Vicissitudes in Clinical Trial Research Subjects, Participants, Patients Howard B. Burchell, MD, PhD St. Paul, Minnesota
It has been said that "few scientists are as skilled as epidemiologists at tormenting clinicians" [1]. Possibly the ethicist and news reporter are adept in tormenting both. I enjoy a spirited disputation, but some physicians, perverse as h u m a n nature is, may have joined unthinkingly in the current popular sport of clinical trial "bashing" to the detriment of public health advances. I assume that the majority of practitioners have not organized and directed clinical trials but have been supportive, and keenly aware of the benefits to be derived from them. Recent challenges regarding the ethics of some trials could not have escaped notice. These have emphasized that the physician and the scientist have different moral responsibilities in health affairs [2-5]. Any attendant publicity will have been recognized as potentially having both salutary and detrimental effects on medical care and the growth of knowledge. In the first category of benefits, the investigator will have been reminded of the requirement for "equipoise" (lack of conviction of which arm of a treatment trial is better) as he or she faces the randomization of his or her patient into different arms of treatment; of the essentiality of the informed consent procedure; and of the need of knowledge of the ethical guidelines published from various international commissions and by the U.S. National Institutes of Health. In the category of a possible negative impact, there could be engendered a smoldering distrust of the physician-scientist, possibly amounting to panic in a few minority groups; a resulting dearth of recruits for scientifically desirable studies; and the drying up of needed financial support. Any distrust that might be inflamed will have a spillover effect on attitudes to medical research in general. It is an interesting coincidence that David Feldshuh's drama, "Miss Evers' Boys," has been playing at a Minneapolis theater at this time, w h e n editorials have appeared in our medical journals on the ethics of clinical trials. The play is based on the Tuskegee study (1932-1972), which attempted to establish the natural history of untreated syphilis in a group of African-Americans in a county in the State of Alabama [6-9]. The Tuskegee study properly has been defended for its inception, but certainly attempts to defend it after the point at which penicillin was available are not convincing. In retrospect, this study Address reprint requests to: Howard B. Burchell, MD, PhD, 260 WoodlawnAvenue, St. Paul,
MN 55105. ControlledClinicalTrials13:18,5-189(1992) © ElsevierSciencePublishingCo., Inc. 1992 655Avenueof the Americas,New York,New York10010
185 0197-2456/92/$5.00
186
H.B. Burchell will remain an odious stain on the escutcheon of the U.S. Public Health Service, albeit a paradoxical side effect of a grand scheme to control the disease nationally. It is difficult to understand h o w the study could have continued for so long. Some glimmer of insight comes when it is recalled that it stemmed from a surveillance study (of what was actually occurring) rather than a clinical therapeutic trial. Perhaps it is a fantasy, but from a utilitarian viewpoint, the health of the community might have benefitted. That is, might not the study have improved the health statistics of the local population? From the knowledge gained by some residents, Macon County might have fared better than neighboring counties in terms of the ravages of syphilis. However, many of the 400 or so "volunteers" w h o were deprived of treatment, sometimes by subtle coercion or alleged "guileful deceit" [7], probably suffered preventable progress of their aortitis. Yet even now there are no hard, unassailable data by which one can quantitate the benefit of penicillin in late syphilis. As indefensible as the trial now is, I think that it has been inappropriately maligned by a columnist-ethicist in a St. Paul newspaper [10] stating that the subjects were in an infectious stage, that no behavioral or medical information was given to them, and that none had therapy. Exaggeration by a critic in pursuit of a just cause can be a virtue, but the adjective heinous w h e n applied to the Tuskegee study seems inappropriate. Such criticism is mild relative to that which has appeared in the lay press, wherein comparison has been made to medical practices of the Nazi scientists. Another eminent academician has used the word infamous to categorize the study [11]. One reviewer, Beryl Byman [12], speaking of the recent