Undertaking expert review

under the ICH M7 guidelines

ACEMS/JEMS, Tokyo, November 2019

CEO

chris.barber@lhasalimited.org

Dr Chris Barber

Agenda

• Introducing Lhasa

• The purpose of ICH M7

• Publications and supporting guidance

• Examples of expert review

• How accurate is expert review?

Lhasa is an educational charity that develops in sili

Head office in Leeds, UKNot-for-profit

Educational charity

A membership organisation

Data & knowledge sharing

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Regulators &

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Proprietary data mining

Predictive software

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Purge

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projects

Publications &

presentations

FDA NIHS eTRANSAFE

eTOXPMDA

MHRAUSP

ICH M7

• Assessment and control of DNA reactive

(mutagenic) impurities in pharmaceuticals

to limit potential carcinogenic risk.

Is the impurity mutagenic?

Is the impurity present in the final API?

What are the potential impurities?

Implement a control strategy

reagents, intermediates,

impurities, degradants…

Ames test or in silico methods

Analytical or in silico methods

Lhasa provides a suite of tools

• We work with industry and regulators to provide data and

tools that support safe decision-making

Is the impurity mutagenic?

Is the impurity present in the final API?

What are the potential impurities?

Implement a control strategy

reagents, intermediates,

impurities, degradants…

Ames test or in silico methods

Analytical or in silico methods

Using in silico tools to predict mutagenicity

• ICH M7 supports using 2 complementary in silico predictions in place of an Ames study

• Expert system + statistical system - see Barber, C. Reg. Toxicol. Pharmacol. 2017, 84, 124

• ICH M7 Recommends the use of expert review

• Publications showing the importance, impact and application of expert review

• Establishing best practise in the application of expert review of mutagenicity under ICH M7.

Barber, C.., Reg. Toxicol. Pharmacol. 2015, 73, 367

• Use of in silico systems and expert knowledge for structure-based assessment of potentially

mutagenic impurities. Sutter, A.., Reg. Toxicol. Pharmacol. 2013, 67, 39

• Principles and procedures for implementation of ICH M7 recommended (Q)SAR analyses.

Amberg, A.., Reg. Toxicol. Pharmacol. 2016, 77, 13

• See https://www.lhasalimited.org/library/ for papers, posters, and videos…

Undertaking Expert Review

Expert assessment of 2 in silico predictions

A dihalonaphthalene Compound 13

Expert Review

M7 classification

?

A dihalonaphthalene Compound 13

Indicates

confidence in

the prediction

Expert Review

M7 classification

?

https://www.lhasalimited.org/products/sarah-nexus.htm#Confidence

Distinguishing between expert and statistical systems for application under ICH M7 Barber, C. Reg. Toxicol. Pharmacol. 2017, 84, 124

Review the expert predictionINACTIVE

• No alerts

• No misclassified

• Identifies features found in

false negative predictions

• No unclassified• Identifies features not

present in public datasets

• Expert agrees with Derek

Expert Review

M7 classification

?

It's difficult, but important, to make negative predictions.

Williams. Reg. Toxicol. Pharmacol. 2016, 76, 79

Review the statistical prediction

Expert Review

M7 classification

?

Low confidence prediction

• Worth reviewing carefully

Tricyclic aromatics

fire a different Derek

alert (phenanthrenes)

Fires Derek nitro alert

• Positive analogues not relevant• prediction over-ruled by expert

Expert review

• Inactive prediction

• No misclassified features

• Weak positive prediction (6%)

• Activity of compounds in Sarah are associated with other

functional groups that fire alternative Derek alerts.

• Most similar compound gives negative results

Non-mutagen

Class 5

Expert Review

M7 classification

?

An aryl acid chloride Compound 9

Expert Review

M7 classification

?

An aryl acid chloride Compound 9

Expert Review

M7 classification

?

Both positive predictions

are weak – needs

investigation

Review the expert prediction

• Equivocal

• There is evidence both for

and against mutagenicity

• Derek alert warns user that positive Ames is NOT driven by the compound

Expert Review

M7 classification

?

Specific comment that activity is dependent

upon the solvent used. Mechanism that

creates the active species is described

Review the statistical prediction

Expert Review

M7 classification

?

