Pharmacological testing of recombinant human erythropoietin: Implications for other biotechnology products

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Abstract
The development of recombinant DNA and large‐scale cell culture technologies has introduced a wide range of biotechnology products or “biologics” including cytokines, vaccines, peptides, hormones, growth factors, and monoclonal antibodies that are being used in the diagnosis, prevention, and treatment of various diseases. As with any new drug development program, pharmacologic evaluation is critical to an understanding of that new drug entity. A well‐designed general/safety pharmacology program contribues to the overall safety assessment of that new entity, provides important information to the design of early clinical trials, assists in resolving any issues that arise during preclinical or clinical development, and assists in deciding whether to continue its development. This has been the case for many small molecular weight compounds and is no less important for the new biotechnology products. Because of their complex structural and biological characteristics, biotechnology products present unusual challenges in their development, resulting in pharmacology programs designed on a “case by case” basis. The pharmacologic evaluation of r‐HuEPO may well serve as an model for understanding some of the potential issues associated with the development of biologics. With r‐HuEPO being marketed worldwide for approximately five years, clinical data are available to assess the predictive value of the pharmacology studies. An analysis of these data serves as a guide to determine which preclinical studies best reflect the clinical data. Appropriate design of a pharmacology program depends on an understanding of the structure of the molecule, the mechanism of action at the cellular level, species specificity, and the clinical plan. On this basis a program can be developed to accurately assess the potential non‐pharmacologic effects and ultimately establish a benefit‐to‐risk ratio.