symposium on race, prejudice, and health care in Minneapolis, which focused on the Tuskegee "experiment," discusses "medical racism" at some length. While I do not deny its existence, I do not believe that her account is scrupulously factual in respect to Tuskegee, and she also invites a comparison to the Nazi crimes. I admit a thread of similarity wherein the German Nazi and some U.S. public health officials assigned different values for lives in different populations, but I find it repugnant to equate the magnitude of the wrongs in the Nazi medical experiments and the Tuskegee study. The malficence of the study exposed by later analysts reflects ignominiously, in retrospect, not only on the Public Health Service but on our health care system in general. That the study was a product of racism has been alleged and accepted as truth by many. The statement "It could not have happened to a white cohort" was accepted as a truism by the Alabama investigating committee [6] and by Jones [7], but there is reasonable doubt that it was fundamental, despite the need existing in some minds, to determine whether syphilis manifested itself differently in blacks than in whites. The story of the study is told in meticulous detail by Jones [7]--the beginnings, its course, and its demise--but I believe he could have treated the medical profession more kindly. It is noteworthy that the pathological findings derived from the study were presented at the open meeting of the World Congress of Cardiology in 1954 without resultant gross ethical criticism. This paper [9] listed many supporting or sponsoring agencies. The Alabama committee laconically comments that these agencies 20 years later apparently wished to dissociate themselves from the study [6], referring to actions also discussed by Jones [7]. There has always been in the thinking of people, an undercurrent of loathsomeness about syphilis. The public reaction to the
Vicissitudes in Trial Research
187
Tuskegee study bears some similarity to the criticisms in 1912 of Hideyo Noguchi and the Rockefeller Hospital for testing of "Luetin," a product believed to be derived from the syphilitic spirochete, on patients including children. The brunt of the attack was borne by collaborating physicians [13]. The current editorials on the ethics of clinical trials provide a needed service, highlighting the different loyalties of a caring physician w h o has "patients" and a scientist w h o has "subjects" and "numbers." If this essential difference is always remembered, collaborative efforts will be happier and more productive. The Hellmans' editorial in the New England Journal of Medicine [2] brilliantly outlines the physician's idealistic, nonutilitarian, Samaritan relationship to his or her patient. I think one weakness in their argument is the lack of adequate recognition of the foibles in physicians' convictions. In the accompanying editorial, Passamani [3] offers a rebuttal in defense of the randomized trial. Possibly, however, he may discard too facilely other avenues in the research approach and some of his good answers illustrated by his samples of various trials may have more complex interpretations than discussed. It is possible for a physician to be both the caregiver and the scientist, but she or he will sometimes be torn in a battle between an intuitive individualized therapeutic inclination and a feeling of loyalty, with a locked-in sense of adherence, to protocol. The dilemma is succinctly outlined by Alvan Feinstein, w h o labels the fundamental distinction in the two policy viewpoints as "societal" vs "Samaritan." His choice of the word "Samaritan" is a good one. He implies that randomization may be unacceptable sometimes, but also that Samaritan judgments have led to past delusions about the merits of particular therapeutic choices [14]. It is not only our medical journals but also the newspapers that editorialize on alleged errors of scientists insisting on careful trials. As an example, the Wall Street Journal has taken the position that any promising therapy should be given to patients with a serious progressive disease, such as Alzheimer's and AIDS [15]. The designer of a clinical trial would wish to have the cohort under examination be as homogeneous as possible, aiming to keep the study economical with a high probability of yielding an answer. Huge numbers will compensate for some inhomogeneity and may even give a statistical answer to the question of whether marginal potential benefit or harm exists, but this strays from the physician's interest in obtaining the best possible treatment for an individual patient. There