Use of Placebos in Study Designs Instead of Standard of Care in Medication
Introduction to the Use of Placebo:
In the pursuit of gaining knowledge and scientific advancement for the purpose of establishing new medical treatments, clinical trials provide us with the path to enlightenment. That is why special consideration needs to be given in the preparation and conduct of a trial. This is especially true with regards to the design of a clinical trial. How a trial is designed holds significant importance in order to preserve the validity and integrity of the data gathered. It is also important because a well designed trial offers minimized risk exposure to participants while producing useful results. Since the early days of clinical research, the use of placebo, or a sugar pill, as a control has been common practice. Trials were designed to use placebo in attempt to make a substantial quantitative assessment of efficacy in comparison to a new medicinal drug. This was an accepted method of research when standard treatments to various illnesses were so few and yet to be discovered. However, modern medicine and research now offer several treatment options. This has changed the way research is conducted since many standard treatments have replaced the use of placebo as a control to be used in comparison with newer investigational drugs. Despite these changes, there are still many trials that continue to use a placebo control even when there is a standard care of treatment available. As a result, the use of placebo controls despite the availability of standard of care medication has raised serious concern and debate amongst researchers and bioethicists alike.
Clinical research strives to further our knowledge of science and medicine. It also serves for the betterment of mankind through the discovery of treatments for many conditions, and providing alternative options for managing illnesses. While much advancement has been made, many have brought on various ethical dilemmas. The use of a placebo control is one of the topics that have increased ethical consciousness. Some believe that placebo-controlled trials are necessary while others argue that the idea of taking a subject off of their current treatment and to place them on placebo is indeed seemingly unethical. This is especially true in cases of serious diseases. Consequently, the research and ethics community has turned to documents such as the Nuremberg Code (1947), the Declaration of Helsinki (World Medical Association [WMA], 1964), the Belmont Report (The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, 1978), and the International Conference on Harmonization’s [ICH] Harmonised Tripartite Guideline for Good Clinical Practice (1996) to address the matter.
FDA’s Advocacy for the Unethical Use of Placebo:
With the ethical issues raised in the use of placebo, some concerns have been addressed in federal regulations and official guidelines but others are still subject to debate. There are many aspects of the issue which call for deliberation. One concern is in regards to the deception of research participants. Many research subjects do not participate in a study with the anticipation of being treated with placebo. They tend to have idealistic impressions believing that they will be given a new drug that will cure them. This may lead to unintentional false hope and deception of subjects (Miller, Wendler, & Swartzman, 2005). In a meager attempt to resolve this problem, federal regulations require disclosure to subjects. This is part of the basic elements of informed consent as stated in 21 CFR Part 50 (FDA Informed Consent of Human Subjects, 2005). During the informed consent process, subjects must be given full disclosure in regards to the nature of the trial, as well as the risks and benefits involved. In placebo-controlled trials they must be told that they may either receive the drug being tested or they may receive a placebo.
Although informing patients of the possibility of receiving placebo fulfills part of the investigator’s responsibility as per the regulations, it hardly fulfills ethical responsibility. The investigator and the rest of the study team must recognize that there is no guarantee that the subject truly comprehends what is involved in the trial and what the use of placebo entails. This is especially true in subjects with serious illnesses. They are likely to be unable to assess the risks and benefits of the trial and may only focus on the benefits because they are already at the mercy of their illness. Thus there is no justification to place a subject with a serious illness on placebo as it would clearly compromise their health and well-being.
On the other hand, the use of placebo-controlled in not-so-serious illnesses still offers very little justification. In efforts to inform subjects, investigators will do everything they can, but subject will hardly be as informed about the treatment option as their physicians. Thus physicians, as well as investigators, are more capable of determining whether it is rational for a subject to be placed on placebo for a period of time and be deprived of an accepted treatment.
There are is an increased number of trials in the United States conducted with the use of placebo as a control. However, in instances when there is an already approved treatment for the condition under study, the FDA does not make mention of a requirement to use the approved treatment in place of placebo (Rothman, Michels, & Baum, 2000). Although it stresses the protection of subjects and ensuring their safety by obtaining their informed consent, this is hardly enough.
Ethical Guidance on the Use of Placebo:
Whereas the Code of Federal Regulations offers limited direction, the Declaration of Helsinki explicitly mentions the circumstances in which placebo may be used. According to paragraph 29 of the Declaration it 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.” (WMA, 1964). Thus, placebo-controlled trials should only be used in the absence of existing proven therapy. The Declaration goes further to elaborate that if there is proven therapy available, placebo-controlled trials may be ethically acceptable under the following circumstances:
Where for compelling and scientifically sound methodological reasons its use is necessary to determine the efficacy or safety of a prophylactic, diagnostic or therapeutic method; or
Where a prophylactic, diagnostic or therapeutic method is being investigated for a minor condition and the patients who receive placebo will not be subject to any additional risk of serious or irreversible harm (WMA, 1964).
