Overview status of preclinical safety assessment for immunomodulatory biopharmaceuticals

Scientists from academia, industry, FDA, European and Japanese regulatory groups met to discuss key considerations that are central to the safe and expeditious development of novel biologic agents that are thought to act by modulation of the host immune system. In the presentations and case studies, particular attention was given to the current clinical experience with immunosuppressant agents. Many new biologic agents (such as humanized monoclonal antibodies) have been developed to interact in a highly specific manner with their target. However, their pharmacologic properties may be more complex than originally appreciated, impacting on clinical trial designs. The goal of preclinical safety assessment should be to provide some assurance that patients will be protected from any unacceptable risks by defining "safe" and "active" doses. For immunomodulatory molecules, particular attention is paid to defining potential for increased risks of lymphoproliferative disorders, opportunistic infections, and immune impairment. To address these issues, a wide variety of preclinical studies, mainly in non-human primates, have been performed for the purpose of assessing the potential risk of drug-induced, human immunotoxicity. Case studies presented at this symposium showed the feasibility of assessing humoral and cell-mediated aspects of the immune system, using antigen and neoantigen challenges, immunohistochemical, and flow cytometric (FACS) methods. In some cases, homologous forms of the biologic agent and "humanized" transgenic models have been used to assess potential clinical risks. These data have been useful in providing some assurance that severe adverse effects would not be induced in patients. Despite these limitations, it is important that industry sponsors provide information to regulatory authorities, the clinical investigator, and patients that provides the best feasible basis for risk assessment, safe clinical trial design, informed consent, and eventually, appropriate labeling. It is recognized that existing preclinical models often have significant limitations. Consequently, the sponsor's and regulatory authority's experienced judgement has determined whether or not the purported benefits of the novel therapeutic agent are balanced by the potential short- and long-term risks. In this field of development, preclinical models often need to reflect recent technology innovations; therefore, these models are not always "validated" in a conventional sense. Experience to date suggests that improved methods and approaches are needed as these agents are developed for use in lower or moderate risk patient populations. Consequently, there is an increased need for an industry/regulatory partnership in order to achieve progress in these risk assessment areas.