have been inequities in the selection of subjects in respect to gender, race, and age, but surely a critic's first question should not be, " H o w many w o m e n (blacks, retirees) have been included:? Had these populations been excluded, the question "why?" would indeed be relevant, and additional studies might be suggested without necessarily casting umbrage on the intent or scientific design of the study under scrutiny, or "bashing it" outrightly. I do not agree that the randomized trial is the "one and only" approach to the testing of a n e w drug or procedure, though it ranks highest on our list of effective methods. One alternative method, applicable to some chronic stable diseases, utilizes a crossover design, with the patients acting as their o w n control. Designers of studies in recent years have carefully considered the ethics of their proposals, and have built in mechanisms for safety and the
188
H.B. Burchell need to terminate a trial if there is clear evidence of either harm or benefit. In recent decades, the word significant has been appropriated by scientists for mathematical probabilities, but credence should be given to the term clinical significance where results are also to be interpreted in terms of quality of life. What can be distilled from the plethora of available publications to guide us? I think the following can be stated: (1) There should be further emphasis on education of both the lay public and medical students in trial design and regarding the benefits from the results of a properly conducted trial. (2) There must be continued vigilance in the employment of the consent decree with full disclosure of facts regarding the trial, approaching the goal of "informed consent". (3) There should be continued effort on the part of physicians to understand the intricacies of the designs of any study. For example, what are the questions being asked? What is their importance? How does the concept of statistical "power" address the specific questions concerning recruitment, ethics, and cost? (4) There must be constant attention to the sensitivities of the patients under study, with respect paid to the fact that they are still "patients" and conversations about their illness and the incentives to enter a trial should not be hurried. A secondary lesson from the Tuskegee study analysis is that attempted wit and facetiousness in correspondence, even when apparently born of fatigue and frustration, may reflect badly on the profession when uncovered years later. It is disquieting to me to hear reports that a seemingly increasing number of potential recruits to a study have not been entered because of "patient's refusal" (or the doctor's?). If this is a trend, it is a grievous one, and the profession has the responsibility to reverse it. Continuing education of both the profession and the public is required with free interchange of opinions between the two.
REFERENCES
1. Simpson RJ, White A: Editorial. Getting the handle on the prevalence of coronary disease. Br Heart J 64:291-292, 1990 2. Hellman S, Hellman DS: Of mice but not men. Problems of the randomized clinical trial. N Engl J Med 324:1585-1589, 1991 3. Passamani E: Clinical trials. Are they ethical? N Engl J Med 324:1585-1589, 1991 4. MacIntyre IM: Tribulations for clinical trials. Poor recruitment is hampering research. Br Med J 1099-1100, 1991 5. BurcheL1HB: Digitalis associated mortality after myocardial infarction: Moral responsibilities in recommending clinical trials. Int J Cardiol 29:105-106, 1990 6. A report of the Alabama Committee of the U.S. Commission on Civil Rights. The Tuskegee study. 1973 7. Jones JH: Bad blood. The Tuskegee syphilis experiments. New York, Free Press, 1981 8. Rockwell DH, Yobs AR, Moore MB: The Tuskegee study of un-treated syphilis. Thirty year observation. Arch Intern Med 114:792-798, 1964 9. Peters JJ, Peers JH, Olanski S, Cutler JC, Gleeson JA: Untreated syphilis in the male Negro: Pathologic findings in syphilitic and non-syphilitic patients. J Chronic Dis 1:127-148, 1955 10. Caplan A: Syphilis study increased fear, loathing. St. Paul Pioneer Press, June 10, 1991, Column 1, 9C
Vicissitudes in Trial Research
189
11. Silver GA: (Letter) The infamous Tuskegee study. Am J Public Health 78:1500, 1988 12. Byman B: Out of the shadow of Tuskegee. Fighting racism in medicine. Minn Med 74:15-20, 1991 13. Lederer S: Hideyo Noguchi's Luetin experiment and the antivivisectionists. Isis 76:31-48, 1985 14. Feinstein AR: Clinical Epidemiology: The Architecture of Clinical Research. Philadelphia, WB Saunders, 1985, pp 7(34-705 15. Editorial: Requiem for Alzheimer's patients. Wall Street Journal, July 19, 1991, p A12
