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Implementation of CDISC Standards at Nycomed Ph. USE, Basel (19 -21 October 2009) Nycomed Implementation of CDISC Standards at Nycomed Ph. USE, Basel (19 -21 October 2009) Nycomed Gmb. H, Dr. B Traub CDISC Implementation at Nycomed 1

Agenda l Background l Clinical Data Warehouse l CDISC implementation l Electronic data submission Agenda l Background l Clinical Data Warehouse l CDISC implementation l Electronic data submission within e. CTD l Conclusions and outlook CDISC Implementation at Nycomed 2

Partnering – Together for medicines that matter Nycomed is actively seeking partnerships – Co-development Partnering – Together for medicines that matter Nycomed is actively seeking partnerships – Co-development from early research on – In-licensing for marketing by Nycomed – Out-licensing where Nycomed is not present CDISC Implementation at Nycomed 3

The R&D Operating Model – contribution of Data Science In-house - State-of-the-art statistical capabilities The R&D Operating Model – contribution of Data Science In-house - State-of-the-art statistical capabilities • - - Data cleaning process and database set-up outsourced (to a large proportion) Flexible data management capacities available for in-house processing as well as for supervision of Data Management CROs - Study specific statistical reporting and generation of analysis data bases outsourced with flexible resources for CRO supervision. For statistical input into protocol and drug development plans Maintenance of standards • Data acquisition • Data integration • - Outsourced Data quality Ensure availability of integrated clinical trial data for pooled analyses (Data Warehouse Development, operation and maintenance) CDISC Implementation at Nycomed 4

Heterogeneous Data Sources l CRO databases – Standardised data based on Nycomed requirements (CDISC Heterogeneous Data Sources l CRO databases – Standardised data based on Nycomed requirements (CDISC SDTM and ADa. M datasets) – Analysis datasets in proprietary format l Data from in-licensing partners – What-ever-they-have structures (now and in future) l Legacy data from two prior companies – What-ever-we-have structures CDISC Implementation at Nycomed 5

Agenda l Background l Clinical Data Warehouse l CDISC implementation l Electronic data submission Agenda l Background l Clinical Data Warehouse l CDISC implementation l Electronic data submission within e. CTD l Conclusions and outlook CDISC Implementation at Nycomed 6

Clinical data warehouse / Nycomed Business scope Clinical Trial Data is the assets of Clinical data warehouse / Nycomed Business scope Clinical Trial Data is the assets of our company. To ensure – Data security – compliance with regulations (21 CFR part 11, ICH E 9) – And fast data availability for all data-related questions We decided to implement a clinical data warehouse solution focussing on l Standardized data storage (CDISC SDTM 3. 1. 1) to – Ensure data integrity and allow to explore across studies – Efficient exchange of clinical trial data with external and internal partners l Non-standardized data storage to – Enable fast and secure data acquisition from partners in licensing projects – Provide a platform for storage of legacy data / databases CDISC Implementation at Nycomed 7

Data flow and data processing Full package delivery after TFL finalisation Full service CRO Data flow and data processing Full package delivery after TFL finalisation Full service CRO trial data Code lists Data Mgmt. + SDTM+ADa. M+ TFL SAS Data Warehouse code 1. xml SDTM + define. xml SAS Datasets NYC . sas 7 bdat Data- . xpt Define. xml DM AE . . . import Define. xml Non standard DM CDISC Implementation at Nycomed Data flow AE . . . 8

Dpt. Data Integration Standards 1. Mainly responsible to define, develop in-house data standards based Dpt. Data Integration Standards 1. Mainly responsible to define, develop in-house data standards based on CDISC SDTM and ADa. M 2. Coordinates CRO interfaces / deliverables and processes 3. Data exchange between Nycomed and partners in particular data import process definition and operation 4. QC concepts 5. Data warehouse operation and maintenance CDISC Implementation at Nycomed 9

Dpt. Data Integration Standards – the CDISC team CDISC Implementation at Nycomed 10 Dpt. Data Integration Standards – the CDISC team CDISC Implementation at Nycomed 10

Agenda l Background l Clinical Data Warehouse l CDISC implementation l Electronic data submission Agenda l Background l Clinical Data Warehouse l CDISC implementation l Electronic data submission within e. CTD l Conclusions and outlook CDISC Implementation at Nycomed 11

Processes on study and project level l CDISC project plan. – Deliverables, timelines, contact Processes on study and project level l CDISC project plan. – Deliverables, timelines, contact persons, responsibilities, process descriptions – QC plans l SDTM annotated CRF (a. CRF) l SDTM and ADa. M specification (URS) – Contain all information about domains, variables, computation rules, etc – Basis to create the define. xml file l Communication: – ‘issue logs’ – Emails (restricted to organisational or administrative messages ) l SAS programming: external provider are required to do all programming of SDTMs, ADa. M and TFLs in SAS. (SAS program validation acc. to provider SOPs). CDISC Implementation at Nycomed 12

CRO CDISC project plan + QC plans NYCO resources CRO resources SDTM ADa. M CRO CDISC project plan + QC plans NYCO resources CRO resources SDTM ADa. M mapping a. CRF Specifications Data + Define. xml Issue log, ……. . QC Review approval NYCO Review approval • Technical checks reports • QC plan reports • Validation reports • Web. SDM Continuous development of NYC-internal standards CDISC Implementation at Nycomed 13

Data flow and data processing DM plans SAP SDTM a. CRF SDTM specs ADa. Data flow and data processing DM plans SAP SDTM a. CRF SDTM specs ADa. M specs CRO CRF Clinical trial database Data SAS data ADa. M LAB DM Supp. DM ADSL MH AE efficacy . . . Supp. AE safety DV Data Trial design TFL . . . Trial. . . BDRM population flags CDISC Implementation at Nycomed SDTM SAS IE Data Electronic data (Lab ECG, . . . ) SAS Define. xml 14

a. CRF and SDTM define CDISC Implementation at Nycomed 15 a. CRF and SDTM define CDISC Implementation at Nycomed 15

