Journal of Pain & Palliative Care Pharmacotherapy. 2014;28:138–151. Copyright © 2014 Informa Healthcare USA, Inc. ISSN: 1536-0288 print / 1536-0539 online DOI: 10.3109/15360288.2014.908994

COMMENTARY

Moral Justification of Phase 1 Oncology Trials Alex Dubov AB STRACT This article attempts to answer the following normative questions: Can one consider the design of Phase 1 trials ethically appropriate due to the unfavorable ratio of risks and benefits? What are some ethical safeguards for Phase 1 oncology research? A comparative review of literature contributed to the consolidation of the proposed ethical framework for Phase 1 oncology trials. This framework gives a special attention to issues of therapeutic misconception and vulnerability. The benefits and dangers associated with the enrollment in trials are described as well as the absence of alternatives, treatment-specific optimism, and vagueness in factual presentation during the informed consent process. The notion of therapeutic misconception is contrasted with optimism despite realism that stems from psychological, cultural, and religious factors and not necessarily from the lack of information. Close attention is given to the possible ways in which the inherent uncertainty and resulting cognitive biases may affect the informed consent process and the definition of therapeutic misconception. The article ends with recommendations for an ethical way of enrolling palliative patients in early stages of oncology research, giving special attention to provision of adequate consent, protection of vulnerability, and avoidance of therapeutic misconception. KEYWORDS vulnerability

informed consent, Phase 1 oncology trials, risk-benefit ratio, therapeutic misconception,

most no one would regard these practices as inherently problematic. Some commentators go even further pointing out that there is a moral obligation to participate in research because these patients have benefited from treatments resulting from clinical research conducted on individuals in the past. Moreover, the literature studying the motives for enrolling in Phase 1 trials highlights the importance of altruism in motivating participation.3 Although it is never the main reason to participate, many research subjects identify altruism as a very important motivation to join the trial.4 This can be one of the answers to the question why a vulnerable patient in the last stages of cancer who likely have exhausted standard treatment options would choose to participate in a trial that would not benefit him or her directly.5 Some other possible answers can be found in the poorly designed informed consent process and resulting therapeutic misconception.6 On the other hand, some researchers would argue that the experimental therapy may still provide benefits, even when there is no intention. The goal of this article is to continue the conversation on moral justification of Phase 1 oncology drug

INTRODUCTION Major areas of ethical concern regarding Phase 1 oncology trials are the unfavorable risk to benefit ratio and therapeutic misconception as the result of flaws in informed consent practice.1 Critics have argued that these studies are geared toward purely scientific interests of determining safety and dosage for the new compound while not promising to participants some valid benefits.2 This practice of exposing subjects to risk for the benefit of others raises ethical concerns. It appears that participants of Phase 1 trials are being used as mere means to collect the information to benefit future patients. However, it is worth mentioning that many other everyday activities follow the same pattern. Thus, speeding ambulances put pedestrians at risk for the benefit of the patients they carry and humanitarian forces expose their volunteers to some risk in order to benefit the population they serve. AlAlex Dubov is a PhD candidate in healthcare ethics at the Duquesne University Center for Healthcare Ethics, Pittsburgh, Pennsylvania, USA. Address correspondence to: Alex Dubov, 437 Maple Avenue, Pittsburgh, PA 15218, USA (E-mail: [email protected]).

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trials. It opens with an exploration of moral foundations of Phase 1 oncology trials, with special attention to the issues of therapeutic misconception and vulnerability. When these concepts are defined in the context of oncology trials, the paper discusses moral arguments against and in support of Phase 1 cancer studies. The dangers associated with the enrollment in Phase 1 trials will be presented, as well as the absence of alternative choices, treatment-specific optimism, and vagueness in factual presentation during the informed consent. On the other hand, some possible benefits, including disease stabilization, decrease in tumor size, and many psychological advantages, will be introduced in the section dealing with arguments supporting moral validity of Phase 1 trials. The notion of therapeutic misconception will be contrasted with optimism, despite realism that stems from psychological, cultural, and religious factors, and not necessarily from the lack of information. Close attention will be given to the possible ways in which the inherent uncertainty and resulting cognitive biases may affect the informed consent process and the definition of therapeutic misconception. Even though there is ample empirical research on intuitive decision-making and risk perception, the normative reflection on this topic is lacking. Although some researchers think that emotional responses to risk in choices under uncertainty create biases that need to be improved upon rationally, many other voices consider emotions an essential part of practical rationality. The last part of this paper, tracing the connection between uncertainty, misconception, and informed consent, outlines possible ways in which emotions influence judgments about morally acceptable risks. The paper ends with recommendations for the ways to avoid misconception and to protect the vulnerable.

MORAL FRAMEWORK FOR PHASE 1 ONCOLOGY TRIALS If one were to develop a moral framework pertaining specifically to Phase 1 oncology trials, two principles would become prominent. First, this framework would include guidelines on how to deal with the vulnerable subjects and would define the meaning and limits of this vulnerability. This definition would include cognitive and circumstantial factors that influence terminally ill patients’ choices.7 Second, a greater degree of pessimism about subjects’ present health conditions and a greater degree of optimism about the future may lead to therapeutic misconception. Many patients who enter Phase 1 trials cognitively recognize a very low probability of personal health benefit. Having exhausted all other op C

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tions, they decide to participate in research as a last resort.8 This is not to exclude other patients joining trials from purely altruistic considerations. In his recent study, Truong et al. document that more than half of the respondents considered altruism as a very important motivation to join the trials and one in seven respondents thought it was their main reason for joining.9 This section will address those patients seeking a direct benefit from participation and will provide the more detailed overview of therapeutic misconception and vulnerability.

