1. FDA/Industry Statistics Workshop - 29 September 2006
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

3. 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.

4. 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

5. 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!

6. 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

7. 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.

8. And the verdict?
We DID produce an electronic submission that met 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

9. Now to details…

10. Who? 15 core team members from industry FDA involvement Interactions:
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

11. 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

12. 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)

13. 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

14. CDISC Pilot Submission Package Content
PDF TOCs and eCTD folder structure

15. Building the CDISC Pilot
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

16. 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!

17. Illustration of the Pilot Submission Package

18. Ideally would also have included a link to reviewer’s guide
Top of Define file
Table of Contents
Ideally would also have included
a link to reviewer’s guide

19. Define file: List of Analysis Datasets

20. Define file: Metadata for ADSL

21. Define file: Code List

22. Define file: Computation Method

23. Define file: List of Tabulation Datasets

24. Define file: List of Analysis Results

25. Define file: Analysis Results Metadata

26. Define file: Linked to Study Report

27. Inclusion of Programs? Elected to not include entire “program”
Included program code in metadata for repeated measures analysis
This WAS used in the review

28. 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

29. 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

30. 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

31. Thank you!
CDISC Pilot
XML
and
You
SDTM
ADaM
ODM