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World J. Surg. 23, 1210 –1214, 1999 WORLD Journal of SURGERY © 1999 by the Société Internationale de Chirurgie Issues in Surgical Randomized Controlled Trials Robin S. McLeod, M.D. Departments of Surgery and Public Health Sciences, Division of General Surgery, University of Toronto, Mount Sinai Hospital, 600 University Avenue, Room 449, Toronto, Ontario M5G 1X5, Canada Abstract. As technology expands and health care resources become more limited, there is increasing pressure on surgeons to evaluate surgical procedures and technology to ensure they are effective. No longer is evidence from case series acceptable, and treatments must be evaluated in randomized controlled trials. The power of the randomized controlled trial is that because of its rigorous design the risk of random or systematic (bias) error is minimized and thus the risk of making an incorrect conclusion about the efficacy of a treatment is minimized. The randomized controlled trial has been widely accepted for evaluating the efficacy of medical treatments but less so for surgical procedures. Many cite methodologic issues related to surgical issues as the reason for this, including concerns related to standardization of the surgical procedure, timing of surgical trials, difficulties with blinding of subjects and investigators, ethics of surgical trials, and patient and surgeon acceptance of surgical trials. These issues are discussed in this paper as are possible strategies to minimize their effect. otic therapy alone [1], trials comparing various antibiotic regimens for treatment of intraabdominal sepsis [2], and new drug therapies being tested in patients with acute ulcerative colitis where previously surgery was accepted as the only alternative [3]. For the investigator, the challenge when performing an RCT is ensuring that the two groups are truly the same and that protocol deviations do not occur that could invalidate the results because of random or systematic errors. Performing an RCT that is methodologically rigorous is difficult no matter what treatments are being compared, and most clinical researchers agree that performing trials where one or two surgical therapies are being evaluated are especially challenging. The focus of this paper is a discussion of some of the problems encountered in surgical trials and some of the possible solutions to them. The randomized controlled trial (RCT) is considered the optimal design for determining treatment effectiveness. The power of the RCT is that subjects are randomly allocated to two (or sometimes more) treatment groups and are followed in an identical manner prospectively with the outcome of interest defined a priori. Thus the groups are similar with respect to both known (or measured) and unknown attributes except for the treatment they receive. Therefore it can be assumed that if a difference is observed it is due to a difference in the effectiveness of the two treatments. Randomized controlled trials are a phenomenon of the latter part of the twentieth century. Previously, most clinicians relied on careful observation to make deductions about the efficacy of a treatment. There are many examples of accepted therapies that were introduced to clinical practice without being tested in an RCT, including appendectomy, antibiotics for treating intraabdominal infections, and colectomy for ulcerative colitis. What these interventions have in common is that the treatment effects are so large, compared to the alternative or no treatment, that their effectiveness is self-evident; RCTs are unnecessary to confirm these observations. More commonly, in modern medicine technologic developments or surgical interventions lead to small increments in survival or perhaps no difference in survival, only improvement in quality of life. It is necessary, therefore, that extraneous factors are controlled to be certain that the observed difference is indeed due to the treatment. Even therapies that were once accepted without question are being evaluated in RCTs. Thus there are trials comparing appendectomy to antibi- Standardization of the Surgical Procedure In medical trials the dosage can be standardized, and compliance can be measured. Furthermore, the prescribing physician is not a variable. In surgical trials, however, standardization of a procedure may be difficult because surgeons vary in their experience with, and their ability to perform, a surgical technique; there may be individual preferences when performing the procedure; and there may be technical modifications to the procedure as it evolves. Furthermore, differences in peri- and postoperative care may affect the outcome. Many view this as a major limitation when performing surgical trials, but one can look at the issue from the opposite viewpoint. In medical trials, there must be continuous monitoring of patients to ensure compliance with taking medication for the duration of the trial. In surgical trials, once the procedure is completed, “compliance” no longer becomes an issue, monitoring is unnecessary, and strategies to ensure compliance are not needed. Standardization is an important issue when designing a surgical trial, and a certain minimum is mandatory. The amount of standardization may vary depending on the question being asked, similarly to the fact that compliance may vary in a medical trial. Thus a trial where surgical technique is highly controlled (i.e., few surgeons who are experts in the field using a similar