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An Update on the CDISC SDTM/ADaM Pilot Project. Cathy Barrows, Ph.D. GlaxoSmithKline Co-Leader of CDISC Pilot Project CDISC ADaM Team. FDA/Industry Statistics Workshop - 29 September 2006. http://www.cdisc.org/. CDISC Pilot Project was to….
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An Update on the CDISC SDTM/ADaM Pilot Project Cathy Barrows, Ph.D. GlaxoSmithKline Co-Leader of CDISC Pilot Project CDISC ADaM Team FDA/Industry Statistics Workshop - 29 September 2006
CDISC Pilot Project was to… • Demonstrate that data submitted to the FDA using the CDISC Standard will meet the needs and expectations of both medical and statistical FDA reviewers. • Produce a worked example implementation of the available CDISC standards.
How? • By conducting a case study • legacy data (real clinical trial data, warts and all) CDISC SDTM domains and ADaM datasets and associated metadata • submission of case study package to FDA for mock review • And in the process, identify any issues to be resolved in SDTM and ADaM models
FOCUS: the package not the process • Choices/decisions guided by • timeline • realities of a team of volunteers from multiple companies • quick, efficient, effective - not necessarily the most preferred option • are not making recommendations re process!
Pilot Submission Deliverables • Submission package • Includes SDTM datasets, analysis datasets, all relevant metadata, analysis results, abbreviated report • Review package tied together using metadata in DEFINE.XML • Summary report of the pilot submission project • issues encountered, strengths and weaknesses • incorporate what we learned from the FDA feedback • Both to be made available to the public on the CDISC website
Criteria for success of the Pilot Project • FDA statistical and medical reviewers will evaluate the submitted datasets (SDTM and AdaM), metadata and documentation • Usable with their tools? • Reproducibility of analyses, derivations? • Navigable? • Contents – what and where are OK? • etc.
And the verdict? • We DID produce an electronic submission thatmet the reviewers’ needs • The overall tone of the reviewers’ feedback was very positive • noted easier learning curve • The FDA review was very thorough and they provided constructive criticism • Issues encountered both by team and in FDA feedback are already beginning to be addressed by CDISC teams
Who? • 15 core team members from industry • FDA involvement • Unprecedented level of involvement • Provided co-leadership • 18-20 employees involved • 12 consistently in contact with team • includes medical and statistical reviewers • Interactions: • regular team teleconferences • Feb. face-to-face meeting to define the project (expectations/requirements) • Pre-submission encounter • Feedback from review
FDA representatives - expectations, requirements, wish list • Key messages: • Consistency, accuracy, completeness are extremely important - follow the specifications! • Define file crucial, but needs to be accurate • Clear mapping between the plans for analysis, the tabulation data, the analysis data, and the analyses performed • SDTM and Analysis datasets should be available for both medical and statistical reviewers
Presubmission “Encounter” • Important opportunity to communicate about those crucial data-type issues that we run out of time for at “usual” meetings • Discussed data to be submitted - structures, variables • FDA was able to make specific requests, for example: • Hy’s Law analysis dataset (liver hepatotoxicity)
Legacy data used in the pilot submission • Real clinical trial data, provided by Eli Lilly • Data de-identified, documents redacted • Indication: Alzheimer’s • Randomized, double-blind, placebo-controlled, parallel-group study • Three treatment arms: low dose, high dose, placebo • Approximately 300 patients, multiple centers • Representative set of endpoints and analyses included in package
CDISC Pilot Submission Package Content • PDF TOCs and eCTD folder structure
Legacy documents received Building the CDISC Pilot Submission Package Decisions regarding data analysis Note that “create” includes QC steps. Map blank CRF to SDTM (aCRF) Write SAP Receive legacy data Coding of events data & con.med. data Create SDTM data metadata Create analysis data metadata Create SDTM datasets (little derived data) Write reviewer’s guide Create 0-obs SDTM datasets Create 0-obs analysis datasets Create analysis datasets Generate analyses Write cover letter Derived data to SDTM Write study report Create DEFINE Create XPT files Finalize SDTM datasets Create analysis results metadata
Presentation of the Define • FDA expectation: Pilot package in Define.xml • The Define file integrates • tabulation dataset (SDTM) metadata • analysis dataset (ADaM) metadata • analysis results (ADaM) metadata New implementation! Exciting!
Top of Define file Table of Contents Ideally would also have included a link to reviewer’s guide
Inclusion of Programs? • Elected to not include entire “program” • Included program code in metadata for repeated measures analysis • This WAS used in the review
Next Steps:Wrap up tasks for this iteration • Some revisions to current package • Implement some of the FDA feedback • Fix a few things that are errors or oversights • Incorporate some things we wish we had done • Complete the project report • Publish the package and the project report
Future iterations might: • Fully and completely work this example (rather than a subset) • More fully develop the metadata • Include datasets in the DEFINE file, instead of separately XPT files • Use studies from other therapeutic areas • Go beyond a single study • Test submitting different sets of sponsor data (e.g., NDA, safety update) • Address how to send updates (e.g. additional derived variables) effectively • Test newer versions of models, e.g.: • ADaM • PK data • Pre-clinical data • ODM • Test other analysis strategies
Wisdom is scar tissue in disguise Our Advice - It’s worth it! Or, as one FDA Review Team member said: In order to get a standard we have to suffer
CDISCPilot ADaM ODM XML SDTM and You Thank you!
