Medical and Pediatric Oncology 3: 141-147 (1977)
Moral Dilemmas in Clinical Cancer Experimentation Melvin J. Krant, M.D., Joseph L. Cohen, M.D., and Charles Rosenbaum, M.D. Department of Medicine, Tufts University School of Medicine, Medford, Massachusetts, and Lemuel Shattuck Hospital, Boston, Massachusetts
An examination of certain moral tensions that have developed in clinical cancer experimentation is offered. It is argued that the individual partner must be addressed in his singular unique postion, rather than as a potential for the future good. Volumes have been written in the past two decades regarding human experimentation (2,6). In large part, such writings reflect a formalization of concern for individual rights and individual dignity that were aborted by medical experimentation in the Germany of the 1930s and 1940s. Heightened inspection of the nature of human experimentation in democratic civilizations has evolved, and ethical questions have been raised as to when a human can be considered as an appropriate subject for experimentation. The older notion that a person was an appropriate subject for experiments simply because he was involuntarily, or voluntarily, housed in an institution such as a jail or a civic hospital (he “owed” something to society) has been challenged, and such individuals are no longer considered as suitable subjects because of their status (4, 12). A person being cared for in a government-run hospital does not “owe” something to his doctors because of the charitable nature of care given and effort expended in his behalf (8). Articulations such as the Nurenberg and the Helsinki Declarations on Human Experimentation have attempted to formulate guidelines for operational conduct in this area (1). Many national medical societies have similarly attempted the codification of ethical behavior in regard to human experimentation, and the United States government has brought forth sets of regulations in regard to projects supported by federal grants or contract funds that attempt to protect individuals from “undue inducement or any element of force, fraud, deceit, duress, or other form of constraint or coercion” t o participate as a research subject (9). These various promulgations attempt to resolve conflicts inherent in medical progress through human experimentation, but leave certain arguments unexamined that continue to exist as sources of ethical tension. These may, in part, be posited as follows. First, disease is considered as an enemy of the people, and attempts made to modify, if not eradicate, human misery attendant to disease processes are socially worthy. Second,
Address reprint requests to Melvin J. Krant, M.D., Co-director of Oncology Unit, Lemuel Shattuck Hospital, 170 Morton Street, Boston, MA 02130.
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in order to acquire knowledge as to disease status and control, increased levels of research and experimentation are required, and such research and experimentation must include, and be performed on, human beings. In the ultimate analysis, the proper study of mankind is man. Third, people who would study disease processes in man as such must deal with individuals as intact persons, and the professionals qualified to do this must be approved and licensed by society to do so, namely be physicians or their surrogates. Fourth, experimentation in relationship to disease categories should be performed as a class action, namely clinical cancer research must be conducted, in general, on cancer patients, and must be conducted in establishments prepared to accommodate appropriately such people, namely hospitals or institutions resembling or connected with hospitals. Within these understandings a number of moral tensions have developed. They may be stated roughly as follows: a) Since disease is an enemy of the people, and since progress against disease must be elaborated, at least in part, on individuals now possessing the disease, and since society, in the form of the federal government, is pouring substantial funds into the fight against the enemy, such sick people do “owe” something to mankind and to “the common good,” and should be expected to contribute themselves for the sake of another patient in the future. The sick of today “owe” this to the future, even if such sick individuals have little or nothing to gain (and in fact may have something to lose) by making the contribution of themselves; b) since the physician is accorded responsibility for the care of the sick, the physician has been encouraged to recognize that he is in a unique position for obtaining data from the sick, for “the common good,” that therefore a major responsibility of the physician is the accumulation of such data. Furthermore, the physician should be rewarded for such efforts, via salary, reputation, appointments, etc.; c) since institutions such as hospitals, or special categorical centers, are the gathering places of the especially sick, such institutions should expand and grow larger in their efforts to “accumulate” the sick, so that these individuals can benefit from previous research made applicable to their cases by trained specialists, and, by being collected together, allow more research to be conducted. Furthermore, physicians are employed by these institutions for the purpose, in part or wholly, of conducting research. Several emotional forces operate to enhance the tensions implicit in these factors. For the physician in charge of cancer patients, clinical cancer investigation in the form of protocol studies offers a relief from the “helplessness” and the “involved anguish” feelings that can afflict him in his responsible caring and decision-making for a patient, especially if that patient has a hopeless illness. The protocol, or the study, may serve to shift responsibility for the outcome of the patient from the physician to a more distant source. In the case of the younger physician, an innocence and lack of experience in clinical research, and his enthusiasm for helping “eradicate” disease, may influence the manner of his approaching patients and offering them the opportunity of receiving drugs. In addition, there is the desperation felt and expressed by patients for a treatment, any treatment, for their condition. Cancer, of course, is the sine qua non of despair, and the news media’s endless reporting of breakthroughs merely compounds these issues by suggesting to patient, family, and physician alike that there is always a treatment available that should be tried. The attitudes created by a “disease-as-enemy, good-of-society, government-grantingmoney, physician-gathering-data, and hospitals-and center-expansion’’ climate generate certain moral tensions relative to Judeo-Christian constructions regarding medical care, which have been examined and reexamined in the wake of the Nazi holocaust. These constructions can be looked upon as follows. a) Each person is unique in himself, in his
