SAE Reconciliation How to handle ‘a waterfall’ of SAEs? Albert Hage Astellas Pharma Europe BV The Netherlands

How to reconcile this?

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

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

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

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

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

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)

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

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

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

SAE Reconciliation Plan

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

CIOMS Form

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

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

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

SAE Reconciliation Plan

Line listings

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

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)

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

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

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

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

Questions

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