|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Journal of Clinical Oncology, Vol 24, No 30 (October 20), 2006: pp. 4793-4795 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.05.7125
Are We Taking Without Giving in Return? The Ethics of Research-Related Biopsies and the Benefits of Clinical Trial ParticipationDepartment of Medicine, Division of Hematology/Oncology, The Indiana University School of Medicine, and The Indiana University Cancer Center, Charles Warren Fairbanks Center for Medical Ethics, The Indiana University Center for Bioethics, Indianapolis, IN
Department of Medicine, Section of Hematology/Oncology, The University of Chicago, and The University of Chicago Cancer Research Center, The MacLean Center for Clinical Medical Ethics, Chicago, IL We accept that individuals with life-threatening disease, such as those with cancer, can allow themselves—or parts of themselves—to be used for research purposes. In the setting where the proposed research carries some degree of risk of harm, it is recognized that this research can only be allowed if there is the prospect of benefit to an involved subject and/or the subject has given informed consent for the research.1,2 Clinical trials of experimental anticancer agents typically involve at least some prospect of potential benefit for involved patients and certainly require patients’ informed consent.3 Yet there are research activities in which cancer patients are asked to participate in which any prospect of direct benefit is absent. One specific example of this is when a cancer patient is asked to allow that a sample of his or her tissue, such as malignant biopsy material, may be used for additional and future research. This typically has involved benchside or translational research on excess tissue that was obtained solely for clinical purposes and that would otherwise be unexamined or unused. In this setting, although no prospect of direct benefit might be present for the involved patient, there is also no added risk to the patient from the research; thus, any ethical concerns about the use of such tissue for research purposes is recognized as minimal. However, an increasing number of cancer patients enrolling in clinical trials of a newer generation of molecularly targeted agents are being asked to undergo additional research biopsies beyond that which would otherwise be needed for their clinical care. The advantages of these additional biopsies for cancer investigators include access to freshly obtained tissue samples, over which the investigators have more specific control with regard to their preservation, storage, and proposed uses. Such additional research-related biopsies create more significant ethical concerns because they contain no direct benefit to patients, and the performance of the biopsies clearly carries some (more than minimal) risk. Therefore, in these cases, we must acknowledge that something is being taken from a research participant: in this situation, there is risk to the giver, there is no direct benefit to the giver, and—typically—little to nothing of value is being returned to the giver. Is this ethical? Whether it is ethical or not for a patient to give something of value (the biopsy) and receive nothing of benefit in return hinges on the voluntary nature of the giving and the patient’s ability to provide meaningful informed consent. Thus, to determine if a cancer patient’s giving of a research-related biopsy is truly voluntary and ethical requires an understanding of the patient’s perceptions about the risks involved in the giving and his or her understanding of the lack of direct benefit. Is altruism alone ever a direct benefit? In this issue of the Journal of Clinical Oncology, Agulnik et al4 have conducted research exploring these very issues. In their study, data are presented from surveys of 241 cancer patients, 1,347 medical oncologists, and 123 institutional review board (IRB) members from academic institutions in Canada regarding their perceptions of serial tumor biopsies performed to acquire tissue for correlative research. This practice, although it is increasingly common, has received little scrutiny from the research community. Although at least one review suggests that research-related serial biopsies done in early-phase clinical trials may be performed successfully with limited physical morbidity,5 few published studies present data supporting the unequivocal value of the practice. We commend the authors, therefore, for supplying data for a much-needed debate on the entire practice. However, the overwhelming majority of patients surveyed were not actually enrolled in clinical trials and, by definition, provided responses to what, for them, could only be described as a hypothetical situation: undergoing a serial biopsy for research purposes as a component of a clinical trial. Because the numbers of patients actually enrolled in clinical trials who were surveyed in this research was small (n = 10), it is impossible to draw conclusions about whether the attitudes reported by cancer patients not enrolled in clinical trials are a good surrogate for understanding the attitudes of enrolled patients. Although medical oncologists and IRB personnel were asked whether research biopsies were worthwhile, the overall acceptability of such biopsies to patients (perhaps the topic of most interest in this case) was not examined in this study. Therefore, we do not know from the data presented how patients feel about this practice overall. It is interesting to note that among clinic patients surveyed, one third of them in this cohort agreed that the need for a research-related biopsy would deter them from enrolling onto a clinical trial, suggesting that there may be more reluctance to undergo such biopsies on the part of patients than the authors of this study suggest. Equally noteworthy, 42% of surveyed clinic patients in this study agreed that a research-related biopsy would influence their health and care, with another 15% agreeing that the biopsy may or may not influence their health and care. This finding raises perhaps the most significant ethical question surrounding the use of serial biopsies for research purposes: if patients understood that research-related biopsies would provide no benefit to their own health or care, would they still find the practice acceptable? Findings from this study suggest that at least a substantial minority of patients do not report an understanding of the nonbeneficial nature of research-related biopsies. Thus, the perceived acceptability of the practice must be understood in light of this potential misunderstanding. In fact, the authors seemingly have assessed the perceived risks of these correlative biopsies almost to the near exclusion of any perceived benefits. A negative ethical view of the practice of serial research-related biopsies would hold that clinical trials that require such biopsies take advantage of this lack of clarity in the minds of patients; it is sensible that a perception of personal benefit is likely to influence positively the acceptability (or voluntary nature) of the practice to patients and research participants. Further supporting the notion that subjects may not understand the issues at stake, the survey results also suggest that patients have an