Informed consent for biomedical research in acute care medicine.

CONCEPTS informed consent, biomedical research

Informed Consent for Biomedical Research in A c u t e Care Medicine [Spivey WH, Abramson NS, Iserson KV, MacKay CR, Cohen MP: Informed consent for biomedical research in acute care medicine. Ann Emerg Med November 1991;20:1251-1265.] INTRODUCTION William H Spivey, M D Informed consent has long been recognized as an essential component of any research study. It serves as the basis of a partnership between the physician/researcher and patient to improve the quality of medical care. The process of informed consent allows the patient to become knowledgeable about the research process and its potential benefits and risks. It also provides an opportunity for open discussion of uncertainties in medical care. Problems arise, however, when there is not adequate time to fully inform a patient about the research or the patient is unable to understand the research due to coma or altered mental status or if under duress. With the emergence of physicians specializing in acute care medicine and a greater emphasis being placed on early intervention in acute disease states, acute care research has increased dramatically. New therapies for cardiac and brain resuscitation, myocardial infarction, and cerebral infarction have been developed in recent years and are continuing to emerge. This research is often conducted on patients who are under duress, have an altered mental status, or, ill some cases, may be in cardiac arrest. Few people would argue that research in these and other areas of acute care medicine is both necessary and beneficial to society. However, this research raises the question, how do we conduct investigative studies and at the same time protect the rights of the patient to be fully informed and decide whether to participate in the research? At the American Association of Medical Colleges annual meeting in October 1990, a panel of four experts discussed the issue of informed consent in acute care research. Each of the participants in the conference offered a unique perspective of the problem. Norman Abramson, MD, principal investigator of the Brain Resuscitation Clinical Trial III, which has used the concept of deferred consent to obtain consent in patients undergoing experimental therapy for cardiac and cerebral resuscitation, discussed informed consent from the viewpoint of an investigator who has conducted research with patients in cardiac arrest. Ken Iserson, MD, an emergency physician and fellow at the University of Chicago Center for Clinical/Medical Ethics, offered an overview of the problems as seen by an ethicist. Charles MacKay, PhD, Director of Program Development and Evaluation in the Office for Protection from Research Risks at the US National Institute of Health, discussed the current NIH regulations and how they address the issue of informed consent in acute and emergency care. Morton Cohen, Esquire, professor of law at Golden Gate University, who has successfully litigated cases involving the rights of mentally ill and the elderly to informed consent regarding treatment, discussed the legal issues involved and the perspective of a patient advocate to the informed consent process. Although the background and experience of each participant in this conference was different, several points were made repeatedly. Research in acute disease processes and therapy is important to the future benefit of

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Annals of Emergency Medicine

William H Spivey, MD, FACEP*

Philadelphia, Pennsylvania Norman S Abramson, MD, FACEPt Pittsburgh, Pennsylvania Kenneth V Iserson, MD, MBA, FACEP~Tucson, Arizona Charles R MacKay, PhD§ Bethesda, Maryland Morton P Cohen, EsqII San Francisco, California From the Department of Emergency Medicine, Medical College of Pennsylvania, Philadelphia;* the Resuscitation Research Center, University of Pittsburgh;t Arizona Bioethics Program and Section of Emergency Medicine, University of Arizona College of Medicine, Tucson;* Project Clearing Office, National Institute of Health, Bethesda, Maryland;§ and Golden Gate University, San Francisco, California.II Received for publication June 10, 1991. Accepted for publication July 22, 1991. These are the proceedings of the panel discussion "Informed Consent' for Biomedical Research in Acute Care Medicine," presented at the 101st annual meeting of the Association of American Medical Colleges, October 10, 1990, and sponsored by the Society for Academic Emergency Medicine, the American College of Emergency Physicians, and the American Board of Emergency Medicine. Address for reprints: Mary Ann Schropp, Society for Academic Emergency Medicine, 900 West Ottawa Street, Lansing, Michigan 48915.

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INFORMED CONSENT Spivey et al

society. In order to conduct this research, investigators must make every reasonable effort to ensure the safe participation of patients in the study and involve the patient and/or family in the consent process. Finally, the individual patient's welfare must be the primary concern of the investigator. This is more important than long-term benefits of the research to society.

INFORMED CONSENT FOR CLINICAL RESUSCITATION RESEARCH Norman S Abramson, MD Central to our society's philosophy of the ethical conduct of human research is the protection of patient rights and welfare. "Patient rights" generally refers to the concepts of autonomy and self-determination. Informed consent is one of the tools used to accomplish this goal of protecting human rights. There are several requirements for a patient to provide valid consent for medical treatment. First, the patient must have decision-making capacity, ie, must be mentally capable of understanding the situation and consenting. He or she must be in emotional state that allows information to be evaluated and a reasoned conclusion to be reached. Second, he or she must be legally competent. Third, there is the requirement for "volunteeriness," an awkward term used by the President's Commission for Biomedical Ethics. I believe the intentional use of this awkward term was intended to emphasize their belief that a patient with a threatening medical disease cannot really be considered to be in a position of having free choice. However, that patient should at least be free from coercive influences when making a decision on medical therapy. Finally, information must be disclosed to the patient that is comprehensible to the patient and adequate for making an informed decision. The amount of information to be divulged continues to be a source of controversy among patients and medical providers.

Exceptions to Informed Consent for Research There are generally recognized exceptions to the requirement for obtaining informed consent for medical therapy.1 These include: Waiver by patient. A patient may waive his or her rights to be informed and to consent for medical therapy. Therapeutic privilege. In narrowly defined circumstances, a physician may decide that providing information to the patient and placing the responsibility for making a treatment choice on the patient is harmful (usually on a psychological basis). Incompetence. The patient is deemed not capable, usually through mental incapacity, to understand information and to make a decision. In this case, the next of kin is usually requested to consent for the patient. However, the next of kin is required to do what is best for the patient. Emergency exception. If a life-threatening emergency exists and treatment must be rendered immediately to prevent harm, a physician may provide emergency medical care for a patient without obtaining consent. In this situation, the physician must do what he or she believes is best for the patient. This restriction does not limit the use of innovative therapies or experimental efforts as long as the patient's best interest is the motivator of the decision. 116/1252

The provision of medical therapy is generally considered to be quite a different situation from clinical research. Here the decisions being made and the procedures conducted are also aimed at developing generalizable advances in knowledge (which may or may not benefit the individual patient). In clinical research, treatment allocation is usually decided using a predesignated mechanism, eg, randomization, rather than by individualized consideration of what is best for the patient. Here, it is often said, the best interests of the patient are not the primary consideration. Thus, the emergency exception has not been considered applicable. Studies have shown that well-educated (as well as less educated, I suppose) adults are likely to overrate the accuracy and precision of their knowledge. Indeed, studies of physicians' clinical behavior have demonstrated this as well.2, 3 In other words, things don't always go as we expect. There is much of "standard therapy" about which our "knowledge" is uncertain, eg, tonsillectomies, hysterectomies, and so on. We often don't know what is best for the patient, and what we think is best today will be different tomorrow (or in ten years). Thus, one can persuasively argue that the provision of medical care (with the patient's best interests in mind) and the conduct of scientific research are, in many areas not as disparate as we might have believed. In addition, our approach to obtaining consent for clinical research should not be that different from our approach to obtaining consent for medical therapy.

Clinical Resuscitation Research Medical therapy often must be initiated and conducted in a relatively immediate time frame. Outcome of patients with such life-threatening medical emergencies can be divided into three general categories: survival in an awake state, survival in a comatose state, and death. Historically, our approach for brain resuscitation has been to wait until patients are resuscitated from the initial insult and then, when they are (it is hoped) in a relatively stable state, to initiate experimental measures aimed at enhancing brain recovery. Time limitations as well as the emotional state of family members (if they are even available) preclude the traditional informed consent process from being concluded prior to the initiation of experimental therapy.

Consent for Clinical Resuscitation Research There is a spectrum of possible solutions to the problem of obtaining consent in this situation. We can grant absolute status to the patient rights of autonomy and self-determination, thus precluding the conduct of such research. Or we can ignore individual rights and decide that this research is of such importance to society that these rights are justifiably ignored. The tendency of our society is to try to reach a compromise position, a middle ground where both extremes are afforded some recognition. Various regulatory agencies have attempted to strike such a balance. The requirements for waiver of consent, as recommended by the Food and Drug Administration, are perhaps the most straightforward approach. 4 These include life-threatening situation; inability to communicate; insufficient time; and no alternative therapy having equal or greater likelihood of benefit. The first three points are obviously satisfied during clinical resuscitation research. The fourth presents a problem


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in that it requires pre-existing knowledge that the experimental therapy is preferable to the standard therapy. If the investigator actually believes this, and if he or she is unable to discuss the choices with the patient, then the investigator should not treat the patient with anything but what he or she believes to be best therapy. However, as we have discussed previously, such initial preferences are often inaccurate. In fact, it is the purpose of the research to elucidate these very facts. Department of Health and Human Services (DHHS) regulations propose a different set of criteria for waiver of consent: 5 research is not practical without a waiver; whenever appropriate, information is provided after participation; there is minimal risk; and rights and welfare not adversely affected. The first point is satisfied in resuscitation research where immediate therapy is needed and the emotional state of the relatives (and the mental state of the patient) in the time frame available will not allow consent to be obtained. The second point is easily satisfied. The third point presents a problem in that the regulations seem to require that the acceptable level of risk of the experimental therapy is to be no more than that level encountered in normal life by a normal subject, eg, medical examination of a normal patient in a doctor's office. This is too restrictive when applied to patients who are near death at the time they are entered into a clinical trial. Obviously, the prognosis of these patients is poor any side effects of the experimental therapy may not significantly worsen their prognosis. Often such patients might, outside of a clinical study, receive the experimental therapy anyway (in desperate situations treatment often includes innovative therapies). The risk of subjecting the patient to the research process, ie, making a treatment choice by a predetermined research study mechanism, can only be known when the study is completed. If the risk:benefit ratio of the experimental therapy were already known, the study would be unnecessary. The final point of the DHHS regulations concerns patient rights and welfare. Whether the patient's welfare is adversely affected can only be known when the trial is completed. As far as rights are concerned, it is important that not only should the physician have no reason to prefer one therapy over another, but the patient also should not have any reason for having a preference. That preference does not have to be rational or congruent with the physician's preference.

