Transcript Slide 1

Where is SAS Going In Pharma,
Healthcare and Public Health
Edward D. Helton, Ph.D.
SAS Scientist, Regulatory and Biomedical Affairs
CDISC BOD & Chair Elect
HL7 BOD (ex-officio) RCRIM Co-Chair, OCCR CHAIR
Copyright © 2007, SAS Institute Inc. All rights reserved.
Published at www.nejm.org May 21, 2007
(10.1056/NEJMoa072761)
Effect of Rosiglitazone on the Risk of Myocardial Infarction
and Death from Cardiovascular Causes
Steven E. Nissen, M.D., and Kathy Wolski, M.P.H.
21 May 2007
GlaxoSmithKline responds to NEJM article on Avandia
Copyright © 2007, SAS Institute Inc. All rights reserved.
Some FDA, PhRMA, CDISC, HL7 and NCI Priorities
 Critical Path (Unambiguous and Transparent)
 caBIG -- Grids and Institutional Memory
 Standard Data, CRFs, e–Source
 EHR/EMR, vMR,
 e-SUB, Industry Architecture
 Healthcare and Pharma Interface (BRIDG)
 e-Platform (industry and regulatory interfaces )
Copyright © 2007, SAS Institute Inc. All rights reserved.
SAS Interest, Participation and Contributions
 Data Standards and Standard Data Collection
 Interface of Healthcare and Therapeutic Product
Development – FDA e-Platform Project
 Standard Methods of Analysis and Reporting for
Safety and Efficacy plus new algorithms of data
mining
 Predictive Medicine – “OMICS” and Phenotype
 Compliant/Part 11 Validated Institutional Memory
and Global Databases to Annotate and Curate the
Institutional Knowledge
Copyright © 2007, SAS Institute Inc. All rights reserved.
CDISC Business Case Stages
2005-2006
 Stage I: CDISC-Gartner Project
• Interviews with representatives of Biopharmaceutical
Companies, Contract Research Organizations, and
U.S. Food and Drug Administration
 Stage II: Gartner Top-down Estimates
 Stage III: CDISC Bottom-up Estimates
 Stage IV: PhRMA-Gartner-CDISC Project
• PhRMA sponsored project, including interviews
conducted by Gartner and CDISC
Copyright © 2007, SAS Institute Inc. All rights reserved.
Stage II: Industry Value Assessment of Standards –
Gartner’s Top-down Estimate
Total estimated industry spend on R&D in 2004:
 $49.3 Billion (source: PhRMA)
Percentage of R&D allocated to clinical trials:
 39 – 45% of the R&D budget
Percentage improvement by automating the clinical trials
process (including use of data interchange standards):
 30 – 50%
Industry savings from automation and standards:
 $5.8 to $6.6 Billion annually (based on 30% improvement)
Copyright © 2007, SAS Institute Inc. All rights reserved.
Stage III: Opportunities with Standards – CDISC’s Bottom-up
Analysis, Per Submission
(Based on Tufts and CMR metrics and CDISC assumptions)
Final
Protocol
Protocol
Setup
First Pt.
Enrolled
2m
Study startup (5m)
Last Data
Available
Data Validation/Audit
DB
Lock
2m
Study conduct (4m LPO->DBL)
Cycle Time Reduction per trial
2m
2m 1m
Analysis
Final
Report
1m
Report
Analysis/reporting
~5 m/trial
Resource Savings
4m
Submission Prep (12m)
Copyright © 2007, SAS Institute Inc. All rights reserved.
Assuming 2-3 trials reap benefits,
time savings ~14-19m out of 59m =
~20-29% (1-1.5 years) time savings,
which translates to
$40-260 M cost/resource savings
Impact of CDISC Standards on Clinical Study Activities
Study Start-up
Study design
Protocol development
CRF development
DB Structure/validation
Edit Checks/validation
LAB/ECG specs
Site/PI Identification
Site evaluation
Site initiation
Patient recruitment plan
Critical documents
IRB approvals
Training of team/sites
Randomization plan
Test article prep
Statistical analysis plan
Analysis table shells
5 months - 80%
Study Conduct
Patient recruitment
Data acquisition
Data exchange
SD verification
Site monitoring/audits
Transfer of lab/ECG data
Site audits
Database QA and lock
Analysis programming
Initial stat tables
Study closeout/archive
Analysis/Reporting
Data analysis
Safety assessment
Analysis table
preparation
Clinical assessments
Report generation
Submission
ISS/ISE preparation
Clinical-Statistical
integrated report
Listings, tabulations
and datasets
eCTD file structure
modules (2-5)
12 months
Patient participation 5 months – 50%
+ 4 months – 40%
(mean = 11.8
studies/submission)
= Clinical trial activities that can be streamlined with standards
XX% = Projected change from benchmark w/ standards, based on business case metrics
Copyright © 2007, SAS Institute Inc. All rights reserved.
eSource Data Interchange (eSDI) Initiative
 CDISC requested to develop team and lead initiative as neutral, nonprofit organization
 Purpose of eSDI Initiative
• to facilitate the use of electronic technology in the context of
existing regulations for the collection of eSource data in clinical
trials for regulatory submission by leveraging the power of the
CDISC standards, in particular the Operational Data Model (ODM).
•
Note: eSource pertains to eDiaries, ePRO, eDCI, Electronic Health Records…
 Overarching goals:
• to make it easier for physicians to conduct clinical research,
• collecting data only once in an industry standard format for multiple
downstream uses, and thereby
• to improve data quality and patient safety
Copyright © 2007, SAS Institute Inc. All rights reserved.
Standard
Description
Implementation
Version Release Date
SDTM, SEND
Content standards; ready for regulatory
submission of CRT; >9,000 downloads
2004*
ODM
CDISC Transport Standard for acquisition,
exchange, submission (define.xml), archive
2001*
Define.xml
Case Report Tabulation Data Definition
Specification (CRTDDS)
2005*
LAB
Content standard – available for transfer of clinical
lab data to sponsors
2002
ADaM
General Considerations document; analysis
dataset examples; IG in preparation
2004
Protocol
Collaborative effort to develop machine-readable
standard protocol with data layer
In progress
Developing standard terminology to support all
CDISC standards
2006 (Pkg1)
Clinical data acquisition (CRF) standards
In progress
Representation
Terminology
Codelists
CDASH
Copyright © 2007, SAS Institute Inc. All rights reserved.
Pkg 2 in progress
* From specification referenced in FDA Final Guidance
Copyright © 2007, SAS Institute Inc. All rights reserved.
Copyright © 2007, SAS Institute Inc. All rights reserved.
Copyright © 2007, SAS Institute Inc. All rights reserved.
CDISC in the “World of Standards”
World Health Organization (WHO)
International Conference on
Harmonization (ICH)
EFPIA
JPMA
EMEA
MHLW
PhRMA
U.S. Dept. of Health and Human Services
(HHS)
U.S. FDA
NIH/NCI
CDC
NLM
RCRIM Technical Committee
CDISC
ADaM SDS ODM
Health Level 7 (HL7)
LAB
MedDRA
Protocol
Representation
eCTD
= Organization
Copyright © 2007, SAS Institute Inc. All rights reserved.
Reference
Information Model
RIM
SNOMED
LOINC
CDA
BRIDG Model
= Dictionary,
Codelist
= Standard
= Model
= Document Standard,
or Architecture
Optimizing the Process
data
conception
Healthcare
Delivery
(e)Source
Documents
EHR
eSource
auto
reconciliation
Copyright © 2007, SAS Institute Inc. All rights reserved.
(e)CRFs
Clinical
Research
Today’s Situation
Medical
Records
Copyright © 2007, SAS Institute Inc. All rights reserved.
Vision:
Medical Research
Informs
Healthcare
Interoperability
Through
Harmonized
Standards
Copyright © 2007, SAS Institute Inc. All rights reserved.
Towards interoperability…..
HL7 Reference Information Model
(RIM) V3
Designed for healthcare
Biomedical Research Integrated
Domain Group (BRIDG)
Model
Domain Analysis Model Developed for Clinical
Research
CDISC Models
Copyright © 2007, SAS Institute Inc. All rights reserved.
Data Flow Using CDISC Standard Linking Clinical
Research and Healthcare
= ODM (transport)
Electronic
Health Record
= SDTM and Analysis Data (content)
= Protocol information (content)
Patient Info
HL7 and/or
ODM XML
HL7 and/or
ODM XML
= Source data
(other than SDTM/CRF data)
Clinical Trial
Data
Protocol
Representation
Trial Design
(SDTM)
Analysis Plan
Clinical Trial
Protocol
Copyright © 2007, SAS Institute Inc. All rights reserved.
Patient Info
ODM
XML
Clinical
(CRF or eCRF)
Trial Data
(defined by
SDTM)
(e)Source
Document
Integrated
Reports
Administrative,
Tracking, Lab
