Jack Leitmeyer
Director, Adverse Experience Information
Management
Worldwide Product Safety
Merck & Co., Inc.

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Compliance with Government Laws and Regulations
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Timely and Accurate Monitoring of the Safety Profile of Products
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Limitation of human data in clinical trials
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Small study populations
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Restricted enrollment
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Limited long term safety data
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Widespread use of the product in the post-marketing environment
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Benefit–risk safety profile changes over time

Adverse Experience Reporting to FDA
Pre-Approval - To IND
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7 calendar day reports (telephone or facsimile)
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Unexpected fatal or life-threatening experience associated with the use of the drug
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15 calendar day reports to IND
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From All Studies Worldwide (Serious, Drug-Related and Unexpected)
Findings from tests in laboratory animals suggesting a significant risk to humans (mutagenicity, teratogenicity, carcinogenicity)
Spontaneous Reports from Marketing Outside the U.S. (Serious and
Unexpected)
Reports in the scientific literature including unpublished manuscripts
(Serious and Unexpected)
Reports from foreign regulatory authorities (Serious and Unexpected)
Annual IND reports
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From Studies Worldwide (Serious)

Adverse Experience Reporting to FDA
Post-Approval - To IND
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15 calendar day reports to IND
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From IND Studies (Serious, Drug-Related and
Unexpected)
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Annual IND Report
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From IND Studies (Serious)
Post-Approval - To NDA
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15 calendar day reports to NDA
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From All Studies Worldwide (Serious, Drug-Related and Unexpected)
Spontaneous Reports Worldwide (Serious and Unexpected)
Periodic Reports to NDA

21 CFR 312.44
Phase 1, 2 or 3
(b)(1)(vii) “The sponsor fails promptly to investigate and inform the Food and Drug Administration and all investigators of serious and unexpected adverse experiences in accordance with part 312 section 32 or fails to make any other report required under this part.”

21 CFR 314.80 (K)
“If an applicant fails to establish and maintain records and
make reports required under this section FDA may
withdraw approval of the application and, thus, prohibit continued marketing of the drug product that is the subject of the application.”

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Product
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People
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Call Center
Data Mining
Applications
Clinical (MedDRA) /
Drug Dictionaries
Reports / Queries
AE database
Regulatory
Submission database
Investigator Portal
Clinical Trial data
Imaging System
Product Labeling
Clinical Literature
Clinical Risk Mgt.
Regulatory Agencies
Business Partners

Role of the AE Information Professional o Helpful Experience:
• Clinical terminology
• Worldwide safety regulations
• Technology
• Six Sigma Methodology

Role of the AE Information Professional o Safety Database Oversight o Reference Data Management o Document Management o Dictionary Management o Queries / Reports o Quality Control

Role of the AE Information Professional o Safety Database Oversight
• Information moving electronically between business partners and regulatory agencies
• Managing large datasets (over a million episodes)
• Mapping data fields across systems
• What data are required by safety department and regulatory agencies
• Algorithms for information flow
– Routing algorithms for data entry
– Routing to countries / agencies / business partners
– Rules for reportability

Role of the AE Information Professional o Safety Database Oversight – ICH E2B
• ICH = International Conference on Harmonization
• ICH E2B - Standardized essential data elements for electronic transmission of individual case safety reports:
1. Patient characteristics
2. Reactions/Events
3. Results of tests and procedures relevant to investigation of patient
4. Drug(s) Information (e.g., status, generic, tradename, marketing authorization number)
5. Narrative Case Summary (e.g., case summary, sender’s opinion of overall diagnosis/syndrome or reclassification of reporter terms)

Role of the AE Information Professional o Reference Data Management
• Clinical Trial protocol and site numbers
• Allocation schedules
• Drug formulations
• Routes of administration
• Country Lists
• NDA / IND numbers
• Journal Titles
• etc.

Role of the AE Information Professional o Document Management
• Record Retention Policy
• “Official” Files – paper / electronic records
• Patient Privacy
• Access to shared procedures
• Access to training material

Role of the AE Information Professional o Dictionary Management
• Medical Dictionary for Drug Regulatory
Activities (MedDRA*)
• Company procedures related to global standard dictionary
• Feedback to MedDRA Maintenance and
Support Services Organization (MSSO)
• Participation in Industry User Group
• Drug Dictionary
* MedDRA® is a registered trademark of the International Federation of
Pharmaceutical Manufacturers and Associations (IFPMA).

Role of the AE Information Professional o Queries / Reports
• Provide output for monitoring product safety and responding to safety questions.
• Ensure proper validation and testing (21 CFR Part 11)
• Information Specialist can provide input on:
• What data fields are available ?
• Search all versions, latest versions, or latest completed versions?
• Have the data values changed over time as regulations, procedures, and databases have changed ?
• What MedDRA terms / term groupings should be used to query the database ?
• What is the best format for the output?
• What is correct skill set required for writing and executing database queries?

Role of the AE Information Professional o Quality Control
• Data Entry sampling
• Coding Review
• Electronic submission tracking
• Compliance monitoring

o Evolving Regulations o Global Harmonization o Electronic Transfer of Data o Links to External Databases o Data Mining