Monoclonal antibodies developed as anticancer drugs have revolutionized modern medicine, and an increasing number of therapeutics is in clinical use or in the pipeline. As with small molecules, successful drug development is based on chemical-pharmaceutical quality, non-clinical pharmacology/toxicology, and well-designed clinical trials. However, the unique features of protein products such as monoclonal antibodies require a specific development programme.
Key quality aspects for monoclonal antibody therapeutics include derivation of from biological sources, complex manufacturing process, and inherent structural complexity and heterogeneity. Thus, for complete product characterisation and quality determination, a combination of physicochemical and biological tests together with the production process and its control is required. This also includes comprehensive assessment of microbial, viral and TSE safety. Since also minor differences in product quality attributes can impact pre-clinical and clinical outcomes, manufacturing changes can be critical, and require demonstration of comparability between pre- and post-change product.
In-depth understanding of the pharmacodynamic, pharmacokinetic and toxcicological properties derived from appropriate preclinical studies is essential for successful drug development. In comparison to conventional small molecules however, the non-clinical testing programme needs to be specifically tailored for monoclonal antibodies. As antibodies can be highly species-specific, the establishment of relevant animal models to assess pre-clinical safety and to establish clinical dosing can be a significant challenge. Robust knowledge on the mode of action is prerequisite for development of bioassays, which are important tools to monitor batch release to assure safety and efficacy.
In general, clinical development of monoclonal antibodies as anticancer therapeutics follows the approach as for conventional cytotoxic drugs. If there are potential factors of risk involved with first human administration, risk mitigation strategies for the first-in-man trial should be applied by the sponsor. Differences to clinical development of small molecules include bioanalytical analysis, dose escalation strategies, and approaches to establish optimal therapeutic doses. The phenomenon of unwanted immunogenicity can affect dose exposure, safety profile and efficacy. Since animal models are not predictive for humans, a potential immune response should be carefully monitored during clinical trials. Study designs for confirmatory trials are usual comparable to those applied for cytotoxic drugs.
In summary, development of anticancer monoclonal antibodies should follow an integrated, interdependent “threesome” process, and usually involves product-specific approaches. Quality data, non-clinical safety data and efficacy data are interlinked, and should be looked at as a whole. This thesis identifies cornerstones for a successful development of those molecules, with particular focus on IMPD requirements for clinical trial application in the EU.
Pages: 60, Annex (1): 1 Page