Some critics who argue in defense of placebo controls state that placebo is preferable than the use of an active drug because it offers a fixed reliable point of reference. This claim is rather unsubstantiated since the placebo effect is a changing phenomenon that varies based on a subject’s fluctuating outlook (Rothman & Michels, 2000). One of the biggest advocates of placebo-controlled trials is the FDA. They focus their approval of a drug on the statistical significance of whether or not it is more effective than placebo. Although this method of comparison provides more treatment options, it does not determine how a new treatment compares with the best treatment currently available.
In attempt to defend the use of placebo controls, some argue that the E-10 report found in the International Conference for Harmonization guidelines allows the use of placebo controls even when effective treatment exists (ICH, 1996). Even if subjects are not exposed to the risk of death or permanent injury, withholding effective treatment may not lead to serious harm but it will likely cause discomfort to the subject. The Nuremberg Code, which was the first international document after World War II addressing the ethical conduct of human experimentation, states that an “experiment should be so conducted as to avoid all unnecessary physical and mental suffering and injury” (1949). Thus this would suggest that the use of placebo in place of available standard of care treatment places the subject at risk for unnecessary suffering.
Furthermore, the Belmont Report specifies the three principles underlying research, which are autonomy, beneficence, and justice (1979). The rule of beneficence emphasizes the obligation to protect subjects by two rules which are to “do not harm” and to “maximize possible benefits and minimize possible harm” (The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, 1979). Taking this into consideration, it is difficult to see how trials that use placebo controls instead of standard care can maintain the rule of beneficence. In fact, this approach seems to do the exact opposite. Minimizing benefit to subjects while maximizing possible harm is a direct consequence of delaying treatment by using placebo in place of available therapies.
Placing subjects in placebo-controlled trials even when there are effective therapies available places subjects in harm’s way. The ethical codes mentioned above were established to safeguard subjects from such vulnerability. These ethical codes collectively enforce the principle that every subject, regardless of whether they are in the active group or the control group, is entitled to receive the best available treatment. The use of placebo in place of standard care of treatment goes against this ethical principle, since it advocates denying subjects of an effective therapy.
There are still a number of conditions being investigated that have no available treatment of care to replace the placebo control. Therefore, the placebo will most likely continue to be used in clinical trials. However, trials in which a standard care of treatment is available for use as a control should be used whenever possible. These trials can determine not only the efficacy of a drug but whether or not the investigational drug can outperform the current standard of treatment in order to prove whether or not it is the best form of treatment available. If a placebo is used in a clinical trial, the study team must carefully consider the need and ethical basis for a placebo-controlled trial. Specifically, they need to pay particular attention to how the placebo will be used in the design of the trial, its effects on the subject population, and the duration of treatment needed to retrieve substantial results. Regardless of critics’ opinions, the ones who are ultimately responsible for the justification of the use of placebo in a trial are the investigators, sponsors, and institutional review boards. They are the ones held accountable for the protecting safety of subjects and maintaining the integrity of trial data.
FDA Informed Consent of Human Subjects 21 C.F.R. § 50 Subpart B (2005, April 1). Retrieved March 1, 2007, from http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=50&showFR=1&subpartNode=21:18.104.22.168.19.2
International Conference for Harmonization [ICH] Harmonized Tripartite Guideline. (1996, June 10). Guideline for Good Clinical Practice. Retrieved March 1, 2007, fromhttp://www.ich.org/LOB/media/MEDIA482.pdf
Miller, F., Wendler, D., Swartzman, L. (2005, September). Deception in research on the placebo effect. Public Library of Science, 2(9): e262. Retrieved March 3, 2007, from http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1198039
Rothman, K., & Michels, K. (1994, August 11). The continuing unethical use of placebo controls. The New England Journal of Medicine, 6(331): 394-398. Retrieved March 2, 2007, from http://content.nejm.org/cgi/content/full/331/6/394?ijkey=9da722a53b7fc37662295461f8694c77c0d4603e&keytype2=tf_ipsecsha
Rothman, K., Michels, & K., Baum, M. (2000). For and against: Declaration of Helsinki should be strengthened. British Medical Journal, 321(7258): 442-445. Retrieved March 3, 2007, from http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1127802
The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. (1979, April 18). The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research. Retrieved March 3, 2007, from http://ohsr.od.nih.gov/guidelines/belmont.html#gob2
The Nuremberg Code. (1947). Retrieved March 3, 2007, from http://ohsr.od.nih.gov/guidelines/nuremberg.html
World Medical Association [WMA]. (1964). The Declaration of Helsinki. Retrieved March 2, 2007, from http://www.wma.net/e/policy/b3.htm