The Field Trial: Fredrickson’s “Indispensable Ordeal” 1968
In 1968, the U.S. National Heart Institute (NHI) faced a decision that would profoundly affect the course of CVD epidemiological research, preventive cardiology, and the public health. Experienced CVD-prevention researchers, who had carried out a successful Institute-supported pilot trial of dietary modification to lower cholesterol levels, declared that it was, indeed, feasible to conduct a “definitive” diet trial to prevent heart attacks. They made a strong recommendation to organize a national test of the “diet-heart hypothesis.”
This clear and urgent recommendation from a group of highly regarded leaders in CVD research precipitated an almost panicked, painful, and prolonged administrative deliberation at the National Institutes of Health (NIH). The quandary and delay stymied and frustrated the waiting experts and, for the CVD research community as a whole, introduced a period of inactivity that we refer to as “The Pause.” The involved and impatient proposers of the definitive trial were fully prepared and poised for the undertaking. But they also had indicated in their recommendations that they were ready to respond to any rational alternative national plan of research, including one that would address the larger question of whether heart attacks might be prevented at all, by any and all means. But NIH leaders, overwhelmed with the design, operational, staffing, and funding challenge of such a complex and costly undertaking, spent the better part of three years arriving at their decision.
Donald Fredrickson, then-NHI director, delivered a revealing account of the weighty institutional decision he faced in a lecture to the New York Heart Association at the Waldorf Astoria hotel in New York City in January, 1968. Yes, major field trials were “indispensable,” he acknowledged, but added, “They will continue to be an ordeal. They lack glamour, they strain our resources and patience, and they protract the moment of truth to excruciating limits” (Fredrickson 1968, 992). In what today seems a lecture-length sigh, Fredrickson responded to the recommendations that he knew were forthcoming from the Diet-Heart Pilot Trial investigators with a long elaboration of his generic concerns about the national burden of large, expensive clinical trials. His thoughts, in fact, presaged the modern era of NIH-supported and centrally directed mass field trials of chronic disease prevention.
Bemoaning the fact that, “the uncertainties of our endpoints seem to make it de rigueur to study many [thousand] subjects,” Fredrickson outlined his reliance on the experience of predecessor epidemiological observations and trials, and then announced how future field trials should and would be designed and managed, under the banner of quality control, strictly from the center—the National Institutes of Health (NIH). At that unsettled moment, and in the absence of national policy on CVD prevention research, the scientific community hung on his every word, including his enumeration of the newly devised official requirements for a successful trial:
- proper definition of the problem;
- inclusion of cost-benefit analysis in the study design;
- knowledge of recruitment response, participation, and compliance rates; and
- proper interpretation of what is learned from a trial and whether “we must begin all over again.”
While he lamented the ambivalent results of past field trials, he propounded his widely quoted conclusion that, “Man is complicated, but he is also often unique as a test system,”–hence, scientists must proceed with the “indispensable ordeal” of field trials. Fredrickson believed that better trials could be carried out and that biometricians had been sent “to the rescue.”
“We have learned the cost of compromise,” he said, “of cutting numbers of subjects too close in fleeting attempts at economy, of neglecting randomization and the double blind, when they are feasible, because of inconvenience or the interposition of false issues, [of] failing to standardize methods or, worst of all, of having misguided faith in endpoints that perniciously soften with time” (ibid.).
In analyzing the challenge that lay ahead, he allowed that uncertainty about sample size for trials had largely disappeared due to knowledge from the Framingham, Tecumseh and other NHI-sponsored projects about incidence and mortality rates and their basis for stratification according to risk. These purportedly “good” NHI-supported epidemiological researches had strengthened the scientific base for trial design. Guessing and intuition had “given way to a benevolent tyranny of statisticians” and their “twin watch dogs of probability, alpha and beta” (ibid., 989).
But trials in atherosclerosis are so large, he said, mainly because of biological uncertainties such as those about their clinical endpoints. He quoted the observation of William Farr whom he labeled “the Father of Epidemiology”: “Stone cold hath no fellow” (ibid.). In other words, death is the most reliable endpoint for epidemiological studies. The great problem he saw was that the cost of an equivocal answer in a major clinical trial is on a wholly different scale than failure of a laboratory or clinical experiment.
His main preoccupation was with the recommendation from the “distinguished and hard-working panel of experts who concluded from the Diet-Heart [Pilot] Study that the diet can be altered so as to lower cholesterol levels in free-living Americans” (ibid., 987). But such a study, aimed at preventing first heart attacks by diet, would dwarf the already huge and expensive Coronary Drug Project, costing as much as $10 to $20 million dollars a year for up to ten years!
“Unthinkable?” Fredrickson asked in his talk to the Heart Association. “Not unthinkable,” he answered. “The economic cost of premature coronary artery disease easily exceeds $1 billion a year. A positive step that reduces this toll would be proportionately worth it in cost” (ibid.).
He wrestled further with his personal burden as well as with the collective burden of making the decision to conduct major field trials. “Society has reason to rely upon us. We have every desire to respond. In doing so, however, we are duty bound to move carefully and mount with skill barriers that have unhorsed our predecessors. . . .The process of dispossessing uncertainty is painful and hoary with constraints” (ibid. 988). His caution gave fair warning that NIH might not embrace the exuberant positivity of the Diet-Heart Pilot investigators for mounting “the definitive diet trial.”
Fredrickson pointed out that he had begun to prepare his Institute’s bureaucracy to assure quality of review and handling of proposals and operations of large clinical trials. He had mobilized his staff, study sections, Advisory Council, and appropriate experts, he said, to examine all protocols for adequacy of study design, to consider alternatives to a given design, to outline areas of doubt and of agreement, and to approve only the studies that measured up fully to the quality of research that competes for resources (ibid., 991).
At the end of his talk, the director conceded that, with all the inherent difficulties of conducting field trials, “Still, they are among the most challenging tests of our skills. I have no doubt that when the problem is well-chosen, the study is appropriately designed, and that when all the populations of concern are made aware of the route and the goal, the reward can be commensurate with [the] effort. If, in major medical dilemmas, the alternative is to pay the cost of perpetual uncertainty, have we any choice?” (ibid., 992).
Despite this grudging green light, it would take several years for the issue of diet-heart and other preventive trials to be resolved in Bethesda and for the nation’s central policy on epidemiological research to evolve and finally emerge. As for the proposed definitive Diet-Heart Trial–it never happened. (Henry Blackburn)
Reference
Fredrickson, D. S. 1968. The field trial: Some thoughts on the indispensable ordeal. Bulletin of the New York Academy of Medicine 44: 985-93.