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

1

Session 3Basic Results Database

Deborah A. Zarin, M.D.

Background

Specific Results Data Elements

Data Entry and Display Mockups

2

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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EsomeprazoleN=1,216

OmeprazoleN=1,209


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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EsomeprazoleN=1,216

OmeprazoleN=1,209


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


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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


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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


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


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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BaselineClinical

Characteristics

Edit

Add


Name:Measure Type:

Unit:

Positive Biopsy for H. pylori--Select--

CancelOK

ContinuousCategoricalTime to Event

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BaselineClinical

Characteristics

Edit

Add


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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EsomeprazoleN=1,216

OmeprazoleN=1,209


Prilosec (omeprazole), capsule [AstraZeneca LP]

39



EsomeprazoleN=1,216

OmeprazoleN=1,209


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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?

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

Documents

data entry data display

valid data tabular data

date results

results reporting

published results

clinical trial results

review slide

approach slide