ICH M7 Expert Review Examples Dr. William Drewe Principal Global - - PowerPoint PPT Presentation

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ICH M7 Expert Review Examples Dr. William Drewe Principal Global - - PowerPoint PPT Presentation

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ICH M7 Expert Review Examples Dr. William Drewe Principal Global Alliance Manager will.drewe@lhasalimited.org Introduction 8 example compounds with varying expert rule-based and statistical-based results Derek and Sarah results will be

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ICH M7 Expert Review Examples

Principal Global Alliance Manager

will.drewe@lhasalimited.org

  • Dr. William Drewe
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Introduction

  • 8 example compounds with varying expert rule-based

and statistical-based results

  • Derek and Sarah results will be presented
  • You will be asked to assess each example and vote

accordingly

  • Lhasa will then present an expert call*

*All expert calls made on the examples are solely the opinion of experts at Lhasa Limited and are made here for guidance purposes only

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Likely to conclude positive Very strong evidence would be needed to overturn both predictions Uncertain Likely to conclude positive without strong evidence to

  • verturn a positive

prediction Likely to conclude positive Lack of a second prediction suggests insufficient evidence to draw any other conclusion System 1 System 2 Positive Positive Positive O.O.D. or equivocal Positive Negative Negative O.O.D. or equivocal Negative Negative Uncertain

Conservatively could assign as positive. May conclude negative with strong evidence showing feature driving a ‘no prediction’ is present in the same context in known negative examples (without deactivating features)

Likely to conclude negative Expert review should support this conclusion – e.g. by assessing any concerning features (misclassified, unclassified, potentially reactive..)

O.O.D. = out of domain

Establishing best practise in the application of expert review of mutagenicity under ICH M7 Regulatory Toxicology and Pharmacology 2015, 73, 367-377

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What kind of arguments can be used?

  • Adequate Ames data available
  • Ames test does not assess the hazard caused by the

compound class adequately

  • Toxicophore identified by one system has not been

adequately assessed by the other

  • Toxicophore identified is not causative of activity
  • Nearest neighbours are not adequately similar to support

prediction

  • Data available for nearest neighbours is not of sufficient

quality to support prediction

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Examples

  • Example 1
  • Example 2
  • Example 3
  • Example 4
  • Example 5
  • Example 6
  • Example 7
  • Example 8
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Example 1

3-chlorophthalide 6295-21-2

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Review high level predictions

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Expert Review M7 classification

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Review the expert prediction

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Expert Review M7 classification

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Review the expert prediction

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Expert Review M7 classification

  • Alkyl halides are electrophilic species that are capable of

directly alkylating DNA

  • Evidence against benzyl halides being active in the

Ames test:

  • Give a cytotoxic response
  • Lack of mutagenicity of secondary benzyl halides

has been attributed to extra stability of the benzyl carbocation and formation of unstable DNA adducts which spontaneously cleave prior to replication

  • Cyclic alkyl halides are less mutagenic
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Review the statistical prediction

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Expert Review M7 classification

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Review the statistical prediction

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Positive hypothesis is identified for alkyl chlorides

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Review the statistical prediction

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Expert Review M7 classification

Supporting training set examples contain a variety of alkyl chlorides including benzyl derivatives No examples with a similar substitution pattern compared to the query compound

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Expert review

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Expert Review M7 classification

  • Alert 027 for alkyl halides fires
  • Evidence to suggest that secondary benzyl

derivatives may not be active in the Ames test

  • Positive hypothesis identified for alkyl

chlorides

  • No negative examples with a similar

substitution pattern

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Please make your Selection

a) Class 3 – Alerting structure b) Class 5 – No alerts or alerting with sufficient data to demonstrate lack of mutagenicity c) Unsure

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M7 Classification – Example 1

  • Derek plausible prediction
  • Alerts 027 for alkyl halides fires
  • No strong evidence to overturn the Derek prediction
  • Sarah positive prediction
  • Positive hypothesis identified for alkyl chlorides
  • No negative examples with a similar substitution

pattern to support overturning the prediction

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Expert Review M7 classification

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M7 Classification – Example 1

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Expert Review M7 classification

