Historical Background To Preclinical Safety Assessment

It is often forgotten that the first "blockbuster" drug, sulfanilamide, was discovered and developed in an era devoid of regulatory oversight and guided only by free-market forces. Domagk discovered the antibacterial properties of Prontosil in 1932, and with the subsequent discovery in 1935 that the active moiety was the off-patent and widely available substance sulfanilamide, a number of companies rushed to make preparations for sale to the public. This explosion of therapy options was unfettered by requirements for medicines to be tested for efficacy or safety, although preparations could receive the endorsement of the American Medical Association [1] . Thus, in 1937, when the S.E. Massengill Company of Bristol, Tennessee, sought to prepare a flavored syrup, it simply identified an appropriate excipient to dissolve the drug, prepared 240 gallons of the raspberry-tasting Elixir Sulfanilamide, and marketed it across the nation. Unfortunately, the excipient chosen was diethylene glycol, also used as an antifreeze. We now know this agent to be lethal to a

Biomarkers in Drug Development: A Handbook of Practice, Application, and Strategy, Edited by Michael R. Bleavins, Claudio Carini, Malle Jurima-Romet, and Ramin Rahbari Copyright © 2010 John Wiley & Sons, Inc.

large number of species, causing acute kidney injury at relatively modest doses. Before Elixer Sulfanilamide was identified as the causative agent and pulled from pharmacies, 34 children and 71 adults died. A year later, Congress passed the 1938 Federal Food, Drug and Cosmetic Act, requiring pharmaceutical manufacturers to show product safety before distribution [1]. Thus, society transitioned from its former free-market approach to pharmaceutical development to one of safety testing (initially in animals), careful clinical trials, and government oversight.

Safety testing as it is practiced today owes most of its form to procedures developed by the U.S. Food and Drug Administration (FDA) for testing food [2]. As early as 1949, the publication of "Procedures for the Appraisal of the Toxicity of Chemicals in Foods" began to formalize the practices the agency expected industry to follow in safety testing [3]. These practices included standard study designs and expectations as to what experimental observations would be recorded. They have evolved into the descriptive toxicity tests well known to modern toxicology [4]. Key to the value of these tests is not only their experimental design in terms of dose, route of administration, and duration, but also the endpoints evaluated, going beyond the observations of overall animal behavior and health. Thus, a battery of clinical pathology tests examining urine, hematological parameters, and serum chemistry is commonly evaluated [ 5]. Importantly, a number of tissues from the animal are examined both macroscopically and microscopically after sacrifice, and this histopathological examination allows for the identification of unusual and subtle lesions and changes following compound treatment [6].

In the arena of pharmaceutical product development, these studies, carried out in at least two animal species, one rodent and one nonrodent, are used to assure the safety of human subjects exposed to experimental doses of novel compounds [7]. The types and durations of studies required to support safety in various types of clinical studies have been codified by the International Conference on Harmonisation (ICH) and described in their guidelines on nonclinical safety studies [8]. Even so, human subjects need to be monitored for "adverse events and/or laboratory abnormalities identified in the protocol as critical to safety evaluations" [9].

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