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The Need for Randomized Controlled Trials
Editorial The Need for Randomized Controlled Trials The Cochran Initiative THOMAS
N.
M.D. M.D.
WISE,
JAMES J. STRAIN,
Received April \9. \996; accepted April 19. 1996. From the Department of Psychiatry. Georgelown University School of Medicine. Washington. DC; and the Department of Psychiatry. Mt. Sinai Medical Center. New York. Address reprint requests 10 Dr. Wise. Fairfax Hospital. 3300 Gallows Rd.• Falls Church. VA 22046. Copyrighl © 1996 The Academy of Psychosomatic Medicine.
D
espite the recognition that psychological factors enhance the morbidity and mortality in various medical disorders, further data is needed to convince policymakers and physicians who are developing clinical guidelines in other specialities that psychiatric intervention should be included. In fact. the strength of the evidence from randomized controIled trials (RCT) may detennine the guidelines' position with regard to psychosocial issues. I Two recent reports from the Netherlands and the United Kingdom demonstrate the effectiveness of cognitive behavioral therapy in patients with chronic fatigue syndrome, as weIl as the more generalized problem of "medicaIly unexplained physical symptoms.,,2.3 Both studies used a randomized controIled trial. RCTs may detennine the effectiveness of treatment by minimizing the possibility that there will be a positive bias that augments the study effect. Both selection bias and infonnation bias are reduced via blinding the data until final assessment. Unfortunately. accessing such studies is often difficult. Thus. the Cochran Centre (Oxford University, Oxford, England), funded by the United Kingdom's National Health Service, has been established and charged with facilitating systematic reviews of known RCTs by rigorous protocols. It is named after Archie Cochran. an epidemiologist who urged physicians to become aware of what is now known about disease states and appropriate interventions. 4 The Centre also conducts and publishes meta-analyses of series of RCTs on a given topic. The review process is laborious. as it requires hand review of journals. since MEDLINE and other on-line search methods fail to list many critical articles. To date. consultation-liaison psychiatry has not been reviewed by the Cochran organization. Two cautions prevail with regard to the authority of the RCT to provide clear evidence of the most appropriate treatment approach. First. although the RCT may yield a statisticaIly significant effect of the treatment over placebo. there may be real questions as to the clinical meaning of the effect. For example, it was reported in the New England Journal ofMedicine that tacrine was superior to placebo in assisting Alzheimer patients retain cognitive functioning.~ However. as the editorial pointed out. there was a methodological concern of selecting patients for the study who were positive reactors to the medication. and that retaining a few words and some limited functions of activities of daily living may not be of sufficient clinical merit to warrant using an expensive medication that also has the potential for hepatic damage. 6 In the words of the commentator: "The jury is still out." That RCT did not unequivocaIly answer the question. A second study was conducted that eliminated the selection bias of the earlier work; the results
VOLUME 37 • NUMBER 6 • NOVEMBER - DECEMBER \996
499
Editorial
were much more robust, indicating the drug's effectiveness. 7 That is the point of Archie Cochran's admonishment-to analyze the results we have, to know their value. On the other hand, there are other biases that may foster a Type II error in clinically effective treatments: one being the presence of a significant clinical benefit that is masked or ignored because of a lack of a statistical significance when compared with a comparison group. Van Hemert has discussed the limitations/conditions that tend to dilute the true effect of the intervention in question. 7 In this situation, a finding is dismissed based on the lack of the study data reaching statistical significance. Without a rational appeal to the measurable clinical effectiveness, or the methodological confounds that may have sufficiently attenuated the robustness of the results, an opportunity for a viable intervention may be lost. It isn't just that it is an RCT that makes it the best science, it is the quality of the RCT and how this RCT compares with others attempted. These two limitations may compromise adequate guidance for clinical decision making, but they would most likely be considered by the Cochran review group. The RCT is not perfect, but at this time it offers a significant advantage over the case report, retrospective studies, open trials, or uncontrolled interventions, which constitute so many reports in all fields of medicine. As studies improve in their methodological qualities, for example, taking into account the severity of the medical illness, a new level of data will be available for clinical decision making. To our fortune, the Academy supports and encourages its members to participate in the Cochran Initiative to evaluate RCTs of importance to our work. Such an effort by the Academy membership to respond to this challenge will actively advance information now available, which is so difficult to find, and not always so easy to understand with regard to its value in the clinical decision-making arena. Thus, the Academy's Task Force on Comorbidity and Outcomes has attempted to bring together and critique the effects of outcome studies. 