technique) is analogous to the medical trial where only compliant patients are randomized. This may be viewed as an efficacy trial. If the surgical maneuver is less controlled, it may be viewed as an effectiveness McLeod: Issues in Surgical RCTs trial. In other words, the question is: “Is this surgical procedure effective when performed by many different surgeons without special expertise with this procedure?” Depending on the design of the trial, the generalizability of the results varies. No matter what strategy is adopted, it is essential that the investigator describe how the procedure was performed and by whom so the reader can determine whether the results are applicable to his or her practice and the technique can be replicated. It is as important to standardize the technique of the control operation as it is for the new operation. It is often easier to do so, as the procedure may be more “mature” and the technique may be more standardized. Other aspects of care deemed important, such as prophylactic antibiotic usage and postoperative care, should also be standardized. Several strategies may be instituted to ensure that uniformity in surgical technique is achieved and that the effect of the surgeon as a variable is minimized. First, one can ensure that there is a consensus among participating surgeons on how to perform at least the critical aspects of the procedure. Prior to the trial, teaching sessions may be held to improve standardization. Manuals may be produced that describe and illustrate the accepted technique. Second, during the trial measures can be instituted (e.g., pathologic examination of resection margins, radiographic evidence of vessel patency) to audit the surgical performance. If results are suboptimal, performance may be improved by providing feedback to surgeons. Third, patients may be stratified by the surgeon. There may still be variation in how the procedure is being performed, but stratification ensures that there is not an imbalance between groups. Finally, participation may be limited to a small number of surgeons or only those for whom there is documentation that a satisfactory number of procedures have been performed or there is evidence they can perform it adequately. The advantage of the latter strategy is that uniformity of technique is more likely. It increases the likelihood of observing a treatment effect, as only experts are included. The disadvantage is that the results may be less generalizable. Timing of Trials Chalmers argued that the first patient on whom a surgical procedure is performed should be randomized [4]. However, his reasoning was mainly based on ethical concerns rather than methodologic ones. Most surgeons agree that there is a learning curve for any procedure and that modifications to the technique are frequently made at its inception. By including these early patients, one would almost certainly bias the results against the new procedure. It might also inhibit modifications being made as experience with the procedure increases. Alternately, if modifications are not made, the procedure, as it is performed in the trial, might be obsolete at the completion of the trial, and thus the results might have little impact. Delaying the institution of a trial until the procedure has been perfected also has its hazards. A trial may be difficult to initiate when the procedure has become widely accepted not only by the surgical community but also by patients. The paucity of RCTs testing surgical therapies may be due in large part to this dilemma related to the timing of the trial. However, the EC-IC Bypass and NACET studies are examples of trials that were performed even though the procedures had already gained wide acceptance [5, 6]. On the other hand, laparoscopic cholecystectomy has not been formally evaluated in any large trials [7, 8]. 1211 Although this may be a significant failure to evaluate a new surgical procedure adequately, it may be an example of where an RCT is unnecessary because laparoscopic cholecystecomy so clearly results in less pain and earlier discharge (the main outcome variables). Certainly, if trials had been performed early, almost certainly they would have been biased against laparoscopic cholecystecomy with respect to bile duct injuries. There is therefore no optimal time to test a procedure in an RCT. If at any time after its introduction there are clinicians who are uncertain of the effectiveness of a procedure, a randomized controlled trial should be performed. Investigators must accept that this may not be the definitive trial because procedures are continually being “fine tuned,” and other technical and pharmaceutical advances in the field may alter the indications for surgery. Medical oncologists are always planning a new trial as they complete one based on the results of previous trials. This same attitude should be adopted by surgical investigators. Blinding of Subjects and Investigators Bias may occur owing to the lack of blinding of patients or investigators (or both) in any clinical trial whether it is assessing medical or surgical therapies. This is of great concern in surgical trials, where it is known that surgery often has a significant placebo effect [9]. In trials comparing medical and surgical therapies, blinding may be impossible because sham operations are generally unethical. Even in trials comparing two surgical operations there may be difficulty blinding patients and investigators if the incisions differ or the operations differ in magnitude. Creative