Class 3

Alerting structure

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Examples

  • Example 1
  • Example 2
  • Example 3
  • Example 4
  • Example 5
  • Example 6
  • Example 7
  • Example 8
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Example 2

N-(4-bromo-phenyl)-benzene-1,2-diamine 100953-52-4

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Review the expert prediction

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Review the expert prediction

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  • Candidate for alert 351 (aromatic amine or amide)
  • Phenyl substitution of secondary amine excluded and electron

withdrawing group present on the aromatic ring is deactivating

  • Primary amine group does not activate due to ortho aromatic amine

substitution which may cause steric hindrance

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Review the statistical prediction

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Review the statistical prediction

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Positive hypothesis is identified for aromatic amines. However, is overruled by the nearest neighbours mostly giving negative results.

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1st example may help dismiss the first aromatic

  • amine. With it being the free amine and having the

same substitution pattern.

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Good strain data for example 1

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4th example (negative) is para substituted rather than ortho substituted.

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Review the statistical prediction

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Good strain data for example 4

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Review the statistical prediction

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7th example is also para substituted and positive. However, it also contains a nitro group.

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Expert review

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  • Negative with no misclassified or unclassified

features

  • Near miss of alert 351
  • Exclusion based on limitations in substitution

allowed on second amine group in ortho diamines

  • Positive hypothesis for aromatic amine
  • verruled by nearest neighbours
  • 2 negative nearest neighbours are relevant

and electronically similar to both amines in query structure

  • Data lacking for ortho-substituted aromatic

amines

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Please make your Selection

a) Class 3 – Alerting structure b) Class 5 – No alerts or alerting with sufficient data to demonstrate lack of mutagenicity c) Unsure

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M7 Classification – Example 2

  • Derek inactive prediction
  • Exclusion from alert 351 based on steric hindrance

around aromatic amine

  • Query compound may adopt a conformation with less

steric hindrance and potential to intercalate

  • Sarah positive prediction
  • Two most similar relevant examples are negative
  • No data for this type of ortho-substitution relating to

steric influence

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Expert Review M7 classification

While there is limited data available relating to this type

  • f ortho-substitution of an aromatic amine, the same

substitution in the para position gave negative results. No need to overturn Derek and/or Sarah.

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M7 Classification – Example 2

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Expert Review M7 classification

Class 5

No alerts or alerting with sufficient data to demonstrate lack of mutagenicity

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Examples

  • Example 1
  • Example 2
  • Example 3
  • Example 4
  • Example 5
  • Example 6
  • Example 7
  • Example 8
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Example 3

N-(4-azidosulfonylphenyl)acetamide 2158-14-7

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Review the statistical prediction

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Training set does not include any example covering the sulfonyl azide fragment

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Review the statistical prediction

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By replacing the outside domain sulfonyl azide fragment by an azidomethyl fragment, a positive prediction was reported matching the existing azide hypothesis

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Additional Information – Vitic

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No Ames data available for N-(4-Azidosulfonylphenyl)acetamide (OOD)

  • r for N‐(4‐(Azidomethyl)phenyl)acetamide (predicted positive).

For the 1st nearest neighbour to N‐(4‐(Azidomethyl)phenyl)acetamide: Benzyl azide 622-79-7 (most relevant example), positive results observed in TA100+S9. Overall calls from various datasets for 622-79-7: Positive Ames data were reported for various benzyl azide derivatives.

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Expert review

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  • Plausible prediction
  • Fires alert 318 for Azide, hydrazoic acid or azide

salt

  • Out of domain sulfonyl azide fragment
  • Sarah does have a positive hypothesis for

azides

  • Benzyl azide and various derivatives are

positive

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Please make your Selection

a) Class 3 – Alerting structure b) Class 5 – No alerts or alerting with sufficient data to demonstrate lack of mutagenicity c) Unsure

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M7 Classification – Example 3

  • Derek plausible prediction
  • No reason to doubt
  • Sarah out of domain
  • OOD due to sulfonyl azide fragment
  • Positive hypothesis for azides
  • Vitic
  • Positive data for benzyl azide and derivatives

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M7 Classification – Example 3

