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 focusUrologyTransplantationDermatologyAnti-infectivesCardiovascularOncologyDiabetesCNS

5

Astellas Pharma Europe

Clinical Data Science DepartmentEDC and CDS SupportData ManagementClinical ProgrammingBiostatistics

Currently we have a staff of more than 50 people of 14 nationalities

We are responsible for all Ph. I – IV studies in EuropeProviding scientific input into clinical drug development plans, synopses and

protocolsCollection, cleaning, analysis and reporting of clinical data from clinical studiesData pooling and integrated analyses to support regulatory submissions

6

Definition

A serious AE is any untoward medical occurrence that at any dose

Results in deathIs life threateningResults in persistent or significant disability/incapacityResults in congenital anomaly, or birth defectRequires 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 significantClinical: Patient’s last visit according the study protocol

7

Overview of the process

Two departments are involved

Drug Safety and PharmacovigilanceClinical Data Science – Data Management section

8

Overview of the process - DSP

SAE data is collected in Safety DatabaseVia SAE Report Form and data entry

Data validation100% check of entered items

Medical reviewMedical evaluationMedDRA coding of event

FinalizationAsk for follow-up informationLock 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 moduleVia CRF and double data entryOr Directly via EDC

Data cleaning will be performed

According to Data Validation SpecificationsQuery handling processMedDRA coding of eventMedical 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 SOPCreate Data Management Plan

Working Practice DocumentDMP Module 2: Enter and validate study data

SAE Reconciliation process is described Appendix 4List 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 availableWe have an approved SAE Reconciliation Plan

12

SAE Reconciliation Plan

13

Initial process

Timing is near the end of a studyData in both databases have been cleaned CIOMS forms from DSP will be retrievedManual comparison of CIOMS forms with Clinical DatabaseDiscrepancies will be queried by DMThe Site will answer the QueryDM 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 DatabaseBoth 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 SAEsWe 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 asTransplantationOncologyCV in patients undergoing surgery

And these indications have loads of SAEs

Transplantation: 1000-1500/1000 patientsOncology: 20/40 patientsCV: 100/1000 patients

17

Intermediate solution

How to handle this?

We have looked how it was done at our Transplantation Unit siteBroaden the range of acceptanceLimited the number of items to be reconciledReceive weekly line listings (excel) from Safety database instead of CIOMS

formsPerform an ongoing reconciliation, which starts directly after DM cleaning

processOngoing final check and mark patients when reconciledAll 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 timelinesTiming 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 processDifficult to control changesVery 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 DatabaseLink the SAE data of the EDC Clinical Database with the Safety Database

To support computerized reconciliation checksNew changes in both databases can be spotted immediatelyPreferably 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 TeamMake 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.EventStart DateStop DateRelationship/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 databasesCombined DSP/DM training for Investigators, Monitors and DSOsCoordination needed to limited the number of Queries to the sitesUse the information of the other database for updates

Possible faster reporting of SAEs in EDC system than in Safety databaseReconciliation process should wait until DSP has finalized their processPossibility 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 systemsWill be a critical success factor

Process

Global process is neededTendency 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.EventStart DateStop DateRelationship/Causality

And:

For related SUSARs only