Sac. .Sci. Med.

Printed in

Vol.

Great

33, No.

5, pp. 569-577,

0277-9536191 53.00+ 0.00 Pergamon Press plc

1991

Britain

ACCRUAL

TO CANCER CLINICAL TRIALS: DIRECTIONS FROM THE RESEARCH LITERATURE CAROLYN COOK GOTAY*

National Cancer Institute, Division of C&X

Prevention and Control, Bethesda, MD 20892. U.S.A.

Abstract-Although randomized clinical trials are the predominant method used to evaluate cancer therapies, only a small proportion of potential participants actually enter onto trials. This paper analyzes the research literature on accrual to cancer therapy trials. The research shows that nonparticipation is influenced by physician and patient variables, as well as by characteristics of the specific protocols. Trials design, especially pre-existing treatment preferences, pose significant problems for physicians and patients. Intervention strategies have focused on alternate trial designs, improving the informed consent process, and increasing knowledge about trials. Additional research should focus on the perspectives of patients who accept and decline trial participation and on interventions designed to affect accrual. Future studies need to be sensitive to patient quality of life considerations as well as practical and ethical issues. Key

words-clinical

trials, neoplasms, patient participation,

INTRODUCTION Advances in cancer treatment can only be achieved through subjecting promising approaches to rigorous scientific testing. The Phase III clinical trial, wherein patients are randomly assigned to one of two or more treatment conditions and outcomes are assessed on a prospective basis, is the predominant research design for identifying significant differences among cancer therapies. However, only a small proportion of cancer patients participate in clinical trials research; for example, fewer than 26,000 of the estimated one million annual new cancer cases in the United States enroll on National Cancer Institute-sponsored clinical trials [I]. Low and slow accrual mean that answers to research questions are long in coming, and potentially life-saving treatments may be delayed in development and application. Hence, identification of barriers to optimal clinical trial accrual, as well as the development of strategies to surmount such obstacles, are of critical importance. The purpose of this paper is to provide a critical review of the research literature on variables associated with accrual to cancer treatment clinical trials. The accrual process has been conceptualized as a multifaceted process, with characteristics of physicians, patients, and trial design all having an influence on trial participation. Table 1 provides an overview of variables which will be discussed. These include some common to physicians and patients: correlates of trial participation (e.g. demographic characteristics), attitudes towards trials (e.g. do individuals have a positive appraisal of clinical trials research?), and motivations for participation (e.g. why do physicians make referrals to trials and why do patients choose to enroll?); and variables related to the trials design and process (e.g. informed consent).

Address correspondence to

Dr Carolyn Cook Gotay, the EMMES Corporation, 11325 Seven Locks Road, Suite 214, Potomac, MD 20854, U.S.A.

randomized controlled trials

Interventions that have been reported for enhancing trials participation are reviewed, as well as implications for future research. WHO GETS ONTO TRIALS?

To understand the implications of observations like ‘fewer than 3% of cancer patients enter onto clinical trials,’ additional information is required; for example, how many of the 97% of patients who do not participate in trials would be medically appropriate candidates? Few efforts have been made to collect such data. However, Table 2 is based on the findings from such unusual studies; all of these used chart audits or ongoing patient logs to describe a broader population of cancer patients [2-81. This approach allows the calculation of the proportion of patients who meet the entry criteria for trial participation (i.e. eligible patients) out of the larger patient group, as well as the proportion of these eligible patients who actually end up participating in the clinical trial. These studies differ in a number of ways, including how the study populations were defined: for example, all patients with specified sites [3,4,7, 81 or sites and Table I. Variables associated with accrual to cancer treatment clinical trials Physician

choracrerisfics

Demographic correlates of referral to trials Attitudes towards clinical trials Motivations for referral Parienr

characteristics

Demographic correlates of trial participation Attitudes towards clinical trials Motivations for participation Trial

characferistics

Availability of trial Patient ehgtbthty Trial design Informed consent procedures Mode of presentation of information

