CBER CDISC Test Submission
Dieter Boß
CSL Behring, Marburg
20-Mar-2012
Clinical Studies Referred to in the BLA
• Pivotal US Study
• Interim analysis of another running study
• EU pivotal study
• EU PK study
• Supportive data from study run in the 90ies
• 2 CROs
1. Pivotal study + still running study
2. Mapping of supportive legacy studies
ISS / ISE
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Contents of Submission Datasets Package
• For all studies SDTM domains were created
 Following SDTM IG 3.1.2
• Pivotal study / interim analysis of running study
 conventional analysis datasets
• Integrated Summary of Safety (ISS)
 Data of 3 studies
 Recoding to MedDRA version used in pivotal study
 Analyses partially based on SDTMs of underlying studies
 Analysis datasets according to ADaM 2.1
• Integrated Summary of Efficacy (ISE)
 Data of 2 studies
 Analysis datasets according to ADaM 2.1
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Pre Test Submission Telecon
• Telecon with CBER staff to discuss submission plans
 First question of CBER staff:
Has the analysis been built on the provided SDTMs?
• Open Questions addressed
Submission plan
 SDTMs for all studies
 Conventional analysis datasets analysis of pivotal study
 ADaM compliant datasets for ISS and ISE
Amount of test submissions (3)
Contents of test submission
 (Submission Planning Checklist, SDTM / analysis of 1 study,
reviewers guide, commented Open CDISC validator findings)
• Highly recommended to contact CBER
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Submission Planning Checklist
• Start early!
• Reflects the following information
 CDISC models and their version
 Information on studies submitted
 SDTM domains per study
 Integrated summary datasets
 Analysis datasets for efficacy and safety
 All supplemental qualifier variables
• Template can be found on CBER web site or will be provided by
CBER
• Has to be available for pre-BLA Meeting
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CBER Web Site on CDISC Submissions
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Issues from CBER Review of Submission
Planning Checklist
• Provide deviations domain (were listed as SuppQual to DS
for early terminators)
• Avoid SuppQuals (mainly for DS domain)
-> Use DSTERM for reasons of early termination
• Append codelists, if allowed (SuppQuals had been used to
contain original verbatim text entries)
-> further mapping into standard terms done e.g. for units
• Use timing vars Visit, Visitnum for those CMs that had to be
given on a specific study day
-> agreed that this will not be implemented as CM was collected as
rolling record
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Test Submission – Round 1
• Sent in to CBER via submission gateway
• CBER staff informed via e-mail to make them aware
• 1st time Define Validation failed
 Duplicate ‘Coded Value‘ for some LabTests and Units
 Required Data Types empty (for LBALL, VSALL, PEALL)
 Duplicate ItemDef element (Domain, StudyId, YesNo)
-> Define Validation was not done accurately
 ISO9601 was not listed as external codelist
 Medical coding tables were not listed as external codelists
-> Unsure how to correctly handle this, FDA provided sample
• CSL was requested to resolve issues before further
discussions
• New Define.xml to be provided, no new datasets requested
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Test Submission – Round 2
• Open CDISC Validator findings :
 Sentence case for AEBODSYS, MHBODSYS
-> common issue
 No baseline result available for some subjects in LB, QS, VS
 Missing units for tests having no units
 Missing exposure record for subjects randomized not treated
 ~ENRF/ ~STRF not available if dates were missing
-> due to CRF design
 AE start date after last disposition
-> due to legacy data
-> CBER staff acknowledged our comments/explanation for the above
 Expected variables missing in trial design TATRANS (TA), ARMCD
(TV)
-> had to be corrected
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Time Frame of Test Submission
• 1st test submission 21-Jul-11
• FDA commented on 02-Aug-11
• 2nd test submission 19-Aug-11
• FDA commented on 25-Aug-11
• Formal report received on 07-Sep-11
• Discussion of open issues/questions with FDA
representatives on 20-Sep-11
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Meeting to Discuss Findings with CBER Staff
• Meeting was helpful
• Constructive and easy going
• CBER staff made clear that datasets are sufficient as is
• Recommended changes could be done on our discretion
• Recommendation to explain mapping issues in Validation
and Data Interpretation Report
• Agreed that explanations can be given as comments to
Open CDISC Validator report
-> Validator report was commented and provided
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Issues with eCTD Finalization
• If changes to SDTMs became necessary everything
needed to be re-run to ensure consistency
• Names of directories and files incl. SAS programs
refer to eCTD validation criteria
Only lower case characters, dashes
File extension left as .sas
Standard programs/macros of the CRO had their names
changed to be able to be uploaded in eCTD
• Submitter Validation and Interpretation Report replaced
by commented Open CDISC validator reports
PDF of commented report generated for submission
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Thank you!
Questions?
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