1. SAE Reconciliation How 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 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 Process
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 : And: Study No. Patient No.
Event
Start Date
Stop Date
Relationship/Causality
And:
For related SUSARs only