CAROLYN Coon GOTAY

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Table 2. Records-based % Eligible’

studies of referrals % Entered

lo clinical Reasons

Doctor

trials for non-entry Patient

(%)d

Study’

N

Logistics

Other

Lee (1980) McCusker (1982) Study 1 Study 2 Begg (1983) Lee (1983) Martin (1984) Lucas ( 1984) Hunter (1987)

653

I2

53

94

6

NA

NA

454 767 3534 II03 2687 57 44156

33 42 34 24 43 44 22

75 20 47 47 38 0 33

50 NA 52 85 68 64 50

21 NA I9 I5 32 32 32

13 NA I7 NA NA 0 IO

II NA I2 NA NA I2 7

‘Comparable percentages across studies were computed, based on information provided in the articles; studies bIncludes patients for whom a protocol was available and who met eligibility requirements. ‘Indicates percentage of eligible patients who enrered onto protocol. ‘Indicates percentage of eligible patients not entered onto protocol for reason named.

stages for which trials were available [2]; or all patients seen at given institutions [5,6]. The resultant populations ranged from a large group of newlydiagnosed patients being considered for a variety of treatment protocols [2], to a small sample for a trial of local tumor excision vs simple mastectomy for early-stage breast cancer [7]. Therefore, the percentages listed in Table 2 should be interpreted with caution. However, what is striking is that across the board, fewer than half of the available patients were eligible for a particular trial; of these, considerably smaller numbers were actually entered onto study. This implies that both eligibility requirements and other variables play important roles in explaining why patients do not enter clinical trials. Table 2 also reports reasons for failure to accrue eligible patients onto the trial. Since this information was based on limited information available in patient charts or logs, only broad categories of reasons were presented in the research reports. It can be seen that, overall, physician-related variables were the major factor related to failure to accrue patients in these studies. Physician factors included medical considerations other than those explicitly listed in the protocol eligibility requirements [5-81, as well as physician preference for a specific treatment option [2,5]; sometimes the specific reason why a physician did not approach an eligible patient for participation was not specified [3]. Patient refusal to participate (due to, e.g. concern about randomization (2,7] and preference for a specific treatment option [7]) and logistical concerns (e.g. patients moving out of town, distance between the patient’s home and the treatment setting) also were frequently-cited. Additional research has provided additional information that enlarges on this general taxonomy. PHYSICIAN-RELATED

VARIABLES

listed by first author.

clinical trials research, the Community Oncology Program [IO].

Clinical

Physician attitudes towards clinical trials

Taylor et al. examined physician perspectives in two areas that had been previously identified [I 1, 121 as barriers to clinical trial participation: informed consent, and the role of the physician. Regarding informed consent, 170 breast cancer specialists from eight countries which varied in informed consent legislation were surveyed [13, 141;overall, about twothirds of the physicians placed at least ‘some of their patients on clinical trials. Respondents completed a self-administered questionnaire plus an hour structured personal interview. The results indicated that obtaining informed consent was a significant problem for some physicians, and that most received little training in how to accomplish this. Findings were not qualified by age or specialty. Physician role orientation was investigated [IS] in 484 cancer specialists around the world (out of a possible total of 556); because this was a convenience sample, the population this represents is unclear. The respondents completed a mailed questionnaire containing 30 yes-no questions regarding their attitudes towards research and clinical practice. The aim of the questionnaire was to ascertain the extent to which physicians ascribed to a ‘therapist’ vs ‘experimenter’ philosophy. Results showed that few physicians could be categorized as extreme examples of either pole; most (78%) reflected a blend of ‘therapist’ and ‘experimenter’ attitudes towards their roles. Nonetheless, there was considerable variability in views about uncertainty and decision-making allegiance to individual versus aggregates of patients, the relationship between patient care and research, and the priority of research within the practice. Orientation did not vary with age, specialty, or country.

