Phase II Clinical Research Design in Cardiology

Clinical trials demonstrate the best of medical expertise and epidemiological elegance. From the simple building blocks of contemporaneous control groups, randomization, and blinding, they assemble a clear picture of the nature of the treatment-effect relationship. This accomplishment has earned them the star ascendant position in cardiovascular research.Their advantage was demonstrated with Bradford Hill’s work on streptomycin, and as knowledge of the pathogenesis of atherosclerotic disease produced possibilities for new treatments, cardiovascular researchers applied this new research tool to identify effective therapies in a sequential approach (Figure 1).Figure 1. The traditional phases of clinical trials. *The study takes place before Food and Drug Administration approval.This work accelerated with clinical trials demonstrating treatment benefits for chronic diseases such as hypertension,1,2 lipid abnormalities,3,4 and heart failure,5,6 cementing their role in identifying new therapies to prevent the sequela of cardiovascular disease in vulnerable populations.However, the limitations of early clinical trial interpretation also appeared. The findings of the Multiple Risk Factor Intervention Trial (MRFIT),7 the International Verapamil SR/Trandolapril Study (INVEST),8,9 the Early Versus Late Intervention Trial With Estradiol (ELITE),7,10 the Cardiac Arrhythmia Suppression Trial (CAST),11,12 and the US Carvedilol program controversy13–19 together served to undermine the confidence of cardiologists in the interpretation of clinical trial results. Thought leaders in the field identified the interpretation problem (ie, the hyperreliance on P values to reflect positive results for any analysis in a clinical trial) and called for a fundamental change in the design and analysis of clinical trials.Subsequent work produced the following clinical trials principles: (1)There should be clear and prospective declaration in the written protocol about all important aspects of the clinical trial with particular emphasis on the end points …