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© 1999 American Society for Clinical Oncology Impact of Therapeutic Research on Informed Consent and the Ethics of Clinical Trials: A Medical Oncology PerspectiveFrom the Section of Hematology-Oncology and the MacLean Center for Clinical Medical Ethics, University of Chicago, Chicago, IL. Address reprint requests to Christopher K. Daugherty, MD, MC 2115/Section of Hematology-Oncology and the MacLean Center for Clinical Medical Ethics, University of Chicago, 5841 S Maryland Ave, Chicago, IL 60637-1470; email kdaughe{at}mcis.bsd.uchicago.edu
PURPOSE: To create a more meaningful understanding of the informed consent process as it has come to be practiced and regulated in clinical trials, this discussion uses the experience gained from the conduct of therapeutic research that involves cancer patients. DESIGN: After an introduction of the ethical tenets of the consent process in clinical research that involves potentially vulnerable patients as research subjects, background that details the use of written consent documents and of the term "informed consent" is provided. Studies from the cancer setting that examine the inadequacies of written consent documents, and the outcome of the consent process itself, are reviewed. Two ethically challenging areas of cancer clinical research, the phase I trial and the randomized controlled trial, are discussed briefly as a means of highlighting many dilemmas present in clinical trials. Before concluding, areas for future research are discussed. RESULTS: Through an exclusive cancer research perspective, many current deficiencies in the informed consent process for therapeutic clinical trials can be critically examined. Also, new directions for improvements and areas of further research can be outlined and discussed objectively. The goals of such improvements and research should be prevention of further misguided or ineffective efforts to regulate the informed consent process. CONCLUSION: To ignore this rich and interesting perspective potentially contributes to continued misunderstanding and apathy toward fulfilling the regulatory and ethically obligatory requirements involved in an essential communication process between a clinician-investigator and a potentially vulnerable patient who is considering clinical trial participation.
THE CONCEPT of informed consent, which acknowledges the rights of patients to participate voluntarily in health care, applies both to clinical practice and clinical research.1,2 Informed consent in clinical research is related to—but recognized as being more stringent than—informed consent outside the context of clinical trials.3 This heightened consent standard exists for at least two reasons. First, from an ethical perspective, a patient who is considering clinical trial participation is always viewed as potentially vulnerable.4 As a result of this potential vulnerability, he or she may have great difficulty in appreciating the differences between the therapeutic and research aspects of a given alternative of care or treatment. Without this distinction, patients cannot make uncoerced and autonomous health care decisions. Thus, the informed consent process, and the ethics of clinical research, require that such a clear distinction be made.5,6 Second, physician-investigators are seen as having an intrinsic conflict of interest in their roles as both a physician for an individual patient and a scientific investigator attempting to develop improved methods of medical care and treatment.3,4,7 Within the sole context of a therapeutic relationship, the physician places his or her patient's interests above all else.8 However, within the context of clinical research, investigators have additional interests that may not be relative to their patients' interests.7,9-13 From an ethical perspective, many concerns exist about the ability of clinical investigators to provide the requisite information to patients regarding participation in research in such a way that allows patients to recognize the distinction between research and therapy.6,14,15 In an attempt to emphasize the importance of this distinction, most ethical regulations that govern clinical research have focused on the informed consent process as a means of protecting potentially vulnerable research subjects from physical and psychologic harm.3,4,16 These regulations have relied heavily on written informed consent documents to achieve full disclosure of the important elements of consent, including the risks of research participation, the nature of the research, and alternatives to research participation. However, from their inception to the present day, many critics have recognized the imperfections in the methods used to regulate the informed consent process.15,17-22 More recent empirical research on informed consent, a great proportion of which has been conducted in the cancer setting, may be helpful to identify objectively the current problems and deficiencies associated with written consent documents and their oversight. As will be reviewed, several studies reported over the last 20 years have increasingly demonstrated that although regulations are being followed, informed consent documents have become increasingly unreadable, lengthy, and uninformative.23-25 Indeed, they may actually be interfering with what might otherwise be an ethically appropriate informed consent process for patients, including not only those with cancer but any patient considering therapeutic clinical trial participation. Many of these deficiencies may be understood best by beginning with an examination of the earliest foundations of regulatory requirements for cancer clinical research, some of which date back to a half century ago, and by a brief review of the history of informed consent—both the term itself and its contextual meanings.
