Module 9 2024

03/09/2024

Nonclinical testing of biologics

Typical studies and phasing shown below • Timing is case-by-case, based on duration of clinical trials • Toxicology study duration must equal or exceed clinical study dosing duration

During Phase 2 or longer term clinical use (>13wks)

FIH-Enabling Tox Package

In parallel with Phase 3

Discovery Phase

• In cerebro/In vitro • Pharmacology disease models • Pharmacodynamic models (in vitro/ex vivo/in vivo) • ADCC/CDC • Cytokine release (if required)

• Reproductive toxicology study

• 26wk chronic tox • Carcinogenicity Risk Assessment

• 13wk tox study in pharmacologically

relevant species (or 4wk if justified)

• Safety pharmacology (CV, CNS, Respiratory, Excretion) • Tissue Cross Reactivity (human) • Immunotoxicity

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Nonclinical testing of biologics - FIM Repeat dose toxicology study – design & duration

Paracelsus 1493 – 1541

Needs to mimic the intended human route of exposure and regimen :

"All things are poison & nothing is without poison, only the dose makes a thing be poison."

• mAbs and Fabs typically IV or SC but can be IM or inhalation • Routes such as intra-vitreous or intrathecal also used • Max dose usually based on 10-fold multiple of human for low risk molecules • Consider whether affinity/potency difference between animal and human impacts doses • 100- 200mg/kg common as highest dose in primates (don’t need MTD) • Can be limited by highest feasible dose (mg/mL NBE and ~2mL/kg in human) • Duration should mimic the needs of the clinical trials to be conducted • FIH-enabling studies typically either 4 or 13 weeks duration (flexible) • Longest study typically 26 weeks in monkey

150px-Paracelsus

MTD = maximum tolerated dose

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Preclinical Testing of Biologicals – Sept 2024

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