First ASCO Ethics Course

NEW ORLEANS—In response to the requirement by the Department of Health and Human Services that clinical researchers complete a course on research ethics prior to receiving grant funds, ASCO's Ethics Committee developed a forum to discuss the pressing ethical issues that oncologists confront regularly. The first such forum, held at this year's ASCO's Annual Meeting on the day before the official start of the meeting, covered the quality of informed consent, use of stored tissue and medical records, conflict of interest, and the ethics of research that doesn't benefit the participants. “This was not a basic course,” said Committee Chair Ezekiel J. Emanuel, MD, PhD, Chair of the Department of Clinical Bioethics at the Warren G. Magnuson Clinical Center at the National Institutes of Health, who co-chaired the forum. Because oncologists deal with the issues in their daily practice, the forum organizers specifically designed a course and course book that was well beyond “Ethics 101” and would be a useful resource down the road, he said. They also placed a high degree of emphasis on data so that the various aspects of each issue could be discussed rationally. “We need data in order to understand these issues,” Dr. Emanuel emphasized during his introduction. Quality of Informed Consent The session's other co-chair, Steven Joffe, MD, MPH, an instructor in pediatrics at Harvard Medical School and Dana-Farber Cancer Institute, discussed the data available on the quality of informed consent. The vast majority of these studies are observational, with only a few interventions aimed at improving the consent process, he said. Informed consent differs between the clinical and research settings in numerous ways, Dr. Joffe elaborated. Specifically, a patient who is considering enrolling in a clinical trial must understand that the potential treatment is not proven and that this is a pursuit of general knowledge.Figure: Ezekiel J. Emanuel, MD, PhD, said it is acceptable to expect people to participate in research when the risks are comparable to what they experience in everyday life.This point is of substantial concern because numerous surveys have shown that there is a broad misconception in some segments of the general public that there is a therapeutic benefit to participating in clinical trials. Also, clinicians need to inform patients that while they are on the clinical trial the physician and the patient need to adhere to the treatment protocol, which may alter the physician-patient relationship. Surveys have also found other preexisting beliefs that are a potential problem in the quality of informed consent, he said, including a lack of understanding about what a trial or trial design is and the idea that the trial might provide better initial treatment. Approximately half of the patients in one survey thought they might get a placebo (Comis RL, Miller JD, Aldig© CR, Krebs L, Stovall E: JCO 2003;21[5]:830–835). A similar number thought trial patients were “treated like guinea pigs,” a phrase that Dr. Joffe admitted he doesn't entirely understand but thinks is an “unfavorable perception.” Readability of Consent Forms The readability of consent forms continues to be a problem. Although the forms are supposed to be written at an eighth grade reading level, very few of them actually are, Dr. Joffe said. Dr. Emanuel and his colleagues are working on a template for a standardized consent form, drawing on numerous existing forms from different Internal Review Boards. In terms of intervention trials, which aim to find mechanisms that improve the efficacy of the consent process, Dr. Joffe pointed to a relatively old trial, from 1996, in which a third-party nurse educator called the patients several days after the initial consent consultation (Aaronson NK: JCO 1996; 14:984–986). In this study, from the Netherlands, patients who were considering enrolling in Phase II or III trials were randomized to either receive a phone call from a nurse a few days after the standard consent interview or not. One week later both groups were interviewed regarding their knowledge, anxiety, and decision making around the trial and consent. The intervention was associated with significantly increased understanding, and there was a nonsignificant trend toward a drop in enrollment in the intervention group. There was no difference in anxiety. Regarding the drop in enrollment rates, Dr. Joffe said, “My guess is this is a real finding and that the numbers are just too small to prove it.” Several members of the audience commented that they think there is a general reluctance on the part of both researchers and their trial sponsors to get into the “guts of consent,” as one speaker phrased it, because of this very worry: If consent itself becomes a study within the main study, then more patients will drop out as they become more informed about trials and the real benefits, or lack thereof, afforded individual participants. Stored Tissue & Records Access to banked tissue is becoming ever more important with the advent of genomics and proteomics and the desire to look for correlates of response or overall prognosis, noted Rebecca D. Pentz, PhD, Professor of Hematology and Oncology Research Ethics at Winship Cancer Institute at Emory University. Yet it is not always clear which previously banked samples fall under human subjects' research guidelines and what consent is required to allow ongoing use of prospectively collected tissue. Human subjects research covers both patients and patient samples that contain identifiable private health information, Dr. Pentz continued. If the sample is coded, such that it can be linked to personal identifiers or has personal identifiers attached, it is definitely covered. Samples are not considered human subjects research if they are anonymous with no personal identifiers attached or anonymized, with such identifiers permanently removed. In the case of deceased individuals, the samples are not considered human subjects, but the rules of the Health Insurance Portability and Accountability Act (HIPAA) covers their use. HIPAA specifies that researchers must attest to the fact that it is necessary to use some protected health information, that