A definition of informed consent for clinical research that encompasses all relevant aspects of the process remains somewhat elusive; varying definitions have been described.1-4 Generally, it is viewed as a process of communication between a patient-subject and a clinician-investigator regarding an investigational or experimental treatment. Within this communication process, several elements must be disclosed. These include the type of research to be performed, the risks and benefits of the treatment or research, the unproven nature of the research, the alternatives other than participation in the clinical trial, and, finally, the subject's freedom to withdraw or not to participate in the research without any detrimental effect on the patient's continued access to adequate health care. Separate from the issue of disclosure within this process is the issue of actual understanding on the part of the patient of these disclosed elements. Whether the definition of informed consent should include an actual understanding of these elements, or how much of an understanding it should include, remains a matter of controversy.1,15,26 However, from an ethical standpoint, it is accepted that the process of informed consent requires at least some attempt on the part of clinician-investigators to help patients understand those aspects of the consent process that have been disclosed to them so that they may decide autonomously and voluntarily to participate.27,28 Other elements that have been described as an important part of the informed consent process include maintaining the confidentiality of a research subject's participation and, controversially, possible disclosure of potential conflicts of interest on the part of the clinician-investigator. Historically, rudimentary evidence, which dates back more than two centuries, exists for the ethical and legal requirements of patient consent to treatment outside the context of clinical trials.1,2 This early history seems to relate predominately to patients who simply consent to receive therapy; it does not necessarily relate to disclosure to the patient of the commonly recognized modern-day elements of informed consent, eg, the risks and alternatives of the therapy, let alone an understanding of these elements. Regarding informed consent in the therapeutic research setting, evidence of investigators pursuing consent through any concerted and conscientious efforts dates back to only the past 50 years.1,2,29,30 Although there is some historical evidence that earlier clinical researchers were sensitive to the importance of subjects' consent to research,31 this seems to have been relevant only from the standpoint that it was viewed as freeing the experimenter from culpability in the event of harm to the subject. Also, it is informed consent within the research setting of the last half century that has used some of the more recent concepts, including use of a written consent document and the need for actual understanding on the part of the research subject (rather than simple disclosure) of the elements of consent. Thus, despite a much longer history of the requirements of patient consent to therapy, true informed consent as defined within the clinical trial and therapeutic research setting is clearly, and almost exclusively, a concept of the second half of the 20th century.1,2,14,29-31 This history is a complicated one, shaped as much by social forces as by medical factors. These social forces have most significantly included litigation concerns and evolving policies of the federal government in its role in regulating the clinical research process. As a result, informed consent is viewed currently and most commonly as a means of protection of a potentially vulnerable research subject from harm.3,4
The Term "Informed Consent" More recently, however, the final report of the President's Advisory Committee on Human Radiation Experiments provides an earlier, and perhaps more interesting, history of the term informed consent.35 Through the committee's extensive research of archival materials from the Atomic Energy Commission (AEC), a little known letter was rediscovered, written in 1947 by the general manager of the newly formed AEC to a clinical investigator on an obscure and new requirement regarding the need for "informed consent." The letter was written specifically in response to the investigator's request to allow the declassification of data from government-sponsored radiation research on cancer patients, so that it might be reported and published by the investigator. As exemplified in the letter, the newly formed AEC clearly had significant concerns about potential litigation problems because of the use of seemingly vulnerable cancer patients as subjects of research without any documentation of consent. Undoubtedly, it will require further examination of these historical foundations of informed consent to know what impact these early and vague policies had on subsequent guidelines and regulations developed by the United States federal government in the regulatory conduct of clinical research. Yet, there is some evidence to suggest that these early policies did influence the subsequent guidelines developed and used in establishing the National Institutes of Health Clinical Center and in government-sponsored research within the Department of Defense and branches of the armed services.35 Whatever the case, this history clearly shows that informed consent, either as a term or a concept, was discussed within the context of clinical research a full decade before its previously recognized origins within the realm of medical malpractice and litigation. It is equally important that cancer was the disease within which the context of this discussion took place.
Consent Forms
Continued Shaping of the Regulatory Process for Consent Beecher's cancer research examples, and the other reports described, put much of the medical research process into the public spotlight. The subsequent public and medical community outcry led to regulations in the late 1960s and early 1970s that resulted in greatly increased scrutiny of government-sponsored clinical research.3,14,40 Clinical researchers themselves undoubtedly became more sensitive to the issues regarding the use of patients, including those with cancer and others, as research subjects. Other events, including the disclosure to the public of the United States Public Health Service Syphilis Studies (also known as the Tuskegee Syphilis Study1,3,41) as well as the thalidomide experience and subsequent passage of the 1962 amendments to the Food, Drug, and Cosmetic Act,42 also had great impact on the regulatory requirements for informed consent in clinical research. All of these events eventually led to the creation of the National Commission for the Protection of Human Subjects in Biomedical and Behavioral Research. The resulting recommendations of the commission led to the present requirement and pervasive practice of formalized institutional review of clinical research protocols.4