• Low confidence prediction

• Worth reviewing carefully

• Tricyclic aromatics fire

a different Derek alert

(phenanthrenes)

• Fires Derek nitro alert

• Closest analogues are active for other reasons - they do not support a positive prediction

• No hypothesis

for acid chloride

Expert review

Non-mutagen

Class 5

Expert Review

M7 classification

? • Positive prediction with equivocal reasoning for acid halide

• DMSO-dependent activity observed for this class

• Observed activity will depend upon solvent NOT compound

• Weak positive prediction

• Positive compounds can be explained by presence of other

groups

• Recommend retesting in a non-reactive solvent

• Predict this will be inactive

Bis aniline ether Compound 10

Expert Review

M7 classification

?

Compound 10

Expert Review

M7 classification

? Conflicting predictions

Review the expert prediction

Negative prediction made

• Derek predicts inactive (and explains why)

Expert Review

M7 classification

?

Near-miss to alert 351 which defines the electronics

of a para substituent needed for activity

Review the statistical prediction

Expert Review

M7 classification

?

Low confidence prediction

• Worth reviewing carefully

Similar compounds show

different activities (activity cliff)

A close negative

analogue…

• Weak prediction – likely to be close to activity cliff• Conservatively - insufficient evidence to class as negative

Positive hypothesis

for aromatic amines

…and has been

tested in 5 strains

Expert review

Mutagen

Class 3

Expert Review

M7 classification

?

• Conservatively classified as positive

• Expert review noted that a negative result is likely

• Inactive prediction

• No misclassified features

• Near-miss of alert 351 for aromatic amine

• Positive but low confidence

• The compounds most similar have mixed Ames results

• Positive compounds do not have any additional toxicophores

• Insufficient data to dismiss a positive prediction

Accuracy of expert review + in silico predictions

• The reproducibility of the Ames study has been reported as ~85%

• Mutagenesis 2009, 24, 359; J. Chem. Inf. Model. 2009, 49, 2077

• Expert review + 2 in silico systems are reported to give an accuracy > 90%

• Sutter.. Regul. Toxicol. Pharmacol. 2013, 67, 39

• In silico predictions have identified false positive Ames results

• Gunther. Reg Pharm Tox 2017, 91, 68

• Expert review of any Ames result is important

• Purity : “..highly potent mutagens such as aromatic nitro impurities could cause a

positive Ames result if present ..at levels as low as 0.00002%”

• GLP testing in 5 strains to OECD standards

Summary

• In silico systems should support the user

• ‘Hard’ predictions require more expert review

• Use all supporting evidence

• Confidence in each prediction?

• Do ‘similar’ analogues alert for different reasons?

• Strain data of key negative analogues?

• Take a conservative approach

• If not sure, test or rely on a purge argument

Hard Examples

Low confidence

Mis- or unclassified

Poor coverage of

important fragments

Own knowledge /

proprietary data disagrees

Conflicting predictions

Equivocal or no prediction

Activity cliff

Thank you ありがとうご

Head office in Leeds, UKNot-for-profit

Educational charity

A membership organisation

Data & knowledge sharing

Honest broker

Sponsor

PhDs

Teaching

lecturesWork

experienceAcademic

Agrochem

Biotech

Chemical

CROCosmetic

Generics

Personal Products

Pharma

Government

Tobacco

MIP-DILI

Regulators &

Governmental Agencies(38 are members of Lhasa)

Proprietary data mining

Predictive software

(expert & machine learnt)

Purge

Toxicity Metabolism

Degradation

Undergrad

projects

Publications &

presentations

eTRANSAFE

eTOX

FDA NIHSPMDA

MHRAUSP

Skills of an expert or an expert team 専門家や専門家チームのスキル

DrugMetabolist

Chemist化学者

Toxicologist毒物学者

Chemicalreactivity

Similarity

Chemicalstructure

Impurityprofile

Reactivemetabolites Metabolic

activationMetabolicprofile

(Q)SAR

Protocol and limitations of Ames assay

Mechanismsof activity

Analyticalchemistry

Functionalgroups

Processchemistry

Interpretation of strain data

How in silicosystems workstrengths/limitations

Supporting data

Where to focus