Safety assessment of biotechnology-derived pharmaceuticals: ICH and beyond

Many scientific discussions, especially in the past 8 yr, have focused on d efinition of criteria for the optimal assessment of the preclinical toxicit y of pharmaceuticals. With the current overlap of responsibility among cent ers within the Food and Drug Administration (FDA), uniformity of testing st andards, when appropriate, would be desirable. These discussions have exten ded beyond the boundaries of the FDA and have culminated in the acceptance of formalized, internationally recognized guidances. The work of the intern ational Committee on Harmonisation (ICH) and the initiatives developed by t he FDA are important because they (a) represent a consensus scientific opin ion, (b) promote consistency, (c) improve the quality of the studies perfor med, (d) assist the public sector in determining what may be generally acce ptable to prepare product development plans, and (e) provide guidance for t he sponsors in the design of preclinical toxicity studies. Disadvantages as sociated with such initiatives include (a) the establishment of a historica l database that is difficult to relinquish, (b) the promotion of a check-th e-box approach, i.e., a tendancy to perform only the minimum evaluation req uired by the guidelines, (c) the creation of a disincentive for industry to develop and validate new models, and (d) the creation of state-of-the-art guidances that may not allow for appropriate evaluation of novel therapies. The introduction of biotechnology-derived pharmaceuticals for clinical use has often required the application of unique approaches to assessing their safety in preclinical studies. There is much diversity among these product s, which include the gene and cellular therapies, monoclonal antibodies, hu man-derived recombinant regulatory proteins, blood products, and vaccines. For many of the biological therapies, there will be unique product issues t hat may require specific modifications to protocol design and may raise add itional safety concerns (e.g., immunogenicity). Guidances concerning the de sign of preclinical studies for such therapies are generally based on the c linical indication. Risk versus benefit decisions are made with an understa nding of the nature of the patient population, the severity of disease, and the availability of alternative therapies. Key components of protocol desi gn for preclinical studies addressing the risks of these agents include (a) a safe starting dose in humans, (b) identification of potential target org ans, (c) identification of clinical parameters that should be monitored in humans, and (d) identification of at-risk populations. One of the distinct aspects of the safety evaluation of biotechnology-derived pharmaceuticals i s the use of relevant and often nontraditional species and the use of anima l models of disease in preclinical safety evaluation. Extensive contributio ns were made by the Center for Biologics Evaluation and Research to the ICH document on the safety of biotherapeutics, which is intended to provide wo rldwide guidance for a framework approach to the design and review of precl inical programs. Rational, scientifically sound study design and early iden tification of the potential safety concerns that may be anticipated in the clinical trial can result in preclinical data that facilitate use of these novel therapies for use in humans without duplication of effort or the unne cessary use of animals.