Transcript Lhasa ICH M7 Database - Use Cases.ppsx

Lhasa ICH M7 Database – Use Cases
Dr Angela White
Database Overview
SDF upload or add data via interface
Assay data:
-Results +/-S9
- Study number
-Batch numbers
-Positive controls
-Comments section
SAR:
-Derek predictions (automatic)
-QSAR
-In house QSAR predictions
Search via (Q)SAR call
Compound details:
-Structure
-CAS numbers
-Compound name
-Molecular weight
ICH M7 class
Comments stored e.g. expert
opinion/PDE/AI
Lhasa Database
Search via structure
• Exact
• Similarity
• Substructure
Logs origin of each
compound e.g.
degradant, impurity
Search by Data
• By study type
• Endpoint
• Batch number
Word, SDF or Excel export of search results
2
Use Case 1: ICH M7 Compliant Assessment of API
Chemistry
– ICH M7 requires
“...assessment and control of mutagenic impurities that reside or are reasonably expected to reside in final drug
substance or product.”
– To comply with ICH M7, potential sources of impurities i.e. synthetic intermediates, reagents,
degradants need to be assessed.
–
–
–
–
–
Existing mutagenicity data identified
SAR assessment (QSAR and knowledge based tool)
(Q)SAR outcome examined alongside “expert knowledge”
ICH M7 class 1-5 assigned
Identify the need for Ames testing or control
– This database can help with ICH M7 assessments by reducing duplication of effort:
–
–
–
–
–
Holds all (Q)SAR information
Holds mutagenicity/carcinogenicity data
Store ICH M7 class
Store additional information e.g. PDE, expert knowledge assessment
Provides visibility and traceability
3
Tracking ICH M7 Assessments
4
Applying Expert Knowledge
Unclassified Features/Out of Domain Assessments
– For some compounds SAR assessment may need to be supplemented with expert
knowledge e.g. Unclassified features/Out of Domain.
– The database can be used to help answer:
– Do we have structurally similar compounds with Ames data?
– Does the Ames data suggest a risk with my compound?
– Knowledge and ‘expert opinion’ can be stored in the database for future reference
– Visible to all users – no duplication of effort
5
Ames Testing Compounds
– Decide to Ames test compound
– Is the test compound common to another API program?
– What is the impact on the other project if the Ames result is positive?
– Allows tracking of data so risk management plans can be put in place prior to Ames
testing.
6
Preparing an ICH M7 Table for Regulatory Submission
7
Use Case 2: Working in Non-mutagenic Chemical Space
– As the database houses both structural and mutagenicity data it can be a resource for
medicinal chemists
– Search for motif of interest:
–
Exact search – do we have Ames data on this specific fragment?
–
Substructure/similarity search – Do we have Ames data for structurally similar compounds?
–
e.g. which aromatic amine building blocks are Ames negative
– Allows proactive selection i.e. work in lower risk chemical space
8
Concluding Remarks
–
The database allows the tracking and traceability of (Q)SAR assessments and
Genotoxicity data
– Which programs are associated with each compound – understanding the impact of new data
– Prevents duplication of effort:
– External data searches/Ames data captured
– Provides consistency of conclusions – stores expert opinions
– Allows quick access to information and retrieval of information
– Exports can be used as a basis for ICH M7 submissions
– Data can be used by medicinal chemists to support low risk drug design
– Can promote interrogation of data to improve (Q)SAR
– e.g. How many compounds associated with an alert/QSAR call are Ames positive vs Ames
negative?
9