Placebo-Controlled Trials and Active-Control Trials in the Evaluation of New Treatments. Part 2: Practical Issues and Specific Cases

Abstract

Placebo controls are commonly used in clinical trials of investigational treatments because they have important advantages. In recent years, some have criticized the use of placebo-controlled trials when effective alternative therapy exists, regardless of the expected effect of the therapy. In part 1 of this paper, ethical arguments are addressed and the interpretive problems inherent in the use of active-control equivalence trials to establish efficacy of a new treatment are clarified. However, uncertainties may complicate decisions about appropriate use of placebo controls in some situations. Part 2 discusses more fully the ethical considerations for using placebo controls in particular medical settings. The value and relevance of placebo-controlled trials of new agents in situations in which proven effective therapy is available are also explored.

Practical Application of International Standards and Guidelines to Address Ethical Challenges in Clinical Trials

“…Comparisons may be made with placebo, no treatment, and different active controls or with different doses of the drug/vaccine under investigation. The choice of the comparator depends, among other things, on the objective of the trial, the disease, and the context of the trial [2,13]. Choosing control group for clinical trial remains a challenge, particularly when carrying out the trial in developing countries where the best treatment is not available [13] or standard treatment has serious side effects [14].…”

“…The sound methodological reasons should include the following conditions: the disease with a high placebo response rate, the disease with a waxing and waning characteristic; and current proven treatment is known to have severe toxicity that patients refuse to use it [4,14,16].The ethical justification should be provided in the protocol [17] and the study should be carefully monitored and rescue treatment should be readily available when required [14]. As a general rule, it is not ethically acceptable to use placebo-controlled trial design when effective therapy that is known to prevent death or irreversible morbidity exists [4,6,7,13,14,16].…”

“…The choice of the comparator depends, among other things, on the objective of the trial, the disease, and the context of the trial [2,13]. Choosing control group for clinical trial remains a challenge, particularly when carrying out the trial in developing countries where the best treatment is not available [13] or standard treatment has serious side effects [14]. However, when the best current treatment is not available locally, the best nationally available treatment or the so called 'established effective treatment' may be accepted, provided that it has acceptable side effects [7].…”

Clinical Trials in Cardiovascular Medicine

“…This is referred to as an active controlled trial. 3,4 Randomized controlled trials typically involve the randomization of patients to either the control or test treatment (ie, randomized concurrent control). These trials are the gold standard for evaluating new therapies, and they form the foundation for the highest level of recommendations in practice guideline documents that stress evidence-based medicine 5 ( Figure 1).…”

Placebo-Controlled Trials, Ethics of

“…For instance, some argue that the use of placebo controls is acceptable when withholding or delaying an established effective treatment poses low or acceptable risks to participants (WMA, 2013;Emanuel and Miller, 2001). Placebo use is more controversial still in the context of research in low-or middle-income countries (LMICs) when it is used in the presence of an established effective intervention that is not available in the community in which the trial is conducted (e.g., because it is too costly or complex to implement) (London, 2001;Ellenberg and Temple, 2000). This illustrates that the use of placebo controls in clinical trials is both ethically complex and controversial.…”