It has been said that "few scientists are as skilled as epidemiologists at tormenting clinicians" [1]. Possibly the ethicist and news reporter are adept in tormenting both. I enjoy a spirited disputation, but some physicians, perverse as h u m a n nature is, may have joined unthinkingly in the current popular sport of clinical trial "bashing" to the detriment of public health advances. I assume that the majority of practitioners have not organized and directed clinical trials but have been supportive, and keenly aware of the benefits to be derived from them. Recent challenges regarding the ethics of some trials could not have escaped notice. These have emphasized that the physician and the scientist have different moral responsibilities in health affairs [2-5]. Any attendant publicity will have been recognized as potentially having both salutary and detrimental effects on medical care and the growth of knowledge. In the first category of benefits, the investigator will have been reminded of the requirement for "equipoise" (lack of conviction of which arm of a treatment trial is better) as he or she faces the randomization of his or her patient into different arms of treatment; of the essentiality of the informed consent procedure; and of the need of knowledge of the ethical guidelines published from various international commissions and by the U.S. National Institutes of Health. In the category of a possible negative impact, there could be engendered a smoldering distrust of the physician-scientist, possibly amounting to panic in a few minority groups; a resulting dearth of recruits for scientifically desirable studies; and the drying up of needed financial support. Any distrust that might be inflamed will have a spillover effect on attitudes to medical research in general. It is an interesting coincidence that David Feldshuh's drama, "Miss Evers' Boys," has been playing at a Minneapolis theater at this time, w h e n editorials have appeared in our medical journals on the ethics of clinical trials. The play is based on the Tuskegee study (1932-1972), which attempted to establish the natural history of untreated syphilis in a group of African-Americans in a county in the State of Alabama [6-9]. The Tuskegee study properly has been defended for its inception, but certainly attempts to defend it after the point at which penicillin was available are not convincing. In retrospect, this study Address reprint requests to: Howard B. Burchell, MD, PhD, 260 WoodlawnAvenue, St. Paul,
MN 55105. ControlledClinicalTrials13:18,5-189(1992) © ElsevierSciencePublishingCo., Inc. 1992 655Avenueof the Americas,New York,New York10010
185 0197-2456/92/$5.00
186
H.B. Burchell will remain an odious stain on the escutcheon of the U.S. Public Health Service, albeit a paradoxical side effect of a grand scheme to control the disease nationally. It is difficult to understand h o w the study could have continued for so long. Some glimmer of insight comes when it is recalled that it stemmed from a surveillance study (of what was actually occurring) rather than a clinical therapeutic trial. Perhaps it is a fantasy, but from a utilitarian viewpoint, the health of the community might have benefitted. That is, might not the study have improved the health statistics of the local population? From the knowledge gained by some residents, Macon County might have fared better than neighboring counties in terms of the ravages of syphilis. However, many of the 400 or so "volunteers" w h o were deprived of treatment, sometimes by subtle coercion or alleged "guileful deceit" [7], probably suffered preventable progress of their aortitis. Yet even now there are no hard, unassailable data by which one can quantitate the benefit of penicillin in late syphilis. As indefensible as the trial now is, I think that it has been inappropriately maligned by a columnist-ethicist in a St. Paul newspaper [10] stating that the subjects were in an infectious stage, that no behavioral or medical information was given to them, and that none had therapy. Exaggeration by a critic in pursuit of a just cause can be a virtue, but the adjective heinous w h e n applied to the Tuskegee study seems inappropriate. Such criticism is mild relative to that which has appeared in the lay press, wherein comparison has been made to medical practices of the Nazi scientists. Another eminent academician has used the word infamous to categorize the study [11]. One reviewer, Beryl Byman [12], speaking of the recent symposium on race, prejudice, and health care in Minneapolis, which