The University Group Diabetes Program (UGDP): A Famous Early Randomized Clinical Trial (RCT)

There’s a view that the University Group Diabetes Program (UGDP) was very important in the development of clinical and preventive trials in this country, particularly because of the effective involvement and collaboration of NIH staff with clinicians, clinical investigators, statisticians and epidemiologists. It was also important for other lessons learned from it.

The staff of the coordinating center, which moved in the early stages of the study from the University of Minnesota to the University of Maryland, was the nucleus of the coordinating center for the equally historic Coronary Drug Project (CDP), having earned its credentials in the UGDP. Moreover, the Coronary Drug Project historically was one of the more effectively run of any trial in history and an important predecessor, though unfortunately not always followed as a model, to the whole generation of preventive trials of the 1970s and 1980s.

A sketch and a chronology of events of the trial in the first edition of Curt Meinert’s text on trials (Mienert 1986) are each succinct and revealing. The sketch states simply:

The UGDP was a randomized, controlled, multicenter clinical trial designed to evaluate the effectiveness of long-term hypoglycemic drug therapy in preventing or delaying he vascular complications of diabetes (newly diagnosed, non-insulin dependent, adult-onset diabetes). . . The tolbutamide and phenformin treatments were terminated in 1969 and 1971, respectively, because of lack of efficacy. The two insulin treatments were continued to the end of planned patient follow-up (1975), but were not judged to be any more effective than placebo medications in prolonging life or in delaying the onset and development of vascular complications.

Meinert’s chronology of UGDP usefully documents its events but hardly reflects the drama attendant on the leaking of negative results on tolbutamide three weeks prior to their scientific presentation. Furious accusations, testimony, and injunctions followed the June 14, 1970 meeting of the American Diabetic Association in St. Louis, where the tolbuamide evidence was finally presented.

Fred Goetz, pioneer investigator in the UGDP, remarked on the quandary of the investigators in that trial in the late 1960s, when the early findings of the ineffectiveness of the widely used drugs developed:

“When we looked at ourselves in the UGDP we realized that we were in the peculiar situation of being the only physicians or health-related individuals aware of the possibly serious risks from using the (oral anti-diabetic) medication in the study (Tolbutamide). The rest of the world of medical care was blissfully unaware of this.

What were our responsibilities therefore? They were to our own subjects, who in good faith had entered the study with oral informed consent.

What was in our minds with these Monte Carlo odds? Here we were with the data before us. We had no choice but to act” (Goetz 2001)

The Wall Street Journal leak was solved when it was learned that the ADA itself routinely releases its program and abstracts prior to their annual meeting. The finding that, at best, oral hypoglycemic drugs were ineffective relative to diet and insulin created an explosion in the diabetes medical establishment. Joined by the drug industry and its consultants, it delivered severe attacks on the UGDP design and operation, including personal attacks on the investigators with implications of dishonesty. It also pursued landmark litigation about the ownership of research data acquired with government funding in efforts to reanalyze the data.

Outstanding critics of the study were Richard Gubner, editor of the industry-sponsored Medical Tribune and former medical director of the Equitable Life Assurance Company, Nathan Horowitz, publisher of the Medical Tribune, whose language in attacks was unacceptable, and Alvin Feinstein, the principal design critic, who in essence accused the investigators of fraud.

Goetz recounts that “UGDP began with an act of Congress on the part of a legislator’s personal hunt for solutions to diabetes and his dropping a special pot labeled for diabetes into the budget of NIH. The NIH staff people went to Max Miller at the Cleveland Clinic to ask what they should do with this new money. Miller got a few people together, including Chris Klimpt who was finishing his doctorate at Hopkins. Finally a group was assembled to talk about studying the natural history of diabetes.

Miller had a drive to examine what he called the “Joslin Clinic way” of looking at diabetes, which troubled him greatly and had to do with rigid control of hyperglycemia. Oral hypoglycemics had just been approved by the FDA and were on the shelves of neighborhood pharmacies all over the country. He felt that the Joslin people were preaching in a messianic way their doctrine of tight control yet had demonstrated no evidence to stand on in respect to long-term benefits and freedom from complications and survival.

Among the group there came a gradual shift then from the idea of another natural history study to a clinical trial with the new oral agents now available and the possibility of ethically studying non-insulin dependent diabetes with these new preparations compared to placebo. All this was carried out in a period of scandalous trials on anticoagulants and pulmonary embolism, estrogens and coronary disease, and other situations in which randomization had been poor and investigators would fudge. [In contrast] the proposal for UGDP was a very tight and effective randomized protocol.

