Affiliations of authors: S. Joffe, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, and Department of Medicine, Childrens Hospital, Boston; J. C. Weeks, Department of Adult Oncology, Dana-Farber Cancer Institute, Boston, and Department of Medicine, Brigham and Womens Hospital, Boston.
Correspondence to: Steven Joffe, M.D., M.P.H., Center for Outcomes and Policy Research, 454 BRK Suite 21, Dana-Farber Cancer Institute, 44 Binney St., Boston, MA 02115 (e-mail: steven_joffe{at}dfci.harvard.edu).
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ABSTRACT |
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INTRODUCTION |
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Given the differing objectives of research and practice, investigators in studies that involve human subjects necessarily have divided loyalties (37). On the one hand, they must conduct valid and valuable science with an eye toward generalizable knowledge and future patients. On the other hand, they have a duty to promote the rights, welfare, and dignity of the research participants (8). Because of the fiduciary obligations inherent in the patientphysician relationship, this tension is most complex and acute when research involves patientsubjects rather than healthy volunteers (3,5,6,9).
Although the exact line between research and practice can be difficult to define, recognition of the conceptual difference between the two is critical for understanding and evaluating a clinical trial (7,10). Research participants often fail to appreciate the distinction between the aims of research and those of clinical care. According to the National Bioethics Advisory Commission (11), this blurring of boundaries results in the "therapeutic misconception," which is
. . . [T]he 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. . . . It is not a misconception to believe that participants probably will receive good clinical care during research. But it is a misconception to believe that the purpose of clinical trials is to administer treatment rather than to conduct research.
The therapeutic misconception arguably constitutes the most important threat to the validity of informed consent to research (12,13).
Clarity about the different goals of research and practice seems essential if we are to help our patients decide about participating in clinical trials (5,14). However, the views of physicianinvestigators about the purposes of clinical trials have received little attention (4). In a preliminary survey, we were surprised to find that there is controversy among academic oncologists about the underlying purpose of cancer clinical trials (15). We conducted the current study to explore this issue further among a national sample of oncologists. Specifically, we examined whether oncologists views about clinical trials varied by oncology specialty or by academic affiliation.
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MATERIALS AND METHODS |
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We used the American Society of Clinical Oncology (ASCO) Membership Directory for 2000 to identify a stratified random sample of 1120 medical oncologists, pediatric oncologists, and other oncology subspecialists (i.e., gynecologic, radiation, surgical, and urologic oncologists). The three strata were equally represented to permit reliable comparisons across specialties. We could not locate an additional 13 physicians that were initially selected from the directory. Physicians were eligible if they were listed as Active or Associate (i.e., in-training) members of ASCO and had a U.S. mailing address. We excluded physicians at the Dana-Farber Cancer Institute, Brigham and Womens Hospital, and Massachusetts General Hospital because we had previously conducted a related study at those institutions (15). We conducted the initial mailing of the surveys in March, 2001. Three weeks later, we mailed a second copy of the survey to the nonrespondents.
Survey Instrument and Measures
We developed the survey instrument specifically for this study. The instrument was three pages long and included 20 items. We had previously used an expert panel to validate the key items in the survey (15,16). A cover letter that accompanied the survey was signed by the investigators, and described the studys purpose as "to better understand physicians attitudes and beliefs about cancer clinical trials." In addition to the questions presented here, the survey included a series of items (which will be reported on separately) that asked how physicians expectations of the outcomes of randomized trials influenced their decisions about recommending enrollment.
The primary outcomes of this study were as follows: 1) the reasons why physicians offer clinical trial enrollment to individual patients; and 2) physicians perceptions of the underlying (i.e., societal) purposes of clinical trials. The first survey question asked, "There are many reasons why physicians may enroll individual cancer patients in clinical trials. Thinking about the patients to whom you offered clinical trial participation over the past year, what were the main reasons why you offered enrollment?" Respondents were instructed to rank the top four reasons, in order, from a list of options (see below). We did not consider there to be a single best answer to this question.
