Towards evidence based bioethics
1 Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine; 115 Blockley Hall, 423 Guardian Drive, Philadelphia, PA 19104-6021, USA
Use of epidemiological methods to study human behaviour is necessary to create an evidence base to inform ethical positions in medicine and science
Introduction
Bioethics has to date largely consisted of analyses of the moral underpinnings of appropriate behaviour in science and medicine. Although such theoretical writings often make important contributions to public health, they often contain unfounded assumptions about human behaviour. I describe recent examples in which assumptions made in theoretical writings were later repudiated, or in which empirical work served further to clarify positions taken in theoretical pieces. Paralleling the rise of evidence based approaches to clinical medicine, these examples show that further emphasis on empirical analysis is needed to promote more balanced, and evidence based, bioethics.
, 百拇医药
In 1988 Benjamin Freedman noted that perception, rather than reality, controls the generation and resolution of ethical issues.1 Writing during the first decade of the HIV/AIDS epidemic, he was referring to how the debate on doctors' duties to render care to AIDS patients was influenced by doctors' perceptions of the risk that patients might transmit the virus to them, rather than the actual risk conferred, which was not yet known. In the absence of evidence, intuition and perception have useful roles.
, http://www.100md.com
But what ought to guide ethical deliberations once evidence becomes available Although evidence emerged that the risk of HIV transmission from patient to doctor is extremely low,2 3 resolution of many doctors' fears lagged behind and perception led several doctors to continue refusing to treat patients infected with HIV. I argue that, although Freedman correctly noted that perception often controls the generation as well as the resolution of ethical issues, this statement is only half true when placed in the normative realm: perception ought to govern the generation of ethical issues, but reality must often govern their resolution.
, http://www.100md.com
The rise of evidence based medicine
Traditional medical teaching held that clinical experience, observation, and acumen would lead to optimal care for patients. Although these remain laudable goals, we now know that seemingly logical clinical insights may turn out to be seriously flawed when scientifically scrutinised. Two examples from the cardiovascular literature will illustrate the point.
In the 1950s, several cardiologists and surgeons logically presumed that they could improve the quality of life of patients with angina pectoris by shunting a greater percentage of the cardiac output through the coronary vessels. Surgeons began ligating the internal mammary arteries to force more oxygen rich blood to the myocardium. The belief that this would ameliorate chest pain was supported by early case series, in which patients experienced both symptomatic relief and improvements in exercise tolerance postoperatively. However, when the procedure was tested in a randomised trial comparing arterial ligation and sham surgery (in which the skin on the chest was incised but the arteries left intact), it quickly became evident that the benefits of the procedure were no greater than those obtainable with the surgical equivalent of a placebo.4 5
, 百拇医药
A second example concerns the proper management of patients with myocardial infarction. Cardiologists, noting that ventricular arrhythmias represented the most common cause of death immediately after myocardial infarction, reasoned that administering drugs to suppress these arrhythmias should improve survival. Testing this sensible theory in a placebo controlled trial yielded a disconcerting lesson: not only were class Ic antiarrhythmic agents ineffective, they were actually associated with an increased risk of death.6 Doctors soon accepted both sets of results; arterial ligation and postinfarction class Ic antiarrhythmic drugs were quickly eliminated from our therapeutic armamentarium.
, 百拇医药
Errors in bioethical theory
Just as these examples highlight changing evidentiary standards in clinical medicine, a similar transition is needed in bioethics. Consider the ongoing debate on the ethics of paying patients to participate in research studies. Many ethicists have argued that paying research subjects represents an undue inducement—"undue" because financial incentives may alter patients' decision making processes such that they will not appropriately consider the risks of participating.7-12 If payment blinded patients to the risks of research participation it would preclude patients from granting fully informed consent and thereby violate their autonomy.
, http://www.100md.com
Although it was reasonable to assume, a priori, that payment represents an undue inducement to participate in a trial, two recent empirical studies have found no evidence to support this concern. In the first study, my colleagues and I investigated the willingness of 126 hypertensive patients to participate in placebo controlled trials of experimental antihypertensive drugs.13 Using a 3x3 within subjects factorial design, in which we varied risk level and payment and presented each patient with all nine possible combinations, we found that patients' valuations of the importance of risk were not attenuated at higher payment levels.
, http://www.100md.com
In the second study, Bentley and Thacker studied the willingness of 270 healthy pharmacy students to participate in various randomised trials in which the severity of risk and monetary inducement were similarly varied.14 Using a different method—a 3x3 between subjects design, in which each participant was randomly assigned to receive only one scenario—these authors found almost identical results to our own. In both studies, increasing levels of payment and decreasing levels of risk were each associated with increased willingness to participate, but the effect of risk was similar across payment levels (although both studies were specifically powered to detect such effect modification if it existed).13 14
, 百拇医药
Ethicists have also argued that the influence of financial inducements may be particularly strong among poorer members of society,15 and that this disproportionate influence may unjustly persuade one segment of society to participate in trials that may benefit all. This argument too has been proffered without any evidence regarding the extent to which the concern manifests—it was not known whether patients with different incomes were differentially influenced by set payments. In the same study described above, we investigated this second question by comparing the responsiveness of more and less wealthy patients to increasing payment levels.
, http://www.100md.com
Surprisingly, we found that patients with incomes above the median were influenced by higher payments to a significantly greater extent than patients with incomes below the median.13 When asked to explain why their willingness to participate did or did not change with increasing payment levels, poorer patients were more likely to make statements such as "Money doesn't mean anything when it comes to your health." Taken together, these results undermine many of the theoretical challenges to the practice of paying research participants.
, 百拇医药
Evidence has countered ethical theory in other situations as well. Beauchamp and Childress reviewed how ethicists and state legislatures have supported the "reasonable person standard" (in which the amount of information disclosed is expected to meet the requests of any reasonable person) to guide the appropriate type and amount of information disclosure in seeking informed consent, although evidence shows that patients often make decisions before and independent of the process of receiving information.16 Citing studies of patients making decisions on family planning, kidney donation, endoscopy, and breast cancer therapy, these authors argue that evidence has cast doubt on theoretical arguments for what should count as adequate disclosure to patients. As another example, Roberts described how observational studies of decisional capacity and risk assessment among patients with mental illness should serve to alleviate prior theoretical concerns about the ethics of research among such patients.17
, 百拇医药
More balanced bioethics
Theory must certainly maintain a prominent role in bioethics. Elucidating the moral justification for appropriate behaviour provides compelling guidance for our actions. Furthermore, innovative theories and arguments are critical for ethics to advance. For example, the persuasive writings of Kant and others, on how individuals have the right to self determination, have largely spurred the recent democratisation of medicine and increase in respect for patients' autonomy in guiding their health care.18 19
, 百拇医药
Unlike the original theories, that paying research subjects represented undue or unjust inducements, this principle of respect for autonomy does not presuppose any empirically verifiable claims and so is not subject to repudiation by evidence. However, because understanding this principle does not allow us to determine how much autonomy in making decisions patients want, which models for shared decision making work best, or how doctors ought to be trained to make these models work, an important role remains for the series of studies aimed at understanding this issues.20-22
, 百拇医药
Summary points
Bioethical theory often rests on unproved assumptions about human behaviour
Empirical analyses can document the extent to which ethical concerns manifest in reality and can identify ways in which these concerns can be mitigated
Theoretical and empirical approaches can work synergistically to promote more balanced bioethics
Theoretical and empirical approaches therefore may work synergistically in different ways. In the case of paying research participants, the original theoretical arguments identified the potential for ethical problems; empirical studies later showed that these problems do not manifest as was assumed; and more recent theoretical work has incorporated this evidence into a refined discussion of the issues.23 In the case of disclosing information as a means of respecting autonomy, a primary ethical principle was established, and evaluations of its implementation have indicated the need for new strategies to uphold this principle.
