SAE Reconciliation How to handle a waterfall of

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

How to reconcile this? 2

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

Astellas Pharma European R&D centre in Leiderdorp, The Netherlands Organization of 350 employees Broad spectrum of departments covering R&D Our therapeutic focus ØUrology ØTransplantation ØDermatology ØAnti-infectives ØCardiovascular ØOncology ØDiabetes ØCNS 4

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

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

Overview of the process Two departments are involved ØDrug Safety and Pharmacovigilance ØClinical Data Science – Data Management section 7

Overview of the process - DSP SAE data is collected in Safety Database ØVia SAE Report Form and data entry Data validation Ø 100% check of entered items Medical review ØMedical evaluation ØMed. DRA coding of event Finalization ØAsk for follow-up information ØLock 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) 8

Overview of the process - DM SAE data is collected in Clinical Database ØSAE data is part of AE data module ØVia CRF and double data entry ØOr Directly via EDC Data cleaning will be performed ØAccording to Data Validation Specifications ØQuery handling process ØMed. DRA coding of event ØMedical review 9

SOP/Working Practice Document SAE Reconciliation is performed by Data Management (with support of DSP) ØFor this we need a SAE Reconciliation Plan Process is embedded in DM SOP ØCreate Data Management Plan ØWorking Practice Document ØDMP Module 2: Enter and validate study data ØSAE Reconciliation process is described ØAppendix 4 ØList 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 10

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

SAE Reconciliation Plan 12

Initial process ØTiming is near the end of a study ØData in both databases have been cleaned ØCIOMS forms from DSP will be retrieved ØManual comparison of CIOMS forms with Clinical Database ØDiscrepancies will be queried by DM ØThe Site will answer the Query ØDM will check the resolved Query and make a judgment ØNo update needed (clarification)/No update possible (re-query) ØClinical Database have to be updated by DM (for paper Queries) ØForward Query/Screenshot EDC to DSP to update the Safety Database ØBoth the Clinical and the Safety Database have to be updated ØPerform a final check shortly prior to Database Soft Lock 13

CIOMS Form 14

Initial process The life of a Data Manager was easy and simple in Leiderdorp ØWe perform a lot of Phase I studies with hardly any SAEs ØWe 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 15

New indications Nowadays life is not so easy any more ØAs we got involved in more difficult indications such as ØTransplantation ØOncology ØCV in patients undergoing surgery And these indications have loads of SAEs ØTransplantation: 1000 -1500/1000 patients ØOncology: 20/40 patients ØCV: 100/1000 patients 16

Intermediate solution How to handle this? ØWe have looked how it was done at our Transplantation Unit site ØBroaden the range of acceptance ØLimited the number of items to be reconciled ØReceive weekly line listings (excel) from Safety database instead of CIOMS forms ØPerform an ongoing reconciliation, which starts directly after DM cleaning process ØOngoing final check and mark patients when reconciled ØAll other processes remains the same 17

SAE Reconciliation Plan 18

Line listings 19

Intermediate solution Feedback ØWith this process we where able to meet tight timelines ØTiming is delicate ØAn early start has the disadvantage of less clean data and a consistent flow of data changes due to other cleaning processes ØWith 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 ØIt is still a manual process ØDifficult to control changes ØVery 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 20

Future process Which improvements can we make? ØSystem interface between EDC system and Safety Database ØLink the SAE data of the EDC Clinical Database with the Safety Database ØTo support computerized reconciliation checks ØNew changes in both databases can be spotted immediately ØPreferably with a tracking tool of outstanding discrepancies and accepted inconsistencies Ø Agree upon a standard set of variables to reconcile for all studies ØCurrently this list is discussed within a Study Team ØMake clear agreements between DM and DSP ØResponsibility for follow-up actions (like missing data) ØTimelines (focus for DSP is reporting; for DM database lock) 21

Future process What are the minimal requirements? ØIs there any regulation or should this be defined per company? ØIs the following item list for reconciliation acceptable? ØStudy No. ØPatient No. ØEvent ØStart Date ØStop Date ØRelationship/Causality ØShould the focus be on related SUSARs only? ØManufacturer’s and/or Investigator’s causality to Study Drug is Possible or Probable 22

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

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

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 25

Questions 26

Discussion topic Only to be reconciled is : ØStudy No. ØPatient No. ØEvent ØStart Date ØStop Date ØRelationship/Causality And: ØFor related SUSARs only 27