JOURNAL OF THE AMERICAN GERIATRICS SOCIETY Copyright © 1975 by the American Geriatrics Society
Vol. XXIII, No.7 Printed in U.S.A.
Medical Experimentation in the Elderly JOEL E. BERNSTEIN, MD* and F. KIRK NELSON, MS, JD
University of Tennessee Medical Units, Memphis, Tennessee ABSTRACT: Participation in human experimental research constitutes a major problem for the geriatric subject. Because there is a high incidence of noncontagious disease in the elderly, they are the group most useful for the study of new therapeutic agents or procedures. However, normal aging processes, often coupled with disease of the central nervous system, render elderly persons less able to comprehend the nature and risks of such studies. These factors permit easy exploitation of geriatric subjects in medical experimentation, with possible exposure to a significant risk of serious drug reactions and unnecessary hospitalization. Recent federal regulations have given "special protections" to children, prisoners and the mentally infirm in experimental research, to guard against abuse of their human rights. A basic requirement is that informed consent be carefully obtained and documented. Such "special protections" should now be extended to geriatric subjects so that there will be no further exploitation in the course of valid clinical research. Psychologic changes associated with aging have been documented extensively in the literature (3, 4). The normal aging process of the nervous system results in a loss of neurons and a progressive decrease in the weight of the brain, especially after the sixth decade (5, 6). Other changes with aging include progressive vascular and connective tissue degeneration and alterations in cerebral circulation. In addition to these normal aging changes, cerebrovascular disease, trauma, neoplasms, vitamin deficiency states, and degenerative disease of the central nervous system further impair the geriatric patient's cognitive powers. Thus, the nature and risks of a new treatment or procedure may be as incomprehensible to an elderly patient as to a child or mentally handicapped person. Perhaps most easily exploited among the elderly are the terminally ill, and patients who are conveniently accessible as subjects because of hospitalization, but for whom the experiments have no direct relevance. In some hospitals it has long been acceptable practice to perform clinical investigations on such subjects, with little or no explanation of the procedure. This attitude has been based not only on the investigator's preemptive right to know, but also on the clear operational principle of quid pro quo. In return for medical care, the subject is expected to donate his body for investiga-
Recently, new federal regulations (1, 2) have been proposed that would sharply limit the participation of children, prisoners, and the mentally infirm in experimental research, and further provide for more stringent review committees to monitor such research. These recent regulations state that "informed consent is the keystone of the protection of human subjects involved in research," and that "certain categories of persons have limited capacity to consent to their involvement in such activities." The regulations then propose "special protections" for the mentally infirm, prisoners and children. The details will not be discussed in this paper. However, these codes do establish a minimal level of conduct far above that which has prevailed until the present. Such "special protections" should now be extended to geriatric subjects. Since almost all noncontagious diseases increase in incidence with increasing age, it is apparent that many subjects exposed to an experimental agent or procedure will be in the geriatric age group. Thus, exploitation of this group in medical research may exceed that of children or the mentally handicapped.
