This is an extraordinary book. Oxford University Press had the good judgment to reprint 45 commentaries William Silverman wrote for the quarterly Paediatric and Perinatal Epidemiology during the 10 years since its inception in 1987. Thirty-nine have been updated by brief addendums; four include critical responses from readers. As a bonus, the book includes a shortened version of the author's 1994 Windermere Lecture to the British Paediatric Association.
The collection is a joy to read. It evokes a pleasure akin to that at first encountering Montaigne's Essays and sharing the reflections of a wise, erudite, and humane man whose life is one of engagement with ideas, events, and values. Bill Silverman, professor of pediatrics emeritus at Columbia University, brings to bear on contemporary medical issues the logic of science, an abiding concern for the welfare of infants, and a vigorous defense of the rights of their parents. His essays should be savored, dipped into and returned to (rather than read consecutively from cover to cover), thought about, debated, and reread.
Silverman asks us to consider whether the preoccupation of institutional review boards with informed consent makes sense without a parallel requirement that the scientific design of the research be valid and the question that it asks be worthwhile. His skeptical comments about modern medicine's furor therapeuticus recalls Montaigne's aphorisms, two of which seem particularly apposite here: "Nothing is so firmly believed as what a man knows least" and "Abstinence from doing is often as generous as doing, but it is not so apparent."
The commentaries cover a multiplicity of topics, from observer bias to sampling and representativeness, from eugenics to euthanasia, from information overload to random assignment. I can only hint at the intellectual riches in this slim book by singling out a few for brief discussion.
The author reminds us how readily desperate patients and their families can be persuaded by a charismatic figure that he or she has a panacea by sketching a brief history of the distinguished royal commission Louis XVI thought it necessary to appoint in 1784 to investigate the claims of Franz Anton Mesmer on the miraculous powers of animal magnetism. Sensational medical claims continue to roil universities and governments more than two centuries later. Many will recall the clamor about the cancer-curing properties of laetrile and the way it destroyed a researcher's previously unblemished academic career. The personal convictions of key members of Congress and pressure on others from their constituents made it necessary for the National Institutes of Health to create an office of alternative medicine.
The problem is worldwide, I might note. An Italian physician, Luigi Di Bella, crafted a "cancer cocktail" that he insisted had cured "thousands." His advocates demanded that the government's health insurance program reimburse patients for the "treatment" (at a cost of up to $6,500 per month). The health ministry was so besieged by protests at its refusal to pay that it had to respond by organizing multicenter trials, even though no reputable oncologist endorsed the product. Not 1of the 134 patients in the trial showed any indication of remission; three quarters were dead within three months of "treatment" ("Italy Pulls Plug on Unproven Cancer `Cure,"' by A. Abbott. Nature 1998;394:514). Yet, the matter remains a political football. Although Dr. Di Bella had formally approved the protocols before study began, he now insists that they were not valid. The more things change, the more they remain the same.
Silverman queries the claim that a physician cannot "in good conscience" recommend that a patient participate in a randomized clinical trial if he or she believes one treatment to be better than the other. As Silverman points out, "belief" is no warranty of truth, even when experts agree but decisive clinical studies have not yet been done. He tells the cautionary tale of the response of the medical community to the introduction of antiarrhythmic drugs. The new agents appeared to suppress ventricular arrhythmias; moreover, they aborted premature ventricular contractions. Because the effect on premature ventricular contractions was taken as a proxy for the real end point -- preventing sudden death from cardiac causes -- the number of prescriptions written for these drugs rose precipitously. When clinical observation suggested that the new agents might actually induce lethal cardiac arrhythmias, the National Heart, Lung, and Blood Institute sponsored the Cardiac Arrhythmia Suppression Trial. The results demonstrated unequivocally that the drugs caused a higher-than-expected mortality rate. They were withdrawn from the market. How had clinicians been so misled? Drug toxicity mimicked the very events the drugs were intended to avert. Drug-induced sudden deaths were ascribed to the underlying abnormalities. Only a randomized clinical trial could distinguish the actions of the drug from the natural course of illness.
The need for circumspection in the design of randomized clinical trials was demonstrated some 44 years ago by an adventitious finding. In 1954, a controlled trial was undertaken to determine whether a promising new antibiotic (oxytetracycline) was more effective than the standard regimen (penicillin and sulfisoxazole) in preventing infection among small neonates. Two young doctors (one of whom was Bill Silverman), studying the relation between serum bilirubin levels and kernicterus in that group of infants, discovered that kernicterus was occurring much more frequently among infants in the standard-treatment group. This unanticipated finding became the stimulus for sequential experimental designs that include independent monitoring committees charged with conducting interim analyses of results ("peeking") to look for evidence of clinically significant benefit or harm before the formal completion of the trial.
When are there enough data to settle a therapeutic controversy? After the introduction of extracorporeal membrane oxygenation for desperately ill neonates in the late 1970s, the survival rate of the infants appeared to improve dramatically. Practitioners were so convinced of its value that extracorporeal membrane oxygenation units multiplied rapidly. Two randomized trials of extracorporeal membrane oxygenation were carried out in the 1980s, but they failed to satisfy some critics because of design flaws and the small numbers of subjects. Neonatologists in the United Kingdom were less enthusiastic than those in the United States because of concern about long-term disability and uncertainty about effectiveness. When a randomized trial of extracorporeal membrane oxygenation was carried out in the United Kingdom in 1993, peeking revealed that the rate of death or severe disability in the treated group was half that among those in the conventional-care group; accordingly, the trial was terminated. Was the third trial ethical?
Silverman, who had been among the skeptics, argues that it was, but appends to his essay a response from John Lantos who, well before the third trial was undertaken, was convinced by existing evidence that extracorporeal membrane oxygenation worked. Had he been on the ethics review panel, he tells us, he would not have approved the trial because the control subjects were placed at unnecessary risk. Because he chose not to respond to Lantos's rejoinder, Silverman has quite properly left it to the reader to weigh the arguments, as all doctors must in making clinical decisions. In medical practice, certainty is unattainable, but it is often difficult to determine when the degree of uncertainty has been reduced enough to justify a confident conclusion.
Reviewed by Leon Eisenberg, M.D.^M
Copyright © 1998 Massachusetts Medical Society. All rights reserved. The New England Journal of Medicine is a registered trademark of the MMS.
--This text refers to an out of print or unavailable edition of this title.
"This compilation...deserves the widest possible readership within and beyond the medical community. As a pioneer in neonatology and controlled clinical trials, the author brings unparalleled experience to these pieces....The essays are pithy, scholarly, lucid, iconoclastic, and suffused with the author's humanity and humor."--Rob Schechter,
Amazon"[Silverman] encourages us to respond by questioning the evidence that informs our decisions, by distinguishing between the values we need when acquiring knowledge and those we need when applying it, and by recognizing that all medical previleges are granted to us by our patients. This book...offers succour to those of us who fear that most of the world's troubles are caused by people who have the courage of their convictions and yearn to hear from those like Silverman who have the courage of their doubts."--
British Journal of General Practice"This is an extraordinary book....[these] essays should be savored, dipped into and returned to rather than read consecutively from cover to cover, thought about, argued with, and reread."--
The New England Journal of Medicine"We can only be grateful that the distilled wisdom of a great man is at least in part encapsulated within 200 pages of highly readable prose....a unique collation of topics that are always thought provoking,usually challenging and sometimes downright aggravating."--
Paediatric and Perinatal Epidemiology"
Where's the evidence? is a collection of 45 short, thoughtful and challenging essays in which Silverman continues to hold up a mirror to medical practitioners."--
Journal of the Royal College of Physicians of London
