Clinical Safety Evaluation of Novel Biologics

Abstract

Novel biologics -- monoclonal antibodies, antibody-drug conjugates, bispecific antibodies, CAR-T cell therapies, and mRNA-based therapeutics -- represent the fastest-growing segment of pharmaceutical development, with over 150 new biological approvals in the past five years and a pipeline containing over 2,000 biological candidates in active clinical development. Their complex mechanisms of action, immunogenic potential, and often profound effects on the immune system create safety profiles that differ fundamentally from small-molecule drugs and that standard pharmacovigilance approaches -- designed for traditional drugs -- may systematically fail to detect or characterise. We evaluated five clinical safety evaluation frameworks for novel biologics across 28,642 patients enrolled in biologic clinical programmes at four European academic pharmacovigilance centres (Madrid, Paris, Berlin, and Stockholm) from 2016 to 2023, covering monoclonal antibodies (oncology and immunology), ADCs, bispecific T-cell engagers, CAR-T therapies, and mRNA vaccines. We compared: standard trial-embedded safety monitoring, enhanced real-world pharmacovigilance, biomarker-guided safety prediction, immune monitoring with mechanistic safety characterisation, and ML-integrated adverse event anticipation. Our Biologic Safety Evaluation Score (BSES-B) integrates adverse event detection sensitivity, mechanistic understanding, risk stratification accuracy, post-marketing signal speed, and clinical management guidance. ML-integrated adverse event anticipation achieved the highest BSES-B (0.926), predicting serious adverse events with AUROC 0.84 a median of 12.4 days before clinical manifestation, while immune monitoring with mechanistic characterisation (BSES-B 0.914) provided the deepest understanding of toxicity mechanisms enabling targeted management strategies.