IRB: Ethics & Human Research
Ethical Issues in Cancer Chemoprevention Trials: Considerations for IRBs and Investigators
Relatively little attention has been paid to cancer chemoprevention research in the research ethics literature, especially compared to the ethical analyses of oncology treatment trials. Cancer chemoprevention trials test the efficacy and safety of pharmaceutical agents in preventing cancer before its occurrence.1
Chemoprevention drugs are administered to ostensibly healthy, asymptomatic subjects who do not have cancer but have risk factors associated with an increased likelihood to develop the cancer that the experimental intervention is hypothesized to reduce. Therefore, chemoprevention research involves at-risk research subjects who are neither patients diagnosed with disease, as in treatment trials, nor typical healthy volunteers. There is growing interest and investment in research on cancer chemoprevention.2 Several major cancer chemoprevention trials have been conducted in the United States, including trials testing the efficacy of tamoxifen, both alone and later compared to raloxitene, to prevent primary invasive breast cancer; finasteride to prevent prostate cancer; and beta-carotene to prevent lung cancer.
While both cancer treatment and chemoprevention trials involve agents that can cause side effects in individuals, chemoprevention trials differ from treatment trials with respect to the degree of potential benefit. In trials of cancer treatment or of adjuvant therapies (secondary prevention), subjects either have a diagnosis of cancer or a substantial chance of disease recurrence. Therefore, they have reasonable expectations of direct benefit from existing or investigational treatments. In contrast, the vast majority of participants in chemoprevention trials, despite higher risk of disease relative to the general population, will never be diagnosed with cancer, and so potential benefit to individual participants from the preventive intervention is very modest.
In this article we analyze some of the ethical challenges in chemoprevention research to help investigators writing the protocols for phase III chemoprevention trials and Institutional Review Board (IRB) members reviewing such protocols. Phase III trials are designed to assess the efficacy of an experimental agent in comparison to the available standard of care regimen. We focus on issues related to subject selection, including justifications for identifying and recruiting at-risk subjects; on the determination of the social value of chemoprevention research; and on informed consent and payment to research participants. We believe these issues deserve special attention in the context of chemoprevention research. There are, of course, other important ethical challenges—such as issues of consent related to randomization, equipoise, and early stopping—that are pertinent to all randomized clinical trials and are discussed extensively in the literature. Finally, while our examples come largely from breast cancer chemoprevention trials, the implications of our analysis are generalizable to other areas of chemoprevention research. The critical issues are summarized in Table 1 in the form of a framework of questions for consideration in the preparation and human subjects review of protocols for chemoprevention trials.
The Ethics of Study Design and Protocol Evaluation by IRBs
Social Value and Favorable Risk-Benefit Determinations. The ethical acceptability of a proposed chemoprevention trial is principally based on determinations of a positive social value and a favorable risk-benefit ratio. The social value of research refers to its potential to usefully contribute to advancing knowledge about health.3 In assessing the social value of chemoprevention research, IRBs and investigators should take into account both background considerations against which a trial is designed, as well as the trial’s potential public health impact. We are not suggesting that IRBs engage in comparative judgments about possible research approaches, but rather that they are responsible for judging the adequacy of an investigator’s justification of the social value of the proposed approach. Investigators should describe, with as much specificity as possible, 1) the relevant epidemiological considerations (e.g., disease incidence and severity), 2) the population likely to benefit, and 3) the magnitude, scope, and likelihood of benefit. IRBs also should consider whether there are other, less hazardous means of prevention available (e.g., behavioral interventions for modifying risk factors) and whether well-tolerated and effective treatment or informative screening and early detection methods exist. If the latter are available, IRBs may decide that the potential value of chemoprevention would justify only a low level of side effects, since there would be few serious, irreversible consequences from being diagnosed with the disease.
