Factors that influence the recruitment of patients to Phase III studies in oncology†
The perspective of the clinical research associate
Version of Record online: 17 SEP 2002
Copyright © 2002 American Cancer Society
Volume 95, Issue 7, pages 1584–1591, 1 October 2002
How to Cite
Wright, J. R., Crooks, D., Ellis, P. M., Mings, D. and Whelan, T. J. (2002), Factors that influence the recruitment of patients to Phase III studies in oncology. Cancer, 95: 1584–1591. doi: 10.1002/cncr.10864
See related editorial on pages 1397–400, this issue.
- Issue online: 17 SEP 2002
- Version of Record online: 17 SEP 2002
- Manuscript Accepted: 11 APR 2002
- Manuscript Revised: 26 FEB 2002
- Manuscript Received: 13 DEC 2001
- Hamilton Regional Cancer Center Foundation
- clinical research associate;
- focus group;
- clinical trial recruitment;
- patient participation
The multiple determinants of a patient's decision to enter into a clinical trial have been explored largely from the perspectives of patients and their physicians. Little research has involved clinical research associates (CRAs) formally, despite their central role in the process of recruitment. The current study was initiated to explore the factors that influence the decision of patients with cancer regarding clinical trial entry, specifically from the perspective of the CRA.
Two focus groups of CRAs from the Hamilton Regional Cancer Center were organized. A skilled facilitator guided both groups through exploratory and subsequent confirmatory phases of discussions, which were audiotaped for review and coding using a process of consensus employing intercoder triangulation.
The two groups identified a number of factors that they believed influenced the recruitment process. Numerous physician and patient factors were reaffirmed, such as the impression of the scientific merit of a study or the sense of personal benefit, respectively. More uniquely, CRAs identified information transfer within the informed consent process as a major aspect of their specialized role. It was believed that full disclosure of information, in terms of both the content and the techniques and styles of delivery, was an important predictor of recruitment success. The groups quickly reached consensus on which factors they believed were the most important overall with respect to influencing study recruitment.
CRAs appear to have a unique role in the process of recruiting patients to active clinical trials. They believe that they have an important influence on recruitment success. Further research to validate this impression is required, because, ultimately, a greater understanding of the relative roles of physician and patient factors and, potentially, CRA factors will be important in the development of ethical and supportive strategies to optimize the recruitment of patients with cancer into randomized clinical trials. Cancer 2002;95:1584–91. © 2002 American Cancer Society.
It has long been recognized that disappointingly low proportions of patients with cancer are recruited into randomized clinical trials.1, 2 Estimates have ranged to as low as 2–3% of patients overall.2–5 Poor accrual is a threat to the timely completion of increasingly large studies, which are necessary given the demands to properly evaluate newer cancer treatments while avoiding the potential for random error associated with small studies.
Recruitment for a clinical trial is a complex, multistep process. Protocol eligible patients must be identified, the study concept must be introduced, and the risks and benefits of experimental therapy as well as standard treatment must all be outlined. The applicable trial specific issues, such as placebo control and randomization, must be discussed. The content and context of this discussion likely will influence the patient's decision whether or not to enter into a specific clinical trial.
Although this discussion generally has taken place between the physician and the patient, increasingly, the patient is in close contact with specifically trained clinical trials personnel. A clinical research associate (CRA) is the most generic terminology used to label such a person, and includes clinical trials nurses and clinical data managers. To varying degrees, the CRA reviews the trial specific information, solicits a decision, and formally obtains a signature indicating informed consent to enter the clinical trial.6 The CRA role is a delicate balance between actively promoting the potential benefits of clinical research involvement and the traditional nursing role of patient advocacy.7, 8 The role of the CRA is recognized for its importance and for the potential to influence patients' decisions regarding clinical trial entry.9 Unfortunately, there is little evidence that this role has been studied well or evaluated prospectively.
