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Suspended judgment ethics, evidence, and uncertainty
SUSPENDED JUDGMENT Ethics, Evidence, and Uncertainty Valerie Mike, PhD Department of Public Health, Cornell University Medical College, New York, New York
An article in the August 7, 1989, issue of The Boston Globe carried the headline "A Harvard study on newborns draws fire: Doctors faulted for limiting lifesaving treatment" [1]. The story was yet another installment in the controversy concerning extracorporeal membrane oxygenation (ECMO), a recent innovation in the field of neonatal intensive care. This time, however, the results of the clinical trial and the ensuing debate were reported by the mass media 4 months before the study was published in a peer-reviewed medical journal [2]. ECMO has been proposed as a lifesaving treatment for infants with respiratory failure who have expected neonatal mortality of at least 80% with conventional ventilator support. It is a highly invasive and expensive procedure. It involves cardiopulmonary bypass, to provide adequate time and conditions for recovery of the impaired lungs. Pioneered by Robert Bartlett and associates, ECMO was tested by this team in a randomized clinical trial (RCT) [3]. The outcome was strongly in favor of ECMO, but the study design had been of the randomized play-the-winner type and provoked controversy [4]. It so happened that of 12 patients in the study, only I had been assigned to conventional treatment; this patient died, and all 11 ECMO patients survived. The Harvard study, using a different adaptive design, has been the second RCT undertaken for the assessment of neonatal ECMO. The results are again in favor of ECMO, but problems persist, involving ethical as well as medical considerations. The issues are well known: When is it appropriate to carry out an RCT? When should patient entry cease? What is the absolute mandate for informed consent? For ECMO there is the added problem of patient selection; other investigators are reporting equally good results without ECMO [5J and some are critical of the treatment given the control group in the trial. In the meantime, the technology is in a phase of rapid diffusion.
This section is edited by William A. Silverman, M D . Address reprint requests to: Valerie Mikd, PhD, Department of Public Health, Cornell University Medical College, 1300 York Avenue, New York, NY 10021. Received November 2, 1989; revised March 7, 1990. Controlled Clinical Trials 11:153-156 (1990) © Elsevier Science Publishing Co., Inc. 1990 655 Avenue of the Americas, New York, New York 10010
153 0197-2456/90/$3.50
154
v. Mik6
ECMO is now being used for treating full-term newborns, but its future adaptation for premature infants has implications far beyond the field of neonatal medicine. On the occasion of the recent Webster decision of the Supreme Court on abortion, Justice Sandra Day O'Connor expressed the view that Roe v. Wade is on a collision course with modern technology. A key issue is that of fetal viability, now believed to be at 24 weeks of gestation, the time needed for sufficient lung development to permit gas exchange. But what if the newborn can be put on a type of heart-lung machine--be given E C M O - to allow time for lung maturation? The enormous potential of this technology can hardly be exaggerated, with the need for continued evaluation of its effectiveness, criteria for its use, and its long-term consequences. National debates concerning RCTs---when to terminate the trial and make treatments available for nonresearch patients---are prominent also in other major areas, including life-threatening diseases such as AIDS [6] and cancer [7]. There are complex questions pertaining to ethics and scientific evidence. The Nuremberg Code of 1947 [8] is usually cited as the first code of ethics for human experimentation concerned with the rights of the subject; it deals explicitly with informed consent and the quality of the research to be performed. In the United States federal regulations for the conduct of clinical research came into being in the 1970s, after years of discussion and study; the first policy statement on institutional peer review and patient consent as prerequisites for funding by the Public Health Service was issued in 1966 [9]. In 1974, Congress passed the National Research Act and created a commission to propose basic ethical principles and develop guidelines for the protection of human subjects of research. This work became the basis of the final federal regulations. In its so-called Belmont Report [10] the commission identified three basic ethical principles consonant with the major traditions of Western thought: respect for persons, beneficence, and justice. Respect for persons is essentially the principle of autonomy, the right to self-determination; application of this principle to clinical research translates into informed consent. The second principle, beneficence, dates back to Hippocrates: help, or at least do no harm. In clinical research it calls for a careful assessment of risks and benefits. The third principle deals with distributive justice, the fair sharing in society of benefits and burdens; in clinical research it should govern the selection of subjects. In another article I have suggested