Correlates of trial parbcipation

Motivation for participation

Several studies have investigated correlates in referral patterns. Increased accrual was found according to: location of practice (i.e. hospital clinics and group practices had higher accrual rates than individual private practices); board certification [9]; high proportion of practice consisting of cancer patients [9]; specialty (internists over surgeons) [4]; training in a setting with a cancer center [4]; and participation in a National Cancer Institute program designed to increase the participation of community physicians in

Several physician surveys regarding reasons for non-participation in trials have been conducted. One study [13, 141 asked clinical cooperative trials group investigators why a clinical trial comparing segmental mastectomy and total mastectomy had encountered unexpected problems in patient accrual. Of the 91 respondents (out of a possible 94) who responded to a mailed questionnaire, 25 had enrolled all their eligible patients on the trial. Of the remaining 66 physicians, the most frequent reason for non-referral

Accrual to cancer clinical trials was concern about the impact of randomized clinical trials on the doctor-patient relationship (cited by 73%). Other frequently mentioned issues included problems in obtaining informed consent (38%), disliking discussions of uncertainty (23%), and conflict between clinician and scientist roles (18%). A small study [9] of 23 cancer physicians is noteworthy in representing all of the medical oncologists and hematologists in the state of Maine. The most common reason for participating in clinical trials was to advance cancer medicine. The use of randomization did not constitute a serious impediment to enrolling patients for these physicians. Travel time was the most frequently-mentioned patient characteristic associated with non-referral. Toxicity was the most commonly-cited protocol characteristics associated with non-enrollment. No association was found between physician variables and patterns of participation (although the number of cases in this study allow little statistical power to detect such a relationship). Langley et al. [I61 assessed the views of several professionals involved in the trials process: oncologists (n = 52), clinical trials and senior staff nurses (n = 26), and family physicians (n = 23); this represented all ‘available’ personnel. Respondents participated in two studies: an interview about various reasons influencing trial entry; and a rating of eight hypothetical clinical scenarios that systematically varied with respect to quality of design, impact on patient-physician rapport, and ease of obtaining informed consent. Regarding reasons for trial entry, oncologists and nurses both ranked the “need for more scientific information about the disease” first, while family physicians were most likely to endorse “opportunity to improve regular patient care.” The scenario ratings showed that scientific design was most important for oncologists and family physicians, with nurses rating design and impact on physician-patient relationship of equal importance; consent issues were relatively unimportant in all groups. A physician survey, part of which focused on clinical trials participation, was conducted as part of a larger study to evaluate the impact of the National Cancer Institute (NCI) Community Clinical Oncology Program (CCOP) [IO]. One aim of the CCOP was to increase the participation of community physicians in clinical trials research. Three groups of physicians in twelve Iocations across the United States took part in telephone interviews: physicians participating in the CCOP (n = 148); non-CCOP physicians in medical specialties that frequently treat cancer (n = 505); and other specialties (n = 1787). Results indicated that knowledge about trials, referring, and enrolling patients for trials were all highest among CCOP physicians, followed by cancer-relevant specialties, and then by other physicians; e.g. the proportions enrolling cancer patients on clinical trials over the past year were 70%, 58%, and 30% respectively. Among physicians who had enrolled at least some patients, the most prevalent reason for not enrolling others among all three groups was patient/family objections, cited by 41% overall. Other frequentlymentioned deterrents were: patient ineligibility (24%); other physicians making the referrals (24%);

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and patient status (20%). Among the CCOP physicians, several other reasons were also named by at least one-fifth of respondents: poor quality of available clinical trials (24%); transportation problems (23%); their preference for their own treatment regimen (20%). PATIENT-RELATED

FACTORS

Correlates of lrial participation

Although results of studies which investigated correlates of patient entry onto protocol were not completely consistent (not surprisingly, given the varying protocols, correlates, and populations), certain correlates emerged. Patients entered onto protocol were generally in better condition: they tended to be younger [2,8]; although age made no difference in Ref. [4], heavier [8], had better performance status [8], and had a higher socioeconomic status [4]. On the other hand, no differences were found according to race [3,4,6], sex [38], marital status [4], religion [4], or Medicaid coverage [4]. Attitudes towards clinical trials amongpatients and the public