Acquisition Info
ODM
XML
CRF, Analysis
Data
Operational &
Analysis
Databases
ODM XML
Define.xml
SDTM Data,
Analysis
Data,
Metadata
Regulatory
Submissions
End-to-End Seamless Integration;
Semantic Interoperability
Open Data Model - XML based, CDISC compliant
Investigator
EDC
ODM
CDMS
Op DB
LAB
Subject
Patients
SDTM
ADaM
Approval
Pharma
Physician
Medical & Statistical
Reviewers
Source: Dave Iberson-Hurst
Copyright © 2007, SAS Institute Inc. All rights reserved.
Site to Sponsor to FDA Data Flow
Healthcare
Drug Sponsor
CDISC Content and Interchange
CDASH
CDASH
ODM
Interchange:
HL7 output file
CDISC Content
Trial Design
FDA Reviewers
Sponsor
Data
Warehouse
(ODM)
Site Data
Archive
(ODM)
Copyright © 2007, SAS Institute Inc. All rights reserved.
MedWatch AE
Reports (ICSR)
Data Checker
and Loader
Janus
FDA/NCI
Analytical Data
Warehouse
Review
Tools
Constant Standards and Anticipated Transitions for
Clinical Research
(Includes ODM XML for Submission Transition Period)
Content
Sponsor
Protocol
Transport
Paper
Content
ODM XML
V3 XML
Sponsor
CRF Data
Submission
CRTs
Transport
Paper/PDF
Content
Sponsor
Transport
XPT V5/PDF
2002
Copyright © 2007, SAS Institute Inc. All rights reserved.
ODM XML
ODM XML
2007
2009
V3 XML
2012
Retrieve Form for Data-Capture
 Retrieve Form for Data Capture (RFD), is an
integration profile jointly developed by CDISC and
IHE, which addresses the problem of integrated data
capture for patient care and clinical research.
 SAS software used as the data receiver and the
validated archive for this industry wide
demonstration of capturing the electronic health
record.
Copyright © 2007, SAS Institute Inc. All rights reserved.
Clinical Site Before and After RFD
Disease Registry
Entry Form
Clinical Trial
Sponsor
Case Report Form
Public Health Org.
Outbreak Report
Adverse Event
Data
EHR
Copyright © 2007, SAS Institute Inc. All rights reserved.
Safety Org.
•The
•Site site
staffstaff
mustengage
engage
just one systems.
system: the
with multiple
EHR
•Primary
and secondary
•The
uses EHR
do nottakes
align.over as
the pivotal data broker
•Primary and secondary
uses of data align
Source: L. Bain, CDISC Liaison to Healthcare
Figure 1B Submission Data Flow – Emerging State
Derivation
Programs*
Analysis
Programs*
Submission
Standard
Tools
Pat Y1 Y2 X1 X2
Pat Y1 Y2 X1 X2
ADaM
Submission
Custom
Pgms
SAS Transport
Statistical
Reviewer
Raw
Data
Submission
SDTM
SAS Transport
Derived
Data`
Company
A
Standard Tools
Patient Profile Viewer
WebSDM
JMP
etc.
Company
B
Company
C
*
*
*
JANUS (FDA)
*Structure and process is the discretion of the Sponsor.
Copyright © 2007, SAS Institute Inc. All rights reserved.
Medical
Reviewer
Protocol
Data Collection
& Mgmt
Analyses
& Reporting
CDISC SDTM Study
Summary (subset of CTR)
Clinical Trial Tracking,
Summary, Registry
Structured Eligibility
Criteria
Structured Eligibility
Criteria
BRIDG
Terminology
CDISC Trial Design Part I
(arms, elements, visits)
CDISC Trial Design Part II
Planned assessments
& interventions
(NCI Study Calendar)
CDISC Statistical
Analysis Plan
Submission
CDISC Trial Design Part I
SDTM(arms, elements, visits)
CDISC Trial Design Part II
SDTM Planned assessments
& interventions
(NCI Study Calendar)
CRF Data
(AE data)
LAB Data
Genomics Data
ECG
SAE Reports
Analysis Dataset
Metadata
CDISC Statistical
Analysis Plan
CDISC Study Data
Tabulation
Model (SDTM)
(CRF data and other, inc. SEND)
Analyses
CDISC ADaM
(analysis datasets)
Other Protocol
Template Sections
and Attachments
Report and/or
Submission
Preparation
Report Template
Content, etc
American Health Information Community
2 February 2007 - DHHS
 Population Health and Clinical Care Connections
Workgroup ( previously Biosurveillance
Workgroup)
 Bidirectional Communication, Case reporting,
Adverse Event Reporting and Response
Management
Copyright © 2007, SAS Institute Inc. All rights reserved.
Sentinel Network TO
Promote Medical Product Safety
7-8 March 2007
Copyright © 2007, SAS Institute Inc. All rights reserved.
MedWatchPLUS