, 百拇医药
Conclusion
There will always be a need for thoughtful writing about social and philosophical perspectives on clinical care and biomedical research. Such theoretical writings place our practices as doctors and investigators into appropriate contexts and provide constant checks to ensure that these practices are responsive to changing circumstances. Furthermore, many timely issues are not amenable to scientific investigation and instead require persuasive theoretical arguments so that change can be implemented. In cases where investigation is possible, however, "position pieces" that rely on as yet unverified claims should be viewed as hypothesis generating until the claims are properly evaluated, just as early experimental results must await confirmation by larger studies before being accepted. Applying this scientific method to bioethics—thereby creating more evidence based bioethics—will serve our patients, research participants, and profession best.
, 百拇医药
Competing interests: None declared.
References
Freedman B. Health professions, codes, and the right to refuse to treat HIV-infectious patients. Hastings Center Rep 1988;April/May: 20-25.
Cardo DM, Culver DH, Ciesielski CA. A case-control study of HIV seroconversion in health care workers after percutaneous exposure. N Engl J Med 1997;337: 1485-90.
Centers for Disease Control. Case-control study of HIV seroconversion in health-care workers after percutaneous exposures to HIV-infected blood—France, United Kingdom and United States, January 1988-August 1994. MMWR Morb Mortal Wkly Rep 1995;44: 929.
, 百拇医药
Cobb LA, Thomas GI, Dillard DH, Merendino KA, Bruce RA. An evaluation of internal-mammary-artery ligation by double-blind technic. N Engl J Med 1959;260: 1115-8.
Dimond EG, Kittle CF, Crockett JE. Comparision of internal mammary artery ligation and sham operation for angina pectoris. Am J Cardiol 1960;5: 483-6.
The Cardiac Arrhythmia Suppression Trial I. Preliminary Report. Effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction. N Engl J Med 1989;321: 406-12.
, 百拇医药
Dickert N, Grady C. What's the price of a research subject Approaches to payment for research participation. N Engl J Med 1999;341: 198-203.
Grady C. Money for research participation: does it jeopardize informed consent Am J Bioethics 2001;1: 40-4.
Macklin R. "Due" and "undue" inducements: On paying money to research subjects. IRB: a review of human subjects research 1981;3: 1-6.
McGee G. Subject to payment JAMA 1997;278: 199-200.
, http://www.100md.com
McNeil P. Paying people to participate in research. Bioethics 1997;11: 390-6.
Wilkenson M, Moore A. Inducement in research. Bioethics 1997;11: 373-89.
Halpern SD, Karlawish JHT, Casarett D, Berlin JA, Asch DA. Empirical assessment of whether moderate payments are undue or unjust inducements for participation in clinical trials. Arch Intern Med 2004;164: 801-3.
Bentley JP, Thacker PG. The influence of risk and monetary payment on the research participation decision making process. J Med Ethics 2004;30: 293-8.
, http://www.100md.com
Viens AM. Socio-economic status and inducement to participate. Am J Bioethics 2001; 1.
Beauchamp TL, Childress JF. Respect for autonomy. Principles of biomedical ethics. 4th ed. New York: Oxford University Press, 1994: 120-88.
Roberts LW. Evidence-based ethics and informed consent in mental illness research. Arch Gen Psychiatry 2000;57: 540-2.
Bayer R, Oppenheimer GM. Toward a more democratic medicine: sharing the burden of ignorance. AIDS Doctors: voices from the epidemic. New York: Oxford University Press, 2000: 156-69.
, 百拇医药
Coulter A, Rozansky D. Full engagement in health. BMJ 2004;329: 1197-8.
Joffe S, Manocchia M, Weeks JC, Cleary PD. What do patients value in their hospital care An empirical perspective on autonomy centred bioethics. J Med Ethics 2003;29: 103-8.
Heesen C, Kasper J, Segal J, Kopke S, Muhlhauser I. Decisional role preferences, risk knowledge and information interests in patients with multiple sclerosis. Mult Scler 2004;10: 643-50.
, 百拇医药
Azoulay E, Pochard F, Chevret S, et al. Half the family members of intensive care unit patients do not want to share in the decision-making process: a study in 78 French intensive care units. Crit Care Med 2004;32: 1832-8.
