Monoclonal antibodies--regulatory challenges.

The development of new monoclonal antibodies (mAbs) is a still evolving field in finding new therapeutics. Structurally, mAbs have evolved over the past years by change from fully murine molecules to chimaeric antibodies or even humanized or fully human molecules. Although being "monoclonal" in terms of specificity, mAbs can be heterogeneous with respect to molecular features like microheterogeneity and glycosylation due to their complex manufacturing processes. Small changes in these processes can have considerable consequences on the product and also clinical safety and/or efficacy. Thus, quality, non-clinical and clinical data should not be seen as separate fields, but can impact on each other. For clinical trials of mAbs, non-clinical data from relevant species are required to evaluate the potential toxicity. Demonstration of relevance can be a challenging task, and should not be restricted to comparison of amino acid sequence of the target. Non-clinical development should also be seen as a tool for proactive risk identification. For first-in-human clinical trials, recent incidences have had considerable impact on regulatory handling, and have meanwhile led to a European guideline on risk identification and mitigation. For pivotal clinical trials, the requirements for mAbs are in principle the same as for other, non-biotechnological products. However, based on their long half-life and particular mechanism of action, enhanced safety measures can become necessary for mAbs to adequately detect and characterize also unexpected adverse reactions.