that these three principles lend full support to the promulgation of an ethics of evidence [11], by which I mean standards for the creation, assessment, and communication of evidence. Affecting both research and practice, the main considerations are as follows: (1) According to the principle of autonomy patients (or their surrogates) have the right to make their own decisions about treatment. Yet in the general health care setting a patient cannot possibly give "informed" consent if the recommended procedures have not been properly evaluated. The required information is not available, and the patient is usually not even aware of the extent of medical uncertainty. (2) The principle of beneficence is directly relevant to an ethics of evidence. It is unethical to use powerful diagnostic and therapeutic procedures without sound assessment of their safety and effectiveness. Thus clinical studies without proper statistical design are themselves unethical. (3) The principle of justice has implications that exceed the
Ethics, Evidence, and Uncertainty
155
fair selection of research subjects. It can be interpreted to mean access to adequate medical care for all. It could then be argued that if only those procedures were used that are safe and really effective, the savings could provide medical coverage for the nearly 40 million Americans now without health insurance. This would also result in better medical care for all. Anyone concerned with justice therefore has a stake in the ethics of evidence. Space does not permit a full development of these points, but I expect no quarrel from readers of this journal. My main interest here is in a further extension of the basic thesis. There is a vast difference between codes and the world of reality. Nearly three decades were to pass after the Nuremberg Trials, with shocking medical practices reported here and abroad [12,13], before public opinion was sufficiently aroused to produce legislative action. The Tuskegee Syphilis Experiment (conducted by the U.S. Public Health Service) was not stopped until 1973, 8 months after the Associated Press broke the story [14]. Less well known is the fact that at the time of the Nazi atrocities there were already legally binding regulations in Germany--issued in 1931---concerning new therapy and human experimentation, and that they were more stringent than the subsequent Code of Nuremberg [15]. Professional responsibility, the ethics of research and therapy, informed consent, and quality of proposed research were addressed in detail. This early awareness can also be seen in the scientific realm, such as the book on methods of clinical research published in 1932 by Paul Martini, a professor of medicine at the University of Bonn [16]. Martini speaks of the controlled clinical trial as the ideal tool for the assessment of new therapies. He refers to the "Simultanmethode," alternating assignment of patients in a two-arm trial, as already known in the literature. He also voices criticism of the poor quality of much clinical research, resulting in unnecessary and even harmful medical procedures. He warns that in order to save money for insurance carriers, patients are often discharged from the hospital before their condition is resolved. This in turn interferes with the completion of clinical studies and in the long run makes for a false economy. My aim in suggesting an ethics of evidence has not been to propose yet another code, when codes have so often been notoriously ignored. Change occurs when conditions are right and there is widespread awareness. My aim is to speak of an ethics of evidence as a means of consciousness raising, of increasing awareness. There is a strong ethical basis for developing the best possible evidence for medical procedures, and the time may be right for a wider hearing. Yet there is a dual challenge. I believe that an ethics of evidence also carries a mandate to call attention to the ultimately irreducible nature of uncertainty. For the specialist in statistical methodology the concepts of evidence and uncertainty complement each other. There is a need to define and further clarify the relationship of these two concepts in an interdisciplinary context, in terms accessible to other professionals and the lay public. In a recent article published in this journal [17], I cited examples of moral philosophers passing judgment on RCTs without clear insight into the complexities of statistical theory. The uncertainties inherent in statistical inference are seen again with the adaptive designs used in the ECMO trials, compounded with other ethical aspects of RCTs. In bringing these vexing dilem-
156
v. Mik6 mas before the public, there is also the d a n g e r of obscuring medical uncertainties, such as the patient selection criteria for ECMO. Neonatal ECMO is but one example of the far-reaching implications of medical technology. A n d questions concerning RCTs pertain also to AIDS, cancer, and other major diseases affecting large segments of the population. Perhaps there has n e v e r b e e n a greater n e e d for a systematic, educated, and morally aware a p p r o a c h to the problem of evidence and uncertainty.
This research was supported by funds from the National Endowment for the Humanities and the National Science Foundation.