Several public opinon surveys demonstrate general support for patient participation in clinical research. Self-administered questionnaires of attitudes of American cancer patients (n = 104) cardiology patients (n = 84), and members of the general public (n = 107) regarding clinical trials found no difference in willingness to participate in trials on the basis of age, sex, or subgroup [17]. A large majority of respondents (71%) believed that patients should take part in randomized clinical trials, while II % indicated that they would not personally participate. The most frequently-reported reason was to get the best care possible. Structured interviews with 114 outpatients in a Danish internal medicine clinic (181 showed that the vast majority of respondents (98%) approved of patient participation in clinical trials, and no differences were found according to socioeconomic status. these individuals also supported the need for patient informed consent. A survey [19] of 1022 persons (representative of the British population in terms of geography, sex, socioeconomic status, marital status, and occupation) focused on willingness to participate in four hypothetical clinical trials. About two-thirds of respondents said that they would take part in a hypothetical trial comparing standard treatment to a new therapy for either an unspecified chronic disease or early stage, curable cancer. Given two specific diseases and treatment outcomes (mastectomy versus lumpectomy for breast cancer, amputation versus bone graft for bone cancer), about 40% of respondents indicated a willingness to take part in a clinical trial. Younger people and those of higher socioeconomic status were less willing to participate; these groups were also more likely to express the wish for more information and greater patient participation in treatment decisions. Other studies have also shown that patient preferences vary with age and status. A questionnaire measuring preferences for information and hopeless-

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CAROLYN COOK CiOTAY

ness among 256 cancer patients found that younger patients wanted more information and a greater role in decision-making. The desire for more information and active involvement in care was correlated with less hopelessness, controlling for age, medical status, and other demographic variables [20]. A study [21] of 75 women with advanced breast cancer also showed youth and education were positively correlated with a willingness to challenge physician authority. The link between desire for participation in treatment decision making and less likelihood of trial participation was further supported by a recent study (221 which examined the preferences of colorectal cancer patients for enrolling in a hypothetical clinical trial. Thirty-five of the 60 patients reported that they would have declined trial entry. Compared to the patients who would have gone on trial, these ‘refusers’ wished to be actively involved in making decisions about their treatment; they were also less willing to accept short-term toxicity for gains in long-term survival. Motivations for participation

Only a few studies have asked patients why they did or did not choose to participate in clinical trials. Interviews with 144 cancer patients currently enrolled on Phase II or III clinical trials [23] indicated that the primary motivations for accepting treatment were beliefs that it would fight illness, trust in the physician, benefits seen to outweigh risks, belief that illness would get worse without this treatment, trust in the hospital, and the information provided by the physician; each of these reasons was endorsed by 86% or more of patients. In a study [24] of trial participation among patients who had completed a sarcoma clinical trial (n = 48) and those who had declined initial participation or dropped out of protocol treatment (n = 28), the most prevalent reasons for accepting treatment related to self-interest (e.g. desire for cure), while the primary reasons for non-participation related to the specific treatments under investigation in the trial. For patients eligible for an extremity soft-tissue protocol, where amputation was being contrasted to limb sparing surgery plus immunotherapy and/or chemotherapy, initial refusal was most frequent; whereas, for patients eligible for a head-neck-trunk soft tissue sarcoma protocol comparing the additional benefit of immunotherapy over limited surgery, radiation therapy and chemotherapy, nonparticipation was split between initial refusal to participate and later withdrawal from treatment. CHARACTERISTICS

OF THE PROTOCOL

Protocol availability

For a protocol to be available for an individual patient: (a) a clinical trial suitable to the patient’s disease must be ongoing; and (b) the physician must be aware of the protocol. Regarding the first condition, there appears to be no protocol ongoing for many patients; only 40% of more than 44,000 newlydiagnosed cancer patients in one study [2] had a protocol available for site and stage of disease. In some diseases that affect large numbers of patients, there may be a dearth of promising areas of scientific

inquiry. Physicians’ lack of awareness about clinical trial activity also certainly must make a contribution to low accrual (i.e. if a physician is not aware that a protocol is ongoing, it is unavailable to his/her patient), but how big a role this factor plays is not known. Patient eligibility

