Adverse immunostimulation in early phase clinical trials: Key findings and recommendations based on the...

The emergence of therapeutic proteins has coincided with an increase of acute adverse immunostimulation (AIS). AIS has occured in clinical trials despite compliance with regulatory guidelines on preclinical evaluation and its incidence is anticipated to increase even further. AIS may have significant impact on trial participants and clinical staff exposed to the adversity and can severely hamper progression of investigational medicinal products (IMPs) in drug development processes. We aim to increase understanding of the mechanistic basis and clinical presentation of AIS by presenting 3 recent cases of drug-induced AIS in early phase clinical trials, conducted at the Centre for Human Drug Research (Leiden, The Netherlands), in the light of ICH S6, S8 and Food and Drug Administration guidelines for AIS evaluation.

We strongly encourage increased vigilance for AIS at early stages in the drug development process. Although AIS can probably never be fully mitigated by preclinical studies alone, preclinical evaluations for IMP-induced AIS allows anticipation on its potential occurrence in subsequent clinical studies. The limited information available on the exact mechanisms behind AIS and uncertainties on the relevance of animal species warrant further research into the translatability of the mechanisms underlying AIS between species and models. Implementation of evidence-based, IMP-specific AIS management, mitigation and monitoring protocols will facilitate AIS recognition and mechanistic understanding, translating into more rational clinical management of AIS. This will improve the overall efficiency of the drug development process while fostering a strong collaborative relationship between pharmaceutical companies and investigators, ultimately helping design and conduct high-quality clinical trials that are equally safe and informative.