The Empirical Basis for the Discovery of New Therapies

THE EMPIRICAL BASIS FOR THE DISCOVERY OF NEW THERAPIES JAMES S. GOODWIN* It is commonly held that a major change in the search for new therapies took place some time in the early decades of this century. Therapies used before that time, whether efficacious or not, are considered to have been derived on empirical grounds, while many therapies introduced in the past half-century are seen as the product of scientific reasoning. It is said that we have now entered the age of "rational drug design" [1, 2]. Indeed, "empirical" has become something of a dirty word in pharmacology [3]. Such a broad dichotomy as empirical versus scientific or rational does have some validity for understanding how therapies are introduced, but the usefulness of this distinction is limited. Empirical is defined as "relying or based solely on experiment and observation rather than theory" [4]. In this article, I will argue that the discovery of new therapies has always been and will continue to be an empirical science. The vast majority of efficacious ancient and modern drugs were discovered and initially used without any understanding of how they work. To the extent that we deny or ignore that reality in our future attempts to discover new therapies, we risk fostering a system wherein potentially efficacious treatments may be overlooked while inefficacious therapies are accepted [5]. I shall propose five patterns by which we understand how new therapies are discovered. These patterns apply to both ancient and modern times. Each of the five ways has resulted in important advances in therapeutics , and each is still a valuable path for the discovery of new therapies . Two major goals in the search for new therapies are to avoid The preparation of this manuscript was supported by a grant from the Dreyfus Medical Foundation. The author thanks Drs. Shirley Murphy, Tom Anderson, Barry Blackwell, Daniel McCarty, Shrinivas Murthy, Frederick Goodwin, and Jean Goodwin for their comments and suggestions, and welcomes suggestions or corrections from interested readers. *Department of Medicine, University of Wisconsin Medical School, Milwaukee Clinical Campus, 950 North 12th Street, Milwaukee, Wisconsin 53233.© 1991 by The University of Chicago. All rights reserved. 0031-5982/92/3501-0750$1.00 20 James S. Goodwin ¦ Discovery ofNew Therapies accepting useless treatments, or placebos, and to avoid rejecting potentially efficacious treatments, a process we have previously termed the tomato effect [5]. A third goal in the search for new therapies, to adequately access toxicities related to the treatments, does not differ among the five paths of new drug discovery and will not be considered here. Each of the five ways of discovering new therapies has different strengths and weaknesses with respect to accepting useless treatments and missing useful ones. Five Ways New Therapies Are Discovered The classification proposed is arbitrary, and there are many examples of overlap, where the discovery process for a given therapy fits into more than one category. There are surely other ways of categorizing the discovery of new therapies. This represents one attempt at ordering that process. New therapies can be seen as resulting from one or more of the following processes: 1.An unpremeditated or unexpected finding. 2.Mass screening. 3.Copycat or me-too variation on existing drugs or treatment. 4.Understanding how a previously discovered, efficacious drug works. 5.Breakthrough in understanding a physiologic or pathophysiologic process. As mentioned earlier, all of these have contributed important new therapies; none should be disparaged. I hope to show that overreliance on any one of these processes to the detriment of the others results in a less than optimal atmosphere for the discovery of new therapeutics. In particular, a bias against the "empirical" methods of drug discovery would be inappropriate. UNPREMEDITATED FINDINGS The word "serendipity" is often used to describe unpremeditated findings, but the derivation of that word does not reflect the creativity and rigor required to turn unpremeditated findings into scientific discovery . Pasteur's comment that chance favors only the prepared mind is often quoted but perhaps not fully appreciated—most people leave out the word "only." Unpremeditated findings most often contribute to the discovery of new therapies in the context of ongoing rigorous scientific investigation [6]. It is important to remember...