focused on the Tuskegee "experiment," discusses "medical racism" at some length. While I do not deny its existence, I do not believe that her account is scrupulously factual in respect to Tuskegee, and she also invites a comparison to the Nazi crimes. I admit a thread of similarity wherein the German Nazi and some U.S. public health officials assigned different values for lives in different populations, but I find it repugnant to equate the magnitude of the wrongs in the Nazi medical experiments and the Tuskegee study. The malficence of the study exposed by later analysts reflects ignominiously, in retrospect, not only on the Public Health Service but on our health care system in general. That the study was a product of racism has been alleged and accepted as truth by many. The statement "It could not have happened to a white cohort" was accepted as a truism by the Alabama investigating committee [6] and by Jones [7], but there is reasonable doubt that it was fundamental, despite the need existing in some minds, to determine whether syphilis manifested itself differently in blacks than in whites. The story of the study is told in meticulous detail by Jones [7]--the beginnings, its course, and its demise--but I believe he could have treated the medical profession more kindly. It is noteworthy that the pathological findings derived from the study were presented at the open meeting of the World Congress of Cardiology in 1954 without resultant gross ethical criticism. This paper [9] listed many supporting or sponsoring agencies. The Alabama committee laconically comments that these agencies 20 years later apparently wished to dissociate themselves from the study [6], referring to actions also discussed by Jones [7]. There has always been in the thinking of people, an undercurrent of loathsomeness about syphilis. The public reaction to the
Vicissitudes in Trial Research
187
Tuskegee study bears some similarity to the criticisms in 1912 of Hideyo Noguchi and the Rockefeller Hospital for testing of "Luetin," a product believed to be derived from the syphilitic spirochete, on patients including children. The brunt of the attack was borne by collaborating physicians [13]. The current editorials on the ethics of clinical trials provide a needed service, highlighting the different loyalties of a caring physician w h o has "patients" and a scientist w h o has "subjects" and "numbers." If this essential difference is always remembered, collaborative efforts will be happier and more productive. The Hellmans' editorial in the New England Journal of Medicine [2] brilliantly outlines the physician's idealistic, nonutilitarian, Samaritan relationship to his or her patient. I think one weakness in their argument is the lack of adequate recognition of the foibles in physicians' convictions. In the accompanying editorial, Passamani [3] offers a rebuttal in defense of the randomized trial. Possibly, however, he may discard too facilely other avenues in the research approach and some of his good answers illustrated by his samples of various trials may have more complex interpretations than discussed. It is possible for a physician to be both the caregiver and the scientist, but she or he will sometimes be torn in a battle between an intuitive individualized therapeutic inclination and a feeling of loyalty, with a locked-in sense of adherence, to protocol. The dilemma is succinctly outlined by Alvan Feinstein, w h o labels the fundamental distinction in the two policy viewpoints as "societal" vs "Samaritan." His choice of the word "Samaritan" is a good one. He implies that randomization may be unacceptable sometimes, but also that Samaritan judgments have led to past delusions about the merits of particular therapeutic choices [14]. It is not only our medical journals but also the newspapers that editorialize on alleged errors of scientists insisting on careful trials. As an example, the Wall Street Journal has taken the position that any promising therapy should be given to patients with a serious progressive disease, such as Alzheimer's and AIDS [15]. The designer of a clinical trial would wish to have the cohort under examination be as homogeneous as possible, aiming to keep the study economical with a high probability of yielding an answer. Huge numbers will compensate for some inhomogeneity and may even give a statistical answer to the question of whether marginal potential benefit or harm exists, but this strays from the physician's interest in obtaining the best possible treatment for an individual patient. There have been inequities in the selection of subjects in