The UGDP basically wrote the Bible of randomized clinical trials that has been scripture every since, incorporating, of course, the elements of design from Bradford Hill and other predecessors. UGDP became a case study.

The first patient was entered in the cold of February of 1961. Presentation of tolbutamide results was made at the American Diabetes Association in June, 1970 in St. Louis, where the weather was hot and steamy and tempers hot and steamy. The tension was just fantastic. (Goetz 2001)

The UGDP developed in the era of the Helsinki Declaration which declared that the one-to-one relationship between investigators and patients took precedence always over any general benefit to society. According to Goetz, this was “very clear and made very good sense. This is where tempers rose and people were saying, ‘You’re crazy. You’re saying that this drug which has been considered a boon to mankind, the first new treatment for diabetes in 40 years, is a danger?’”

The tolbutamide results had been leaked, apparently, by the practice of the American Diabetes Association to make the program and its abstracts available to the press prior to its annual meeting. Suddenly, the Wall Street Journalo of May 21, reported the results with this headline: “Tolbutamide results on Dow Jones ticker tape.” The Washington Post estimated that the drug may have caused as many as 8,000 deaths. These were followed by a crash of Upjohn Company stock. At the June meeting of ADA in St. Louis, “everybody was pretty hot by then.”

Due to the 50 per cent mortality rates in the main study groups, the diabetologists of the country felt that the UGDP treatment had simply been inadequate or inappropriate, particularly in regard to the full degree of control of hyperglycemia, irrespective of aspects of the trial design that they might or might not understand.

Goetz indicated that, “the day-to-day practice in the study was to ignore blood sugar results, to record them, but to ignore them and not alter the dose accept in the insulin variable treatment group. Since UGDP, of course there have been many studies including the United Kingdom Study with thousands of patients indicating that there is a benefit of good control in regard to reduced cardiovascular events in adult-onset diabetes, as well as improved microvascular disease endpoints, including a study of insulin-required diabetes in which results of controls were quite favorable and on the announcement of which the Joslin Clinic people wore big buttons in their lapels that read,’ we told you so.’ Goetz also opined that, “UGDP suffered particularly from the lack of the glycosylated hemoglobin measurement, an integrated index of glucose control.”

The American Diabetes Association committees met just before the UGDP paper was to be presented at the plenary session. Everybody was keyed up and George Thorn’s right hand person, Peter Forrester, stood up and, without intimate details of the UGDP study, said ‘Well, it’s a flawed study, we know that.’

According to Fred Goetz, Alvin Feinstein’s tactics, the expert witness for the drug industry, were “to patronize us as lambs led to the slaughter by some sinister forces masking themselves as scientists.” Those sinister forces were presumably the Maryland statistical people, Chris Klimt and company. Though Feinstein wrote pertinent discussions on the issues of the UGDP, he concluded there was fraud and implied investigator dishonesty. The outcry spread widely throughout the community. Only one well-regarded diabetologist, a European, stood up and said “Colleagues, forebear. The study has been carried out by the approved scientific method. There is no reason to think it was not so done. Let us be careful before condemning something!”

The controversy and residual doubts about the study led to two independent audits of the study and its data, one by a blue-ribbon committee of the International Biometrics Society and the other by the FDA. According to Meinert, neither found any basis to reject the conclusions of the study. Meinert’s heroic chronology addresses and replies to each critcism of the study (Meinert 1986).

A separate issue in the furor over the case was the question whether the Freedom of Information Act required investigators to release all the data to whomever requested it. The Supreme Court decided 6 to 2 that they did not have to release the data. Nevertheless, UGDP data are now generally available since they were deposited in a database at Ann Arbor. After the fact, there apparently has not been much of a demand for the data.

In summary, the UGDP stimulated much thought and elevated the science of clinical trials and the study of diabetes, irrespective of any other contribution. According to Fred Goetz, “as time has passed, I think UGDP was given not its full due of respect, but a grudging respect.”

Spin-offs from UGDP include the Diabetes Type 1 Trial and a study of transplanting healthy kidneys into diabetics, as well as separate studies on retinopathy and its laser treatment, all “broader aspects of UGDP.” Goetz calls the present-day studies of diabetic complications in relation to the degree of glycemic control, the “granddaughter studies of UGDP.” (Henry Blackburn)

References

Meinert C. 1986 Clinical Trials: Design, Conduct and Analysis. New York-Oxford: Oxford University Press

Goetz, Frederick in an interview conducted by Henry Blackburn, 24 August 2001. History of Cardiovascular Epidemiology Archive. University of Minnesota.