SDTM specs / dataset metadata CDISC Implementation at Nycomed 16 SDTM specs / dataset metadata CDISC Implementation at Nycomed 16

SDTM specs / variable and value level metadata CDISC Implementation at Nycomed 17 SDTM specs / variable and value level metadata CDISC Implementation at Nycomed 17

Define. xml l Guidelines and rules – CRT-DDS V 1. 0 (define. pdf will Define. xml l Guidelines and rules – CRT-DDS V 1. 0 (define. pdf will not be accepted) – CDISC ‘Metadata Submission Guidelines, Appendix to the SDTM IG V 3. 1. 1’ – CDISC ODM V 1. 2 standard (machine-readability) – Naming conventions according to ICH e. CTD l Separate define files for SDTM and ADa. M domains; l Consistency checks: – Number of datasets and variables included – Dataset names and labels – Variable names, labels, data type (expressed in ODM terminology) – Order of variables within a dataset – Consistency of values of variables regulated by controlled terminology – Data warehouse requirements CDISC Implementation at Nycomed 18

QC l Quality control of SDTM, ADa. M datasets is based on – Nycomed QC l Quality control of SDTM, ADa. M datasets is based on – Nycomed CDISC standards – QC check plan – Web. SDM edit checks of SDTM datasets l Expectation to the CRO – Enhanced by study/project specific checks to the Web. SDM checks – Choose appropriate tools to carry out the checks – Nycomed relies on compliance to good clinical - and good programming practice l Internal QC – Checksum / xpt files – Schema conformity to ODM 1. 2 – Consistency checks SDTM / ADa. M (such as primary keys, variable naming and completeness, Null values ) – Final SDTM contents check after data warehouse upload (SDTM-TFL) CDISC Implementation at Nycomed 19

Web. SDM checks CDISC Implementation at Nycomed 20 Web. SDM checks CDISC Implementation at Nycomed 20

Deliverables summary l CDISC project plan and summary document l SDTM a. CRF – Deliverables summary l CDISC project plan and summary document l SDTM a. CRF – Annotation of variables and variable values – Top level bookmarks l CDISC SDTM datasets (. xpt/. sas 7 bdat) + define. xml l CDISC ADa. M datasets (. xpt/. sas 7 bdat) + define. xml – SAS programs for ADa. Ms (. pdf/. sas) – SAS programs for TFLs (. pdf /. sas) l Final specification documents – SDTM – ADa. M l Quality Checks (QC) – QC plans – QC reports (in particular Web. SDM edit check reports) – Validation reports CDISC Implementation at Nycomed 21

Agenda l Background l Clinical Data Warehouse l CDISC implementation l Electronic data submission Agenda l Background l Clinical Data Warehouse l CDISC implementation l Electronic data submission within e. CTD l Conclusions and outlook CDISC Implementation at Nycomed 22

FDA- e. CTD guidelines and requirements http: //www. fda. gov/Drugs/Development. Approval. Process/Forms. Submission. Requirements/Electronic. FDA- e. CTD guidelines and requirements http: //www. fda. gov/Drugs/Development. Approval. Process/Forms. Submission. Requirements/Electronic. Submissions/ucm 153574. htm CDISC Implementation at Nycomed 23

CDISC Implementation at Nycomed 24 CDISC Implementation at Nycomed 24

Reviewers guide l e. CTD data submission using CDISC standards l PK data of Reviewers guide l e. CTD data submission using CDISC standards l PK data of PK and Phase I studies were submitted in original format + define. pdf l Phase I studies – Partly mapped into CDISc – safety – ADa. Ms were created only for one study l Phase II- III trials: complete mapping to CDISC SDTM 3. 11 – Huge amount of legacy data conversion – Analysis of enhanced program trials as well as pooled analysis were based on CDISC ADa. M l CDISC part of reviewers guide is based on the CDISC ADa. M pilot – Main focus on folder structure and folder contents, file types, physical and logical links of files – Description of deviations from guidelines – Document contains no details about data contents CDISC Implementation at Nycomed 25

CDISC Implementation at Nycomed 26 CDISC Implementation at Nycomed 26

CDISC Implementation at Nycomed 27 CDISC Implementation at Nycomed 27

ADa. M define / results metadata CDISC Implementation at Nycomed 28 ADa. M define / results metadata CDISC Implementation at Nycomed 28

Agenda l Background l Clinical Data Warehouse l CDISC implementation l Electronic data submission Agenda l Background l Clinical Data Warehouse l CDISC implementation l Electronic data submission within e. CTD l Conclusions and outlook CDISC Implementation at Nycomed 29

Lessons learned Contracting external partners for CDISC data conversion tasks is more than just Lessons learned Contracting external partners for CDISC data conversion tasks is more than just telling the partner to refer to the current CDISC SDTM/ADa. M and define. xml standards l Important – CROs experience, stable CDISC standard SDTM V 1. 1 / IG V 3. 1. 1 – Electronic data submission within e. CTD is a very specific task, following the guidelines is key! – CDISC knowledge / training of employees l In general, the CDISC standards are of high value and in particular the results published from the SDTM/ADa. M pilot provided excellent examples CDISC Implementation at Nycomed 30

Thank you Nycomed Gmb. H Dr. Berthold Traub Associate Director Data Integration Standards T Thank you Nycomed Gmb. H Dr. Berthold Traub Associate Director Data Integration Standards T + 49 (0) 7531 84 3025 www. nycomed. com berthold. [email protected] com CDISC Implementation at Nycomed 31