As previously noted and shown in Table 2, many patients do not satisfy the numerous specific criteria (e.g. one analysis of nine trials found an average of 23 exclusion criteria per study [25]) that are required to be eligible for a specific trial. DESIGN

No treatment arm designs

Trials with a ‘no treatment’ arm may pose particular difficulties for patients and physicians. Only one study has been identified that addressed this issue: an assessment of anxiety among 68 patients who had been randomly assigned to receive either adjuvant chemotherapy or observation following total or modified radical mastectomy for breast cancer [26]. These patients completed two standardized measures of anxiety before randomization and three times during the next year. No statistically significant differences were found between the two groups. One problem in generalizing these results is that they are based on patients who consented to randomization and, presumably, were prepared to accept no treatment; the refusal rates for the protocol are not reported, but it is likely that the people most apt to become anxious did not enroll in this trial. Treatment arms of unequal attractiveness

A clinical trial is conducted to determine if one treatment is superior, in the absence of evidence to favor one arm over another. However, both patients and physicians may have pre-existing preferences for a specific treatment. For example, a consecutive series of breast cancer patients treated between 1979 and 1987 found that all 153 had a preference for mastectomy or conservation treatment [27]. Several randomized studies of these two treatments have experienced great difficulty in accruing patients [7, 11, 12,281. Patient preferences for one of the study treatments (and their ability to obtain the desired treatment outside the context of the trial) appear to limit their willingness to take part in randomized trials. Physician preferences for particular study arms have also been documented. Mackillop and his colleagues (29,301 conducted a mailed survey of 118 physicians who treat pulmonary neoplasms regarding how they themselves would wish to be treated if they had lung cancer. While treatment recommendations varied according to case scenario, physicians had specific preferences and many would not consent to participate in some of the clinical trials currently ongoing. Moore et af. [31] conducted a similar study among 204 British and North American experts in genitourinary cancer; they found that substantial majorities of physicians would be unwilling to participate (or to recommend participation to their patients) in most of the six (actual ongoing) trials which were presented. Their major reason was preference for one

Accrual to cancer clinical trials

or the other of the treatment arms. Along similar lines, a recent study of 369 Canadian physicians [32] indicated that a wide range of treatment options for hypothetical breast cancer scenarios were judged to be preferred, acceptable, and unacceptable within the group. However, despite the diversity of recommendations, individual physicians were highly confident about their own choices; the authors refer to this phenomenon as ‘micro-certainty/macro-uncertainty.’ While these three studies assessed physicians’ hypothetical treatment decisions, a study of actual physician behavior yielded consistent results [33]. One hundred consecutive patient-physician interactions regarding decisions for adjuvant therapy in breast cancer were videotaped and analyzed. Communication about clinical trials was found to be ineffective in many cases; frequently, physicians recommended a regimen similar to the experimental treatment arm in ongoing studies. As the researchers point out, “physicians acted as if the trial question was answered. . . (which) suggests a serious lack of consensus on what questions to ask in clinical trials and whether or not these questions have been answered” [p. 11921. The process of informed consent

