Sins of Omission — Cancer Research without Informed Consent
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《新英格兰医药杂志》
Avir Kagan was an attending physician at Brooklyn's Jewish Chronic Disease Hospital (JCDH) in 1963, when he received a surprising request: Would he participate in an experiment in which live cancer cells were injected into chronically ill patients? Although Kagan said no, some of his colleagues agreed. By 1964, an enormous controversy had erupted, and the hospital's staff was being compared to Nazi physicians who had performed brutal experiments in concentration camps.
How did it happen that 22 patients received injections of cancer cells without their knowledge? On the 40th anniversary of this scandal, what can it teach us about the ethics of human experimentation?
The physician who spearheaded the experiment, Chester M. Southam, was a respected clinical investigator at the Memorial Sloan-Kettering Cancer Center who was studying the immunology of cancer. He had injected cancer cells into hundreds of patients with cancer, generating nodules that grew for several weeks before regressing. In contrast, similar injections in healthy volunteers showed much more rapid rejection.1 These findings suggested that patients with cancer lacked immunity to their disease, but Southam wanted to make sure that this phenomenon was not attributable solely to their debilitated state. So he sought out chronically ill people who did not have cancer.
Southam approached Emanuel E. Mandel, director of the Department of Medicine at JCDH. Mandel agreed to cooperate, and it was he who asked Kagan to participate. When Kagan declined, Mandel recruited a resident physician to perform the injections. Although details of what occurred remain disputed, some facts are clear. Twenty-two patients received injections of a "cell suspension." The word "cancer" was never mentioned to the subjects. Southam later justified this omission in two ways. He believed, first, that there was no risk that cancer would develop and, second, that the word "cancer" caused "bizarre, defensive" reactions on the part of patients — hence, the word had been omitted for their sake.2
When Kagan and his colleagues David Leichter and Perry Fersko learned that the experiment had proceeded, they resigned from JCDH. Meanwhile, William A. Hyman, a member of the hospital's board of directors, had grown alarmed and sued the hospital to obtain the records of the patients. It was Hyman's lawsuit that alerted the media, resulting in "the hottest public debate on medical ethics since the Nuremberg trials of Nazi physicians."2 Indeed, it was Hyman and other critics at JCDH who had first termed Southam's experiments "acts which belong more properly in Dachau."1
Hyman eventually won his lawsuit, but it was another legal proceeding — a 1964 hearing before the Board of Regents of the University of the State of New York — that most clearly revealed the ethical issues at stake. During that hearing, New York State Attorney General Louis L. Lefkowitz sought to revoke the medical licenses of Southam and Mandel. The heart of the state's case was that the investigators had not obtained valid informed consent from the subjects. Southam stated that there had been oral consent. But according to Lefkowitz, a substantial number of the patients "had not sufficient mental or physical ability to comprehend what was being told to them or what was being done to them," and those patients with such capacity had been misled.1
What were the standards for informed consent at the time? It is not surprising that Hyman had drawn the analogy to the Nazis. As part of the legal proceedings against Nazi doctors at Nuremberg in 1946, U.S. justices had drafted the Nuremberg Code for human experimentation, which stated that "the voluntary consent of the human subject is absolutely essential." Kagan later admitted that his objections had not been based on the code, however3; he and his fellow critics had simply believed that the experiments were "morally wrong."1 During the hearing, Lefkowitz did not hide his outrage, declaring that "every human being has an inalienable right to determine what shall be done with his own body." He termed the events "unprofessional, immoral and shocking to one's sense of fairness."1 Southam mounted a spirited defense, stressing, first, that omitting the word "cancer" had been "a sincere professional judgment, based upon extensive scientific and clinical experience,"1 and, second, that despite Nuremberg, investigators rarely obtained informed consent. Several renowned researchers, including the surgeon I.S. Ravdin of the University of Pennsylvania, took the stand to corroborate this claim.
In finding Southam and Mandel guilty of "fraud or deceit" and unprofessional conduct, the Board of Regents in 1966 rejected both arguments. The decision demonstrated that the winds of change were blowing in medicine; the traditional ethical standards invoked by the researchers were becoming obsolete. The regents stated that the investigators' claim that they had acted as compassionate physicians was irrelevant. The experiment had not been part of "the usual doctor–patient relationship," so there was "no basis for the exercise of their usual professional judgment."1 Thus, even though Southam and Mandel wore white coats, they were researchers, not clinicians. In response to Southam's second point, the regents found the lack of informed consent at other hospitals not reassuring, but distressing. "Zeal for research," they wrote, "must not be carried to the point where it violates the basic rights and immunities of a human person."1
When Harvard Medical School professor Henry K. Beecher published his exposé of unethical research in the Journal later in 1966,4 the JCDH scandal was among the 22 cases he cited. Yet Beecher merely asked investigators to be more conscientious in obtaining informed consent. True change would not occur until after the Tuskegee Study, in which black men with syphilis were intentionally left untreated from 1932 to 1972. The post-Tuskegee outcry propelled the formation of the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, the publication of the commission's Belmont Report, and, ultimately, the proliferation of institutional review boards to monitor experimentation.