Deferred Consent For more than a decade, we have been wrestling with this problem of informed consent in resuscitation research. We have adopted and adapted the concept of obtaining deferred consent, as first proposed by Fost and Robertson. 6 In resuscitation research studies such as those described previously, we will enter the patient into the study and initiate the experimental therapy prior to discussing it with patient's family. Once the patient is stabilized and the initial experimental therapy is begun, we will then discuss this with the family. All information that would have been provided had they been approached using the traditional prospective consent mechanism will be discussed. Families then have the opportunity to determine whether the patient will continue in the study, ie, 20:11 November 1991

continue to receive the experimental therapy and participate in study follow-up and data collection. They are assured that if the patient is withdrawn from the study, standard therapy will be provided without any compromise. We have developed guidelines for the use of this deferred consent mechanism that are similar to the previously mentioned federal guidelines/regulations for exceptions to informed consent in human research, but with some significant differences. Our guidelines require that patients be incompetent, a life-threatening emergency exists, the investigator does not (and cannot) know which therapy is better; and there are no meaningful additional risks to the patient. The first two points have already been discussed and are similar to the federal regulations. The third point requires that, because of the state of information available, the investigator truly does not and cannot know which treatment is better. Our final point is that any additional risk to the patient as a result of being in the study be so minimal as to be acceptable. Clearly, this is intended to be applied to patients such as those we have been studying in our clinical trials of brain resuscitation. Their prognosis is so poor that a possible risk of an experimental therapy does not significantly worsen it. This position has been reviewed by Miller, who suggests alternative criteria: 7 the patient is comatose; a lifethreatening emergency exists; the probability of death with experimental or control therapy is not greater than the probability of death with usual therapy; the probability of normal outcome is greater with experimental or control therapy than with usual therapy; and the study can provide evidence on the difference between tested therapies. His first two points agree with ours. His fifth adds an important additional requirement that the study be well designed so that its successful completion will provide meaningful information His third and fourth points are problematic. They reduce to a requirement that no additional harm be encountered by the patient if entered into the study and that outcome will probably be better than if not entered. Again, the problem is that these requirements assume knowledge gained only after the study is actually completed. We have reinterpreted Miller's points to require that there be reason to believe that the experimental therapy is beneficial and little reason to believe it is harmful. However, we believe that it is not necessary to know this with "medical certainty." Available standard medical therapy may be relatively effective' with little risk. In this case, the patients will' probably prefer the established therapy to an experimental therapy. Here, prospective consent must be obtained prior to entering a patient into clinical research. However, available standard medical therapy may not be effective and/or may have high risk. In this case, the patients will probably always prefer the "new" (experimental) therapy. An acceptable consent process to be used for clinical research in this latter situation is not clear. Between these two extremes is the state of "clinical equipoise," ie, the established accepted (standard) treatment and the "new" (experimental) treatment are considered to be equal. 8 Here a novel consent process, eg, deferred consent, seems acceptable. It now seems that to benefit the brain, therapy must be


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started very early (probably during the initial insult itself). Thus, we are now entering patients into clinical trials during the resuscitation process. Again, traditional prospective consent is not possible to obtain. We are now faced with a new problem with regard to the consent process. For patients who survive in a comatose state, we can proceed with the previously described deferred consent mechanism, although often, as in our current study, the experimental therapy is completed by the time the family is informed. Consent is obviously a misnomer in such a situation, and the process is rather one of supplying information and seeking ratification. The new problem arises when patients are not resuscitated successfully. These patients were clinically dead at the time they were entered into the study and have remained dead. Approaching the grieving family and adequately explaining the complexities of the clinical trial is almost impossible. Their reaction to such information is often difficult to predict. Some of the institutional review boards (IRBs) of our participating hospitals have decided that a consent process should not be attempted in such a situation. Some require letters of information to be sent to the family later, others do not. An optimum solution is not apparent. Is informed consent needed for resuscitation research? Is it meaningful? One may go through the motions of obtaining consent, trying to satisfy regulations that don't apply to the situation. Theoretically, patients might be advised in advance, eg, a sign is placed in front of the hospital or a notice is run in the local newspaper describing the research being conducted in a certain hospital or in a certain city. In this way, patients admitted to that hospital might expect to be part of that study if they satisfy study entry criteria. At least patients would then be forewarned, even though they would not have a choice. Perhaps national tribunals could be established to further evaluate and approve such clinical research, thus reflecting society's needs and desires, whatever the solution, it seems likely that IRBs will (appropriately) maintain a pivotal role in the evaluation and approval of clinical research projects. In our view, the use of the emergency exception to enter patients into clinical research is rational and appropriate.

Some human research in emergency medicine and critical care has been thwarted by consent requirements. This is especially true for research into those medical events that are sudden, unexpected, and require rapid lifesaving intervention, often in patients without decision-making capacity. Patients involved in these types of medical crises will, for purposes of this discussion, be termed "acute care" patients. They are the relatively few emergency or critical care patients who suffer unexpected events that carry a high probability of mortality or severe morbidity unless immediate medical intervention is provided. For these acute care patients, scientifically validated emergency and critical care can be lifesaving. In many instances, however, traditional treatments for such patients are based only on anecdote, personal experience, or animal experiments. The lack of a firm scientific foundation for lifesaving medical care appears antithetical to society's as well as patients' interests. In part, the lack is due to a strict consent requirement that has limited human research in acute care. The consent requirements for human research were put in place to prevent use of human research subjects without their knowledge or against their will for a "societal good." Thus, two compelling interests appear to be at odds: the need for human acute care research, and the need to protect these vulnerable patients. Accordingly, a question that can no longer be avoided is the following: Should acute care research be permitted without the prospective consent of the patient or a relative? As a means of resolving the apparent dilemma, I propose to examine the meaning of autonomy on which the informed consent requirement is based, and the standard method of IRB review, a mechanism for ensuring that ethical parameters of research are observed.

Conclusion

Autonomy

We must continue our efforts toward improving the human condition. Vigorous protocol review processes for approval of clinical research are already established. Obtaining patient consent for participation in clinical resuscitation research is appropriate, but the process must realistically fit the situations being studied.

REFERENCES 1. Meisel A: The "exceptions" to the informed consent doctrine: Striking a balance competing values in medical decision making. Wis L Rev 29, p 413-488.

between

2. Shapiro AR: The evaluation of clinical predictions. N Engl J M e d 1977;296: 1509-1513. 3. Koran LM: The reliability of clinical methods, data and judgments. N EngI ] Med 1975;293:642-646, 695-701. 4. Federal Drug Administration (FDA) of the United States: Protection of Human Subjects. 21 CFF, § 50.23 [1981). 5. Department of Health and Human Services (DHHS] of the United States: Protection of Human Subjects. 45 CFR § 46.116(d) {1981). 6. Fost N, Robertson J: Deferring consent with incompetent patients in an intensive care unit. IRB 1980;2:5-6.

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7. Miller BL: Philosophical, ethical and legal aspects of resuscitation medicine: De ferred consent and justification of resuscitation research. Crit Care Med 198g;16: 1059-1062. 8. Freedman B: Equipoise and the ethics of clinical research. N Engi J Med 1987; 317:141-145.

INFORMED CONSENT IN ACUTE CARE RESEARCH Kenneth V Iserson, MD, MBA, FACEP Introduction

The principle of respect for patient autonomy is commonly understood to mean that competent adults may choose whether and what to accept as medical treatment, as long as their decision does not harm third parties, is not illegal, or does not compromise the integrity of medical practitioners. However, respect for autonomy is broader than this i n t e r p r e t a t i o n suggests. It also includes acknowledgment of and compliance with what a person could reasonably have wanted if he or she cannot express that wish. If the exercise of autonomy is the expression of a patient's wishes, it is important to ask what it is that a patient who currently lacks decision-making capacity might want. Is it more likely than not, for example, that an acute care patient who is presently unconscious would agree to participate in a research protocol? Although some assume otherwise, studies suggest that many people are inclined to be altruistic in such situations. Some are even


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likely to donate replaceable and nonreplaceable body parts while still alive. Nonetheless, this altruistic t e n d e n c y has its limits.t, ~ P a t i e n t s m i g h t w e l l agree to p a r t i c i p a t e in " t h e r a p e u t i c " research in an effort to advance m e d i c a l knowledge in order to help others, but t h e y are simultaneously likely to be risk-aversive. R e a s o n a b l e p e o p l e g e n e r a l l y s e e k o u t a c h a n c e for greater self-benefit in their medical t r e a t m e n t . If all treatm e n t m e t h o d s a p p e a r e q u i v a l e n t , an a l t r u i s t i c p a t i e n t m a y be inclined to participate in a study that has a chance of providing scientifically valid i n f o r m a t i o n for future patients. Clinical researchers u s u a l l y s e e the therapeutic research protocols t h e y supervise as m o r e beneficial to patients than conventional treatment. Otherwise, they w o u l d not be doing the research. 3 But any supposed "benefit" m u s t also be evaluated from the patient's viewpoint. If the "benefit" is only to one organ system, such as restarting the heart in a circumstance w i t h o u t any chance for a p a t i e n t ' s meaningful survival, this w o u l d probably not be seen by a patient as beneficial. 4 Patients with decision-making capacity who make a knowledgeable, a u t o n o m o u s decision for t h e m s e l v e s norm a l l y evaluate their own burden-benefit equation rather than accepting a researcher's risk-benefit analysis. If their own equation is favorable, patients m a y believe that their a u t o n o m y is being overridden if t h e y are not p e r m i t t e d to participate in a research project. This holds true also for those who cannot make independent medical decisions because of their current medical condition. Thus, respect for autonomy, based on a c o m m o n altruistic attitude, favors a p a t i e n t ' s i n c l u s i o n in c o m p e t e n t l y p l a n n e d and risk-aversive acute care research.

