Correspondence
Should the Declaration of Helsinki Be Revised?
N Engl J Med 1999; 341:1851-1853December 9, 1999
- Article
To the Editor:
Dr. Brennan's case against revising the Declaration of Helsinki (Aug. 12 issue)1 makes many good points but seems problematic with respect to cultural valuation, distributive justice, and utilitarianism. That not all countries “have the commitment to . . . the Anglo-American [ethical] tradition” implies a hierarchy within which Anglo-American ethics are deemed superior. England, the United States, and other developed nations once claimed virtue in exporting Western culture to the “uncivilized.” Are we now unwittingly advancing ethical colonialism? We might be able to learn much about ethics from non–Anglo-American societies.
In addition, in the real and manifestly unjust world, strict interpretation of distributive justice — namely, “that the burdens of research be equally borne, and the benefits equally enjoyed” — may be unrealistic. Must investigators end injustice before conducting studies that may someday reduce it? Informed consent is potentially at odds with distributive justice. If informed individuals and communities want to participate in research, whose ethics should have veto power over their free and informed choices? I have occasionally volunteered to be a subject in research studies that were uncomfortable and of unlikely personal benefit. I was free to choose to do so; this is a privilege I would not want to deny others. Further complicating matters, the distribution of supposed medical justice before the therapeutic possibilities are discovered by scientific study is a reversal of common sense. Clinical trials sometimes expose favorite therapies and standards of care as bad medicine. The prevention of trials on the basis of a priori guesses about outcomes and downstream effects on therapeutic justice demonstrates a misunderstanding of science and risks delaying improvements in standards of care.
But most important, when 35 million persons infected with the human immunodeficiency virus (HIV) need better therapies, can we ethically hold medical progress hostage to an intellectual debate over utilitarianism? In another context (public health), we routinely ask people to put themselves at risk (albeit minor risk and always with informed consent) for the unlikely benefit of themselves but the certain benefit of others (e.g., the vaccination of boys against rubella to maintain the herd immunity that typically makes the vaccination of individual children unnecessary).
The unquestioned principle of fully informed consent should be powerful enough to cover issues of the distribution of benefits and risks. The global context within which medical research now operates requires a global approach to ethics that incorporates the beliefs and wishes of all, that supports individual and community decisions for or against participation, and that strives to bring the benefits of medical science within the reach of as many as possible, on the way to reaching everyone.
1 ReferencesDavid M. Morens, M.D.
University of Hawaii, Honolulu, HI 968221
Brennan TA . Proposed revisions to the Declaration of Helsinki -- will they weaken the ethical principles underlying human research? N Engl J Med 1999;341:527-531
Full Text | Web of Science | Medline
To the Editor:
Can medical research be ethically unsupportable yet scientifically valid? The recent example of controversy over HIV-treatment trials in developing countries recalls the closing chapters of Sinclair Lewis's 1925 novel Arrowsmith. 1 Attempting to conduct a controlled therapeutic trial during an epidemic plague, Martin Arrowsmith experiences the intrinsic conflict that exists for any investigator-clinician. Faced with two imperatives in the midst of a suffering populace, he must decide whether to watch and measure experimental results or to treat and hope for the empirical success he suspects can be achieved. Because Arrowsmith's funding is linked to future patents for therapy, his roles as investigator and as clinician conflict. In the end, he fails to achieve untainted scientific results, and he compromises the ethics governing both of his roles.
Method, not intent, makes an experiment scientifically valid and ethically defensible. Henry K. Beecher knew this when he wrote “Ethics and Clinical Research” for the Journal in 1966.2 He also knew it when he articulated the cardinal principles of ethical human investigation in “Experimentation in Man,” published in 1959, before the Declaration of Helsinki was first issued in 1964.3 He understood that a utilitarian calculus should have no role in human experimentation and that the role of the investigator-clinician contained inherent conflicts of interest with respect to the subject-patient. We would be wise not to forget Beecher's points. The present debate over revisions to the Declaration of Helsinki, however, suggests that we have.
As we seek new treatments for illness, we cannot let the desire to stem tragic losses of human life poison collective reason and destroy social covenants. The values of science and the industries that profit from the realizable promises of science cannot trump all other considerations in the arena of human experimentation. Human rights are more basic than derived knowledge.
3 ReferencesVincent J. Kopp, M.D.
University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-70101
Lewis S. Arrowsmith. New York: Harcourt, Brace, 1925.