Research on Consent Forms and Current Consent Practices Soon after the implementation of modern-day regulatory requirements for consent forms and the consent process, objective information became available that questioned the effectiveness of such regulations to ensure adequate informed consent. The most comprehensive and earliest example of this was a large study of institutional review boards (IRBs) and consent forms that involved 61 institutions, 2,000 clinical researchers, and more than 1,000 research subjects.18 The study examined clinical research trials within and outside the cancer setting. The study investigators concluded that it was questionable whether subjects found consent forms useful. Moreover, these forms were found to be unreadable. Using standardized readability scales, only 7% of the consent forms were found to be readable at the periodical level, a level that generally has been accepted as the norm by which consent forms should be measured. Also, there seemed to be no measurable impact of IRB review on the readability of consent forms or their utility. Overall, the single largest group of consent forms reviewed by many IRBs, ie, those used to convey information to potentially vulnerable patients deciding whether to become the subjects of research in clinical trials, are those used in the cancer setting.23 Also, a significant proportion of the empiric research conducted examining the informed consent process has been in this setting.23-25 Thus, it is in this setting in which a great deal can be learned about the current practice of informed consent in all therapeutic clinical trials, even those outside the context of cancer research. In fact, it was cancer researchers who were among the first clinical investigators to make a concerted effort to conduct empiric research on the use of modern-day and standardized consent forms. One of the earliest of these studies was by Muss et al,43 who performed a survey of 100 patients with breast cancer after they had gone through an informed consent process regarding adjuvant chemotherapy and had signed written consent documents. The survey results showed that although regulatory requirements were fulfilled for the use of written consent documents, these documents had little impact on patient knowledge or decisions about receiving adjuvant chemotherapy. Unfortunately, based on the empiric data available, little has changed over the subsequent two decades since these early reports. Again, it has been in the cancer setting that much of the subsequent confirmatory empiric research on the consent process for therapeutic clinical trials has been performed. Although reviewed elsewhere,23-25 a few of these studies merit highlighting and discussion. An example of one such study is that by LoVerde et al44 in 1989, in which readability analyses of nearly 100 consent forms were performed by these investigators; more than half of the consent forms pertained to therapeutic cancer research protocols. Not surprisingly, more than a full decade after the earlier reports, among the authors' conclusions was the fact that consent forms were actually becoming increasingly unreadable and lengthy, with no probable impact on improvement of patient understanding or decision making. Even more recently, Grossman et al45 reported on the readability of consent forms for cancer research protocols at one institution. Many of the consent forms were those used for multi-institutional trials, cooperative group trials, or both. Only 1% to 6% of the consent forms were readable at the eighth grade level, and the mean scores were measured at a level equivalent to at least 2 years of college education. The authors concluded that despite the multilevel review process of consent forms by national cooperative, institutional, and departmental groups, consent forms continue to be unreadable and thus potentially provide no meaningful written information to cancer patients considering research participation. This conclusion has been supported by many other reports by investigators using readability analyses and other empiric techniques applied to the use of cancer clinical research consent forms.46-61
Results From Manipulation of Consent Forms and the Consent Process Undoubtedly, the use of consent forms for clinical trials of new anticancer agents is one such setting in which these issues have great significance, especially if there is to be continued recognition of the value of patient-subject autonomy and the moral importance of the consent process as a mechanism of protection for potentially vulnerable patients attempting to make difficult decisions about their medical care. Separate from the content of the consent forms themselves, concerns also exist about the overall impact of the forms on different aspects of the consent process, including its outcome and the decision-making process of patients before the eventual decision to actually participate in a therapeutic clinical trial. Because of research on the consent process in which the consent form (or the process itself) within the cancer clinical research setting is manipulated in a controlled environment, meaningful empiric information has become available that sheds light on these complex and interrelated issues. In an insightful study, Llewellyn-Thomas et al62 examined the informed consent and medical decision-making processes of cancer patients who were considering participation in a clinical trial. In this study, 90 patients with colon cancer were divided randomly into three groups and given written information that was either positively, negatively, or neutrally framed in its description of the risks and benefits of participation in a specific clinical trial that involved adjuvant chemotherapy for colorectal carcinoma. The cancer patients were then surveyed about their willingness to participate in the described clinical trial. The written descriptions provided to the three groups of patients was the only source of information for the chemotherapy that was to be part of the clinical trial. All of the patients who participated in the study were eligible for the described clinical trial. The accompanying survey studies performed by the investigators found no differences in cancer-patient willingness to participate in the clinical trial based simply on how the written information described the risks and benefits of clinical trial participation. Other research of note is by Simes et al.63 These investigators evaluated a randomized comparison of two different consent procedures for cancer clinical trial participation. They compared a consent process that used total disclosure through a written consent form, ie, the conventional process of obtaining consent in clinical trials, with simple verbal disclosure at the discretion of a patient's individual oncologist. This latter consent process allowed oncologists to discuss with their patients the particular elements of consent according to their own (or their patients') priorities, without the use of a written consent document. The cancer patients were being asked to participate in one of several randomized clinical trials for which they were eligible. Surveys of patients were conducted at the time of subject consent to research participation, or nonconsent to participation, and then again 3 to 4 weeks later. The surveys were designed to measure the impact of the two different consent processes on patient understanding, patient anxiety, and the physician-patient relationship. The survey results showed that total disclosure with the use of a written consent form did lead to a better understanding for the patient-subjects about the risks and the nature of research. In addition, there was increased anxiety on the part of the patients in regard to participating in the clinical trial. There was also less willingness on the part of patients who were randomized to the total (written) disclosure consent process to participate in a clinical trial. Interestingly, however, these differences between the two groups were not seen at the follow-up survey 3 to 4 weeks later. The authors were unable to find any significant detrimental impact on the physician-patient relationship with the use of total disclosure in the consent process. In the clinical trial setting, several other studies have examined the potential impact of different information-provision methods on the informed consent process. It is of note that in their recent review of different methods of information provision in clinical trials across the entire spectrum of disease processes, Edwards et al64 found that nearly 60% of these studies were conducted by cancer investigators and focused on clinical trials that involved cancer patients as research subjects. As shown by Edwards et al and as evidenced by the above-mentioned research, despite the format of presentation, information provision may have little impact on patient-subject understanding.