Institutional Review Boards In accordance w i t h the Hippocratic c o m m i t m e n t "to do good or at least do no harm, ''s investigators have a d u t y to "abstain from engaging in research projects involving hum a n subjects unless t h e y are satisfied that the hazards involved are believed to be predictable. ''6 To supervise and m o n i t o r investigators' assessments, IRBs weigh the rights of prospective subjects and conduct a risk:benefit analysis in a s y s t e m a t i c and nonarbitrary manner. As a m a t t e r of course, IRBs m a k e t h e i r a s s e s s m e n t i n d e p e n d e n t of researchers once researchers s u p p l y a d e q u a t e i n f o r m a t i o n r e g a r d i n g t h e p r o t o c o l . C u r r e n t l y , IRBs e m p h a s i z e risk:benefit ratios and the consent process w h e n t h e y consider w h e t h e r to approve a research protocol. A l t h o u g h the r e q u i r e m e n t for informed consent in hum a n research is often perceived as inflexible, current IRB rules do allow an exception to the rules governing consent. T h e regulations of the D H H S for prospective h u m a n research by federally funded i n s t i t u t i o n s require informed consent from each subject or the subject's legal representative unless each of the following four waiver conditions is met: the research involves no m o r e t h a n m i n i m a l risk to subjects ( M i n i m a l r i s k is defined as t h e " p r o b a b i l i t y and m a g n i t u d e of h a r m that is n o r m a l l y encountered in daily life or during the performance of routine physical or psychological e x a m i n a t i o n s or tests."7). T h e waiver or alteration will not adversely affect the rights and welfare of the subjects; the research could not practicably be carried out w i t h o u t the waiver or alteration; w h e n e v e r appropriate, the subjects will be provided w i t h p e r t i n e n t information after participation. 8 20:11 November 1991

These regulations n e i t h e r " l i m i t the a u t h o r i t y of a physician to provide emergency medical care ''6 nor pre-empt applicable federal, state, or local laws. The latter point is a cautionary s t a t e m e n t because California and other states have modified the rules to further restrict research and increase patient autonomy. 9 A comparable set of rules from the FDA, although apparently p e r m i t t i n g a similar exception to consent, are not useful for m o s t research protocols, as t h e i r " c o m p a s s i o n a t e e x c e p t i o n " to c o n s e n t is for a o n e - t i m e u s e o n l y a n d c a n n o t be u s e d for an e n t i r e research p r o t o c o l J 0

Alternatives to Consent If respect for a u t o n o m y and the probability of a l t r u i s m suggest that acute care patients w o u l d w a n t to participate in acute care research and current federal rules regarding h u m a n research allow for an exception to the consent req u i r e m e n t , w h a t a l t e r n a t i v e s to on-site, p r o s p e c t i v e pat i e n t i n f o r m e d c o n s e n t m i g h t be used in a c u t e care research? Current alternatives that have been suggested include prospective patient consent in a l i m i t e d variety of circumstances, deferred consent, and no consent. O n l y the first has the chance to include one essential e l e m e n t of the informed consent process - an increased clinician-patient dialogue. Prospective patient consent in acute care research applies to illnesses that repeatedly need acute intervention, such as asthma, sickle cell disease, and chronic obstructive lung disease. Patient p e r m i s s i o n for participation in a specific research protocol is obtained before the p a t i e n t is in a n o t h e r m e d i c a l c r i s i s J 1 In such instances, t r u l y informed consent can be obtained for acute care studies and fulfills consent criteria similar to those obtained in other h u m a n research. A n o t h e r possibility proposed by Abramson, Meisel, and Safar is "deferred consent. ''12 Using the deferred consent process, a p a t i e n t w h o presents in an acute care situation is i m m e d i a t e l y entered into a research protocol. Before clinicians a d m i n i s t e r additional drug doses or perform additional experimental procedures, surrogates, generally relatives, are asked to consent to continuing the patient on the protocol. As Miller observes, the process is not one of obtaining consent, but rather a process of "ratification. ''13 Safar agrees that " 'deferred consent' (is) a logistic comprom i s e . . , a misnomer, ''14 and Meisel claims that "the t e r m 'deferred consent' . . . (is used) . . . for political or rhetorical purposes, since federal r e g u l a t i o n s m a d e the t e r m 'cons e n t ' a fetish. 'q4 A l t h o u g h A b r a m s o n r e p o r t e d t h a t the concept is well accepted by IRBs) s it is a misleading and unnecessary substitute for " i n f o r m e d consent." T h e deferred c o n s e n t p r o c e s s r a i s e s t h e q u e s t i o n of w h a t role relatives should play in giving consent for research. Surrogates such as relatives not infrequently give p e r m i s s i o n for patients w h o cannot themselves consent. Except for parental consent for children, however, it is not clear w h e t h e r family or friends have the legal or moral a u t h o r i t y to m a k e such d e c i s i o n s J 6 N e i t h e r is it certain that surrogate decision makers always have the best wishes of the patient in mind. Safar found that using the d e f e r r e d c o n s e n t p r o c e s s in m o r e t h a n 700 s e q u e n t i a l cases of p o s t - r e s u s c i t a t i o n coma, no f a m i l y m e m b e r rem o v e d a p a t i e n t from studies already in progress except w h e n further t r e a t m e n t was seen as f u t i l e J 4 So great a level of agreement suggests that at least some


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families used neither a substituted judgment nor a best interest standard in agreeing to their relative's participation. Even with an assurance that an appropriate surrogate judgment would be used by relatives, the urgency of evaluation and treatment, as well as the usual absence of a suitable surrogate, make it impossible to obtain substitute consent in most acute care situations. Therefore, extra patient protection is needed if acute care research on human beings is to occur.

A Plan for Acute Care Research In light of the problems associated with obtaining consent, why should acute care research take place at all? Although I alluded earlier to the importance of such research, the question deserves further consideration. As Ruth Macklin pointed out, the ethics of not doing research involve consideration of the consequences of conducting research. 17 This requires an understanding of, and agreement about, the utility of the many possible outcomes of the research - including those that cannot be known in advance. It is clear that some disutility is attached to failing to do research that would benefit people who might otherwise be helped, and it is not in society's interest for this to occur. Further, computer models, bench experiments, and animal research cannot be directly extrapolated to human beings. Human application of laboratory research requires clinical validation. Therefore, it is vital to society that acute care research continue, including, after appropriate preliminary studies, research on human beings. But it also seems apparent that added protections must be installed to regulate this research, such as the addition of a lay advisory panel, concurrent IRB oversight of studies, and greater involvement of the on-line physicians. IRBs are constituted to determine the scientific validity of research, and especially the subjects' risk:benefit ratio. But at ]east in their review of acute care human research studies, the IRB should not only fully evaluate the risk:benefit equation, but also the personal burden:benefit ratio that might exist for enrolled patients. A vital addition to their current evaluation will be to assess the probable burden:benefit ratio for patients, including the chance for meaningful survival after a "beneficial" outcome. Determining the burden:benefit ratio for prospective subjects may be difficult for IRBs. To assist in this process, a patient-surrogate review panel could be formed as an adjunct to the IRB for review of nonconsent acute care research. This would address the fact that society has a different perception of medical care and research than do most health care researchers. The public commonly expects unrealistic benefits from acute care; the perception of harm from medical research is similarly exaggerated. Fost suggests that one way to bring "full information to the public" is to open the process of medical research to greater public scrutiny by establishing an independent lay oversight board, is His proposal would involve individuals who, although not themselves candidates for the research, would behave as if they were. An extension of this concept is to have such a board review acute care research protocols in which informed consent for the participant would not be sought prospectively. In each instance, the board would be composed of the same class of person as those enrolled in the study. By 120/1256

including members of comparable age, gender, race, socioeconomic, and medical characteristics as patients who would be in the study, the board would be likely to represent patient preferences more accurately than a typical IRB could represent them. In research on children, parents or legal surrogates would participate. Such a lay oversight board would interact with the IRB, ruling on the study prior to or after the IRB's own review. For logistical simplicity, the same lay advisory boards could be used repeatedly, when appropriate for particular studies, such as a panel of cardiac patients for different studies during cardiac arrests or a panel composed mainly of young men for several different trauma studies. Both the IRB and the lay board review would need to be favorable for a study without patient consent to proceed. IRBs must extend their purview to include not only prospective but also concurrent oversight of ongoing studies. This increased role for the IRB contrasts to the static prereview approval that is now the norm. If researchers are to presume, rather than explicitly obtain, patient consent for some acute care research, there may be a greater suspicion of, if not a chance for deviation from, approved protocols. Because the patients entered into acute care research protocols are an extremely vulnerable population by virtue of their lack of decision-making capacity and critical medical condition, it behooves the IRB to extend its role to concurrent monitoring of these acute care studies. Although an expanded IRB review could decide on the appropriateness of an acute care human research protocol that lacks patient consent, the ultimate decision to implement an acute care protocol rests with the bedside clinician, and if aware, the patient. Individual physician/researchers have a responsibility independent of the IRB to morally evaluate studies in which they will participate. 19 The on-line physician should always make the final determination whether a particular protocol was appropriate for his or her patient. This onqine clinical responsibility mandates that clinicians involved in acute care studies receive in-depth information about both the rationale for and design of the research protocol. They will then be better able to make beneficent patient-specific decisions. In addition, if a patient has any information-processing capability, his or her refusal to participate in the protocol would preclude inclusion. There should never be any attempt to suppress information about the patient's involvement in research. If a patient recovers any ability to understand information at a later point, he or she should receive all information pertinent to participation in the study. In any case, relatives should be kept informed about what is occurring, although their permission is not requested or required. Because the actual requirement of informed consent (as usually understood) cannot be met in most acute care research, there should be post hoc disclosure to the patient or relatives and increased IRB oversight regarding ethical aspects of such proposals, both before and after they are implemented. The post hoc disclosure necessarily entails a willingness to withdraw the patient from the protocol if patient or family requests this.

