Module 9 2024

03/09/2024

Nonclinical testing of biologics Assessing Clinical Risk

In vitro and in vivo immunosafety data combined to inform risk assessment and human dose selection for NBEs

Reproduced from Brennan and Kiessling (2017)

The Organisation for Professionals in Regulatory Affairs

Preclinical Testing of Biologicals – Sept 2024

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EMA Guideline (2017) : Guideline on strategies to identify and mitigate risks for first-in-human and early clinical trials with investigational medicinal products EMEA/CHMP/SWP/28367/07

Nonclinical testing of biologics Assessing Clinical Risk

Proceed into Clinical Studies

Modelling to define correct approach : • Minimal Biological Effect Level (MABEL) OR • Pharmacologically active dose (PAD) OR

(with clinical monitoring)

Acceptable

Calculate the Therapeutic Index – No magic correct number!

•

Anticipated therapeutic dose range (ATD)

STOP (or reassess therapeutic dose?)

Unacceptably small

Therapeutic Index is derived by dividing exposure (AUC or Cmax) in most sensitive nonclinical species by expected or known exposure in the human. Typically, a value of at least 10-fold is ideal but may differ if severe, unmonitorable toxicity was observed. N.B Therapeutic Index also known as safety margin, safety multiple or exposure multiple

The Organisation for Professionals in Regulatory Affairs

Preclinical Testing of Biologicals – Sept 2024

22

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