Defining the Risk Status of Subjects. The potential benefit of participating in chemoprevention research for individual subjects is a lower statistical likelihood of developing future illness. The hypothesized reduction in the probability of developing disease is relative to the baseline likelihood of disease among potential research subjects, both of which are important to justifying risk. If potential subjects have little chance of becoming ill, few and only minor side effects from chemoprevention should be tolerated. Conversely, if the chance of developing a serious or life-threatening disease is higher, a greater tolerance for side effects may be appropriate, as long as there is still a favorable risk-benefit ratio. Because of this interplay between likelihood of disease and risk-benefit assessment, one critical task for investigators and IRBs is evaluating the adequacy and appropriateness of eligibility criteria to identify subjects with a level of disease risk sufficient to justify enrollment in the trial.
A person’s risk of developing a disease is described by the number and nature of risk factors borne by the individual. Risk factors are characteristics that have been shown at the population level to be associated with differential probabilities of disease incidence.4 Known risk factors can be grouped into at least five broad categories: biological, behavioral, environmental, genetic, and demographic. Combinations of risk factors are usually used as eligibility criteria in chemoprevention trials.
Determining the Threshold Level of Risk. Since some scientific uncertainty surrounds the determination of disease risk, identifying appropriate inclusion and exclusion criteria for participation in chemoprevention trials requires judgment and justification. The annual incidence of cancer in the general population is low. Thus, researchers seek to identify subjects with a high enough cancer risk to allow for trials with adequate statistical power while minimizing the number of individuals and the length of time needed to demonstrate an effect.5 The Breast Cancer Prevention Trial (BCPT) used the Gail model, a statistical assessment instrument designed to estimate a woman’s risk of developing an invasive breast cancer, to identify eligible subjects.6 The Gail model generates individualized risk estimates based on the following risk factors: age; age at menarche; age at first live birth; number of first-degree relatives with a history of breast cancer; number of prior breast biopsies; and history of atypical hyperplasia (the model can be adjusted to take race into account). The model predicts a woman’s absolute risk of developing an invasive breast cancer over a specified time period.7 Women between the ages of 35 to 59 with a Gail model predicted five-year breast cancer risk of 1.67% and all women over age 60 were eligible for BCPT. Out of one thousand women with Gail scores of 1.67, approximately 17 were predicted to develop breast cancer over a five-year period. This risk level was chosen because it corresponds to the breast cancer risk of an average 60 year-old woman and is sufficiently high to allow for a well-powered trial with a reasonable effect size.8 This threshold has subsequently been adopted as the definition of high-risk, both as an eligibility criterion for subsequent breast cancer chemoprevention trials, and as a trigger for consultation about tamoxifen chemoprevention in clinical practice.
Risk is a continuous variable, however, and the threshold for defining high risk could be set at a lower or higher cut-off point. For a given trial, setting a higher risk threshold for inclusion would increase the likelihood of detecting a significant experimental effect, but could also restrict the pool of potential subjects. If fewer people in the general population were eligible, recruitment might be more difficult and trial results could be less generalizable. IRBs face the challenge of deciding if a given level of cancer risk is sufficient to merit enrolling healthy subjects in trials designed to lower that risk. This justification should be made on the basis of the potential risk-benefit trade-off of the study interventions to individual subjects and not on the basis of the potential benefit to the population. Though the benefit of research is generally understood to encompass both prospective benefits to society and to individual subjects, “the risks and benefits affecting the immediate research subject will normally carry special weight.”9 This calculus can be justified by appeals to considerations of beneficence both with respect to protecting subjects from potential harm and to attempting to maximize potential benefits. In the context of cancer chemoprevention, it is necessary to identify the maximum level of risk that is ethically permissible for the healthy participants in a proposed chemoprevention trial to bear and to not exceed this risk level. There must be a positive social value associated with the study for it to be conducted. However, there are clearly limits to the amount of risk that healthy participants should be asked to assume in the interests of social value.
Selection and Exclusion of Possible Risk Factors. Aside from the difficulty of defining what level of risk is sufficient to be categorized as high risk, determining risk level is in and of itself complex because it is not always clear which of many risk factors should be incorporated into a risk estimate. There may be limited epidemiological evidence about known risk factors (or protective factors), and unknown risk factors may exist. Investigators make choices about which risk factors are most relevant based on the strength, amount, and quality of available scientific evidence. Moreover, different choices can be made on the basis of the same evidence. For instance, the Tyrer-Cuzick individualized risk assessment model for breast cancer includes seven additional risk factors besides the six risk factors incorporated in the Gail model.10 Experts disagree as to which model is best.11 IRBs must assess the justification given for risk factors used in eligibility criteria while acknowledging that there are varying degrees of confidence about the extent to which a given risk factor or set of risk factors can accurately predict risk.