Given our current stringent criteria for ensuring informed consent, it is easy to condemn the research performed on the JCDH subjects as outrageous. The goal of history, however, is to judge the past according to the standards of the time. In that light, what is so striking about this story is not primarily that enthusiastic researchers convinced themselves that it was acceptable to inject cancer cells into unknowing patients but, rather, that a few young physicians refused to participate and even resigned in order to protest the ethical impropriety of using people as a means to an end. Although the JCDH was not Nazi Germany, a line between the permissible and the unacceptable had nevertheless been crossed. Modern researchers, tempted by prestigious grants and generous funding from industry, should recognize the potential insidiousness of conflicts of interest even among scientists with the best of intentions.5
Although the regents voted to suspend the licenses of Southam and Mandel, the denouement of this story was complicated. Ultimately, the doctors were simply put on probation. And although Southam remained emotionally haunted by what had happened, his career suffered little. The paper based on the JCDH experiments, showing that the rejection of the cancer cells was as rapid in the chronically ill patients as in healthy subjects, was published in the Annals of the New York Academy of Sciences in 1964 without any mention of the lack of informed consent. And in 1968, Southam was elected president of the American Association for Cancer Research, which he saw as vindication for his having been unfairly singled out, according to his daughter. By all accounts, he was revered by his patients.3 He died in 2002.
Kagan became a full-time staff physician at Coney Island Hospital, where he eventually became medical director. He has no regrets about what he did 40 years ago. "They were overzealous," he said recently about the investigators. "Did they care at all about what they were doing? They probably didn't."
Source Information
From the Department of Medicine and the Mailman School of Public Health, Columbia University Medical Center, New York.
References
Katz J. Experimentation with human beings: the authority of the investigator, subject, professions, and state in the human experimentation process. New York: Russell Sage Foundation, 1972:9-65.
Langer E. Human experimentation: cancer studies at Sloan-Kettering stir public debate on medical ethics. Science 1964;143:551-553. [Full Text]
Preminger BA. The case of Chester M. Southam: research ethics and the limits of professional responsibility. Pharos Alpha Omega Alpha Honor Med Soc 2002;65:4-9.
Beecher HK. Ethics and clinical research. N Engl J Med 1966;274:1354-1360.
Drazen JM, Koski G. To protect those who serve. N Engl J Med 2000;343:1643-1645.(Barron H. Lerner, M.D., P)
How did it happen that 22 patients received injections of cancer cells without their knowledge? On the 40th anniversary of this scandal, what can it teach us about the ethics of human experimentation?
The physician who spearheaded the experiment, Chester M. Southam, was a respected clinical investigator at the Memorial Sloan-Kettering Cancer Center who was studying the immunology of cancer. He had injected cancer cells into hundreds of patients with cancer, generating nodules that grew for several weeks before regressing. In contrast, similar injections in healthy volunteers showed much more rapid rejection.1 These findings suggested that patients with cancer lacked immunity to their disease, but Southam wanted to make sure that this phenomenon was not attributable solely to their debilitated state. So he sought out chronically ill people who did not have cancer.
Southam approached Emanuel E. Mandel, director of the Department of Medicine at JCDH. Mandel agreed to cooperate, and it was he who asked Kagan to participate. When Kagan declined, Mandel recruited a resident physician to perform the injections. Although details of what occurred remain disputed, some facts are clear. Twenty-two patients received injections of a "cell suspension." The word "cancer" was never mentioned to the subjects. Southam later justified this omission in two ways. He believed, first, that there was no risk that cancer would develop and, second, that the word "cancer" caused "bizarre, defensive" reactions on the part of patients — hence, the word had been omitted for their sake.2
When Kagan and his colleagues David Leichter and Perry Fersko learned that the experiment had proceeded, they resigned from JCDH. Meanwhile, William A. Hyman, a member of the hospital's board of directors, had grown alarmed and sued the hospital to obtain the records of the patients. It was Hyman's lawsuit that alerted the media, resulting in "the hottest public debate on medical ethics since the Nuremberg trials of Nazi physicians."2 Indeed, it was Hyman and other critics at JCDH who had first termed Southam's experiments "acts which belong more properly in Dachau."1
Hyman eventually won his lawsuit, but it was another legal proceeding — a 1964 hearing before the Board of Regents of the University of the State of New York — that most clearly revealed the ethical issues at stake. During that hearing, New York State Attorney General Louis L. Lefkowitz sought to revoke the medical licenses of Southam and Mandel. The heart of the state's case was that the investigators had not obtained valid informed consent from the subjects. Southam stated that there had been oral consent. But according to Lefkowitz, a substantial number of the patients "had not sufficient mental or physical ability to comprehend what was being told to them or what was being done to them," and those patients with such capacity had been misled.1
What were the standards for informed consent at the time? It is not surprising that Hyman had drawn the analogy to the Nazis. As part of the legal proceedings against Nazi doctors at Nuremberg in 1946, U.S. justices had drafted the Nuremberg Code for human experimentation, which stated that "the voluntary consent of the human subject is absolutely essential." Kagan later admitted that his objections had not been based on the code, however3; he and his fellow critics had simply believed that the experiments were "morally wrong."1 During the hearing, Lefkowitz did not hide his outrage, declaring that "every human being has an inalienable right to determine what shall be done with his own body." He termed the events "unprofessional, immoral and shocking to one's sense of fairness."1 Southam mounted a spirited defense, stressing, first, that omitting the word "cancer" had been "a sincere professional judgment, based upon extensive scientific and clinical experience,"1 and, second, that despite Nuremberg, investigators rarely obtained informed consent. Several renowned researchers, including the surgeon I.S. Ravdin of the University of Pennsylvania, took the stand to corroborate this claim.
