1 session 3 basic results database deborah a. zarin, m.d. background specific results data elements...
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Session 3Basic Results Database
Deborah A. Zarin, M.D.
Background
Specific Results Data Elements
Data Entry and Display Mockups
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Enactment
Expanded Clinical Trial Registry
1 yr 2 yr 3 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
12/26/07 9/27/08 3/27/09 9/27/10
New AdministrationTransition Phase
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Activities to Date
Results Reporting
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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
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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
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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
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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
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Data Entry
Data Display
12/07
Develop Basic Table Shells
1/08 7/082/08 4/08 5/08 6/08 8/08 9/083/08
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!
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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
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Results Database Mockups
Proposed Approach
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Data in Mock-ups Based on Published Results
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Results RecordBackground
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:
AstraZenecaAstraZeneca 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 1999Study Completion Date: August 2000
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Published Baseline Data
Source: Richter JE et al. Am J Gastroenterol. 2001 Mar;96(3):656-65.
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Results RecordBaseline Demographics
Baseline Demographics
EsomeprazoleN=1,216
OmeprazoleN=1,209
Age Mean Age (SD): 46.5 (12.5) 46.8 (12.3) Number ≥ 65 Years: 108 121 Number < 65 Years: 1,108 1,088Gender Female: 494 449 Male: 722 760Ethnicity White: 1,134 1,133 Other: 82 76
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Results RecordBaseline Demographics
Baseline Demographics
EsomeprazoleN=1,216
OmeprazoleN=1,209
Age Mean Age (SD): 46.5 (12.5) 46.8 (12.3) Number ≥ 65 Years: 108 121 Number < 65 Years: 1,108 1,088Gender Female: 494 449 Male: 722 760Ethnicity White: 1,134 1,133 Other: 82 76
Prilosec (omeprazole), capsule [AstraZeneca LP]
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Results RecordBaseline Clinical Characteristics
Baseline Clinical Characteristics
EsomeprazoleN=1,216
OmeprazoleN=1,209
Positive Biopsy for H. pylori Number with Characteristic: 90 96 Number without Characteristic: 1,126 1,113Los Angeles Classification Grade A: 427 386 Grade B: 470 502 Grade C: 257 240 Grade D: 60 80 Missing: 2 1History of GERD
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Results RecordBaseline Clinical Characteristics
Baseline Clinical Characteristics
EsomeprazoleN=1,216
OmeprazoleN=1,209
Positive Biopsy for H. pylori Number with Characteristic: 90 96 Number without Characteristic: 1,126 1,113Los Angeles Classification Grade A: 427 386 Grade B: 470 502 Grade C: 257 240 Grade D: 60 80 Missing: 2 1History of GERD
Los Angeles ClassificationGrade A One or more mucosal breaks not
more than 5 mm in maximum lengthGrade 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
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Published Participant Flow
Source: Richter JE et al. Am J Gastroenterol. 2001 Mar;96(3):656-65.
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Results RecordParticipant Flow
Participant Flow
Esomeprazole Omeprazole
Target Enrollment: 2,080 1,040 1,040Actual Enrollment: 2,425 1,216 1,209Completed: 2,316 1,161 1,155Discontinued 109 Dropped Out: 88 45 43 Excluded: 21 10 11
Total
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Published Primary Outcome
Source: Richter JE et al. Am J Gastroenterol. 2001 Mar;96(3):656-65.