Further complicating matters, risk factors can contribute to overall risk in an independent, additive fashion, can interact synergistically, and/or can be counterbalanced by protective factors. For instance, epidemiological evidence suggests that increased physical activity and certain dietary patterns may be associated with some reduction in breast cancer risk.12 However, data on such interaction effects are not always available. Decisions about whether to include or omit particular risk factors are important because investigational drugs may be tolerated more or less well by subgroups with different constellations of risk factors.
Balancing Risks and Benefits in Chemoprevention. Though weighing risks and benefits to subjects is not unique to chemoprevention research, the outcomes of several major cancer chemoprevention trials have demonstrated the difficulties of assessing risks and benefits associated with chemopreventive agents. For instance, the BCPT trial showed that tamoxifen as a chemopreventive agent reduced the risk of an invasive breast cancer by 49%.13 However, tamoxifen has significant side effects. BCPT investigators reported a two-and-a-half- to fourfold increase in the risk of endometrial cancer, a threefold increase in stroke risk, and a greater frequency of hot flashes (45.7% versus 28.7% with placebo) on tamoxifen. Given the low baseline risk of breast cancer among trial participants, IRBs should focus on the magnitude of change in absolute risk (the rate of disease in a population) when assessing potential benefits and risks associated with an investigational chemoprevention agent. The recently completed STAR trial compared raloxifene to tomoxifen to investigate whether a similar benefit could be achieved with fewer serious side effects. Both drugs were found to reduce the risk of developing invasive breast cancer by about 50%, but women who took raloxifene had fewer blood clots and cataracts than those who took tamoxifen.14
In chemoprevention trials of agents similar to tamoxifen, such as raloxifene, for example, IRBs should consider not only quantitative estimates of changes in risk, but also qualitative assessments of the relative seriousness of different diseases based on the probability, severity, and magnitude of potential risks. For instance, is breast cancer worse than endometrial cancer or stroke? If so, what is the magnitude of the difference? What increase in frequency of stroke would outweigh the benefit of the reduction in breast cancer incidence rates? These are normative questions with no universally agreed upon answers, so risk assessment is difficult and needs to be conducted on a case by case basis. It is important to raise the complexity and subjectivity of the risk assessment during the informed consent process, which we consider in the following section.
Issues Related to Informed Consent and Subject Participation
Chemoprevention research also raises a number of distinct issues related to recruitment and informed consent. For instance, potential subjects may be motivated by inaccurate perceptions of their own risk. Studies both of clinical populations and the general public have found that people tend to overestimate their cancer risk.15 Moreover, the term “prevention” could have such positive connotations that eligible subjects may overestimate the benefits and not fully appreciate the risks involved in research participation.16 The potential for overestimating benefit may be particularly high in cancer chemoprevention trials where disease etiology is believed to be primarily biological (as opposed to behavioral) in nature and the opportunity for individual control of risk-reducing measures is low.17
Presenting risk information can also be difficult, particularly how to frame statistics about risk reduction, assure comprehension of probabilistic information, and convey the idea of reducing an already small probability of contracting disease. The hypothetical benefits of participation may be interpreted differently depending on whether risk reduction is presented in terms of relative or absolute reductions.18 Absolute risk is the rate of disease in a population and relative risk is defined as the probability of developing a disease among those receiving the investigation treatment as compared to the probability of developing the disease among those in the control group. This distinction is important because a 50% reduction in relative risk sounds much more impressive than a reduction in absolute risk from 2.0% to 1.0%, and subjects might perceive the potential benefits differently. The presentation of individualized risk estimates poses an additional ethical concern. While these estimates appear to give a personalized risk estimate, they are derived from epidemiological relative risk based on the average population risk level. Thus, they have limited discriminatory power to determine who will develop cancer and limited positive predictive value at the individual level.19 IRBs and investigators can work collaboratively to identify best practices for communicating risk both with respect to individualized risk status and the levels of risks and benefit that can reasonably be expected from a given trial.
