Rethinking the necessity of long-term toxicity studies for biotherapeutics using weight of evidence assessment.

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  • Additional Information
    • Source:
      Publisher: Elsevier Country of Publication: Netherlands NLM ID: 8214983 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1096-0295 (Electronic) Linking ISSN: 02732300 NLM ISO Abbreviation: Regul Toxicol Pharmacol Subsets: MEDLINE
    • Publication Information:
      Publication: <2003>- : Amsterdam : Elsevier
      Original Publication: New York : Academic Press, [c1981-
    • Subject Terms:
      Biological Products*/toxicity ; Biological Products*/adverse effects ; Toxicity Tests*/methods ; Toxicity Tests*/standards; Animals ; Humans ; Risk Assessment/methods ; Risk Assessment/standards ; Time Factors
    • Abstract:
      The registration of biotherapeutics for chronic indications requires 6-month toxicity studies. However, extensive experience has shown that the non-clinical safety profiles of biotherapeutics are generally predictable. This suggests that conducting multiple studies, especially a 6-month study may not be necessary. In a meta-analysis of 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 differences in the safety profiles between the two study durations and their relevance to human risk assessment. Our analysis revealed that most clinically relevant toxicities could 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 out 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 that 3-month toxicity studies may be sufficient to support late-stage clinical development for a majority of standard biotherapeutic programs. This pragmatic and science-based approach aligns with the goal of advancing 3R's initiatives in nonclinical safety assessment.
      Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
      (Copyright © 2024 Elsevier Inc. All rights reserved.)
    • Contributed Indexing:
      Keywords: Biotherapeutics; Chronic; Immunogenicity; Long-term; Monoclonal antibodies; Pharmacology; Proteins; Short-term; Sub chronic; Toxicity
    • Accession Number:
      0 (Biological Products)
    • Publication Date:
      Date Created: 20240927 Date Completed: 20241017 Latest Revision: 20241104
    • Publication Date:
      20241105
    • Accession Number:
      10.1016/j.yrtph.2024.105710
    • Accession Number:
      39332576