(Stroke. 1996;27:1903-1909.)
© 1996 American Heart Association, Inc.
Articles |
Ethical Considerations in Clinical Neuroscience
Current Concepts in Neuroclinical Trials
the Department of Neurosurgery and Neuroclinical Trials Center, Virginia Neurological Institute (W.A.A.), and the Departments of Physical Medicine and Rehabilitation and of Psychiatric Medicine (S.N.M.), University of Virginia Medical School (Charlottesville).
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Abstract |
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Background Ethical decision making in clinical trials has become increasingly emphasized at many levels of the review process.
Summary of Review Ethical concepts applicable to neuroclinical trials are reviewed. The discussion is directed toward ethical concerns that investigators must consider and justify prior to institutional review board submission. Risk-benefit analysis, methodology (randomization, placebo, design), and consent (informed, deferred, waived) are reviewed and guidelines of the Office for Protection From Research Risk are described.
Conclusions Investigators proposing neuroclinical trials face increasing ethical scrutiny by institutional review boards. Attention to ethical issues early in the trial planning process is recommended.
Key Words: clinical trials • ethics, medical • informed consent
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Introduction |
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The ethics of human experimentation have been debated continuously since evidence of systematic abuse and disregard for human welfare in the name of "medical science" was formally documented.1 2 3 Despite formation of various commissions, principles, and guidelines,4 5 6 7 an ethical debate continues, fueled by those who question whether human experimentation, particularly randomized clinical trials, can be ethically justified.8 9 10 11 12 For example, Katz13 wonders "when, if ever, is it justified to use human beings as subjects for research, considering they also serve as means for the ends of others?" These views contrast with those of others who feel experimentation in one form or another has always been a part of medical science and is essential for enhancing medical practice.14 15 16 Actually, contemporary clinical investigation is a complex endeavor that appears only distantly related to the experimentation undertaken by the physician on an individual basis "since time immemorial."11 In fact, the boundaries between experimentation in clinical practice and research involving human subjects were clearly drawn in the Belmont Report.6
In the case of neuroclinical trials (NCTs), recent developments in pharmacology have led to numerous efforts principally designed to assess the safety and efficacy of agents believed to improve outcome after stroke and associated disorders.17 18 19 20 As NCTs become increasingly applied to clinical problems, the ethical aspects of experimentation in neurological populations are certain to receive increased scrutiny. Consequently, a discussion of contemporary ethical issues in NCTs may increase awareness of ethical problems and promote resolution of ethical conflicts. Accordingly, this article focuses on ethical concerns that all investigators must consider and justify before submitting a proposal to institutional review boards (IRBs). In structuring our review, we chose to examine risk-benefit concerns, then design issues, and finally consent problems. While other organizational formats are possible, our discussion focuses on critical issues such as risk first and then proceeds to review how risk and benefit concerns are woven into design and consent issues. Whenever possible, the Office for Protection From Research Risks (OPRR) manual on protecting human subjects is referenced to provide a link between ethical issues and current clinical practice recommended by the OPRR.21
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Risk |
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Risk to study participants is the dominant ethical concern in all experiments. In addition, IRBs are certain to place significant emphasis on the justification of risk. In fact, the discussion of risk-benefit analysis is the first topic presented in the OPRR guidebook.21 In some cases, risks may be "minimal," but any risk that exceeds what is "ordinarily encountered in daily life" or during "the performance of a physical or psychological examination" must be justified by investigators.21
Investigators should begin a risk analysis very early in the investigation planning process. Although a risk assessment is necessary before submitting a protocol for review, how assessments should be completed remains controversial. Nonetheless, investigators are required to identify and assess the significance of risks and potential physical, psychological, social, and economic harm to study participants. Particular attention must be paid to vulnerable populations. When risks are apparent, investigators must describe how these risks will be limited or minimized.21
At the present time, risk assessment strategies include the use of empirical data and opinions of experts and nonexperts. Various models for assessing risk-harm relationships have been delineated, and these models often include both objective and subjective aspects of harm, as well as estimates of the probability and magnitude of harm.22 Participation of potential or an actual subset of study participants in risk assessment may be helpful in determining the subjective component of risk assessment, but experts are clearly in the best position to analyze objective risks. Therefore, investigators will be expected to establish an explicit assessment of objective risks before an IRB submission.
Although risk is most often mentioned in the literature with respect to risk-benefit relationships, the relationship between risk and harm is also important. Risk and harm are related but not necessarily equivalent. Risk is a complicated construct that refers to the "probability and magnitude" of harm.22 Considerations in determining risk before initiating clinical trials would include an assessment of amount or degree of potential damage, the duration of damage, and the irreversibility or permanence of damage.22 In some cases, quantification of risks is advocated, but a thorough risk assessment is the minimal standard.
