Ethical aspects of clinical trials: the attitudes of the public and out-patients
P. Riis is no longer at Copenhagen University Hospital.
Dr Søren Madsen MD, Research Associate, Department of Medical Gastroenterology C, Copenhagen University Hospital at Herlev, Herlev Ringvej 75, DK-2730 Herlev, Denmark (fax: + 45 44 94 40 56; e-mail: firstname.lastname@example.org).
Abstract. Madsen S, Holm S, Riis P (Copenhagen University Hospital, Herlev, and University of Copenhagen, Blegdamsvej, Denmark). Ethical aspects of clinical trials: the attitudes of the public and out-patients. J Intern Med 1999; 245: 571–579.
Objectives. To investigate attitudes to clinical research amongst potential research participants.
Setting. Two medical out-patient clinics and the background population.
Subjects. A total of 508 randomly selected citizens in Copenhagen County (64% responded) and 200 consecutive patients attending the out-patient clinics (64% responded).
Outcome measures. Attitudes toward different aspects of clinical research.
Results. Positive attitudes toward medical research were disclosed. The majority found scientific testing necessary, although only a minority considered participation a moral obligation. Both personal benefits and altruistic motives for participation were highly rated, whereas former positive experiences from trial participation had only minor impact on decisions. Several respondents stated former trial participation had changed their attitudes negatively. Lack of feedback of results was of major importance for this change. Attitudes are significantly influenced by the presence of independent research ethics committees, whereas trial technicalities such as drawing lots and blinding was found problematic by only a few respondents. Altruistic motives of physicians to conduct trials were highly rated by a majority of respondents, but the motive of promoting doctors’ careers was also judged important. Respondents rated nondiscomforting procedures as acceptable or having only a small impact or strain on their lives.
Conclusion. Attitudes toward medical research are positive amongst out-patients and the general public. Altruistic and nonaltruistic motives both concerning trial participation and concerning the motives of physicians to conduct medical research were rated highly. Lack of feedback concerning results of trials to participants was important for a negative change in attitude toward participation.
The ultimate goal of clinical trials as a part of medical research is to benefit future patients. This contrasts, to some extent, with treatment of disease outside a trial setting, where only benefits to the individual patient are in focus.
The fraction of eligible patients participating in clinical trials has been relatively low, and has declined further in recent years. The result has been more time needed for completion of trials, thereby postponing answers to important questions. Other important consequences are the rising costs due to increased numbers of participating centres and increased risk of unpredictable bias when applying trial results from small, less consecutive samples to total patient populations. The problems occur worldwide, but have been most pronounced in oncological trials [1–5].
This situation is only partly explained by ‘physician factors’ (the feeling of a compromised doctor–patient relationship, or unease by asking for informed consent, etc.) [6, 7], which means that ‘patient factors’ have been increasingly important in recent years.
Little is known about patients’ either accepting or refusing participation. Despite this lack of knowledge, the media has in recent years been studded with negative statements and attitudes toward clinical trials, particularly trials connected with serious diseases.
To investigate attitudes amongst potential research participants toward clinical research we performed a questionnaire-survey in the background population of Copenhagen County and amongst patients attending two out-patient clinics of the Copenhagen University Hospital at Herlev, Copenhagen County.
Materials and methods
Questionnaires were mailed to 508 randomly selected citizens in Copenhagen County (PUB) and handed out to 100 consecutive patients attending a Medical Gastroenterological (GAS) Out-patient clinic and to 100 patients attending a Rheumatological (REU) Out-patient Clinic at Copenhagen University Hospital at Herlev.
The questions dealt with different aspects of clinical trials. Most were on a multiple-choice form, with an additional opportunity to answer some of the questions in free text.
Statistical analyses were based on the software CSS/Statistica 3.1 (StatSoft, Tulsa, Oklahoma, USA), using nonparametric statistical tests (chi-squared, Kruskal–Wallis’ and Wilcoxon–Pratt’s signed rank tests) with 0.05 as the level of significance.
