1. CBER CDISC Test Submission Dieter Boß CSL Behring, Marburg 20-Mar-2012

2. 2 2 4-Sep-15 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

3. 3 3 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 4-Sep-15

4. 4 4 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 4-Sep-15

5. 5 5 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 4-Sep-15

6. 6 6 CBER Web Site on CDISC Submissions 4-Sep-15

7. 7 7 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 4-Sep-15

8. 8 8 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 4-Sep-15

9. 9 9 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 4-Sep-15

10. 10 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 4-Sep-15

11. 11 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 4-Sep-15

12. 12 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 4-Sep-15

13. 13 Thank you! Questions? 4-Sep-15