May 4, 2016

Using In Silico Software to Generate an ICH M7 Submission

and Expert Review

GTA WORKSHOP

Workshop Chairs

• Chris Barber • Catrin Hasselgren • Roustem Saiakhov

Facilitators

• Suman Chakravarti• Kate Kearney• Richard Williams• Laura Wirpza• Glenn Myatt • Kevin Cross

AGENDA

• The Basics• Introduction to Hands on Exercises• Work on Case Studies• Perspectives from MultiCASE, Lhasa and

Leadscope• Wrap Up

Expert Rule Based vs. Statistical Methods

• ICH M7 requires use of 2 complimentary systems to maximize coverage

• Statistical – built by statistical mining of training data sets– Build “from scratch” or modify models with new data– Expert input - choice of descriptors and algorithm

• Expert Rule Based– Expert relates structural features to toxicity– Data curated from literature or generated to support rule

development– Supported by examples, a proposed MOA, explanation of

the scope of the rule– Statistical mining of data – define mitigating factors

Choosing Systems

• System that helps you make an expert conclusion– Coverage of your chemical space– Supporting information to aid expert review of

predictions• Compliant with OECD principles

– e.g defined domain of applicability• Accepted by regulators

– Well characterized, publications, used by or familiar to regulators

Choosing Systems

• “Makes my life easier” considerations– Presentation of supporting information– Availability of supplemental information– Easy access to literature references, supporting

databases– Batch loading – Generation of reports for internal use – Generation of reports for regulatory submission– Good technical support

Combining Results – Overall Prediction

Combining Results – Overall Prediction

Expert Judgment

When Is Expert Review Necessary?

• ICH M7 says expert review “if warranted”• Experience says – Always! It adds value• Amount of effort will vary

2 Systems Negative

ConflictingEquivocal

OOD

Expert Review – The Value

• Any positive prediction concluded mutagenic– Simple and conservative….BUT– Drives control or Ames testing– May lead to unacceptable # of false positives

• 2 Negative predictions concluded not mutagenic– Expert review improves negative predictivity– Identify reactive features “missed” by 2 systems

• Out of domain predictions– Identify compounds that can support your conclusion

• Expert review of published data

“How To” Conduct Expert Review

• Details, supported by practical examples– Barber et al., Reg Tox Pharm 2015. 73(1), 367– Powley. Reg Tox Pharm 2015. 71(2),295 – Amberg, et al., Reg Tox Pharm 2016. 77, 13

• Some systems guide user through expert review process

• Critical review of information supporting each prediction

“How To” Conduct Expert Review

• Negative predictions– confirm query chemical is within applicability domain– No structural features that suggest reactivity

• Check validity of mitigating factors for alerts

• Positive predictions– Confirm relevance to query chemical

• Statistical – check supporting training set chemicals for alert– Run training set chemical through expert systems to identify

other more likely causes of activity

• Alert’s structural environment – is it relevant?• Similarity to API or other chemicals reported not mutagenic

Regulatory Submission – Expert Review

• What and how much information should be provided re: expert review?– Convince yourself → convince others

Regulatory Submission – Expert Review

• Conclusion consistent with predictions– Detailed description of expert review not needed

• Conclusion is different from the prediction(s)– Strong scientific rationale

• Steric influences, reactivity, more knowledge of SAR• Experimental data on other related compounds• Supporting literature references

Regulatory Submission Information

• (Q)SAR systems used and version numbers• For each structure

– Experimental data if it exists– (Q)SAR results for each system– Overall conclusion– Class 1 – 5 assignment– Information relating to expert review

• Market application– Bacterial mutagenicity study reports are required– Reports from systems not required but may be

included.

Next Up….HANDS ON EXERCISES