The questionnaire-survey was performed in 1996. All approached patients in the out-patient clinics gave both verbal and written informed consent before answering. Regular informed consent was not obtained from the PUB group, as the mere answering was judged to be a sufficient consent. The survey fulfilled the demands of Danish law and the Helsinki Declaration II. It was approved by the Research Ethics Committee of Copenhagen County.
In the groups PUB, REU and GAS, respectively, 64%, 61% and 67% fully or partly answered the questionnaire. The median age (25% and 75% percentiles in parentheses) was in PUB 47 years (32–60), in REU 58 years (49–70) and in GAS 47 years (34–62). Thus the REU respondents were older than respondents in the two other populations (PUB versus respondents in out-patient clinics: P = 0,00009; PUB versus REU: P < 0.00001; PUB versus GAS: P = 0.08; REU versus GAS: P = 0.003). More respondents in the out-patient clinics than in PUB had chronic diseases requiring hospitalization within the preceding year (PUB 10.8%; REU 39.3%; GAS 41.8%) and/or more than 6-yearly contacts with a physician (PUB 9.3%; REU 83.1%; GAS 61.2%) (P < 0.00005). More respondents in the out-patient clinics had formerly taken part in clinical trials than those in PUB (PUB 16.8%; REU 38.3%; GAS 38.8%) (P < 0,00005).
Attitudes toward trials
Only a few former trial participants stated that the experience had changed their attitude toward clinical trials in a negative way (PUB 9.3%; REU 0%; GAS 3.8%), whilst a majority showed no change in attitude (PUB 64.8%; REU 77.3%; GAS 88.5%). The remaining respondents had their attitude changed in a positive way (PUB 25.9%; REU 22.7%; GAS 7.7%). One recurrent reason for negative change in attitude given in free text by several respondents in all three groups was that they had never received information about the results of the trial in which they had participated. As typical examples, two respondents in PUB wrote:
The system fails by not informing participating patients of trial results. This leaves you with a feeling of being rejected and worthless as soon as the trial is over.
Results of tests to be published should be sent to all participating patients. At the least we want to know the results of our participation.
Regarding the general attitude toward clinical trials, approximately 90% were either very positive, positive or positive with reservations. Respondents in the out-patient clinics were more positive than respondents in PUB (P = 0.04) ( Table 1). Several respondents stated in free text, that their concerns either originated from ‘affairs’ covered in the media or they expressed unease regarding economic influence on trials of the pharmaceutical industry.
Attitudes toward medical research.
Only approximately 10% had a negative attitude toward a personal participation in a clinical trial. GAS respondents showed a more positive attitude toward self-participation (PUB versus respondents in out-patient clinics: P = 0.007; PUB versus REU: P = 0.2; PUB versus GAS: P = 0.005; REU versus GAS: P = 0.2) ( Table 1). More than 90% of respondents were either positive or hesitating (approximately half of each) toward family or friends participating in trials, whilst only a small minority was negative. There were no differences between groups ( Table 1). Respondents in PUB were more positive toward participation of family or friends than toward personal participation (P = 0.0005). This was not seen in either REU or GAS.
Almost all respondents stated, that the presence of public research ethics committees in Denmark was important to their attitude toward medical research. No differences between groups were seen ( Table 1).
About one-third of respondents felt a moral obligation to participate in medical research due to benefits to the respondent and his or her friends related to results of former and future clinical trials. A borderline significant difference (P = 0.052) between respondents in PUB and the out-patient clinics was found, with the respondents in the out-patient clinics feeling such an obligation to a larger extent than those in PUB ( Table 1). One respondent in PUB wrote in free text:
In some way there is a moral obligation to participate, but at the same time we only have one life to live, and I cannot blame anyone if they put this higher. I would probably appreciate the feeling of a moral obligation by others, but I am uncertain regarding my own.