Immediately following the question about the reasons for enrolling individual patients, we asked, "From a societal point of view, what are the main purposes of cancer clinical trials? In considering your reply, please consider general purposes that are true across phase I, II and III trials" (underlining as in the survey). Respondents were again asked to rank the top four purposes from the same list of options as above. We viewed "to improve the treatment of future cancer patients" as the most appropriate answer (i.e., the one that should be ranked first) to this question (1,17). The remaining questions addressed demographic and practice characteristics of the respondents.
Statistical Analysis
Our primary objective was to examine whether beliefs about the societal purposes of clinical trials and the reasons for enrolling individual patients varied according to the specialty or academic affiliation of the respondent. We also considered potential associations between these views about trials and the number of patients a respondent had enrolled in trials, whether the respondent had ever served as a principal investigator, whether the respondent worked in industry, time since the respondent had graduated from medical school, the number of new patients the respondent saw per month, and the respondents sex and training status. Because these latter analyses were exploratory and considered hypothesis-generating, we made no adjustments for multiple comparisons. In evaluating associations, we focused on the top-ranked response to each question. Unless otherwise noted, we tested bivariate relationships with the use of the Pearson chi-square test for categorical data and the Wilcoxon rank-sum test for ordinal data. When independent variables involved three or more categories (e.g., specialty, academic affiliation), we evaluated global rather than pairwise tests of association in bivariate analyses to minimize multiple comparisons. All statistical tests were two-sided.
To evaluate which variables were independently associated with the outcomes, we calculated adjusted odds ratios (ORs) and 95% confidence intervals (CIs) using a logistic regression model for each dependent variable. Variables that were statistically significant in the bivariate analyses at P<.1 were entered into the initial models. In addition, because academic affiliation and specialty (the primary independent variables) were closely associated, we included both variables in the initial regression models regardless of their statistical significance in the bivariate analyses. Using backward stepwise elimination, those variables that did not achieve P<.05 in the regression model were sequentially dropped. We used Stata 5.0 for Windows (Stata Corp., College Station, TX) to analyze the data.
Our sample-size calculations assumed a 50% response rate and a 5% alpha error for two-sided tests of statistical significance. We wanted to be able to detect a 20% absolute difference between specialties with a power greater than 90%. A sample size of 1120 also ensured a greater than 90% power to detect 20% absolute differences in responses by academic affiliation, assuming that one-third of the respondents were full-time academic physicians. The Institutional Review Board of the Dana-Farber Cancer Institute approved this study.
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RESULTS |
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A total of 547 physicians (48.8%) responded to the survey. Of these, seven physicians reported feeling unqualified to participate in the survey, and one physician returned a largely incomplete survey. Response rates differed by specialty: 60.1% of pediatric oncologists, 42.3% of medical oncologists, and 44.7% of other oncology subspecialists responded (P<.001).
Table 1 shows the characteristics of the respondents. As expected, we observed numerous differences between specialties. In particular, pediatric oncologists were more likely than other oncologists to self-identify as full-time academics, to have been the overall or institutional principal investigator of a clinical trial, and to be female. In addition, although pediatric oncologists saw the fewest new patients per month, they reported enrolling more patients in a clinical trial during the previous year than the other oncologists.
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Table 2 presents the most common reasons respondents gave for enrolling individual patients in clinical trials. Most pediatric oncologists (64.1%) reported that the main reason they enrolled individuals in trials was to ensure that those patients received state-of-the-art treatment, whereas 32.3% reported enrolling individuals primarily to improve future therapy. Medical oncologists were divided between selecting ensuring state-of-the-art treatment for participants (42.8%) and improving future therapy (40.5%) as the main reasons they enrolled individuals in trials. By contrast, only 25.2% of the other oncology subspecialists reported enrolling individuals to ensure that they received state-of-the-art treatment, whereas 62.6% reported that the main reason they enrolled patients was to improve future therapy. Other reasons for enrolling patients were rarely cited by any of the three groups of oncologists.