maneuvers may be required to minimize unblinding. As an example, in a trial comparing minicholecystectomy to laparoscopic cholecystectomy, a large dressing covering the entire abdomen was used to blind surgeons, nurses, and patients to the procedure performed [8]. The lack of blinding may be minimized by choosing a “hard” outcome measure, such as recurrence of disease or death. However, more often the important outcome is a change in symptoms or quality of life, and outcome may be biased by knowing which treatment group the subject is in. Because the quality of life assessment made by the patient is of greatest importance, blinding may be impossible. In these situations, the potential for bias may be minimized if a hard outcome measure is also assessed and it correlates with the patient’s subjective assessment. For example, in the VA Cooperative Study Group on Gastroesophageal Reflux Disease (GERD), patients’ assessments of their reflux symptoms plus endoscopic findings were recorded [10]. If possible, assessments should be performed by an independent assessor who is unaware of the treatment group the patient is in. For example, an endoscopist or a radiologist should be “blinded” when they perform procedures or interpret results. Finally, by explicitly defining outcome criteria a priori, bias may be minimized even if the assessors are unblinded. A blinded panel may also be used to review results of tests using these criteria but without knowledge of the treatment allocation. The importance of blinding may vary depending on the trial and the primary outcome measure. For instance, if the outcome measure is all-cause mortality, even if there is no blinding the results will probably not be biased. On the other hand, if the primary outcome is quality of life, lack of blinding may potentially bias the 1212 results and the investigators should spend considerable effort to minimize it. Analyzing Results For the most part, analysis of the results is the same irrespective of the treatments being evaluated. Most statisticians agree that an intention to treat analysis is the preferred method. Also known as an effectiveness analysis, it is performed by including all randomized patients in the analysis. Patients are always analyzed in the group to which they were randomized. Peto et al. argued that if the failure to complete the trial or receive the correct treatment occurred owing to chance there should be an equal proportion of patients with protocol deviations in each group [11]. If so, by including all patients in the analysis the treatment effect, if there is one, may be reduced; otherwise, the results are not biased. On the other hand, if the failure is due to an effect of the treatment (e.g., toxicity or intolerance of the treatment), it is not due to chance; and omission of those patients from the analysis might bias the results in favor of one of the treatments. Finally, all events that occur after randomization must be included in the analysis. Thus if a patient is randomized to surgery but dies while waiting for surgery, that death is included as an event in the analysis. Similarly, all operative events and postoperative deaths must be included. It is inevitable that some patients do not complete the trial for whatever reason. For the trial to have internal validity, the number of protocol deviations must be minimized. In surgical trials there is a greater risk that patients who are randomized to one treatment may not receive it or may receive the alternative treatment. Steps to minimize this alteration must be instituted. For example, patients often have a preference for one therapy or another. Although an investigator is always anxious to accrue as many patients as possible, it is important that the patient is willing to accept either treatment. If not, if such patients are randomized to the less preferred treatment, they may withdraw from the trial and seek the preferred treatment outside the trial situation. Second, in a trial comparing two surgical therapies, patient consent is obtained preoperatively but randomization is performed intraoperatively only after it has been determined that it is feasible to perform both procedures. Again this method minimizes the risk of crossovers. If a crossover does occur, the patient should be analyzed in the group to which he or she was randomized. Finally, even if the need to assess whether a procedure is feasible is not an issue, randomization should be delayed until immediately preoperatively to decrease the chance of adverse events occurring between the time of randomization and surgery or subjects changing their minds about participating in the trial, especially if one anticipates a delay in surgery. Potential crossovers may not necessarily be considered crossovers depending on the trial design. One possible trial question might be “Is surgery better than medical therapy?” If patients in the medical group require surgery, rather than considering them as crossovers they might be considered treatment failures, with surgery being an outcome measure. In a second scenario the question might be “Is early surgery better than medical therapy followed by surgery if medical therapy fails?” rather than “Is surgery better than medical therapy?” The former is a relevant clinical question and mimics usual care in many instances. If this were the question, obviously surgery is part of the “treatment World J. Surg. Vol. 23, No. 12, December 1999 package” for the second group; and if surgery is performed in any of