Therapeutic Misconception Paul Appelbaum, Loren Roth, and Charles Lidz introduced the term “therapeutic misconception” in 1982. They linked the term with subjects’ confusion about the purpose of the study, implying that therapeutic misconception occurs when “a research subject fails to appreciate the distinction between the imperatives of clinical research and of ordinary treatment, and therefore inaccurately attributes therapeutic intent to research procedures.”10 The same concept of confusion about the purpose of research is present in a more recent definition of the problem by the National Bioethics Advisory Commission (2001): “the belief that the purpose of a clinical trial is to benefit the individual patient rather than to gather data for the purpose of contributing to scientific knowledge.”11 Although most researchers agree about the moral obligation to make sure there is no misconception regarding the nature and intent of study, some argue for permissibility of misunderstanding about the possible benefits from participation.12 Taken into consideration that those eligible to enroll in a Phase 1 trial have exhausted standard treatment options, it is understandable that these people will hope for improvement of their conditions despite logical arguments or evidence. Nevertheless, quite often these unreasonable expectations of benefits reflect problems found in research design. The presence of therapeutic misconception among participants of Phase 1 trials has been empirically documented. For example, Joffe et al. states that 30% of patients enrolled in Phase 1 oncology trials thought that the experimental therapy was proven to be the most efficient treatment targeting their specific type of cancer.13 Among 144 participants involved in the study by Daugherty et al., 73% enrolled in a Phase 1 trial hoped for “anticancer response,” such as cure or remission, whereas 61% understood the nature of experiments was to determine efficacy of this new drug.14 Some bioethicists state that the mere fact of research subjects volunteering for a study that will not benefit them and most likely harm them gives

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enough reasons to believe that they were not well informed, failed to understand, or were forced into the study. Many critics also point out the tendency of recruiters to overexaggerate benefits and minimize the risks of research participation, contributing to the formation of misconception in participants.15 The investigators may adopt therapeutic language instead of experimental, using expressions such as “this drug may result in tumor shrinkage,” “you may experience relief of your symptoms,” “results in animals are promising,” or “this may induce an immune response to your cancer.”16 The struggle in researchers’ presentations between not promising much while not really taking away hope is well documented in the literature as the main factor in therapeutic misconception.17 The Phase 1 oncology research demonstrates the striking contrast between clinical and research settings. Most of the moral issues around this type of research are rooted in the inability of patients to distinguish between the two, and failure of the researchers to convey the differences. The principal concern of clinical ethics is patients’ well-being. In the clinical research setting, patients receive therapy that is not selected for the considerations of their individual well-being, but on the basis of completion of the experiment. This difference is less than obvious to the patients/participants. Throughout the course of their illnesses, they have been used to framing their interactions with medical professionals around the expectation of receiving personal care. These expectations are carried into the research setting. Usually the recruitment process for a trial happens during one’s visit to a physician, while s/he is trying to find help with some clinical issues. When a patient, and now a subject, first gets to meet the research team, s/he may recognize some other physicians and nurses wearing white coats or scrub suits. This is exactly the image used to associate with treatment. In addition, the subject’s own physician has recruited her/him into the trial that that doctor may now be in charge of carrying out. The patient is not to be blamed for expectation of treatment. Therefore, during the description of goals and procedures of the experiment, the investigator has a moral obligation to spell out differences between therapy and clinical research to avoid misconceptions.18

Vulnerability of Participants Two factors emerge while defining vulnerability in the context of clinical research. The first relates to a number of mental or cognitive circumstances that may prevent one from giving informed consent. The second factor refers to a variety of circumstances that make one more vulnerable and susceptible to coer-

cion and manipulation.19 Nevertheless, despite the fact that there are many guidelines and regulations on how to deal with vulnerable populations in medical research, the concept of vulnerability remains ambiguous. The definition provided by the Council for International Organizations of Medical Sciences (CIOMS) states that “vulnerability is perhaps best conceived as the relative or absolute inability to protect one’s own interests.”20 In addition, the Belmont report bases its definition of vulnerability in one’s dependent status and compromised ability for consent. While looking at these definitions, it is easy to notice that the notion of vulnerability is reduced to either ability for consent or susceptibility to harm. If the concept is closely connected to one’s ability of giving voluntary informed consent, then terminally ill patients who participate in Phase 1 trials may not be considered as a vulnerable population. Should Phase 1 oncology research subjects be considered as “medically vulnerable”? From a legal standpoint, a vulnerable person lacks the capacity for making informed choices. However, most terminally ill oncology patients are found somewhere in between, having the capacity to consent and not being able to exercise that capacity due to the nature of their circumstances. Their illness often makes them weak; it causes pain and a great deal of discomfort. Knowing that there is no effective treatment available may produce anxiety and other emotional stress, while medications, especially analgesics, directly affect their cognitive abilities. Taking into consideration all these factors, it is difficult to talk about free and informed choice to participate in a Phase 1 trial. In addition, researchers who recruit patients for these trials are often their physicians and have the patients’ trust and confidence. They, sometimes consciously and more often unconsciously, use this trust and their patients’ vulnerability to their advantage. Thus, their presentation of risks and benefits from the participation in experiments is often vague, and, as one study reported, 96% of investigators use words “treatment” or “therapy” without adding modifying words such as “experimental” or “research” in their written communication.21 The National Bioethics Advisory Committee makes a provision for this kind of vulnerability by introducing the subcategory of “situational cognitive vulnerability.” Under this provision, research subjects may have the capacity to decide for themselves; however, they might be in “situations that do not allow them to exercise their capacities effectively, such as stressful emergencies.”22 This report, as well as other literature, does not offer guidelines on how one can better understand the ways in which terminally ill patients face decision-making stressors and how to Journal of Pain & Palliative Care Pharmacotherapy

