SAE Reconciliation How to handle ‘a waterfall’ of SAEs?

1. SAE ReconciliationHow to handle ‘a waterfall’ of SAEs? Albert Hage Astellas Pharma Europe BV The Netherlands

2. How to reconcile this?

3. Topics • Astellas Pharma Europe • Overview of the process • Initial process • Intermediate solution • Future process • Conclusion • Questions • Discussion topic

4. Astellas Pharma Europe • European R&D centre in Leiderdorp, The Netherlands • Organization of 350 employees • Broad spectrum of departments covering R&D • Our therapeutic focus • Urology • Transplantation • Dermatology • Anti-infectives • Cardiovascular • Oncology • Diabetes • CNS

5. Astellas Pharma Europe • Clinical Data Science Department • EDC and CDS Support • Data Management • Clinical Programming • Biostatistics • Currently we have a staff of more than 50 people of 14 nationalities • We are responsible for all Ph. I – IV studies in Europe • Providing scientific input into clinical drug development plans, synopses and protocols • Collection, cleaning, analysis and reporting of clinical data from clinical studies • Data pooling and integrated analyses to support regulatory submissions

6. Definition • A serious AE is any untoward medical occurrence that at any dose • Results in death • Is life threatening • Results in persistent or significant disability/incapacity • Results in congenital anomaly, or birth defect • Requires in-subject hospitalization or leads to prolongation of hospitalization • Other medically important events An SAE will be followed until • Safety: Resolved or judged to be no longer clinically significant • Clinical: Patient’s last visit according the study protocol

7. Overview of the process • Two departments are involved • Drug Safety and Pharmacovigilance • Clinical Data Science – Data Management section

8. Overview of the process - DSP • SAE data is collected in Safety Database • Via SAE Report Form and data entry • Data validation • 100% check of entered items • Medical review • Medical evaluation • MedDRA coding of event • Finalization • Ask for follow-up information • Lock case and report to authorities within 7 days (fatal and life-threatening) or 15 days (for related non-fatal SUSARs - Serious unexpected suspected adverse drug reactions)

9. Overview of the process - DM • SAE data is collected in Clinical Database • SAE data is part of AE data module • Via CRF and double data entry • Or Directly via EDC • Data cleaning will be performed • According to Data Validation Specifications • Query handling process • MedDRA coding of event • Medical review

10. SOP/Working Practice Document • SAE Reconciliation is performed by Data Management (with support of DSP) • For this we need a SAE Reconciliation Plan • Process is embedded in DM SOP • Create Data Management Plan • Working Practice Document • DMP Module 2: Enter and validate study data • SAE Reconciliation process is described • Appendix 4 • List of items to be reconciled • For each study a DMP Module 2 will be created and signed off by Data Manager, Study Manager and Pharmacovigilance Physician

11. SAE Reconciliation process • The SAE Reconciliation process can start • The data in the Clinical and Safety databases are available • We have an approved SAE Reconciliation Plan

12. SAE Reconciliation Plan

13. Initial process • Timing is near the end of a study • Data in both databases have been cleaned • CIOMS forms from DSP will be retrieved • Manual comparison of CIOMS forms with Clinical Database • Discrepancies will be queried by DM • The Site will answer the Query • DM will check the resolved Query and make a judgment • No update needed (clarification)/No update possible (re-query) • Clinical Database have to be updated by DM (for paper Queries) • Forward Query/Screenshot EDC to DSP to update the Safety Database • Both the Clinical and the Safety Database have to be updated • Perform a final check shortly prior to Database Soft Lock

14. CIOMS Form

15. Initial process • The life of a Data Manager was easy and simple in Leiderdorp • We perform a lot of Phase I studies with hardly any SAEs • We have relative light indications as Urology with a low number of SAEs (10-20/1000 patients) • Due to the low number of SAEs it was manageable to perform SAE reconciliation with this process and not jeopardizing the Database Hard Lock timelines

16. New indications • Nowadays life is not so easy any more • As we got involved in more difficult indications such as • Transplantation • Oncology • CV in patients undergoing surgery • And these indications have loads of SAEs • Transplantation: 1000-1500/1000 patients • Oncology: 20/40 patients • CV: 100/1000 patients

17. Intermediate solution • How to handle this? • We have looked how it was done at our Transplantation Unit site • Broaden the range of acceptance • Limited the number of items to be reconciled • Receive weekly line listings (excel) from Safety database instead of CIOMS forms • Perform an ongoing reconciliation, which starts directly after DM cleaning process • Ongoing final check and mark patients when reconciled • All other processes remains the same

18. SAE Reconciliation Plan

19. Line listings

20. Intermediate solution • Feedback • With this process we where able to meet tight timelines • Timing is delicate • An early start has the disadvantage of less clean data and a consistent flow of data changes due to other cleaning processes • With a late start the workload will shift to the end with a possibility that the process is not finalized on time or the quality is reduced • It is still a manual process • Difficult to control changes • Very time consuming • The process should be made more efficient to handle a high number of SAEs as we are also constantly aiming to reduce the timelines

21. Future process • Which improvements can we make? • System interface between EDC system and Safety Database • Link the SAE data of the EDC Clinical Database with the Safety Database • To support computerized reconciliation checks • New changes in both databases can be spotted immediately • Preferably with a tracking tool of outstanding discrepancies and accepted inconsistencies • Agree upon a standard set of variables to reconcile for all studies • Currently this list is discussed within a Study Team • Make clear agreements between DM and DSP • Responsibility for follow-up actions (like missing data) • Timelines (focus for DSP is reporting; for DM database lock)

22. Future process • What are the minimal requirements? • Is there any regulation or should this be defined per company? • Is the following item list for reconciliation acceptable? • Study No. • Patient No. • Event • Start Date • Stop Date • Relationship/Causality • Should the focus be on related SUSARs only? • Manufacturer’s and/or Investigator’s causality to Study Drug is Possible or Probable

23. Future process • Which contemplations do we have? • Organizational • Information from the ‘source’ will vary gradually in both databases • Combined DSP/DM training for Investigators, Monitors and DSOs • Coordination needed to limited the number of Queries to the sites • Use the information of the other database for updates • Possible faster reporting of SAEs in EDC system than in Safety database • Reconciliation process should wait until DSP has finalized their process • Possibility that in Clinical Database symptoms are reported and only a diagnosis in the Safety Database

24. Future process • Which contemplations do we have? • Technical • Probably manual linking needed of the SAEs in the two database systems • Will be a critical success factor Process • Global process is needed • Tendency is to work more on Global or Trans-Atlantic studies • Process should be feasible to outsource to DM CRO

25. Conclusion • This presentation gave an overview of Astellas’ current process and the way forward we would like to make • We need an efficient SAE reconciliation process which fulfills the need of Clinical, Safety and regulations • We like to use today for discussions on industry best practice • We are looking forward to the outcome of the discussion groups, we have some questions and we would be very happy if we could leave the meeting with the answers

26. Questions

27. Discussion topic Only to be reconciled is : • Study No. • Patient No. • Event • Start Date • Stop Date • Relationship/Causality And: • For related SUSARs only