2
Beecher HK . Ethics and clinical research. N Engl J Med 1966;274:1354-1360
Full Text | Web of Science | Medline3
Beecher HK . Experimentation in man. JAMA 1959;169:461-478
Web of Science | Medline
To the Editor:
In an otherwise excellent discussion of clinical trials and ethics, Dr. Levine (Aug. 12 issue),1 referring to article 11.3 of the Declaration of Helsinki, claims that “the requirement that all patients be assured of the best proven therapeutic method rules out the development of all new treatments except those for diseases for which there are no proven therapeutic methods.” This statement is wrong and reflects a widespread misunderstanding about the role of placebos in clinical trials.
A placebo is a device for blinding with respect to a treatment and, as such, is always specific to that particular treatment. Its use does not in itself require any withdrawal of standard effective treatments. Since nursing care, clean air, fresh water, and sound diet are all highly effective remedies for any disease (as becomes clear if we take the counterfactual view of causality and consider what would happen if they were withdrawn), the implication that the use of a placebo involves denying all effective treatment would, indeed, make all placebo-controlled trials impossible.2 . . .
2 ReferencesStephen Senn, Ph.D.
University College London, London WC1E 6BT, United Kingdom1
Levine RJ . The need to revise the Declaration of Helsinki. N Engl J Med 1999;341:531-534
Full Text | Web of Science | Medline2
Senn S. Statistical issues in drug development. Chichester, England: Wiley, 1997.
To the Editor:
The Declaration of Helsinki may need modernization, but this should not weaken the protections or standards it now embodies. The declaration should continue to uphold its aims (the protection of human subjects) and to set an ideal standard. When necessary, people can explore compromises to facilitate practical means of meeting the aims of the declaration. People do violate the declaration, as Levine points out, but probably more out of an inability or unwillingness to create a practical means of upholding its aims within the context in which they are working than because the declaration is “out of touch” with contemporary thought.
Cheryl Cox Macpherson, Ph.D.
St. George's University School of Medicine, St. George's, Grenada, West IndiesTo the Editor:
. . . I believe that we have to revise seriously the ethics behind the widespread practice of carrying out enormous multicenter studies — in both industrialized countries and developing countries — more for the profit associated with enrollment than for the well-being of patients.
Miguel O'Ryan, M.D.
University of Chile, Santiago, ChileTo the Editor:
In challenging the distinction between therapeutic and nontherapeutic research, Dr. Levine should have commented on the important differences among the types of relationships between investigators and subjects. Volunteers responding to advertisements are very different from patients approached by their own physicians. Normal subjects know that they will not personally benefit from the research. They can say no freely, because they need never see the investigator again. By contrast, patients do not have the option of simply ignoring a request. Some patients may fear that saying no will injure a relationship on which they depend. Others may cling to Dr. Brennan's notion of a doctor–patient relationship “governed by justice, altruism, and virtue, not by [marketplace] efficiency”1 and not recognize that the ones most likely to benefit from the research are the investigators themselves.
Another issue that needs to be explored is the ethical basis for placebo-controlled trials in which patients are “washed out” from active treatment. According to Dr. Levine, giving placebos to untreated patients with mild hypertension is unlikely to cause harm. But the intentional exacerbation of a condition for the purpose of testing a treatment violates the ethical principle of nonmaleficence. There are reports in the press of psychiatric patients who allegedly suffered irreversible harm after “washout” from active treatment. In my own field, the study of type 2 diabetes, this design was used in studies of all three thiazolidinediones recently approved by the Food and Drug Administration.2-4 In one trial, patients were not told in the consent form that their medications for diabetes were to be stopped as part of the study. In other trials, fasting plasma glucose levels in excess of 400 mg per deciliter on two consecutive clinic visits was used as a criterion for lack of efficacy. These studies were conducted with American patients. Dr. Brennan need not look to the Third World for examples of how patients can be exploited for the sake of “efficiency.”
Patients have a right to expect that whatever their doctor suggests is within a generally accepted standard of medical practice. Patients should be free to volunteer for riskier research as well. But a free choice requires that the proposition be put to them by someone on whom they are not dependent.
(The views expressed are those of the author and do not necessarily reflect the official position of the Food and Drug Administration.)