Conclusion "Acute care" research should be permitted even without prospective consent of patients or relatives so long as certain conditions prevail. If there is intensified IRB re-


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view of the research design, on-going oversight of the research, and an a c k n o w l e d g m e n t that either an aware patient or the on-site clinician can refuse to enter a patient into the protocol, acute care research m a y be performed in an ethical manner, u l t i m a t e l y benefiting future patients and all of society.

Dr Iserson did the majority of work on this discussion while at the University of Chicago Center for Clinical Medical Ethics.

REFERENCES 1. Oswalt RM: A review of blood douor motivation and recruitment. Transfusion 1977;17:123-135. 2. Spital A, Spiral M: Living donation. Attitudes outside the transplant center. Arch Intern Med 1988;148:1077-1080. 3. Schafer A: The ethics of the randomized clinical trial. N Engl J Med 1982;307: 719-724. 4. Schneiderman LJ, Jeeker NS, Jonsen AR: Medical futility: Its meaning and ethical implications. Ann Intern Med 1990;112:949-954. 5. Reiser SJ, Dyck AJ, Curran WJ (eds): Ethics in Medicine: Selections from the Hippocratic Corpus. Cambridge, Massachusetts, MIT Press, 1978, p 7. 6. World Medical Assembly: Declaration of Helsinki Helsinki, Finland, 1964; Revised Tokyo, Japan, 1975. 7. Department of Health and Human Services (DHHS) of the United States: Protection of Human Subjects 45 CFR 46.102, 1978. Revised March 8, 1983. 8. Department of Health and Human Services IDHHS) of the United States: Protection of Human Subjects 45 CFR 46 ll(a}, 1978. Revised June 18, ]991 as: Federal Policy for the Protection of Human Subjects: Notices and Rules. 9. California Natural Death Act [1976], CA Health and Safety Code Sec. 7185-7195 {Supp i987). 10. Food and Drug Administration (FDAI of the United States: Protection of Human Subjects 50 CFR 50.23, 1981. 11. Spivey WH: Informed consent for clinical research in the emergency department. Ann Emerg Med 1989~18:766-77I. 12. Abramson NS, MeiseI A, Safar P: Deferred consent: A new approach for resuscitation research on comatose patients. JAMA 1986;255:2466-2471. 13. Miller BL: Philosophical, ethical, and legal aspects of resuscitation medicine. I Deferred consent and justification of resuscitation research. Crit Care Med 1988~16: 1059-1062. 14. Schaffner KF, Snyder JV, Abramson NS, et al: Philosophical, ethical, and legal aspects of resuscitation medicine. III. Discussion. Crit Care Med 1988;i6:1069-1076. 15. Abramson N: Panel on critical care research, AAMC meeting, October 23, 1990, San Francisco, California. 16. Buchanan A, Brock DW: Deciding for others. The Milbank Quarterly 1986~64(suppI 2):17-94. 17. Macklin R: On the ethics of not doing scientific research. Hastings Center Report 1977;7:11-13. 18. Fost NC: A surrogate system for informed consent. JAMA 1975;233:8004803. 19. Iserson KV: Physician ethics in human research: The role of medical publications. Ann Emerg Med 1990;19:828-930.

ROLE OF THE INSTITUTIONAL REVIEW BOARD IN EMERGENCY MEDICAL RESEARCH Charles R MacKay, PhD I will outline the points that the IRB should consider in reviewing emergency m e d i c a l research and e x a m i n e the set of issues from the p o i n t of view of the role of the IRB. This role is fundamental, cast in federal regulations in a growing tradition in this c o u n t r y over the last 30 years, a n d mirrored internationally. The role allows the IRB considerable authority, but the a u t h o r i t y is very carefully cir20:11 November 1991

c u m s c r i b e d in the words of the r e g u l a t i o n s and in the body of tradition surrounding IRBs. Before we b l a m e IRBs and l o o k to t h e m for s a l v a t i o n and i n t e r v e n t i o n , it is i m p o r t a n t to understand just w h a t they are empowered to do. The Belmont Report, w h i c h r e p r e s e n t s the r e s u l t s of four years of deliberations by the N a t i o n a l C o m m i s s i o n for the Protection of H u m a n Subjects (NCPHS), defined research as "a s y s t e m a t i c study intended to yield generalizable knowledge." The Regulations of the D e p a r t m e n t of H e a l t h and H u m a n Services use the same definition (45 Code of Federal R e g u l a t i o n s [CFR] 46.102[e]). I cite this definition to r e m i n d us that we are in a situation called research, which, in a sense, is an a m e n d m e n t of the implicit social contract w i t h physicians. Research is a special situation w i t h special rules. There are historical reasons for this; there has been a history of abuses of individuals in research. There also are practical reasons rooted in the very heart of the physician's moral responsibility to those he or she serves. You m a y know, or should get to know, a book called the Physician's Covenant by W i l l i a m May. Professor M a y explores the various roles of the physician - the healer, the parent, the fighter, the scientist. Those roles are not usually in h a r m o n y and to disengage oneself from the moral imperatives of each of these roles requires a great deal of discipline, thought, reflection, and in some cases, as we will see, special rules. Even in clinical practice, where the "best i n t e r e s t " of the individual patient is the aim, it is n o t always easy to d e t e r m i n e w h a t is the best interest. W h e n is it t i m e to stop "fighting" the disease and to help the patient resign h i m s e l f or herself to acceptance of sickness or death? W h e n the c o m p l i c a t i n g imperatives of research are present, t h e p h y s i c i a n - r e s e a r c h e r m u s t b a l a n c e a i m s t h a t challenge the j u d g m e n t of the physician still further. This tension can be noted in the contrasting approaches to the balance between the good of the individual and the interests of society in the formulations of the H e l s i n k i Code as contrasted w i t h The Belmont Report, as will be noted. Research also forces a n e w and uncomfortable discipline on the physician. For example, the physician-scientist who wants to do r a n d o m i z e d clinical trials is faced w i t h quite a n u m b e r of additional considerations to w h i c h he or she is expected to adhere. N o t the least, of course, is this overriding consideration of the r e q u i r e m e n t for IRB review.

Research and Society The definition of research is abstract, but its connotations are risk. Let's look briefly at the expectations and perceptions of research on the part of individuals and society. W h e n the regulations were put in place in the great period of ferment between 1975 and 1985, research still had sinister connotations in our society. Since then, there has been an increasing perception that research is a benefit, a good. Expectations are raised. N o doubt the AIDS e p i d e m i c has forced a r e v o l u t i o n in our t h i n k i n g , b u t there are other factors that contribute to the heightened expectations about the benefits of research. We've done a good job p r o m o t i n g and w i n n i n g acceptance for research. The reforms of the 70s and 80s restored the public's confidence in research. The generally shared perception today is that research will benefit us in the long run. We've seen a shift away from research as suspect, as threatening, to


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one in which it is seen as an increasing benefit. It is often the "last, best hope." These developments have prompted an initiative for a systematic reconsideration of the IRB function to determine in what ways it needs modification to keep pace with social and scientific changes. One potential area is the research done in acute care emergency settings. The emergency situation accentuates many of the challenges to the physician's Complex role. The special situation of research also involves the constraints of regulations. Society's task is to continue to calibrate the proper balance to benefit individuals.

The IRB and Regulation of Research

•

The IRB is the forum in which we seek the proper balance of interests. It must protect the subject, it must further research, and it is an agent of the institution. The mission, the available resources, and the priorities of the institution are factors that the IRB must work into that balance as well. Thus, liability concerns are part of what goes into the thinking of IRBs, even though that concern is not in the regulations. The first thing that the regulations tell the IRB about emergency medicine is: "nothing in these regulations is intended to limit the authority of the physician to provide emergency medical care to the extent that the physician is permitted to do so under applicable federal state or local law." This is consistent with some of the remarks from Professor Cohen, who indicated that the regulations necessarily give precedence to state, local, or federal law. We need to keep in mind as we move through this discussion that there are many blurred areas. The demands of competing, even conflicting, imperatives are intensified in the emergency setting, where there are very few options and intervention must be immediate. Some of the uncertainties in this area, and they are considerable, fall into the realm of the philosophy of medicine and the philosophy of science. Questions of certitude, of epistemology, of what is all behind it, have important ethical implications as well. This overriding uncertainty and equivocal nature of these activities of research in the setting of clinical care are why we have found it necessary to develop some special rules. Although rules have been formulated, there remain unresolved tensions. They are reflected in the performance of IRBs and investigators as well as in the unresolved tensions between the philosophy incorporated in the Code of Helsinki and that incorporated in the Belmont Report. For example, "therapeutic privilege" is alive and well in the Code of Helsinki and that is why the United States does not subscribe to it; in our land, the law does not recognize the so-called "therapeutic privilege." The Belmont Report is more equivocal on another question in the way the balance of interest between the individual and society is to be factored. It is quite at variance with the quote of Helsinki that says, "... never under any circumstance is there any societal interest that outweighs the interests of the individual patient." That is the only rubric under which physicians can do research in the Code of Helsinki in the context of clinical care. Beyond these theoretical and philosophical situations, there are a 122/1258

number of practical factors to consider.

Waiver of Consent Do the regulations permit the waiver of consent in the emergency situation? This "waiver" provision is found in the Federal Code of Regulations (45 CFR 56.116(d)). Essentially, this provision authorizes the IRB to waive the requirement for informed consent, which is contained in the regulations, "provided the IRB finds and documents that: 1) the research involves no more than minimal risk to the subjects; 2) the waiver or alteration will not adversely affect the rights and welfare of the subjects; 3) the research could not practicably be carried out without the waiver or alteration; and 4) whenever appropriate, the subjects will be provided with additional pertinent information after participation" [46.116(d)]. The first step in the process of determining whether to waive consent is the definition of minimal risk. The definition of "minimal risk" is "that the risks of harm anticipated in the proposed research are not greater, considering probability and magnitude, than those ordinarily encountered in daily life or during the performance of routine p h y s i c a l or p s y c h o l o g i c a l e x a m i n a t i o n s or t e s t s " [46.102(g)]. Here we are talking about probability and magnitude, risk of harm, greater than those encountered in daily life of the subjects. Previous drafts of this definition made reference to the "daily life of healthy people." That change represents a very important difference. The phrase "healthy people" was dropped out because it would have imposed a standard on research involving ill people that severely restricted a range of beneficial research and could have had the effect of stifling advances in therapeutic intervention. Consequently, in determining whether informed consent may be waived, the IRB must look to the situation that the subject faces in the emergency medical situation. Common sense and sound moral judgment impel us to refrain from exploiting the subject's extremely vulnerable situation by carrying out research procedures not related to the subject's condition or not intended to benefit the subject. But it is entirely appropriate and within the understanding of "minimal risk" in this subpart of the regulation to use even highly invasive procedures that carry major risks but are intended to benefit the subject or have at least as favorable a risk:benefit ratio as alternative procedures. The IRB's task in discharging its responsibility under the regulations does not end with the determination of "minimal risk." The other conditions must also be fulfilled. Chief among these is the condition that the rights and welfare of the subjects not be adversely affected by the waiver. The IRB, together with the researcher, is probably best situated as to determine whether there is any "adverse affect on welfare" of the subject. But this determination often may call on the IRB to deal with limited data, clinical uncertainties, or controversies raised by innovative interventions whose benefit is undemonstrated or speculative, and hazards that hasten death or, perhaps worse, prolong dying with no measurable gain in reducing morbidity or restoring function or quality of life. Many IRBs will find it uncomfortable to venture into this realm.


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Right of the Subject T h e r e is a basis in l a w for a l l o w i n g i n t e r v e n t i o n s to save a life in e m e r g e n c y s i t u a t i o n s in w h i c h i n f o r m e d consent is not possible. The extension of that provision to the setting of research obviously moves us into an area of great u n c e r t a i n t y and legal risk. Even w h e n the requirem e n t s of the federal regulations are waived w h e n we find ethical justification, legal barriers m a y still exist. T h e regulations r e m i n d us that, " C o m p l i a n c e w i t h these regulations will in no w a y render inapplicable p e r t i n e n t federal, state, or local laws or r e g u l a t i o n s " [45 CFR 46.101(g)]. However, in m y own view, if the interventions in the research carry a risk:benefit ratio equivalent to the situation of clinical practice and have prospect or i n t e n t i o n of benefitting or improving the subject's condition, it is reasonable to conclude that one can p r e s u m e consent. Ordinarily, research ethics place high priority on respect for persons, autonomy, and informed consent. But if consent is not legally possible, as w i t h children, or n o t possible at all, as w i t h u n c o n s c i o u s persons, the e t h i c a l req u i r e m e n t m u s t be e x a m i n e d to determine, w h e t h e r it is a p p r o p r i a t e or r e a s o n a b l e . S o m e e t h i c i s t s c o n s t r u e inf o r m e d c o n s e n t to research as an a b s o l u t e and, consequently, rule out research w h e n the subject is not able to give consent. This is a philosophically defensible position but its societal costs m a y m a k e it less t h a n persuasive to those w h o wish to m a k e progress in emergency and acute care medicine. The standard it holds up m a k e s other gains in society's agenda impossible. Of course, w h e n the subject is not able to consent, alternative "proxy" or "substit u t e " p e r m i s s i o n is needed. The condition of w h e t h e r the research could practicably be c a r r i e d o u t w i t h o u t t h e w a i v e r s e e m s r e l a t i v e l y straightforward, and the other authors have e m p h a s i z e d that not waiving consent w o u l d retard or prohibit valuable and needed research. As to the fourth condition, the IRB has sufficient discretion to decide w h e t h e r "after-thefact" informing and consent to continue in the research or to allow the data to be used is appropriate. That will very likely depend on a host of considerations.

Role of the IRB N o w we turn to w h a t the job of the IRB is in this setting. The IRB, following established criteria, is required to m a k e sure the risks to subjects are m i n i m i z e d by using procedures that are consistent w i t h sound research design. The IRB imperative in emergency medical research, in m y view, calls for rigorous a t t e n t i o n to research design to ensure t h a t valid r e s u l t s are o b t a i n e d b e c a u s e of b u r d e n s p l a c e d on s u b j e c t s w h o c a n n o t t h e m s e l v e s assess t h e risks. W h a t is the n u m b e r of subjects? W h a t is [t~e hypothesis that is being tested? W h a t w o u l d be done to validate it? W h a t are t h e e x c l u s i o n and i n c l u s i o n criteria? W h a t evidence or clinical experience appears to support the hypothesis? Keep in m i n d that there is a f u n d a m e n t a l disadvantage in this type of research that m a y n o t exist in other settings. You m a y have no knowledge of the patient's background. There has been very l i k e l y no chance for personal r e l a t i o n s h i p , no k n o w l e d g e of previous m e d i c a l history. You are really just looking at one of the disadvantages of 20:11 November 1991

the specialization of m e d i c i n e that we face in our society. Your role as clinical researcher allows you to try some int e r v e n t i o n s on t h i s i n d i v i d u a l , p e r h a p s w i t h o u t full k n o w l e d g e of w h a t has caused the condition, in an att e m p t to m a n i p u l a t e b o d i l y processes to restore s o m e semblance of life, perhaps to facilitate recovery. That is a difficult s i t u a t i o n in w h i c h to operate and is very constraining. It takes great courage and conviction on the part of the physician to w a n t to w o r k in the circumstances because one is deprived of the reinforcing concepts and experiences that m a k e some of the difficult t r e a t m e n t decisions and interventions meaningful. Accordingly, the IRB m u s t look at the situation m u c h more carefully than usual. It has grounds to require that t h e r e are good a n i m a l data, p e r h a p s e v e n s o m e p i l o t studies, or other results or reports that indicate promise for this potential therapy. It m a y need some explanation as to w h y the existing therapy seems futile. At w h a t point is r a n d o m i z a t i o n appropriate? The IRB has an intensified obligation in this setting to do more t h a n it c o m m o n l y does. It should look to see that the procedures do not necessarily expose subjects to risk. H o w m a n y of the risks are necessary, and w h a t are the risks? For example, w h a t are the gains in the example cited of studying high-dose epinephrine? For instance, the protocol discusses m o n i t o r i n g spontaneous circulation for six hours. Of course, knowledge in this area can only be expected to be incremental; we can't expect miracles in our first step. But is the IRB prepared for and is the investigator preparing the IRB to understand that this m a y be an arduous and slow project? That we m a y inch along and that the salvage rate m a y be depressingly low in early stages? We are constrained to count our gains by different measures. So in weighing the risks here, in deciding w h e t h e r they are necessary or not, w h e t h e r a proposed "salvage" i n t e r v e n t i o n of i n d e t e r m i n a t e o u t c o m e is w a r r a n t e d by the i n c r e m e n t a l gain, the IRB m u s t begin to put itself in the place of the researcher and the science in gauging the i m p o r t a n c e of the knowledge to be gained. T h e r e g u l a t i o n s i d e n t i f y a n o t h e r c r i t e r i o n for IRB approval: "Risks to subjects are reasonable in relation to anticipated benefits and the i m p o r t a n c e of the knowledge." T h i s is a challenge for the IRB. H o w i m p o r t a n t is this knowledge to society? It is one thing to say acute care research is very i m p o r t a n t . However, is this p a r t i c u l a r p r o t o c o l very important, or is it just i m p o r t a n t to you because you, the researcher, thought of it, w a n t to pursue it, w a n t to publish it, and w a n t to upgrade the quality of acad e m i c medicine? T h e IRB m u s t ask itself these probing questions, and it does not always do so. In this case, the IRB is required to exercise m u c h more oversight than norm a l because there m a y be no o p p o r t u n i t y for the p a t i e n t or the patient's representative to give consent or to participate in the research. It's i m p o r t a n t to notice the provision in this section of the regulations [46.111(a)(2)] that the IRB should c o n s i d e r o n l y t h o s e risks and benefits t h a t m a y result from the research.