REFERENCES 1. Knox RA: A Harvard study on newborns draws fire: Doctors faulted for limiting life-saving treatment. The Boston Globe, August 7, 1989 2. O'Rourke PP, Crone RK, Vaeanti JP, Ware JH, Lillehei CW, Parad RB, Epstein MF: Extracorporeal membrane oxygenation and conventional medical therapy in neonates with persistent pulmonary hypertension of the newborn: A prospective randomized study. Pediatrics 84:957-963, 1989 3. Bartlett RH, Roloff DW, Cornell RG, Andrews AF, Dillon PW, Zwischenberger JB: Extracorporeal circulation in neonatal respiratory failure: A prospective randomized study. Pediatrics 76:479-487, 1985 4. Ware JH, Epstein MF: Extracorporeal circulation in neonatal respiratory failure: A prospective randomized study [Commentary]. Pediatrics 76:849-851, 1985 5. James LS: The need for ECMO may be avoided [Letter to the editor]. Contemp Pediatr 4:11, 1987 6. Marshall E: Quick release of AIDS drugs. Science 245:345-347, 1989 7. Marx JL: Drug availability is an issue for cancer patients, too. Science 245:346347, 1989 8. Nuremberg Code. Trials of War Criminals before the Nuremberg Military Tribunals under Control Council Law No. 10. Washington, DC, US Government Printing Office, 1949, vol 2, pp 181-182 9. Swazey JP: Protecting the "animal of necessity": Limits to inquiry in clinical investigation. Daedalus 20:129-145, 1978 10. National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research: The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research. Washington, DC, DHEW Publication (OS) 78-0012, 1978 11. Mik4 V: Toward an ethics of evidence---and beyond: Observations on technology and illness. Res Philos Tech 9:101-113, 1989 12. Beecher HK: Ethics and clinical research. N Engl J Med 274:1354-1360, 1966 13. Pappworth MH: Human Guinea Pigs. Boston, Beacon, 1967 14. Jones JH: Bad Blood: The Tuskegee Syphilis Experiment. New York, Free Press, 1981 15. Sass HM: Reichsrundschreiben 1931: Pre-Nuremberg German regulations concerning new therapy and human experimentation. J Med Philos 8:99-111, 1983 16. Martini P: Methodenlehre der therapeutischen Untersuchung. Berlin, Verlag von Julius Springer, 1932 17. Mik6 V: Philosophers assess randomized clinical trials: The need for dialogue. Controlled Clin Trials 10:244-253, 1989
An article in the August 7, 1989, issue of The Boston Globe carried the headline "A Harvard study on newborns draws fire: Doctors faulted for limiting lifesaving treatment" [1]. The story was yet another installment in the controversy concerning extracorporeal membrane oxygenation (ECMO), a recent innovation in the field of neonatal intensive care. This time, however, the results of the clinical trial and the ensuing debate were reported by the mass media 4 months before the study was published in a peer-reviewed medical journal [2]. ECMO has been proposed as a lifesaving treatment for infants with respiratory failure who have expected neonatal mortality of at least 80% with conventional ventilator support. It is a highly invasive and expensive procedure. It involves cardiopulmonary bypass, to provide adequate time and conditions for recovery of the impaired lungs. Pioneered by Robert Bartlett and associates, ECMO was tested by this team in a randomized clinical trial (RCT) [3]. The outcome was strongly in favor of ECMO, but the study design had been of the randomized play-the-winner type and provoked controversy [4]. It so happened that of 12 patients in the study, only I had been assigned to conventional treatment; this patient died, and all 11 ECMO patients survived. The Harvard study, using a different adaptive design, has been the second RCT undertaken for the assessment of neonatal ECMO. The results are again in favor of ECMO, but problems persist, involving ethical as well as medical considerations. The issues are well known: When is it appropriate to carry out an RCT? When should patient entry cease? What is the absolute mandate for informed consent? For ECMO there is the added problem of patient selection; other investigators are reporting equally good results without ECMO [5J and some are critical of the treatment given the control group in the trial. In the meantime, the technology is in a phase of rapid diffusion.