only what is necessary will be used, that the subject is really deceased, and that the researcher will only use the protected information in a research setting. Historically consent requirements were waived when the risk was minimal, when the subject's rights were not adversely affected, when the research could not be practically carried out without a waiver, and when subjects would be provided with the information about the study later. That situation has changed, however, Dr. Pentz said, because the perceived risk of identification through DNA no longer seems minimal. When Ask for Consent, and for What? The next question is when should one ask for consent and for what. The timing of collection is important, according to Dr. Pentz. For preexisting samples, anonymizing the samples obviates the need for obtaining consent. However, because some identifying information is required to make the samples scientifically useful, an alternative approach is to obtain a waiver of HIPAA authorization from a local institutional review board (IRB). “The upside of this approach is that you don't have to contact all of the patients,” she said. “The downside is that you have to keep close records of all protocols” for which the tissue is used. If the IRB declines to provide a waiver and requires consent for the use of previously banked samples, there is a strong possibility that an authorization bias will be introduced into the study. It may, therefore, not be worth doing. This sort of problem was modeled in a hypothetical situation in a study published earlier this year by Canadian researchers with the Institute for Clinical Evaluative Sciences in Toronto (NEJM 2004;350:1414–1421.) Getting Consent for New Samples One of the big issues in asking for consent for prospectively banked tissue is how broad a consent one should request. Although Dr. Pentz said that several guidelines suggest giving patients various levels of consent to choose from—for example, no consent, consent for this study only, consent for future studies—she does not recommend this option. In a study that she performed with Dr. Emanuel and David Wendler, PhD, Head of the Unit on Vulnerable Populations in the Department of Clinical Bioethics at the NIH, the team asked patients about banking tissue for future research. Two study populations were included. A group from Winship Cancer Institute was predominantly white, nearly half had completed college, and 32% of made more than $80,000 annually. The second group was from the Winship Cancer Institute at Grady Memorial Hospital and were predominantly black, 26% had some college, and 84% made less than $20,000 annually.Figure: Steven Joffe, MD, MPH, said that although informed-consent forms are supposed to be written at an eighth grade reading level, very few of them actually are.A similar proportion of patients in the two groups had concerns about the repercussions of allowing research, including the impact on their insurance and employment. However, nearly twice the fraction of patients (21% vs 12%) at Grady had concerns that more tissue would be taken than medically necessary if they agreed to allow their tissue to be stored and used for future research. Additionally, 62% of patients at Emory preferred to let the researchers choose what diseases the tissue would be used to study, compared with 45% at Grady. Twelve percent at Grady preferred to have a checklist of diseases to choose from vs 7% at Emory. Either option was fine for 29% of patients at Emory and 40% at Grady. When asked if they wanted to consent only once or for each project, 62% of patients at Emory said once was fine, vs 38% at Grady. At Grady, 16% wanted to consent on each project, whereas 9% did at Emory. The remainder either thought there was no need for consent or had no strong feeling. Based on preliminary analysis of the data, the researchers concluded that a minority of patients want to retain control over where and when their tissue was used. Both Dr. Pentz and Dr. Emanuel expressed concern over using this option in a clinical research setting because tracking it becomes very complicated. “I think it should be one question,” said Dr. Emanuel. “Either you're in the research pot or you're out of it.” Dr. Pentz and Dr. Joffe both suggested that in a consent form for a research study, the request for consent for banking tissue needs to be in a separate section with a separate signature line, if not in a completely different form. Also, Dr. Pentz emphasized that based on the preliminary results from the Emory-Grady study that extra emphasis needs to be placed on educating individuals in an underserved population about the protections of their confidentiality. “I do think we need to reassure underserved populations because there is a lower level of trust,” she said. Ethics of ‘No-Benefit’ Research In his portion of the session, Dr. Emanuel addressed the question of performing research where there will be no benefit to the patient participants. Because there is little or no information about this in the medical literature he reached into basic philosophy and described the principle of mutual benefit. Based on this logic he concludes that as long as the patients are not asked to take on more risk than they would incur in their normal lives, then it is ethical to ask them to participate in research for society's benefit and that, in general, we as individuals in a larger society have the responsibility to do so. He provided two examples from everyday life to illustrate the principle of mutual benefit: If you are standing near a swimming pool and a child falls in, you would be expected and morally obligated to jump in and save the child. If, however, you witness an airplane crash into a freezing river, you are under no such obligation because the risk to yourself is too great. If you choose to jump into the freezing water, that is considered heroic, rather than obligatory, because it extends beyond a normal risk. Several members of the audience commented that they think there is a general reluctance on the part of both researchers and their trial sponsors to get into the “guts of consent,” as one speaker phrased it, because if consent itself becomes a study within the main study, then more patients will drop out as they become more informed about trials and the real benefits, or lack thereof, afforded individual participants. 