# Presentation: 674205

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

- Background
- Specific Results Data Elements
- Data Entry and Display Mockups

## Expanded Clinical Trial Registry

**Enactment**

- 1 yr

- 2 yr

- 3 yr

- 18 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 Administration
- Transition Phase

## Activities to Date

- Results Reporting

## 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

## 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

## 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

## 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

## Data Entry

- Data Display

**12/07**

- Develop Basic Table Shells

**1/08**

**7/08**

**2/08**

**4/08**

**5/08**

**6/08**

**8/08**

**9/08**

**3/08**

- 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!**

## 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

## Results Database Mockups

- Proposed Approach

## Data in Mock-ups Based on Published Results

## Results RecordBackground

- 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:

**AstraZeneca**
- 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

## Published Baseline Data

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

## Results RecordBaseline Demographics

- 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**

## Results RecordBaseline Demographics

- 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**

## Results RecordBaseline Clinical Characteristics

- 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**_

## Results RecordBaseline Clinical Characteristics

- 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**_

**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

## Published Participant Flow

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

## Results RecordParticipant Flow

- Results RecordParticipant 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**

## Published Primary Outcome

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

## Results RecordPrimary Outcome

- 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%)

_**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*

## Proposed Data Entry Process 

## 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

## Two-Step Data Entry Process

- Specify “parameters” of results tables
- Baseline Demographic Categories
- Baseline Clinical Characteristics
- Detailed Outcome Measures
- Enter data

## Measurement Types

**Dichotomous**

**Continuous (Years)**

**Multiple Categories**

## Time To Event

**Time To Event**

## 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

## Specifying ParametersArms & Baseline Demographics

- Specifying ParametersArms & Baseline Demographics

- Comparison of Esomeprazole versus Omeprazole in GERD
- AstraZeneca
- NCT00002222

**Background**
- Brief Title:
- Sponsor:
- Unique ID:

**Name****	****	****Type****	****	****	****Description****	**
- Esomeprazole	Experimental		40 mg
- Omeprazole 	Active Comparator	20 mg

**Arms**
- _Edit_

*Initially “prepopulated” from registry*

**Baseline**
**Demographics**
- _Edit_
- _Add_

**Category****	****	****	****	****	****	**
- Age
- Gender
-   Male
-   Female
- Ethnicity

*Update or modify Arms*

*“**Prespecified” demographic categories*

## Entering Data Baseline Demographics

- Entering Data Baseline 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

- 1,216

- 1,209

- 494

- 449

- 943

- 722

- 760

- 1,482

- 2,425

- 1,216

- 1,209

- 2,425

## Specifying ParametersBaseline Clinical Characteristics

- 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*

## Specifying ParametersBaseline Clinical Characteristics

- 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--

**Cancel**

**OK**

- Continuous
- Categorical
- Time to Event

## Specifying ParametersBaseline Clinical Characteristics

- Specifying ParametersBaseline Clinical Characteristics

**Baseline**
**Clinical**
**Characteristics**
- _Edit_
- _Add_

**	****            ****Measure ****	****	****     **_**Sub-Categories**_
**Name****	****            Type****	****     Unit****	****Name****	****Description****	**
**1.Positive Biopsy **
**for H. Pylori****       ****Categorical  Number**
**2.Los Angeles Classification**

## Specifying ParametersOutcome Measures

**	****	****	****	****	****   ****Measure**
**Name****	****	****	****	****Unit****	****   Type**
**1.Heartburn Resolution at Week 4****	****Number****	**** Dichotomous**
**2.Time to First Resolution****	****	****Days****	**** Time to Event**
**	****	****	****	****Median****	****  ****Continuous****	****  **

- Specifying ParametersOutcome Measures

**Primary**
**Outcome Measures**
- _Edit_
- _Add_

**	****	****	****	****	****   ****Measure**
**Name****	****	****	****	****Unit****	****   Type**
**Healed Esophagitis at Week 8****	****Number****	****   Dichotomous**

*Initially “prepopulated” from registry*

*Update or modify Primary Outcome Measures*

**Secondary**
**Outcome Measures**
- _Edit_
- _Add_

## Entering Data Outcome Measure

- 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

- 1,216

- 1,209

- 2,425

- 77

- 191

- 268

- 1,139

- 1,018

- 2,157

- 2.8

- 1.4-3.2

*Percentages may be calculated*

- <0.001

*Method for describing “hypothesis” TBD*

## 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

## 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

## Results RecordBackground

- 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:

**AstraZeneca**
- 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

## Results RecordBaseline Demographics

- 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**

## Results RecordBaseline Clinical Characteristics

- 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**_

## Results RecordParticipant Flow

- Results RecordParticipant 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**

## Results RecordPrimary Outcome

- 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%)

_**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*

## How to Facilitate Rational Use of Data

- Provide context
- Study design
- Background information
- Consider linking to systematic reviews
- Link to other resources

## 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?