Session 3 Basic Results Database Deborah A. Zarin, M.D.

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

2. Pilot Quality Control Project • Recommendation to Secretary – Narrative Summaries Expanded Clinical Trial Registry REGISTRY New Administration Transition Phase Public Meeting 9/27/07 12/26/07 9/27/08 3/27/09 9/27/10 90 d 1 yr 18 m 2 yr 3 yr Enactment Expansion by Rulemaking: Final Rule Additional Adverse Events Data RESULTS Launch Basic Results Database Linking to existing results information at FDA and NIH

3. Activities to Date Results Reporting

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. 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. 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. 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. Data Entry Data Entry Prototype Beta Data Entry Production Data Entry Develop Basic Table Shells Freeze Requirements Requirements Discussions, Analysis XML DTD (alpha) XML DTD (final) XML DTD (beta) Today! 12/07 1/08 2/08 3/08 4/08 5/08 6/08 7/08 8/08 9/08 9/27/09 Begin Display Display Mock-Up Beta Display Production Display Data Display DRAFT – 1/31/08

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. Results Database Mockups Proposed Approach

11. Data in Mock-ups Based on Published Results

12. Results RecordBackground Efficacy and Safety of Esomeprazole Compared With Omeprazole in Gastroesophageal Reflux Disease (GERD) Patients With Erosive Esophagitis: A Randomized Controlled Trial Study Results Sponsored by: Information Provided by: ClinicalTrials.gov Identifier: AstraZeneca AstraZeneca NCT11112222 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. Published Baseline Data Source: Richter JE et al. Am J Gastroenterol. 2001 Mar;96(3):656-65.

14. Results RecordBaseline 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: 1,108 1,088 Gender Female: 494 449 Male: 722 760 Ethnicity White: 1,134 1,133 Other: 82 76

15. Prilosec (omeprazole), capsule [AstraZeneca LP] Results RecordBaseline 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: 1,108 1,088 Gender Female: 494 449 Male: 722 760 Ethnicity White: 1,134 1,133 Other: 82 76

16. Results RecordBaseline 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. Results RecordBaseline Clinical Characteristics 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 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

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

19. Results RecordParticipant Flow Participant Flow Total 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

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

21. Results RecordPrimary Outcome Primary Outcome Esomeprazole N=1,216 Omeprazole N=1,209 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%) * * 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. Proposed Data Entry Process

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

25. Measurement Types Dichotomous Continuous (Years) Multiple Categories

26. Time To Event

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. Specifying ParametersArms & Baseline Demographics Comparison of Esomeprazole versus Omeprazole in GERD AstraZeneca NCT00002222 Background Brief Title: Sponsor: Unique ID: Initially “prepopulated” from registry Arms Edit Name Type Description Esomeprazole Experimental 40 mg Omeprazole Active Comparator 20 mg Update or modify Arms Baseline Demographics Edit Add Category Age Gender Male Female Ethnicity “Prespecified” demographic categories

29. Entering DataBaseline Demographics Baseline Demographics Age Age: ≥ 65 Years: < 18 Years: Gender Female: Male: Ethnicity White: Arms Esomeprazole Omeprazole Total Mean SD Mean SD 46.5 12.5 46.8 12.3 108 121 229 1,108 1,088 2,196 1,209 2,425 1,216 494 449 943 722 760 1,482 1,209 2,425 1,216

30. Specifying ParametersBaseline 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 Name Type Unit Name Description Initially blank; User to specify characteristics of interest

31. Specifying ParametersBaseline Clinical Characteristics Baseline Clinical Characteristics Edit Add Measure Sub-Categories Name Type Unit Name Description Name: Measure Type: Unit: Positive Biopsy for H. pylori --Select-- Continuous Categorical Time to Event OK Cancel

32. Specifying ParametersBaseline Clinical Characteristics Baseline Clinical Characteristics Edit Add Measure Sub-Categories Name Type Unit Name Description 1.Positive Biopsy for H. PyloriCategorical Number 2.Los Angeles Classification

33. Specifying ParametersOutcome Measures Initially “prepopulated” from registry Primary Outcome Measures Edit Add Measure Name Unit Type Healed Esophagitis at Week 8 Number Dichotomous Secondary Outcome Measures Edit Add Measure Name Unit Type 1.Heartburn Resolution at Week 4Number Dichotomous 2.Time to First ResolutionDays Time to Event MedianContinuous Update or modify Primary Outcome Measures

34. Entering DataOutcome Measure Percentages may be calculated Primary Outcome Measures Subjects Analyzed: With Event: Without Event: Statistical Test: Comments: Results Value: 95% CI: p: Healed Esophagitis at Week 8 Arms Esomeprazole OmeprazoleTotal 1,216 1,209 2,425 77 191 268 1,139 1,018 2,157 Log-Rank Test Intention to Treat (ITT) Population 2.8 1.4-3.2 <0.001 Method for describing “hypothesis” TBD

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. 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. Results RecordBackground Efficacy and Safety of Esomeprazole Compared With Omeprazole in Gastroesophageal Reflux Disease (GERD) Patients With Erosive Esophagitis: A Randomized Controlled Trial Study Results Sponsored by: Information Provided by: ClinicalTrials.gov Identifier: AstraZeneca AstraZeneca NCT11112222 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. Prilosec (omeprazole), capsule [AstraZeneca LP] Results RecordBaseline 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: 1,108 1,088 Gender Female: 494 449 Male: 722 760 Ethnicity White: 1,134 1,133 Other: 82 76

39. Results RecordBaseline 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. Results RecordParticipant Flow Participant Flow Total 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

41. Results RecordPrimary Outcome Primary Outcome Esomeprazole N=1,216 Omeprazole N=1,209 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%) * * 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. How to Facilitate Rational Use of Data • Provide context • Study design • Background information • Consider linking to systematic reviews • Link to other resources

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?