Dunn LB, Gordon NE. Improving informed consent and enhancing recruitment for research by understanding economic behavior. JAMA 2005;293: 609-12., 百拇医药(Scott D Halpern,)
Use of epidemiological methods to study human behaviour is necessary to create an evidence base to inform ethical positions in medicine and science
Introduction
Bioethics has to date largely consisted of analyses of the moral underpinnings of appropriate behaviour in science and medicine. Although such theoretical writings often make important contributions to public health, they often contain unfounded assumptions about human behaviour. I describe recent examples in which assumptions made in theoretical writings were later repudiated, or in which empirical work served further to clarify positions taken in theoretical pieces. Paralleling the rise of evidence based approaches to clinical medicine, these examples show that further emphasis on empirical analysis is needed to promote more balanced, and evidence based, bioethics.
, 百拇医药
In 1988 Benjamin Freedman noted that perception, rather than reality, controls the generation and resolution of ethical issues.1 Writing during the first decade of the HIV/AIDS epidemic, he was referring to how the debate on doctors' duties to render care to AIDS patients was influenced by doctors' perceptions of the risk that patients might transmit the virus to them, rather than the actual risk conferred, which was not yet known. In the absence of evidence, intuition and perception have useful roles.
, http://www.100md.com
But what ought to guide ethical deliberations once evidence becomes available Although evidence emerged that the risk of HIV transmission from patient to doctor is extremely low,2 3 resolution of many doctors' fears lagged behind and perception led several doctors to continue refusing to treat patients infected with HIV. I argue that, although Freedman correctly noted that perception often controls the generation as well as the resolution of ethical issues, this statement is only half true when placed in the normative realm: perception ought to govern the generation of ethical issues, but reality must often govern their resolution.
, http://www.100md.com
The rise of evidence based medicine
Traditional medical teaching held that clinical experience, observation, and acumen would lead to optimal care for patients. Although these remain laudable goals, we now know that seemingly logical clinical insights may turn out to be seriously flawed when scientifically scrutinised. Two examples from the cardiovascular literature will illustrate the point.
In the 1950s, several cardiologists and surgeons logically presumed that they could improve the quality of life of patients with angina pectoris by shunting a greater percentage of the cardiac output through the coronary vessels. Surgeons began ligating the internal mammary arteries to force more oxygen rich blood to the myocardium. The belief that this would ameliorate chest pain was supported by early case series, in which patients experienced both symptomatic relief and improvements in exercise tolerance postoperatively. However, when the procedure was tested in a randomised trial comparing arterial ligation and sham surgery (in which the skin on the chest was incised but the arteries left intact), it quickly became evident that the benefits of the procedure were no greater than those obtainable with the surgical equivalent of a placebo.4 5
, 百拇医药
A second example concerns the proper management of patients with myocardial infarction. Cardiologists, noting that ventricular arrhythmias represented the most common cause of death immediately after myocardial infarction, reasoned that administering drugs to suppress these arrhythmias should improve survival. Testing this sensible theory in a placebo controlled trial yielded a disconcerting lesson: not only were class Ic antiarrhythmic agents ineffective, they were actually associated with an increased risk of death.6 Doctors soon accepted both sets of results; arterial ligation and postinfarction class Ic antiarrhythmic drugs were quickly eliminated from our therapeutic armamentarium.
, 百拇医药
Errors in bioethical theory
Just as these examples highlight changing evidentiary standards in clinical medicine, a similar transition is needed in bioethics. Consider the ongoing debate on the ethics of paying patients to participate in research studies. Many ethicists have argued that paying research subjects represents an undue inducement—"undue" because financial incentives may alter patients' decision making processes such that they will not appropriately consider the risks of participating.7-12 If payment blinded patients to the risks of research participation it would preclude patients from granting fully informed consent and thereby violate their autonomy.
, http://www.100md.com
Although it was reasonable to assume, a priori, that payment represents an undue inducement to participate in a trial, two recent empirical studies have found no evidence to support this concern. In the first study, my colleagues and I investigated the willingness of 126 hypertensive patients to participate in placebo controlled trials of experimental antihypertensive drugs.13 Using a 3x3 within subjects factorial design, in which we varied risk level and payment and presented each patient with all nine possible combinations, we found that patients' valuations of the importance of risk were not attenuated at higher payment levels.