An additional issue faced by most investigators involves absolute versus relative risks. For example, stroke patients are exposed to multiple risks by virtue of their medical condition. If edema, hypotension, ischemia, vasospasm, and associated treatments are normal risks for this population, then how should objective and subjective risk assessments be structured to reflect risk in patient populations? So far, this question remains unanswered, but research focused on risk assessment in patient populations may eventually shed light on how participants (patients) actually assess both objective and subjective risks. At some point, investigators may be able to quantitatively weigh the relative risk of participation in the context of the patient's particular diagnosis and clinical situation.
Despite attempts to define objective and subjective risks, potential risks to trial participants are notably population and context dependent. Regardless, some researchers have argued that risks in NCTs are minimal. These researchers point out that many lifestyles are inherently more risky than most experiments.23 Accordingly, investigators must decide what risks are ethically justified given the specific clinical situation. This may best be accomplished by using experts to establish objective risks and nonexperts to determine subjective risks. As mentioned previously, investigators may consider empirically examining the reasonableness of risk via analog studies that determine what risks potential participants find acceptable given a certain set of medical circumstances. Research has shown that explanations for specific choices often emerge when participants are given options.24 Ultimately, IRBs and/or study participants will decide whether risks are significant enough to preclude proceeding with the trial or precipitate refusal via informed consent. By addressing risk early in the planning process, investigators may become cognizant of risk-benefit imbalance and take steps to mitigate risks and ethical concerns related to risk-benefit imbalance.
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Benefit |
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A discussion of risks ultimately focuses attention on benefit. Many ethicists believe participants in clinical trials benefit minimally from research, whereas researchers typically argue that patients directly benefit from participation. Of course, direct benefit to participants may depend on the research question and the methodology used. For example, in randomized, placebo-controlled designs, a proportion of patients receive conventional care and a placebo. In such cases, it is difficult to argue for benefit from a placebo, even though a placebo effect is found in many studies.25 Nevertheless, there is anecdotal evidence that patients who participate in clinical trials show reduced rates of morbidity and mortality regardless of group assignment (placebo or treatment), presumably due to the increased attention, control, and monitoring inherent in these trials. Although this finding has not been empirically validated, it makes intuitive sense. In any case, investigators should develop a specific measure of benefit to participants.26 Phase II trials and clinical experience may provide a substantial basis for determining benefit. Like risk, benefit may be perceived differently by different participants, and a measure of the subjective benefit of participation may facilitate IRB review.
A frequently cited criticism of clinical trials focuses on benefits that accrue to the investigators rather than participants.8 9 13 16 Although researchers certainly may benefit from clinical trials regardless of outcome, the assertion that research investigators' primary motivation for pursuing research relates to promotion and finances ignores other factors such as dedication to patients and advancement of medical science. Even though clinical investigators may personally benefit from research, and therefore indirectly gain benefit from subjects who participate in clinical trials, this does not mean that NCTs are intrinsically unethical. In the final analysis, researchers should be aware and not deny that clinical trials are potentially beneficial to academic and personal careers, but ultimately, investigators must be able to plan and execute ethical investigations.
In any clinical trial, specific benefits for individual research participants may vary, and when limited direct benefit is apparent, the most ethically appealing situation is when risks are also minimal. This is especially true when consent cannot be obtained from potential participants because of incapacity. When direct benefit is minimal and risks are high, this places a burden on the researcher to ethically justify such imbalance. In such cases, researchers may want to reflect on whether they would be willing to expose themselves or their loved ones to the proposed risk-benefit of the trial.
Ultimately, IRBs are directed to determine whether the risks to participants are "reasonable" in relation to anticipated benefits.21 If relative risks (objective and subjective) greatly outweigh direct benefits, IRBs are unlikely to sanction the trial and subjects are likely to decline participation. Given contemporary ethical guidelines and practices, IRBs are certain to be critical of attempts to rationalize or minimize obvious risk-benefit imbalances.
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Methodology |
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Sound methodology is critical in any experiment, but in cases where human subjects are exposed to risks, proper methodological design and technique takes on an even more important role. In most comparative clinical trials, the efficacy of two or more therapeutic interventions is evaluated. Depending on the experimental design, various ethical issues may arise. Because randomized clinical trials are perceived to be the "gold standard" for evaluating the efficacy of a new or uncertain therapy, ethical issues related to randomized clinical trials are reviewed and discussed first. Then, some of the most salient issues likely to be addressed by IRBs, regardless of design, will be reviewed. Some but not all of the topics we discuss are described in the OPRR Manual.21
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Randomization |
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Selection or assignment bias is a well-known threat to internal validity, but randomization theoretically balances groups with respect to covariates such as age, education, injury severity, medical complications, and so on, which may influence treatment outcome. When studies combine double blinding with randomization, experimenter and participant biases are believed to be effectively controlled.27 Despite gaining a status as the standard for controlled clinical trials, randomized designs are not without methodological problems.28 29 Nonetheless, proponents of randomization cite the necessity of randomizing participants in clinical trials to eliminate bias in subject assignment.