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Table 2 presents the most common responses given by the oncologists to the survey question about the societal purposes of clinical trials. Pediatric oncologists were the least likely to report that the main purpose of trials is to improve future therapy; 38.2% of pediatric oncologists (versus 19.5% of medical oncologists and 13.1% of other oncology subspecialists) said that the main purpose of trials is to ensure state-of-the-art treatment for trial participants.
Table 3 shows the results of bivariate and multivariable analyses of associations between respondents characteristics and their beliefs about the purposes of clinical trials. In addition to variation by specialty, the results of bivariate analyses indicated that full-time academic physicians were less likely than part-time or nonacademic physicians to report that trials are intended primarily to improve future therapy. Physicians who worked for industry were more likely to choose this option than those who did not work for industry.
In the multivariable analyses, pediatric oncologists (OR = 0.3, 95% CI = 0.2 to 0.5) and medical oncologists (OR = 0.6, 95% CI = 0.3 to 0.9) were less likely than other oncology subspecialists to report that the main purpose of trials is to advance future therapy (Table 3). Physicians who worked for industry were more likely than physicians who did not work for industry to identify advancement of future therapy as the main purpose of trials (OR = 4.6, 95% CI = 1.1 to 20.5).
After controlling for specialty, none of the following variablesacademic affiliation, number of new patients per month, number of trial patients enrolled per year, physician sex, training status, prior service as a principal investigator, or time since graduation from medical schoolwas statistically significantly associated with respondents beliefs about the purposes of trials (data not shown).
Physicians reasons for enrolling individual patients in clinical trials were strongly associated with their beliefs about the societal purposes of trials. Among the 204 physicians who reported enrolling individual patients primarily to improve future therapy, 186 (91.2%) also identified advancement of future therapy as the major societal purpose of clinical trials. By contrast, among the 261 physicians who reported that they entered individual patients into trials for other reasons, only 135 (51.7%, P<.001) identified improving future therapy as the major societal purpose of trials. This relationship persisted after we controlled for specialty, academic affiliation, and industry employment (data not shown).
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DISCUSSION |
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We observed a striking heterogeneity in the responses of the survey respondents, most of whom described high levels of personal involvement with clinical research, to both of these questions. Although many of the physicians reported that they offered trial enrollment to ensure that their patients received state-of-the-art therapy, others viewed trial participation primarily as a way to improve treatment for the future. Similarly, respondents disagreed about the underlying societal purposes of clinical trials. Although a majority of respondents reported that the main purpose of trials is to advance future treatment, a substantial minority reported that trials exist primarily to ensure state-of-the-art therapy for the participants themselves.
Responses to both survey questions varied by oncology specialty. Pediatric oncologists were more likely than medical oncologists to view trials as a way to ensure state-of-the-art therapy for participants, regardless of whether they were asked to consider trial enrollment from the perspective of the individual patient or from that of society. Medical oncologists, in turn, were more likely than other oncology subspecialists to view trials in this way. Interestingly, these views parallel the relative prominence of clinical research in the day-to-day practice of these disciplines. For example, in the United States, approximately 70% of pediatric cancer patients, versus only 1%4% of adult patients, enroll in a clinical trial (19,20). Furthermore, in our survey, pediatric oncologists reported enrolling the largest fraction of their patients in trials, whereas other oncology subspecialists reported enrolling the smallest. Several other associations were also apparent from our analyses. Full-time academic physicians were more likely than other physicians to enroll individuals in trials to improve future treatment. In addition, physicians who worked for industry appeared more likely than those who did not to view trials primarily as a means to improve treatment for future patients. However, this analysis was exploratory and therefore merits confirmation. We did not observe the hypothesized association between academic affiliation and respondents views about the societal purposes of trials.