An exception is a study published by Aaronson et al. in which eligible patients were randomized between the standard means of clinical trial recruitment and the standard means of recruitment plus a follow-up phone call from a clinical trials nurse.10 The objective of the phone call was to discuss specific issues relating to the clinical trial the patient was asked to consider entering. Although the extra phone call resulted in improved information transfer and reduced patient anxiety, there was no impact on the rate of study entry by the patients. It appeared that the majority of patients had made their decisions regarding clinical trial entry before the actual follow-up phone call was placed. From outside the oncology literature, Kaye et al. reported on the success of patient recruitment into a hypothetical antibiotic study. Pleasant, nonthreatening recruiters who stressed the benefits of study entry were more successful at obtaining consent from patients to enter the study.11 Unfortunately, the aspects of behavior that were construed as pleasant and nonthreatening were not discussed specifically.
The list of factors that may influence accrual to clinical trials is developed more completely in the literature from the perspectives of physicians and patients.12 A physician's self-impression of his or her role as a clinician or as a researcher, their level of concern that the formal process of obtaining informed consent will have a negative impact on the patient-physician relationship, and their difficulty discussing uncertainty and all have been suggested as potentially influential factors.13, 14 Physicians' impressions of the scientific merit of a study, the potential for toxicity, the success of current therapy, prior training involving clinical research, and the role of local principal investigator for a specific trial also have predicted levels of accrual success.15, 16
From the patient's perspective, higher levels of socioeconomic status and, specifically, the type of employment have predicted study entry.17 Although hypothetical studies have suggested that altruistic motives may direct patients toward study entry, a sense of personal benefit must exist when the real situation is encountered.18 Patients who are less willing to share decision-making or patients with higher expectations of standard therapy are less likely to enter clinical trials.19, 20 Physician recommendations and the opinions of physicians as surrogate patients also appear to influence patient decisions to become research participants.21, 22
The current study was initiated to provide a broader understanding of the factors that may influence patients' decisions regarding entry into randomized, Phase III clinical trials. This understanding was sought by exploring the factors that influence recruitment from the perspective of the CRA and specifically to discuss the impact of the CRA on the success of patient recruitment. Focus group interviews were selected as the preferred method of research for this endeavor, because they are designed to acquire in-depth descriptive or qualitative information about the issues involved in a specific research topic.23–25 Guided by a skilled facilitator, a focus group has the potential to bring to light details of complex experiences and the reasoning behind actions, beliefs, and values.24 Focus groups provide a rapid and cost-effective means of obtaining views, needs, and ideas from informed participants, and, compared with individual interviews, a wider range of issues is more likely to emerge due to the interactive effects of the group.23–26
MATERIALS AND METHODS
Two focus group interviews were conducted with CRAs from the Hamilton Regional Cancer Center (HRCC). Convenience samples of CRAs were recruited from the Department of Clinical Trials. Individuals with experience in the recruitment of patients with cancer to Phase III studies were invited by letter to participate in the focus group. The letter outlined in detail the purpose of the focus group, with broad sample questions provided as examples for possible discussion, as follows: In what ways do you have an influence on a patient's decision to enter a clinical trial? What is it you do that makes you successful? What is happening when you are not successful? What would you do to improve recruitment to clinical trials? What other factors affect recruitment in you experience?
In both instances, an experienced focus group leader (D.C.), who was external to the Department of Clinical Trials, facilitated and guided the focus group discussions. An observer (J.R.W.) was present to provide a descriptive, written assessment of the session. The observer was an HRCC physician involved in clinical research and clinical trials recruitment. The discussions were tape recorded with the knowledge of the group members. The focus groups were guided first through an exploratory phase in which issues that the group thought influenced recruitment were generated and discussed. The group leader had an outline of content areas to be addressed, and sample questions were available as prompts, although these seldom were necessary to stimulate discussions (see the examples above).
