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Randomized Controlled Trials Mark a Golden Anniversary

Judith Randal

It would be hard to think of anything more central to medical progress than the knowledge made possible by randomized controlled trials. Today's physicians in virtually every specialty —oncology emphatically included — pay close attention to the results of those trials, and tomorrow's doctors surely will too. So why were there no RCTs until after World War II? And what did it take to make them a reality?

A good place to get answers to these questions was provided in London last October when the British Medical Journal held a 2-day international conference to commemorate the 50th anniversary of the appearance in the BMJ on Oct. 30, 1948, of "Streptomycin Treatment of Pulmonary Tuberculosis."

The first RCT to be completed and, therefore, the first to be published, it was run by England's Medical Research Council and pitted streptomycin and bed rest against bed rest alone, which was then the standard TB therapy. It accrued its first patients in January 1947.

Richard Doll, F.R.C.P., was the conference's keynote speaker. Now emeritus professor of medicine at Oxford University, he was on the MRC committee that planned the landmark trial and in addition was first the student and then the colleague of the trial's designer, the late Austin Bradford Hill (see sidebar).

Doll recalled for the conference that there had been some use, before the streptomycin trial, of studies that assigned alternate patients to one or the other of two (rarely more) treatments. While this was, he said, better for comparison purposes than the then-still-common practice of using historical controls or no controls at all, it had "a major disadvantage."

The problem in such a trial, he said, was that the investigator knew what treatment the last patient entered into it would receive and thus also knew the treatment the next one would get. That being the case, bias could — and according to Doll often did — creep into the judgments investigators made when deciding whether patients who might be candidates for a trial actually met the trial's criteria. In the streptomycin trial, by contrast, the order in which patients came into the study had no bearing on the treatment they got; that was, instead, decided by luck of the draw. (Every time a patient was enrolled in the trial a sealed envelope containing a card was opened at the project's central office. Cards marked S sent patients to streptomycin treatment; those marked C to be a bed rest only control.) With that, it became possible to avoid patient selection bias; the era of randomization had dawned. The wonder was that no one had thought of it before.

The truth of the matter was that Austin Bradford Hill actually had. In 1937, he wrote a series of articles for The Lancet (later issued as a textbook) on the principles of experimental design for medical research. He subsequently told Doll that he had thought about recommending randomization then, but feared that the concept would "scare off the average practioner" and so had decided against it. However, by late 1946, when the streptomycin trial was planned, circumstances had conspired to get Bradford Hill off the hook.Go



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Photograph courtesy of Ernie Branson

 
Rigid Controls

At the heart of the situation was the fact that the then-new antibiotic was being made in quantity only in the United States, where it was subject to rigid export controls. Thus two factors were at work when the British government managed to buy 50 kilograms of the American product for the MRC.

One factor was that the efficacy of streptomycin for TB was then somewhat uncertain. So when it was decided that the MRC would use most of the purchase for pulmonary tuberculosis, it was also decided — because there was not enough of the drug for every pulmonary patient in England anyway — that it would be ethical for the study to have an untreated control group.

The other factor in play was that this could have been done by following the old protocol of assigning alternate patients to the S and C groups, but this, of course, would have meant that the clinicians who selected them knew which patients went where. As was noted by Alan Yoshioka, a history of science doctoral candidate at Imperial College, London, and an invited speaker at the recent meeting, when all this occurred TB was common in Britain. Not only had the dramatic benefits of streptomycin in a U.S. trial on guinea pigs with tuberculosis garnered considerable press attention, but many emergency appeals for the drug were broadcast on the British Broadcasting Corporation, while a black market for it had developed as well.

This was, besides, the time of the slogan in England of "fair shares for all." Yoshioka, therefore, suggested that the MRC's clinicians probably welcomed randomization because it "relieved them" of any direct responsibility for allocating a scarce resource.

A half century and some 300,000 RCTs later, it could be argued that if Nobel prizes in medicine and physiology were awarded for methodological innovations, Bradford Hill surely would have merited consideration. Still, the mood at the recent conference was not entirely self-congratulatory either. Also, aired at the meeting, which had an international audience of some 450 physicians, scientists, and others, were views about problem areas that need to be addressed.

Iain Chalmers, M.B., B.S., for example, called it "of the utmost importance," before undertaking a new study, to do "a systematic review" of the existing clinical research on that topic. Not to, said Chalmers, who is at Oxford University where he heads the United Kingdom Cochrane Center, "risks both repeating work that has been done already and repeating its mistakes."



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Iain Chalmers Photo courtesy Strat Mastons/MRC

 
Chalmers also called for routine updating of systematic reviews, readily available registries of ongoing trials, and — as a further hedge against wasting resources — not doing a trial without first being sure that "it will address an important unanswered question." Too often, he said, trials pose questions that "are of more interest to researchers than patients and have little relevance to clinical practice."

A telling illustration of how RCTs can come up short was a study presented at the meeting by Caroline Sanders of the Department of Social Medicine at the University of Bristol. Using the Cochrane Controlled Trials Register, which, Sanders said, is the most comprehensive source of RCTs available in all specialties, she and her colleagues focused on how many of them dealt with quality of life issues, though not necessarily exclusively, and how well.

Among their findings was that cancer trials more often reported on these concerns than other trials, but that, as of 1997, the latest year for which data were available, "this was true of fewer than 10%" of them.

Moreover, the methodology the reports were based on, according to the researchers, often left much to be desired.

For example, the participation of patients in this regard was generally limited to their filling out a questionnaire which gave them little, if any, opportunity to express their personal views. And in about 30% of the studies, it was not clear whether the information about patient quality of life had even come from patients or merely reflected the judgments of health professionals.

But perhaps what troubled many at the conference the most was that pharmaceutical firms shape so much of what is done with RCTs that their priorities can trump both those of patients and physicians.

"Me Too" Drugs

It was noted, for example, that many companies spend enormous sums on RCTs in order to get regulatory approval of drugs in therapeutic categories that have already brought them considerable success — so-called "me too" drugs.

As Salim Yusuf, M.D., D.Phil., who is director of cardiology at McMaster University in Hamilton, Ontario, put it, "When we already have eight classes of anti-hypertensive agents, do we really need another?"

A related complaint was lodged by John Kirwan, M.D., F.R.C.P., of the University of Bristol in Bristol, England. Kirwan, a rheumatologist, reported having recently reviewed an RCT in which an anti-inflammatory drug being readied for the market had been pitted against an older one and seemed to be far superior for osteoarthritis of the knee.

After a more careful reading, however, he noticed that the dose used in the trial for the control drug was "inadequate" while the dose for the newcomer drug had been far larger. "Unfortunately," he said, "this sort of practice is quite common and easily overlooked by busy practitioners. . . . What I would like to see is trials of educational approaches that help people to live with chronic conditions and to avoid the side effects of therapy."



             
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