8 requires that the physician "preserve the accuracy of the results" in publications and that reports "not in accordance with the principles laid down in this Declaration should not be published." With respect to medical research combined with professional care, the Declaration states that "the potential benefits, hazards and discomfort of a new method should be weighed against the advantages of the best current diagnostic and therapeutic methods" and that "every patient, including those in a control group, if any, should be assured of the best proven diagnostic and therapeutic method." With respect to nontherapeutic biomedical research involving human participants, the Declaration asserts that the physician is "to remain the protector of life and health of that person on whom biomedical research is carried out;" that the participants should be volunteers regardless of health status; and that "the interest of science and society should never take precedence over considerations relating to the well-being of the subject."
The Belmont Report of the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research (1979) expands the scope of the Nuremberg Code and the Declaration of Helsinki to include behavioral research involving the use of human participants. It adopts a threefold classification of the basic ethical principles governing biomedical and behavioral research involving use of human participants in terms of (a) respect for persons, (b) beneficence, and (c) justice....
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