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reduce the consequences of those stressors.23 Some may argue that participants in Phase 1 trials should not be regarded as vulnerable as a group. Thus, Seidenfeld et al.24 report that the majority of research subjects in Phase 1 trials are white, middle-aged, and well educated. They have private health insurance and are well enough to be self-sufficient physically. In addition, they have some knowledge of side effects of oncology treatments from their previous experiences, and their decision to participate is not influenced by the stress of recent diagnosis. Nonetheless, these researchers recognize that Phase 1 oncology trial participants might still be considered vulnerable due to their terminal diagnoses and susceptibility to harm from the experimental agents. They point out the need for further evidence of this vulnerability, as well as for some moral safeguards to protect it.24

MORAL ARGUMENTS AGAINST PHASE 1 ONCOLOGY TRIALS The risks of participation in Phase 1 trials include the possibility of death from toxic effects, adverse reactions, and multiple commitments such as blood draws, biopsies, radiological evaluations, etc. This section addresses the problem of ethical justification for Phase 1 clinical trials by looking at the issues of risks and benefits and informed consent. The question of exploitation is raised regarding the patients’ recruitment for these kinds of studies where high risks cannot be justified by few benefits.25 Moreover, it seems illogical for a patient to enroll in such studies, knowing about the possible risks while not expecting benefits in return. This fact may point to the problems within the informed consent procedure. There might be issues in disclosure of information, patients may fail to understand the presented facts, or they might be coerced into participation.26 Can any of these statements be proved?

Arguments Based on Risk-Benefit Assessment A number of voices in the literature object to the morality of Phase 1 trials on the grounds of an unfavorable risk to benefit ratio. For instance, Annas writes that according to the guidelines of the Nuremberg Code and the Helsinki Declaration, Phase 1 cancer trials should not involve terminally ill patients, since there is no reasonable probability that the research will benefit the subjects.27 Some may think that terminally ill patients have nothing to lose because of the fatality of their prognosis. Palliative care specialists point out that there are fates worse than  C

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death.28 The considerably short number of days a patient has left to live can be made even shorter by the ineffective experimental therapy. It will take away the quality of life patients hope for in their last days. Instead of spending their time in the family circle, giving their last goodbyes, and doing things they have enjoyed the most, patients might have to suffer from pain and potential toxic effects of an unsuccessful treatment.29 The anticipated toxicity of these new treatments is still not clear. This is exactly the reason why researchers have to start with Phase 1 and a small number of subjects who are being exposed to the new drug in gradually increasing increments. In other words, side effects and toxicity are what researchers are after in Phase 1 trials, while trying to determine the maximal tolerated dosage. What are the dangers of being involved in Phase 1 research? Studies have documented death from toxicity, even as they add that it is a very rare occurrence. According to a study that started in 1970 and was published in 1990, the overall toxicity death rate was approximately 0.5%.30 The two subsequent studies published in 2004 and 2005 confirmed these results by reporting rates between 0.54% and 0.57% for death from toxicity.31 The severity of the side effects and their possible impact on subjects’ lives are less well documented. Most researchers admit that vomiting, nausea, and other side effects are expected and very common. One recent study claimed that as many as 10% of participants demonstrated serious, although non–life-threatening, incidents of toxicity during the study. The consequences of 85% of these events can be partially or completely reversed.32 The statistical data are even higher in the study conducted by the National Cancer Institute that reports a 15% rate of life-threatening side effects.33 In addition, most researchers accept that the symptom management needs of subjects entering Phase 1 studies are not well described and their palliative care needs are not well understood. Since only 11% of drugs that are tested during Phase 1 trials are eventually approved, some researchers claim that involvement of end-stage oncology patients in these trials is rather a way to avoid or delay the difficulty of dealing with end-of-life decisions for both physicians and patients.34 Medical equipoise is defined as a state of uncertainty regarding the pros and cons of either therapeutic arm in clinical research.35 This concept was applied for harm-benefit evaluation in early stages of oncology trials. In this approach, risks and benefits associated with the trial of research substances represent one “component” of the experiment, and are justified by reference to the clinical equipoise. The risks and benefits, not directly related to the trial of

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research substances, represent the other “component” of the experiment and are balanced against social and scientific benefits.36 The reference to the clinical equipoise seems promising in providing a reliable way to calculate a harm-benefit ratio in experimental interventions. Following the definition, in the case of oncology trials, equipoise would represent a state of uncertainty about the relative harms and benefits provided as the result of the trial as opposed to those offered by standard treatment. These risks are balanced against future social and scientific benefits of the trial. The use of the clinical equipoise was criticized by some bioethicists as paying less attention to the differences between treatment received by patients during the trial than to the treatment provided in a clinic, where doses can be adjusted and treatments combined. The appeal to the clinical equipoise does not take into consideration the nature of the risk to benefit tradeoff in which individual harms are weighed against social benefits.37

Arguments Based on Informed Consent Objections to Phase 1 trials based on consent almost always include an absence of alternative choices in the presentation of trials. Fewer than 1% of consent forms mention hospice or palliative care as an alternative.38 In addition, the discussion about expected quality of life is often absent from the consent process. One study presents the discrepancy between investigators’ presentations of the issue and patients’ understanding. Although 73% of researchers claimed that they discussed changes in quality of life, only 28% of patients reported receiving this information.39 As mentioned above, the general understanding of goals and benefits of studies by patients is very low. This fact was often attributed to the poor design of informed consent. In one instance, 93% of the participants answered positively when asked whether they understood most or all of the information presented about the Phase 1 trial; however, only 31% were able to recall that the purpose of the trial was to find a right dose.40 The literature relates these gaps in understanding to selective perception and treatmentspecific optimism that protects research subjects from depression. Nevertheless, there is a difference between vague presentation of facts in order to fuel patients’ hopes and expectations, and letting a patient misinterpret information as a way to cope with psychological distress. The goal of informed consent is to provide protection by assuring that potential research subjects understand the research they are about to join, as well as its risks and benefits and available alternatives. According to a federal provision, the length of