Impact of Other Supplementary Methods on Improving Informed Consent Although the potential impact on the informed consent process has not been examined for all of these interventions specifically for clinical trials,70,74,75,79 the results from all of these studies are likely to be meaningful for any setting in which a cancer patient is considering a therapeutic intervention (whether experimental or otherwise). An overview of these interventions is provided in Table 1. Although the majority of the studies have shown improvements in increasing patient comprehension, many of these improvements have been modest at best. In addition, some of the interventions may have the potential to detract from what patients and physicians view as the central component of the consent process, ie, direct verbal communication.65
Other significant research contributions within the cancer setting to the informed consent literature can be found elsewhere.23-25,64 It is again worthwhile to note that these contributions by cancer investigations are rather exclusive, at least relative to similar research done in other disease settings. Arguably, as discussed later, this research should continue to be conducted in the cancer setting where the information gained may have some of the greatest relevance and where cancer investigators and their colleagues already have begun to produce a wealth of meaningful and thoughtful results on which to build.
Although difficult problems exist in the informed consent process for all phases of clinical research, from an ethical perspective, these difficulties are probably intensified at each end of the clinical trial spectrum. More specifically, it is within phase I and phase III cancer trials that many ethical dilemmas remain unaddressed. Several of these dilemmas have arisen as a result of uncertainty toward what the actual structure and outcome of the informed consent process should be for patients considering participation in these trials.
Dilemmas of Phase I Trials If patients were to participate in phase I trials solely for altruistic reasons, ie, to help forward cancer research and potentially help future cancer patients, phase I trials would probably carry less ethical conflict. Also, this would imply that the traditional informed consent process might achieve more readily the desired ideal outcome of understanding all elements of consent, including an understanding of the nature of phase I research and the alternatives to trial participation, because these less vulnerable patients would not necessarily be seeking benefit for themselves. However, the objective information available about the informed consent process for patients who participate as research subjects in phase I trials shows that altruism is not the primary motivation for patients in such clinical research. In addition, as reviewed below, the empiric studies that examine the phase I consent process highlight the true ethical dilemmas associated with this early stage of clinical research.
Empiric Research on the Phase I Cancer Trial Consent Process Investigators at the University of Chicago conducted an in-depth survey study of 27 patients with cancer who had given informed consent to participate in phase I trials at their institution.89 Concurrently, the oncologists identified by the surveyed patients as responsible for their care and consent were also surveyed. Eighty-five percent of patients decided to participate in a phase I trial for reasons of possible therapeutic benefit, 11% because of the advice or trust of physicians, and 4% because of family pressure. Ninety-three percent said they understood all (33%) or most (60%) of the information provided to them about the trial in which they had decided to participate. Only 33% were able to state the purpose of the trial in which they were participating; patients who were able to state the purpose of phase I trials as dose-escalation or dose-finding studies were more educated (P = .01). The surveyed oncologists had wide-ranging beliefs regarding expectations of possible benefits and toxicities for their patients participating in a phase I trial. The authors concluded that patients who participate in phase I trials are almost exclusively motivated by the hope of therapeutic benefit. Although altruistic feelings are perhaps present, they seem to have a limited role in patients' motivation to participate in these trials. Subsequent studies conducted by these investigators in a much larger series of subjects have found similar findings. In fact, in larger series of subjects, quantifiable survey data show that patients may even be less aware of the research purposes of phase I trials, and are unable to recall whether alternatives to clinical trial participation, including palliative care or other nonexperimental therapies, were either discussed with or disclosed to them.90,91 This is despite the fact that all surveyed patients had signed consent forms that detailed the research purpose of phase I trials and the alternatives to trial participation. Tomamichiel et al92 conducted an analysis of the communication process involved in informed consent for cancer patients who agreed to participate in phase I trials. The researchers performed a quantitative examination of information exchange by applying a validated communication model to taped conversations between cancer patients and physicians who were discussing whether to participate in a phase I trial. They recorded three consecutive conversations between the investigator responsible for phase I studies, the research nurse, and the patient's relatives and friends. The authors concluded that the informed consent procedure was satisfactory from a quantitative point of view. Interestingly, they found that the most important items of information were acceptably communicated to patients. However, they also stated that greater attention should be given to the indirect messages and implied criticism of patients to improve their participation in decision making. They also concluded that physicians should become more skillful in providing adequate information and improving their methods of communication. Yoder et al93 conducted a prospective study that involved entry and exit interviews of 37 patients with advanced cancer participating in phase I trials. Patients were interviewed at the time of decision to enter a phase I trial and again when they came off the trial. The investigators specifically sought to examine patients' expectations in addition to their overall experiences from participation in a phase I trial. They found that patients expected slightly increased support from family members and received more support than expected. Perhaps not surprisingly, patients' expectations for tumor response and increased communication with their physicians were not met. Their expectations were also not met regarding improvement of symptoms such as fatigue, nausea and vomiting, and weight loss. They noted that strong themes that emerged from the data were hope and optimism. They concluded that an issue that needs further exploration is the extent to which patients accurately understand information in the consent form and in the consent process itself. Their findings also support the importance of communication between the patient and family and all members of the health care team and stress the importance of oncology nurses who may be able to mediate