While some commentators focus on the specific impact of random treatment assignment, others have investigated the broader topic of differences in clinical outcomes between research participants and “real” patients in the community setting. Some studies have suggested that research participation may be associated with improved clinical outcomes [ 9– 14]. These data have led some to recommend trial participation as a means to better treatment [ 15]. For instance, the National Comprehensive Cancer Network's clinical practice guidelines in oncology state that “the best management for any cancer patient is in a clinical trial” [ 15]. Yet these conclusions are not based on strong evidence [ 16]. In particular, comparisons of research participants versus non-participants often include non-participants who do not meet trial eligibility criteria [ 16]. Because of stringent eligibility criteria, trial participants tend to be younger and healthier than non-participants in the community [ 16– 18]. Trial participation may also be the only means of access to some therapies: if the investigational therapy is available only in the research setting and turns out to be superior to existing therapies, trial participants who were allocated to the newer agent would be more likely to benefit. Further, the supportive clinical care that participants receive as part of research in resource-rich settings associated with some clinical trials may also be associated with superior outcomes. Recognizing these flaws in the existing data, a recent review of the literature called for more studies that assess the impact of participation in clinical research on patient outcomes in a methodologically rigorous manner [ 16].

It is particularly timely to disentangle the issues surrounding the effect of research participation on patients. There has recently been increased emphasis on designing trials that compare commercially available, clinically relevant alternatives [ 19– 21]. Some authors have advocated substantial increases in funding of “pragmatic” trials enrolling large numbers of patients in community practice settings [ 19]. Additionally, Medicare's policy has recently been modified so as to provide reimbursement for some new therapies only if patients receive them in the setting of a clinical trial [ 22]. Unlike in the previous paradigm, which viewed randomized trials as a tool to evaluate the efficacy of novel therapeutic agents, these innovations will likely result in many more patients encountering the decision of trial enrollment in the setting of routine clinical care. Prospective participants who are asked to participate in these pragmatic trials will have to decide whether to receive therapy that was selected via randomization or to select treatment with the input of their clinician.

The finding that randomized research participants and non-participants tend to achieve similar clinical outcomes also contradicts prior studies suggesting that trial participation may be associated with superior clinical outcomes [ 9– 14]. Many of the previous studies that reported such a difference failed to account for the numerous differences between clinical care and clinical research that may influence patient outcomes, including the fact that research participants are often younger, healthier, and treated by clinicians with more experience in treating patients with the condition of interest. Specifically, we restricted the present analysis to studies that included only patients who were eligible for RCT participation and had access to similar treatments whether or not they chose to enroll in the RCT. Hence, while our study sample was therefore restricted to a relatively small subset of RCTs, our findings suggest that the purported benefit of trial participation is probably due to baseline differences between participants and non-participants, or to differences in treatments received.

All of the studies included in the present analysis allowed access to the experimental therapies to patients who refused trial enrollment. It is unclear whether our results can be generalized to randomized trials that include newer, and potentially more efficacious, therapies that are not available outside the research setting. However, a recent analysis found that only 36% of trials presented at an annual meeting of the American Society of Clinical Oncology yielded “positive” results [ 32]. These findings contradict the widespread assumption that access to experimental therapies is beneficial [ 33– 38]. Future work should explore whether participation in randomized trials of otherwise unavailable agents is associated with superior clinical outcomes.

While our comprehensive and systematic search identified far more manuscripts than prior reviews of this topic that we are aware of, our final sample size is small relative to the number of RCTs conducted annually [ 39]. As a result, although our findings were consistent across disease entities and different types of intervention, they may not be generalizable. As noted in prior reviews, many of the primary studies did not control for differences in baseline health characteristics [ 16, 39]. We used an implicit, dual review approach to account for this potential bias, stratifying manuscripts according to baseline differences between trial participants and non-participants. Ideally, future work employing primary data would enable multivariate analysis of patient-level information, to account for important patient characteristics that may affect patient outcomes. The increasing use of electronic medical records represents a tremendous opportunity for establishing longitudinal registry databases to facilitate follow-up of patients who are offered trial enrollment, yet decline.

Our results should be interpreted with several considerations in mind. We restricted our analysis to the primary outcomes assessed in the included studies. In particular, many studies assessed the outcome of mortality, and there may have been differences in the probability of other adverse events, satisfaction, or quality of life between RCT participants and non-participants. Similarly, clinical trials may include additional research procedures, such as blood draws and lumbar punctures that do not affect patient outcomes but that pose burdens to participants. Additionally, random assignment refers only to the investigational agent. Even among RCT participants, clinician-investigators generally have some latitude regarding other aspects of care that are administered to their patients and can therefore provide individualized care that consists of interventions that are distinct from the investigational agent. Similarly, clinicians may halt existing treatment for patients who are offered a choice of enrolling in a study. In these instances, if a patient is provided one of the treatment interventions offered in the study—whether selected with randomization or by patient choice—it is possible that the initial treatment may have been superior to either of the treatments under investigation. Further, publication bias might have yielded underestimates of differences between RCT participants and eligible non-participants, as investigators may have been reluctant to report data from the non-participants in their registries if they did not support the generalizability of their RCTs. Finally, there may have been important differences in health status between randomized and nonrandomized patients that were not reported by the investigators. However, given that the vast majority of the study samples in our sample found no difference in health outcome between groups, one would have to invoke a systematic over- or underestimation of health status in the randomized groups across multiple studies in order to instill bias in this synthesis.

Numerous studies indicate that RCT participants often fail to understand that their treatments will be determined by random assignment [ 18, 40– 42]. For example, a recent analysis found that half of parents who decided whether to enroll their children in a leukemia trial did not understand that treatment allocation would be determined by chance [ 18]. The failure to understand randomization is often regarded as part of a broader phenomenon, termed the “therapeutic misconception,” according to which individuals assume that research treatments are based on physicians' decisions regarding what is best for them [ 1, 43]. In this context, our findings have important implications for the informed consent process. In addition to explaining randomization, investigators should also explain that, in general, there is little evidence to support that participating in randomized trials is either helpful or harmful.

What do our findings say about the impact of clinical judgment and patient preferences on clinical outcomes? Although clinicians and patients may be reluctant to forego clinical decision-making, our data suggest that undergoing randomization, rather than individualized treatment recommendations by clinicians, is not harmful. This conclusion calls into question clinicians' ability to determine which therapy is superior for their patients in the setting of clinical equipoise, i.e., when there is uncertainty in the expert community about which treatment is superior for patients in general [ 44]. It has also been suggested that some patients who are not randomly assigned to a treatment may achieve a better outcome not because of an objective therapeutic effect, but because they were assigned to the treatment arm they preferred—a logical extension of the placebo effect [ 45]. To account for this possible “preference effect,” some have called for incorporating patient treatment preferences into the analysis phase of RCTs [ 45]. Our data provide preliminary evidence that this preference effect does not bias the outcomes of RCTs: patients who received a treatment preferred by themselves or their clinicians did not experience superior outcomes. These findings are consistent with the result of a recent review in which the authors stratified patients according to treatment received and then compared the outcome of patients who were randomized versus those who selected each therapy [ 46].