* Clinical Instructor in Medicine and Dermatology, University of Tennessee Medical Units, Memphis. Address for correspondence: Joel E. Bernstein, MD, 3030 Jackson Avenue, Memphis, TN 38112. 327
BERNSTEIN AND NELSON
tional use. Such practice on the part of many investigators ignores the most basic right a research subject has - the right of consent. Whatever the merits of the investigation, the dignity and right of the individuals who contribute to its pursuit must be respected and protected. The most basic question that can be raised in regard to informed consent is: Does anything such as informed consent exist? Legally the answer seems to be an unequivocal yes. A subject may not be used or touched without his permission (7). In other words, there may be no unconditional assault, battery, or invasion of privacy. Legal decisions clearly indicate that in all uncommon treatments or procedures, the risks involved must be disclosed (8, 9). Such decisions have only excluded the need for disclosure when the disclosure would so seriously upset the patient that he would be unable to weigh dispassionately the potential risks and benefits that would attend his participation in the study. Two serious misunderstandings have arisen with respect to this legal requirement for informed consent: 1) the patient need not be told when the explanation is too difficult or complex, and 2) the patient need not be advised if the procedure entails negligible risks. In regard to "1)," the courts have held that the requisite scope of a physician's disclosure is determined by the patient's need, and that need is whatever information is material to the patient's decision (8). In regard to "2)," the courts have recognized that an untoward effect arising from a presumed small risk is just as actionable as any other (8). A "very small" chance of death or serious disability may well be significant in respect to the potential benefit of the treatment or procedure involved. According to the purely legal view, therefore, informed consent has been secured when the subject has been fully informed as to the medical risks and benefits involved and then signs a quasi-legal statement agreeing to subject himself to the treatment with full assurance of his rights to discontinue at any time. However, the child and the mentally handicapped cannot comprehend the nature and risks of a treatment or procedure. Recently, it has been questioned whether real informed consent can even exist: "How can the layman comprehend the importance of his perhaps not receiving, as determined by the luck of the draw, the highly touted new treatment that his roommate will get? How can he interpret the information that 328
Vol. XXIII
an intravascular catheter and radio-opaque dye injection have an 0.01 percent probability of leading to dangerous thrombosis or cardiac arrythmia?" (10). The answer is that the layman can hardly comprehend this information, when even the investigators themselves often may not be aware of every potential risk involved in their experiments. Educated consent cannot in fact be further assured by detailed explanations of procedures. The comprehension of medical information given to untutored subjects may be inversely correlated with the elaborateness of the material presented (11). Practically speaking, experimental research must continue, and thus informed consent, with all its flaws, is clearly required. How can the geriatric subject be provided the same kind of protection given children, the mentally infirm and prisoners? Such protection can be insured if the following conditions for obtaining and documenting informed consent are followed: 1. The subjects chosen for studies are sufficiently intelligent or educated so that they can understand the goals, nature, and hazards of an experiment. Subjects with impaired mental status are not suitable for use as experimental subjects unless they have a disorder for which the new treatment or procedure is clearly indicated and may prove of significant benefit. 2. The subjects chosen for studies are able to exercise free will in granting consent. Consent should not be requested when the expectations of peripheral benefits such as free medical care or increased attention from the physician may be an overriding or determining factor in their participation. 3. The investigator informs all subjects of all conceivable risks associated with participation in the study. Explanations should be complete but concise, and preferably in language easily understood by the layman. 4. Documentation of the steps involved in obtaining such informed consent, and the formal consent statement itself, are carefully preserved in the records. There will be cases in which an elderly subject's mental status is so impaired that he cannot reasonably comprehend the nature, risks and benefits of a new treatment or procedure. In such a case, when experimentation appears
July 1975
MEDICAL EXPERIMENTATION IN THE ELDERLY
to be ethically warranted, it may be necessary to secure the signature of a spouse, child, or sibling of the patient. Securing such consent from a close relative is desirable, but one must be aware of its legal limitations. Although there are no cases directly pertinent to the geriatric subject, there are decisions that would seem to render second-party consent invalid. Although the courts have ruled that in the case of children, disclosures must be made to the parents (12), they have also ruled (13) that "the legal authority of parents to consent extends only to those procedures which are necessary for the child's care." A similar argument holds true for the geriatric subject - no person has the legal right to give consent for the involvement of an individual in an activity not for the benefit of that individual. Participation in human experimental research poses a significant problem for geriatric subjects. They are the group most useful for the study of new therapeutic agents or procedures because, in them, there is a high incidence of clinically apparent disease. Nevertheless, they can be unknowingly and painfully exploited in such research studies. Hospital admission of many elderly patients has been precipitated by such experimental treatment procedures, and additional complications often arise during the course of hospitalization. It has been reported that the incidence of adverse drug reactions in patients over 60 years of age is two and a half times that in a younger group (14), and that the median age of patients hospitalized with drug reactions is 60 years (15). These figures