the flow of information between physicians and patients. Japanese investigators conducted a similar study in an attempt to characterize the motivation, comprehension, and expectations of patients who had given informed consent to participate in phase I trials at the National Cancer Center in Japan.94 Before they were given any investigational agents, 32 of 33 subjects were approached and completed a multiple-choice questionnaire that addressed these issues. Interestingly, 63% of the subjects stated that they did not expect any benefit from participation in the study but wished to participate anyway. Only 19% of the subjects were found to be motivated (in closed-ended questioning) to participate in phase I trials by the possibility of therapeutic benefit. Nine percent stated they were participating because it seemed a better choice than no treatment, and 6% mentioned altruistic reasons for participation. However, when questioned about their expectations, despite their responses given for motivations to participate in phase I trials, more than half the subjects indicated that there might be personal benefit to themselves. In addition, slightly more than one third of the subjects (35%) believed that it was possible that their cancer could be cured, and 12 subjects fully expected to be cured as a result of participation in a phase I trial. The investigators found that older adults had slightly higher expectations of cure from participation in a phase I trial (although this did not reach statistical significance). With closed-ended questioning, most patients seemed to comprehend the major features of a phase I trial, namely its investigational nature, the unknown effects of the agent investigated, and the unclear benefit to themselves. Also, nearly 60% of the patients anticipated they might suffer severe or life-threatening side effects from participation. As many as 43% of subjects were able to indicate accurately (again, in closed-ended questioning) the research purpose of a phase I trial as a dose-determination study. One disturbing finding from these studies is the potential discrepancies among what has been disclosed to patients, what they think they understand, and what they may actually understand. For example, the University of Chicago study found that 90% of patients stated they understood all or most of the information provided to them about the phase I trial in which they had agreed to participate.89 However, only approximately one third of the patients could state the purpose of a phase I trial, and an even smaller proportion of patients could state the research purpose of phase I trials in a much larger study.91 This discrepancy likely results from several factors, including inadequate informed consent. It may also involve the methodologic difficulties of determining what a patient actually understands in relation to the information they have been given. Despite the data from these studies, we still do not have good empirical understanding of the factors that encourage patients to choose phase I trial participation over other alternatives of care. The information gained from this research strongly suggests that the current process of obtaining informed consent for phase I trials may be inadequate to ensure that such advanced-cancer patients understand both the nature of the research in which they are participating and the alternatives to trial participation. In addition, despite recognition of the potential vulnerability of a patient with advanced cancer, it is not known how that vulnerability specifically affects their ability to give what is otherwise perceived as adequate informed consent. It is possible that several poorly understood, and seldom studied, factors play a vital role in shaping the informed consent process for potentially vulnerable patients with advanced cancer considering participation in phase I trials. These likely include relatively subtle and less apparent factors that may exist in other health care decision-making environments for advanced-cancer patients, eg, a patients' awareness of certainty of death95-97 and their cultural and ethnic backgrounds.98 In addition, advanced-cancer patients' religious or spiritual beliefs, their degree of hope and emotional well-being, and their attitudes toward medical decision making may influence the consent process. Further research will be required to better understand and delineate these issues and their importance on the informed consent process in this difficult and highly charged setting. Such research undoubtedly will contribute to our knowledge of the informed consent process within all phases of cancer research, and may even apply to other clinical research outside the cancer setting in which potential therapeutic benefits may be similarly unlikely.
Ethics, Informed Consent, and Randomized Phase III Trials Much of the debate about ethical issues in phase III trials has focused on the issue of equipoise. As originally defined by Fried,106 equipoise is viewed as a state of genuine uncertainty on the part of a clinical investigator or treating physician toward the comparative merits of different treatments for a patient's specific disease process, such as cancer. Some have argued that equipoise must exist for an individual investigator or physician in regard to an individual patient, so that he or she can ethically ask (or encourage) that patient to participate in an appropriately designed phase III trial. Others have argued that a broader definition of equipoise be accepted to justify randomized phase III trials—specifically, that clinical equipoise need not exist for an individual physician or investigator, but need only exist within a specified medical community.107,108 In the cancer setting, clinicians, researchers, and ethicists have debated this issue of equipoise (whether it should be applied as an individual versus a community standard), and whether randomized studies are ethical at all.99,103,104,109 The empiric research available from the cancer setting strongly suggests that the issue of equipoise remains unresolved for investigators, clinicians, and even patients.110-115 The available evidence also suggests that many oncologists view the informed consent process requirements within randomized clinical trials as too cumbersome or potentially threatening to the patient and doctor-patient relationship, to the extent that they are a significant obstacle to patient accrual to phase III trials.111,116,117 Returning to the process of informed consent in phase III trials, with the issue of equipoise in mind, Freedman107 rationally argued that an individual physician or investigator is not the sole arbiter of appropriate or acceptable medical practice. Rather, the medical community as a whole determines equipoise, and as long as equipoise truly exists, an individual physician can remain ethically and morally justified in encouraging patients to participate in a phase III trial, even if the physician is not in equipoise. Regarding the informed consent process itself, Royall118 extended this argument, noting that in situations that involve an autonomous patient, the decision to participate in a randomized study is not the physician's but the patient's. This is certainly the case as long as an adequate (perhaps ideal) process of informed consent can be conducted, including full disclosure of alternatives to randomized trial