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individuality, and in his personal relationship to God and society. b) The individual good and the common good are the same and cannot be made distinct except in certain emergencies such as wartime (but even here, individuals should not be made to kill if they conscientiously object). c) Granting the coercive nature of despairing disease, those t o whom a patient turns for help must protect that patient and his family from exploitation deriving from his weakened position vis-a-vis rational decision-making, and such protection is for the common good. In other words, a weakened individual cannot be made to sacrifice his right to the full protection of society against exploitation. d) The common good is recognized when the physician’s loyalty is only to his patient for the patient’s good and not for any other good, and, thusly, nothing should be done in the name of treatment that is not for the patient’s direct benefit. e) Individual persons should be in control of their destinies at all times, being offered and weighing alternatives without fear of reprisal. Alternatives in this situation mean other ways of managing a life struggle, rather than a new treatment. The moral tensions alluded to operate in clinical cancer, especially in research with new agents. In order to structure the tensions, let us pose two operational questions. The first is: Should a physician ever ask h s patient to enter into a clinical experiment, such as the taking of a new drug, or a new treatment, without full loyalty to the patient? That is, can the physician request his patient to take an experimental drug that is not clearly and specifically for his patient’s benefit? For example, the National Cancer Institute (NCI) continues an elaborate program for screening new agents for therapeutic potential in malignant disease. The NCI requires “Phase I” clinical trials in humans in order to evaluate the limiting toxicity and the reversability of toxicity of a drug in man, and to establish a suitable dosage to permit evaluation of therapeutic effect in a future patient ( 3 , 7 , 10). Frequent clinical and laboratory examinations are required to monitor toxicity, but direct benefit to the patient is clearly stated as not the primary objective of the trial. Clinical investigators associated with Phase I trials are required to choose patients for the study who have cancer, but who have reached the stage where they are “not amenable to standard forms of therapy,” and yet whose expectant survival is sufficient to allow completion of the study. Guidelines and publication from the NCI make no mention of ethical issues in these studies, but clearly the intent is exploitative, suggesting that sick individuals be used for such studies. The physician’s loyalty is twisted from care for the good only of his present patient towards gathering data for an unnamed patient in the future. Under the guise of care, the patient may be kept in the hospital for experimental purposes by investigators who have “access to adequate laboratory and hospital facilities for clinical research and patient care” (3). In Phase I clinical trials, the physician enters a patient into a study in order to produce toxicity, to measure and define it, and to follow the drug effects (and separate these from disease effects) without truly believing that he is doing something for the patient’s own good. The physician may argue that desperately ill patients reach out for any straw in the wind and therefore gladly take the new drug, and that since there is no standard drug treatment available that can help the patient why not use the new drug? Such arguments force us to search for motives - is the patient’s despair being exploited for the investigator’s benefit? The second question is: If a physician believes that he has a mandate to enter a patient with advanced cancer into a Phase I type study, where clearly the benefit to the patient is not the primary objective (even though the drug would not be tested if potential benefit did not exist), under what circumstances can this be suggested? If the physician’s
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loyalty is for the individual patient’s good, and only h s good, then the physician cannot enter a patient into a study; he can only suggest to the patient that he, the patient, might wish to become a part of the study for the common good. In other words, the physician can ask the patient if he would like to volunteer for an experiment that will in all likelihood not help him, but might in fact harm him. Promises of benefit (derived from preclinical data) cannot be used to persuade. The issue here is informed consent, but clearly the intent of the informed consent must be understood as a true act of volunteerism. If the informed consent document is seen as an obstacle to be hurdled in order to get on with a study, and if we argue that the sick person desparately wants to be treated and could not tolerate “knowing” what is really happening, for then we would be stealing away his “hope,” are we not taking advantage of his weakened state? Are we not paternalistically deceiving him, supposedly for his own good, but perhaps really for ours? Do we wish to protect people from pain by deception? In such instances, the coercive nature of disease, and the obligatory dependence on the physician, will force patients (and their families) to agree to sign. But the patient is not volunteering; he is being coerced. The eager physician, in his loyalty to the study, or to the granting agency, is capitalizing on the victimization of the patient by his needs. (Victimization, in this sense, implies a dependency without complete trust.) There is no reason why a patient cannot, and might not, volunteer to enter a Phase I experiment, knowing full well that the intended benefit of the experiment is for another patient in the future, and not for himself. People are altruistic, and they do volunteer for many reasons. Fantasy or magical thinking may frequently play a role in such