1. 1 Session 3 Basic Results Database Deborah A. Zarin, M.D. Background Specific Results Data Elements Data Entry and Display Mockups

2. 2 Enactment Expanded Clinical Trial Registry 1 yr2 yr3 yr18 m Linking to existing results information at FDA and NIH Launch Basic Results Database Expansion by Rulemaking: Final Rule Additional Adverse Events Data REGISTRY RESULTS 90 d Public Meeting 9/27/07 Pilot Quality Control Project Recommendation to Secretary – Narrative Summaries 12/26/079/27/083/27/099/27/10 New Administration Transition Phase

3. 3 Activities to Date Results Reporting

4. 4 Results Reporting: Preliminary Activities Trans-NIH Working Group on Clinical Trial Results Reporting in 2004 “Scientific Challenges in the Registration of Clinical Trials” Expert Meeting in November 2006 Commissioned review of existing results databases

5. 5 Conclusions from Preliminary Activities Two basic models: structured narrative vs. tabular Data input should be formatted in a way that facilitates provision of comprehensive and valid data Tabular data (vs. narrative) would be easier to curate

6. 6 Activities since Sept. 2007 FDAAA mandated “tabular form” for “basic results” Specific content of tables identified in law Challenge is to determine method for data entry that would facilitate provision of structured data for –Heterogeneous trial types –Heterogeneous variable types

7. 7 Basic Results Tables Demographic and baseline characteristics –Overall and by arm Participant flow Values for primary and secondary outcomes –By arm –Scientifically appropriate tests of statistical significance

8. 8 Data Entry Data Display 12/07 Develop Basic Table Shells 1/087/082/084/085/086/088/089/083/08 Data Entry Prototype Display Mock- Up Beta Data Entry Beta Display Freeze Requirements Production Data Entry Production Display DRAFT – 1/31/08 Begin Display XML DTD (alpha) XML DTD (beta) XML DTD (final) 9/27/09 Requirements Discussions, Analysis Today!

9. 9 Current NLM Thinking Developing a model that would allow the registrant to enter information about the trial and the variables, and then enter data into tables Professional Services Contracts at NEMC and OHSU –Evaluate templates using 40 clinical trials, starting with parallel design intervention studies –Process of iterative revisions –Process for public comment and review

10. 10 Results Database Mockups Proposed Approach

11. 11 Data in Mock-ups Based on Published Results

12. 12 Results Record Background Efficacy and Safety of Esomeprazole Compared With Omeprazole in Gastroesophageal Reflux Disease (GERD) Patients With Erosive Esophagitis: A Randomized Controlled Trial Sponsored by: Information Provided by: ClinicalTrials.gov Identifier: AstraZeneca NCT11112222 Study Results Background Study Purpose: To further evaluate the efficacy and tolerability of esomeprazole relative to that of omeprazole in healing erosive esophagitis and resolving accompanying symptoms of GERD. Study Design: multicenter, double-blind, randomized, parallel group Study Start Date: June 1999 Study Completion Date: August 2000

13. 13 Published Baseline Data Source: Richter JE et al. Am J Gastroenterol. 2001 Mar;96(3):656-65.

14. 14 Results Record Baseline Demographics Baseline Demographics Esomeprazole N=1,216 Omeprazole N=1,209 Age Mean Age (SD): 46.5 (12.5) 46.8 (12.3) Number ≥ 65 Years: 108 121 Number < 65 Years: 1,1081,088 Gender Female:494 449 Male:722 760 Ethnicity White: 1,1341,133 Other: 82 76

15. 15 Results Record Baseline Demographics Baseline Demographics Esomeprazole N=1,216 Omeprazole N=1,209 Age Mean Age (SD): 46.5 (12.5) 46.8 (12.3) Number ≥ 65 Years: 108 121 Number < 65 Years: 1,1081,088 Gender Female:494 449 Male:722 760 Ethnicity White: 1,1341,133 Other: 82 76 Prilosec (omeprazole), capsule [AstraZeneca LP]

16. 16 Results Record Baseline Clinical Characteristics Baseline Clinical Characteristics Esomeprazole N=1,216 Omeprazole N=1,209 Positive Biopsy for H. pylori Number with Characteristic: 90 96 Number without Characteristic: 1,126 1,113 Los Angeles Classification Grade A: 427 386 Grade B: 470 502 Grade C: 257 240 Grade D: 60 80 Missing: 2 1 History of GERD

