1959

Launching of The University Group Diabetes Program Study (RCT using insulin, tolbutamide, and diet) to resolve long-standing controversy about the effects of diabetic control on future vascular disease. By 1967, there was a clear trend for patients on tolbutamide to die of cardiovascular causes (versus placebo) and in 1969, UGDP’s executive committee voted to stop using tolbutamide. Critics of the decision pointed out that deaths were concentrated in four clinics, raising questions about selection or management of patients in these clinics; proponents of UGDP study found that, statistically, variations in mortality among the clinics were no more than expected by chance and that known differences in risk factors could not explain the increased mortality in these clinics. Critics also held that tolbutamide had been administered in inappropriate high dosage and that many patients at study onset were sicker than UGDP assumed and so should not have been on oral hypoglycemics in the first place. To a minority, “the debate raised questions concerning the appropriate role of statistical methods in clinical investigation” (Marks, 204ff; quote at 213). In fall of 1970, FDA decided to alter the package label that accompanied tolbutamide, which led to a crisis for the proponents of oral hypoglycemics and to a 15-year legal battle to reverse the FDA’s decision. Only in 1984 did the FDA take final action on the drug (215ff.). . . . “The FDA’s ruling had become a measure of the scientific community’s judgment. Either the agency issued a warning to physicians, or it did not. The idea that the FDA might have issued a warning and acknowledged uncertainty about the study met with studied incomprehension. . . . To the study’s critics, the controversy represented the usurpation of clinical expertise and physician autonomy in favor of statisticians and bureaucratic dictates” (225).