1. Database Lock to DSMB Meeting Pushing a button well takes 2-4 weeks
Kevin A. Buhr
Director, University of Wisconsin Statistical Data Analysis Center

2. Our Group
University of Wisconsin Statistical Data Analysis Center (SDAC)
Independent statistical support for DMC-monitored industry trials (mostly Phase 3)
Variety of large (programs w/ 5-15 trials; large CV trials with ~10000 subjects) and small projects (n=30, 2-week intervention in orphan disease)

3. DMC Requirements The DMC wants a report that is: Current Correct
Complete
Comprehensible
Customizable to evolving requirements
No single requirement dominates all the others; they all are important.

4. Importance of Data Currency
Recent, typical project:
Two Phase 3 trials, 4-5 years, n=11000
DMC teleconference 2-3 times per year
DMC report distributed one week in advance
Delay from data transfer to DMC TC
Range weeks, median 3.5 weeks
Report delivered one week before TC

5. Importance of Data Currency
Typical evolution of a potential safety signal (or, in this case, “non-signal”), as actually reported:
Note: results simulated based on actual distribution.

6. Importance of Data Currency
Theoretical “perfect” reporting:
All events captured on date of occurrence
Snapshot/report generated day of DMC meeting
DMC happy to review in an hour or two
So, “unattainable”

7. Data Currency in Perspective
Comparison of actual and “perfect” data:

8. Data Currency in Perspective
Early in trial
Signal is sensitive to additional data
Signal is also sensitive to sampling error and random noise
Degree of uncertainty is very high
Later in trial
Signal has stabilized
Even in context of ongoing rapid enrollment, 3-5 weeks worth of additional data will rarely materially change results
This doesn’t mean data currency is unimportant, but that it can and should be balanced against other requirements.

9. EDC Effect on SDAC Workflow
Currency of data has little effect on SDAC workflow
Before and after EDC, we received SAS snapshots
Improved data quality doesn’t materially increase our efficiency
Defensive programming
Validation
Isn’t particularly easier w/ 5 errors versus 500 errors

10. CDISC for Interim Reporting
Problems solved by SDTM were never serious bottlenecks in our workflow:
Standardizing names and formats for variables
Specification of trial metadata (epochs, etc.)
Adapting existing analysis code to new project
These are “fixed cost” (and generally low cost) items for interim reporting

11. What Does Speed the Process?
In our experience, we’ve had good luck with:
Regular, frequently, as-is data transfers (e.g., monthly)
A strong build system (e.g., draft reports for multi-protocol projects built within hours of new data transfer)
An agile, continuous integration workflow
Statistician-programmers with soup-to-nuts responsibility for blocks of content
Nonetheless, we consider a reasonable snapshot-to-distribution timeline to be measured in weeks, not days.

12. Backup

13. EDC Effect on Overall Process
Compared to days of paper CRFs:
Data are far more current/up-to-date
EDC eliminates many classes of errors, though introduces some new ones
EDC streamlines query resolution process
Facilitates frequent, as-is snapshots
Large net positive effect on data currency and quality

14. CDISC for Interim Reporting
CDISC SDTM is mixture of:
Extreme inflexibility (no extra variables allowed)
Extreme flexibility (FA domain, SUPP* domains, RELREC mechanisms)
Compared to a direct mapping of eCRF to a “raw” dataset, SDTM:
Obscures traceability (particularly if mapping contains some errors or relies on perfectly clean data)
Obscures investigator “intention” where data are inconsistent
We may waste time “unmapping” SDTM to original form
Often, SDTMs often not ready early enough
May need to start with raw and switch to SDTM

15. SDAC Workflow Receipt of new data Data checking / dataset exploration
Data preprocessing
Analysis dataset creation
Graphical and tabular presentation
Report compilation
Quality assurance

16. Programming Ahead vs. Behind
In our experience, report programming is an ongoing process: