Director Pfizer Groton, Connecticut, United States
The registration of biotherapeutics for chronic indications typically requires 6-month toxicity studies, as outlined in the ICH S6 guidance. However, extensive experience over several decades has shown that the non-clinical safety profiles of standard biotherapeutics are generally predictable. This suggests that conducting multiple toxicity studies especially 6-month study may not be necessary. In a meta-analysis of standard biologics developed for non-oncology indications over last 25 years at Pfizer, we compared organ system findings between short-term (1-3 month) and long-term (6-month) animal studies. Our goal was to determine if there were any significant difference in the safety profiles between the two study durations and their relevance to human risk assessment. Our analysis revealed that most clinically relevant toxicities can be detected in shorter-term studies (87%; 26/30 programs). This suggests either an undifferentiated safety profile between short-and long-term studies, or anticipated toxicities based on the modality, such as immunogenicity or exaggerated pharmacology. However, for 4 of 30 programs (13%), long-term studies did identify either potential new toxicities or more severe manifestation of exaggerated pharmacology, leading to modifications in clinical trial designs and human risk assessment. Our experience suggests, up to 3-month short-term toxicity studies may be sufficient to support late-stage clinical development and registration for majority of standard biotherapeutic programs. The decision to conduct chronic studies can be based on a weight of evidence approach, considering nonclinical safety signals, monitorability, and emerging clinical safety signals. This pragmatic, science-based approach aligns with the goal of advancing 3R's initiatives.