8 Drs. Wayne Katon and Junius Gonzales reviewed RCTs of psychiatric interventions in primary care settings. 9 Through Dr. Richard Mayou in the Department of Psychiatry, Oxford University, Drs. Roger Kathol and James Strain have established relationships with the Cochran Centre and have asked to be part of a review committee that would target RCTs of particular interest to the consultationliaison field. Such a group is now in formation, and their findings would be an essential resource for the members of our Academy. 500
PSYCHOSOMATICS
Editorial
References I. Gill DBE. Adams CE: Randomized controlIed trials in the JOUrnlJI of Psychosomatic Research. 1956-1993: a prevalence study. J Psychosom Res 1995; 39:949-956 2. Speckers AEM. Van Hemen AM. Spinhaven P. et a1: Cognitive behavioural therapy for medically unexplained physical symptoms: a randomized controlIed trial. BMJ 1995; 311:1328-1332 3. Sharpe MT. Hawton K. Simkin SI. et a1: Cognitive behavioural therapy for the chronic fatigue syndrome: a randomized controlIed trial. BMJ 1996; 312:22-26 4. Cochran AL: 1931-1971: A Critical Review. with PanicularReference to the Medical Profession in Medicines for the Year 2000. London. England. Office of Health Economics. 1979 5. Davis KL. Thai U. Garnzu ER. et a1: DoUble-blind. placebo-controlIed multicenter study oftacrine for Alzheimer's disease. N Engl J Med 1992; 327: 1253-1259 6. Growdon JH: Treatment for Alzheimer's disease. N Engl J Med 1992; 327:1306-1308 7. Van Hemen AM: Dilution of effect: a systematic bias in the randomized controlIed trial. J Psychosom Res 1995; 8:933-935 8. Saravay SM. Strain 11: APM task force on funding implications of consultation-liaison outcome studies-special series: introduction: a review of outcome studies. Psychosomatics 1994; 35:227-232 9. Katon W. Gonzales J: A review of randomized trials of psychiatric consultation-liaison studies in primary care. Psychosomatics 1994; 35:268-278
VOLUME37.NUMBER6.NOVEMBER-DBC8MBERI~
SOl
N.
M.D. M.D.
WISE,
JAMES J. STRAIN,
Received April \9. \996; accepted April 19. 1996. From the Department of Psychiatry. Georgelown University School of Medicine. Washington. DC; and the Department of Psychiatry. Mt. Sinai Medical Center. New York. Address reprint requests 10 Dr. Wise. Fairfax Hospital. 3300 Gallows Rd.• Falls Church. VA 22046. Copyrighl © 1996 The Academy of Psychosomatic Medicine.
D
espite the recognition that psychological factors enhance the morbidity and mortality in various medical disorders, further data is needed to convince policymakers and physicians who are developing clinical guidelines in other specialities that psychiatric intervention should be included. In fact. the strength of the evidence from randomized controIled trials (RCT) may detennine the guidelines' position with regard to psychosocial issues. I Two recent reports from the Netherlands and the United Kingdom demonstrate the effectiveness of cognitive behavioral therapy in patients with chronic fatigue syndrome, as weIl as the more generalized problem of "medicaIly unexplained physical symptoms.,,2.3 Both studies used a randomized controIled trial. RCTs may detennine the effectiveness of treatment by minimizing the possibility that there will be a positive bias that augments the study effect. Both selection bias and infonnation bias are reduced via blinding the data until final assessment. Unfortunately. accessing such studies is often difficult. Thus. the Cochran Centre (Oxford University, Oxford, England), funded by the United Kingdom's National Health Service, has been established and charged with facilitating systematic reviews of known RCTs by rigorous protocols. It is named after Archie Cochran. an epidemiologist who urged physicians to become aware of what is now known about disease states and appropriate interventions. 4 The Centre also conducts and publishes meta-analyses of series of RCTs on a given topic. The review process is laborious. as it requires hand review of journals. since MEDLINE and other on-line search methods fail to list many critical articles. To date. consultation-liaison psychiatry has not been reviewed by the Cochran organization. Two cautions prevail with regard to the authority of the RCT to provide clear evidence of the most appropriate treatment approach. First. although the RCT may yield a statisticaIly significant effect of the treatment over placebo. there may be real questions as to the clinical meaning of the effect. For example, it was reported in the New England Journal ofMedicine that tacrine was superior to placebo in assisting Alzheimer patients retain cognitive functioning.