volunteering. It may not be necessary to analyze all the reasons for potential volunteering, except that one must be on the lookout for resentment if a “getting-better’’ bargain was hidden in the volunteering and such improvement does not appear. But a patient can make a sane judgement to volunteer only if he is fully aware of his diagnosis and its implication, and if he is aware that he is at liberty to say “no” without losing his medical support. In that manner, his informed consent is an educated “yes.” The problems of divided loyalities for the physician-experimenter must be acknowledged, and it should be recognized that a significant tension is created when the physician’s loyalty to the patient’s good is subtly eroded by an investigator’s loyalty to his research project. Thus, it can be suggested that the physician in charge of the patient should not be the same individual as the experimenter in a project. The two individuals, in fact, should not be interdependent, and the caring physician must not feel himself in a coercive position vis-a-vis the experimenting physician. In that manner the caring physician can assist the patient in his decision-making, including saying “no” and accepting alternatives to his care, without the patient feeling that he has no alternative but to acquiesce, or be abandoned. (Of course, here we must question whether we are training physicians to be emotionally mature enough to take on such caring responsibility.) Now, obviously, the basic morality in such a situation resides in the physicians themselves. Separating the care-giver from the experimenter is frequently difficult, especially in an institution, or a department, where the senior medical people see their major role as researchers, and not care-givers. Many large cancer centers are indeed research-oriented, and large gains have come about in the past decade from clinical investigation. Neither an institutional committee decision, nor protocol document, will prevent physicians from persuading a dependent patient to consent to an experiment, when the ethos of the institution is experimental. This issue is one of education and moral examination. Can the physician be explicit in recognizing where loyalty does reside? Can he resist
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the temptation to aver that he gives better care by doing research? Can he differentiate research that is truly for a particular patient’s best interest, and research that is for some common good at the sacrifice of the singular individual? Can a physician understand the value dimension, much honored in our culture, of trust without victimization, and a person’s right of self-control, so that a decision is reasonable from his (the patient’s) viewpoint? Can we help a weakened individual to maintain that posture? Can the physician resist a patient’s urgency through despair to take any form of experimental treatment offered (if only it would make him better), and thus avoid exploitation, by making sure that the patient understands why, and for what, he is volunteering? The opposite of exploitation is volunteerism, or, as Paul Ramsey and Hans Jonas have advocated, the establishment of a “covenental bond” between patient and physician (5,9). As Jonas states, “human experimentation, for whatever purposes, is always also a responsible, non-experimental, definitive dealing with the subject himself - and not even the noblest of purposes abrogates the obligations that this involves.” It thus follows that a patient who does not know that he has cancer, and that he is volunteering because of his cancer for future cancer patients, can never be entered into Phase I studies. At no time can the physician “protect” his patient from his diagnosis and expect him t o be an appropriate volunteer in such a clinical experiment. In such circumstances, it is of critical importance that the word “cancer” be used (or its symbolic equivalent in disorders such as leukemia, lymphoma, or Hodgkin’s disease), in a consent form. The form may well say that the individual patient involved clearly understands that he has cancer, that he has received all possible treatment that might have benefitted him, and that he is now volunteering for a new drug trial that will have little to no chance of helping him to improve, but might help another person with a similar disease sometime in the future. In those cases where the physician feels that his patient could not tolerate knowing his condition by name and symbolic implication, in a language fully understood by the patient, then that person should not be a part of a clinical Phase I trial. In those situations where a physician feels that his patient cannot grasp the nature of the volunteering act, then also the patient should not be entered into a clinical trial. And where the clinical trial is for the physician’s benefit - to avoid a feeling of helplessness and not knowing what to do next for a patient - then the patient should not be pushed into a trial. Further, the investigator should not be in a position to exploit his physician-caring role in this circumstance. The physician should help his patient reach a decision which affords continuing care irrespective of the individual’s accepting or rejecting the new drug. Such a requirement may well challenge existing bedutilization policies. To tell a patient that he can stay in a hospital bed only if he acquiesces for a clinical trial is to coerce brutally. Obviously the patient should not be in a hospital if he does not require hospital care, nor should he be out of the hospital if he truly requires the safekeeping available in a hospital. Phase I1 and Phase 111 clinical trial studies offer a somewhat different perspective, inasmuch as the efforts in these trials are more clearly therapeutic for the individual patient. New and experimental treatments are applied for the patient’s benefit. However, the language in many of the protocols carries the none too subtle implication that the patient is granted a privilege in being allowed to be part of a study. Such phrases as “The patient qualifies if he has _ _ , or is ineligible if he has --____’’ suggest an objectifying attitude of the physician toward that person. In addition, invariably protocols use the plural pronoun “they” in discussing patients, rather than the singular pronoun “he” or “she.” The language of the multiple tends to diminish the importance of the singular individual, who, as is being argued, must be a partner to the experiment.