The fact that respondents varied in their reasons for enrolling individuals in trials, and that many focused on trials as a way to optimize therapy for their patients, should not be surprising. Encouraging a patient to enroll in a trial can certainly be in his or her best interest. For instance, preliminary data sometimes suggest the efficacy of an intervention, even though it remains under study. Furthermore, such interventions are often unavailable outside the confines of a clinical trial. The recent case of STI-571 (21,22) exemplifies a drug that was widely known to be efficacious against several types of tumors while it was still under evaluation in phase I and II trials. Thus, physicians who viewed STI-571, even prior to its regulatory approval, as state-of-the-art therapy for some patients with chronic myelogenous leukemia or gastrointestinal stromal tumor were certainly acting as rational advocates for their patients. Other motives given by respondents for enrolling patients in trials, including helping patients to maintain hope and having something to offer when no standard options are available, may also arguably be reasonable motivations for offering trial enrollment in particular circumstances. At the same time, however, the recent example of high-dose therapy for metastatic breast cancer, which was widely adopted on the basis of preliminary reports that were subsequently not confirmed by randomized controlled trials, indicates the need for circumspection when making treatment recommendations based on early-phase trial data (2326).
It is more difficult to interpret respondents views about the underlying societal purposes of trials than to understand their reasons for enrolling individuals in trials. Foundational texts of research ethics, such as the Belmont Report (1) and the Declaration of Helsinki (18), describe the purpose of research as the development of generalizable knowledge. Numerous commentators have noted that research participants tend to confuse the objectives of treatment with those of clinical research (5,11,13,27). These authors emphasize the need to preserve the distinction between research and practice (10), and they reinforce that clinical trials are "not a form of individualized medical therapy; [they are] a scientific tool for evaluating treatments in groups of research participants, with the aim of improving the care of patients in the future" (7).
In this light, it is notable that 13%38% of the respondents in our survey believed that ensuring state-of-the-art therapy for trial participants, rather than improving the treatment of future cancer patients, is the main societal purpose of trials. This finding suggests that there is a lack of consensus among oncologists about the nature of the relationship between research and treatment in cancer clinical trials. Further discussion of this relationship is important because the belief that trials exist primarily to benefit participants eliminates the possibility of conflict between the scientific and therapeutic objectives of trials, and therefore negates the underlying rationale for attending to the ethics and regulation of clinical research.
The claim that the primary purpose of trials is to benefit participants directly has particular implications for the process of informed consent. If we view research and clinical objectives as potentially in conflict, we arguably have a duty to challenge patients therapeutic misconceptions when obtaining consent from them. For example, Appelbaum and colleagues (13) suggest that when explaining a trial to a patient, one should include statements such as the following: "Because this is a research project, we will be doing some things differently than we would if we were simply treating you for your condition. Not all the things we do are designed to tell us the best way to treat you, but they should help us to understand how people with your condition in general can best be treated" (italics in the original). By contrast, if there is no conflict between research and clinical care, then the therapeutic misconception no longer presents a problem when obtaining informed consent.
What might explain our data? Our findings might be due simply to variability in education about research ethics (28). Alternatively, the physicians responses to the survey questions might have been influenced by the belief that trial participants may have better outcomes than nonparticipants. (29) Even if it exists, however, such an "inclusion benefit" is not the purpose of clinical research (4,7,11). Our results might also indicate that some oncologists (particularly pediatricians) tend to view trial protocols as clinical practice guidelines.
Another possible explanation for our findings is that, as noted by Miller et al. (4), physicians may experience tension between their roles as clinicians and as research scientists. Given physicians intensive socialization as therapists who are expected to place the best interests of patients first, many physicians who practice in research-intensive settings may deny those aspects of trials that challenge their self-image as healers. In support of this hypothesis, we found that respondents beliefs about the underlying purpose of trials were closely associated with their reasons for enrolling individual patients in trials, which suggests that it may be difficult to distinguish the function trials play in the clinical setting from their broader societal mission. Our finding that industry physicians, who are generally not involved in direct patient care, placed greater emphasis on advancing future therapy than did physicians who did not work for industry, provides further evidence of the challenge that physicianinvestigators face in separating clearly their two roles.
This interpretation of our results is consistent with the few empirical data available. Taylor and colleagues have shown that most cancer physicians, even those with substantial trial involvement, adopt the perspective of a therapist rather than that of an experimenter when considering research participation (3032). For example, when physicians participating in a cooperative group were asked in an open-ended question to describe the benefits of physician involvement in randomized trials, only 20% of respondents cited societys best interest as a major reason for physician participation, whereas 39% cited advantages to subjects themselves (32).
