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Summary in Thirty Seconds
Rigorous clinical trials rely on a well-established set of ethical guidelines to ensure the safety of participants as they contribute their time to the advancement of scientific knowledge and treatment development.
Participant trust in research and research institutions is arguably the most significant factor associated with research participation, and this relies on the belief that a researcher is acting ethically and following established guidelines to protect participants as they give their time to advance scientific knowledge.
Four facets of ethics in a clinical trial include clear and complete informed consent, placebo use, randomization procedures, and participant protection.
The highest quality clinical oncology research is ethical because its ultimate goal is to improve and/or save the lives of people while producing the best results for those who develop these treatments.
The Ethical Bedrock of Clinical Trials
Without rigorous clinical trials, the life-saving treatments many take for granted would not exist. These trials rely on a well-established set of ethical guidelines to ensure the safety of participants as they contribute their time to the advancement of scientific knowledge and treatment development. Such guidelines were developed and evolved based on several factors,[1] including the need to have a systematic set of principles to guide research, difficult ethical issues arising from studies, and the need to protect subjects because of unethical treatment in the past (e.g., the Tuskegee Syphilis Trials[2]). These past abuses, though rare, continue to affect the trust of certain populations in clinical trials; thus, trial enrollment rates in these populations suffer.[3] Yet, participant trust in research and research institutions is arguably the most significant factor associated with research participation.[4]
Trust in Clinical Research
Smirnoff et al.[5] define clinical research trust as “the belief by the study participant that his/her interests (e.g., full disclosure, balance of risk/benefit, prudent data usage) are considered before the interests of the study or the researcher.” The bedrock of patient trust is the belief that a researcher is acting ethically and following established guidelines to protect participants as they give of their time to advance scientific knowledge.
Ethical guidelines in CCTs have been outlined in a variety of ways. Nardini[6] suggests four facets of ethics in a CCT:
Informed consent
Placebo Use
Randomization
Participant protection
Informed Consent
Informed consent requires three major features: It must be voluntarily given, it must be expressed by a competent/able subject, and it must contain adequate information.[7] This last feature includes risks/benefits, understanding of the procedure or compound to be administered, acknowledging the use of randomization/blinding, understanding the voluntary nature of participation, and understanding the purpose of the research. Applebaum et al.[8] point out that a CCT participant may not recognize that the purpose of the study is not necessarily the best treatment for him/her but for the clinical (or disease) group to which they belong. Nevertheless, a clear and comprehensive, but concise informed consent process with form(s) written in understandable language is crucial for an ethical CCT.
Placebo Use
Placebos are used because both patients and practitioners have expectations that may significantly impact and complicate the analysis of a treatment effect. However, a significant concern about using placebos is the problem of deception. People in the placebo wing of a trial must believe that they are receiving a working treatment for the placebo effect to work fully. A meta-analysis of 186 clinical trials of various types involving over 16,500 patients[9] estimated the placebo effect to be as high as 54% of the overall treatment effect. Additionally, people with an ongoing medical condition have been shown to have a greater placebo effect than healthy controls.[10] However, within oncology, while placebo effects have been seen in measures of pain, appetite change, and performance status, they are rarely seen in tumor response measures.[11] The National Cancer Institute states that “Placebos are rarely used in cancer treatment clinical trials. They are only used when there is no standard treatment.”[12] So while placebo effects are important to control for, in CCTs, they appear to have little effect on the commonly used outcome measures in CCTs involving tumor response.
Randomization
A challenge with randomization (and the concomitant use of double-blinding—both participant and researcher) is that patients cannot necessarily receive individualized treatment decisions for their condition.[13] And because of randomization, participants may end up in the wing of a CCT that receives the less effective treatment. Furthermore, this less effective treatment may provide a worse outcome than the standard of care currently available.[14] Nevertheless, those conducting CCTs do all they can to ensure the best possible treatment for a participant even if this may result in removal from a clinical trial. Still, randomization is an important aspect of CCTs, leading to far better “real word” applicability results.
Participant Protection
Those who stand to gain from a CCT are often not the ones who take the risks and bear the burden of participating in a trial, most obviously if that trial has a placebo control in a random clinical trial design. Researchers, developers, and clinicians must balance hope and realism as they work together to explore and introduce innovative treatments.[15] However, some subjects might be willing to take a high-risk treatment chance or even participate in a trial where they have little-to-no hope of personally benefitting while knowing others will. An example of the latter is when a person with a terminal form of cancer agrees to participate in a toxicity (Phase O) trial[16] in the absence of any direct therapeutic benefit. The World Medical Association’s Helsinki Declaration for Medical Research Involving Human Subjects requires that “the wellbeing of the individual research subject must take precedence over all other interests.”[17] This is a vital point—that participants are protected and prioritized over everything else in a clinical trial. Such precedence is key for patient trust in CCTs.
Ethics and CCTs
Developing and introducing life-altering and life-saving drugs is the ultimate goal of CCTs. In the past decades, the survival rate of various types of cancer, with and without treatment, has been well-established, significantly reducing the need for placebo-controlled randomized trials. But even if these two ethical aspects are somewhat minimized, the need for informed consent and participant protection remain paramount in CCTs.
There are many other aspects of ethics in CCTs (e.g., lack of conflict of interest in investigators, issues related to payment of participants, diversity in CCTs, confidentiality issues, etc.). The highest quality clinical oncology research is ethical because its ultimate goal is to improve and/or save the lives of people.[18] And with this ethicality comes its crucial partner, participant trust in the CCT.
While guidelines have been established and enforced, ethics in CCTs continue to evolve. As much as possible, CCTs must be conducted with transparency, realism, and ongoing vigilance to meet the highest ethical standards producing the best results first for people with cancer and secondarily for those who develop these treatments. Steadfast application of ethics in CCTs will enhance patient trust, generating more reliable progress and discovery in the treatment of cancer.
[1] Ethics in Clinical Research | Clinical Center Home Page (nih.gov) [2] Jones JH. Bad Blood: The Tuskegee Syphilis Experiment, expanded edition. New York: The Free Press; 1993 [3] Ethnicity and Disease. 2012; 22(2):226–30 [4] AJOB Empir Bioeth. 2018 Jan-Mar;9(1):39-47 [5] ibid [6] Ecancermedicalscience. 2014; 8: 387 [7] Berg JW, et al. Informed Consent: Legal Theory and Clinical Practice 2nd Ed. New York: Oxford University Press; 2001 [8] Clin Trials. 2012 Dec; 9(6): 748–761 [9] Trials. 2021 Jul 26;22(1):493 [10] Psychosomatic Medicine: May 2017; 79(4): 388-394 [11] J Natl Cancer Inst. 2003 Jan 1;95(1):19-29 [12] Placebos in Cancer Clinical Trials - NCI [13] N Engl J Med. 1991;324(22):1585–9 [14] World Medical Association. Declaration of Helsinki, 6th revision. 2008 [15] Clinical Ethics. 2020;15(1):29-38 [16] Nat Rev Cancer. 2007;7:131–9 [17] ibid [18] Curr Oncol. 2006 Apr; 13(2): 55–60