Personal views: Evaluating new treatments
Authors: Lawrence Cranberg
Journal: BMJ (1998)

Evaluating new treatments  

Fifty years ago medicine entered a new phase in evaluating new medical treatments in the form of randomised clinical trials, with control patients often given placebos. At the same time there was a widely accepted view that retrospective controls were “inherently fallacious.” But 20 years ago, this argument was challenged in the BMJ, and retrospective controls were advanced as an alternative to randomisation.


It was recognised that the advent of modern computer technology made more practical the use of retrospective controls by facilitating the storage and retrieval of detailed medical data on past cases, and in comparing past with current medical experience. The BMJ endorsed this view. But the intervening 20 years have seen little change in practice. Today, randomised clinical trials with placebos are, with few exceptions, the prevailing method of evaluating new treatments. Yet alternatives surely warrant more attention than they have received—in particular, what is now usefully called a “computrial.” 


Alternatives surely warrant more attention than they have received



A computrial is one which admits all suitable patients to the same experimental treatment, while controls are drawn from the records of patients who have received treatment in historically recognised, leading treatment centres, not just random treatments. Controls are matched individually by computer with appropriate software to the trial patients for all significant prognostic factors. A computrial generates not just statistical summary data on the collective response to the new treatment. It creates a record which can be cross analysed for the effects of particular prognostic factors, with implications for individual patient treatment, and it compares a new treatment with the best of the old. It eliminates placebos and the deterring uncertainty that faces every patient in a randomised trial as to whether he or she is receiving the newest treatment or is being relegated to the passive role of a control.

The computrial concept claims respectable origins. In 1965 the late Sir Austin Bradford Hill, in his famous Heberden Oration, Reflections on the Controlled Trial, expressed reservations about the indiscriminate use of randomised trials, and discussed in favourable terms the use of retrospective controls based on patient histories instead. On 19 November 1979 the BMJ published my paper, repeatedly rejected since 1972, “Do retrospective controls make clinical trials ‘inherently fallacious’?” which challenged the then accepted view.

Debate started with a concurrent editorial, “Randomised controlled trials?” that endorsed my views, citing the power of computers to match trial patients with historical controls, and concluded with these words: “The controlled trial has been placed on too high a pedestal and needs to be brought back to earth.” Some readers wrote in support; others were opposed. The debate ended six months later with my rejoinder to critics.

With such a send off from the editors of BMJ, computer enabled clinical trials with retrospective controls should soon have had their day, at least on an experimental basis, particularly with the explosive growth in numbers and power of computers. This has not been the case, however, despite many strong criticisms of randomised trials over the years.

Heartened by the response to my 1979 publication, I have repeatedly encouraged use of what I now call computrials, but the effort has been unproductive even though the original concept has been expanded to include use of computers to particularise treatment to individual patients rather than provide statistical results only, and emphasis is placed on controls that have received the best treatment medicine had to offer before the new treatment appeared. The most recent experience with one of the world’s leading pharmaceutical companies is worth recording because it has lessons for medical innovators generally. Its essential result was a refusal to engage in discussions among colleagues, and a summary rejection of the written, fully documented proposal, with no reasons given.

The ethical and management issues raised in the encounter just described with the technical staff of a world famous pharmaceutical company may be as important as the ethical issues involved in randomised clinical trials themselves. If there is no dialogue among colleagues on matters that affect the evaluation and use of a company’s innovative products how can you assume that issues raised have been dealt with in good faith, and that serious concerns of cost, efficacy, and ethical propriety are not being buried to conceal excessive costs and ethical shortcomings of current practices, or that official favour is being curried at the expense of scientific advance? 

A colleague takes the view that only legislation that relieves the United States Food and Drug Administration of responsibility for evaluating the efficacy of drugs will improve the present situation. My own view is that the FDA is a responsible agency, and that it will in due course accept a less theoretically rigid and more empirical policy towards evaluating new drugs and other treatments if the medical and scientific community says it should.