the document should be short enough for someone to read it entirely and language used should be easy to understand.41 Many authors point to the fact that the consent forms used for oncology trials are difficult to follow, make extensive use of medical terminology, and are written in a language that is almost inaccessible for an average patient. Given the role of institutional review boards (IRBs) in developing regulations to ensure an appropriate balance of risks and benefits and to protect research subjects, it is possible to suggest that provision of an adequate consent form that corresponds with the needs of individual research subjects should be among IRBs’ top priorities. In addition to the flaws in the written communication of consent information, researchers point out the many problems in the ways physicians present patients with information during the informed consent process. Thus, Sankar reports that the majority of researchers rarely explain all the components of informed consent to patients. His study documented the fact that compensation for injury was never discussed orally, and that confidentiality and the right to withdraw were discussed in only 6% of consent sessions.42 The ideal presentation should be twofold: physicians would first provide all the necessary information to the patient, and second, they must explain the information in an unbiased way to facilitate the informed and voluntary choice of patients. However, the duty of disclosure of information and legal liability has started to define the meaning and intent of informed consent, leaving behind the second leg of expression of patients’ autonomous choices. Thus, in a recent interview, researchers asked physicians: “What does the term informed consent mean to you?” Only 26% of the doctors mentioned the connection between informed consent and patients giving permission or agreeing to treatment, and only 9% understood consent as patients making a choice about participation in a study or stating a preference about treatment options.43 It is obvious that the majority of clinical investigators recognize only the informationgiving component of informed consent. Their consenting practice focuses on explaining the nature of the condition and experiment so that the subject understands what is about to take place. For them, consent implies only telling things to patients, not asking anything, such as permission. Issues in consent discussions were documented in a number of studies. Often researchers would frame the presented information in the way most convenient for them, leaving out or emphasizing different parts. They would discuss benefits that were unlikely or would not differentiate between research and treatment, while confusing the unproven with the known. Journal of Pain & Palliative Care Pharmacotherapy

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They would present the experimental treatment as effective, while also mentioning that the research was still needed.44 In the study of 272 various Phase 1 consent forms by Horng and Ezekiel and colleagues, in the section of benefits 5% mentioned a cure, 53% mentioned prolongation of life, 96% mentioned tumor shrinkage, and 7% mentioned access to diagnostic tests. Interestingly, in more than 50% of the forms, the allusion to the possibility of benefits was found in other sections as well, by including statements such as “some patients have benefited from treatment with this drug,” or “this drug has shown some promise in this disease and has improved patients’ blood counts.” In addition, only 42% of documents made a distinction between experimental treatment and the procedures performed for the purposes of clinical care.45

MORAL ARGUMENTS IN SUPPORT OF PHASE 1 ONCOLOGY TRIALS In 2005, the New England Journal of Medicine published an extensive review of 460 Phase 1 oncology trials in which 10,402 participants out of the 11,935 total research subjects were evaluated on how the experimental treatment had influenced their illness and whether the drugs in question were safe. This review was conducted between 1991 and 2002 and sponsored by the National Cancer Institute. The outcomes of the research were surprisingly positive. In only 20% of all the Phase 1 trials the experimental drug was tested by itself. Accordingly, only 4.4% of the participants demonstrated clinical response. On the other hand, when the experimental drug was tested in combination with at least one approved drug (which happened in 46% of cases), 18% of the patients experienced clinical response, and an additional 34% achieved stabilization in the course of their disease or a slight improvement that was considered less than partial response. The authors of the study conclude: “These data suggest that participants may benefit more from current phase 1 oncology trials than previously believed.”46 This is very possible also because of the recent trend of researchers making preliminary judgments about the beneficial impact of the tested drugs. How much can Phase 1 clinical oncology trials benefit their participants?

Arguments Based on the Risk-Benefit Assessment Advocates of Phase 1 trials are fast to point out that the distribution of risks and benefits may not be easily calculated. It has been noticed that Phase 1 studies rarely test a new chemotherapy drug. On the contrary, most of the researched substances were  C

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vaccines, immune modulators, and other less toxic agents. The primary role of these agents is to control rather than kill cancer cells; therefore, one should look for different types of responses and consequently benefits.47 The most expected benefit in this case would be the stabilization of tumor growth and some shrinkage, which actually has been reported in a recent study. The overall response rate in this study was 10.6%, including both complete and partial responses, and 34.1% had stabilization or some tumor shrinkage.48 Palliative care specialists may object that the tumor size is not that important for their patients, as all they want is to live longer and have quality of life. Nonetheless, for some types of cancer, such as lung malignancies, the tumor size is critical for survival expectations. Alongside the physical advantages, proponents of Phase 1 trials mention important psychological and social benefits that motivate patients to enroll in the experiments. Daugherty et al. says that 65% of research subjects expected to receive psychological benefits from their participation.49 In another study, 78% of respondents experienced some level of comfort from having to come to the clinic for follow-up and study-related tests. This opportunity for regular contact with their physician was beneficial for reducing their level of anxiety by knowing that all other therapies were exhausted. Having to cope with the hard reality of knowing that they have an incurable disease while still hoping that there might be a treatment, patients express optimism regarding their participation in the trial as their way of not giving up. Even though most patients may realize that the chances of benefiting are very low, they choose to believe despite all odds that they will be among the lucky ones to see improvement. By thinking optimistically, they believe to positively influence the likelihood of experiencing individual benefit.50 Many oncology specialists perceive Phase 1 trials as incorporating the notion of therapeutic intent from an individual perspective of participants. Their therapeutic views are supported by recent studies. A study conducted in 2008 at a UK hospital involved researchers reviewing 29 Phase 1 oncology trials with a total of 212 participants. The study focused on a “clinical benefit rate” that was calculated by means of adding the total partial responses (tumor shrinkage of at least 50%) and stabilizations of illness condition. The researchers reported that the clinical benefit rate was 9% partial response and 44% stabilization, with the total of 53% in the first 6 to 8 weeks of research therapy. This rate was 36% after 3 months, and 26% after 6 months.32 The editorial commentary for this study suggested, “There was nothing in the objective outcome data of these early-phase studies that even