17. 17 Results Record Baseline Clinical Characteristics Baseline Clinical Characteristics Esomeprazole N=1,216 Omeprazole N=1,209 Positive Biopsy for H. pylori Number with Characteristic: 90 96 Number without Characteristic: 1,126 1,113 Los Angeles Classification Grade A: 427 386 Grade B: 470 502 Grade C: 257 240 Grade D: 60 80 Missing: 2 1 History of GERD Los Angeles Classification Grade A One or more mucosal breaks not more than 5 mm in maximum length Grade B One or more mucosal breaks more than 5 mm in maximum length, but not continuous between the tops of two mucosal folds Grade C Mucosal breaks continuous between the tops of two or more mucosal folds, but involving less than 75% of the esophageal circumference Grade D Mucosal breaks involving at least 75% of the esophageal circumference

18. 18 Published Participant Flow Source: Richter JE et al. Am J Gastroenterol. 2001 Mar;96(3):656-65.

19. 19 Results Record Participant Flow Participant Flow Esomeprazole Omeprazole Target Enrollment: 2,080 1,040 1,040 Actual Enrollment: 2,425 1,216 1,209 Completed: 2,316 1,161 1,155 Discontinued 109 Dropped Out: 88 45 43 Excluded: 21 10 11 Total

20. 20 Published Primary Outcome Source: Richter JE et al. Am J Gastroenterol. 2001 Mar;96(3):656-65.

21. 21 Results Record Primary Outcome Primary Outcome Healing at 8 weeks (ITT) Number with Event 1,139 (93.7%) 1,018 (84.2%) Number without Event 77 (6.3%) 191 (16.8%) Esomeprazole N=1,216 Omeprazole N=1,209 * * Value: 2.8 [95% CI 1.4-3.2] Statistical Significance: p < 0.001 Statistical Test: Log-rank Test Method for displaying “statistics” TBD

22. 22 Proposed Data Entry Process

23. 23 Data Entry Mechanisms Electronic Data Interchange – upload data in XML format Manual Data Entry – enter data using a Web-based Results Registration System (RRS) –analogous to the Protocol Registration System (PRS) for the registry

24. 24 Two-Step Data Entry Process 1.Specify “parameters” of results tables –Baseline Demographic Categories –Baseline Clinical Characteristics –Detailed Outcome Measures 2.Enter data

25. 25 Measurement Types Dichotomous Continuous (Years) Multiple Categories

26. 26 Time To Event

27. 27 Basic Results Data Entry System Prepopulates certain data elements from registry, if provided (e.g., Arm Description) Lists some prespecified baseline demographics (e.g., gender, ethnicity) Allows users to enter and edit tables –Column labels: e.g., Arms –Row labels: e.g., demographics, outcome measures –Cells: e.g., measurement values

28. 28 Specifying Parameters Arms & Baseline Demographics Comparison of Esomeprazole versus Omeprazole in GERD AstraZeneca NCT00002222 Background Brief Title: Sponsor: Unique ID: NameTypeDescription EsomeprazoleExperimental40 mg Omeprazole Active Comparator20 mg Arms Edit Initially “prepopulated” from registry Baseline Demographics Edit Add Category Age Gender Male Female Ethnicity Update or modify Arms “Prespecified” demographic categories

29. 29 Entering Data Baseline Demographics Baseline Demographics Age Age: ≥ 65 Years: < 18 Years: Gender Female: Male: Ethnicity White: Arms Esomeprazole Omeprazole Total MeanSDMeanSD 46.512.546.812.3 108121229 1,1081,0882,196 1,216 1,209 494449943 7227601,482 2,425 1,216 1,2092,425

30. 30 Specifying Parameters Baseline Clinical Characteristics Baseline Demographics Edit Add Category Age Gender Male Female Ethnicity Designate additional relevant demographic categories Baseline Clinical Characteristics Edit Add Measure Sub-Categories NameTypeUnitNameDescription Initially blank; User to specify characteristics of interest

31. 31 Specifying Parameters Baseline Clinical Characteristics Baseline Clinical Characteristics Edit Add Measure Sub-Categories NameTypeUnitNameDescription Name: Measure Type: Unit: Positive Biopsy for H. pylori --Select-- CancelOK Continuous Categorical Time to Event