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In every Phase I1 and Phase 111 study, toxicity is expected and drug modification is scheduled in relationship to toxic side effects. The newer the agent, and the less tried the treatment, the more toxicity that can be expected in any clinical trial. Thus it is clear that although the experimental treatments are therapeutically directed for the benefit of the patient, much about the harmful effect of these treatments is to be worked through in the Phase I1 as well as Phase 111 studies, and the patients stand risks of hurt as well as potential benefit. Therefore, each and every person who consents to such an experiment should clearly understand the experimental nature of the treatment, the reasons why he is consenting to the treatment, and what he can expect from such treatment. Again, we are dealing with volunteerism as opposed to obligation or to paternalistic control. The desperate nature of cancer and reliance and dependence on the physician are again potent forces leading to a patient’s accepting an offered treatment. Such an experiment frequently results in the patient’s hospitalization or multiple out-patient visits, expenses in transportation, problems in family care, charges for in-hospital stays, and at-home problems, not to mention human costs. Thus, there is all the more reason for the physician-investigator to clearly examine whether his loyalties are t o the patient for the patient’s good only, or if his loyalties are to a study for the sake of accumulation of data. Clearly, informed consent of an educated type should be rigorously required, and this cannot be obtained when a patient neither comprehends nor understands the nature of his diagnosis and why he is volunteering for this therapeutic experiment. A physician’s paternalistic wish to d o good for his patient cannot be enough. Since loyalty to the study (with fiscal and other rewards) is more than a subtle pressure to enter patients into Phase I1 and Phase 111 studies, there is all the more need to protect the patient from a utilization in which his good is made secondary to the requirements for research data collection. Arguments have been posed that no new treatments would have even evolved if physicians were constantly hampered in their efforts to help patients, as they now are. Dr. Ehlich would never have been allowed to bring his arsenicals into the clinical world if he had to put up with the restrictions that now exist in clinical drug trials. These arguments are specious at best, for romanticizing the past does not reflect the “big-business” operations that exist today. We are not dealing with singular and individual clinicians doing what they can for their patients. Instead we are dealing with heavily sponsored and rewarded research, all part of a general war. (Besides, we have no idea of the damage, if not death, brought about by good intentions in the past.) The issue today is systematized, institutionalized, heavily capitalized research, and such efforts requires continuous, and careful, scrutiny. In summary then, by declaring a war against cancer, and amplifying such jargon, and by providing strong financial persuasion for investigators to conduct experiments on human cancer patients today for the sake of the patient of tomorrow, an operative climate has been created that erodes time-honored and respected physician-patient relationships. A tension has been created that cancer patients do “owe” themselves for future cancer patients, that physicians as investigators can act on patients even if not for the good of the individual patient, that loyalty is primarily to a study and not to the patient, and that informed consent in an educated manner of a particular patient is a problem and not an essential in clinical cancer experimentation. We offer this paper not as an accusation, but as a questioning of the actual and potential erosion in time-honored values our society has placed on individual human life (including how such a life should end), on the dignity of the individual person, and on Aesculapian authority. We should constantly reexamine what we do in the name of human experimentation and the common good, and
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question whether the common good can ever be furthered by utilizing despairing people for experiments unintended, or only marginally intended, for their singular good. There is undoubted value in human experimentation, from the physician’s, the society’s, and the invididual’s viewpoints. But the larger the efforts become, the greater is the possibility that certain cherished human values will be eroded. REFERENCES 1. Calebresi, G. Reflections on medical experimentation in humans. In “Ethical Aspects of Experimentation with Human Subjects” (Freund, R., ed.). Daedalus, Spring, 98, (quoted therein). 1969. 2. Freund, P. (editor). “Ethical Aspects of Experimentation With Human Subjects.” Daedalus, Spring, 98, 1969. 3. “General Consideration for the Clinical Evaluation of Drugs: Clinical Guidelines for Anti-Cancer Drugs: Final Draft, February, 1973.” Food and Drug Administration, Washington, D.C., 1973. 4. Havighurst, C. D. Compensating person injured in human experimentation. Science 169: 153157,1970. 5. Jonas, H. Philosphical reflections on experimenting with human subjects. Daedalus. 98:219247, 1969. 6. Latimer, I., and Newman, R. W. (editors). “Clinical Investigation in Medicine: Legal, Ethical, and Moral Aspects.” Boston: Law-Medicine Research Institute, 1963. 7. Louis, J. Coordinated Phase I studies for co-operative chemotherapy groups. Cancer Chemother. Rep. 16:99-105, 1962. 8. Morris, R. C., Jr. Guidelines for accepting volunteers; consent, ethical implication, and the function of a peer review. Clin. Pharm. Therap. 13:782-759, 1972. 9. Ramsey, P. The ethics of a cottage industry in an age of community research medicine. New Engl. J . Med. 284:700-706,1971, 10. Schneider, B. Early clinical trials with anticancer agents; Phase I and I1 studies. Cancer Chemother. Rep. 16:61-67, 1962. 1 1. U.S. Public Health Service. Protection of the individual as a research subject. Federal Register, Aug. 23, 1974. 12. Wolfensberber, W. Ethical issues in research with human subjects. Science 169:153-157, July, 1970.