confirm the dangers that such experimentation may pose for the elderly subject, and emphasize that special precautions must be taken to ensure the right of these subjects to a truly informed consent. REFERENCES 1. Federal Register, Vol 39, May 30, 1974, pp 18914-18920. 2. Federal Register, Vol 39, August 23, 1974, pp 30618-30657. 3. Welford AT and Birren JE: Behavior, Aging, and the Nervous System. Springfield, lIIinois, Charles C Thomas, Publisher, 1965. 4. Birren JE (Ed): Handbook of Aging and the Individual: Psychological and Biological Aspects. Chicago, University of Chicago Press, 1959. 5. Goldman R: Decline in organ function with aging, in Clinical Geriatrics, ed. by I Rossman. Philadelphia, JB Lippincott, 1974, pp 19-48. 6. Carter AB: The neurologic aspects of aging, Ibid., pp 123-141. 7. Ladimer I: Rights, responsibilities, and protection of patients in human studies, J Clin Pharmacol 7: 125,1967. 8. Simonaitis J: More about informed consent, (Part 1), JAMA 224: 1831, 1973. 9. Simonaitis J: More about informed consent, (Part 2), JAMA 225: 95,1973. 10. Ingelfinger FJ: Informed (but uneducated) consent, N England J Med 287:465, 1972. 11. Epstein LC and Lasagna L: Obtaining informed consent. Form or substance, Arch Int Med 123:682,1969. 12. Holder AR: Informed consent. I. Its evolution, JAMA 214:1181,1970. 13. Proposed rules set guidelines for clinical research on humans, JAMA 227:13, 1974. 14. Hurwitz N and Wade OL: Intensive hospital monitoring of adverse reactions to drugs, Brit Med J 1:531, 1969. 15. Hurwitz N: Admissions to hospital due to drugs, Brit Med J 1 :539, 1969.
329
Vol. XXIII, No.7 Printed in U.S.A.
Medical Experimentation in the Elderly JOEL E. BERNSTEIN, MD* and F. KIRK NELSON, MS, JD
University of Tennessee Medical Units, Memphis, Tennessee ABSTRACT: Participation in human experimental research constitutes a major problem for the geriatric subject. Because there is a high incidence of noncontagious disease in the elderly, they are the group most useful for the study of new therapeutic agents or procedures. However, normal aging processes, often coupled with disease of the central nervous system, render elderly persons less able to comprehend the nature and risks of such studies. These factors permit easy exploitation of geriatric subjects in medical experimentation, with possible exposure to a significant risk of serious drug reactions and unnecessary hospitalization. Recent federal regulations have given "special protections" to children, prisoners and the mentally infirm in experimental research, to guard against abuse of their human rights. A basic requirement is that informed consent be carefully obtained and documented. Such "special protections" should now be extended to geriatric subjects so that there will be no further exploitation in the course of valid clinical research. Psychologic changes associated with aging have been documented extensively in the literature (3, 4). The normal aging process of the nervous system results in a loss of neurons and a progressive decrease in the weight of the brain, especially after the sixth decade (5, 6). Other changes with aging include progressive vascular and connective tissue degeneration and alterations in cerebral circulation. In addition to these normal aging changes, cerebrovascular disease, trauma, neoplasms, vitamin deficiency states, and degenerative disease of the central nervous system further impair the geriatric patient's cognitive powers. Thus, the nature and risks of a new treatment or procedure may be as incomprehensible to an elderly patient as to a child or mentally handicapped person. Perhaps most easily exploited among the elderly are the terminally ill, and patients who are conveniently accessible as subjects because of hospitalization, but for whom the experiments have no direct relevance. In some hospitals it has long been acceptable practice to perform clinical investigations on such subjects, with little or no explanation of the procedure. This attitude has been based not only on the investigator's preemptive right to know, but also on the clear operational principle of quid pro quo. In return for medical care, the subject is expected to donate his body for investiga-
Recently, new federal regulations (1, 2) have been proposed that would sharply limit the participation of children, prisoners, and the mentally infirm in experimental research, and further provide for more stringent review committees to monitor such research. These recent regulations state that "informed consent is the keystone of the protection of human subjects involved in research," and that "certain categories of persons have limited capacity to consent to their involvement in such activities." The regulations then propose "special protections" for the mentally infirm, prisoners and children. The details will not be discussed in this paper. However, these codes do establish a minimal level of conduct far above that which has prevailed until the present. Such "special protections" should now be extended to geriatric subjects. Since almost all noncontagious diseases increase in incidence with increasing age, it is apparent that many subjects exposed to an experimental agent or procedure will be in the geriatric age group. Thus, exploitation of this group in medical research may exceed that of children or the mentally handicapped.
