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CREATIVITY IN NEW DRUG DEVELOPMENT: AN ACADEMIC CHALLENGE* LEON I. GOLDBERGt Until quite recently in the history of medicine, the development of a new drug required only two stages—discovery of a biologically active material and assessment of relative risks and benefits in a patient. Contrast that simple procedure with the complex process mandatory in most countries today. Hundreds of individuals—scientists and nonscientists —are interposed between the innovator and the ultimate consumer . The route is so hazardous that the vast majority of new drug candidates do not survive, and those that do are 10 years old or older before they reach the prescription pad. Certainly surviving drugs are safer and more effective today. But alas, the long road to application has stifled creativity, and the golden age of drug discovery may be drawing to a close [1-4]. Most writers looking into this problem have concluded that innovations in drug development have been hampered by the imposition of federal regulations on the pharmaceutical industry. Unfortunately, the usual solution offered—radical revision of drug laws—is unlikely to occur in the foreseeable future. In view of this impasse, alternative pathways must be explored. The purpose ofthis presentation is to suggest that academia can and should become more active in creative developmental drug research. But before discussing how this can be accomplished, it is necessary to understand how new drugs are discovered and developed today and to learn ofthe problems which impede the system. My comments are based on experiences in the United States, but the conclusions should be applicable to Canada and most countries in western Europe as well. The creation and ultimate availability of new drugs are largely con- ?Based on the second J. F. McCreary Lecture presented at the University of British Columbia, Vancouver, B.C., Canada, October 18, 1976. tProfessor of medicine and pharmacology, University of Chicago, Chicago, Illinois 60637.© 1978 by The University of Chicago. 0031-5982/78/2102-0002$01 .00 188 I Leon I. Goldberg ¦ Creativity in DrugDevelopment trolled by three forces: the pharmaceutical industry, which has assumed the major responsibility for innovation and development; governmental agencies, which are responsible for proof of safety and efficacy and, in a growing measure, the cost of drugs; and consumer "advocates," who have become more concerned about ethical problems ofclinical research and adverse effects and less impressed by potential benefits of new drugs. The drug-development process can be conveniently divided into preclinical and clinical segments. The great majority of new drugs are created by medicinal chemists in the pharmaceutical industry, usually in collaboration with pharmacologists. Medicinal chemists in industry have the ability and facilities to synthesize thousands of extraordinarily complex molecules, and most pharmaceutical firms have competent scientists and equipment for screening these chemicals for pharmacological activity . Interesting compounds are examined in detail by pharmacologists with sophisticated techniques in a broad range of test systems, from subcellular particles to intact animals. Compounds with potential therapeutic applications are then submitted to toxicological examination which usually includes determinations of lethal doses in at least three species of animals and pathological studies for detection of organ toxicity . An estimate is made of a therapeutic ratio by comparing a presumed effective dose in a series of animal models with toxic doses in the same species. Potentially useful compounds are now considered for clinical pharmacology. This is a crucial period in the life of a new chemical entity, and only a few compounds of hundreds synthesized will be investigated in man. Decisions on which of several analogues to proceed with is extremely difficult. Judgments must be made both with regard to the estimated therapeutic index and after consideration of a number of other factors, including duration of effect, oral absorption, and cost of production. Compounds chosen for human study must then undergo additional toxicological evaluations and pharmacokinetic studies to determine how the drug is metabolized and excreted in animals. Finally, the drug must be prepared in a form which is stable and bioavailable. Now a new set of actors enters the stage. The clinical pharmacologist has the responsibility of administering the drug to a human being for the first time (phase I). He must thoroughly review the preclinical data, and if...


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