Randomization in Acute Care Research Based on the provision that IRBs should consider only the risks associated w i t h the research, I w o u l d propose to


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argue along the following lines in answer to the following question: Does the use of randomization, w h i c h clearly places research o u t c o m e above benefit to the patient, nullify the underlying a s s u m p t i o n of " p r e s u m e d or i m p l i e d consent" in the emergency setting? The p r e s u m p t i o n of consent is based on benefit to the patient. W h e n randomization is used as part of the study design, the benefit to the patient, w h i l e a possible outcome, is subordinated to a research aim. However, if we examine a situation in w h i c h two innovative interventions are compared, or a n e w i n t e r v e n t i o n is compared w i t h an existing standard of care, then the research procedure of r a n d o m i z a t i o n need not nullify the p r e s u m p t i o n of c o n s e n t in the case of u n c o n s c i o u s patients or subjects. Outside the research setting, one ordinaril}¢ w o u l d p r e s u m e consent for either procedure as having the possible benefit. T h e y are of equivalent therapeut i c efficacy. ( P r e s u m a b l y , t h e r e s e a r c h e r also is in a position of equipoise.) The added risk of research in the use of randomization, I w o u l d propose, is negligible. Cert a i n l y t h e o v e r a l l r i s k s of t h e i n t e r v e n t i o n s m i g h t be great, but these w o u l d be faced by the patient outside the research setting. He or she w o u l d be expected to encounter t h e m w h e t h e r or not the research takes place. I w o u l d argue that, in this case, either i n t e r v e n t i o n is "best available" or " o n l y alternative." T h e artifice of r a n d o m i z a t i o n ought n o t to i m p o s e a s t a n d a r d for c o n s e n t in the research s e t t i n g t h a t w o u l d n o t be required and is foreign o u t s i d e research, in the emergency medical setting, w h e n the study design calls for r a n d o m i z a t i o n b e t w e e n (or among) therapeutic equivalents. A n y of these therapeutic equivalents m i g h t be used l e g i t i m a t e l y in t h e i m m e d i a t e l y l i f e - t h r e a t e n i n g or disabling situation w i t h o u t consent because of the p a t i e n t ' s i n a b i l i t y to consent. T h e a r g u m e n t t h a t r a n d o m i z a t i o n requires i n f o r m e d consent is valid w h e n consent can be obtained and "plac e b o " or " w i t h h o l d i n g of t r e a t m e n t " is the c o m p a r i s o n w i t h k n o w n effective interventions. However, to extend the r e q u i r e m e n t to a situation in w h i c h obtaining consent is impossible and to argue that r a n d o m i z a t i o n is not appropriate in acute or emergency care research w h e n and because consent is not possible is u n d u l y restrictive and sounds like a catch 22. There are other criteria in the regulations and that the IRB m u s t consider. First, the selection of subjects m u s t be equitable. One m u s t be cautious in the selection of a class of people, for example, indigent street people or the homeless, w i t h o u t any advocacy, who are involved in self-destructive a l c o h o l i c behaviors. Conceivably, i n t e r v e n t i o n aimed at these individuals could be part of a plan to assist t h e m on the road to recovery. But, u n l e s s research on acute care i n t e r v e n t i o n in lethal alcohol t o x i c i t y is really part of an i n s t i t u t i o n a l c o m m i t m e n t for long-term rehabilitation in alcohol clinics, these individuals can appear to be solely exploited by the research. Perhaps the fragm e n t a t i o n of overspecialization suggests questions about whether selection of subjects can be equitable w h e n the overall benefit to individuals is not part of the equation. As to the other criteria relating to informed consent, the r e m a r k s of Professor C o h e n are forceful. Every a t t e m p t 124/1260

m u s t be m a d e to duplicate as far as possible even the appearances of trying to look out for the best overall interests of the patient. It is not s o m e t h i n g that the physician should p r e s u m e on his or her own. The IRB m i g h t assist in this. In " T h e P a t i e n t as P a r t n e r , " Robert Veatch proposes the use of surrogate panels assembled prior to the p r o p o s e d research t h a t m i g h t be c o n s u l t e d as w a y s of judging w h a t is reasonable in the consent process. These panels m i g h t be useful to cite as a l i n e of defense in a legal process and offer reassurance to the IRB that people agree w i t h the k i n d of interventions being proposed in the acute care setting. More important, I think, is the extent of data and safety m o n i t o r i n g that should a c c o m p a n y these studies. Intensive oversight by the IRB or by an appropriate independent m o n i t o r i n g m e c h a n i s m is critical. This includes patient monitoring, w i t h study m o n i t o r i n g as well. Difficult questions m u s t be asked. W h a t are the data starting to show? Should an IRB l i m i t p e r m i s s i o n for these trials and review t h e m after a few cases to see w h a t the results have been? Should they expect m o r e frequent reporting back from the researcher so that they are really sharing w i t h the investigator the responsibility of m o n i t o r i n g the trial? Finally, a m o n g the criteria are the a d d i t i o n a l protections t h a t are n e e d e d in the case of v u l n e r a b l e populations. Are all d e t e r m i n a t i o n s and e n t r y in the p r o t o c o l done by the physician who is the principal investigator, or is someone there to give an independent reading, even to act as an advocate? Is the d e t e r m i n a t i o n that the individual is not able to consent made by the investigator or is it made by a separate individual, another physician, someone in the emergency department? I t h i n k that those are safeguards that we m u s t consider. The IRB has a variety of interests that it m u s t protect that are m o r e broad and societal. There is a fiduciary res p o n s i b i l i t y here t h a t one owes to the c o m m u n i t y . We have begun to see an erosion of public confidence in the expectation that physicians will do all they can to save people's lives. Some people state a fear t h e y m a y be all o w e d to die to salvage t h e i r organs for t r a n s p l a n t purposes. Recent studies have reflected that, in spite of years of education and acts of Congress, the public is not willing to take the risk to say "I will be an organ donor" because they believe that they m a y not get the best treatm e n t available. So, in our present case we m u s t ask " C a n we afford to take risks in emergency m e d i c i n e in doing research and risk losing the public trust?" I believe that IRBs m u s t consider that issue w h e n they reflect on the mission, priorities, and resources of the institution. N o t every i n s t i t u t i o n can aspire to carry out this scientifically and ethically difficult research.

THE EMERGENCY EXCEPTION TO INFORMED CONSENT: DOES IT EXTEND TO H U M A N EXPERIMENTATION? Morton P Cohen, Esq I was asked to answer certain specific questions in regard to the current state of the law of informed consent and of duress as they apply to research in emergency situations. I will also give some consideration to the future of


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e x p e r i m e n t a t i o n in light of t h e e n o r m o u s changes n o w occurring in the area of h e a l t h law. Over the years, I have been involved w i t h a considerable a m o u n t of litigation in the area of medical ethics. For example, I have litigated cases in regard to the rights of the m e n t a l l y ill to informed consent regarding a n t i p s y c h o t i c drugs; cases concerning the rights of the elderly and quasiincapacitated people to refuse c h e m i c a l and physical restraints; legal problems regarding the use of anectine to be a d m i n i s t e r e d to p r i s o n e r s in California; the use of Antabuse as a condition of probation for former prisoners; e x p e r i m e n t a t i o n as to psychosurgery; and other legal/ethical issues of that nature. As a result, I have some knowledge in regard to the problems of medical research from an applied perspective. I also have t a u g h t h e a l t h law for a n u m b e r of years to m e m b e r s of the legal profession and to h e a l t h providers.

Duress in Consent to Treatment One of the concerns that exists in acute care research has to do w i t h the p r o b l e m of duress for the patient in research situations. It is i m p o r t a n t to u n d e r s t a n d that the law i n t e r p r e t s duress v e r y differently from t h e w a y in w h i c h nonlawyers m i g h t t h i n k of duress and coercion. For example, w h e n an individual has a gun to his head and is told if he doesn't rob the bank, s o m e o n e will be killed, the law says that is adequate for purposes of a defense of duress, so that the individual is not guilty of the crime. A similar definition of duress is present where v o l i t i o n in the transfer of property is at issue, as where an individual is writing his will w i t h a gun to his head, and the determ i n a t i o n is m a d e as to w h e t h e r the will has validity. However, for purposes of n o r m a l situations of m e d i c a l t r e a t m e n t and of particular interest to y o u as to the need for informed consent in experimentation, duress m a y be treated differently. For example, you w o u l d t h i n k it l i k e l y to be u n l a w f u l if an individual, in a situation involving A n t a b u s e as a condition of probation for d r u n k driving, were t01d, in court, "you will get a year in jail or you can agree to a t r e a t m e n t program of A n t a b u s e . " You w o u l d t h i n k that n o r m a l l y this would be considered a coerced or at least duressed consensual process. The law w o u l d not. The law generally w o u l d say that the individual has had t h e o p p o r t u n i t y to m a k e an i n t e l l i g e n t a n d k n o w i n g choice. Of course t h e r e has been pressure, b u t t h e r e is pressure on all of us in any situation as to w h a t we m a y do. T h a t does n o t c o n s t i t u t e coercion so as to n e g a t e choice unless, for some reason, such as experimentation, the use of the A n t a b u s e were itself improper.

