Nonclinical safety evaluation of biotechnologically derived pharmaceuticals.

The primary objectives of nonclinical safety evaluation for pharmaceutical products are to identify potential target organ toxicity, provide a safe starting dose for clinical trials, and establish dose-response relationships. These objectives do not differ in concept for either small molecular weight compounds or biotechnologically derived pharmaceuticals; they are important for both. The complex structural and biological characteristics of biotechnologically derived pharmaceuticals, however, dictate that different approaches to their safety evaluation are needed. Although their novel mode of production initially raised concerns about their safety, improvements in analytical and manufacturing procedures have largely minimized the perceived risks. It is primarily their exaggerated pharmacodynamic properties that produce the toxicity observed in nonclinical studies. Even though most of these products will require a case-by-case, scientifically based approach, knowledge gained from both nonclinical and clinical evaluation of these novel products have highlighted some general principles with regards to their safety evaluation. These principles include the importance of evaluating species in which the biotechnologically derived pharmaceutical is biologically active, the potential impact of immunogenicity on the interpretation of multiple dose toxicity study results, and the need for both highly sensitive and specific analytical methods to measure their pharmacodynamic properties. An understanding of these principles forms the basis for the development of a scientifically sound nonclinical safety evaluation program.