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Class 3

Alerting structure

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Examples

  • Example 1
  • Example 2
  • Example 3
  • Example 4
  • Example 5
  • Example 6
  • Example 7
  • Example 8
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Example 4

4-tert-butyl-2-fluoroaniline 129373-04-2

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Review the expert prediction

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Review the expert prediction

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Review the statistical prediction

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Review the statistical prediction

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Review the statistical prediction

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Review the statistical prediction

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Review the statistical prediction

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Expert review

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  • Inactive with no misclassified or unclassified features
  • Exclusion based on electronics relating to halogenated anilines

being deactivated towards nitrenium formation

  • Some evidence that halogen and methyl substitution are also

negative

  • Sarah Nexus identifies a positive hypothesis for

aromatic amine which is overruled by nearest neighbours

  • There are two nearest neighbours that are particularly

relevant in terms of electronics on the aromatic ring

  • One of these compounds is similar enough to the query

compound to make the result hard to dismiss

  • Analysis of detailed data reveals a number of alkyl

fluorinated aromatic amines with positive results as well as other alkyl halide substituted amines

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Please make your Selection

a) Class 3 – Alerting structure b) Class 5 – No alerts or alerting with sufficient data to demonstrate lack of mutagenicity c) Unsure

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M7 Classification – Example 4

  • Derek inactive prediction
  • Exclusion from alert 352 based on a good argument
  • Sarah negative prediction
  • Nearest neighbours to query compound activating

aromatic amine hypothesis mostly negative

  • There is are two relevant examples which are positive

and most appropriate for read across

  • Other compounds with similar electronics give mixed

results

  • The positive results for the nearest neighbours cannot be

ignored and as a result the negative predictions from both Derek Nexus and Sarah Nexus cannot be accepted.

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M7 Classification – Example 4

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Expert Review M7 classification

Class 3

Alerting structure* *However there is potential for compounds of this type to return a negative result in the Ames test

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Examples

  • Example 1
  • Example 2
  • Example 3
  • Example 4
  • Example 5
  • Example 6
  • Example 7
  • Example 8
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Example 5

Tropolone tosylate 38768-08-0

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Review the statistical prediction

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Review the statistical prediction

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Review the statistical prediction

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Expert review

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  • Inactive with no misclassified or unclassified features
  • Equivocal prediction
  • No hypothesis identified
  • Activity of nearest neighbours is associated with

structural features enabling them as alkylating agents

  • Parent alcohol and sulfonic acid are negative examples

in the training set

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Please make your Selection

a) Class 3 – Alerting structure b) Class 5 – No alerts or alerting with sufficient data to demonstrate lack of mutagenicity c) Unsure

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M7 Classification – Example 5

  • Derek inactive prediction
  • Inactive prediction with no misclassified or

unclassified features

  • Sarah equivocal prediction
  • Equivocal prediction overruled as positive examples

are not relevant and parent compounds are negative examples in the training set

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M7 Classification – Example 5

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Class 5

No alerts or alerting with sufficient data to demonstrate lack of mutagenicity

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Examples

  • Example 1
  • Example 2
  • Example 3
  • Example 4
  • Example 5
  • Example 6
  • Example 7
  • Example 8
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Example 6

2-phenylsulfanylaniline 1134-94-7

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  • Candidate for alert 351
  • Thiol group too large and may not be cleaved
  • Steric hindrance at N atom
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Review the statistical prediction

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Expert review

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Expert Review M7 classification

  • Inactive with no misclassified or unclassified features
  • Near miss of alert 351
  • Exclusion based on sterics relating to ortho-substitution rather

than electronics

  • Evidence for this class is limited
  • Identifies a positive hypothesis for the aromatic amine
  • Some similar compounds to the query in terms of

electronics – all positive and activate alert 251 as substitution not in the ortho-position

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Please make your Selection

a) Class 3 – Alerting structure b) Class 5 – No alerts or alerting with sufficient data to demonstrate lack of mutagenicity c) Unsure

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M7 Classification – Example 6

  • Derek inactive prediction
  • Exclusion from alert 351 based on steric hindrance

around aromatic amine

  • Query compound may adopt a conformation with less

steric hindrance and potential to intercalate

  • Sarah positive prediction
  • Positive supporting compounds have the same

electronic environment as query

  • No data for this type of ortho-substitution relating to

steric influence

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Expert Review M7 classification

The lack of knowledge around this type of substitution

  • f an aromatic amine makes it difficult to accept the

negative prediction from Derek Nexus. Examples in Sarah Nexus support positive result.