The observer (J.R.W.) provided a summary of the discussion prior to a second confirmatory phase. This second phase sought input from the groups on the relative importance of all the identified factors potentially influential on patient accrual (see Table 1). This list of factors was organized into physician factors, patient factors, and CRA-based factors. Within each of these groups, there were general factors, trial specific factors, and encounter specific factors. The list included factors that were identified previously in the medical literature as well as all of the factors that were newly identified by the focus groups. All factors were ranked on a three-point scale ranging from very important, to somewhat important, to of little importance in terms of influencing trial accrual.
|Clinician versus researcher perspective|
|Impression of impact on patient relations|
|Comfort discussing uncertainty|
|Role as principle investigator|
|Impression of trial's scientific merit|
|Success of standard therapy|
|Impression of trial's toxicity|
|Strength of recommendation|
|General attitudes regarding research|
|Patient's sense of personal benefit|
|Patient's expectations of standard therapy|
|Opinions of physician surrogates|
|Patient's impression of toxicity|
|Patient's impression of time commitment|
|Opinion of family and friends and other support|
|Presence of a placebo arm|
|Source of learning of trial availability|
|Patient's sense of strength of physician recommendation|
|Patient's sense of strength of CRA's recommendation|
|Impression of recruiter's personality|
|Success of information transfer|
|Adequate time for decision making|
|CRA's confidence with study background|
|CRA's impression of scientific merit|
|CRA's impression of toxicity|
|Strength of CRA's recommendation|
|Adequate time to obtain consent|
Audiotapes were reviewed subsequently and summarized. Summary notes were generated and coded independently by the researchers (D.C. and J.R.W.). Codes that described aspects of more comprehensive categories were combined through a process of consensus, employing intercoder triangulation.23 Because no new content areas were revealed with the second focus group, no further focus groups were organized.
All invited CRAs attended their respective focus groups. The first group included five nurses and two clinical data managers, and the second focus group included five nurses and one data manager. All participants were from the Clinical Trials Department of the HRCC. Each focus group discussion lasted just over 1 hour.
All members of the department's staff complete person-based orientation in which approaches to issues (e.g., the concept of randomization) are reviewed. Many have completed workshops and courses dealing with the complexities of clinical research. All staff members had independent experience with recruitment to Phase III clinical trials. Within the two focus groups, the level of this experience ranged from 1 year to 12 years, with a mean of > 3 years. Typically, at the HRCC, physicians will discuss with potential patients the rational for a specific study and will outline the general requirements of the study. Clinical trials personnel are then asked to review the patient to ensure that eligibility criteria are met, to discuss the details of the study, and to obtain formal signed consent. In the majority of patients, signed consent is not obtained at the time of the first meeting.
The HRCC is large, academic, tertiary care cancer clinic involved in all phases of cancer research. The Clinical Trials Department, at this time, had a dedicated staff of 10 full-time equivalent (FTE) clinical trials nurses and 4 FTE data managers. The department works with a number of industry partners and cooperative groups, including the National Cancer Institute of Canada (NCIC) Clinical Trials Group, and the Radiation Therapy Oncology Group. Clinical trials-related activity can be summarized by averaging the calendar years 1999, 2000, and 2001 when, on average there were 38 Phase III studies and 19 Phase I or II studies open to accrual at any time. Although 67% of these active studies were Phase III trials by design, approximately 727 of 953 patients (76%) who were enrolled on studies during this period were entered into Phase III studies. The CRAs successfully accrued these 727 patients after formally approaching 1308 patients, for a success ratio of 56%. This is slightly below the 64% success rate achieved for early phase studies, in which 353 patients were approached to accrue 226 patients. Of the average 38 active Phase III studies, cooperative groups supported 31 studies, and 7 studies were supported by industry. Success with accrual was slightly higher in the industry studies, with 114 of 178 of approached patients (64%) agreeing to entry compared with 613 of 1130 approached patients (54%) agreeing to entry for cooperative group studies. There was an average of seven placebo-controlled Phase III studies active at any time: Support for these studies was split evenly between industry and cooperative groups. Accrual success to these studies was 66% overall, with 124 patients entered of 189 patients approached.
The focus group participants believed that the attitudes of the individual physicians and patients influenced success with trial recruitment, as suggested in the medical literature.