4 ReferencesRobert I. Misbin, M.D.
Food and Drug Administration, Rockville, MD 208571
Brennan TA . Proposed revisions to the Declaration of Helsinki -- will they weaken the ethical principles underlying human research? N Engl J Med 1999;341:527-531
Full Text | Web of Science | Medline2
Misbin RI . Comment on the ethics of placebo-controlled trials in patients with type 2 diabetes mellitus. J Clin Endocrinol Metab 1999;84:823-824
CrossRef | Web of Science | Medline3
Medical officer's review of the new drug application for Avandia, 1999. Rockville, Md.: Food and Drug Administration, 1999.
4
Medical officer's review of the new drug application for Actos, 1999. Rockville, Md.: Food and Drug Administration, 1999.
Author/Editor Response
Dr. Levine replies:
To the Editor: Dr. Kopp relies on the authority of Hen-ry Beecher to support his view that “a utilitarian calculus should have no role in human experimentation.” Drs. Morens and Brennan each also implied that they consider utilitarian reasoning intolerable. These statements, which most likely reflect disagreement with the conclusions of some particular utilitarians, indicate a misunderstanding of the nature of utilitarian reasoning. Utilitarianism is simply a method of ethical analysis that evaluates the ethical rightness of human behavior in terms of the expected consequences. All ethical codes and regulations in the field of research ethics contain requirements for utilitarian reasoning; for example, in the unrevised Declaration of Helsinki, article II.6 states that clinical research must be justified in terms of its consequences — specifically, “by its potential diagnostic or therapeutic value for the patient.”
Dr. Senn quotes one of my sentences in which placebos are not mentioned and then pronounces it “wrong,” apparently because it reflects a “misunderstanding about the role of placebos.” I find this puzzling. At no point did I say that placebos require a “withdrawal of standard effective treatments.” I did say that the evaluation of a new therapy often requires that effective treatments be withheld at least from those who will receive the new therapy. I also stated that the use of a placebo control was generally acceptable when such use did not expose the patient-subject to a substantial risk of death or disability that could be prevented by using an active therapy as a control.
I agree with Dr. Misbin that there are important differences between the investigator–subject relationship and that between physician-investigators and their patient-subjects.1-3 This is one important reason to take steps to reduce the likelihood of accepting the “fallacy of the package deal.”
Drs. Misbin, Kopp, and O'Ryan are concerned that subjects might be exploited to serve the interests of industry or of investigators. In industrialized countries, it is commonly believed that this possibility can be minimized by the establishment of standards requiring informed consent and equitable selection of subjects. In the so-called developing countries, the Declaration of Helsinki has little more to offer. As I mentioned in my article, the international ethical guidelines promulgated by the Council for International Organizations of Medical Sciences provide far superior safeguards against the exploitation of residents of resource-poor countries.4
I partially agree with Dr. Misbin that, in some cases, patients should be invited to become research subjects by someone other than the professional on whom they are dependent for health care3; the institutional review board should determine the necessity for using this method in particular protocols.
I disagree with Dr. Macpherson's contention that the Declaration of Helsinki should “set an ideal standard.” As I have argued elsewhere, idealistic guidelines contribute to widespread noncompliance by setting unrealistic expectations.4 Ethical codes and guidelines should be very practical statements of what we believe investigators can and should do today. Idealistic visions of what we hope we can expect in the future should be presented in the prefaces to or commentaries on these documents and should be clearly distinguished from the guidelines.
4 ReferencesRobert J. Levine, M.D.
Yale University School of Medicine, New Haven, CT 065201
Levine RJ . Clinical trials and physicians as double agents. Yale J Biol Med 1992;65:65-74
Web of Science | Medline2
Levine RJ . Informed consent in research and practice: similarities and differences. Arch Intern Med 1983;143:1229-1231
CrossRef | Web of Science | Medline3
Levine RJ. Ethics and regulation of clinical research. 2nd ed. New Haven, Conn.: Yale University Press, 1988.
4
Levine RJ. International codes and guidelines for research ethics: a critical appraisal. In: Vanderpool HY, ed. The ethics of research involving human subjects: facing the 21st century. Frederick, Md.: University Publishing Group, 1996:235-59.
- Citing Articles (1)
Citing Articles
1
Joseph A. Carcillo, R. Scott Watson. (2002) Is the randomized, controlled trial in children an endangered species?. Pediatric Critical Care Medicine 3:2, 197-199
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