DESIGN AND MANAGEMENT OF LARGE MULTICENTER CLINICAL TRIALS

By the last half of the 1960s, clinical scientists and administrators were agreed that pharmacologic intervention in hypertension had progressed through its developmental stages. A number of relatively safe and individually effective drugs had been developed--effective in the sense that they produced a substantial and relatively consistent reduction of blood pressure in hypertensive patients. These conclusions had been established through animal studies, small human trials, and larger controlled studies in individual clinics and laboratories. It remained to be shown, however, that intervention with blood-pressurelowering drugs could reduce the major late effects of hypertension: premature mortality and increased risk of cerebral vascular disease, congestive heart failure, and renal disease. That elevated blood pressure carried with it the hazard of such late consequences had been well established from actuarial statistics, from longitudinal community surveys, and from clinical observation. There was a strong presumption that drug treatment was effective in this respect, but no proof. Clinicians were beginning to comment upon the disappearance of malignant hypertension, for example. The United States Veterans Administration, with its network of medical care facilities extending across the U.S.A., had a long history of success in the design and conduct of cooperative, multicenter clinical trials, dating from its landmark investigations of chemotherapy for pulmonary tuberculosis. The VA's relatively tight administrative apparatus made it a natural locus for such development. Its Cooperative Studies Evaluation Committee provided a central review mechanism applicable to a broad array of proposed studies. Thus, it was natural that the Veterans Administration would decide to establish a tightly designed, controlled, multicenter trial of the late effects of antihypertensive medication. Dr. Edward Freis assumed major responsibility for the organization and development of protocols, and the applications passed internal review. The rest is history. Scientists will be discussing the results of this landmark investigation for years to come. The trials established that combination therapy for moderate and severe hypertension produced a substantial reduction in all-cause mortality and major morbidity, at least in middle-aged male U.S. war veterans. Remaining at issue were the effects in women, in mild hypertensives, and in less highly selected segments of the population. Furthermore, effects on coronary heart disease were unclear and remain controversial. At a critical stage in this history, a decision had been made that the cooperative, multicenter clinical trial was the investigative tool of choice for answering an important question. Why and how are such decisions made? Although the Veterans Administration, the National Cancer Institute, the National Heart Institute, the armed forces, and other groups here and abroad had developed and applied this methodology in the 195Os, to this date little attention has been