these patients, they would not be considered crossovers. The results would be analyzed based on the primary outcome measure that had been chosen a priori. Ensuring Adequate Accrual of Patients Patient recruitment is often difficult no matter what RCT is undertaken, but for surgical trials it may be even more difficult. Even for diseases with a high incidence or prevalence, it may be difficult to accrue patients because only a subgroup of the population are eligible. Surgical therapy may be indicated in only some patients with the disease. Some patients may have co-morbidities that preclude surgery. There may be different manifestations or stages of the disease, and the entry criteria may restrict inclusion to only some of the patients with the disease. For instance, although cancer of the colon and rectum is the third commonest cancer in North America, few patients would be eligible for a trial comparing abdominoperineal resection to local excision. Similarly, although peripheral vascular disease is relatively frequent, relatively few patients have isolated stenosis of the iliac artery amenable to stenting or bypass procedures. Patients may also have strong preferences for one therapy or another and refuse to participate in a trial. For instance in the NSABP trial comparing mastectomy to lumpectomy, accrual was hampered because patients often had strong preferences for one of the procedures [12]. Finally, there may be few surgeons experienced in performing a procedure (e.g., laparoscopic colectomy). Because patient accrual is the most common reason for failure of a trial, proper planning before the trial starts is required to minimize the likelihood of failure on this basis. Successful completion is more likely if a multicenter rather than a single center trial is undertaken. Adequate funding is mandatory to allow hiring of research assistants who can ensure that all eligible patients are approached to participate. During the planning stages patient accrual should be realistically estimated taking into consideration the number of patients who have the condition seen at each institution each year, the proportion who would be eligible, and the proportion who would consent to participate. Researchers tend to overestimate the number of patients available for study and who will agree to participate. Patient participation is variable but often ranges between 10% and 50% of those eligible depending on the treatments, the intensity and length of the follow-up, and the invasiveness of the follow-up investigations. The number of participating centers and the duration of patient accrual may be determined based on these estimates. With medical trials, because of regulatory agency restrictions it is unusual that the new therapy is available outside the trial, which may be an incentive for patients to participate in the trial. Because there are usually no restrictions on surgical therapies, there may be less incentive for patients to participate in a surgical trial. The investigators therefore might consider not performing the new surgical procedure outside the trial. This decision must be made considering the resources available and the ethics of restricting the procedure to the trial. Patient Issues As discussed previously, patient preferences may limit the feasibility of a surgical trial. In a medical trial, patients may be ran- McLeod: Issues in Surgical RCTs domized to one arm or the other with the possibility that at the conclusion of the trial they can receive the more efficacious treatment if the disease is not progressive and the treatment is reversible. Surgical procedures, however, are almost always permanent, so patients will not have an opportunity to benefit from the results of the trial. For example, although anterior resection is generally favored over abdominoperineal resection in patients with rectal cancers if it is technically possible, concerns exist that the local recurrence rate may be higher after anterior resection. Despite this concern, an RCT has not been performed, probably because of the reluctance of patients to be randomized to receive a permanent colostomy with no hope of having it reversed if anterior resection were found to be equivalent or superior to abdominoperineal resection. Furthermore, as in this situation, if the treatments are unequal, it may be even more difficult to accrue patients to participate than in situations where the treatment alternatives are perceived to differ little in their magnitude. Generally, when there is a medical option or a less radical or invasive surgical procedure being compared to another surgical procedure, patients tend to have definite preferences regarding therapy [12]. Additionally, accrual may be hindered because there is a lot of emotion associated with surgery itself, and patients often are preoccupied with these other issues. Moreover, they may be reluctant to leave the decision as to what therapy they will receive to chance alone. Other issues, such as patients feeling like a “guinea pig,” are common to both medical and surgical trials but again may be of greater significance in surgical trials. Obviously, patients must be allowed the freedom to decide whether they want to participate in a trial. Investigators must recognize some of these issues so they can realistically estimate how many patients will consent to participate. Solicitation of patient opinions may be helpful when planning trials and thus increase accrual [13]. Surgeon Issues Unlike the release of new medicines, surgery