, http://www.100md.com
In the second study, Bentley and Thacker studied the willingness of 270 healthy pharmacy students to participate in various randomised trials in which the severity of risk and monetary inducement were similarly varied.14 Using a different method—a 3x3 between subjects design, in which each participant was randomly assigned to receive only one scenario—these authors found almost identical results to our own. In both studies, increasing levels of payment and decreasing levels of risk were each associated with increased willingness to participate, but the effect of risk was similar across payment levels (although both studies were specifically powered to detect such effect modification if it existed).13 14
, 百拇医药
Ethicists have also argued that the influence of financial inducements may be particularly strong among poorer members of society,15 and that this disproportionate influence may unjustly persuade one segment of society to participate in trials that may benefit all. This argument too has been proffered without any evidence regarding the extent to which the concern manifests—it was not known whether patients with different incomes were differentially influenced by set payments. In the same study described above, we investigated this second question by comparing the responsiveness of more and less wealthy patients to increasing payment levels.
, http://www.100md.com
Surprisingly, we found that patients with incomes above the median were influenced by higher payments to a significantly greater extent than patients with incomes below the median.13 When asked to explain why their willingness to participate did or did not change with increasing payment levels, poorer patients were more likely to make statements such as "Money doesn't mean anything when it comes to your health." Taken together, these results undermine many of the theoretical challenges to the practice of paying research participants.
, 百拇医药
Evidence has countered ethical theory in other situations as well. Beauchamp and Childress reviewed how ethicists and state legislatures have supported the "reasonable person standard" (in which the amount of information disclosed is expected to meet the requests of any reasonable person) to guide the appropriate type and amount of information disclosure in seeking informed consent, although evidence shows that patients often make decisions before and independent of the process of receiving information.16 Citing studies of patients making decisions on family planning, kidney donation, endoscopy, and breast cancer therapy, these authors argue that evidence has cast doubt on theoretical arguments for what should count as adequate disclosure to patients. As another example, Roberts described how observational studies of decisional capacity and risk assessment among patients with mental illness should serve to alleviate prior theoretical concerns about the ethics of research among such patients.17
, 百拇医药
More balanced bioethics
Theory must certainly maintain a prominent role in bioethics. Elucidating the moral justification for appropriate behaviour provides compelling guidance for our actions. Furthermore, innovative theories and arguments are critical for ethics to advance. For example, the persuasive writings of Kant and others, on how individuals have the right to self determination, have largely spurred the recent democratisation of medicine and increase in respect for patients' autonomy in guiding their health care.18 19
, 百拇医药
Unlike the original theories, that paying research subjects represented undue or unjust inducements, this principle of respect for autonomy does not presuppose any empirically verifiable claims and so is not subject to repudiation by evidence. However, because understanding this principle does not allow us to determine how much autonomy in making decisions patients want, which models for shared decision making work best, or how doctors ought to be trained to make these models work, an important role remains for the series of studies aimed at understanding this issues.20-22
, 百拇医药
Summary points
Bioethical theory often rests on unproved assumptions about human behaviour
Empirical analyses can document the extent to which ethical concerns manifest in reality and can identify ways in which these concerns can be mitigated
Theoretical and empirical approaches can work synergistically to promote more balanced bioethics
Theoretical and empirical approaches therefore may work synergistically in different ways. In the case of paying research participants, the original theoretical arguments identified the potential for ethical problems; empirical studies later showed that these problems do not manifest as was assumed; and more recent theoretical work has incorporated this evidence into a refined discussion of the issues.23 In the case of disclosing information as a means of respecting autonomy, a primary ethical principle was established, and evaluations of its implementation have indicated the need for new strategies to uphold this principle.