Duress in Experimentation Superimposed on this set 9 f legal values, however, is the question of duress and coercion in experimentation. Here, both because of the terrible history of n o n c o n s e n s u a l research in Nazi G e r m a n y and the distrust of the p o s s i b i l i t y of e c o n o m i c and egotistical m o t i v e s in the researcher, the courts tend to be wary of the possibility of duress to an even greater extent t h a n w i t h earlier referred-to situations of the " b a n k robber" w i t h a gun to his head. Thus, in a case involving a prisoner desiring psychosurgery, the court 20:11 November 1991

refused to p e r m i t it because of the i n h e r e n t l y coercive potential of the prison-mental hospital setting. Thus, in regard to the specific questions as to w h e t h e r consent for an e x p e r i m e n t a l study obtained from a patient presenting w i t h acute myocardial infarction or the family of such a patient is legally inadequate due to duress, the answer is that such consent w o u l d not be insufficient due to duress as to the beneficial t r e a t m e n t of that individual. However, as to experimentation, where the law is more inquisitive, the consent m i g h t prove to be inadequate, not due to duress, but because of the possibility of coercion. Assuming, however, u n l i k e the psychosurgery case cited above, that no coercion enters the consensual process as to the experiment, I see no reason w h y it would not be otherwise acceptable.

The Requirement of Informed Consent The second area of the law I will address concerns exp e r i m e n t a t i o n for the patient in extremis. Undoubtedly, the issue of duress as it affects voluntariness in the m a t t e r of i n f o r m e d c o n s e n t is an i m p o r t a n t one. But perhaps m o r e i m p o r t a n t l y , b o t h b e c a u s e of w h a t has been presented today by a n u m b e r of the speakers, and the clash of personal a u t o n o m y w i t h the need for m e d i c a l research, is the issue of the emergency situation w h e r e i n obtaining inf o r m e d c o n s e n t for purposes of t r e a t m e n t and research m a y be legally necessary but factually impossible.

Basic Law Regarding Informed Consent The requirements of informed consent came out of a 1914 N e w York case, Slowindorff v N e w York, in w h i c h Judge Cardoso said, "Every h u m a n being of a d u l t years and s o u n d m i n d is e n t i t l e d to d e t e r m i n e w h a t be done w i t h his own body." This is still the law today. Appended to this cardinal rule in regard to consent is the patient's need for sufficient i n f o r m a t i o n w i t h w h i c h to m a k e the t r e a t m e n t d e t e r m i n a t i o n t h a t is i m p o s e d on the basic rule. Furthermore, to this basic set there is an exception to the need for i n f o r m e d c o n s e n t w h e r e an e m e r g e n c y occurs.

The "Emergency" as an Exception to Informed Consent The emergency exception is really built on the Good S a m a r i t a n rules, w h e r e t h e i n d i v i d u a l is encouraged to come to the aid of another and, in doing so, is i m m u n i z e d from subsequent damages lawsuit. Most states have perm i t t e d people, particularly those in h e a l t h professions, to use the fact of an emergency "rescue" as a defense to the possibility that they acted negligently w h e n they came to the aid of another. Indeed, one or two states have gone further and criminalized the failure of individuals to come to the aid of others where an emergency existed.

The Definition of the Term "Emergency" Incorporated into the emergency doctrine are a n u m b e r of different considerations, such as the fact that it is m o s t often used in regard to negligence suits for damages. If y o u were going to be using an emergency for purposes of perm i t t i n g an IRB t h e right to approve on a research protocol


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without requiring informed consent, then you should be aware of the legal considerations of that exception to the normal rules of informed consent. The next issue concerns the definition of the emergency. I have recently brought a lawsuit regarding the need of informed consent for the treatment of elderly people in nursing homes, with particular emphasis on the problem of chemical restraints. The suit is currently in the negotiating stage, with the likely o u t c o m e being a new set of regulations for the State of California. What the State and I have agreed on as a definition of emergency in regard to the treatment of elderly people in skilled nursing facilities is that "an emergency exists where there is an unanticipated condition in w h i c h immediate action is necessary for preservation of the patient's life, or to prevent serious disability or alleviate severe physical pain, and it is impracticable to obtain the required consent, and provided that the action taken is within the customary practice of physicians of good standing in similar circumstances." That last phrase m a y have a similar usefulness and limitation in regard to the research or experimentation in an emergency without informed consent, as well as in regard t o the ordinary nonconsensual treatment of the individual without informed consent. The State has agreed to the above definition as to patients' rights in nursing home treatment, and we are throwing out the existing regulations wherein there is no definition whatsoever.

The Regulatory Process and Its Relationship to Informed Consent It is a good idea to have some understanding of the regulatory process and its application because, particularly in regard to the current federal research regulations, it is crucial to recognize that merely because the IRB regulations currently say something, it is not necessarily good law. The fact of the matter is that those regulations are as vulnerable to lawsuits in regard to the absence of patient a u t o n o m y as anything else might be. At the outset, it is important to note that the current federal regulations concerning h u m a n research promulgated by the DHHS do permit the possibility of research without informed consent, even in nonemergency situations, if it is impracticable to do otherwise; the welfare and rights of subjects will not be adversely affected; and, m o s t importantly, "the research involves no more than minimal risk to the subjects." Nevertheless, these regulations (contained in the CFR) appear to be at odds with existing regulations in the same code in regard to the nursing home individual. In that set of regulations, one of the patient's rights is the right to refuse to participate in experimental research. That is in the federal as well as the California regulations. The problem is that regulations are often promulgated i n response to particular interests and have less than the force of statute, less than the force of court-determined precedent, and certainly less than the force of constitutional rights. It is against that backdrop that we m u s t analyze the concern as to the need for informed consent for research in an emergency. 126/1262

Let us assume that a research protocol has been developed for a randomized experiment to be performed during what all agree is an emergency. Thus, were it not for the fact of the research, all agree that informed consent would not be necessary. Let us further assume that it has been presented to an IRB that has approved the performance of the research without informed consent because it is to be done during an emergency. Still further, let us assume that the IRB is authorized by existing federal regulations to grant such n o n c o n s e n s u a l authority. Are there valid legal theories to invalidate the regulations and therefore the particular research? I believe currently that there are.

Legal Vulnerability of Federal Research Regulations There is a tripod of legal rights that supersedes all regulations. Thus, if there are no protective regulations, or if those regulations are insufficiently protective, the individual m a y turn to other legal rights for protection. These m a y go well beyond the use of a malpractice action that might allege damages as to the nonconsensual experimentation for failure of the standard in regard to the adequacy of care as to that individual. The tripod of rights is made up of the Constitution, e:~isting statutes, and, as a method of injunction to prevent the research, the c o m m o n law, all of which m a y supersede regulations. In the federal system there is no c o m m o n law, and all that is available are the Constitution and federal statues. Each state has its own c o m m o n law, and each state is very different. For example, the State of Missouri, in regard to N a n c y Cruzan, would not permit the discontinuation of treatment unless there was clear and convincing pre-existing evidence with regard to her desires; the N e w Jersey law is different.

Constitutional and Statutory Rights of Privacy In California and a number of other states, there are specific constitutional provisions that override regulatory processes. In the privacy provision of the California constitution, there is a fundamental right of patient autonomy. It comes within privacy, and it has been spelled out by the California Supreme Court. That right would supersede a regulatory process if it were not in keeping with the constitutional right granted. Similarly, there are statutes that supersede the rights that were given within the regulations. Even federal regulations would be superseded by the state statutes if more protective, unless there were some form of federal supersession of the California statutes. In California, the Health and Safety Code #7160, for example, states in an introductory paragraph that the legislature finds that every individual has a fundamental right to make his or her own care decisions, so that even if the C o n s t i t u t i o n did not so provide, the statute would grant protection. As an example of law superseding regulations, the lawsuit regarding the elderly m e n t i o n e d earlier sought to eliminate regulations that precluded informed consent for the elderly in California. The statutory right of a u t o n o m y was one o~ the bases for this lawsuit. The regulatory rights were insufficiently protective because the regulations were not as considerate of the individual as the statute


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and would therefore be invalidated.

Differences Between State and Federal Systems When coupled with the c o m m o n law and the state or federal constitutions, regulations - often written before the recent surge of patients' rights cases and statutes will not be accepted by the states, w h i c h appear to be more protective of individual a u t o n o m y than the federal courts. For example, that is w h a t has been happening around the country with regard to the right to die. Although there is a federal decision in the Cruzan case that grants limited a u t o n o m y protections, only Maine, N e w York, and Missouri have followed Cruzan. The remaining states are giving enormously greater consideration to patient a u t o n o m y and to informed consent as an aspect of it. This surge in individual a u t o n o m y has happened in regard to the mentally ill and to the termination of treatment for competent people, and it will ensure that there is a limitation on the ability to do noninformed consent research in an emergency in the future, if plaintiffs' lawyers are able to bring cases with sympathetic fact patterns.

Current Constitutional Values in Privacy The systemic positioning of the federal regulations regarding informed consent involves a substantially different situation from that having to do with the actual constitutional rights in what we c o m m o n l y call privacy, but is n o w often being included as a liberty without due process. If you read the abortion cases and th~ Cruzan case recently before the Supreme Court, you do not any longer read about privacy, you read about the liberty interest of the individual, apparently because the US Supreme Court has begun to move toward elimination of consideration of a fundamental privacy right. This seeming reduction of protection in the federal system apparently is in particular consideration of the abortion situation under Roe v Wade.

Patient Autonomy Under the Federal Constitution For N a n c y Cruzan or similar patients, the considerations are no longer that they have fundamental interests that could be overcome only by a state's compelling showing. Instead, the US Supreme Court has decided that they only have ordinary interests that can be overcome by a state's mere rational showing. The Court has not yet gone that far in the abortion cases, but this is what is at stake, which will eventually influence the law regarding experim e n t a t i o n w i t h o u t i n f o r m e d consent. If the Supreme Court should go in the direction of ordinary rather than f u n d a m e n t a l liberty interests in the next few abortion cases, they m a y make a drastic change in the law regarding all aspects of patient autonomy, either reducing it considerably, or passing the baton to the states.