In finding Southam and Mandel guilty of "fraud or deceit" and unprofessional conduct, the Board of Regents in 1966 rejected both arguments. The decision demonstrated that the winds of change were blowing in medicine; the traditional ethical standards invoked by the researchers were becoming obsolete. The regents stated that the investigators' claim that they had acted as compassionate physicians was irrelevant. The experiment had not been part of "the usual doctor–patient relationship," so there was "no basis for the exercise of their usual professional judgment."1 Thus, even though Southam and Mandel wore white coats, they were researchers, not clinicians. In response to Southam's second point, the regents found the lack of informed consent at other hospitals not reassuring, but distressing. "Zeal for research," they wrote, "must not be carried to the point where it violates the basic rights and immunities of a human person."1
When Harvard Medical School professor Henry K. Beecher published his exposé of unethical research in the Journal later in 1966,4 the JCDH scandal was among the 22 cases he cited. Yet Beecher merely asked investigators to be more conscientious in obtaining informed consent. True change would not occur until after the Tuskegee Study, in which black men with syphilis were intentionally left untreated from 1932 to 1972. The post-Tuskegee outcry propelled the formation of the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, the publication of the commission's Belmont Report, and, ultimately, the proliferation of institutional review boards to monitor experimentation.
Given our current stringent criteria for ensuring informed consent, it is easy to condemn the research performed on the JCDH subjects as outrageous. The goal of history, however, is to judge the past according to the standards of the time. In that light, what is so striking about this story is not primarily that enthusiastic researchers convinced themselves that it was acceptable to inject cancer cells into unknowing patients but, rather, that a few young physicians refused to participate and even resigned in order to protest the ethical impropriety of using people as a means to an end. Although the JCDH was not Nazi Germany, a line between the permissible and the unacceptable had nevertheless been crossed. Modern researchers, tempted by prestigious grants and generous funding from industry, should recognize the potential insidiousness of conflicts of interest even among scientists with the best of intentions.5
Although the regents voted to suspend the licenses of Southam and Mandel, the denouement of this story was complicated. Ultimately, the doctors were simply put on probation. And although Southam remained emotionally haunted by what had happened, his career suffered little. The paper based on the JCDH experiments, showing that the rejection of the cancer cells was as rapid in the chronically ill patients as in healthy subjects, was published in the Annals of the New York Academy of Sciences in 1964 without any mention of the lack of informed consent. And in 1968, Southam was elected president of the American Association for Cancer Research, which he saw as vindication for his having been unfairly singled out, according to his daughter. By all accounts, he was revered by his patients.3 He died in 2002.
Kagan became a full-time staff physician at Coney Island Hospital, where he eventually became medical director. He has no regrets about what he did 40 years ago. "They were overzealous," he said recently about the investigators. "Did they care at all about what they were doing? They probably didn't."
Source Information
From the Department of Medicine and the Mailman School of Public Health, Columbia University Medical Center, New York.
References
Katz J. Experimentation with human beings: the authority of the investigator, subject, professions, and state in the human experimentation process. New York: Russell Sage Foundation, 1972:9-65.
Langer E. Human experimentation: cancer studies at Sloan-Kettering stir public debate on medical ethics. Science 1964;143:551-553. [Full Text]
Preminger BA. The case of Chester M. Southam: research ethics and the limits of professional responsibility. Pharos Alpha Omega Alpha Honor Med Soc 2002;65:4-9.
Beecher HK. Ethics and clinical research. N Engl J Med 1966;274:1354-1360.
Drazen JM, Koski G. To protect those who serve. N Engl J Med 2000;343:1643-1645.(Barron H. Lerner, M.D., P)