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Results RecordPrimary 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%)
EsomeprazoleN=1,216
OmeprazoleN=1,209
*
* Value: 2.8 [95% CI 1.4-3.2] Statistical Significance: p < 0.001Statistical Test: Log-rank Test Method for displaying
“statistics” TBD
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Proposed Data Entry Process
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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
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Two-Step Data Entry Process
1. Specify “parameters” of results tables– Baseline Demographic Categories– Baseline Clinical Characteristics– Detailed Outcome Measures
2. Enter data
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Measurement Types
Dichotomous
Continuous (Years)
Multiple Categories
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Time To Event
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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
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Specifying ParametersArms & Baseline Demographics
Comparison of Esomeprazole versus Omeprazole in GERD AstraZenecaNCT00002222
BackgroundBrief Title:Sponsor:
Unique ID:
Name Type DescriptionEsomeprazole Experimental 40 mgOmeprazole Active Comparator 20 mg
Arms
Edit
Initially “prepopulated” from registry
BaselineDemographics
Edit
Add
CategoryAgeGender Male FemaleEthnicity
Update or modify Arms
“Prespecified” demographic categories
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Entering Data Baseline Demographics
BaselineDemographics
AgeAge:
≥ 65 Years:< 18 Years:
Gender
Female:Male:
EthnicityWhite:
Arms Esomeprazole Omeprazole Total
Mean SD Mean SD46.5 12.5 46.8 12.3
108 121 229
1,108 1,088 2,1961,216 1,209
494 449 943722 760 1,482
2,425
1,216 1,209 2,425
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Specifying ParametersBaseline Clinical Characteristics
BaselineDemographics
Edit
Add
CategoryAgeGender Male FemaleEthnicity
Designate additional relevant demographic categories
BaselineClinical
Characteristics
Edit
Add
Measure Sub-CategoriesName Type Unit Name Description
Initially blank; User to specify characteristics of interest
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Specifying ParametersBaseline Clinical Characteristics
BaselineClinical
Characteristics
Edit
Add
Measure Sub-CategoriesName Type Unit Name Description
Name:Measure Type:
Unit:
Positive Biopsy for H. pylori--Select--
CancelOK
ContinuousCategoricalTime to Event
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Specifying ParametersBaseline Clinical Characteristics
BaselineClinical
Characteristics
Edit
Add
Measure Sub-CategoriesName Type Unit Name Description
1.Positive Biopsy
for H. Pylori Categorical Number
2.Los Angeles Classification
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MeasureName Unit Type
1.Heartburn Resolution at Week 4 Number Dichotomous
2.Time to First Resolution Days Time to EventMedian Continuous
Specifying ParametersOutcome Measures
PrimaryOutcome
Measures
Edit
Add
MeasureName Unit Type
Healed Esophagitis at Week 8 Number Dichotomous
Initially “prepopulated” from registry
Update or modify Primary Outcome Measures
SecondaryOutcome
Measures
Edit
Add
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Entering Data Outcome Measure
PrimaryOutcome
MeasuresSubjects Analyzed:
With Event:Without Event:
Statistical Test:Comments:
ResultsValue:
95% CI:p:
Healed Esophagitis at Week 8
Arms Esomeprazole Omeprazole Total
Log-Rank TestIntention to Treat (ITT) Population
1,216 1,209 2,425
77 191 268
1,139 1,018 2,157
2.8
1.4-3.2
Percentages may be calculated
<0.001Method for describing “hypothesis” TBD
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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
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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
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Results RecordBackground
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:
AstraZenecaAstraZeneca 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 1999Study Completion Date: August 2000
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Results RecordBaseline Demographics
Baseline Demographics
EsomeprazoleN=1,216
OmeprazoleN=1,209
Age Mean Age (SD): 46.5 (12.5) 46.8 (12.3) Number ≥ 65 Years: 108 121 Number < 65 Years: 1,108 1,088Gender Female: 494 449 Male: 722 760Ethnicity White: 1,134 1,133 Other: 82 76
Prilosec (omeprazole), capsule [AstraZeneca LP]
39
Results RecordBaseline Clinical Characteristics
Baseline Clinical Characteristics
EsomeprazoleN=1,216
OmeprazoleN=1,209
Positive Biopsy for H. pylori Number with Characteristic: 90 96 Number without Characteristic: 1,126 1,113Los Angeles Classification Grade A: 427 386 Grade B: 470 502 Grade C: 257 240 Grade D: 60 80 Missing: 2 1History of GERD
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Results RecordParticipant Flow
Participant Flow
Esomeprazole Omeprazole
Target Enrollment: 2,080 1,040 1,040Actual Enrollment: 2,425 1,216 1,209Completed: 2,316 1,161 1,155Discontinued 109 Dropped Out: 88 45 43 Excluded: 21 10 11
Total
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Results RecordPrimary 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%)
EsomeprazoleN=1,216
OmeprazoleN=1,209
*
* Value: 2.8 [95% CI 1.4-3.2] Statistical Significance: p < 0.001Statistical Test: Log-rank Test Method for displaying
“statistics” TBD
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How to Facilitate Rational Use of Data
• Provide context– Study design
– Background information
• Consider linking to systematic reviews
• Link to other resources
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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?