Tóm tắt

Professor Gerhard Zbinden recognized in the 1970s that the standards of the dayrnfor testing new candidate drugs in preclinical toxicity studies failed to identifyrnacute pharmacodynamic adverse events that had the potential to harmrnparticipants in clinical trials. From his vision emerged the field of safety pharmacology, formally defined in the International Conference on Harmonizationrn(ICH) S7A guidelines as “those studies that investigate the potential undesirablernpharmacodynamic effects of a substance on physiological functions in relationrnto exposure in the therapeutic range and above.” Initially, evaluations of smallmolecule pharmacodynamic safety utilized efficacy models and were an ancillary responsibility of discovery scientists. However, over time, the relationshiprnof these studies to overall safety was reflected by the regulatory agencies who, inrndirecting the practice of safety pharmacology through guidance documents,rnprompted transition of responsibility to drug safety departments (e.g., toxicology). Events that have further shaped the field over the past 15 years include thernICH S7B guidance, evolution of molecular technologies leading to identificationrnof new therapeutic targets with uncertain toxicities, introduction of data collection using more sophisticated and refined technologies, and utilization of transgenic animal models probing critical scientific questions regarding novel targetsrnof toxicity. The collapse of the worldwide economy in the latter half of the firstrndecade of the twenty-first century, continuing high rates of compound attritionrnduring clinical development and post-approval and sharply increasing costs ofrndrug development have led to significant strategy changes, contraction of thernsize of pharmaceutical organizations, and refocusing of therapeutic areas ofrninvestigation. With these changes has come movement away from dedicatedrninternal safety pharmacology capability to utilization of capabilities withinrnexternal contract research organizations. This movement has created thern4 A.S. Bass et al.opportunity for the safety pharmacology discipline to come “full circle” andrnreturn to the drug discovery arena (target identification through clinical candidate selection) to contribute to the mitigation of the high rate of candidate drugrnfailure through better compound selection decision making. Finally, the changing focus of science and losses in didactic training of scientists in whole animalrnphysiology and pharmacology have revealed a serious gap in the future availability of qualified individuals to apply the principles of safety pharmacology inrnsupport of drug discovery and development. This is a significant deficiency thatrnat present is only partially met with academic and professional society programsrnadvancing a minimal level of training. In summary, with the exception that thernfuture availability of suitably trained scientists is a critical need for the field thatrnremains to be effectively addressed, the prospects for the future of safetyrnpharmacology are hopeful and promising, and challenging for those individualsrnwho want to assume this responsibility. What began in the early part of the newrnmillennium as a relatively simple model of testing to assure the safety of Phase Irnclinical subjects and patients from acute deleterious effects on life-supportingrnorgan systems has grown with experience and time to a science that mobilizesrnthe principles of cellular and molecular biology and attempts to predict acuternadverse events and those associated with long-term treatment. These challengesrncall for scientists with a broad range of in-depth scientific knowledge and anrnability to adapt to a dynamic and forever changing industry. Identifyingrnindividuals who will serve today and training those who will serve in the futurernwill fall to all of us who are committed to this important field of science.