Despite general consensus regarding the methodological utility of randomization, the use of this technique has been viewed as creating an ethical dilemma.30 For example, some ethicists view randomization as a breach of a physician's duty to act in the patient's best interest. Recently, Hellman and Hellman8 argued that control subjects in randomized designs "must be given either an unsatisfactory treatment or a placebo." Actually, in most NCTs, experimental therapy is evaluated against conventional care and a placebo. As such, even though a placebo is administered, patient/participants are not deprived of conventional care, which greatly diminishes ethical concerns regarding individualized care. In such cases, minimal standards for conventional care would require "state of the art" care that is typically provided in equivalent clinical (nonresearch) situations. Anything less would be difficult to justify and would likely result in a negative IRB evaluation.
Because of concerns about individualized care, Freedman14 has attempted to address the ethics of randomization by defining particular circumstances when random assignment is acceptable. Freedman developed the term "clinical equipoise," which refers to a state where "genuine uncertainty" regarding the relative merit of a treatment exists. In other words, investigators truly embrace the null hypothesis. In clinical equipoise, investigators are searching for a superior therapeutic intervention without the advantage of a priori empirical knowledge or clinical clarity regarding the merits of one therapy versus another. When clinical equipoise exists, Freedman believes randomization is justified.14
In some double-masked, randomized designs, equipoise can exist for the duration of the trial, yet problems arise when equipoise is prematurely or possibly even inappropriately disturbed. Therefore, when using randomized designs, conditions and standards needed to disturb equipoise must be specified. As such, when submitting IRB proposals, investigators should define what conditions would lead to unmasking a trial. In other words, the evidentiary standards used to argue against equipoise must be specified. For example, if an investigator "knows" a treatment is superior and does not recommend this treatment, then this behavior is unethical. Nevertheless, the standard for knowing varies depending on the clinical problem, methodological strategy, and the investigator. Consequently, definition of the standard for disturbing equipoise should be established before submitting a research protocol for IRB review.
In many cases, statistical significance and treatment effect size (clinical observation and/or quantitative analysis) may be considered critical factors in decision making, but some ethicists argue that personal bias or a simple hunch is sufficient to disturb equipoise.30 Despite these arguments in favor of a qualitative indexing of equipoise, statisticians recommend dealing with the accumulating evidence problem by using data-monitoring committees.31 In any case, investigators need to formulate a plan to deal with accumulating evidence. More specifically, the OPRR presents guidelines that encourage investigators to consider (1) whether a data-monitoring process should be established, (2) how trials will be terminated, and (3) the basis for termination of the trial.21 Addressing these three areas before submitting a protocol for IRB review will greatly facilitate the review process.
Alternatives to randomized designs have been proposed and applied in many investigations. Those opposed to randomized designs frequently recommend use of historical controls,12 but the use of historical controls permits bias in patient selection, as well as differences in care simply due to changes in conventional medical practice over time. In other words, treatment and control groups typically are not equivalent. Other attempts to avoid randomized designs, such as matching and blocking, often leave investigators open to criticism because of an inability to control all factors or covariates that might influence outcome.27
Some designs, such as "play the winner," have incorporated an element of randomization with special attention to successful outcome.32 For example, in the "play the winner" design, initial assignment to experimental and control groups is based on a randomized strategy, but successive assignment is based on odds suggested by outcome data. Therefore, if experimental therapy A is more successful than conventional therapy B, the probability of receiving therapy A is increased proportionately to the positive outcomes observed at end points of the trial. While this strategy lends itself well to short-term discrete outcomes (life versus death), more complicated (quality of life) extended (1 month or greater) outcomes make adjustments to group assignment quite difficult.
In one way or another, all adaptive procedures are designed to maximize the assignment of patients to superior treatments, which mitigates the concern that investigators value science more than individual patients. Unfortunately, adjustment procedures and alternative designs may ultimately increase threats to internal validity and weaken confidence in experimental outcome. As previously mentioned, randomized designs are by no means without problems. Sound execution of the experiment is essential. Investigators must "act in such a way that what is true can be verified to be so."33 In other words, it may not be "enough to do what one believes is best, but what is in accord with sound scientific evidence."15 In fact, the OPRR encourages IRBs to examine the scientific soundness of all proposed research.21 Poorly designed trials are arguably unethical regardless of risk.