This section is edited by William A. Silverman, M D . Address reprint requests to: Valerie Mikd, PhD, Department of Public Health, Cornell University Medical College, 1300 York Avenue, New York, NY 10021. Received November 2, 1989; revised March 7, 1990. Controlled Clinical Trials 11:153-156 (1990) © Elsevier Science Publishing Co., Inc. 1990 655 Avenue of the Americas, New York, New York 10010
153 0197-2456/90/$3.50
154
v. Mik6
ECMO is now being used for treating full-term newborns, but its future adaptation for premature infants has implications far beyond the field of neonatal medicine. On the occasion of the recent Webster decision of the Supreme Court on abortion, Justice Sandra Day O'Connor expressed the view that Roe v. Wade is on a collision course with modern technology. A key issue is that of fetal viability, now believed to be at 24 weeks of gestation, the time needed for sufficient lung development to permit gas exchange. But what if the newborn can be put on a type of heart-lung machine--be given E C M O - to allow time for lung maturation? The enormous potential of this technology can hardly be exaggerated, with the need for continued evaluation of its effectiveness, criteria for its use, and its long-term consequences. National debates concerning RCTs---when to terminate the trial and make treatments available for nonresearch patients---are prominent also in other major areas, including life-threatening diseases such as AIDS [6] and cancer [7]. There are complex questions pertaining to ethics and scientific evidence. The Nuremberg Code of 1947 [8] is usually cited as the first code of ethics for human experimentation concerned with the rights of the subject; it deals explicitly with informed consent and the quality of the research to be performed. In the United States federal regulations for the conduct of clinical research came into being in the 1970s, after years of discussion and study; the first policy statement on institutional peer review and patient consent as prerequisites for funding by the Public Health Service was issued in 1966 [9]. In 1974, Congress passed the National Research Act and created a commission to propose basic ethical principles and develop guidelines for the protection of human subjects of research. This work became the basis of the final federal regulations. In its so-called Belmont Report [10] the commission identified three basic ethical principles consonant with the major traditions of Western thought: respect for persons, beneficence, and justice. Respect for persons is essentially the principle of autonomy, the right to self-determination; application of this principle to clinical research translates into informed consent. The second principle, beneficence, dates back to Hippocrates: help, or at least do no harm. In clinical research it calls for a careful assessment of risks and benefits. The third principle deals with distributive justice, the fair sharing in society of benefits and burdens; in clinical research it should govern the selection of subjects. In another article I have suggested that these three principles lend full support to the promulgation of an ethics of evidence [11], by which I mean standards for the creation, assessment, and communication of evidence. Affecting both research and practice, the main considerations are as follows: (1) According to the principle of autonomy patients (or their surrogates) have the right to make their own decisions about treatment. Yet in the general health care setting a patient cannot possibly give "informed" consent if the recommended procedures have not been properly evaluated. The required information is not available, and the patient is usually not even aware of the extent of medical uncertainty. (2) The principle of beneficence is directly relevant to an ethics of evidence. It is unethical to use powerful diagnostic and therapeutic procedures without sound assessment of their safety and effectiveness. Thus clinical studies without proper statistical design are themselves unethical. (3) The principle of justice has implications that exceed the
Ethics, Evidence, and Uncertainty
155
fair selection of research subjects. It can be interpreted to mean access to adequate medical care for all. It could then be argued that if only those procedures were used that are safe and really effective, the savings could provide medical coverage for the nearly 40 million Americans now without health insurance. This would also result in better medical care for all. Anyone concerned with justice therefore has a stake in the ethics of evidence. Space does not permit a full development of these points, but I expect no quarrel from readers of this journal. My main interest here is in a further extension of the basic thesis. There is a vast difference between codes and the world of reality. Nearly three decades were to pass after the Nuremberg Trials, with shocking medical practices reported here and abroad [12,13], before public opinion was sufficiently aroused to produce legislative action. The Tuskegee Syphilis Experiment (conducted by the U.S. Public Health Service) was not stopped until 1973, 8 months after the Associated Press broke the story [14]. Less well known is the fact that at the time of the Nazi atrocities there were already legally binding regulations