Spring Intro 2023

22/03/2023

Computer Modelling - Regulatory Use for Safety 1. Quantitative Structure Activity Relationship (QSAR) in Genetic Toxicity Assessment & Control of Mutagenic Impurities in Medicines to Limit Potential Cancer Risk - ICH M7 (R1) Feb 2018.

Computational Toxicology assessment should be performed using 2 computer methods (Q)SAR that predict the outcome of bacterial mutation tests: an expert rule-based method and a statistical-based method. Absence of a positive (structural alerts) from 2 complementary computer methods is sufficient to conclude - an impurity isn’t mutagenic. No further test needed

Derek Nexus

2. Modelling Drug:Drug Interactions(DDI): ICH M12 – In many cases, negative findings from early in vitro and clinical studies, in conjunction with model-based predictions, can eliminate the need for additional clinical investigations of an investigational DDI potential.

27

Regulatory “ Sins ”

1. Imagining that a pre-determined set of tox studies will support clinical trials & secure regulatory approval 2. Slavish adherence to guidelines, i.e. Genetox Test with proteins, or teratogenicity test in rabbit with antibiotics 3. Doing an in vivo study when reasoned argument could save time, animals and money. 3Rs Ethics 4. Ignoring unfavourable data. “ It’s all exaggerated pharmacology! Oh, animals are different!” “Oh, it’s a species-specific effect!” 5. Despite ICH, 1 set of tox studies are not necessarily equally acceptable to all regulatory authorities

28

14