Managing clinical uncertainty

The Progress of Experiment: Science and Therapeutic Reform in the United States, 1900-1990

Cambridge University Press,1997 Pp. 258 £45.00$59.95
Jab now, no pain later: a doctor gives typhoid inoculation at a rural school in Texas in the 1940s.

How do we know that a particular drug is effective at the bedside, as well as in the marketplace? What reliable guides do we have for the clinical investigations of an academic medical élite and for the daily prescribing habits of general practitioners? Which intellectual and social tools are most dependable for defining therapeutic merit in theory, practice and law?

The shifting ways in which twentieth-century therapeutic reformers in the United States have grappled with such questions is the focus of Harry M. Marks's bold, nuanced account.

In a century flooded with pharmaceutical marvels (and some notorious iatrogenic tragedies), reformers have seen in experimentalism the most promising foundation for creating a rational therapeutics. Marks is not chiefly concerned with the ways in which new therapeutic possibilities were developed, or with recounting successes and failures. Rather, the story he tells is about how the methods and ideals of science were brought to bear on the management of clinical uncertainty.

The nature and meanings of experimentalism have changed over time, Marks convincingly shows, but its place in the larger programme of therapeutic reformers to bring scientific order to clinical practice remained remarkably durable. Their task was to create reliable criteria for therapeutic evaluation, and to inculcate their conception of a scientific attitude towards therapeutics among the medical rank and file.

Today, the randomized, controlled clinical trial, although not without its critics, is the gold standard of clinical research. Yet even as recently as 1950, therapeutic evaluation relied little on statistics. Early in this century, progressive therapeutic reformers distrustful of commercialism looked on the integrity of experienced researchers consecrated to the ideals of experimental science as the most dependable leaven for clinical practice. In 1906 the American Medical Association founded its Council on Pharmacy and Chemistry to judge independently the claims made by drug companies for their products.

Reformers went on to promote cooperative investigations as a means of pooling expert experience, but it was the character of individual clinicians that was believed to best guarantee the integrity of their therapeutic observations. During the 1930s and 1940s, officials at the US Food and Drug Administration largely adopted the council's approaches to therapeutic assessment in their efforts to regulate drug safety.

After the Second World War, however, therapeutic reformers increasingly sought to purge clinical evaluation of subjectivity, and began to embrace the double-blind, randomized, controlled clinical trial as a more impersonal, scientific standard for assessing and improving therapeutic knowledge and practice. Building on the statistician R. A. Fisher's conception of experimental design, experiments by the British Medical Research Council and the US Public Health Service to use streptomycin to treat tuberculosis during the war introduced the randomized clinical trial.

From the 1950s onwards, Marks observes, therapeutic reformers insisted that trust in numbers — in an experimental method regulated by statistics — should supplant the trust an earlier era had placed in the judgement of experienced researchers. Investigations at the bedside, newly governed by the reign of statistics, could be every bit as scientific as research conducted in the experimental laboratory.

Marks anchors his overarching account of change over time in a series of richly textured case studies, offered, as he rightly insists, not as typical but as powerful exemplars of larger patterns. Prominent nodal points include, from the period between the two world wars, the Cooperative Clinical Group's study of syphilis treatments and the Commonwealth Fund's experiments with serum treatment of pneumonia; the National Research Council's investigations of penicillin during the Second World War and the streptomycin studies conducted by the Veterans Administration and the Public Health Service immediately after the war; and, in the 1960s, the Diet-Heart study and the University Group Diabetes Program study of tolbutamide.

It is through these case studies that we are drawn into the world of therapeutic investigation, including conflicts between the aspirations of researchers and the day-to-day demands on general practitioners; between the purity of experimental design and the realities of patient compliance; and — in the book's most contemporary example, which is invoked but not thoroughly explored — between the political and clinical demands of patient activists and the protocols of therapeutic research on HIV and AIDS.

Readers might well feel uneasy, as I did initially, about Marks's use of the omnibus category “therapeutic reformers”, which encompasses a motley assemblage of pharmacologists, physiologists, statisticians, epidemiologists, journal editors, government physicians and clinical specialists. I would also have liked to learn more about how the American medical profession at large perceived the movement for therapeutic reform and its products; the strategies enlisted to persuade general practitioners of the virtues of randomized, controlled clinical trials; and how what Marks calls a “quintessentially an American story” compares with patterns in other national contexts.

What more than warrants his use of the aggregate term “therapeutic reformers”, however, is the way it underscores how the leading characters in this study constituted a community of believers, a diverse and changing group of physicians and scientists tightly bound together over time and across disciplinary boundaries by their pervading faith that an unfaltering commitment to science would overcome all social, technical and political obstacles to a rational therapeutics. This approach also underscores the usually unacknowledged political nature of this community, and helps to explain what Marks identifies as the problematic conviction of therapeutic reformers that their allegiance to science should make them alone the arbiters of clinical trials and clinical care.

No breezy narrative, this is a challenging historical study, sophisticated in its research and justifiably confident in its analysis. Marks has given us the best study we have of the shifting place and meanings of science in the culture of twentieth-century American clinical medicine. And as the field of medical history increasingly turns its attention to the twentieth century, this work is both a model and a springboard for future scholarship. No one who wishes to understand the world of therapeutic investigation, regulation and practice that doctors and patients live with today can afford to miss this important and engrossing study.

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Warner, J. Managing clinical uncertainty. Nature 390, 669–670 (1997). https://doi.org/10.1038/37750

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