Respondents felt it necessary either always (PUB = 59.6%; REU = 65.6%; GAS = 60.6%) or in most instances (PUB = 36.0%; REU = 26.2%; GAS = 30.3%) to test new drugs with scientific methods before implementing them in general practice. Regarding the necessity to test new diagnostic methods the same pattern was seen (always necessary: PUB = 46.7%; REU = 50.8%; GAS = 53.0%; in most instances necessary: PUB = 40.8%; REU = 41.0%; GAS = 34.9%). Almost none stated no need to test, but approximately 10% stated it necessary not in all, but in some instances (both concerning drugs and diagnostic methods). There were no statistically significant differences between groups.
Attitudes toward drawing lots (i.e. randomization) between treatments were uniform in the three groups, with approximately half the respondents being positive, a third hesitating and the rest being negative. Blinding treatments and attitudes toward clinical trials showed no significant differences between groups. Approximately 80% were either positively or not affected in attitude, whereas little less than 20% of respondents were affected negatively.
In an invented situation, where the respondents had accepted participation in a clinical trial, we asked them to grade the importance of different reasons to participate on a four-point scale (from very important to unimportant) ( Table 2).
Attitudes toward importances of different reasons for consent to participation in an invented trial.
Concerning the wish to get access to the new drug a large majority felt this issue to be either very important or important for their choice. A borderline significant difference was found when comparing PUB and REU (P = 0.07), with REU stating this issue more important. No other differences were found ( Table 2).
Grading the importance of a closer disease monitoring, about nine-tenths regarded this effect as either very important or important. Comparing REU and GAS, a borderline significant difference was found with REU regarding the issue more important (P = 0.07). No other differences were seen ( Table 2).
No differences between groups were found concerning the wish to obtain a good relation to the department performing the study. The statements were distributed with one fourth in each of the possible categories ( Table 2).
A large majority of all respondents regarded the wish to help future patients as either very important or important. GAS respondents stated this issue more important (PUB versus GAS: P = 0.03; REU versus GAS: P = 0.03). There were no significant differences between either respondents in PUB and out-patient clinics as a whole, or between PUB and REU ( Table 2).
Grading importance of positive experiences from former participation in trials showed no differences between groups. Approximately half graded this issue as either very important or important ( Table 2).
We asked the respondents in free text to mention other possible factors, which would influence their possible decision to participate. Approximately a third of all respondents used this opportunity to give a wide spectrum of different factors, including a wish to get better, the seriousness of disease, the prognosis on current treatment, the adverse effects and risks, other options, time necessary, costs, influence from the industry and/or family acceptance. Some general statements which cover the large majority can still be extracted. The nature and seriousness of disease was important to the majority of respondents. The statement of the wish to ‘get better’ or to ‘be cured’ appeared in most responses as did a concern regarding possible adverse effects of the trial drug. Several respondents expressed an importance of the time and money used for their transportation and control visits. Finally, the importance of trusting the physician responsible for a trial was emphasized by several respondents.
Motives for conducting medical research
About one-third of respondents either fully or partly agreed with the statement, that ‘medical research is primarily performed to promote doctors’ careers’ (PUB 35%; REU 29.3%; GAS 39.3%), whilst little less than a third either partly or fully disagreed (PUB 28.4%; REU 31.1%; GAS 23%). The remaining participants neither agreed nor disagreed. There were no differences between groups.
We asked the respondents to grade the importance of five different motives that doctors may have for planning and conducting medical research on a four-point scale (from very important to unimportant). The answers revealed no statistically significant differences between groups ( Table 3).
Respondents’ beliefs concerning doctors’ motives to plan and conduct medical research
We asked the respondents to give, in free text, other possible essential reasons that doctors may have for planning and conducting medical research. A recurrent theme was, that economic interests (support from the pharmaceutical industry) was a major motive, but aspects of curiosity, idealism, competitiveness, personal satisfaction and/or national and international recognition were also commonly emphasized. As examples, three respondents wrote:
Physicians are like other people – different – some are idealists working seriously to improve treatments for the sake of the patients – others are more ego-centred seeking personal advantages.