participation. Royall argued that what is needed for randomized trials to be justifiably conducted, beyond the presence of medical uncertainty (or equipoise) regarding particular therapies, is not physicians without preferences; rather, it is patients who are informed of the uncertainty, ie, the existence of perceived equipoise, and are autonomously willing to consent to randomization. Thus, within the context of phase III trials, the informed consent process becomes one of utmost importance. In the cancer setting this may be especially true because of the life-threatening nature of these diseases and the relative toxicities of potential therapies contained within arms of many randomized trials. Some efforts have been undertaken to examine different methods of obtaining consent for randomized trials and the impact of these methods on the quality of consent.119-122 Again, cancer investigators have led much of the initiative and conducted this research. Many of these investigators have examined alternatives to the conventional methods of informed consent for phase III trials, ie, where subjects first consent to the trial and then are randomized to either standard or experimental treatment. The alternatives to this conventional method of consent and randomization include so-called preconsent randomization, in which subjects are first randomized to one arm of the trial and then asked to consent to participation. As reviewed by Altman et al122 and originally proposed by Zelen,123 these alternatives include single- and double-randomized consent designs. In the single-randomized consent design, eligible subjects are first randomized to one of the treatment arms under study in a trial before consent and without their knowledge. Subjects randomized to standard treatment are simply evaluated with routine follow-up and nothing is said to them about the trial or their participation, ie, no formal consent is obtained from them. Subjects randomized to the experimental arm in such designs are asked for consent to receive the investigational therapy. If these subjects refuse participation, they would then receive standard treatment and be followed similarly to those originally randomized to standard treatment. In the double-randomized consent design, all subjects are first randomized without their knowledge then asked if they would consent to participate, receiving either the standard treatment or the experimental treatment to which they had already been randomized. Those who refused trial participation would then be offered treatment with the opposite arm to which they had been randomized, eg, those who refused standard treatment would be treated with the experimental therapy. Such designs were proposed to make the informed consent process less cumbersome and threatening for a participating physician-investigator. In fact, Zelen123 proposed such trial designs because of practical difficulties in getting physicians to participate in randomized trials, hoping to increase their willingness to participate. The common theme of such designs is that patients are asked to consent to a specific treatment rather than to participate in a randomized trial. Many statistical difficulties arise with such randomized consent designs, including an inability to blind subjects to the treatment. In addition, such designs create both an underestimation and a dilution of possible differences in treatment effects, resulting in larger (and even unpredictable) accrual goals. Significant ethical issues also arise with such designs, including the fact that some subjects would be unaware that they are in a clinical trial. Besides that, many subjects would likely receive biased information about the particular treatment to which they had already been prerandomized by the participating physician-investigator who approached them for inclusion in the trial. Even with such criticisms, nearly a dozen cancer clinical trials have used these or similar consent designs. As reviewed elsewhere,122,123 many of these trials were in the cooperative group setting. Most of these trials had been initiated originally with conventional consent designs but were then modified to include randomized consent designs to improve on slow patient accrual. Several of these trials increased their accrual rates substantially, some by a factor of three to six times the initial accrual rates.124-126 Despite these improvements in accrual, these consent designs remain controversial. The ethical and statistical difficulties have prevented their implementation on a routine basis and they have not been recommended for such use. Gallo et al119 examined the use of such trial designs and compared different preconsent procedures for a hypothetical randomized trial. In this study, more than 2,000 subjects who were otherwise healthy were asked to imagine that they were ill with a life-threatening disease with some prespecified chance for 5-year survival. The subjects were first randomly assigned to three different groups, each with a different likelihood of 5-year survival—80%, 50%, or 20%. The groups then were assigned randomly to four different hypothetical clinical trial participation decision outcomes: (1) one-sided informed consent for randomization in which subjects who refused trial participation would receive the standard treatment; (2) two-sided informed consent for randomization in which subjects who refused participation could choose to receive either the standard treatment or the experimental treatment; (3) subjects knowingly randomized to experimental treatment in which those who refused would receive standard treatment; and (4) subjects knowingly randomized to standard therapy in which those who refused would receive experimental treatment. Of the four consent designs, the group that was least likely to refuse clinical trial entry consisted of those assigned to traditional one-sided informed consent, in which subjects who refused trial participation would then receive standard treatment, with a refusal rate of 16%. Refusal to participate in the trial was highest in the group whose participants could refuse clinical trial participation but still receive the experimental treatment, at a refusal rate of 49%. In general, the more life-threatening the disease was, the less likely subjects were to refuse clinical trial entry that allowed them to receive experimental therapy. On the basis of this research, it can be concluded that a preconsent randomization method is highly inefficient for accrual improvement because subjects knowingly randomized to receive standard treatment would likely refuse clinical trial entry. Some of the ethical problems with randomized phase III designs and conventional consent methods described earlier are apparent in these results, as subjects with more life-threatening disease are less likely to refuse clinical trial entry, presumably with the hope of receiving an experimental (and unproven) therapy. Certainly, continued study and debate about the complex issues of the informed consent process in phase III trials is unquestionably needed. It is likely that a significant portion of this study and debate will continue to focus on the cancer clinical research process. Again, considering their heightened and long-maintained awareness of these issues, cancer investigators are perhaps best qualified to continue to provide guidance toward this research and discussion.