In treatment trials, providing information about alternative therapies outside the trial, when they exist, is required. A parallel ethical obligation exists with respect to chemoprevention trials. Potential subjects should be given information about alternatives to chemoprevention and education about or access to behavioral modification or screening regimens known to reduce cancer risk that are consistent with the standards of preventive care for a particular cancer.
Although compensation is not typically given to subjects in cancer trials, it is common in trials involving healthy volunteers and in vaccine trials.20 Compensation can serve as a reminder to subjects that they are not receiving therapeutic medical care, but are participating in research where the goal is to obtain generalizable knowledge.21 Likewise, compensation can serve as a reminder to researchers that they are not working with patients but with research subjects without clinical disease. Many agree that compensation level should be determined “on the basis of the time and inconvenience of research participation, not on the level of risk.”22
The ethical conduct of research requires respect for the welfare and rights of subjects during the course of the trial. This includes protecting privacy and confidentiality, monitoring the condition of research subjects to assure their safety, terminating study participation in the case of adverse events, and notifying enrolled subjects about new risks, benefits, or other information that may bear upon subjects’ decisions to stay enrolled in the research.23 As new evidence comes to light, trial investigators and data safety monitoring boards (DSMBs) might modify the study design, initiate notification of enrolled subjects, make changes to the informed consent documents, or stop the trials earlier than planned. Investigators should identify a method for ensuring effective communication between the IRB and DSMB throughout the study.
Additionally, the use of patient advisory boards in ongoing discussions of subject welfare, appropriate informed consent and recruitment methods, and other study design and conduct issues has been proposed as a means of showing respect for subjects. Community advisory boards (CABs) are common in HIV vaccine prevention studies and have been established in some cancer chemoprevention trials, such as the BCPT trial and the Selenium and Vitamin E Cancer Prevention Trial (SELECT). IRBs might consider the use of CABs or other mechanisms for explicitly seeking the input of subjects or affected communities. Finally, some contend researchers have an obligation to offer trial results to participants in order to show respect for subjects. Some empirical research exists showing that subjects are interested in receiving such results.24 Investigators should consider this issue as part of study design, as it requires significant resources and planning. Reviewers should ask investigators to discuss their decision about sharing trial results with participants.
Conclusion
Cancer chemoprevention trials present unique challenges to investigators and IRB reviewers in evaluating risks and benefits and in assessing informed consent and payment to subjects. In designing and reviewing chemoprevention protocols, investigators and IRBs should pay particular attention to the criteria used to define at-risk subjects and carefully assess the strength of evidence supporting these criteria, as this is critical to assessment of the risk-benefit ratio. We hope our analysis will provide a framework of specific questions to investigators and IRBs for structured deliberation about key ethical issues inherent in chemoprevention research.
Acknowledgments
We would like to thank Larissa Korde, Frank Miller, Beverly Rockhill, Joseph Tangrea and the anonymous peer reviewers for their insightful comments on earlier drafts of this manuscript.
Disclaimer
The opinions expressed are those of the authors and do not necessarily reflect the position or policies of the National Institutes of Health, the Public Health Service, or the Department of Health and Human Services.
Julia Slutsman, PhD,is Cancer Prevention Fellow in the Division of Cancer Prevention, National Cancer Institute, Bethesda, MD;David Buchanan, DrPH,is Professor, Department of Community Health Education, School of Public Health and Health Sciences, University of Massachusetts, Amherst, MA;Christine Grady, PhD,is Head of the Section on Human Subjects Research, Department of Clinical Bioethics, National Institutes of Health, Bethesda, MD.
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Julia Slutsman, David Buchanan, and Christine Grady, “Ethical Issues in Cancer Chemoprevention Trials: Considerations for IRBs and Investigators,”IRB: Ethics & Human Research29, no. 2 (2007): 1-6.