One distinctive feature of the research protocol for clinical trials is the requirement (in many countries) for the patient to give consent for participation, based on an informed decision. In most cases, patients need to sign a written document (often with legal overtones such as the requirement of a witness to the signature); this procedure clearly separates trials participation from everyday medical practice, and in fact, the process of obtaining informed consent was identified as a barrier by physicians. While a full review of the informed consent literature is beyond the scope of this paper, several studies are directly relevant to cancer clinical trials. The preponderance of evidence indicates that the ideals of fully informed consent are generally not fully achieved [34]. Major deficits in remembrance of the purpose, nature, and complications of treatment were identified in clinical trials patients (n = 200) one day after they had signed a consent form [35]. Despite this 96% said that the amount of information in the consent form was ‘just right’ or ‘too little,’ and three-quarters indicated that the consent information was important in helping them decide about treatment. A survey [23] of 144 cancer patients and 68 oncologists showed that while the consent form itself did not have a great influence, most patients (82%) felt that the form had the right amount of information and was not too technical (74%). In contrast, 79% of physicians judged the consent form to be either ‘much’ or ‘somewhat’ too technical. The most important reason for trials participation was the perceived attitude of the physician: 91% of patients believed that their physicians strongly wished them to participate. Regarding characteristics of the form, a study [21] that varied three levels of detail for 75 advanced breast cancer patients showed that most preferred longer, more detailed forms (although 20% preferred the briefest form); these preferences were not correlated with attitudes towards patient rights or physicians authority, socioeconomic variables (e.g. age,

573

education), nor with patient perceptions of stress, or willingness to accept treatment. About two-thirds or more patients in all groups remained unaware that the best treatment is unknown, even though this point was included in the forms. Scores of the ease of reading the forms showed that all were at the level of an academic magazine. This is consistent with a previous study [36] of surgical consent forms, which indicated that all of the forms studied were written at the upper-division undergraduate or graduate level. Prior to the enactment of regulations requiring written informed consent in Australia, 57 cancer patients being considered for clinical trials were randomly assigned to either total disclosure, accompanied by written consent; or an individualized approach, in which the consent process was at the discretion of each physician and patient [37]. Total disclosure resulted in better understanding of the treatment, side effects, and research aspects of the trial (even though more than half of patients in each group did not understand randomization), increased anxiety, and less willingness to agree to trial participation; when questionnaires were re-administered three to four weeks later, there were no differences between the groups, although the authors do not specify if the individualized group gained in knowledge or vice versa. More patients refused to accept trials participation in the total disclosure condition (5 vs 2); this difference was not statistically significant, although the small study size had little power to detect such a difference. A recent study examined how patient interpretation of the consent form would affect participation in a hypothetical clinical trial [38]. Of the 20 cancer outpatients who said that they would not wish to enroll in a trial of chemotherapy (out of a total sample of 50), 70% said that only information about the risks of treatment was relevant to their decision; the patients who were willing to take part focused on benefits and risks to a much greater extent. Overall, this study noted considerable misunderstanding of information presented in the consent form. Presentation of trial

The way that information is presented can make a difference in decision-making [39], including choices about clinical trial participation. Hypothetical scenarios for lung cancer treatment options were presented to ambulatory care patients (n = 491) and physicians (n = 424) [40]. Surgery was preferred over radiation therapy when: the treatments were specified (e.g. instead of Treatment A, the therapy was identified as surgery or radiation therapy); treatments were described in terms of life expectancy rather than cumulative probability (that is, the probability of surviving initial treatment, 1 year, and 5 years); and the scenario was framed in relation to the probability of living rather than the probability of dying. Fetting et al. [41] presented information to 282 female cancer patients about disease-free survival for a standard chemotherapy regimen either verbally (e.g. the treatment reduces the risk of recurrence) or numerically (e.g. 61% of patients experienced no recurrence). They found that the patients were more likely to choose a hypothetical clinical trial of the standard regimen vs an alternative when survival was

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CAROLYN Cool

described verbally. An even more interesting finding was that individual patient perceptions were the most significant factor in opting for trial participation: patients who were more optimistic about the standard treatment were less likely to wish to enter a trial. The variability in estimated survival was equal in both groups, implying that the presentation of identical numeric information does not ensure uniform interpretation within groups. DISCUSSION