Moral Dilemmas in Clinical Cancer Experimentation Melvin J. Krant, M.D., Joseph L. Cohen, M.D., and Charles Rosenbaum, M.D. Department of Medicine, Tufts University School of Medicine, Medford, Massachusetts, and Lemuel Shattuck Hospital, Boston, Massachusetts
An examination of certain moral tensions that have developed in clinical cancer experimentation is offered. It is argued that the individual partner must be addressed in his singular unique postion, rather than as a potential for the future good. Volumes have been written in the past two decades regarding human experimentation (2,6). In large part, such writings reflect a formalization of concern for individual rights and individual dignity that were aborted by medical experimentation in the Germany of the 1930s and 1940s. Heightened inspection of the nature of human experimentation in democratic civilizations has evolved, and ethical questions have been raised as to when a human can be considered as an appropriate subject for experimentation. The older notion that a person was an appropriate subject for experiments simply because he was involuntarily, or voluntarily, housed in an institution such as a jail or a civic hospital (he “owed” something to society) has been challenged, and such individuals are no longer considered as suitable subjects because of their status (4, 12). A person being cared for in a government-run hospital does not “owe” something to his doctors because of the charitable nature of care given and effort expended in his behalf (8). Articulations such as the Nurenberg and the Helsinki Declarations on Human Experimentation have attempted to formulate guidelines for operational conduct in this area (1). Many national medical societies have similarly attempted the codification of ethical behavior in regard to human experimentation, and the United States government has brought forth sets of regulations in regard to projects supported by federal grants or contract funds that attempt to protect individuals from “undue inducement or any element of force, fraud, deceit, duress, or other form of constraint or coercion” t o participate as a research subject (9). These various promulgations attempt to resolve conflicts inherent in medical progress through human experimentation, but leave certain arguments unexamined that continue to exist as sources of ethical tension. These may, in part, be posited as follows. First, disease is considered as an enemy of the people, and attempts made to modify, if not eradicate, human misery attendant to disease processes are socially worthy. Second,
Address reprint requests to Melvin J. Krant, M.D., Co-director of Oncology Unit, Lemuel Shattuck Hospital, 170 Morton Street, Boston, MA 02130.
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150 Fifth Avenue, New York, N Y 1001 1
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in order to acquire knowledge as to disease status and control, increased levels of research and experimentation are required, and such research and experimentation must include, and be performed on, human beings. In the ultimate analysis, the proper study of mankind is man. Third, people who would study disease processes in man as such must deal with individuals as intact persons, and the professionals qualified to do this must be approved and licensed by society to do so, namely be physicians or their surrogates. Fourth, experimentation in relationship to disease categories should be performed as a class action, namely clinical cancer research must be conducted, in general, on cancer patients, and must be conducted in establishments prepared to accommodate appropriately such people, namely hospitals or institutions resembling or connected with hospitals. Within these understandings a number of moral tensions have developed. They may be stated roughly as follows: a) Since disease is an enemy of the people, and since progress against disease must be elaborated, at least in part, on individuals now possessing the disease, and since society, in the form of the federal government, is pouring substantial funds into the fight against the enemy, such sick people do “owe” something to mankind and to “the common good,” and should be expected to contribute themselves for the sake of another patient in the future. The sick of today “owe” this to the future, even if such sick individuals have little or nothing to gain (and in fact may have something to lose) by making the contribution of themselves; b) since the physician is accorded responsibility for the care of the sick, the physician has been encouraged to recognize that he is in a unique position for obtaining data from the sick, for “the common good,” that therefore a major responsibility of the physician is the accumulation of such data. Furthermore, the physician should be rewarded for such efforts, via salary, reputation, appointments, etc.; c) since institutions such as hospitals, or special categorical centers, are the gathering places of the especially sick, such institutions should expand and grow larger in their efforts to “accumulate” the sick, so that these individuals can benefit from previous research made applicable to their cases by trained specialists, and, by being collected together, allow more research to be conducted. Furthermore, physicians are employed by these institutions for the purpose, in part or wholly, of conducting research. Several emotional forces operate to enhance the tensions implicit in these factors. For the physician in charge of cancer patients, clinical cancer investigation in the form of protocol studies offers a relief from the “helplessness” and the “involved anguish” feelings that can afflict him in his responsible caring and decision-making for a patient, especially if that patient has a hopeless illness. The protocol, or the study, may serve to shift responsibility for the outcome of the patient from the physician to a more distant source. In the case of the younger physician, an innocence and lack of experience in clinical research, and his enthusiasm for helping “eradicate” disease, may influence the manner of his approaching patients and offering them the opportunity of receiving drugs. In addition, there is the desperation felt and expressed by patients for a treatment, any treatment, for their condition. Cancer, of course, is the sine qua non of despair, and the news media’s endless reporting of breakthroughs merely compounds these issues by suggesting to patient, family, and physician alike that there is always a treatment available that should be tried. The attitudes created by a “disease-as-enemy, good-of-society, government-grantingmoney, physician-gathering-data, and hospitals-and center-expansion’’ climate generate certain moral tensions relative to Judeo-Christian constructions regarding medical care, which have been examined and reexamined in the wake of the Nazi holocaust. These constructions can be looked upon as follows. a) Each person is unique in himself, in his
