Implementing a Clinical Immunogenicity Strategy using Preclinical Risk Assessment Outputs.

Immunogenicity to biologics is often observed following dosing in human subjects during clinical trials. Both product and host specific factors may be implicated in contributing to a potential immune response. However, even if such risk factors are identified and eliminated as part of the rational quality by design approaches, the outcome in clinic can be uncertain and challenging to predict. Several tools have been employed to identify these risk factors and consequent mitigation approaches implemented prior to dosing in humans. However, the complexity of the immune system with an interplay of network of immune cells involved in driving a long- term immune response as well as patient characteristics, can make it challenging to predict the outcome in clinic. This perspective will provide an insight into recent advances in the risk assessment approaches that are utilized during preclinical stage of development of a biologic. The outputs from such tools can help to rank order and select the most optimal candidate with the least likelihood of an immune response and can further drive the development of a clinical bioanalytical and immunogenicity monitoring strategy. Such a strategy can be proactively shared with the regulators along with the proposal to streamline clinical immunogenicity and personalizing the outcome based on pharmacogenomics and other patient-related factors. This paper provides a roadmap on performing risk assessments through a systematic identification of risks and their mitigations wherever possible. Recommendations on incorporating the key components of such risk assessments as part of the new regulatory submissions are also provided. Shorter abstract Immunogenicity to biologics is common during clinical trials. Both product and host specific factors have been implicated. Several risk assessment tools can be used to identify and mitigate the risk factors responsible for immunogenicity. An insight into recent advances in the risk assessment approaches will be presented. The outputs can define a risk score and guide the clinical bioanalytical and immunogenicity monitoring strategy. A roadmap on performing risk assessments through a systematic identification of risks and their mitigations wherever possible is provided. Best practices for a risk assessment strategy and recommendations on the content for IND and the Integrated summary of Immunogenicity are also provided.