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remotely suggests that patients who agree to participate as research subjects do not have the realistic potential to achieve a genuinely meaningful degree of individual clinical benefit.”51 In addition, there are new dose-escalation designs that are expected to increase the chances of receiving direct medical benefit; however, these designs have not been successful in reaching this objective.52

Arguments Based on Informed Consent The optimism despite realism is one of the main arguments in moral defense of Phase 1 trials based on consent inadequacy. A number of studies perceive patients’ hopes for benefit as a failure to understand goals and objectives of the experiment. Patients reporting that they joined the trial hoping for benefits does not necessarily indicate their failure to understand the objectives of the trial. More often than not, this belief is the only thing that keeps them going. This hope is often seen as a form of adaptive denial that is common among various groups of patients. When patients are told that fewer than 10% of participants experience any kind of response, most of them think that somehow they will be in that lucky group. Therefore, the lack of ability to explain the goals of Phase 1 trial among the patients may often means that they care less about methodology and more about personal benefit. Their goals are not in conflict with those of the study, since if their tumor does respond, it would not affect the design of the experiment, and if maximum toxicity is determined, it will not be the end of the patients’ goals even though they might be unattainable.53 It is more than likely that the expressions of optimism and expectations of therapeutic benefits in Phase 1 trial participants are not derived from the lack of factual knowledge or flaws in informed consent. There are a number of cultural, psychological, and religious factors that may guide patients’ thinking outside of what is considered reasonable. Frequently, patients see a direct connection between positive thinking and their well-being. They believe that by thinking optimistically and saying words of faith and hope, they may actually change the odds regarding the likelihood of receiving individual benefits. Participants assume their positive attitude is all they have left, and if they were to let it go, the results would be devastating and they would succumb to their disease. Thus, their positive attitude is the sign that they are still alive despite all the bad results and prognoses. To lose hope in this case would mean to lose this battle because, without hope, they are dead. Therefore, they are hoping against all odds, cognitively receiving the information about the chances of benefits, but inter-

preting it on the level of their hopes, fears, and faiths. Under the circumstances of fatal prognosis and increasingly debilitating illness, it is almost unrealistic to expect purely rational responses. One would have to define what is ethical while taking into consideration these hopes and faiths, and not blame lack of information or inadequate consent forms. As it has been shown, there are many other external and internal forces that kindle these hopes, such as families and friends, faith communities, etc.54 The palliative care literature assumes that endstage oncology patients are a vulnerable group, less capable of making autonomous choices. Even though it is possible that some choices these patients make are influenced by the nature of their circumstances and some pressure from relatives and friends, this fact does not give enough evidence to believe that they are not able to make free choices. Most of the other legal choices made by such patients are considered valid and autonomous. For instance, their last wills or “do not resuscitate” orders, or consents for postmortem donation, have never been invalidated on similar premises. Their decision should not be automatically labeled as coerced just because it sounds unreasonable. They might be guided by a different set of values, making their decisions from a larger framework of fighting against the odds and overcoming challenges. A recent study presents data on the role of pressures in decision-making around Phase 1 trials. Only 9% of patients were in the trial due to family influence and 7% were strongly influenced by a clinical researcher. Nevertheless, 75% saw pressure in the fact that their cancer was growing, which does not constitute a case of coercion.55

THE ROLE OF UNCERTAINTY IN DECISION-MAKING ABOUT PHASE 1 TRIALS The decision to participate in a Phase 1 trial is difficult due to the uncertainties involved with predicting potential harms and unknown, but hoped-for, benefits. According to research on choices made under uncertainty, people tend to make predictable and important deviations from decisions that can potentially maximize their well-being.56 Although the standard decision model used in bioethical discussions assumes a rational agent able to weigh harms and benefits in order to make a choice that will be in line with his or her long term values and goals, the reality of complex decisions under uncertainty paints a different picture of benefits and harms calculations.57 In addition to the use of the analytical system of perception that is deliberative, explicit, and slow, patients Journal of Pain & Palliative Care Pharmacotherapy

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often rely on the intuitive system that is fast, implicit, and experiential. These two systems work in parallel but not always in harmony.58 The influence of uncertainty on the decision-making around Phase 1 trials will be discussed in this section.

Uncertainty and Misconception Understanding how emotions affect treatment choices is highly relevant to interpretation of the therapeutic misconception. The decision to participate in a Phase 1 trial is more than just a rational choice, as it involves not only reason, but also emotion. As mentioned in the discussion of vulnerability above, patients make a decision to join the trial in a certain cognitive and emotional state that can lead to misconceptions. Therefore, therapeutic misconception is a good example of how certain emotional states, cognitive biases, and heuristics can influence morally important decisions.59 Cognitive science researchers have shown the difference in decision-making when patients know they are at risk and when they feel at risk. The intuitive feelings are often the way by which patients evaluate dangers present in a trial. In their seminal research, Alhakami and Slovic and colleagues describe the disproportionate relationship between perceived benefit and risk of an activity and the intensity of a positive or negative feeling associated with that activity. When people feel good about an activity, they will think the activity is beneficial and entails low risks. If their feeling toward this activity is negative, the dynamic will be reversed.60 This research demonstrates that patients base their judgments about participation in a trial not only on what they think about it, but also on what they feel about it. Keeping in mind that joining the trial is the only remaining option that involves active treatment, it will most likely be positively perceived by the patients. Loss aversion behavior may represent another intuitive source of misconception. According to the prospect theory, people make decisions based on the potential value of losses and gains rather than the final outcome. They interpret outcomes of a decision as gains and losses, and they are more sensitive to losses than to equally valuable gains.61 This loss-aversive nature of patients’ choices may explain their decisions to join a trial. When they are experiencing a significant loss of health, they will be desperate to correct the loss even when the chances to succeed are slim. The same behavior is demonstrated in gamblers who will continue to gamble after a significant loss in attempts to recoup losses rather than going home. Consequently, people are more risk averse when the probability of benefit is high, but more risk seeking when  C