For randomization to be ethically justified, investigators should theoretically ensure that the results of the study will disturb clinical equipoise. In other words, when the trial is completed, there should be evidence for the superiority of one treatment versus another.15 Despite this theoretical criterion, clinical trials often fail to document the superiority of one therapy versus another, but they frequently show that experimental therapies lack efficacy.27 In this regard, when randomizing patients to experimental and control therapies, the fact that no patient receives less than "state of the art" conventional care greatly mitigates concerns that patients are not receiving individualized care, particularly if the therapy cannot be made universally available until clinical equipoise is definitively disturbed. Most importantly, researchers need to establish firm guidelines for what is acceptable evidence of disturbed equipoise.
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Placebo |
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As in the case of randomization, the use of placebo control subjects has been attacked by critics of randomized trials. In brief, placebos are seen as deceptive and without sufficient justification in most studies.35 Alternatively, proponents of placebo use cite the necessity of controlling for patients' and investigators' preferences and beliefs in all experiments investigating therapeutic efficacy. Unlike the application of placebos in clinical situations involving narcotic withdrawal or anxiety,34 the use of placebos in NCTs is not a covert or inherently deceptive process. In randomized designs, participants (surrogates) are given information regarding the use of placebo, but neither patients nor investigators know whether participants receive placebo or an experimental drug.
In NCTs, the use of placebo is tied to randomization and the notion of experimental rigor, but placebos are also used in nonrandomized designs. To some degree, the use of placebo minimizes the potential for experiment and/or participant bias, which might ultimately influence outcome (disturb equipoise) in a systematic but invalid manner. In other words, placebo groups control bias favoring an experimental therapy, and because experimenter and participant bias has been found to have a profound impact on experimental outcome, the scientific benefit of using placebos is relatively clear.
On the other hand, the risk and harm of placebo use in randomized and nonrandomized trials are not always clear, particularly when clinical equipoise exists and participants receive competent conventional care and a placebo. In fact, the OPRR recommends use of placebo only when conventional care is provided.21 In other words, placebo alone is not an ethically acceptable methodology if an effective treatment (by conventional medical standards) is available. In most NCTs, a number of treatments are used, and these treatments form the basis for conventional care. Even when trials provide "state of the art" conventional care along with placebo administration, investigators should be aware that placebos have traditionally been associated with deception and failure to provide genuine treatment. For example, critics of randomized trials equate placebos with "unsatisfactory treatments," but these critics often refer to studies where conventional care is withheld.8 Therefore, when placebos are used, researchers should emphasize the quantity and quality of conventional care that is provided along with the placebo.
An additional concern related to placebo use involves standards for terminating a trial when sufficient evidence has been gathered to validate or invalidate the therapy in question. If the therapy is invalidated, no harm has been done to the control (placebo) group. In contrast, if the therapy proves valid, then control patients should be afforded an opportunity to receive the validated treatment. In some cases (early and/or single administration pharmacological agents), patients already enrolled in a trial may not benefit from knowledge gained from the trial. Nonetheless, if experimental therapy is superior, one would want to minimize the numbers of successive enrollment of patients given a placebo. Therefore, as mentioned previously, standards for evaluating the experimental therapy at various points in time must be considered before beginning a trial. As soon as equipoise is definitively disturbed, enrollment of subjects in conventional care plus placebo groups can be terminated.
Despite the limited evidence that placebos are harmful to patients who receive conventional care in clinical trials, the use of placebo provokes concern, and investigators should be prepared to justify the use of placebo on methodological and ethical grounds. IRBs are encouraged to be concerned if placebos are used in place of conventional care, and IRBs will certainly want all arms of trials to have maximal therapeutic benefit.21
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Informed Consent |
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Once risk, benefit, and methodological issues have been addressed, investigators need to examine the consent process. Informed consent is a complicated construct, but investigators must decide on the type of consent needed to enroll subjects. Some time ago, Beecher (Katz13 ) described contemporary examples of investigators who failed to disclose risks to participants before involvement in experiments. Beecher concluded that such ethical violations were common and at least in part due to the "ambition" of the investigator. While failing to properly inform potential research participants regarding risks, benefits, and alternatives to participation may seem untenable by today's ethical standards, some ethicists continue to express grave concern about informed-consent procedures in clinical trials.