The groups believed that an enthusiastic physician with an ability to communicate in a fashion that was receptive to the needs of the patient, and, specifically, with an ability to answer questions and to provide a sound rationale for a specific study, lead to enhanced prospects of recruitment. It was felt that such enthusiasm was more likely to be found in physicians with a vested interest in the conduct of the study, e.g., the local principal investigator.
At times, physicians were seen as barriers to recruitment. Numerous examples were shared of physicians who did not want their patients approached for studies that they themselves were not enthusiastic to support. It was suggested that a personal interest in research was required to go that extra mile, specifically referring to the consistency of identifying and approaching patients about entering a study. CRAs felt that physicians set the stage for them, an important point because patients tend to make up their minds quickly.
Patient factors that the focus groups believed had an influence on the success of recruitment also were identified easily. They included the source from which study availability was established: For instance, CRAs observed that, when patients learn of a study from an outside source, such as the local newspaper, they have more trust in the information. CRAs believed they had more difficulty successfully recruiting patients to trials with a placebo arm, with patients often having the preconceived notion that placebo-controlled studies are not good studies to enter. Patients with more extensive disease were more likely to enter any study that gave the hope of extending life; CRAs observed that such patients, in general, were more willing to try new therapies. Patients with few available treatment options were more inclined to enter an available study, whereas patients who thought their chances of potential benefit were small were more likely to decline study entry. The CRAs also suggested that a patient's ethnic or cultural background was a potential factor in the success of recruitment; for instance, it was reported that patients of more Eastern European origin are more likely to do whatever is suggested. The CRAs also felt that a patient's impression of their physician's enthusiasm was important in the decision-making process, because CRAs believe that patients think it must be a good study if the physician thinks it is good.
More unique to the process of understanding the factors influencing recruitment was the CRAs' sense of their own impact on the process. The CRAs believed that their actions also had potential as either a positive influence or a negative influence on clinical trial recruitment. Many of the CRAs tried to remain neutral with respect to making a recommendation to patients who were considering entry into a given study. However, there was widespread agreement that CRAs tended to size up patients, and that, when they had a patient that may be considered a good candidate, they may try just a bit harder. In this context, a good patient typically is in better overall health and appears more willing to be compliant with study requirements. Such a patient may be more likely to receive a follow-up telephone call to encourage questions and to seek a decision regarding study recruitment.
The major role of the CRA was seen as one of information transfer, and CRAs believed that both the content and the style of information delivery were important predictors of recruitment success. They felt that their own impressions of the scientific merit and overall importance of the study had an impact on this component of their performance.
Information transfer was related to the full disclosure of study issues. In general, CRAs felt that recruitment was more successful when they honestly and completely presented the pros and cons of study entry to the patient. CRAs walked the patients through what they might expect by agreeing to enter the study. This information typically included the potential toxicities, the extra time commitment required by the patient for tests and questionnaires, and the follow-up requirements of the study. This attempt to educate patients was seen as an important role. Some felt that presentations that used complementary multimedia, such as laminated display boards and anatomic teaching models, also enhanced their success at recruitment. Questions from patients are encouraged to facilitate decision-making.
The supportive aspect of this information exchange related to the way in which content was reviewed. The CRAs agreed that it is important to make a good first impression, to demonstrate that you care by sitting down, engaging with eye contact, and appearing to have plenty of time. Attempts were made to personalize the information by detailing the patient's disease status and discussing eligibility criteria. CRAs felt that, if they appeared to be informed about a study, it helped to create a bond of trust, and, by being relaxed and confident with the study information, they believed they helped to alleviate patient fears. CRAs agreed that it is important to create a setting in which questions are asked freely and issues are clarified. They also felt that adequate time to support this process was necessary.