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it is low. In the situation of Phase 1 trials, patients may think that the probability of benefiting from the standard treatment is so low that they prefer experimental treatment with some potential and uncertain benefits.62 In addition, people are poor predictors of their future well-being. One of the variables that affect the quality of prediction is the temporal proximity to the event.63 Miscalculation of harms resulting from participation in a trial happens when people have to make decisions in advance and have to parse their current affective state from an emotional state that might be experienced in the future. Loewenstein described this discrepancy between states as “cold-tohot” and “hot-to-cold” empathy gaps. People decide about trial participation in hot-to-cold states when they are emotionally overwhelmed. Often the delivery of bad news (such as terminal cancer) is accompanied with the invitation to join the trial. Patients being devastated by this news may assess their future risks and make decisions discounting the acknowledgment of their present state.64

Uncertainty and Informed Consent Process Adequate information is essential for the informed consent process and decision-making regarding participation in a trial. The type of information most often communicated to patients during the consent process is risk information. Comprehension of this information is a precondition of a rational and informed choice. Because of the inherent uncertainty of the experimental therapy, this risk information needs to be expressed in numbers. The easiest and most common way to express the uncertainty is by using percentages. However, most of the patients exposed to this kind of information will not have the necessary skills to understand risk-benefit ratios.65 For instance, dealing with the percentages, they may perceive the 50% chance as simply a lack of certainty (“might happen, might not happen”). They would disregard small percentages (up to 10%), which characterize many risks of serious complications or death.66 Therefore, most of the important risk information presented to patients is likely to be lost in translations. In addition, not only the information itself, but also its presentation, may affect choices of prospective subjects. Message framing can be a strong predictor of the consecutive choices made by patients. Framing effect occurs when decision-makers respond differently to different but objectively equivalent descriptions of the same problem.67 For example, a study by McNeil et al. presented respondents with information about the outcomes of two treatments for lung cancer. Although the statistics presented were identical, they were framed in terms of survival or mortality

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rates. Even though respondents should react similarly to both statistical presentations, the number of those who favored radiation therapy over surgery went from 18% for those presented with the survival framing to 44% for those presented with the mortality framing.68 The informed consent process is design to protect autonomy and intentionality of patients in making their treatment choices. It is assumed that as long as patients have accurate information on benefits and risks of participation in a trial, they will be able to make the best decision for themselves that reflects their preferences and intentions. Following this train of thought, the duty of the clinical researcher is to offer patients the best data available, free of the investigator’s biases or feelings, and to let patients plug these data into their value systems. There is an assumption that patients have a preestablished set of values that are reflected in the choices they make. However, because these values reflect a hard reality to face and difficult tradeoffs need to be made, they are rarely thought of in advance.69 Although clinicians may tend to think that patients have some fixed ideas about what is important to them and they can choose from among the alternatives an option that best reflects their preference, this doesn’t hold true in most cases. When patients find themselves in a situation that is both complex and unfamiliar, they will not have a preselected set of ideas about what is important to them. When asked, they will answer, but their answers are made up at the moment the question is posed. These constructed answers and values are not permanent and will change based on the way the questions are asked or what kind of information is given.70 The understanding that patients’ values are not stable should lead clinicians to a greater awareness about the way they present information as having a significant impact on what information will be attended to and used by patients.71

SPECIAL PROVISIONS NEEDED IN RESEARCH WITH PALLIATIVE CARE PATIENTS Research subjects in Phase 1 trials are patients living with advanced stages of cancer who have exhausted standard treatment options. The projected survival time for these patients averages between 5 and 9 months.72 Their decision to participate in clinical trials is correlated with the way they perceive their endof-life options. This makes it different from previous decisions about the kind of treatments that might help patients to maintain a higher quality of life or improve their conditions. The decision to participate in a trial requires a full comprehension by the patient of the

lethality of their prognosis, their projected quality of life during and after the trial, the difference between clinical and experimental care, and the available alternatives such as hospice or palliative treatment. Time constraints and medical uncertainty are additional factors that escalate pressure in the decision-making process. Many factors facilitate patients’ decisions to participate in trials such as a hope for a cure, oncologist’s advice, a desire to be cared for, an avoidance of inaction, families’ attitudes toward the trial, previous experiences with anticancer therapies, and an ability to cope with the progressing disease.73 Health care providers should be attentive to these factors in order to facilitate patients’ decision-making processes. The following are some strategies to manage ethical concerns in Phase 1 trials.