In fact, Katz questions whether the informed-consent doctrine borrowed from tort law is applicable to and appropriate for clinical trials. According to Katz, the informed-consent doctrine arose from tort law and was principally designed to provide "minimal disclosure obligations that physicians must fulfill to escape legal liability."13 The threshold for providing information to avoid legal liability may not meet the ethical standard of disclosure necessary for research participation. Moreover, Katz argues that participants (patients) rather than physicians must be protected "whenever human beings serve as means for the ends of others." In other words, Katz believes the standard for informed consent should reflect an emphasis on participant self-determination rather than protection from liability for the research investigator.13
As presently used, typical informed-consent documents require research participants to be provided with information regarding diagnosis, proposed intervention(s) or procedure(s), the known risks and potential benefits of treatment or participation, and the alternatives to treatment or research participation.36 The fundamental spirit of informed consent is that patients should not only be provided with information, but they should know and understand the reasons for treatment and participation, as well as the benefits, risks, and alternatives. In other words, they should enter treatment or research protocols informed, knowledgeable, and voluntarily.
Despite these general guidelines, the standards for disclosure in experiments vary depending on the specific research project and investigator.9 36 Concerns regarding the variable standards for informed consent have lead to the development of various methods for reducing ambiguity and increasing confidence in informed-consent decisions. For example, the concept of reasonableness has been proposed as a guideline for structuring informed-consent procedures. Quite simply, reasonableness refers to the type and amount of information a reasonable person/participant would require to reach an informed decision. Information deemed reasonable would include a thorough and complete disclosure of risks, particularly when risks are known.
Even though informed-consent standards are extensively documented, some clinicians have proposed exceptions to informed-consent protocol. For example, in some cases, full disclosure is not believed to be necessary,37 especially "when it might unduly worry a patient and even persuade him or her not to accept treatment (or presumably, research participation) deemed to be necessary and beneficial." Although limited or modified disclosure has been discussed by some clinicians, actual use of this "therapeutic (research) privilege" seems highly controversial and dubiously ethical in clinical situations, let alone in clinical trials.
Even if participants receive thorough and appropriate information, comprehension of risks and benefits is not guaranteed. In fact, disappointing levels of knowledge and understanding have been observed. Various proposals for increasing comprehension of risks and benefits have met with mixed success.38 For example, readability of informed-consent documents has been manipulated without dramatic increases in comprehension.39 Even providing patients with videotaped disclosure of risks combined with educational interventions may not improve levels of understanding of risks and benefits. Nevertheless, systematic, documented attempts to inform subjects must be undertaken before initiating experimental protocols. The only exception is in cases where consent can be waived.
Federal Food and Drug Administration guidelines (50.23[A]) allow consent waiver when (1) a life-threatening situation necessitating use of a test article occurs and standard treatment is not withheld, (2) potential participants are incapacitated, (3) no time is available to obtain consent from legal representatives, and (4) no equally effective alternative therapy providing a similar likelihood of success is available.40 In contrast, US Department of Health and Human Services guidelines (46.1/6[D][1]) require that research involve no more than a minimal risk before consent can be waived. Minimal risk is defined as risks that are not "greater than those ordinarily encountered in daily life or during performance of routine physical or psychological examinations."
Investigators may be perplexed by differing standards for waived consent, but suggestions from the OPRR21 for IRB review are explicit and include conditions that (1) risk is minimal; (2) participants will not be adversely affected; (3) research success is dependent on waived consent; and (4) subsequent to participation, subjects are provided with appropriate information regarding the experiment. In reality, few trials may meet the standards for waived consent established by the OPRR. Nonetheless, if studies do meet guidelines and IRBs waive the need for consent, signed consent after enrollment need not be obtained for ethical reasons. However, when investigators request waived consent, IRBs are likely to have a high threshold for granting waivers. For example, the OPRR recommends that all decisions to waive consent "be documented in IRB minutes."21
When considering informed-consent issues, investigators should examine all risks in order of importance (significance) before constructing an informed-consent document. In addition to disclosure of risks and benefits of treatment, participants can be given information that typically is not relevant in clinical situations. For example, subjects can be informed that they are participating in a "double-blind" trial that is not scheduled for "unblinding" until completion or at some point in the undetermined future when review of data will be undertaken. Outcome measures such as electrocardiography, Doppler sonography, CT, and others can be described. Information on follow-up requirements or repeated measures can also be provided. In addition, conditions such as medical emergencies and idiosyncratic requests to withdraw can be discussed. In this regard, investigators may want to reflect on definitions of "serious adverse events" and consider guidelines for disclosing information regarding these events to participants. Trial participants are closely monitored with respect to medical status, and situations provoking participant withdrawal from a trial should receive attention early in the design process.