Finally, there may be a sincere belief in the oncology community that, through clinical trials, we have succeeded in harmonizing perfectly the objectives of patient care and those of scientific advancement. The statements by many leaders in oncology that clinical trials represent the optimum care for cancer patients are the most obvious expression of this attitude (33,34). Many oncologists might argue that ethical clinical trials must both offer benefit to the patient and address important clinical or scientific questions. As a result, they might conclude that any effort to define one of these objectives as primary is unnecessary and artificial, and that because the two objectives are obligatory, the possibility of conflict does not arise. Instances in which these objectives might diverge, however, are not difficult to find. For example, in a 1985 review of Eastern Cooperative Oncology Group trials for advanced non-small-cell lung cancer, Simes (2) showed that only 15% of trial participants had objective tumor responses, that median survival was only 4.2 months, that participants spent about one-half of their remaining time receiving protocol therapy, and that 39% of participants had severe or worse toxicity from treatment. In discussing these results, Simes (2) pointed out that although "the value of these clinical trials for the community as a whole seems clear . . . for the individual patient, the decision to participate in the clinical trial may sometimes be difficult. . . ." Similarly, the degree to which clinical and research objectives overlap in classic phase I trials is controversial (35). Whether oncology has perfectly aligned research and clinical care, or whether such reconciliation is even logically possible, are critical questions that require sustained discussion and debate.
There are several limitations to our study. First, the response rates among the medical oncologists and the other oncology subspecialists, although not atypical for surveys that are mailed to physicians (3640), were lower than we would have liked. The large number of physicians who did not return the survey raises the possibility of response bias and makes the point estimates for these two groups somewhat unreliable. We also did not have any demographic data, other than specialty, on the nonrespondents that would facilitate comparisons with those who responded. However, it is important to recall that our primary hypothesis was that physicians views about clinical trials would vary according to specialty. The differences we observed among the three groups of oncologists were too large to be explained by response bias alone. For example, even if 60% of medical oncologists and other oncology subspecialists had responded to our survey, and the distribution of the additional responses was identical to those among pediatric oncologists, the differences we observed would have remained statistically significant. Thus, despite concerns about the response rate, the data confirm our hypothesis. Second, the implications of our data for oncologists who are not members of ASCO or who practice outside the United States are unclear. It is also likely that physicians who do not primarily care for cancer patients have different attitudes about clinical trials than those we observed. Third, we had insufficient power to detect differences (e.g., between academic and nonacademic physicians) within specialties. In addition, tests of association other than those with specialty and academic affiliation were exploratory and should be interpreted in light of the problems raised by multiple testing. Finally, some respondents might have misinterpreted the question about the societal aims of clinical trials. However, to minimize this possibility, we underlined the key phrase in that question, and placed the question after the survey item that asked why physicians enrolled individual patients. The striking variations we observed across specialties also make this explanation improbable because such misinterpretation would tend to bias toward the null and thereby obscure, rather than exaggerate, the differences we observed.
In summary, there appears to be systematic disagreement within the oncology community about the reasons for enrolling individual patients in clinical trials as well as about the underlying purpose of such trials. The pattern of variation in survey responses among oncology specialties suggests that the greater integration of clinical research into professional culture may be associated with differing views about the purposes of clinical trials, perhaps because of the tension that exists between the roles of physician and investigator. Finally, there may be a belief among some cancer specialists that clinical trials seamlessly unite research and therapy. This belief, which challenges conventional doctrines of research ethics, has important implications for how we conduct, review, and regulate clinical trials, as well as how we present them to patients. As a result, this attitude merits discussion among oncologists, trialists, ethicists, patients, and others who have a stake in the conduct of cancer clinical trials. We hope that this debate will lead to a heightened consciousness in the oncology community about the profound challenges and responsibilities implicit in the conduct of clinical research.
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NOTES |
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We thank Lindsay Bryant for her assistance, Craig Earle and Stephanie Lee for their thoughtful critiques of this manuscript, and the physicians who participated in this survey.
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