The necessity of an empathetic approach was emphasized repeatedly. Some patients are informed of their underlying diagnosis and are given detailed prognostic information on the same day that they are approached to consider entering a Phase III study. Many CRAs felt this was an overwhelming experience for the patient, and many patients in this situation were encouraged to take home the consent form for review. CRAs said they often tried to include family members in the discussions and to answer their questions, trying to bring them on board in the hopes that accrual would be optimized. The relation that develops with patients is leveraged, in that patients are aware that the CRA who is obtaining consent likely will be looking after them through at least the active phase of the clinical trial. Therefore, if a good impression is made, the patient may be more likely to join the study to ensure ongoing care with that specific nurse.
Despite the recognized influence of the physician on decision-making, the research associates felt that their role was important and was in no way diminished. It was recognized that involved physicians likely influenced patient's impressions in a more direct fashion, whereas the CRAs spent more quality time with the patients to help them make quality decisions.
In the confirmatory phase of the focus group meeting, the group was presented with the developed list of potential physician factors, patient factors, and CRA-based factors (see Table 1). The group was asked to consider whether there they thought each of the listed factors was very important, somewhat important, or of little importance. Consensus in the group usually was achieved quickly. Very few of the items were rated of little importance. The factors that were very important for both groups are presented in Table 2.
|Role as principle investigator|
|Impression of trial's scientific merit|
|Impression of trial's toxicity|
|Patient's sense of personal benefit|
|Opinion of family and friends and other supports|
|Patient's sense of strength of physician recommendation|
|Patient's impression of recruiter's personality|
|Success of information transfer|
|CRA's confidence with study background|
|CRA's impression of scientific merit|
A patient's decision to enter a clinical trial likely is influenced by a number of factors, many of which have been established from the perspectives of physicians and patients. The central role of the CRA has not been well recognized in the conduct of such research. It would appear to be an area that deserves more formal assessment, because the current study suggests at least the potential to influence patient decisions. Undoubtedly, this potential for impact is dependent on the level of involvement the CRA has with the recruitment process. In our center, CRAs have an important, if not critical role providing the details of specific clinical trial information. Our local policy is too ensure that consent is obtained formally by the respective CRA and, specifically, not by the responsible physician. This central role affords the CRA a tremendous opportunity to develop insight into the process of clinical trial recruitment. CRAs invariably work with a number of physicians for any given study, and most have a number of Phase III studies active at any given time.
The CRAs clearly suggested that physician communication skills were important to the success of recruitment. The physician variability they witness appears to be more an issue of the motivation to communicate well, more than the need to acquire underlying communication skills. Having a vested interest in a trial appears to afford such motivation. This differs somewhat from the recommendations of many authors, who have suggested communication workshops and specific training for physicians who must discuss recruitment into clinical trials with patients.27–29 Unfortunately, the results of such communication workshops have not been consistent.30 For the relatively large group of academic oncologists at the HRCC who are involved in clinical research, communication skills may be relatively homogeneous. Motivating the consistent use of these possibly underutilized skills is a much more taunting task, and this issue likely relates to previous arguments suggesting that successful accrual to clinical trials requires extra time and commitment.16, 31
The CRAs felt even more convinced that their own communication skills were important to the success of recruitment. These skills were seen as key to ensuring high levels of information transfer. It is interesting to note that the study by Aaronson et al. that tested the use of an extra nursing call demonstrated improved information transfer and decreased anxiety, although the intervention did not have an impact on accrual.10 Perhaps our CRAs' impression of the importance of information transfer was misguided as a factor that actually influenced accrual and, more correctly, simply improved the process of informed consent. Patients may be informed better and may be well educated about a specific clinical trial when the CRA has better communication skills, but this may or may not have an impact on their ultimate decision regarding study entry.
In our focus groups the CRAs reported that their impressions of the scientific merit of a study was felt to be an important factor in influencing trial entry. They also suggested that the physician's impression was important. In many situations, it is likely that these impressions of merit are correlated strongly, at least between the local principle investigator and the primary CRA of the trial.