* Clinical Instructor in Medicine and Dermatology, University of Tennessee Medical Units, Memphis. Address for correspondence: Joel E. Bernstein, MD, 3030 Jackson Avenue, Memphis, TN 38112. 327
BERNSTEIN AND NELSON
tional use. Such practice on the part of many investigators ignores the most basic right a research subject has - the right of consent. Whatever the merits of the investigation, the dignity and right of the individuals who contribute to its pursuit must be respected and protected. The most basic question that can be raised in regard to informed consent is: Does anything such as informed consent exist? Legally the answer seems to be an unequivocal yes. A subject may not be used or touched without his permission (7). In other words, there may be no unconditional assault, battery, or invasion of privacy. Legal decisions clearly indicate that in all uncommon treatments or procedures, the risks involved must be disclosed (8, 9). Such decisions have only excluded the need for disclosure when the disclosure would so seriously upset the patient that he would be unable to weigh dispassionately the potential risks and benefits that would attend his participation in the study. Two serious misunderstandings have arisen with respect to this legal requirement for informed consent: 1) the patient need not be told when the explanation is too difficult or complex, and 2) the patient need not be advised if the procedure entails negligible risks. In regard to "1)," the courts have held that the requisite scope of a physician's disclosure is determined by the patient's need, and that need is whatever information is material to the patient's decision (8). In regard to "2)," the courts have recognized that an untoward effect arising from a presumed small risk is just as actionable as any other (8). A "very small" chance of death or serious disability may well be significant in respect to the potential benefit of the treatment or procedure involved. According to the purely legal view, therefore, informed consent has been secured when the subject has been fully informed as to the medical risks and benefits involved and then signs a quasi-legal statement agreeing to subject himself to the treatment with full assurance of his rights to discontinue at any time. However, the child and the mentally handicapped cannot comprehend the nature and risks of a treatment or procedure. Recently, it has been questioned whether real informed consent can even exist: "How can the layman comprehend the importance of his perhaps not receiving, as determined by the luck of the draw, the highly touted new treatment that his roommate will get? How can he interpret the information that 328
Vol. XXIII
an intravascular catheter and radio-opaque dye injection have an 0.01 percent probability of leading to dangerous thrombosis or cardiac arrythmia?" (10). The answer is that the layman can hardly comprehend this information, when even the investigators themselves often may not be aware of every potential risk involved in their experiments. Educated consent cannot in fact be further assured by detailed explanations of procedures. The comprehension of medical information given to untutored subjects may be inversely correlated with the elaborateness of the material presented (11). Practically speaking, experimental research must continue, and thus informed consent, with all its flaws, is clearly required. How can the geriatric subject be provided the same kind of protection given children, the mentally infirm and prisoners? Such protection can be insured if the following conditions for obtaining and documenting informed consent are followed: 1. The subjects chosen for studies are sufficiently intelligent or educated so that they can understand the goals, nature, and hazards of an experiment. Subjects with impaired mental status are not suitable for use as experimental subjects unless they have a disorder for which the new treatment or procedure is clearly indicated and may prove of significant benefit. 