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individuality, and in his personal relationship to God and society. b) The individual good and the common good are the same and cannot be made distinct except in certain emergencies such as wartime (but even here, individuals should not be made to kill if they conscientiously object). c) Granting the coercive nature of despairing disease, those t o whom a patient turns for help must protect that patient and his family from exploitation deriving from his weakened position vis-a-vis rational decision-making, and such protection is for the common good. In other words, a weakened individual cannot be made to sacrifice his right to the full protection of society against exploitation. d) The common good is recognized when the physician’s loyalty is only to his patient for the patient’s good and not for any other good, and, thusly, nothing should be done in the name of treatment that is not for the patient’s direct benefit. e) Individual persons should be in control of their destinies at all times, being offered and weighing alternatives without fear of reprisal. Alternatives in this situation mean other ways of managing a life struggle, rather than a new treatment. The moral tensions alluded to operate in clinical cancer, especially in research with new agents. In order to structure the tensions, let us pose two operational questions. The first is: Should a physician ever ask h s patient to enter into a clinical experiment, such as the taking of a new drug, or a new treatment, without full loyalty to the patient? That is, can the physician request his patient to take an experimental drug that is not clearly and specifically for his patient’s benefit? For example, the National Cancer Institute (NCI) continues an elaborate program for screening new agents for therapeutic potential in malignant disease. The NCI requires “Phase I” clinical trials in humans in order to evaluate the limiting toxicity and the reversability of toxicity of a drug in man, and to establish a suitable dosage to permit evaluation of therapeutic effect in a future patient ( 3 , 7 , 10). Frequent clinical and laboratory examinations are required to monitor toxicity, but direct benefit to the patient is clearly stated as not the primary objective of the trial. Clinical investigators associated with Phase I trials are required to choose patients for the study who have cancer, but who have reached the stage where they are “not amenable to standard forms of therapy,” and yet whose expectant survival is sufficient to allow completion of the study. Guidelines and publication from the NCI make no mention of ethical issues in these studies, but clearly the intent is exploitative, suggesting that sick individuals be used for such studies. The physician’s loyalty is twisted from care for the good only of his present patient towards gathering data for an unnamed patient in the future. Under the guise of care, the patient may be kept in the hospital for experimental purposes by investigators who have “access to adequate laboratory and hospital facilities for clinical research and patient care” (3). In Phase I clinical trials, the physician enters a patient into a study in order to produce toxicity, to measure and define it, and to follow the drug effects (and separate these from disease effects) without truly believing that he is doing something for the patient’s own good. The physician may argue that desperately ill patients reach out for any straw in the wind and therefore gladly take the new drug, and that since there is no standard drug treatment available that can help the patient why not use the new drug? Such arguments force us to search for motives - is the patient’s despair being exploited for the investigator’s benefit? The second question is: If a physician believes that he has a mandate to enter a patient with advanced cancer into a Phase I type study, where clearly the benefit to the patient is not the primary objective (even though the drug would not be tested if potential benefit did not exist), under what circumstances can this be suggested? If the physician’s
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loyalty is for the individual patient’s good, and only h s good, then the physician cannot enter a patient into a study; he can only suggest to the patient that he, the patient, might wish to become a part of the study for the common good. In other words, the physician can ask the patient if he would like to volunteer for an experiment that will in all likelihood not help him, but might in fact harm him. Promises of benefit (derived from preclinical data) cannot be used to persuade. The issue here is informed consent, but clearly the intent of the informed consent must be understood as a true act of volunteerism. If the informed consent document is seen as an obstacle to be hurdled in order to get on with a study, and if we argue that the sick person desparately wants to be treated and could not tolerate “knowing” what is really happening, for then we would be stealing away his “hope,” are we not taking advantage of his weakened state? Are we not paternalistically deceiving him, supposedly for his own good, but perhaps really for ours? Do we wish to protect people from pain by deception? In such instances, the coercive nature of disease, and the obligatory dependence on the physician, will force patients (and their families) to agree to sign. But the patient is not volunteering; he is being coerced. The eager physician, in his loyalty to the study, or to the granting agency, is capitalizing on the victimization of the patient by his needs. (Victimization, in this sense, implies a dependency without complete trust.) There is no reason why a patient cannot, and might not, volunteer to enter a Phase I experiment, knowing full well that the intended benefit of the experiment is for another patient in the future, and not for himself. People are altruistic, and they do volunteer for many reasons. Fantasy or magical thinking may frequently play