respect to gender, race, and age, but surely a critic's first question should not be, " H o w many w o m e n (blacks, retirees) have been included:? Had these populations been excluded, the question "why?" would indeed be relevant, and additional studies might be suggested without necessarily casting umbrage on the intent or scientific design of the study under scrutiny, or "bashing it" outrightly. I do not agree that the randomized trial is the "one and only" approach to the testing of a n e w drug or procedure, though it ranks highest on our list of effective methods. One alternative method, applicable to some chronic stable diseases, utilizes a crossover design, with the patients acting as their o w n control. Designers of studies in recent years have carefully considered the ethics of their proposals, and have built in mechanisms for safety and the
188
H.B. Burchell need to terminate a trial if there is clear evidence of either harm or benefit. In recent decades, the word significant has been appropriated by scientists for mathematical probabilities, but credence should be given to the term clinical significance where results are also to be interpreted in terms of quality of life. What can be distilled from the plethora of available publications to guide us? I think the following can be stated: (1) There should be further emphasis on education of both the lay public and medical students in trial design and regarding the benefits from the results of a properly conducted trial. (2) There must be continued vigilance in the employment of the consent decree with full disclosure of facts regarding the trial, approaching the goal of "informed consent". (3) There should be continued effort on the part of physicians to understand the intricacies of the designs of any study. For example, what are the questions being asked? What is their importance? How does the concept of statistical "power" address the specific questions concerning recruitment, ethics, and cost? (4) There must be constant attention to the sensitivities of the patients under study, with respect paid to the fact that they are still "patients" and conversations about their illness and the incentives to enter a trial should not be hurried. A secondary lesson from the Tuskegee study analysis is that attempted wit and facetiousness in correspondence, even when apparently born of fatigue and frustration, may reflect badly on the profession when uncovered years later. It is disquieting to me to hear reports that a seemingly increasing number of potential recruits to a study have not been entered because of "patient's refusal" (or the doctor's?). If this is a trend, it is a grievous one, and the profession has the responsibility to reverse it. Continuing education of both the profession and the public is required with free interchange of opinions between the two.
REFERENCES
1. Simpson RJ, White A: Editorial. Getting the handle on the prevalence of coronary disease. Br Heart J 64:291-292, 1990 2. Hellman S, Hellman DS: Of mice but not men. Problems of the randomized clinical trial. N Engl J Med 324:1585-1589, 1991 3. Passamani E: Clinical trials. Are they ethical? N Engl J Med 324:1585-1589, 1991 4. MacIntyre IM: Tribulations for clinical trials. Poor recruitment is hampering research. Br Med J 1099-1100, 1991 5. BurcheL1HB: Digitalis associated mortality after myocardial infarction: Moral responsibilities in recommending clinical trials. Int J Cardiol 29:105-106, 1990 6. A report of the Alabama Committee of the U.S. Commission on Civil Rights. The Tuskegee study. 1973 7. Jones JH: Bad blood. The Tuskegee syphilis experiments. New York, Free Press, 1981 8. Rockwell DH, Yobs AR, Moore MB: The Tuskegee study of un-treated syphilis. Thirty year observation. Arch Intern Med 114:792-798, 1964 9. Peters JJ, Peers JH, Olanski S, Cutler JC, Gleeson JA: Untreated syphilis in the male Negro: Pathologic findings in syphilitic and non-syphilitic patients. J Chronic Dis 1:127-148, 1955 10. Caplan A: Syphilis study increased fear, loathing. St. Paul Pioneer Press, June 10, 1991, Column 1, 9C
Vicissitudes in Trial Research
189
11. Silver GA: (Letter) The infamous Tuskegee study. Am J Public Health 78:1500, 1988 12. Byman B: Out of the shadow of Tuskegee. Fighting racism in medicine. Minn Med 74:15-20, 1991 13. Lederer S: Hideyo Noguchi's Luetin experiment and the antivivisectionists. Isis 76:31-48, 1985 14. Feinstein AR: Clinical Epidemiology: The Architecture of Clinical Research. Philadelphia, WB Saunders, 1985, pp 7(34-705 15. Editorial: Requiem for Alzheimer's patients. Wall Street Journal, July 19, 1991, p A12
