Other Considerations
Equipoise
In the 1950s when case-control studies indicated an association between smoking and lung cancer, it would have been unethical to test this with a randomized clinical trial, because there was strong suspicion that smoking was very harmful and of little or no benefit. An important factor in determining whether it is ethical to conduct a clinical trial is "equipoise," which means a balance in which one has sufficient doubt that the treatment is beneficial (justifying withholding it from some subjects) balanced against sufficient belief that it is beneficial (justifying giving to some subjects). Timing of clinical trials can be important, because once the lay public takes up a belief in a new treatment, it may be impossible to rigorously test its efficacy with a clinical trial.
The Ethics of Placebos
When evaluating a new treatment, a major issue is the comparison group. For example, if you are evaluating a new treatment for leukemia, should the control group consist of leukemia patients who are untreated, or should it consist of patients who are being treated by the usual therapy? When should an inactive agent be used, and when should the currently accepted therapy be used as the standard against which one compares the benefits of a new treatment?
The Declaration of Helsinki clearly states:
- The benefits, risks, burdens and effectiveness of a new method should be tested against those of the best current prophylactic, diagnostic, and therapeutic methods. This does not exclude the use of placebo, or no treatment, in studies where no proven prophylactic, diagnostic or therapeutic method exists.
- At the conclusion of the study, every patient entered into the study should be assured of access to the best proven prophylactic, diagnostic and therapeutic methods identified by the study.
Link to Declaration of Helsinki
These principles seem to firmly establish that placebo treatment should never be used when an accepted standard of care exists. In such a case a new therapy should also be compared to the accepted standard of care in order to determine whether the new therapy has advantages over the standard treatment. Nevertheless, there was substantial debate about this when trials were proposed in the 1990s on new treatments to reduce maternal to child transmission of HIV. Previous studies had demonstrated the zidovudine administered to HIV-positive pregnant women reduced the risk of transmission to their children. A series of new trials were proposed to test the efficacy of shorter courses of ziduvodine and other variations. Many of these trials were funded by the US National Institutes of Health (NIH) or Centers for Disease Control and Prevention (CDC). The two tables below contains excerpts from articles presenting different perspectives on this issue. The first was an article by Harold Varmus, M.D. (Director of NIH at the time), and David Satcher, M.D., Ph.D. (Director of CDC at the time) in which they defend the studies proposing the use of a placebo-treated comparison group, largely on the basis that no therapy was available for the vast majority of people in Africa, because they couldn't afford it. The second article was written by George J. Annas, JD, MPH, and Michael A. Grodin, MD from Boston University School of Public Health, in which they attack the proposed trials as unethical. Read the excerpts and the articles in order to determine what you think and what you would decide. Try to list the ethical principles and precedents that may be relevant.
Ethics and Studies of HIV
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Excerpts from "Ethical Complexities of Conducting Research in Developing Countries" by Harold Varmus, M.D., and David Satcher, M.D., Ph.D. N Engl J Med 1997; 337:1003-1005, October 2, 1997.
"... the NIH- and CDC-supported trials have undergone a rigorous process of ethical review, including not only the participation of the public health and scientific communities in the developing countries where the trials are being performed but also the application of the U.S. rules for the protection of human research subjects by relevant institutional review boards in the United States and in the developing countries. Support from local governments has been obtained, and each active study has been and will continue to be reviewed by an independent data and safety monitoring board. To restate our main points: these studies address an urgent need in the countries in which they are being conducted and have been developed with extensive in-country participation. The studies are being conducted according to widely accepted principles and guidelines in bioethics. And our decisions to support these trials rest heavily on local support and approval. In a letter to the NIH dated May 8, 1997, Edward K. Mbidde, chairman of the AIDS Research Committee of the Uganda Cancer Institute, wrote:
These are Ugandan studies conducted by Ugandan investigators on Ugandans. Due to lack of resources we have been sponsored by organizations like yours. We are grateful that you have been able to do so. . . . There is a mix up of issues here which needs to be clarified. It is not NIH conducting the studies in Uganda but Ugandans conducting their study on their people for the good of their people."