Most importantly, all risks should receive appropriate attention in proportion to potential harm to the patient. For example, in one recent study, the risk of blood work (eg, "needle prick") was described in exquisite detail, whereas the withdrawal of medications presumably "known" to result in serious medical complications was barely addressed.9 Such imbalance in disclosure is not desirable or appropriate. In some cases, research examining the reasonableness of informed-consent procedures can be undertaken before submitting a proposal to the IRB. Analog research using subjects with demographics similar to those of potential participants could provide valuable information regarding the consent process that may assist investigators and IRBs in determining the validity of the informed-consent document.
Actually determining whether participants know and understand risks and benefits is a complicated process. Many factors such as intellectual limitations, emotional distress, and educational impoverishment can limit appreciation of risks and benefits. Nonetheless, investigators must attempt to maximize knowledge, understanding, and self-determination (autonomy) in all cases requiring informed consent for research participation. Informed-consent procedures define the relationship between the study participant and the investigator. As such, informed consent has traditionally been viewed as a significant protection for human subjects. Consequently, investigators' informed-consent documents and procedures will be very closely scrutinized by IRBs.
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Proxy Consent |
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In many cases, participants in NCTs are incapacitated by virtue of their neurological disorder or trauma. As such, consent to participate in research is sought from patients' surrogates, usually family members. Consent by legal representatives when the patient is incapacitated is referred to as proxy consent. In such cases, issues of autonomy and consent become dramatically complicated. Even though family members are often called on to make decisions for patients during the normal course of clinical practice, especially in medical emergencies, the extent to which family members can consent for experimental participation has received limited attention in the literature.
Recent theoretical and empirical objections to allowing proxy consent have been detailed principally with respect to clinical practice, but these concerns are applicable to NCTs.41 Concerns in cases of proxy consent principally focus on the ability of surrogates to accurately represent patients' preferred choices. For example, several studies have found a discouraging level of concordance between patients and their proxy decision maker regarding consent for certain types of medical procedures, presumably involving significant risks.41 Even lower concordance regarding research participation may be expected because families are unlikely to engage in discussions regarding willingness to participate in research after a catastrophic event such as a head injury or stroke. Therefore, proxy decisions may reflect what surrogates presume patients would have wanted in such situations, rather than what patients may have actually preferred. In fact, in many clinical situations, proxy decision makers boldly state what their choice would be even if that choice conflicts with the patient's desire. Therefore, although consent for experimental participation in clinical trials is frequently obtained from proxies, this type of consent may not adequately safeguard patient autonomy. In addition, surrogates may refuse participation when patients might have consented.
A solution to this problem has been to require legal documentation or advanced directives for research participation before involvement in trials. Unfortunately, such a strategy simply has the effect of reducing the numbers of participants available for clinical trials, since most persons do not have advanced directives for healthcare decisions, let alone for research participation. Reducing the potential number of participants in NCTs does not address the fundamental issue of proxy consent. While solutions to the proxy-consent issue remain elusive, at the present time, social mores and legal opinion support the concept of proxy consent primarily on the basis that proxies (families) have a supraordinate authority in such matters and, as such, may act in the (presumed) best interest of patients.41 The issue of proxy consent is likely to become increasingly scrutinized by IRBs, but for the time being, obtaining consent for experimental participation from family members appears to be an accepted and reasonable practice.
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Deferred Consent |
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When proxy consent is sought, the patient's representative may be emotionally distraught or not immediately available. Because some treatment protocols may require immediate intervention, investigators have proposed the concept of "deferred consent."42 As initially discussed, deferred consent should be considered when (1) there is a substantial reason for doing so, (2) there is minimal risk of harm to the patient, and (3) the deferral duration is minimized.
Deferred consent is described as a rational and pragmatic approach to obtaining consent in situations when proxy decision makers may be influenced by "anxiety and stress" and are consequently presumed to be unable to give full informed consent.42 As originally proposed, Fost and Robertson42 embedded the deferred-consent issue in the matrix of confusion and rapid decision making that must occur after a neurological emergency. The authors questioned whether the patient would be better served by not burdening decision makers under such circumstances. In addition, the authors question whether "true" informed consent can be obtained in such situations.
Deferred-consent procedures have been strongly criticized by ethicists.43 Ethicists note that deferring consent principally because of a stressful, emotional situation assumes genuine informed consent cannot be obtained, but at the present time, there is no empirical evidence to support this claim.43 44 Moreover, opponents of deferred consent point out that attempting to obtain consent allows patient representatives to refuse secondary to stress or anxiety, which reduces the number of research participants but minimizes the enrollment of some patients who presumably would not want to participate (by proxy choices) in clinical trials.
