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

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 • Expert Vitic Review • Positive data for benzyl azide and derivatives M7 classification

M7 Classification – Example 3 ? Expert Review Class 3 Alerting structure M7 classification

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

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

Review high level predictions ? Expert Review M7 classification

Review the expert prediction ? Expert Review M7 classification

Review the expert prediction ? Expert Review M7 classification

Review the statistical prediction ? Expert Review M7 classification

Review the statistical prediction ? Expert Review M7 classification

Review the statistical prediction ? Expert Review M7 classification

Review the statistical prediction ? Expert Review M7 classification

Review the statistical prediction ? Expert Review M7 classification

Expert review ? • 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 Expert • Review Sarah Nexus identifies a positive hypothesis for aromatic amine which is overruled by nearest neighbours • There are two nearest neighbours that are particularly M7 relevant in terms of electronics on the aromatic ring classification • 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

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

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 • Expert There is are two relevant examples which are positive Review and most appropriate for read across • Other compounds with similar electronics give mixed results M7 classification • 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.

M7 Classification – Example 4 ? Expert Review Class 3 Alerting structure* M7 classification *However there is potential for compounds of this type to return a negative result in the Ames test

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

Example 5 Tropolone tosylate 38768-08-0

Review high level predictions ? Expert Review M7 classification

Review the expert prediction ? Expert Review M7 classification

Review the statistical prediction ? Expert Review M7 classification

Review the statistical prediction ? Expert Review M7 classification

Review the statistical prediction ? Expert Review M7 classification

Expert review ? • Inactive with no misclassified or unclassified features • Equivocal prediction • No hypothesis identified • Activity of nearest neighbours is associated with Expert structural features enabling them as alkylating agents Review • Parent alcohol and sulfonic acid are negative examples in the training set M7 classification

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

M7 Classification – Example 5 ? • Derek inactive prediction • Inactive prediction with no misclassified or unclassified features • Sarah equivocal prediction • Equivocal prediction overruled as positive examples Expert are not relevant and parent compounds are negative Review examples in the training set M7 classification

M7 Classification – Example 5 ? Expert Review Class 5 No alerts or alerting with sufficient data to demonstrate lack of mutagenicity M7 classification

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

Example 6 2-phenylsulfanylaniline 1134-94-7

Review high level predictions ? Expert Review M7 classification

Review the expert prediction ? Expert Review M7 classification

Review the expert prediction • Candidate for alert 351 • Thiol group too large and may not be cleaved • Steric hindrance at N atom ? Expert Review M7 classification

Review the statistical prediction ? Expert Review M7 classification

Review the statistical prediction ? Expert Review M7 classification

Expert review ? • 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 • Expert Identifies a positive hypothesis for the aromatic amine • Review Some similar compounds to the query in terms of electronics – all positive and activate alert 251 as substitution not in the ortho-position M7 classification

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

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 • Expert Sarah positive prediction Review • Positive supporting compounds have the same electronic environment as query • No data for this type of ortho-substitution relating to M7 steric influence classification The lack of knowledge around this type of substitution of an aromatic amine makes it difficult to accept the negative prediction from Derek Nexus. Examples in Sarah Nexus support positive result.

M7 Classification – Example 6 ? Expert Review Class 3 Alerting structure M7 classification

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

Example 7 1-(4-hydroxyphenyl)prop-2-en-1-one 95605-38-2

Review high level predictions ? Expert Review M7 classification

Review the expert prediction ? Expert Review M7 classification

Review the expert prediction ? Expert Review M7 classification

Review the expert prediction ? Expert Review M7 classification

Review the statistical prediction ? Expert Review M7 classification

Review the statistical prediction ? Expert Review M7 classification Most examples are aromatic substituted at beta-carbon which Derek Nexus expects to be negative

Review the statistical prediction ? Expert Review M7 classification No protocol information available for the example

Expert review ? • 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 Expert Review • Negative prediction • Negative compounds mostly have an aryl substituent at the C3 position M7 • Most similar compound is negative, however there is no classification protocol information

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

M7 Classification – Example 7 ? • Derek plausible prediction • No data to support overturning the prediction • Sarah negative prediction • Many supporting examples are not relevant Expert Review M7 classification

M7 Classification – Example 7 ? Expert Review Class 3 Alerting structure M7 classification

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

Example 8 4-(2-bromoacetyl)benzonitrile 20099-89-2

Review high level predictions ? Expert Review M7 classification

Review the expert prediction ? Expert Review M7 classification

Review the expert prediction 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 Expert Review • 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 M7 not observed when using acetone as the solvent [Azuma et classification al. ].

Review the statistical prediction ? Expert Review M7 classification

Review the statistical prediction ? Expert Review M7 classification Relevant supporting negative example Contain additional toxicophore

Review Additional Information ? Expert Review Relevant examples not included in the Sarah Nexus training set due to mixed activity in TA100 M7 classification 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.