Undoubtedly, a meaningful informed consent process will remain an enormously important and undeniable ethical obligation to patients with cancer and others who are asked to become the subjects of research. However, as exemplified throughout the history of cancer clinical research, although the regulatory requirements (including the use of written consent forms) have perhaps allowed a greater scrutiny of research practices and prevented potential abuses, they have had little impact on the quality of the consent process itself. Consent forms themselves remain unreadable, with questionable clinical utility, regardless of their font size or user-friendly appearance. In addition, the current practices by which consent currently is obtained and regulated may detract from what might otherwise be a more meaningful consent process. This may be especially true for potentially vulnerable patients with cancer who are participating in early clinical trials of investigational agents, eg, phase I trials. Perhaps then, with recognition of the inadequacies related to the regulation of informed consent for therapeutic clinical research, many cancer clinical investigators may (understandably) have a certain amount of apathy toward these regulations. Regrettably, such apathy can only result in the rote and meaningless fulfillment of consent requirements. Justifiably, many cancer investigators and physicians have likely asked themselves, Do these forms matter and what utility do they serve? Equally important questions that should also be asked include: What is happening to the consent process itself? Has the attention placed on the forms—and do the forms themselves—inhibit a more meaningful process of communication and consent between patient-subject and clinician-investigator? Conclusive answers to such questions can only come from continued study of these issues, and not from increased regulatory requirements. Considering the breadth of ethical issues in therapeutic research, and their long-standing presence, in oncology, it is arguable that a nearly complete understanding of informed consent can be obtained through an almost exclusive examination of the cancer clinical research process. It may be reasonable to expect that with further research and improvements in the area of informed consent for therapeutic clinical trials, cancer researchers should be prepared to continue to play an important role. Part of the preparation for this leadership will require an awareness of both the history and background of the ethical obligations of clinical investigators. Cancer researchers also need to be aware of the wealth of data that examines the motivations and decision-making processes of patients considering participation in clinical trials that involve investigational therapies. The remaining and most important portion of the leadership in this area will need to come from continued study of these issues. Such continued study can reap benefits through examination of the issues that are omnipresent across the clinical trials spectrum. Such issues include examination of the impact of investigators' conflicts of interest and patients' preferences for information provisions on the consent process. However, to obtain informative answers to the most troubling questions, investigators must focus on the most ethically challenging areas of the informed consent process. For instance, areas in need of examination in the earliest phases of anticancer drug development, eg, phase I trials, are those related to advanced-cancer patients' awareness of both their own life-ending prognoses and the alternatives available to them apart from research participation. Research in this area should seek to determine the correlates of why only some advanced-cancer patients who receive investigational agents seem more willing to recognize the inevitability of their deaths and the presence of reasonable alternatives, including more palliative approaches to their illness.91 From such research we might obtain information that may allow us to better fulfill our obligations as physicians and investigators to ensure that other patients with advanced cancer recognize these important components of the informed consent process in this setting. In addition, the physician-investigators involved in this consent process should be willing to be studied. Research that would attempt to better document the communication process between a cancer patient considering research participation and the physician-investigator involved in the research, would allow a more objective understanding of how the elements of consent are verbally communicated to these patients and what effect they have on the decision to participate.92 An interesting hypothesis that could be studied in this setting is the anecdotal description that says many patients with advanced cancer only hear what they wish to hear. Whether this is true or not is unproven and would require sensitive sociologic and anthropologic methods of study, in addition to use of tape and visual recordings of the informed consent process undertaken in this highly charged setting. In addition, research aimed at examining the most adequately informed, or attempting to empower such potentially vulnerable patients so that they are better informed, would provide further meaningful information to guide future communications.82,127,128 Finally, through study of similarly related issues in other populations of patients with advanced cancer who have not sought such investigational agents or therapies, eg, patients receiving hospice or other palliative care, we may gain meaningful information about how the consent process should be tailored to meet the different ethical needs of this diverse patient population. Many dilemmas continue to remain unaddressed and a lack of informative research exists with regard to later stages of clinical research and drug development in the cancer setting. This has led to continued confusion and arbitrariness toward the consent process for phase II and III clinical trials. Many phase II trials of new agents involve a population of advanced-cancer patients who are unlikely to respond to the investigational agents under study.129 Traditionally, after the initiation of a phase II trial, subsequent patients are accrued with little response or toxicity information available to prospective subjects about prior patients treated or studied in the trial. Important areas of research in the phase II setting would include examination of the preferences of newly participating subjects regarding whether they should, or would wish to, receive the latest and most timely information regarding all previously enrolled subjects. Should prospective patients be given this information? If so, how would it shape the size and accrual rates of phase II trials? From a patient perspective, how many nonresponders need there be in such trials before they would view participation in an unfavorable light? Also, from a clinician's point of view, do the current strict statistical restraints on phase II trials cause slower accrual as information regarding nonresponders becomes available such that it becomes unethical to put a patient on such a trial because of no expectation of reasonable benefit on the part of the clinician? These are issues that are amenable to study and could potentially generate results that would not only improve the consent process in this setting but might even change the size and scope of the traditional process of phase II trial drug development. The physician-investigators who conduct such trials should also be studied to determine their attitudes and current practices toward provision of information and their therapeutic expectations for the subjects they enroll onto such trials. As in the phase I trial setting, many subjects in phase II trials have a uniformly fatal illness; thus, studies of such patients in this highly charged setting, assessing their understanding of their prognoses and alternatives to trial