Module 9 2024

03/09/2024

Nonclinical testing of biologics Post-FIH Testing

Reproductive Toxicity Study :

• Used primarily to provide advice to unintentionally pregnant woman on drug • If two species used in tox programme, typically uses rat and follows small molecule guidance in ICH S5 • If only primate → Enhanced pre and postnatal development study

• Treatment of pregnant female primate from gestation D20 to natural birth

• Dosing stops at birth but dam and pup assessed for 3-6 months post-birth

• Assess infant key organ system development as defined by pharmacology and any other concerns arising during development of molecule

• Design usually agreed at EOP2 meeting with FDA/EMA

• Typically conducted in parallel with Phase 3 clinical studies (design endorsed at End-of-Phase 2 Meetings)

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Preclinical Testing of Biologicals – Sept 2024

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Nonclinical testing of biologics Post-FIH Testing

Genotoxicity : • Generally not relevant as proteins don’t normally interact directly with DNA

• Concern may arise if the mAb interacts with DNA synthesis proteins but classic genotoxicity tests unlikely to be suitable

• Should be considered if mAb is conjugated – Linker? Payload?

Carcinogenicity : • Specific carcinogenicity studies rarely performed for mAbs or other biologics • Carcinogenicity Assessment Document uses Weight-of-evidence approach based on: • mechanism of action • any immunomodulatory effects (which could reduce tumour surveillance) • any histopathology concerns raised in tox studies (pre-neoplastic effects) • Known or potential risk with other molecules with similar pharmacology • Essential to consider whether new carcinogenicity study would provide data that can inform the human risk assessment → If not, then can justify not conducting • Submitted to Health Authorities at EOP2 meetings → FDA approve; EMA acknowledge

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Preclinical Testing of Biologicals – Sept 2024

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