Clinical Research Associates have assumed an expanding role in the conduct and design of clinical trial protocols. The perspectives of these health professionals are presented in the referenced articles, and implications for clinical trials are discussed.
See also pages 1577–83 and 1584–91.
Clinical trials are an essential component of modern health care. The results of randomized clinical trials increasingly define current standards of care. Potential new interventions, increasingly arising from basic research, require rigorous evaluation before their role in improving health outcomes is determined. Low proportions of cancer patients are recruited into clinical trials.
Until the past few years, independent clinical investigators commonly initiated clinical trials, recruited patients, and interpreted and reported the results. More recently, there has been a great increase in the size of clinical trials to ensure that results are reliable and are not influenced by the play of chance.1 Moreover, an increasing proportion of clinical trials are now performed to achieve regulatory approval of a drug or device. This industrialization of clinical research, and especially of clinical trials, has led to the emergence of Contract Research Organizations (CROs) and Clinical Research Associates (CRAs) as increasingly important players in the conduct of clinical trials.2
Many hospitals now employ nurses, pharmacists, and data managers to facilitate the conduct of clinical trials. Some CRAs based in the hospital may be employed directly by clinical trial sponsors to optimize the collection of data and to facilitate the conduct of a trial. Other CRAs are employed by hospitals with the goal of managing the clinical trial process, including submissions to ethics committees, patient recruitment, and monitoring the data collection and follow-up of patients on trials. In North America, a Society of Clinical Research Associates (www.socra.org) has formed in the past 10 years that is dedicated to the continuing education, development, and certification of clinical research professionals. Many CRAs are employed by CROs to streamline the conduct of clinical trials and to gather the increasing clinical data required by regulatory authorities.
These developments and others have prompted members of the International Committee of Medical Journal Editors to publish a statement expressing their concern about the current environment in which some clinical research is conceived, study participants are recruited, and data are analyzed and reported.3 Moreover, the Association of American Medical Colleges has recently approved a report entitled Protecting Subjects, Preserving Trust, Promoting Progress—Policy and Guidelines for the Oversight of Individual Financial Interests in Human Subjects Research.4 Together, these reports raise concerns about the conduct of clinical research, about the competing status of clinician/entrepreneur and treating physician, and about the management of institutional conflicts of interest in the case of research involving human participants.
Patients participate in clinical trials for a variety of reasons. Patients may perceive benefits, such as earlier access to new treatment and more careful monitoring, as part of a trial. However, there has been minimal research examining the relation between understanding a clinical trial and willingness to participate in a clinical trial. Patients' understanding of the experimental aspect of the trial in which they are enrolled and of the treatment they will receive frequently is limited. The complex language and excessive detail of some trial patient information statements and consent forms may confuse rather than enhance patient understanding of what is proposed.5 Edwards et al.6 reported that many patients participated in clinical trials out of self-interest. Moreover, physicians sometimes seemed to have been aware that patients may not have understood fully what was going on. Many patients on that study viewed informed consent as little more than a ritual.
Llewellyn-Thomas et al.7 compared different strategies of presenting information about a clinical trial and reported that patients who demonstrated greater knowledge about the trial were less willing to participate in it. Ellis et al.8 surveyed 545 women at a breast clinic for screening or diagnostic assessment or with newly diagnosed breast carcinoma about their knowledge, attitude toward, and willingness to participate in randomized trials of breast cancer treatment. Women who had a better understanding of issues relevant to clinical trials had more favorable attitudes toward randomized trials and were more willing to consider participation in a clinical trial.
The Quality of Informed Consent questionnaire (QuIC) is an important development in the investigation of clinical trial recruitment approaches.9 The QuIC was designed to measure participant's actual (objective) and perceived (subjective) understanding of cancer clinical trials. Test-retest reliability and face and content validity were excellent, and the questionnaire took an average of 7.2 minutes to complete.
Joffe et al.10 recently reported on the use of the QuIC to measure the quality of understanding among cancer clinical trial participants in Boston who had signed a clinical trial consent form a median of 16 days earlier. Ninety percent of clinical trial participants were satisfied with the informed consent process. Almost half of consent discussions lasted 1 hour. The consent form was signed a median of 6 days after the initial discussion about the trial, and only 28% of participants signed at the first consultation. There was considerable variation in the proportion of correct answers across individual questions in the QuIC. Seventy percent of participants did not recognize that the treatment being researched was not proven to be the best for their disease, and only 28.6% of participants appreciated that they may not receive direct medical benefit from participation.
In this issue of Cancer, two articles from Canada present the perspective of CRAs concerning the development, recruitment, and conduct of cancer clinical trials. Both articles indicate that CRAs in Ontario have a central role in the recruitment of cancer patients to clinical trials and formally obtain a signature indicating informed consent to enter the clinical trial. It seems the CRAs usually are not present during the consultation when the oncologist introduces the notion of clinical trial participation. However, the CRAs clearly have a major role in ensuring that eligibility criteria are met, in describing the relevant clinical trial, and in assisting the patient to come to an informed decision.
Wright et al.11 present the context of the Hamilton Regional Cancer Center. Those authors report that about two-thirds of trials were Phase III by design and that three-quarters of 953 patients who were enrolled over a 3-year period were entered into Phase III trials. The CRAs successfully recruited 56% of patients who were approached for Phase III clinical trials.
