Placebo-controlled trials: good science or medical neglect?

The placebo-controlled clinical trial has a long history of being the standard for clinical investigations of new drugs. By blindly and randomly allocating similar patients to a control group that receives a placebo and an experimental group, investigators can ensure that any possible placebo effect will be minimized in the final statistical analysis. Although this approach to clinical research is scientifically sound, ethical concerns arise in some cases that outweigh the benefits of this protocol design. Even though patients may be advised of the likelihood of being placed in a placebo group and that the intent of the clinical trial is research, not medical care, they often hope for some level of treatment. More importantly, when effective treatments exist, research participants who have progressive, burdensome disease should be given standard treatment as the control agent. Using a recent example of a clinical trial of a new drug for treating rheumatoid arthritis, we argue that research participants who have burdensome, progressive disease should not be exposed to the risks of placebo-controlled trials. Historical controls and active controls may need more people in a particular trial but do not deprive patients of approved treatment. We propose several guidelines for considering the ethical use of placebo controls in clinical trials and call on research regulatory agencies to standardize their recommendations. Summary points The use of placebo controls in clinical research that involves patients who have an active disease for which there is approved treatment is ethically questionable and may represent substandard care The use of active or historical controls in clinical research may address these ethical questions Federal guidelines say that a condition of clinical equipoise should exist before a placebo-control study is started. Although this is a reasonable guideline, sponsors or investigators may be ignoring it Research participants with active disease are likely to believe they will possibly benefit from taking part in trials. This therapeutic misconception may not be obviated by an informed consent form