~ However. as the editorial pointed out. there was a methodological concern of selecting patients for the study who were positive reactors to the medication. and that retaining a few words and some limited functions of activities of daily living may not be of sufficient clinical merit to warrant using an expensive medication that also has the potential for hepatic damage. 6 In the words of the commentator: "The jury is still out." That RCT did not unequivocaIly answer the question. A second study was conducted that eliminated the selection bias of the earlier work; the results
VOLUME 37 • NUMBER 6 • NOVEMBER - DECEMBER \996
499
Editorial
were much more robust, indicating the drug's effectiveness. 7 That is the point of Archie Cochran's admonishment-to analyze the results we have, to know their value. On the other hand, there are other biases that may foster a Type II error in clinically effective treatments: one being the presence of a significant clinical benefit that is masked or ignored because of a lack of a statistical significance when compared with a comparison group. Van Hemert has discussed the limitations/conditions that tend to dilute the true effect of the intervention in question. 7 In this situation, a finding is dismissed based on the lack of the study data reaching statistical significance. Without a rational appeal to the measurable clinical effectiveness, or the methodological confounds that may have sufficiently attenuated the robustness of the results, an opportunity for a viable intervention may be lost. It isn't just that it is an RCT that makes it the best science, it is the quality of the RCT and how this RCT compares with others attempted. These two limitations may compromise adequate guidance for clinical decision making, but they would most likely be considered by the Cochran review group. The RCT is not perfect, but at this time it offers a significant advantage over the case report, retrospective studies, open trials, or uncontrolled interventions, which constitute so many reports in all fields of medicine. As studies improve in their methodological qualities, for example, taking into account the severity of the medical illness, a new level of data will be available for clinical decision making. To our fortune, the Academy supports and encourages its members to participate in the Cochran Initiative to evaluate RCTs of importance to our work. Such an effort by the Academy membership to respond to this challenge will actively advance information now available, which is so difficult to find, and not always so easy to understand with regard to its value in the clinical decision-making arena. Thus, the Academy's Task Force on Comorbidity and Outcomes has attempted to bring together and critique the effects of outcome studies. 8 Drs. Wayne Katon and Junius Gonzales reviewed RCTs of psychiatric interventions in primary care settings. 9 Through Dr. Richard Mayou in the Department of Psychiatry, Oxford University, Drs. Roger Kathol and James Strain have established relationships with the Cochran Centre and have asked to be part of a review committee that would target RCTs of particular interest to the consultationliaison field. Such a group is now in formation, and their findings would be an essential resource for the members of our Academy. 500
PSYCHOSOMATICS
Editorial
References I. Gill DBE. Adams CE: Randomized controlIed trials in the JOUrnlJI of Psychosomatic Research. 1956-1993: a prevalence study. J Psychosom Res 1995; 39:949-956 2. Speckers AEM. Van Hemen AM. Spinhaven P. et a1: Cognitive behavioural therapy for medically unexplained physical symptoms: a randomized controlIed trial. BMJ 1995; 311:1328-1332 3. Sharpe MT. Hawton K. Simkin SI. et a1: Cognitive behavioural therapy for the chronic fatigue syndrome: a randomized controlIed trial. BMJ 1996; 312:22-26 4. Cochran AL: 1931-1971: A Critical Review. with PanicularReference to the Medical Profession in Medicines for the Year 2000. London. England. Office of Health Economics. 1979 5. Davis KL. Thai U. Garnzu ER. et a1: DoUble-blind. placebo-controlIed multicenter study oftacrine for Alzheimer's disease. N Engl J Med 1992; 327: 1253-1259 6. Growdon JH: Treatment for Alzheimer's disease. N Engl J Med 1992; 327:1306-1308 7. Van Hemen AM: Dilution of effect: a systematic bias in the randomized controlIed trial. J Psychosom Res 1995; 8:933-935 8. Saravay SM. Strain 11: APM task force on funding implications of consultation-liaison outcome studies-special series: introduction: a review of outcome studies. Psychosomatics 1994; 35:227-232 9. Katon W. Gonzales J: A review of randomized trials of psychiatric consultation-liaison studies in primary care. Psychosomatics 1994; 35:268-278
VOLUME37.NUMBER6.NOVEMBER-DBC8MBERI~
SOl