Investigators should note that current regulations and regulatory guidelines do not recognize "deferred consent" as a mechanism for informed consent. Further review of deferred consent by the OPRR is likely to occur in the context of issues surrounding waived consent. Until these issues have been addressed and recommendations provided by the OPRR, the use of deferred consent in trials should be avoided, particularly if individual IRBs have not established policies addressing deferred consent.
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Summary |
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In the preceding review, we have discussed a number of ethical issues facing investigators proposing acute NCTs. Although it is difficult to single out or elevate one special ethical concern for investigators, it is certain that future research proposals will be closely scrutinized with respect to consent procedures. The issue of consent is complicated, and some resolution of conflict in the definition of "waived consent" by the Food and Drug Administration and the Department of Health and Human Services is required and may be forthcoming. In addition, the conditions (if any) under which deferred consent is acceptable need further elaboration. Additionally, regardless of design, the use of placebo controls is certain to provoke increased attention. In this regard, we argue that in any case where equipoise exists, those NCTs that provide appropriate conventional care and placebo can be ethically defended. Finally, each clinical trial will present a unique set of ethical issues that investigators must address before submission to the IRB. Attention to ethical considerations (risk-benefit analysis, methodological design factors, and consent procedures) early in the investigation planning process is certain to facilitate IRB review and proper execution of the clinical trial.
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Acknowledgments |
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The authors wish to thank Dr John Fletcher for his thoughtful review and helpful comments.
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Footnotes |
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Reprint requests to Stephen N. Macciocchi, PhD, Department of Physical Medicine and Rehabilitation, Box 30 BRH, University of Virginia Health Sciences Center, Charlottesville, VA 22901.
Received March 19, 1996; revision received July 5, 1996; accepted July 5, 1996.
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References |
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1. Alexander L. The Treatment of Shock From Prolonged Exposure to Cold, Especially in Water. Washington, DC: Combined Intelligence Objectives Subcommittee. Office of the Publication Board, Department of Commerce.1946; Target No. 24, Report No. 250.
2. Berger RL. Nazi science: the Dachau hypothermia experiments. N Engl J Med. 1990;322:1435-1440.[Medline] [Order article via Infotrieve]
3. Trials of War Criminals Before the Nuremburg Military Tribunal. Vol 2, The Medical Case. Washington, DC: US Government Printing Office, 1948.
4. Commission, Report, and Recommendations: Research Involving Those Institutionalized as Mentally Infirm. Washington, DC: US Dept of Health, Education, and Welfare publication (OS) 78-0006; 1978.
5. Commission, Report and Recommendations: Institutional Review Boards. Washington, DC: US Dept of Health, Education, and Welfare publication (OS)78-008; 1978.
6. Commission: The Belmont Report: Ethical Principals and Guidelines for the Protection of Human Subjects of Research. Washington, DC: US Dept of Health, Education, and Welfare publication (OS)78-0012; 1978.
7. US Department of Health and Human Services Rules and Regulations. 45CFR46, 14.116, 1983.
8. Hellman S, Hellman DS. Of mice but not men: problems of the randomized clinical trial. N Engl J Med. 1994;324:1585-1589.[Medline] [Order article via Infotrieve]
9. Katz J. Human experimentation and human rights. St Louis Univ Law J. 1993;38:7-54.[Medline] [Order article via Infotrieve]
10. Rothman DJ. Ethics in human experimentation: Henry Beecher revisited. N Engl J Med. 1987;317:1195-1199.[Medline] [Order article via Infotrieve]
11. Schafer A. The ethics of the randomized clinical trial. N Engl J Med. 1982;307:719-724.[Medline] [Order article via Infotrieve]
12. Weinstein MC. Allocation of subjects in medical experiments. N Engl J Med. 1974;291:1278-1285.
13. Katz J. Ethics and clinical research revisited: a tribute to Henry K. Beecher. Hastings Center Report. 1993;23:31-39.[Medline] [Order article via Infotrieve]
14. Freedman B. Equipoise and the ethics of clinical research. N Engl J Med. 1987;317:141-145.[Abstract]
15. Freedman B. A response to a purported ethical difficulty with randomized clinical trials involving cancer patients. J Clin Ethics. 1992;3:231-234.[Medline] [Order article via Infotrieve]
16.
Kopelman L. Consent and randomized clinical trials: are there moral or design problems? J Med Philos. 1986;11:317-345.
17. Gelmers HJ, Gorter K, de Weerdt CJ, Weizer HJ. A controlled trial of nimodipine in acute ischemic stroke. N Engl J Med. 1988;318:203-207.[Abstract]
18. Ohman J, Heiskanen O. Effects of nimoclopine on the outcome of patients after aneurysmal subarachnoid hemorrhage. J Neurosurg. 1988;69:683-686.[Medline] [Order article via Infotrieve]
19.