Legal Problems With Nonconsensual Experimentation Because of the constitutional, statutory, and c o m m o n law rights regarding individual autonomy, there is a problem of accepting emergency research as an exception to the requirement of informed consent, even if accepted by existent regulations. Furthermore, the informed consent requirements are not merely found in the IRB regulations. 20:11 November 1991

Indeed, the regulations are, for purposes of the lawyer who might potentially bring a lawsuit, one of the least powerful of the armaments in regard to the patient a u t o n o m y in informed consent.

Best Interests and Substitute Decision Making The experimental bypassing of informed consent is reminiscent of the way in which the law deals with the incompetent. Nowadays, there is a dichotomy between the phrase, "best interest" and the phrase "surrogate decision making." The current thrust of the law as to the incompetent individual is that a surrogate decision m a k e r will make that decision instead and that it will be made on the basis the patient would, rather than in that person's "best interests."

Determinations for the Incompetent Patient The issue of determining what an incompetent patient would do if competent is a complex one. Few people have given power of attorney to others, and fewer still in regard to their being h u m a n subjects. N e w Jersey dealt with aspects of this in In re Conroy, which involved the elderly in nursing homes, and Massachusetts did in a case called Matter of Saikewitz, which involved an individual who never had the capacity to give consent. N e w Jersey came out with a very powerful, melded series of concepts in a three-level process. First, if the individual has the capacity, he or she decides. Second, if the individual has not decided, but there is some evidence of pre-existent intent, the substitute decision maker follows it. Third, the individual who has never had the capacity m a y obtain a decision through a hearing process.

Potential for Lawsuits Regarding Nonconsensual Human Research What would I do if I were counsel for you in a situation in which there silhply should be research, but the inability to obtain a valid and informed consent is a barrier to it? I w o u l d hope that, given society's need for future Salk vaccines, there are always ways to work out these problems in order to avoid some lawyer, indeed such as myself, from successfully suing you to prevent that research. Yet, I come from the perspective that seeks to balance the individual a u t o n o m y of the patient with society's need to develop adequate responses to the suffering of its members. I am delighted, from m y litigator's perspective, to hear statements such as "the benefits for purposes of informed consent, if not to the patient, should at least be to the class." Plaintiff's lawyers aren't going to care the slightest about whether people other than the plaintiff are going to receive benefits or not. The most recent cases on the subject are finding that it is fair to conclude that the researcher has a considerable interest in the research. Unfortunately, the Loma Linda and the Barney Clark research projects have not lent a great deal of credibility to the research concept, and in m a n y of the recent cases, the courts are using language that suggests that the motivations of the researcher are otherwise than the improvement of the h u m a n condition. The researcher should have adequate protection with regard to the possibility that


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someone around the corner is going to bring a lawsuit about a failed experiment and preclude future experimentation.

Suggestions for the Future My recommendation is to be cautious. There is a recognizable desire to do this type of work without consent because consent in an emergency is impossible. I suggest that you be able to balance things, to think in an anticipatory m a n n e r in regard to the possibility that somebody might be severely harmed, either by receiving the placebo or failing to obtain the benefits of the experimental drug. Such a patient might bring a case that negatively influences courts around the country. It can be avoided, and m y concern is that physicians have not anticipated this. For example, in a recent article, after speaking about the definition of an emergency situation and saying that the physician is not only authorized but obligated by law to do what is best for the patient, the writer goes on to say that the physician m a y use either of two therapies, the one not generally accepted or the other that m a y be, as long as he is acting reasonably under the circumstances and in the best interests of the patient. If it is not clear which therapy is best, the selection of treatment by a randomization m e c h a n i s m does not constitute a failure to exercise clinical judgment on the part of the physician. Furthermore, says the writer, because the physician does not know which therapy is best, a fundamental requirement for conducting a randomized clinical trial, the use of an emergency exception to allow r a n d o m i z a t i o n treatment allocation as part of a carefully designed research protocol, should be legally justified. Frankly, I believe that if anybody were to depend on that, they would probably be wrong. There are no legal principles behind it. I would love to have a deposition in a situation in which a defendant said, in regard to the different forms of treatment, "I was involved with a research protocol, I wasn't sure which treatment alternative was right, and therefore, I followed the research protocol." First, it is rare that all things are exactly equal, and therefore one choice is probably better than another. Second, the implication is likely to be, particularly to a jury, that the treating physician really just wanted to do the experiment, especially if the physician chose that response for a n u m b e r of patients. The law has become so patient conscious that the considerations will not be what perhaps in the greater good they should be, the improvem e n t of the h u m a n condition, but merely applied in regard to this particular situation. That is what counsel is going to focus on. This is what the insurance company is going to focus on, and this in turn will influence considerably the decision in the Crnzan-type case as a failure to obtain consent for experimentation. If I were to take this issue to trial, as plaintiff's counsel, I would ask, was the attempt made to obtain consent and was adequate consideration given to the attempt? I would ask - did anyone indicate to you that there was then going to be an .experimental dosage of this medication given? Were you alerted? Was the best done for this individual? In emergency research, you should assure that every128/1264

thing regarding the possible p r o t e c t i o n of the patient, short of the exercise of direct patient autonomy, was done. If the intent of the protocol is not even to attempt to obtain direct or indirect informed consent, it obviously will not look good to a judge determining whether informed consent was necessary. The law says that even if there isn't actual justice, there m u s t be the appearance of justice. For purposes of assuring that an investigator is not going to be precluded from being able to conduct research, there has to be the attempt at the appearance of consideration in regard to what this person's decision would have been had they the opportunity to make that decision. If I were the individual suffering from that cardiac arrest and I came to the hospital and was told either that there was a potentially useful drug or alternatively a placebo, what would I say? Well, I would say, "first of all, what are the risks and benefits?" Second, I would say, "I want to know which because I am very m u c h supportive of your research, but I want to be well taken care of." The issue then becomes under what circumstances, given existing law, will courts permit nonconsensua] experimentation. The US Supreme Court, in a recent case, said with regard to a serviceman, that he did not have the right to sue, and they were not, therefore, going to hold that the Nuremburg Code was adopted by the United States. The California Supreme Court in the Moore case said that perhaps the patient does not have a property right in the research situation. Nevertheless, in California, the patient still has the right of bringing the lawsuit on the grounds of the absence of informed consent. If an investigator is going to use the emergency exception and eliminate the need for informed consent in a research situation, then I believe the investigator is going to have to come within the standard of care that permits that exception to eliminate informed consent by going through the processes that are as close as possible to informed consent. In the emergency, or indeed the therapeutic exception where the individual would be too upset by giving them the information, or in regard to the situation where the individuals says, "I don't want to know," it is the physician who is essentially standing in the stead of the patient and making the determination as the patient might.

The Legality of Nonconsensual Randomization I am not really certain about randomization because I k n o w of no cases or statutes directly on this point. I think it is a major problem in a nonconsensual situation, and I am not sure that using an emergency or the therapeutic privilege as the theory around which to avoid informed consent is workable. The problem is, w i t h o u t consent, h o w can the p r o t e c t i o n of the individual's a u t o n o m y , w h e n that person might not have chosen a placebo, be protected. I think that there will be a case concerning the legality of nonconsensual research, particularly if it involves randomization in an experiment. I think that it can be won by those who want to do the research so long as they are adequately considerate of patient autonomy. The law today gives less protection to the researcher in that situation than it does to the individual w h o is bringing the lawsuit. The California Supreme Court and several other


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courts around the country have gone so far in certain drug cases as to say that even if we are not even certain whose product did the harm, it is possible that the i n d u s t r y will be held liable. T h e y are m a k i n g the i n d u s t r y insurers, and m a n y courts are upholding that concept.

Conclusion o u r m e t h o d s of p r o t e c t i o n of i n d i v i d u a l a u t o n o m y

s h o u l d be i m p r o v e d to i n c l u d e a p r o t e c t i v e p r o c e s s w h e r e b y if true informed consent cannot be present, there is a decision as close as possible to w h a t the individual w o u l d have wanted. It is not adequate to s i m p l y say we do n o t need informed consent. It is both legally and m o r a l l y necessary to try to come as close to that informed consent as possible. It is w h a t c o u r t r o o m counsel is going to say to e v e r y o n e - c o n s t a n t l y t h i n k defensively. W i t h t h a t in mind, I w o u l d hope that the research can be done.

See related editorial, p 1267.

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1265/129

Informed consent to research on emergency care.

Informed consent and research.

Informed consent in pediatric research.

Improving validity of informed consent for biomedical research in Zambia using a laboratory exposure intervention.

Mindsets, informed consent, and research.

Is informed consent in research sometimes optional?

Informed consent comprehension in African research settings.

Ethical issues in nursing research. Informed consent.

Improving the informed consent process in international collaborative rare disease research: effective consent for effective research.

Understood consent versus informed consent: a new paradigm for obtaining consent for pediatric research studies.

Valid informed consent in research: an introduction.

Informed consent. Is it bad medicine?

[Schizophrenia and informed consent to research].

Pregnant women's views on informed consent for research in labour.

Facilitating informed consent for EMR research in Quebec.

Informed consent for return of incidental findings in genomic research.

Improved informed consent documents for biomedical research do not increase patients' understanding but reduce enrolment: a study in real settings.

Compensation for injured research subjects. Regulation by informed consent.

Obtaining informed consent for genomics research in Africa: analysis of H3Africa consent documents.

Informed consent: how informed?

Adolescent Self-Consent for Biomedical Human Immunodeficiency Virus Prevention Research.

Meta consent: a flexible and autonomous way of obtaining informed consent for secondary research.

Rethinking Informed Consent in Research on Heroin-Assisted Treatment.

Informed consent.