unacceptably high tolerance for risk potentially associated with serial research-related biopsies. In the study by Agulnik et al,4 patients seem to find risks of a "major complication" of up to 20% to 25% acceptable—much higher than the 1% or 2% risk of major complications believed to be permissible by medical oncologists and IRB personnel. The reasons for this seemingly high tolerance for risk among patients were not explored in the study, but misperceptions about personal benefit to be derived from research-related biopsies make this kind of willingness to accept risk more troubling. Thus, to conclude that subjects readily allow their specimens to be used for research purposes while at the same time failing to study—and thereby take account of—whether this willingness is a result of inaccurate perceptions of benefit leaves us with a significant and unaddressed question. What specific clinical benefits do they believe are occurring from these biopsies relative to their research participation? The issue of risk tolerance among patients considering or enrolled onto clinical trials also is certainly worthy of additional focused study. In examining the ethics of the practice of serial research-related biopsies, we believe it would be helpful to borrow language from the US federal regulations governing research in children, in which issues regarding research involving more than minimal research but no prospect of benefit to the patient have been addressed specifically. Within this framework, the federal regulations require that three ethical conditions be satisfied to allow such research to be undertaken6: the risk represents a minor increase over minimal risk; the intervention or procedure presents experiences to patients that are reasonably commensurate with those inherent in their actual or expected medical, dental, psychological, social, or educational situations; and the intervention or procedure is likely to yield generalizable knowledge about the patients’ disorder or condition that is of vital importance for the understanding or amelioration of the patients’ disorder or condition. The first two of these conditions seems to have been satisfied in the case of serial research-related biopsies. There are data to suggest that serial biopsies may be performed safely and that biopsies are reasonably commensurate with patients’ actual medical experience (86% of clinic patients and 100% of trial patients in the study by Agulnik et al4 reported having had a biopsy). However, whether the widespread practice of serial research-related biopsies yields generalizable knowledge that is of vital importance has yet to be established. There are, as yet, only a handful of articles in the scientific literature in which serial biopsies have been shown to contribute substantially to the advancement of clinical research.7,8 We suspect that a large number of serial biopsies have been performed in conjunction with clinical research during the last decade. Therefore, in addition to the issues addressed by Agulnik et al,4 it is time to examine other—and perhaps more fundamental—questions about the conduct of those biopsies that are exclusively research-related. Are they always scientifically necessary? As a routine research practice, are such biopsies providing relevant data in specific relation to the experimental agents under study? What truly is their value? We need to examine whether the risks, inconveniences, and anxiety borne by patients who submit to them is honored by valid and useful scientific findings that will advance the care of future patients. The burden of proof for these conditions is on investigators and the sponsors involved in clinical trials in which serial biopsies are performed. Finally, we make the following suggestions when including serial research-related biopsies in clinical trials of anticancer agents. First, careful attention should be paid to ensuring patients’ understanding of the nonbeneficial nature of serial research-related biopsies. This might be accomplished either through separate, focused consent for the biopsy portion of the trial or through post-testing of research participants to confirm their correct understanding. Second, serial research-related biopsies should be an optional (not a mandatory) condition of clinical trial enrollment, only if or until the scientific contributions of such biopsies have been fully established. Third, intensive efforts to identify biologic surrogates available through less-invasive means (such as peripheral blood) should continue in an effort to render serial, invasive biopsies—and the risks associated with them—unnecessary. We believe these suggestions have the potential to allow involved research participants to have both a better understanding of the risks and benefits of undergoing research-related biopsies and an increase in their trust in the research process. Our suggestions are also aimed at improving our own confidence in the appropriate and ethical removal of tissue from cancer patients solely for research purposes. Some may have concerns that such efforts might impede the rate at which quality cancer research ought to be taking place. Yet it is difficult to understand these concerns if such efforts aimed at improving cancer patients’ and research participants’ understanding of the risks and lack of benefits from research-related biopsies result in a level of understanding that approaches our own. If these levels of understanding were known to be equal between cancer research participants and the involved investigators, it would then be ethical for us to take without giving, and we need not be so concerned. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest. Author Contributions
REFERENCES 1. The President's Advisory Committee Report on the Human Radiation Experiments. Oxford University Press, 1995 2. US Code of Federal Regulations (CFR) Title 45, Part 46, subpart A, and CFR, Title 21, Part 50, subparts A and B: Regulations and Guidance on Clinical Investigator & IRB Responsibilities. Philadelphia, PA, Clinical Research Resources, 2003 3. Daugherty CK: Impact of therapeutic research on informed consent and the ethics of clinical trials: A medical oncology perspective. J Clin Oncol 17:1601-1617, 1999 4. Agulnik M, Oza AM, Pond GR, et al: The impact and perceptions of mandatory tumor biopsies for correlative studies in clinical trials of novel anticancer agents. J Clinc Oncol 24:4801-4807, 2006 5. Dowlati A, Haaga J, Remick SC, et al: Sequential tumor biopsies in early phase clinical trials of anticancer agents for pharmacodynamic evaluation. Clin Cancer Res 7:2971-2976, 2001 6. Department of Health and Human Services: Report from NHRPAC: Clarifying specific portion of 45 CFR 46 subpart D that governs children's research. http://www.hhs.gov/ohrp/nhrpac/documents/nhrpac16.pdf 7. Friedman HS, Kokkinakis DM, Pluda J, et al: Phase I trial of 06-benzylguanine for patients undergoing surgery for malignant glioma. J Clin Oncol 16:3570-3575, 1998[Abstract] 8. Baselga J, Albanell J, Ruiz A, et al: Phase II and tumor pharmacodynamic study of gefitinib in patients with advanced breast cancer. J Clin Oncol 23:5323-5333, 2005 Related Correspondence
This article has been cited by other articles:
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