32. 32 Specifying Parameters Baseline Clinical Characteristics Baseline Clinical Characteristics Edit Add Measure Sub-Categories Name Type UnitNameDescription 1.Positive Biopsy for H. Pylori Categorical Number 2.Los Angeles Classification

33. 33 Measure NameUnit Type 1.Heartburn Resolution at Week 4 Number Dichotomous 2.Time to First Resolution Days Time to Event Median Continuous Specifying Parameters Outcome Measures Primary Outcome Measures Edit Add Measure NameUnit Type Healed Esophagitis at Week 8 Number Dichotomous Initially “prepopulated” from registry Update or modify Primary Outcome Measures Secondary Outcome Measures Edit Add

34. 34 Entering Data Outcome Measure Primary Outcome Measures Subjects Analyzed: With Event: Without Event: Statistical Test: Comments: Results Value: 95% CI: p: Healed Esophagitis at Week 8 Arms Esomeprazole Omeprazole Total Log-Rank Test Intention to Treat (ITT) Population 1,2161,2092,425 77191268 1,1391,0182,157 2.8 1.4-3.2 Percentages may be calculated <0.001 Method for describing “hypothesis” TBD

35. 35 Data Display Mechanisms Summary result records displayed in a Results Database at ClinicalTrials.gov Results records linked to registry records via NCT number Similar search engine and “look and feel” Details to be determined

36. 36 Results Record Sections Background: e.g.,Title, NCT, Sponsor Baseline Data (Table 1) –Baseline Demographics by Arms –Baseline Clinical Characteristics by Arms –Participant Flow, including dropout and exclusion Outcomes (Table 2), including statistical tests –Primary Outcomes by Arms –Secondary Outcomes by Arms Administrative: e.g., Point of Contact, Certain Agreements

37. 37 Results Record Background Efficacy and Safety of Esomeprazole Compared With Omeprazole in Gastroesophageal Reflux Disease (GERD) Patients With Erosive Esophagitis: A Randomized Controlled Trial Sponsored by: Information Provided by: ClinicalTrials.gov Identifier: AstraZeneca NCT11112222 Study Results Background Study Purpose: To further evaluate the efficacy and tolerability of esomeprazole relative to that of omeprazole in healing erosive esophagitis and resolving accompanying symptoms of GERD. Study Design: multicenter, double-blind, randomized, parallel group Study Start Date: June 1999 Study Completion Date: August 2000

38. 38 Results Record Baseline Demographics Baseline Demographics Esomeprazole N=1,216 Omeprazole N=1,209 Age Mean Age (SD): 46.5 (12.5) 46.8 (12.3) Number ≥ 65 Years: 108 121 Number < 65 Years: 1,1081,088 Gender Female:494 449 Male:722 760 Ethnicity White: 1,1341,133 Other: 82 76 Prilosec (omeprazole), capsule [AstraZeneca LP]

39. 39 Results Record Baseline Clinical Characteristics Baseline Clinical Characteristics Esomeprazole N=1,216 Omeprazole N=1,209 Positive Biopsy for H. pylori Number with Characteristic: 90 96 Number without Characteristic: 1,126 1,113 Los Angeles Classification Grade A: 427 386 Grade B: 470 502 Grade C: 257 240 Grade D: 60 80 Missing: 2 1 History of GERD

40. 40 Results Record Participant Flow Participant Flow Esomeprazole Omeprazole Target Enrollment: 2,080 1,040 1,040 Actual Enrollment: 2,425 1,216 1,209 Completed: 2,316 1,161 1,155 Discontinued 109 Dropped Out: 88 45 43 Excluded: 21 10 11 Total

41. 41 Results Record Primary Outcome Primary Outcome Healing at 8 weeks (ITT) Number with Event 1,139 (93.7%) 1,018 (84.2%) Number without Event 77 (6.3%) 191 (16.8%) Esomeprazole N=1,216 Omeprazole N=1,209 * * Value: 2.8 [95% CI 1.4-3.2] Statistical Significance: p < 0.001 Statistical Test: Log-rank Test Method for displaying “statistics” TBD

42. 42 How to Facilitate Rational Use of Data Provide context –Study design –Background information Consider linking to systematic reviews Link to other resources

43. 43 Some Other Issues to Ponder What constitutes a “minimally acceptable” results record? How to handle disputes over validity of information? Should post-hoc analyses be allowed on database? What external sources should we link to?