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THE RELEVANCE OF MODERN CLINICAL TRIAL METHODOLOGY TO THE PRACTICE OF MEDICINE JACOB E. BEARMAN and BYRON WM. BROWN, JR.* I. Objective Evaluation of Treatments Medical history is replete with examples of treatments that have been adopted too quickly on the basis of unsupported theory and/or incomplete or misleading laboratory evidence. Recent experiences with improperly and incompletely tested drugs are sufficiently well remembered to be easily identified. The experiences with thalidomide are cases in point. But even modes oftherapy that might be questioned become accepted in medical practice. For example, a recently reported clinical study of anticoagulants in acute myocardial infarction was conducted without a "no treatment" group; medical custom favored anticoagulation so strongly that the potential medico-legal problems involved were too great a hazard for the clinicians to face. Yet more recent results bring the use of anticoagulants in acute myocardial infarction into rather serious question. For similar reasons, in some geographic areas, surgeons must resort to radical mastectomy for the treatment of breast cancer, although some physicians raise strong questions about the advantage of such a surgical procedure over simple mastectomy. The fact is that, once adopted, a treatment is difficult to discredit even in the face of evidence of ineffectiveness. The incident was reported recently of the situation at one of our best teaching institutions where chloramphenicol had been tested as a potential agent to reduce infection in abdominal surgery. Long after it had been concluded and reported that the agent was useless for this prophylactic purpose, the surgeons at the institution remained so indoctrinated in the use of the agent that large quantities were still being used for this discredited purpose. The matter of conflicting reports on treatments of choice is one ex- * Division ofBiostatistics, School ofPublic Health, University ofMinnesota, Minneapolis. 259 perienced by every physician. To read some reports, the oral anticoagulants are the treatment of choice for acute myocardial infarction; yet equally vocal groups insist that injectable heparin is the only acceptable treatment. Some reports insist that oral hypoglycemic agents are perfectly satisfactory in the management of diabetes; and these claims are made in the face ofothers that only insulin will serve. In every one ofthe situations here enumerated, dependable initial evaluation on an objective basis is essential. II. Modern Clinical Trial Methodology A methodology involving biométrie principles has been evolved to assure that data collected in clinical studies will furnish a sound basis for scientific conclusions. No result ofscientific investigation is ever "proved" in the sense of being beyond further question. Only in mathematics are results beyond question; scientific conclusions can, by their nature, never attain mathematical certainty. Thus, the best that can be done for any scientific "conclusion" is to exclude all conceivable alternatives; the more alternatives that are excluded, the better is the conclusion verified. Contrarily , the more alternatives not excluded, the less likely is a conclusion to be accepted by colleagues and co-workers. For example, one eminent physiologist held forth informally for an hour recently as to alternative means ofaccounting for results different from those published in a most reputable scientific journal. It is the ability of conclusions to stand up in the purifying crucible ofsuch continuing skepticism that allows them to be accepted ultimately as "fact" by the scientific community. And it must be recognized that such acceptance is guaranteed only until some additional information raises further questions. Such is the environment in which scientific judgments are made and must stand or fall. Such is the manner in which hard scientific fact is established, and slow progress is made. Such is the way in which medical science advances, and such is the test that the results of clinical studies must be prepared to undergo before being accepted. To avoid all possible errors in study method and in evaluation of results is the most efficient method ofpreparing conclusions ofstudies for their tests by the skeptics. It is to help investigators avoid such errors that the principles ofbiométrie design and analysis ofinvestigations have been adapted for application in clinical studies. This methodology, which has been developed over the 260 Jacob E. Bearman and Byron Wm. Brown, Jr. · Clinical Trial Methodology Perspectives in Biology and Medicine · Winter...

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