in Germany--issued in 1931---concerning new therapy and human experimentation, and that they were more stringent than the subsequent Code of Nuremberg [15]. Professional responsibility, the ethics of research and therapy, informed consent, and quality of proposed research were addressed in detail. This early awareness can also be seen in the scientific realm, such as the book on methods of clinical research published in 1932 by Paul Martini, a professor of medicine at the University of Bonn [16]. Martini speaks of the controlled clinical trial as the ideal tool for the assessment of new therapies. He refers to the "Simultanmethode," alternating assignment of patients in a two-arm trial, as already known in the literature. He also voices criticism of the poor quality of much clinical research, resulting in unnecessary and even harmful medical procedures. He warns that in order to save money for insurance carriers, patients are often discharged from the hospital before their condition is resolved. This in turn interferes with the completion of clinical studies and in the long run makes for a false economy. My aim in suggesting an ethics of evidence has not been to propose yet another code, when codes have so often been notoriously ignored. Change occurs when conditions are right and there is widespread awareness. My aim is to speak of an ethics of evidence as a means of consciousness raising, of increasing awareness. There is a strong ethical basis for developing the best possible evidence for medical procedures, and the time may be right for a wider hearing. Yet there is a dual challenge. I believe that an ethics of evidence also carries a mandate to call attention to the ultimately irreducible nature of uncertainty. For the specialist in statistical methodology the concepts of evidence and uncertainty complement each other. There is a need to define and further clarify the relationship of these two concepts in an interdisciplinary context, in terms accessible to other professionals and the lay public. In a recent article published in this journal [17], I cited examples of moral philosophers passing judgment on RCTs without clear insight into the complexities of statistical theory. The uncertainties inherent in statistical inference are seen again with the adaptive designs used in the ECMO trials, compounded with other ethical aspects of RCTs. In bringing these vexing dilem-
156
v. Mik6 mas before the public, there is also the d a n g e r of obscuring medical uncertainties, such as the patient selection criteria for ECMO. Neonatal ECMO is but one example of the far-reaching implications of medical technology. A n d questions concerning RCTs pertain also to AIDS, cancer, and other major diseases affecting large segments of the population. Perhaps there has n e v e r b e e n a greater n e e d for a systematic, educated, and morally aware a p p r o a c h to the problem of evidence and uncertainty.
This research was supported by funds from the National Endowment for the Humanities and the National Science Foundation.
REFERENCES 1. Knox RA: A Harvard study on newborns draws fire: Doctors faulted for limiting life-saving treatment. The Boston Globe, August 7, 1989 2. O'Rourke PP, Crone RK, Vaeanti JP, Ware JH, Lillehei CW, Parad RB, Epstein MF: Extracorporeal membrane oxygenation and conventional medical therapy in neonates with persistent pulmonary hypertension of the newborn: A prospective randomized study. Pediatrics 84:957-963, 1989 3. Bartlett RH, Roloff DW, Cornell RG, Andrews AF, Dillon PW, Zwischenberger JB: Extracorporeal circulation in neonatal respiratory failure: A prospective randomized study. Pediatrics 76:479-487, 1985 4. Ware JH, Epstein MF: Extracorporeal circulation in neonatal respiratory failure: A prospective randomized study [Commentary]. Pediatrics 76:849-851, 1985 5. James LS: The need for ECMO may be avoided [Letter to the editor]. Contemp Pediatr 4:11, 1987 6. Marshall E: Quick release of AIDS drugs. Science 245:345-347, 1989 7. Marx JL: Drug availability is an issue for cancer patients, too. Science 245:346347, 1989 8. Nuremberg Code. Trials of War Criminals before the Nuremberg Military Tribunals under Control Council Law No. 10. Washington, DC, US Government Printing Office, 1949, vol 2, pp 181-182 9. Swazey JP: Protecting the "animal of necessity": Limits to inquiry in clinical investigation. Daedalus 20:129-145, 1978 10. National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research: The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research. Washington, DC, DHEW Publication (OS) 78-0012, 1978 11. Mik4 V: Toward an ethics of evidence---and beyond: Observations on technology and illness. Res Philos Tech 9:101-113, 1989 12. Beecher HK: Ethics and clinical research. N Engl J Med 274:1354-1360, 1966 13. Pappworth MH: Human Guinea Pigs. Boston, Beacon, 1967 14. Jones JH: Bad Blood: The Tuskegee Syphilis Experiment. New York, Free Press, 1981 15. Sass HM: Reichsrundschreiben 1931: Pre-Nuremberg German regulations concerning new therapy and human experimentation. J Med Philos 8:99-111, 1983 16. Martini P: Methodenlehre der therapeutischen Untersuchung. Berlin, Verlag von Julius Springer, 1932 17. Mik6 V: Philosophers assess randomized clinical trials: The need for dialogue. Controlled Clin Trials 10:244-253, 1989