Handling and reconciliation of SAE data: a CRO perspective

1. Gerald Ruiter, Senior Data Manager & Drug Safety Officer IATEC BV, Amsterdam, The Netherlands Handling and reconciliation of SAE data: a CRO perspective

2. Position of CRO: • Different clients with different specific requirements regarding handling and reconciliation of SAE Data: • Third Party Service Provider or • Sponsor

3. IATEC clients • “Big” Pharmaceutical companies • Phase III-IV, observational studies • “Small” Biotech companies • Number is increasing • Phase II studies

4. IATEC usually acts as third-party service provider Client does not delegate sponsor responsibilities Have their own Drug Safety procedures already at high level Pharmaceutical vs Biotech companies • Sponsor responsibilities are often delegated to IATEC

5. SAE handling often limited to review and forwarding of the SAE report to client. DSO keeps track of SAEs in Excel file Periodically Excel files are sent to client for reconciliation purposes. Pharmaceutical vs Biotech companies • IATEC responsible for complete SAE handling and SUSAR reporting • SAE Management System including SUSAR reporting functionality

6. SAE Management System The increasing number of clients that fully delegate their sponsor requirements with respect to SAE/SUSAR handling increases the urge to use a proper SAE Management System

7. SAE Management System • eSafetyNet • Integrated in IATECs Data Management System (eDM) • Allows electronic and continuously reconciliation between Adverse Events entered in eDM and SAEs entered in eSafetyNet

8. SAE Management System • E2B compliant: electr. SUSAR reporting • Ready to be used within the next couple of months • Until then the reconciliation is performed manually

9. Data Subject to Change SAE Data Collection Drug Safety enters data in SAE database Immediate process Investigator completes SAE report Investigator faxes SAE report Patient experiences SAE Data Management enters data in clinical database Monitor collects CRF Investigator completes CRF Delayed process

10. Manual Reconciliation • Performed on different moments in analogy to the SAE data collection: immediate vs delayed to minimize the chance that the clinical trial database is out of synchronization with the SAE data • Different people involved • Highly dependent on proper communication

11. Immediate reconciliation • The investigator is requested to fax SAE report and following CRF pages (not yet monitored) • - Medical and Medication History • - Adverse Events • - Concomitant medications • - End of study page (if outcome is fatal)

12. Immediate reconciliation • The DSO performs an immediate reconciliation between the faxed SAE report and the • - Medical and Medication History • - Adverse Events • - Concomitant medications

13. Immediate reconciliation • Items checked by DSO: • - Subject details: ID, DOB, Gender • - Diagnosis in SAE report vs AE description on CRF AE Form • - Event on AE Form should be marked as “SAE”” • - Severity • - Start Date / Date of Onset • - Stop Date / Outcome Date

14. Immediate reconciliation • Items checked by DSO (cont’ed): • - Study Medication / Concomitant medication: • Description • Start Date / Stop Date • Indication • Likelihood that SAE was caused by this medication vs relation to study medication on AE form

15. Immediate reconciliation • The SAE report is forwarded to the Study Medical Monitor (SMM, a physician) after the immediate reconciliation has been performed by the DSO. • The SMM performs a review on Medical Plausibility on both the SAE report and the faxed CRF pages.

16. DSO completes section 1 of “DSO form 1”

17. SMM completes section 2 of the “DSO form 1”

18. Immediate reconciliation • CRA is main contact between DSO and investigator • Questions resulting from reconciliation/review by DSO and SMM are sent to investigator via the CRA. • Answers to these questions are sent as follow-up information (updated SAE report and updated CRF pages) • The DSO maintains a tracking of the SAEs and the issues.

19. Delayed reconciliation • During collection of CRF data by CRA • - The CRA will monitor the completed SAE report and the completed CRF pages • - CRF pages are sent to the Data Manager • - Updated SAE reports are sent as Follow-up information to the DSO.

20. Delayed reconciliation • During cleaning process by Data Manager • - The Data Manager is alerted by the query management system in case of: • AE flagged as “SAE” • End of Study Reason: SAE • Fatal Outcome • - The Data Manager will check with the DSO whether the SAE has been reported expedited.

21. Delayed reconciliation • During cleaning process by Data Manager • - The DSO will perform a reconciliation between the SAE database and the clinical database on the following items: • Severity • Start Date / Date of Onset • Stop Date / Outcome Date • - The DSO will notify the Data Manager in case of discrepancies

22. Delayed reconciliation • During cleaning process by Data Manager • - The Data Manager will sent out manual queries to the CRA/investigator • - Updates in clinical database will be performed by Data Manager • - Updates in SAE database will be performed by DSO

23. Delayed reconciliation • Periodically by Medical Monitor • - Safety Data from clinical database is printed on listings • - Part of cleaning process • - The listings are checked for medical plausibility and suspected SAEs (not yet marked as SAEs). • - Questions form the Medical Monitor discussed with Data Manager (and DSO in case of SAE issues) • - If necessary, manual queries will be created by the Data Manager for the CRA/investigator • - Immediate reconciliation will start upon receipt SAE report.

24. Delayed reconciliation • Data Review Meeting • - Safety Data from clinical database and SAE database is printed on listings and discussed during Data Review Meeting (last check by Study Team before DB Lock) • - Action items will be described in the data review meeting minutes • - If necessary, manual queries will be created by the Data Manager for the CRA/investigator • - If necessary, the CRA will request the investigator to complete a SAE report which will be sent to the DSO.

25. DSO enters data in SAE database Data Management enters data in clinical database Summary Check by DSO upon receipt Medical Review by SMM Immediate SAE report and CRF completed by investigator Delayed CRA collects CRF CRA on site Cleaning by DM Medical Review by SMM Data Review Meeting by Study Team

26. Investigator completes a SAE Form Data Data Patient experiences a SAE Data Risk-Benefit

27. Statement: • Despite a good reconciliation process the SAE Data only partly reflects the reality - SAE Form partly captures the patient’s condition (limitation). - Investigator’s opinion (interpretation) - CRA can only rely on source on site (complete?)