a role in such volunteering. It may not be necessary to analyze all the reasons for potential volunteering, except that one must be on the lookout for resentment if a “getting-better’’ bargain was hidden in the volunteering and such improvement does not appear. But a patient can make a sane judgement to volunteer only if he is fully aware of his diagnosis and its implication, and if he is aware that he is at liberty to say “no” without losing his medical support. In that manner, his informed consent is an educated “yes.” The problems of divided loyalities for the physician-experimenter must be acknowledged, and it should be recognized that a significant tension is created when the physician’s loyalty to the patient’s good is subtly eroded by an investigator’s loyalty to his research project. Thus, it can be suggested that the physician in charge of the patient should not be the same individual as the experimenter in a project. The two individuals, in fact, should not be interdependent, and the caring physician must not feel himself in a coercive position vis-a-vis the experimenting physician. In that manner the caring physician can assist the patient in his decision-making, including saying “no” and accepting alternatives to his care, without the patient feeling that he has no alternative but to acquiesce, or be abandoned. (Of course, here we must question whether we are training physicians to be emotionally mature enough to take on such caring responsibility.) Now, obviously, the basic morality in such a situation resides in the physicians themselves. Separating the care-giver from the experimenter is frequently difficult, especially in an institution, or a department, where the senior medical people see their major role as researchers, and not care-givers. Many large cancer centers are indeed research-oriented, and large gains have come about in the past decade from clinical investigation. Neither an institutional committee decision, nor protocol document, will prevent physicians from persuading a dependent patient to consent to an experiment, when the ethos of the institution is experimental. This issue is one of education and moral examination. Can the physician be explicit in recognizing where loyalty does reside? Can he resist
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the temptation to aver that he gives better care by doing research? Can he differentiate research that is truly for a particular patient’s best interest, and research that is for some common good at the sacrifice of the singular individual? Can a physician understand the value dimension, much honored in our culture, of trust without victimization, and a person’s right of self-control, so that a decision is reasonable from his (the patient’s) viewpoint? Can we help a weakened individual to maintain that posture? Can the physician resist a patient’s urgency through despair to take any form of experimental treatment offered (if only it would make him better), and thus avoid exploitation, by making sure that the patient understands why, and for what, he is volunteering? The opposite of exploitation is volunteerism, or, as Paul Ramsey and Hans Jonas have advocated, the establishment of a “covenental bond” between patient and physician (5,9). As Jonas states, “human experimentation, for whatever purposes, is always also a responsible, non-experimental, definitive dealing with the subject himself - and not even the noblest of purposes abrogates the obligations that this involves.” It thus follows that a patient who does not know that he has cancer, and that he is volunteering because of his cancer for future cancer patients, can never be entered into Phase I studies. At no time can the physician “protect” his patient from his diagnosis and expect him t o be an appropriate volunteer in such a clinical experiment. In such circumstances, it is of critical importance that the word “cancer” be used (or its symbolic equivalent in disorders such as leukemia, lymphoma, or Hodgkin’s disease), in a consent form. The form may well say that the individual patient involved clearly understands that he has cancer, that he has received all possible treatment that might have benefitted him, and that he is now volunteering for a new drug trial that will have little to no chance of helping him to improve, but might help another person with a similar disease sometime in the future. In those cases where the physician feels that his patient could not tolerate knowing his condition by name and symbolic implication, in a language fully understood by the patient, then that person should not be a part of a clinical Phase I trial. In those situations where a physician feels that his patient cannot grasp the nature of the volunteering act, then also the patient should not be entered into a clinical trial. And where the clinical trial is for the physician’s benefit - to avoid a feeling of helplessness and not knowing what to do next for a patient - then the patient should not be pushed into a trial. Further, the investigator should not be in a position to exploit his physician-caring role in this circumstance. The physician should help his patient reach a decision which affords continuing care irrespective of the individual’s accepting or rejecting the new drug. Such a requirement may well challenge existing bedutilization policies. To tell a patient that he can stay in a hospital bed only if he acquiesces for a clinical trial is to coerce brutally. Obviously the patient should not be in a hospital if he does not require hospital care, nor should he be out of the hospital if he truly requires the safekeeping available in a hospital. Phase I1 and Phase 111 clinical trial studies offer a somewhat different perspective, inasmuch as the efforts in these trials are more clearly therapeutic for the individual patient. New and experimental treatments are applied for the patient’s benefit. However, the language in many of the protocols carries the none too subtle implication that the patient is granted a privilege in being allowed to be part of a study. Such phrases as “The patient qualifies if he has _ _ , or is ineligible if he has --____’’ suggest an objectifying attitude of the physician toward that person. In addition, invariably protocols use the plural pronoun “they” in discussing patients, rather than the singular pronoun “he” or “she.” The language of the multiple tends to diminish the importance of the singular individual, who, as is being argued, must be a partner to the experiment.