is not controlled by a regulatory body such as the Food and Drug Administration (FDA) or Health Protection Branch (HPB). Whereas all medications must undergo extensive investigation prior to their release, new surgical procedures can often be performed with little or no constraint even from the hospital or local ethics committee. Indeed, there may be a number of disincentives to surgeons wishing to undertake a trial to assess a new procedure. First, if a trial is instituted, approval must be obtained from the local ethics committee, a much more detailed consent form would probably be required, the surgeon would have to discuss randomization with the patient, and follow-up for the patient would probably be intensive. On the other hand, if the surgeon were simply to perform the operation, although a consent form would be required it would almost certainly be less inclusive. Economic disincentives may make participation in trials unattractive. Although a physician would be compensated equally whether a patient was or was not entered in a trial, this would not be the case for a surgeon if the patient were randomized to a medical treatment arm. Surgeons might also fear loss of their referral base if they did not embrace a new procedure even though there was concern about its effectiveness. Such was the case with the introduction of laparoscopic cholecystectomy when general surgeons thought their practices were threatened if they did not quickly adopt this 1213 new technology. Finally, funding of surgical trials is often a difficult issue. Pharmaceutical companies, because of pressure from regulatory agencies to perform trials prior to release of medication, are a major source of funding for medical trials. Generally, industry funding is less accessible for surgical trials. Finally, it must be admitted that surgeons seem to place greater reliance on the results of case series. Whether this is because of the historical role of these studies, skepticism about the need for RCTs, or the perceived difficulty of performing surgical clinical trials, it is difficult to know with certainty. Again, many of these issues can be obviated by performing multicenter RCTs and including only surgeons who are committed to resolving the question and performing the trial. Accrual of patients by surgeons who are not committed to a trial because of ethical or financial concerns is almost always poor. To participate in a trial successfully, investigators must have equipoise about the treatments. To alleviate some of the concerns regarding a surgeon’s practice, it is worth noting that surgeons who are involved in trials are often seen as experts in the field and patients preferentially want to be referred to them. Thus rather than detract from their practice, it may in fact enhance it. Second, as resources become more limited, surgeons will feel more pressure to evaluate procedures before they are accepted. Finally, as evidenced by this series of articles, there is a greater awareness of the need for expertise in this area and greater academic prestige for performing good clinical research. Ethical Issues It is often said that it is not ethical to randomize a patient in a trial where one treatment option is surgical. In fact, what is more accurate is that it may not be feasible as discussed previously in the section on “Patient Issues.” So long as there is community equipoise, the patient is well informed, and informed consent is obtained, a trial comparing a surgical to a medical alternative is ethical. Successful completion of many important trials comparing medical and surgical therapies is witness to this [5, 6, 10]. For a trial to be ethical, it is a given that the subject must not be exposed to undue harm or risk. In addition, the trial must be clinically relevant and significant. If not, it is not ethical to solicit patients’ participation even if there is little risk involved. Surgeons, like other investigators, must be certain that they do not have any conflict of interest when performing the trial. Trials assessing new technologies are often industry driven, and surgeon investigators may be financially rewarded for each patient accrued into the study. In such situations, the surgeon may not be objective when discussing the trial with patients and obtaining their consent. Therefore it may be preferable to have a third party involved in this aspect of the trial. Some universities have developed guidelines for obtaining consent in these circumstances. Finally, even before embarking on such a trial, surgeon investigators should believe that the trial has merit, is answering a significant clinical question, and there is uncertainty with respect to the effectiveness of the treatment options. Financial gain should not be the reason for participating in a trial. The issue of third party consent is more likely to be encountered in surgical than medical trials. In trials performed in emergency situations, on trauma victims, or patients in the intensive care unit, the subject may not be able to sign his or her own informed consent, and it may be necessary to rely on third party 1214 consent. This issue is discussed in a later article, but suffice it to say that local ethics committees vary in their opinions regarding third party consent. Conclusions There is agreement that the RCT is the best trial design for determining treatment effectiveness. Although it has been widely accepted for evaluating medical therapies, it has been used much less extensively for evaluating