The literature on accrual to clinical trials illustrates an interesting mix of multidisciplinary research: some studies were conducted by physicians, and others by social scientists. As such, any individual study may be limited in scope and perspective. In addition, specific studies may be criticized on methodological grounds. For example, many studies were based on small sample sizes, which limit the ability to detect differences between groups. Survey studies varied in response rates; low survey participation brings the generalizability of findings into question. No questionnaire or survey (with the exception of Cassileth ef al. [26], who used a standard measure of anxiety) included information about the validity or reliability of the instrument employed. Given the inherent difficulties in assessing attitudes and motives, future use of these and other instruments requires additional psychometric evaluation. Despite these limitations, the literature has identified a compendium of factors that serve as barriers and facilitators to clinical trial participation, which have implications for interventions to influence accrual. A limited number of interventions has been discussed to date, specifically in the areas of protocol development, informed consent, and physician and patient knowledge. Protocol development

One finding seems clear from several studies: in many cases, physicians and patients have pre-existing preferences for one of the study arms. This may be particularly likely when the treatments have widely divergent implications for patient functioning, such as radiation versus surgery. In view of the discomfort with randomization in such situations, alternate study designs could be given serious consideration when appropriate [42]. One variant the ‘prerandomization’ design, involves determining treatment condition prior to obtaining patient consent; only patients in the experimental arm are informed that they are being asked to participate in a clinical trial, and they are informed of their treatment condition at the same time [42]. In the trial of segmental vs total mastectomy discussed earlier [ 1I], accrual increased sixfold after a variant of this design in which consent was obtained from patients in both the experimental and control arms was introduced. Such approaches may reduce patient and physician discomfort with treatment uncertainty; however, they present ethical concerns in that patients may be given more complete and compelling information about the treatment they are to receive [43]. In addition, in order to avoid possible bias in results (due to relationships among pre-existing

GOTAY

patient characteristics, reasons for refusal, treatment, and outcome), patients must be compared ‘as randomized’ rather than ‘as treated,’ that is, a patient randomized to treatment A who refuses and received treatment B must be considered in the A group for analysis” [44, p. 41 I]. As a consequence, differences between treatment arms may be reduced, requiring a larger sample size. Zelen has identified conditions under which the “prerandomization” is an efficient approach [45]. Based on the numbers of patients who are ineligible for specific trials, eligibility requirements warrant careful consideration; not only would less stringent criteria enlarge the pool of eligible patients, but also generalizability of findings may be enhanced [46]. The Medical Research Council of the United Kingdom has adopted this philosophy in their current trial of adjuvant radiotherapy and 5-fluorouracil infusion in colorectal cancer; the only eligibility requirements for this trial are suspected colorectal cancer, no medical contraindications to therapy, and physician uncertainty about the need for adjuvant therapy [47]. The pluses and minuses of such approaches are currently being debated [46,48]. Informed consenl

Research has identified physician concerns about informed consent, as well as the fact that present approaches seem to be deficient, especially in explaining randomization. Aaronson and Zittoun (491 reviewed a number of techniques to improve the informed consent process including: simplified instructions, imposing an interval of time between the receipt of information about the trial and a decision to participate, supplementing verbal and written information with videotapes, and involving an ombudsman to assure that patients are adequately informed. They conclude that additional research is needed to establish the value of all of these interventions, as well as to understand better the informed consent process. Recognizing individual patient differences in desire for information was highlighted as a particularly important area for research. Physician and patient knowledge

Lack of information about opportunities for clinical trial participation constitutes a major potential barrier. Several NC1 programs have addressed increasing knowledge in physicians and patients. A special initiative aimed at increasing clinical trial participation was recently issued [SO]. This plan incorporates publicity and informational activities directed towards enhancing awareness of trials by physicians, other health care professionals, patients, and the public. A preliminary evaluation of one component of the project, a booklet about clinical trials, indicated that the booklet did increase patient knowledge but not necessarily trial participation [Sl]. Two NC1 programs, the Community Clinical Oncology Program (CCOP) and the Cooperative Group Outreach Program (CGOP) were developed to increase the involvement of community oncologists in the clinical trials process, thus enlarging the availability of research protocols especially to patients in their own communities. An evaluation of the CCOP showed that this program substantially

Accrual to cancer clinical trials

increased the numbers of patients on clinical trials [52]. The Physicians’ Data Query (PDQ) system, a computerized database that provides continually updated information about state-of-the-art treatment and ongoing trials to any physician, was developed to enhance access to the most current cancer treatment, as well as increase opportunities for enrolling patients on trials [53]. The ultimate impact of this program remains to be seen.