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In every Phase I1 and Phase 111 study, toxicity is expected and drug modification is scheduled in relationship to toxic side effects. The newer the agent, and the less tried the treatment, the more toxicity that can be expected in any clinical trial. Thus it is clear that although the experimental treatments are therapeutically directed for the benefit of the patient, much about the harmful effect of these treatments is to be worked through in the Phase I1 as well as Phase 111 studies, and the patients stand risks of hurt as well as potential benefit. Therefore, each and every person who consents to such an experiment should clearly understand the experimental nature of the treatment, the reasons why he is consenting to the treatment, and what he can expect from such treatment. Again, we are dealing with volunteerism as opposed to obligation or to paternalistic control. The desperate nature of cancer and reliance and dependence on the physician are again potent forces leading to a patient’s accepting an offered treatment. Such an experiment frequently results in the patient’s hospitalization or multiple out-patient visits, expenses in transportation, problems in family care, charges for in-hospital stays, and at-home problems, not to mention human costs. Thus, there is all the more reason for the physician-investigator to clearly examine whether his loyalties are t o the patient for the patient’s good only, or if his loyalties are to a study for the sake of accumulation of data. Clearly, informed consent of an educated type should be rigorously required, and this cannot be obtained when a patient neither comprehends nor understands the nature of his diagnosis and why he is volunteering for this therapeutic experiment. A physician’s paternalistic wish to d o good for his patient cannot be enough. Since loyalty to the study (with fiscal and other rewards) is more than a subtle pressure to enter patients into Phase I1 and Phase 111 studies, there is all the more need to protect the patient from a utilization in which his good is made secondary to the requirements for research data collection. Arguments have been posed that no new treatments would have even evolved if physicians were constantly hampered in their efforts to help patients, as they now are. Dr. Ehlich would never have been allowed to bring his arsenicals into the clinical world if he had to put up with the restrictions that now exist in clinical drug trials. These arguments are specious at best, for romanticizing the past does not reflect the “big-business” operations that exist today. We are not dealing with singular and individual clinicians doing what they can for their patients. Instead we are dealing with heavily sponsored and rewarded research, all part of a general war. (Besides, we have no idea of the damage, if not death, brought about by good intentions in the past.) The issue today is systematized, institutionalized, heavily capitalized research, and such efforts requires continuous, and careful, scrutiny. In summary then, by declaring a war against cancer, and amplifying such jargon, and by providing strong financial persuasion for investigators to conduct experiments on human cancer patients today for the sake of the patient of tomorrow, an operative climate has been created that erodes time-honored and respected physician-patient relationships. A tension has been created that cancer patients do “owe” themselves for future cancer patients, that physicians as investigators can act on patients even if not for the good of the individual patient, that loyalty is primarily to a study and not to the patient, and that informed consent in an educated manner of a particular patient is a problem and not an essential in clinical cancer experimentation. We offer this paper not as an accusation, but as a questioning of the actual and potential erosion in time-honored values our society has placed on individual human life (including how such a life should end), on the dignity of the individual person, and on Aesculapian authority. We should constantly reexamine what we do in the name of human experimentation and the common good, and
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question whether the common good can ever be furthered by utilizing despairing people for experiments unintended, or only marginally intended, for their singular good. There is undoubted value in human experimentation, from the physician’s, the society’s, and the invididual’s viewpoints. But the larger the efforts become, the greater is the possibility that certain cherished human values will be eroded. REFERENCES 1. Calebresi, G. Reflections on medical experimentation in humans. In “Ethical Aspects of Experimentation with Human Subjects” (Freund, R., ed.). Daedalus, Spring, 98, (quoted therein). 1969. 2. Freund, P. (editor). “Ethical Aspects of Experimentation With Human Subjects.” Daedalus, Spring, 98, 1969. 3. “General Consideration for the Clinical Evaluation of Drugs: Clinical Guidelines for Anti-Cancer Drugs: Final Draft, February, 1973.” Food and Drug Administration, Washington, D.C., 1973. 4. Havighurst, C. D. Compensating person injured in human experimentation. Science 169: 153157,1970. 5. Jonas, H. Philosphical reflections on experimenting with human subjects. Daedalus. 98:219247, 1969. 6. Latimer, I., and Newman, R. W. (editors). “Clinical Investigation in Medicine: Legal, Ethical, and Moral Aspects.” Boston: Law-Medicine Research Institute, 1963. 7. Louis, J. Coordinated Phase I studies for co-operative chemotherapy groups. Cancer Chemother. Rep. 16:99-105, 1962. 8. Morris, R. C., Jr. Guidelines for accepting volunteers; consent, ethical implication, and the function of a peer review. Clin. Pharm. Therap. 13:782-759, 1972. 9. Ramsey, P. The ethics of a cottage industry in an age of community research medicine. New Engl. J . Med. 284:700-706,1971, 10. Schneider, B. Early clinical trials with anticancer agents; Phase I and I1 studies. Cancer Chemother. Rep. 16:61-67, 1962. 1 1. U.S. Public Health Service. Protection of the individual as a research subject. Federal Register, Aug. 23, 1974. 12. Wolfensberber, W. Ethical issues in research with human subjects. Science 169:153-157, July, 1970.