Oczkowski WJ, Hachinski VC, Bogousslavsky J, Barnett HJ, Caruthers SG. A double-blind, randomized trial of PY108-068 in acute ischemic cerebral infarction. Stroke. 1989;20:604-608.
20. Petruk KC, West M, Mohr G, Benoit BG, Gentilli F, Disney LB, Khan M, Grace M, Holness RD. Nimodipine treatment in poor-grade aneurysm patients: results of a multicenter double-blind placebo-controlled trial. J Neurosurg. 1988;68:505-517.[Medline] [Order article via Infotrieve]
21. Protecting Human Research Subjects. Office for Protection From Research Risk Institutional Review Guidebook. Washington, DC: US Government Printing Office Superintendent of Documents, Mailstop SSOP 20402-9328; 1993: sec3/p1-9; sec4/p22-26; sec4/p26; sec4/p25; sec4/p23; sec4/p16; sec3/p16; sec3/p16.
22. Meslin E. Protecting human subjects from harm through improved risk judgments. IRB: A Review of Human Subjects Research. 1990;12:7-10.
23. Levine RJ. Clarifying the concepts of research ethics. Hastings Center Report. 1979;6:21-26.
24. Simel DL, Feussner JR. Clinical trials of informed consent. Control Clin Trials. 1992;13:321-324.[Medline] [Order article via Infotrieve]
25. Connelly RJ. Deception and the placebo effect in biomedical research. IRB: Review of Human Subjects Research. 1987;9:5-7.
26. Chuang-Stein C. A new proposal for benefit-less risk analysis in clinical trials. Control Clin Trials. 1994;15:30-43.[Medline] [Order article via Infotrieve]
27. Byar DP, Simon RM, Friedewald WT, Schlesselman JJ, DeMets DL, Ellenberg JH, Gail MH, Ware JH. Randomized clinical trials: perspectives on some recent ideas. N Engl J Med. 1976;295:74-80.[Abstract]
28. Parmar MK. Pitfalls and biases in the reporting and interpretation of the results of clinical trials. Lung Cancer. 1994;10(suppl 1):S143-S150.
29.
Rabeneck L, Viscoli CM, Horowitz RI. Problems in the conduct and analysis of randomized clinical trials. Arch Intern Med. 1992;152:507-512.
30. Schafer A. The randomized clinical trial: for whose benefit. IRB: Review of Human Subject Research. 1985;7:4-6.
31. Choi SC, Smith PJ, Becker DP. Early decision in clinical trials when the treatment differences are small. Control Clin Trials. 1985;6:280-289.[Medline] [Order article via Infotrieve]
32.
Bartlett RH, Roloff DW, Cornell RG. Extracorporal circulation in neonatal respiratory failure: a prospective randomized study. Pediatrics. 1985;76:479-487.
33. Bronowski J. Science and Human Values. New York, NY: Harper Row; 1965:58.
34. Brody H. Placebos and the Philosophy of Medicine. Chicago, Ill: University of Chicago Press; 1980.
35.
Rothman KJ, Michels KB. The continuing unethical use of placebo controls. N Engl J Med. 1994;331:394-398.
36. Beauchamp TL, Childress JF. Principles of Biomedical Ethics. New York, NY: Oxford University Press; 1989:74-116.
37. Rosner F. The ethics of randomized clinical trials. Am J Med. 1987;82:283-290.[Medline] [Order article via Infotrieve]
38. Taub HA. Comprehension of informed consent for research: issues and directions for future study. IRB: Review of Human Subjects Research. 1986;8:7-10.
39. Duffy TM, Kabance P. Testing readable writing approach to text revision. J Educ Psychol. 1982;74:733-748.
40. US Food and Drug Administration Rules And Regulations 21 CFR 56, Federal Register 46 (January 27, 1981), 8975; revised 1991 (Federal Commission Policy) Federal Register 56 (June 18, 1991), 28003.
41.
Emanuel EJ, Emanuel LL. Proxy decision making for incompetent patients. JAMA. 1992;267:2067-2071.
42. Fost N, Robertson JA. Deferring consent with incompetent patients in an intensive care unit. IRB: Review of Human Subjects Research. 1980;2:5-6.
43. Beauchamp TL. The ambiguities of deferred consent. IRB: Review of Human Subjects Research. 1980;2:6-9.
44. Levine RJ. Deferred consent. Control Clin Trials. 1991;12:546-550.[Medline] [Order article via Infotrieve]
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