, 百拇医药
Conclusion
There will always be a need for thoughtful writing about social and philosophical perspectives on clinical care and biomedical research. Such theoretical writings place our practices as doctors and investigators into appropriate contexts and provide constant checks to ensure that these practices are responsive to changing circumstances. Furthermore, many timely issues are not amenable to scientific investigation and instead require persuasive theoretical arguments so that change can be implemented. In cases where investigation is possible, however, "position pieces" that rely on as yet unverified claims should be viewed as hypothesis generating until the claims are properly evaluated, just as early experimental results must await confirmation by larger studies before being accepted. Applying this scientific method to bioethics—thereby creating more evidence based bioethics—will serve our patients, research participants, and profession best.
, 百拇医药
Competing interests: None declared.
References
Freedman B. Health professions, codes, and the right to refuse to treat HIV-infectious patients. Hastings Center Rep 1988;April/May: 20-25.
Cardo DM, Culver DH, Ciesielski CA. A case-control study of HIV seroconversion in health care workers after percutaneous exposure. N Engl J Med 1997;337: 1485-90.
Centers for Disease Control. Case-control study of HIV seroconversion in health-care workers after percutaneous exposures to HIV-infected blood—France, United Kingdom and United States, January 1988-August 1994. MMWR Morb Mortal Wkly Rep 1995;44: 929.
, 百拇医药
Cobb LA, Thomas GI, Dillard DH, Merendino KA, Bruce RA. An evaluation of internal-mammary-artery ligation by double-blind technic. N Engl J Med 1959;260: 1115-8.
Dimond EG, Kittle CF, Crockett JE. Comparision of internal mammary artery ligation and sham operation for angina pectoris. Am J Cardiol 1960;5: 483-6.
The Cardiac Arrhythmia Suppression Trial I. Preliminary Report. Effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction. N Engl J Med 1989;321: 406-12.
, 百拇医药
Dickert N, Grady C. What's the price of a research subject Approaches to payment for research participation. N Engl J Med 1999;341: 198-203.
Grady C. Money for research participation: does it jeopardize informed consent Am J Bioethics 2001;1: 40-4.
Macklin R. "Due" and "undue" inducements: On paying money to research subjects. IRB: a review of human subjects research 1981;3: 1-6.
McGee G. Subject to payment JAMA 1997;278: 199-200.
, http://www.100md.com
McNeil P. Paying people to participate in research. Bioethics 1997;11: 390-6.
Wilkenson M, Moore A. Inducement in research. Bioethics 1997;11: 373-89.
Halpern SD, Karlawish JHT, Casarett D, Berlin JA, Asch DA. Empirical assessment of whether moderate payments are undue or unjust inducements for participation in clinical trials. Arch Intern Med 2004;164: 801-3.
Bentley JP, Thacker PG. The influence of risk and monetary payment on the research participation decision making process. J Med Ethics 2004;30: 293-8.
, http://www.100md.com
Viens AM. Socio-economic status and inducement to participate. Am J Bioethics 2001; 1.
Beauchamp TL, Childress JF. Respect for autonomy. Principles of biomedical ethics. 4th ed. New York: Oxford University Press, 1994: 120-88.
Roberts LW. Evidence-based ethics and informed consent in mental illness research. Arch Gen Psychiatry 2000;57: 540-2.
Bayer R, Oppenheimer GM. Toward a more democratic medicine: sharing the burden of ignorance. AIDS Doctors: voices from the epidemic. New York: Oxford University Press, 2000: 156-69.
, 百拇医药
Coulter A, Rozansky D. Full engagement in health. BMJ 2004;329: 1197-8.
Joffe S, Manocchia M, Weeks JC, Cleary PD. What do patients value in their hospital care An empirical perspective on autonomy centred bioethics. J Med Ethics 2003;29: 103-8.
Heesen C, Kasper J, Segal J, Kopke S, Muhlhauser I. Decisional role preferences, risk knowledge and information interests in patients with multiple sclerosis. Mult Scler 2004;10: 643-50.
, 百拇医药
Azoulay E, Pochard F, Chevret S, et al. Half the family members of intensive care unit patients do not want to share in the decision-making process: a study in 78 French intensive care units. Crit Care Med 2004;32: 1832-8.
Dunn LB, Gordon NE. Improving informed consent and enhancing recruitment for research by understanding economic behavior. JAMA 2005;293: 609-12., 百拇医药(Scott D Halpern,)