Physicians are human too! Some will always put personal economic advantages before everything else, and the phamaceutical industry is willing to pay.
The wish to struggle with the ‘riddle’, thereby making a meaningful life for themselves together with those similarly disposed. The personal satisfaction to see things develop and reaching a goal and know, that you contribute to this.
Trial demands – attitudes toward impact on life
Respondents were asked to imagine having accepted participation in a clinical trial running for 1 year, and asked to judge the impact or strain on their lives of five different trial procedures on a four-point scale (very great to small) ( Table 4).
Grading of impact/strain on life of different trial procedures
Judgements on impact or strain were not different between groups apart from issue 5 (completion of forms), which the respondents from out-patient clinics judged as less straining than PUB (PUB versus out-patients clinics: P = 0.004; PUB versus GAS: P = 0.009; PUB versus REU: P = 0.07), with no statistically significant difference between REU and GAS. In judging the strain or impact of monthly control visits, monthly blood-samples and nondiscomforting examinations every third month about four-fifths of respondents judged the trial procedure either acceptable or of small impact or strain, whilst one-fifth felt the impact to be either great or very great. Examinations with some discomfort were considered by a minor proportion to be either acceptable or of small impact or strain. No statistically significant differences were found between groups ( Table 4).
The proportion of respondents, 61–67% is acceptable. Some of the nonrespondents probably had an a priori negative attitude toward scientific projects. Due to the anonymous design it was not possible to compare respondents and nonrespondents. That REU respondents were older than PUB and GAS respondents merely reflects the disease spectrum of rheumatic diseases. Neither was it surprising that respondents from out-patient clinics more often had participated in trials, considering their relation to research-active university departments.
In the light of an extensive media debate – largely asserting negative statements about clinical research – it is significant, that a majority of respondents a priori had a positive attitude toward clinical trials. Despite this, several of our respondents stated in free text, that their concerns to some extent originated from ‘stories’ in the media. The result is in agreement with findings of others [8–10], and is supported by the fact, that only a minority stated negative attitudes toward both personal participation and participation of friends or family. That the respondents in the out-patient clinics were more positive than PUB respondents might reflect a closer relationship to the treating physicians/researchers, and an urgent need for access to better treatments. The finding that PUB was more positive regarding trial participation of family or friends than personal participation is interesting. The healthy, nonhospitalized respondents in the public – at some distance to the trial setting – link their potential participation in a trial to a feeling of invulnerability. The respondents in the out-patient clinics possibly considered participation more concretely, because they are in fact diseased, and thus closer to concrete trials. Another aspect could be the apparent conflict between rights and duties in society, illustrated, for instance, by low rates of family acceptance of organ donation from close relatives, whilst at the same time practically all citizens expect to be offered organs to close kindred in need.
Amongst former trial participants with a negative change in attitude following the experience, a common reason was the lack of information afterwards regarding results. Patients having participated in medical research, which may have been time-consuming, involving risks of (or actual) adverse effects of trial drugs, diagnostic examinations, etc. and perhaps even resulted in economical losses due to the participation, are right to feel disappointment and/or even anger toward researchers who did not give any feedback about what resulted from the project. It is understandable that patients with that kind of experience are not likely ever again to participate in trials, as their basic trust toward their physician has been violated. If the endangered species of trial participants [1–5] is to be saved for potential participation in future trials, this demand of follow-up information seems easy, applicable and reasonable.
Practically all respondents claimed that their attitudes toward clinical research were influenced by the presence of the public research ethics committees. The question itself states the existence of research ethics commitees ( Table 1). This possibly represents new information to respondents, as a telephone survey in the general public in 1995 showed that only 30% of respondents were aware of the mere existence of an official control system in Denmark . The level of knowledge in the general public about this public control body is probably unchanged in general, although we cannot exclude that some answers represent reactions to better information. The information apparently gives a sense of security and probably increases willingness to participate in trials, which underlines the importance of informing potential testees , that the study at hand has been reviewed and approved by an ethics committee.
