The uncontrolled clinical trial: scientific, ethical, and practical reasons for being.

According to principles of clinical trial design, the demonstration of efficacy of a new treatment is based on comparing the response in the treated group with that of a control group receiving placebo or another active treatment. The need for a control group is also recommended by the major international institutions that govern the ethics and the practice of clinical research. Despite these principles and recommendations, inspection of a purposive sample of ongoing clinical trials listed in the NIH registry ( http://ClinicalTrials.gov ) reveals that as many as one-third of trials are uncontrolled. Since these trials were approved through a formal evaluation by ethics committees, the lack of adequate control was not perceived as a major deficiency in the study design. Most uncontrolled trials belong to the oncology/hematology area. If two extreme disease conditions for nature and progression are analyzed, such as acute myeloid leukemia (AML) and chronic heart failure (CHF), the difference in the prevalence of uncontrolled trials is very striking. The number of uncontrolled trials is only 13% in CHF, whereas it reaches 66% in the AML group. I believe that the underlying disease condition plays a primary role in orienting the design of the study: oncology and hematology may be fields in which uncontrolled studies are common, whereas in other fields, e.g., cardiology, this phenomenon can be reduced. Within the limitations of the selection process of the examined trials, the current analysis indicates that the clinical trial reality does not strictly follow experimental design theory and official recommendations.