SAE Reconciliation How to handle

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SAE ReconciliationHow to handle a waterfall of
SAEs?

• Albert Hage
• Astellas Pharma Europe BV
• The Netherlands

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How to reconcile this?
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Topics

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

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Astellas Pharma Europe

• European RD centre in Leiderdorp, The
  Netherlands
• Organization of 350 employees
• Broad spectrum of departments covering RD
• Our therapeutic focus
• Urology
• Transplantation
• Dermatology
• Anti-infectives
• Cardiovascular
• Oncology
• Diabetes
• CNS

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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

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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 Patients last visit according the
  study protocol

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Overview of the process

• Two departments are involved
• Drug Safety and Pharmacovigilance
• Clinical Data Science Data Management section

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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)

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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

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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

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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

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SAE Reconciliation Plan
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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

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CIOMS Form
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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

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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

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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

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SAE Reconciliation Plan
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Line listings
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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

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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)

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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?
• Manufacturers and/or Investigators causality to
  Study Drug is Possible or Probable

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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

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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

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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

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Questions
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Discussion topic

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