Limiting Potential Carcinogenic Risk in Drug Development with Reliable Predictions

Q&A with Graham Morgan - Manager, Nonclinical Safety Assessment, Drug Development Services

The synthesis of pharmaceuticals involves many processes incorporating use of reactive chemicals, reagents, solvents and catalysts. Due to changes in chemical processes or degradation, impurities may reside in drug compounds and associated products. Failures in pharmaceutical development can often occur because of impurities that may have toxic potential, which calls for new methods to predict the mutagenic effects of compounds in humans. ICON’s Drug Development Services (DDS) consultant Graham Morgan discusses the challenges and opportunities of in silico (computer modelling or computer simulation) analysis in toxicology, in addition to the future of predictive analytics.

Why is the in silico analysis software important?

Under the scope of the ICH M7 guidance, which outlines the safety and quality risk assessment considerations in identifying, categorizing, qualification, and control of mutagenic properties, it is recommended that most new drug substances and products in development should be tested for mutagenic potential, or the ability to damage DNA. This also applies to marketed products where changes in manufacturing processes could result in new mutagenic impurities.

Our new service offering is an in silico analysis software, called Leadscope.

How does the software work?

The software assesses chemical structures and generates deactivating or activating factors or alerts. Positive or negative predictions are calculated based on the alerts raised and cross-referenced within the software database.

The expert alert model is based on well-defined mutagenicity structural alerts from the literature and against a large database of over 7,000 chemicals with Ames study (in vitro mutagenic assessment in bacteria) data. The structural alert model includes a set obtained from 27,000 pre-defined structural features.

The software has a number of other predictive functions; For further details, please visit their website.

What allows this software to be a standalone product?

The ICH M7 guidance states that in silico data should be generated using an expert and statistically based software, which (as explained above) are both provided by Leadscope.

While ICH M7 does not specify to use multiple software, ICON have approached leading regulatory authorities (FDA, EMEA and NIHS) for their expertise and advice. All confirmed that in silico predictions using Leadscope alone are readily accepted. In addition, data are presented in a format that has also been approved by these authorities. So applying this software can not only reduce development costs, but also ease approval application.

Where do you see the future of technologies such as this software headed?

In time, I would hope that with advancement in technology, other software could be applied to predict outcomes in preclinical and clinical toxicology. This could result in reducing the need for in vivo testing and assist with development of more highly specific products to be approved on the market.