Protecting Vulnerability 1. Avoiding a priori assumption about patients’ vulnerability based on their closeness to death. There is no need to exclude patients from participation in Phase 1 trials simply because of their terminal status. Instead, their potential for vulnerability should be continually evaluated on a case-bycase basis considering their clinical situation and the study design. The vulnerability of prospective participants can be expressed in a number of ways—desire to participate in a trial out of desperation or because of their feeling of indebtedness to the investigator or institution, reduction in decision-making capacity, and difficulty in processing information about the trials. Due to the rapidly changing clinical circumstances of patients and different ways in which their vulnerability can be expressed, their capacity to participate should be evaluated at different points of research process. Many other areas of research (dementia, intensive care unit [ICU], psychiatry) have adopted this “sliding scale” of capacity assessment that can be used in Phase 1 study design.74 2. Avoiding persuasive language during the recruitment phase. There are a number of ways in which the recruiting physician can subtly persuade his prospective subjects to enroll in the study. One of the strategies is in creating a sense of urgency by mentioning limited number of spots or questioning the patient’s eligibility after the initial study presentation. The investigator may also use an overly optimistic language, describing the study as novel and promising or mentioning their excitement about the study, thus implying its potential efficacy. Additionally, investigators may unnecessarily emphasize the lack of available treatment options, reminding his or her patients that there is nothing Journal of Pain & Palliative Care Pharmacotherapy

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else to be done. This also can be accompanied by an unstated assumption that patient will join the trial.75 3. Patient education. Daugherty et al. report a significant improvement in patients’ knowledge about Phase 1 trials as the result of using an educational DVD in the consent process.76 This educational interactive material has been found to decrease patients’ expectations of a cure as an outcome of the experiment. Some other studies stress the necessity of nurses’ involvements in patients’ education.77 They also recommend that this nurse-educator should not be associated with the research project. In this way, the nurse-educator would have a higher degree of impact as compared with the influence of disclosure done by investigators. Some investigators might be afraid that an independent person could discourage patients from entering the study. However, since the risks are high and the benefits are low, the quality of consent plays a very important role regardless of this possibility. 4. Making use of silent opt-out protocols in which patients may remove themselves from the study by inaction. Some researchers suggest this option as a potential way to protect patients from coercion. Realizing that the high dropout rates in palliative care research is something to be expected due to a number of factors such as physical decline, cognitive impairment, or high level of stress, specialists emphasize the need to oversample.78 Despite the fact that the ability to withdraw from participation in a study is usually one of the aspects required by institutional research boards to be spelled out in study protocols, palliative care patients may face unique difficulties with opting out from a Phase 1 study. If this study involves one or more medications, they will need a different prescription upon withdrawal. In case the research compound is an opioid, the subject will have a number of difficulties with obtaining a new prescription and getting it filled in a timely manner due to some state regulations. Therefore, researchers need to provide ways for subjects who opt-out continue to receive adequate pain treatment with minimum interruption.

Ensuring Adequate Consent 1. Dual consent. Given the perspective of progressively diminishing capacity of research participants, investigators should consider the possibility that a substituted decision-maker will provide additional consent. This practice is common in research with dementia patients, where informed  C

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consent is obtained simultaneously from both patients and their families to ensure that caregivers understand the research and they are willing and able to carry out the study responsibilities. In both palliative care and dementia research, these responsibilities are numerous and may include transportation, administering medications, and participating in various assessments. Furthermore, this practice complements the “family-centered” philosophy of palliative care. A proxy consent may not be the same as the one filled by patients. It is a way to inform families about the risks, benefits, and alternatives to research participation and to include them in the decision-making process rather than asking for their substituted judgment.79 2. Availability of alternatives to research participation. In order to ensure adequate consent, investigators should emphasize the availability of alternatives for participation, including palliative care or hospice services. Participants should be made aware of their ability to withdraw from the study while knowing that such a decision will not negatively impact their access to care and supportive treatment. Out of 272 consent forms examined in recent research, 65% of forms mentioned no treatment as an alternative, and only 56% included supportive or palliative care as another option to participation.80 Nitschke points out that the term “no therapy” has negative connotations and should be replaced with “supportive or palliative care without anticancer therapy.”81 3. Educating clinical staff to avoid gatekeeping. Institutional gatekeeping complicates the process of seeking consent from prospective participants. This gatekeeping occurs when clinical staff attempts to protect their patients from distress and burdens of research participation. Medical professionals are often used as referral sources for research involving palliative patients, and their removal of prospective subjects for reasons other than the stated exclusion criteria may cause sample bias. Buss and Arnold82 describe worries of the nursing staff involved in recruitment for Phase 1 studies, including concerns about the importance of research, potential risks for subjects, and ethics of placebo use. They recommend more education for medical staff on research-related issues such as supplying providing physicians with flyers where they can find information about the study/exclusion criteria, and offering information sessions as well as brief faceto-face updates on research progress. 4. Use of short consent documents and appropriate wording. The results of many studies suggest several areas for improvement of consent forms. The terms “drug,” “treatment,” and “therapy” should be

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accompanied by modifying words such as “experimental” or “research.” The lack of these modifiers conveys the message that the experimental drug is an effective treatment. Consent forms should avoid terms such as “doctor,” “drug,” or “patient” that suggest a doctor-patient relationship and replace these words with “investigator,” “study agent,” and “subject,” making it clear that patients are consenting for research rather than treatment.83 Furthermore, the consent forms are generally too long and written at a level that may not be accessible to a person with an average level of education. Based on the suggestion that in an educational situation people may not read an entire document if its longer than 4 pages or 1000 words, it has been proposed to reduce the size of consent forms to match the level of readership. The consent forms should always trace the differences between procedures conducted for research interests and those related to clinical care. There should be a section dealing with the expected benefits, clarifying the fact that Phase 1 studies were not designed to provide clinical benefits for involved subjects, and thus these benefits should not be expected.84