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M7 Classification – Example 6

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Expert Review M7 classification

Class 3

Alerting structure

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Examples

  • Example 1
  • Example 2
  • Example 3
  • Example 4
  • Example 5
  • Example 6
  • Example 7
  • Example 8
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Example 7

1-(4-hydroxyphenyl)prop-2-en-1-one 95605-38-2

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Review the expert prediction

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Review the expert prediction

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Review the expert prediction

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Review the statistical prediction

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Review the statistical prediction

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Most examples are aromatic substituted at beta-carbon which Derek Nexus expects to be negative

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No protocol information available for the example

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Expert review

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  • Plausible prediction – fires alert 664 for alpha, beta-

unsaturated compounds

  • Mutagenicity related to electronegativity and steric hindrance

around the double bond

  • Aryl substituents at C3 are typically negative or have reduced

activity

  • Negative prediction
  • Negative compounds mostly have an aryl substituent at

the C3 position

  • Most similar compound is negative, however there is no

protocol information

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Please make your Selection

a) Class 3 – Alerting structure b) Class 5 – No alerts or alerting with sufficient data to demonstrate lack of mutagenicity c) Unsure

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M7 Classification – Example 7

  • Derek plausible prediction
  • No data to support overturning the prediction
  • Sarah negative prediction
  • Many supporting examples are not relevant

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M7 Classification – Example 7

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Expert Review M7 classification

Class 3

Alerting structure

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Examples

  • Example 1
  • Example 2
  • Example 3
  • Example 4
  • Example 5
  • Example 6
  • Example 7
  • Example 8
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Example 8

4-(2-bromoacetyl)benzonitrile 20099-89-2

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Review the expert prediction

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Derek Nexus does contain alert for the mutagenicity of alkyl halides (alert 027) Review of alert comments:

  • Primary alpha-halo ketones are excluded from alert due to

their inactivity in the Ames test

  • Additionally, studies suggest that some phenacyl bromides

may be oxidised by the DMSO solvent to afford mutagenic phenylglyoxals, which give rise to positive responses that are not observed when using acetone as the solvent [Azuma et al.].

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Review the statistical prediction

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Contain additional toxicophore Relevant supporting negative example

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Review Additional Information

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Relevant examples not included in the Sarah Nexus training set due to mixed activity in TA100 The Ames results of these compounds have been published [Azuma et al.], where it was found that the presence of DMSO resulted in phenacyl bromides being mutagenic.

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Expert review

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Expert Review M7 classification

  • Predicted to be inactive
  • No misclassified or unclassified features
  • Alpha-halo ketones are excluded from an alert
  • Phenacyl bromides can produce negative results in the

Ames test in the absence of DMSO

  • Positive hypothesis identified for alkyl bromides
  • Most relevant example is non-mutagenic in the Ames test
  • Relevant examples that do exist that have conflicting data. The

conflicting data occurs as the Ames test results for phenacyl bromides depend on the solvent system used

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Please make your Selection

a) Class 3 – Alerting structure b) Class 5 – No alerts or alerting with sufficient data to demonstrate lack of mutagenicity c) Unsure

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M7 Classification – Example 8

  • Derek inactive prediction
  • Expert comments in the knowledge base indicate that

phenacyl bromides are non-mutagenic in the Ames test

  • Sarah positive prediction
  • Positive hypothesis identified for alkyl bromides
  • Relevant example is non-mutagenic and support
  • verturning the prediction

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M7 Classification – Example 8

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Class 5

No alerts or alerting with sufficient data to demonstrate lack of mutagenicity

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Examples

  • Example 1
  • Example 2
  • Example 3
  • Example 4
  • Example 5
  • Example 6
  • Example 7
  • Example 8
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Thank You