COMMENTARY

ETHICS

in Clinical Trials By Mirkamal Tolend and Samia Tasmim

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linical trials aim to elucidate the viability of new treatments or interventions on humans, and are indispensable to the progress of medical science. Although double-blind, randomized, controlled trials are the pinnacle of clinical trials, these are not always practical or ethical to conduct for every clinical question. As such, the interplay of ethics, uncertainty, and the need for high quality scientific evidence makes clinical trials unique.

in 1947. Astonishingly, this study, which was supposed to run for six months, went on for 40 years. It finally ended when the Associated Press covered the study and an advisory committee ruled that it was ethically unacceptable. Although the participants and their families were later compensated financially and given medical assistance, this trial is an example of the horrific trials that some groups were subjected to.2

The importance of ethics in clinical research is seen in documents as old as the Hippocratic Oath. Unfortunately, it took a dark period in research history, involving atrocities such as the use of war prisoners for human experimentation in the Second World War, to cement the emphasis of clinical trial ethics. To ensure such unethical research does not recur, explicit codes of ethical conduct were outlined in the Nuremberg Code, the Declaration of Helsinki, and the Belmont Report.1 Currently in Canada, all federally funded research involving humans or human biologic material must strictly adhere to the Tri-Council Policy Statement.

As the potential benefit of clinical research is usually experienced by future patients rather than by the study participants, ideal participants would be motivated purely by altruism to consent to a study. Policies on informed consent, patient safety monitoring, and careful, peer-reviewed assessment of the study’s scientific and methodological rigor are all important to prevent patient exploitation. The reason for participating in a clinical study may not be purely altruistic when there is the problem of undue inducement, meaning that the process of providing voluntary informed consent is influenced by the financial benefits of participating. For some patients, these benefits may outweigh the risks associated with the study.3 Certain patient groups, such as those who do not respond to current standard-of-care treatments or those from low socioeconomic backgrounds, who would be unable to otherwise obtain either the standard or the experimental treatment may be considered especially vulnerable with regard to participating in a clinical trial.4 To avoid exploitation of these study participants, it is important to be aware of the potential reasons patients may expose

One of the longest-running controversial clinical trials was the Tuskegee study of syphilis, which ran for 40 years from 1932 to 1972 in Tuskegee, Alabama.2 600 African American men (with or without syphilis) were simply told the purpose of the study was to evaluate “bad blood�. They acquiesced to the study in exchange for free food, burial insurance and medical tests. Notably, they did not receive treatment for syphilis, even after penicillin became the standard of treatment starting 8 | IMS MAGAZINE FALL 2017 CANCER THERAPEUTICS

themselves to treatments of unproven effectiveness. Thus, the requirement of scientific and ethics review board approvals before the start of clinical trials is important to ensure that patients are not enrolled in studies with obvious flaws in internal validity, the results of which will be of poor quality and not worth the risk of exposing patients to unnecessary risk. Certain biases are important to avoid in clinical trials.5 One prominent example is selection bias, which occurs when the method that is used to sample the cases into the study cohorts leads to a baseline difference between the cohorts. This may differentially affect study results if such a difference confounds the study outcome. Various design-based and analysis-based techniques exist to control for the effect of the confounder variable. These safeguards include matching, restriction, stratification, and multivariable adjustment. However, these techniques can only adjust for known and measured confounders. To protect against bias from known as well as potential unknown confounders, randomization is applied. Hence, a proper randomization is an important design feature in clinical trials to improve internal validity. At times randomization is not possible due to practical or ethical reasons. To account for this, properly controlled observational studies with large sample sizes have become increasingly rigorous in design, yielding high quality evidence for clinical questions not amenable to randomized controlled trials. Ethical issues may affect the interpretation of data. Moving a patient from the treatment