surgical procedures. Many cite the reason for this as methodologic issues related to surgical trials. As discussed in this article, although there are challenges when performing surgical RCTs, in most cases they do not preclude their performance. It is the author’s view that the reason for the propensity of medical RCTs is the requirement by federal regulating bodies to provide clinical trial evidence before medications are released. With this comes financial assistance from pharmaceutical companies to perform trials to evaluate medical therapies. Until now, surgical procedures have been unrestricted, with little pressure and financial assistance available to evaluate them in clinical trials. In the future, however, there will be increasing pressure, not from regulating agencies such as the FDA or HPB but by third party payors or governments who will refuse to fund procedures or technologies without evidence that they are both effective and cost-effective. Thus surgeons will be forced to take up the challenge of evaluating surgical procedures more rigorously. Résumé Au fur et à mesure que la technologie se développe et que les ressources de santé sont plus limitées, on assiste à une pression croissante de la part des chirurgiens à évaluer leurs procédés chirurgicaux et leurs technologies pour s’assurer qu’ils sont efficaces. Ainsi, l’évidence fournie par des cas cliniques isolés n’est plus acceptable et toute thérapeutique doit être évaluée par des études cliniques contrôlées. Le point fort d’une étude contrôlée par randomisation est qu’en vertu de sa conception rigoureuse, le risque d’erreur (biais) que le résultat observé soit du au hasard ou pas, est minimisé et ainsi, le risque de conclure à tort sur l’efficacité d’un traitement quelconque est minimisé. L’étude contrôlée par randomisation a été largement acceptée pour évaluer l’efficacité d’un traitement médical mais l’est beaucoup moins pour un procédé chirurgical. Beaucoup citent des problèmes de méthodologie inhérents à la chirurgie pour expliquer ceci. Ces problèmes sont la standardisation des procédés chirurgicaux, comment choisir le moment propice des essais en chirurgie, les difficultés pour «aveugler» les patients et ceux qui évaluent les résultats, certaines questions d’éthique ainsi que des problèmes d’acceptation du point de vue du patient et du chirurgien. Ces notions sont discutées dans cet article. On évoque également les moyens pour minimiser leurs effets négatifs. Resumen En la medida que se expande el uso de la tecnologı́a y los recursos para la salud se hacen más limitados, se produce una creciente presión sobre los cirujanos en el sentido de evaluar tanto los World J. Surg. Vol. 23, No. 12, December 1999 procedimientos quirúrgicos como la tecnologı́a para determinar su efectividad. El poder del estudio controlado y randomizado reside en que por razón de su riguroso diseño, se minimiza el riesgo de un error aleatorio o sistemático (sesgo) y con ello se reduce al mı́nimo el riesgo de llegar a una conclusión errónea sobre la eficacia de un tratamiento. El estudio controlado y aleatorizado ha sido ampliamente aceptado para la valorización de la eficacia de los tratamientos médicos, aunque no ası́ para la de los tratamientos quirúrgicos. Como explicación de tal fenómeno, muchos citan argumentos de tipo metodológico relacionados con asuntos de naturaleza quirúrgica, tales como lo pertinente a la estandarización del procedimiento operatorio, a la cronologı́a de los ensayos quirúrgicos, a las dificultades para hacer ciego tanto al sujeto como al investigador, a la ética de los ensayos quirúrgicos y a la aceptación tanto por parte del paciente como del cirujano. Tales aspectos son los que se discuten en el presente artı́culo, junto con las posibles estrategias para minimizar su efecto. References 1. Eriksson, S., Granstrom, I.: Randomized controlled trials of appendectomy versus antibiotic therapy for acute appendicitis. Br. J. Surg. 82:166, 1995 2. Barie, P.S., Vogel, S.B., Dellinger, E.P., Rotstein, O.D., Solomkin, J.S., Yang, J.Y., Baumgartner, T.F.: A randomized, double blind clinical trial comparing cefepime plus metronidazole with imipenem cilastatin in the treatment of complicated intraabdominal infections: cefepime intra-abdominal infection study group. Arch. Surg. 132:1294, 1997 3. Lichtiger, S., Present, D.H., Kornbluth, A., Gelernt, I., Bauer, J., Galler, G., Michelassi, F., Hanauer, S.: Cyclosporine in severe ulcerative colitis refractory to steroid therapy. N. Engl. J. Med. 330:1841, 1994 4. Chalmers, T.C.: Randomization of the first patient. Med. Clin. North Am. 59:1035, 1975 5. 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Spechler, S.J.: Comparison of medical and surgical therapy for complicated gastroesophageal reflux disease in veterans. N. Engl. J. Med. 326:786, 1992 11. Peto, R., Pike, C., Armitage, P., Breslow, N.E., Cox, D.R., Howard, S.V., Mantel, N., McPherson, K., Peto, J., Smith, J.G.: Design and analysis of randomized controlled trials requiring prolonged observation of each patient. I. Introduction and design. Br. J. Cancer 34:585, 1976 12. Taylor, K., Margolese, R.G., Soskolne, C.L.: Physicians’ reasons for not entering eligible patients in a randomized clinical trial of adjuvant surgery for breast cancer. N. Engl. J. Med. 310:1363, 1984 13. Kennedy, E.D., Blair, J.E., Ready, R., Wolff, B.G., Steinhart, A.H., Carryer, P.W., McLeod, R.S.: Subjects’ perceptions of their participation in a clinical trial. Can. J. Gastroenterol. 12:287, 1998