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Excerpts from "Human Rights and Maternal-Fetal HIV Transmission Prevention Trials in Africa" by George J. Annas, JD, MPH, and Michael A. Grodin, MD, Am. J. Public Health 1998;88(4):560-563.
"In 1994, the first effective intervention to reduce the perinatal transmission of HIV was developed in the United States in AIDS Clinical Trials Group (ACTG) Study 076. In that trial, use of zidovudine administered orally to HIV-positive pregnant women as early as the second trimester of pregnancy, intravenously during labor, and orally to their newborns for 6 weeks reduced the incidence of HIV infection by two thirds (from about 25% to about 8%). Six months after stopping the study, the US Public Health Service recommended the ACTG 076 regimen as the standard of care in the United States. In June 1994, the World Health Organization (WHO) convened a meeting in Geneva at which it was concluded (in an unpublished report) that the 076 regime was not feasible in the developing world. At least 16 randomized clinical trials (15 using placebos as controls) were subsequently approved for conduct in developing countries, primarily in Africa. These trials involve more than 17 000 pregnant women. Nine of the studies, most of them comparing shorter courses of zidovudine, vitamin A, or HIV immunoglobulin with placebo, are funded by the Centers for Disease Control and Prevention (CDC) or the National Institutes of Health (NIH). Most of the public discussion about these trials has centered on the use of placebos. The question of placebo use is a central one in determining how a study should be conducted. But we believe the more important issue these trials raise is the question of whether they should be done at all. Specifically, when is medical research ethically justified in developing countries that do not have adequate health services (or on US populations that have no access to basic health care)? |
Consider the arguments presented in the two articles referenced above. After reading these articles, consider the issue in light of the principles discussed in the section above on the ethics of conducting clinical trials. Consider the principles established by the Nuremburg Code, the Declaration of Helsinki, and the Belmont Principles. Which position would you choose, based on the principles that have been established?
For additional commentary, see Dr. Marcia Angell's editorial on The Ethics of Clinical Research in the Third World in the New England Journal of Medicine (1997).
See also this video from TED.com in which Boghuma Kabisen Titanji discusses the ethics of doing HIV clinical trials in resource-poor settings.(Filmed in May 2012; posted Jan. 2013.)
Sham Controls for Testing the Efficacy of Medical Devices
Placebo effects can also occur when evaluating the efficacy of a medical device or a medical or surgical procedure. A logical way of evaluating efficacy in this setting would be to perform a "sham" procedure. For example, some investigators believed that Parkinson's disease could be effectively treated by transplantation of fetal tissue into the human brain, a procedure that required anesthesia and drilling holes into the patient's forehead in order to introduce fetal cells into the brain. Olanow et al. enrolled 34 Parkinson's patients into a double-blind study in which patients were randomly assigned to receive fetal cells or a "placebo" surgical procedure. The sham procedure was believed to be necessary to determine whether there was a placebo effect. The investigators found no significant difference between those receive fetal cells and those who did not. The concern, of course, is that the sham-treated subjects are being undergoing general anesthesia and a potentially risky neurosurgical procedure, but without any real expectation of a genuine, lasting benefit. Nevertheless, the IRB and the investigators justified the sham procedure on the basis that it demonstrated no benefit of the transplantation; as a result, it prevented countless numbers of Parkinson's disease victims from receiving a costly, invasive procedure that had no benefit.
Link to article by Olanow et al.
To explore the ethics of using sham controls in greater detail, see the following articles:
- Miller FG and Kaptchuk TJ: Sham procedures and the ethics of clinical trials. J R Soc Med. Dec 2004; 97(12): 576–578.
- Redberg RF: Sham controls in medical device trials. N. Engl. J. Med. 2014;371(10):892-893.