Although the CRAs felt they maintained neutrality with respect to making a recommendation to patients who were considering entry into a given trial, they believed physicians more routinely made such recommendations. The importance of such a recommendation to enter a study has been reported variably in the literature. Through a reported series of personal interviews, patients have suggested a high level of importance for physician recommendations.21 When Siminoff et al. actually measured the strength of both the physician's recommendation and the patient's sense of the strength of the physician's recommendation to enter a clinical trial, there was little correlation between them or with eventual trial entry.32 Consistent with this variability, in the factor-ranking phase of the discussions, it was not the strength of the physician's recommendation or the strength of the CRA's recommendation that was ranked very important: it was the patient's impression of the strength of the physician's recommendation. This may be a subtle difference, but it is a significant difference from the CRA's perspective.
There were a number of other new issues raised within the focus groups that were not ranked subsequently as very important to the success of trials recruitment. This included a number of patient factors, such as toxicity, time commitment, presence of a placebo arm, source of learning of trial availability, patients' sense of the strength of the CRA's recommendation, and the adequacy of time to make a decision. Likewise, CRA factors, including their impression of trial toxicity, the strength of their recommendation, and the adequacy of time to obtain consent, were not ranked very important. This should not be surprising, however, because the intent of the exploratory phase was broad in scope, raising all issues with potential importance, whereas the confirmatory phase forced a more critical assessment of the factors with the intent of establishing some relative importance.
The issue of randomization itself was not raised as a potential factor over the course of the focus group discussions. By design of the focus groups, the topic of randomization would not be an influential factor, because, by definition it would be an element of all Phase III studies. Still, some discussion of the topic may have been expected in relation to earlier phase studies if local data supported the notion that success with accrual was better proportionally. It is also likely that the local approach to discussing the issue is fairly consistent given the standard wording available on NCIC consent forms, which is our single largest sponsor of Phase III studies.
Our focus groups are only the start of a needed, more structured assessment of the role of the CRA in clinical trial accrual. It is premature to make changes to the process of consent or to make recommendations suggesting the optimal circumstances under which to discuss clinical trials entry. It is important to recognize that these focus groups provide an opportunity for the nurses to say what they do or what they think they do rather than providing any objective measure of what they actually do. There is obviously the risk of self-interest in believing that they are central to some aspect of the communicative process and that they have the potential to influence clinical trial accrual. There is the possibility that the impressions of the CRAs are not accurate. Certainly, the issue of the difficulty with placebo-controlled studies that was raised in the exploratory phase of the discussions was not supported with local data. In fact, it even suggested the opposite: that placebo studies had slightly higher proportions of approached patients actually agree to study entry. In ranking the factors, the placebo issue was not ranked as very important. Our results also may be limited by a lack of generalizability to other clinical research settings. It would be useful to organize focus groups with CRAs in other cancer centers to establish the consistency of the voiced opinions.
A greater understanding of the relative importance of physician and patient factors and, possibly, CRA factors and all of their interactions on influencing the process of clinical trial decision-making is important. Most of the potential factors raised in the current focus groups need to be studied and validated systematically, ideally in the context of real-time consent discussions and patient decisions. We plan to follow this work by organizing focus groups with physicians and patients to ensure complete capture of all factors that potentially influence clinical trial accrual. Then, we hope to develop a comprehensive survey that will be administered to the patients, physicians, and CRAs after a patient's decision to enter a clinical trial is made. The results will help provide the necessary focus with which to devise ethical and supportive strategies designed to optimize patient recruitment. We also currently are involved in a multicenter feasibility study that is tape recording consent discussions between patients, physicians, and CRAs.
In general, there is limited research exploring the optimization of recruitment to Phase III studies, and few interventions have been designed to have a positive on impact the recruitment of patients to clinical studies. The myriad of factors that potentially influence the decision to enter a clinical trial has made establishing an interventional focus difficult. Of course, an important ethical balance must be recognized if it is found that the attitudes and beliefs of health care workers are influential factors in the decisions of patients who are approached to enter randomized trials. The profound trust that patients place in researchers and the research enterprise must be acknowledged. The enthusiastic attempts of trial recruitment always must be balanced with a realistic portrayal of the risks and benefits of study interventions.
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