gta workshop using in silico software to generate an ich ... qsar workshop introduction.pdfmay 4,...

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