participation, similarly would be helpful in describing the current deficiencies of the consent process for early clinical trials. Many important issues remain open for study with regard to phase III trials. Certainly, whether physician-investigators believe that true equipoise exists for ongoing phase III trials is an appropriate area of study. An examination of how the perceived degree of equipoise on the part of the physician-investigator discussing phase III participation with a prospective subject will influence the structure of the consent process would be enlightening. Well-designed studies using survey methodologies could easily address this question. One exploratory area that remains unexamined in any significant quantitative way is determining the motivational factors of phase III trial participation for both physicians and patients. For physicians, it is unknown whether they encourage patient participation in phase III trials as a result of their desires to improve care for future patients or whether it relates to their ability to offer their current patients a 50% chance (in a traditional two-arm trial) of receiving a newer and a more innovative (and therefore perceived to be better) therapy. In this regard, from an ethical perspective, the consent process for phase III trials has focused traditionally on the uncertainty of which therapy is best. However, for patients and clinicians, a more practical outcome of the consent process may often result in the participants focusing on one of the arms of a trial as a potentially more desirable therapy. Research in this area would need to first describe the motivations for participation in specific phase III trials for a specific disease process, eg, high-dose chemotherapy and stem-cell rescue for locally advanced breast cancer. Subsequently, interventions could be tested to determine whether they can reshape and even improve the motivations for participation in such trials so that they might be more in agreement with accepted ethical practices and guidelines. These would include the belief that phase III clinical trials offer the best state-of-the-art care regardless of which arm a subject is randomized to and that such trials are the most effective and unequivocal method available to answer certain clinical research questions. Other interesting areas of studies would include examination of the impact of physician bias in regard to encouraging or discouraging clinical trial participation and the reason for so doing. In addition, subsequent longitudinal studies could be envisioned to examine the impact of educational interventions, either early in the training of physicians or in the continuing education setting, on reshaping how physicians discuss phase III trials with prospective subjects. Similar research in related cancer settings has shown that such interventions can improve the communication abilities of oncologists.130 As mentioned above, issues of conflicts of interest are pervasive throughout all phases of clinical research. Studies regarding the informed consent process relative to this complex issue could be conducted to examine how the inclusion of conflicts of interest statements, as an element of the consent process itself, affects the willingness of subjects to participate in a clinical trial. Conflicts of interest statements to be included in such study would disclose the potential for financial and career enhancement of the involved investigators as a result of a subject's participation in a clinical trial. If well-designed studies examining this issue were to show that provision of such information does not negatively affect clinical trial accrual, there would seem to be little argument against providing this type of information in the consent process. The attitudes of cancer patients and their preferences (real or perceived) for information provision have been examined extensively.54,57,62,70,76,112,114,115,131-158 Whereas some research has focused on the clinical research process,54,57,62,70,76,112,114,115,143,144 the vast majority of these studies have been outside the clinical trial setting. This literature clearly shows that patients can have widely differing preferences for both the type and format of information received regarding their prognosis and therapy. In addition, their perception about prognosis and treatment can clearly affect their preferences for information.119,138,141,143,144 More specific research should be conducted to determine whether providing such information according to specific patient preferences can improve the overall communication and consent process for investigational therapies. There is the potential for such research to lead to more accommodation of patients' attitudes and beliefs within clinical trials and to increased trial accrual. In addition, truly innovative interventions that involve cancer patient education materials designed to improve the adequacy of the consent process need continued study. However, the current data clearly support an effort to move away from the traditional consent form, and any of its more modern antecedents, as a singular and important component of the consent process. Such truly innovative methods will need to focus on specific patient needs or requests and even tailor the consent process for each individual subject considering trial participation. The challenge will be to develop such methods while at the same time conforming to well-recognized ethical principals that must be applied to all prospective clinical trial subjects, and also allow continued attention to enforceable and overseeable policy guidelines. Lastly, another innovative area of investigation might be the potential for IRBs to actually become an educational resource for matters related to the informed consent process and research ethics in general. In this mode, IRB members might see themselves more as educators or consultants to clinician-investigators who are seeking the best method to facilitate informed consent for their specific research protocol. IRBs might then focus more on educating and mentoring investigators, rather than view themselves as performing a thankless job of focusing on the fine print of consent forms and enforcing sometimes vague policy. This would not necessarily require a significant change in the current policies of IRBs, but it would require careful initial pilot projects to measure the impact of the change in IRB focus away from written consent forms and protocols and toward the investigators and their need to fulfill their ethical obligations toward the patients they are asking to become research subjects. Although such a shift in focus might not require a significant change in IRB policies, it might result in the need for IRB members with more specific interests and expertise in communications research and medical ethics. In the end, the only way to ensure that the consent process is equitable for all is to emphasize the central role of open, honest communication between a clinician-investigator and a patient who is considering research participation. The field of cancer clinical research, from its early foundations to modern day, provides clear examples in support of this. The regulatory process currently in place has undoubtedly prevented misguided research practices or even intentional research abuses. The regulations themselves undoubtedly have made this communication process more complex. However, streamlining the process is likely to be feasible, but it will require a concerted effort on the part of all those responsible for the conduct of clinical research to continue to take the consent process seriously and to appropriately and constructively adapt to the available empiric information examining this issue.
Supported in part by grants from the American Cancer Society (PRTA-24) and a Career Development Award from the American Society of Clinical Oncology.
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Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