CONCLUSIONS

There are numerous other areas in which warrant additional research, including further specification of the influences on the trials process. The most frequent research strategy in this literature is the use of hypothetical scenarios to elicit treatment preferences [16, 19,22,29-3 1,32,40,41]. This approach yields useful information and has the advantage of enabling the construction of scenarios that can be systematically varied in order to test theories of decision-making. However, whether hypothetical decisions are comparable to patient and/or physician decision-making in the field is an open question. There is much to be gained by actually talking to patients and asking them why they did or did not elect trial participation, yet only one study [24] took this tack, and one other [23] interviewed only patients on trials. This field would be enriched by more such efforts. There is also much room to expand upon current findings. Although a number of variables have been identified (often through physician surveys) as influences on accrual, and some have been studied in more detail, the direct impact of such factors on trial participation itself has not been assessed. For example, deficits in the informed consent process have been noted as a problem; however, would improved consent forms result in a higher likelihood of trial participation? Or is it possible that the opposite would occur: well-informed patients would be more likely to form a treatment preference and less likely to participate in clinical research [22]? The current literature provides the basis for hypotheses like this, as well as a foundation for interventions that require testing in future studies. In addition, quality of life is another consideration whose role in patient and physician decision-making about trials needs to be explored. The effects of cancer treatment on quality of life, and the inclusion of quality of life endpoints in cancer clinical trials, have received increased attention in recent years [53,54]. However, the impact of information about quality of life on trial participation has not been addressed in studies to date. Reports of decisionmaking which includes quality of life information for hypothetical treatments have yielded inconsistent results: McNeil et al. [SS] found that healthy individuals would be willing to chance lower survival to conserve speech in laryngeal cancer treatment, while O’Connor et al. [56] showed that cancer patients were unwilling to trade a decrement in survival for improved quality of life. While the inclusion of quality of life data in consent forms will undoubtedly increase patients’ awareness of the full impact of potential treatments

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[57], the impact of quality of life data on patient enrollment on trials has yet to be ascertained. While certain aspects of the process of accrual to clinical trials can be addressed through changes in protocol design, knowledge, and attitudes, other critical variables must also be considered. For example, a number of studies reviewed indicated the importance of practical barriers like transportation. A particularly compelling concrete problem in the U.S. at present is the refusal of third party reimbursement for ‘experimental’ treatments. This has become a major issue that threatens patient and physician

enrollment in trials research [58]. At present, problems regarding payments for trials tend to be resolved on a case-by-case basis; the ultimate resolution of such concerns is not clear. There must be recognition that any modifications in attitudes and procedures take place within the context of the health care delivery system as a whole. Finally, efforts to expand participation in clinical trials research should be grounded in a respect for the autonomy of the individual [59]. Clinical trials research benefits participants by exposure to new and promising treatments, while ensuring that they receive nothing less than the best standard therapy that is available. At the same time, however, patients may make decisions about their own care on the basis of individual preferences that are unrelated to their support of clinical trials in general [60]. Patients need to be made aware of their options, but supported in the decision they make, even if ultimately some ‘competent patients make irrational choices’ [61]. These choices may, in fact, be at odds with the recommendations of caregivers; a recent study showed that cancer patients believed that intensive treatments with only a small chance of benefit were much more acceptable than did health care professionals and matched controls [62]. The final responsibility-and one that leads to perhaps the most important decision in a patient’s life-must reside with the parties most affected. Acknowledgemenfs-The comments of Anne Bavier, Leslie Ford and Carrie Hunter are gratefully acknowledged REFERENCES

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