Balancing Risks and Benefits 1. Avoiding comiogenic harm. Palliative care by definition is patient centered. The aim of palliative care is to achieve the best quality of life possible for patients approaching their death. Although these concerns about quality of life and avoidance of harm translate into palliative research as well, the patient-centered philosophy will focus not only on clinically determined adverse effects, but also on the subjects’ participation experience as a whole. Within this framework, the phrase “comiogenic harm” would entail subjects’ lived experiences of adverse effects of research participation.85 The more obvious burdens of research participation such as number of surveys, interviews, and study visits are commonly considered in a Phase 1 trial design. Nevertheless, there might be some less obvious concerns that may be unique to the endof-life patients. For instance, burdens of research participation on caregivers should be taken into consideration, data collection instruments should rely on oral rather than written communication (phone calls vs. surveys), and there should be multiple scheduling options for clinic visits to build in as much flexibility as possible. 2. Educating clinical staff to recognize differences between clinical and experimental treatment. It is a very common belief, not only among the patients, but also

among the physicians, that clinical research is a step up from a regular level of care. The recruiting physician usually mentions a more experienced clinical staff involved in the research who will monitor patients very closely and in a more systematic way. Thus, the holistic approach, novel treatments, and the reliance of the research team on the clinical ethical model that sees patients’ interests as the top priority may cloud the ability of the research team to recognize the difference between clinical and experimental treatments. For instance, the National Comprehensive Cancer Network (NCCN), a consortium of 21 leading U.S. cancer institutions, claims, “NCCN believes that the best management of any cancer patient is in a clinical trial.”86 Although this statement was mainly in reference to Phase 3 trials, there is still a need to educate physicians to distinguish between the clinical therapy and the therapy in a context of clinical research. Being able to understand this difference for themselves, they would also be able to explicitly convey this message to their research subjects. 3. Provision of palliative care during the research participation. Although there are some hospice programs that may accommodate patients participating in research trials, clinicians may not always be in favor of merging research with palliative care. They often believe that patients entering Phase 1 trials are not ready for palliative/hospice care. The issue of research participation is commonly perceived in a binary way—there are those who are ready to accept palliative care, and there are also those who are willing to participate in a Phase 1 study. This way of thinking should be replaced by recognition that palliative care patients may value the opportunity to participate in Phase 1 trials for reasons other than those incompatible with palliative care philosophy. Research participation and provision of palliative/hospice care are not mutually exclusive things. On the contrary, accessibility of palliative care may enhance the process of data collection and will enable patients to remain in research, thus reducing attrition rates. There is simply no reason to assume that patients enrolled in a Phase 1 study will not appreciate or benefit from services provided by a team-based palliative care.87 4. Collaborative research. Collaborative research practices involving palliative care patients have received a lot of attention in the literature due to their potential of avoiding latent research burdens, identifying issues that can escape attention of researchers, giving voice to vulnerable/marginalized people, and letting them influence study outcomes that are important to them. These benefits are particularly important for palliative care research; Journal of Pain & Palliative Care Pharmacotherapy

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however, it can be difficult to engage this population as partners in research due to the social, financial, emotional, and medical complexities they are facing. A study by Wright et al. involved patients and their caregivers as co-researchers by leading focus groups of hospice and palliative care patients. They offer a number of practical recommendations regarding involvement of palliative care patients as co-researchers: providing emotional support for all co-researchers, providing extensive training to ensure effective data collection, identifying co-researchers using various strategies, adopting a collaborative dynamic between co-researchers and the experienced researchers, and applying same ethical guidelines for both researchers and co-researchers.88 In another study by Williams et al., community-based participatory method was employed to conduct research in a nursing facility for patients with end-stage acquired immunodeficiency syndrome (AIDS). The study suggests this participatory method as a way to reconcile the methodological rigor of a randomized controlled study in a palliative setting. It highlights benefits of participatory approach to the study of quality-of-life interventions in late-stage disease.89

CONCLUSION This paper addresses the ethical justification for Phase 1 clinical oncology trials by looking at the issues of risks and benefits, informed consent, disclosure, and voluntariness. A closer look at the specific set of values and resulting motivational factors for oncology palliative patients has provided insights on the issue of persuasion in recruitment for oncology trials. In addition, this presentation focuses on the causes of patients’ misconceptions and specific communication styles that may more clearly convey risks and benefits of participation. Message framing in informed consent process can be a strong predictor of the consecutive choices made by patients. Depending on how the information about the risks and benefits of participating in research is framed, clinicians can influence patients’ decision-making. However, many subjective components and predictably irrational patterns can influence one’s decision to enter a trial. Some of these cognitive biases such as difficulty in interpreting risk information, loss aversion behavior, difficulty in predicting future emotional states, and lack of preestablished values may better explain the notion of therapeutic misconception. The interplay between the intuitive and analytical systems of processing information provided an important perspective on the  C

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reasons consent information might be misconstrued by patients. This issue of therapeutic misconception is further contrasted with therapeutic optimism of terminally ill cancer patients, whereas their vulnerability is discussed in the context of the capacity to make informed and autonomous choices. The assessment of benefits and risks from participation in the trial is provided, as well as the review of moral issues related to informed consent practices. It is necessary to consider the role of hope in enrollment of terminally ill patients for oncology studies. Finding ways of expressing and fostering this hope should be balanced with efforts of health care professionals to make sure that the fear of a hopeless end would not become a source of unrealistic endless hope. Thus, educational interventions and palliative care should be important components of every Phase 1 trial. The consent forms should always trace the difference between procedures conducted for research interests and those related to clinical care. There should be a section describing available alternatives for participation in the study. Consent documents should be shorter and use the appropriate wording. The concluding section of the paper offers a number of similar practical recommendations, such as making use of dual consents and silent opt-out protocols; employing collaborative research strategies; and educating clinical staff to avoid gatekeeping, a priori assumptions about subjects’ vulnerability, confusion between clinical and research treatment, and persuasive language during recruitment. Declaration of Interest: The author reports no conflicts of interest. The author alone is responsible for the content and writing of the paper.

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