2. The subjects chosen for studies are able to exercise free will in granting consent. Consent should not be requested when the expectations of peripheral benefits such as free medical care or increased attention from the physician may be an overriding or determining factor in their participation. 3. The investigator informs all subjects of all conceivable risks associated with participation in the study. Explanations should be complete but concise, and preferably in language easily understood by the layman. 4. Documentation of the steps involved in obtaining such informed consent, and the formal consent statement itself, are carefully preserved in the records. There will be cases in which an elderly subject's mental status is so impaired that he cannot reasonably comprehend the nature, risks and benefits of a new treatment or procedure. In such a case, when experimentation appears
July 1975
MEDICAL EXPERIMENTATION IN THE ELDERLY
to be ethically warranted, it may be necessary to secure the signature of a spouse, child, or sibling of the patient. Securing such consent from a close relative is desirable, but one must be aware of its legal limitations. Although there are no cases directly pertinent to the geriatric subject, there are decisions that would seem to render second-party consent invalid. Although the courts have ruled that in the case of children, disclosures must be made to the parents (12), they have also ruled (13) that "the legal authority of parents to consent extends only to those procedures which are necessary for the child's care." A similar argument holds true for the geriatric subject - no person has the legal right to give consent for the involvement of an individual in an activity not for the benefit of that individual. Participation in human experimental research poses a significant problem for geriatric subjects. They are the group most useful for the study of new therapeutic agents or procedures because, in them, there is a high incidence of clinically apparent disease. Nevertheless, they can be unknowingly and painfully exploited in such research studies. Hospital admission of many elderly patients has been precipitated by such experimental treatment procedures, and additional complications often arise during the course of hospitalization. It has been reported that the incidence of adverse drug reactions in patients over 60 years of age is two and a half times that in a younger group (14), and that the median age of patients hospitalized with drug reactions is 60 years (15). These figures
confirm the dangers that such experimentation may pose for the elderly subject, and emphasize that special precautions must be taken to ensure the right of these subjects to a truly informed consent. REFERENCES 1. Federal Register, Vol 39, May 30, 1974, pp 18914-18920. 2. Federal Register, Vol 39, August 23, 1974, pp 30618-30657. 3. Welford AT and Birren JE: Behavior, Aging, and the Nervous System. Springfield, lIIinois, Charles C Thomas, Publisher, 1965. 4. Birren JE (Ed): Handbook of Aging and the Individual: Psychological and Biological Aspects. Chicago, University of Chicago Press, 1959. 5. Goldman R: Decline in organ function with aging, in Clinical Geriatrics, ed. by I Rossman. Philadelphia, JB Lippincott, 1974, pp 19-48. 6. Carter AB: The neurologic aspects of aging, Ibid., pp 123-141. 7. Ladimer I: Rights, responsibilities, and protection of patients in human studies, J Clin Pharmacol 7: 125,1967. 8. Simonaitis J: More about informed consent, (Part 1), JAMA 224: 1831, 1973. 9. Simonaitis J: More about informed consent, (Part 2), JAMA 225: 95,1973. 10. Ingelfinger FJ: Informed (but uneducated) consent, N England J Med 287:465, 1972. 11. Epstein LC and Lasagna L: Obtaining informed consent. Form or substance, Arch Int Med 123:682,1969. 12. Holder AR: Informed consent. I. Its evolution, JAMA 214:1181,1970. 13. Proposed rules set guidelines for clinical research on humans, JAMA 227:13, 1974. 14. Hurwitz N and Wade OL: Intensive hospital monitoring of adverse reactions to drugs, Brit Med J 1:531, 1969. 15. Hurwitz N: Admissions to hospital due to drugs, Brit Med J 1 :539, 1969.
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