6 Points about ‘Mutual Aid’ There are six points of the principle of mutual aid, all of which are relevant to the issue of no-benefit research, he said: ▪ It imposes a positive duty on us to act. ▪ It does not require consent; rather it is imposed on us because we are human beings in a society. ▪ It is not defined by laws or institutions. ▪ It does not apply just to those people who have a particular relationship to us or society. ▪ It does not depend on us knowing the individual in need. ▪ It does not depend on knowing that efforts will be successful. A major caveat to the principle, though, is that it is limited, he said. One is under no obligation to take on extraordinary risk, and we do not judge them as having failed a moral obligation when they choose not to take on that heroic act. And, in fact, IRBs already use “minimal risk” as a criteria for approving research interventions in pediatric studies when there is no prospect of benefit for the patient. We as a culture, however, said Dr. Emanuel, regularly underestimate the risks we are exposed to in daily life. This estimate, though, becomes important when asking people to participate in no-benefit research based on the principle of mutual aid. “The first thing to observe is that minimal risk is not equal to no risk,” Dr. Emanuel said. “This is incredibly important.” He suggests that it is acceptable to expect people to participate in research when the risks are comparable to what they experience in everyday life. Based on the limited data available, the average person has a one in a million chance of dying on any given day and one in 2,593 chance of ending up in the emergency room. That, he points out, is not terribly different from the risk of complication from, say, a venipuncture (1 in 2,667 syncope) or apheresis (1 in 2000 syncope or 1 in 100 sweating and nausea). “I would argue that we can appeal to the principle of mutual aid and ask patients to participate,” said Dr. Emanuel. Considerable Debate There was considerable debate at the end of his presentation. While everyone who spoke thought it was an interesting argument, some were concerned that the risks asked of a patient, such as an extra bone marrow donation for tissue-sampling purposes, carried excessive risk. Others objected strongly to the idea that they (or someone else) would morally judge their patient for choosing not to participate in a trial. Other audience members objected to the hypothesis based on the fact that researchers do not always know the risks, especially in Phase I and II trials. Rebecca D. Pentz, PhD, noted that one of the big issues in asking for consent for prospectively banked tissue is how broad a consent one should request. Her recommendation is that the request needs to be in a separate section with a separate signature line, if not in a completely different form. Finally, someone pointed out that taken at one level, this idea would mean that individuals who have high risks in their daily life could be asked to take on more than their share of the risk in research, and that seemed an objectionable assumption. Dr. Emanuel agreed that would not be appropriate and said that in discussing the principle of mutual benefit, one was talking about average levels of risks, not individual ones. “We walk around everyday assuming that people will assume some risk to help us or others, why not assume that in research?,” Dr. Emanuel said, pointing out that in other countries there is a much more common view of “what do I have to lose versus what is in it for me? “We need to move in that direction,” he said, and suggested that researchers and clinicians should begin to cultivate that cultural change. ASCO's Revised Conflict-of-Interest Policy Now in Effect ASCO's updated conflict-of-interest policy, announced last year, became effective on June 15. In addition to the disclosures required in the previous conflict-of-interest policy, the new version adds outright restrictions on some members, particularly those in leadership roles, said Cary P. Gross, MD, Assistant Professor of Internal and General Medicine at Yale University Hospital. Under the new rules, which were published in the June 15, 2003 issue of the Journal of Clinical Oncology (2003;21:2394–2396) after being approved the previous November, there are two levels of restrictions: One applies to anyone involved in human subjects research; and the other applies to those in leadership roles, including principal investigators, individuals on the executive committee of a trial, or members of a data-safety monitoring board. The general restrictions prohibit finders fees for patient accrual, beyond actual expenses; accrual bonuses; payment contingent on research outcome; and sponsor control of publications or dissemination of trial results. Individuals in leadership roles must adhere to the general restrictions and are additionally prohibited from owning stock or equity in the trial sponsor, receiving royalties or licensing fees, patents, accepting a position as an officer or board member in the sponsoring company, or accepting honoraria in the form of either cash or trips. “This is pretty restrictive, I have to say,” said Dr. Gross, who was the one speaker in the ethics session who is not a member of the ASCO Ethics Committee. Additionally, the fact that there are repercussions for not adhering to the rules—such as being precluded from publishing in ASCO journals, presenting at Society meetings, or membership—is an important step forward, said Dr. Gross. There are, however, exceptions. When a principal investigator has unique skills or knowledge such that the work cannot be done realistically without that person's participation or at another institution, exceptions can be made. An appropriate plan for managing the conflict of interest must be built into the decision-making process for the trial in such a situation. Will the new policy make a difference? Dr. Emanuel thinks so. “People are thinking about it and are worried about what it means for them,” he said.

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