The results of two focus groups of CRAs from the Hamilton Regional Cancer Center are presented. The CRAs acknowledged physician and patient factors that were influential in recruitment to clinical trials and identified ways in which the CRA influenced the recruitment process. Their major role was seen as one of information transfer about the particular clinical trial. CRAs felt that recruitment was more successful if they presented the pros and cons of trial entry, and this process required adequate and quality time. The CRAs felt their own impression of the scientific merit and overall importance of the trial influenced the outcome of discussion with patients. Wright et al. mention they are tape recording consent discussions between patients, physicians, and CRAs. The results of this ongoing research are awaited with great interest.
Grunfeld et al.12 report the outcome of focus groups that were held at six of the eight tertiary referral cancer centers in Ontario seeking the views of CRAs on barriers and facilitators to accrual to cancer clinical trials. The CRAs identified system factors imposed by the sponsor and/or the regulatory authorities as issues that had the greatest impact on their ability to accrue patients. Patients were seen as more knowledgeable about clinical trials than in the past. They noted that media coverage had a significant impact on trial accrual. Financial support of pharmaceutical companies also helped accrual through compensation for extra expenses incurred.
Together, these reports add a new perspective to the investigation of factors that influence recruitment of patients to cancer clinical trials. The appropriate training of CRAs who negotiate consent to clinical trial participation merits review, particularly if the CRA is not present when the oncologist proposes clinical trial entry as a treatment option.
Previous reports have identified the importance of physician behaviors on clinical trial accrual. Albrecht et al.13 videotaped trial consent consultations to explore the relation between oncologists' behaviors and accrual to clinical trials. Patients were more likely to accrue to clinical trials when their oncologist verbally presented items that normally are included in an informed consent document and when the oncologist communicated in a reflective, patient-centered, supportive, and responsive manner. Discussion of the benefits of the protocol, the possible side effects, and addressing patient concerns all were associated with patient decisions to accrue to a trial.
Jenkins et al.14 analyzed 82 audiotaped discussions in the United Kingdom in which consent was being sought by physicians for participation in a randomized clinical trial of cancer treatments. In most consultations, the concept of the trial was introduced by describing uncertainty about treatment decisions, and all physicians used the word trial, but the term randomization was used in only 62% of consultations. Patient information leaflets were not given to 28% of patients, and patient understanding was never checked in 83% of patients. The median duration of consent interviews was less than 15 minutes, and most patients signed the consent document at the first consultation when the clinical trial was discussed.
Butow et al. analyzed 26 tape recordings of oncology consultations in which informed consent to a clinical trial was sought15 and presented the results to a group of interested parties. The consensus opinion of consumers, ethicists, linguists, medical and radiation oncologists, psychologists, and other health professionals was that, when entry in a clinical trial was being proposed, the usual/standard treatment should be presented first, followed by a discussion addressing patient concerns and clearly outlining physician attitudes to this treatment. Subsequently, the clinical trial should be introduced as another treatment option. It is far from certain that this approach is adopted in many institutions that recruit patients to clinical trials. The presence of the clinical trial CRA during these discussions may help ensure that the patient is aware of the standard (nontrial) treatment in their situation.
Verheggen et al.16 interviewed 198 patients who had been approached for clinical trial participation at the University Hospital in Maastricht and 32 clinicians who were recruiting patients to trials. Of the patients interviewed, 86.9% had decided to participate in a clinical trial. That study analyzed how patients who were invited to participate in a clinical trial perceived the quality of information disclosure. Patients were quite satisfied with the oral and written information disclosure. Their trust in medical experiments, their belief in the integrity of physicians, and their interest in medical affairs all had an impact on the way patients perceived information disclosure. These findings underpin recent concerns about physician and institutional competing and/or conflicts of interest in the promotion of clinical trials.4 Verheggen et al. proposed an informed decision-making check list to improve the quality of the informed consent procedure. Only six of the clinicians interviewed perceived the signed informed consent as an adequate indicator of patient understanding.
Fleissig et al.17 recently reported the results from an intervention study to improve communication during consultations about randomized trials of cancer therapy. Those authors hypothesized that providing oncologists with the results of patient questionnaires describing their attitudes toward clinical trials and their preferences for information prior to a discussion about trial participation would increase physician and patient satisfaction and would improve recruitment. Physician knowledge of the patient's questionnaire responses prior to consultation had no impact on recruitment or physician and patient satisfaction. However, responses to the Attitudes to Trials questionnaire were highly predictive of patients' decisions to participate in randomized clinical trials. Sawka and Pritchard18 reviewed this and other studies that investigated techniques for enhancing the provision of information about randomized clinical trials and concluded that patient understanding usually was enhanced, but accrual was not.
The perspectives of CRAs about clinical trial accrual add a new dimension to our knowledge of the variety of factors that have an impact on patients' decisions to participate in clinical trials. In Australia, CRAs normally are not responsible for obtaining consent, but they play an increasing role in information provision. The pros and cons of a third party becoming involved in gaining consent to clinical trial participation merits wide discussion. The QuIC is an appropriate instrument to monitor patients' objective and subjective understanding of the clinical trials on which they have been recruited, and audiotapes of consent discussions will provide insights into the communication factors that have an impact on obtaining consent.