The positive attitudes toward clinical trials are supported by the findings of a large majority that feel it necessary in all or most instances to test both new drugs and diagnostic methods using scientific methods before a general implementation. The high percentages of accepting randomization and blinding are surprising, since these issues in particular have had the attention of the media, with principal statements that these procedures are unethical to patients.
The ‘self-centred’ motives for participation (getting the new treatment, closer disease monitoring and good relationships with the department) were highly rated by all respondents. Importance of both nonaltruistic motives and the altruistic motive of helping future patients is in accordance with the findings of others [8, 9, 12, 13].
In grading importance (from physician’s point of view) of motives to conduct medical research altruistic motives were highly rated by a large proportion. This could seem inconsistent with the two-thirds of respondents regarding the motive of promoting own careers as either important or very important. The impression of a personal benefit as the motive to do research was also expressed in approximately one-third of respondents who either fully or partly agreed with the statement that ‘medical research primarily is performed to promote doctors’ careers’ and in several of the free-text responses. These apparently self-contradictory high importance gradings of both altruism and ‘self-benefit’ as motives for doctors merely reflects the area’s complexity. It is important to stress the necessity of an open discussion of any financial interests from the pharmaceutical industry (including the information in the written information material), as several respondents stated concerns or unease and/or suspicion concerning this issue as an important factor to be considered in the planning and conducting of trials. It is, however, comforting that several respondents also in free text expressed beliefs about altruistic motives for research amongst physicians. Information should probably not be written on paper bearing company logos or names, and should be directed from the responsible physician(s) to the patient. This procedure should, however, not in any way blur or hide information about any involvement of the pharmaceutical company, which has to be given openly.
In the light of large-scale public health system retrenchment programmes in Denmark in recent decades, it is interesting that the wish to minimize total expenses via research was regarded as important by only a third.
In planning future trials it is important to consider the a priori interpretation of strain and impact on life of necessary trial procedures by potential research participants. The findings of this study are in agreement with the findings of Bevan and coworkers, based on interviews with 119 patients, who had never previously been invited to participate in a clinical trial. Bevan et al. found that more than half of their study participants would participate in a future hypothetical trial, irrespective of potential troublesome and/or time-consuming trial procedures .
Others have found that especially transport to and from an out-patient clinic and time-consuming clinic visits constitute a significant problem , in some contrast to our study, in which less than one-fifth of respondents regarded monthly control visits of great or very great impact or strain as a part of a trial, although several respondents in the free text expressed that the time used and the costs would be important factors in their decision about participation, even in an invented trial.
The authors acknowledge Poul Schlichting, DMSc, Medical Gastroenterological Department C, Copenhagen University Hospital at Herlev and Pia Munkholm, DMSc, Medical Gastroenterological Department, Copenhagen University Hospital at Hvidovre for valuable comments to the manuscript and for general guidance. We thank physicians and nurses in the Medical Rheumatological Department, Copenhagen University Hospital at Herlev, especially nurse Gunhild Bukh for the inclusion of patients and collection of questionnaires.
This study was made possible by grants from (alphabetically): Aage Louis-Hansen’s Foundation, Anna og Jakob Jakobsen’s Foundation, Astra Denmark, Beckett-Foundation, Danish Medical Research Council, Danish Research Council for the Humanities, Hede Nielsen’s Foundation, Jacob Madsen’s & Olga Madsen’s Foundation, Medical Research Foundation for Copenhagen, the Faroe Islands and Greenland, Ove Villiam Buhl Olesen og Edith Buhl Olesen’s Foundation, Roche A/S, Sigrid Rigmor Moran’s Foundation, and Vibeke Binder & Povl Riis’ Foundation.
Received 23 June 1998; accepted 22 October 1998.