This initiative will improve the collection and processing of AE
information for all FDA-regulated products

The primary focus is to develop a user-friendly electronic submission
capability for all who provide AE information to FDA

Facilitate submission of AE reports and better allow FDA to efficiently
and effectively use the information to promote and protect the public
health
Lise Stevens-Hawkins, CBER – May 2007 HL7
Copyright © 2007, SAS Institute Inc. All rights reserved.
MedWatchPLUS

Initiative will result in a public interface to FDA, a web-based AE report
environment to support voluntary and mandatory reporting

Considering the use of a “rational questionnaire” user interface design to
guide reporters and facilitate the need to control report quality – based upon
specific user profiles

Rational questionnaire will be developed under collaborative agreement
between NIH and FDA; however we need to constrain the scope
Lise Stevens-Hawkins, CBER – May 2007 HL7
Copyright © 2007, SAS Institute Inc. All rights reserved.
MedWatchPLUS
–

Includes the creation of an agency repository for reports received
through the portal

Includes synchronization of reports received through the gateway and
stored in AE systems

Includes agency harmonization of a variety of vocabulary domains
using NCI EVS and other sources

Data collection “backbone” for the system is the HL7 Individual Case
Safety Report (ICSR) Release 2 Draft Standard for Trial Use
Lise Stevens-Hawkins, CBER -- May 2007HL7
Copyright © 2007, SAS Institute Inc. All rights reserved.
Mission of the Integrated Safety Pilot
 CDISC Team will produce a safety data
submission
• Integrated safety database
• Key safety statistical analyses
• Follow the CDISC Standard (i.e., CDISC Roadmap)
• Assess the applicability of the CDISC Standard to
integrated data
 FDA Review Team will evaluate the submission
• Integrated safety review of data from multiple studies,
compounds, and sponsors
Copyright © 2007, SAS Institute Inc. All rights reserved.
Data to be used in the Integrated Safety Pilot
 Pediatric safety data
• multiple studies and sponsors
• provided by Divisions of Cardio-Renal Drugs and
Pediatric Drugs
• mapped to SDTM by SAS
• documentation available for most of the studies - study
report, blank/annotated CRF, define.pdf
Meet FDA Critical Path Requirements and the Interface
with Healthcare
Copyright © 2007, SAS Institute Inc. All rights reserved.
Standardizing FDA Data to Improve Success in Pediatric Drug Development
Case Study: Harmonizing Pediatric data across sponsors using SAS and the CDISC model
Chris Decker, SAS Institute Inc., Cary, NC ,USA
Julie Maddox, SAS Institute Inc., Cary, NC ,USA

ABSTRACT

The Federal Drug Agency (FDA) has accumulated the largest number
of regulatory submissions of pediatric clinical trial data in the world. In
line with the Critical Opportunities initiated by the FDA in 2006, topic 6,
opportunity 72 describes the development of a pediatrics database with
a key goal for of converting existing electronic datasets from pediatric
studies to a standardized format (CDISC) so that the data can be
imported into a data repository that can be queried. A systematic
analysis of data from across various pediatric trials is difficult because
the data from these studies have been submitted to the Agency in
various non-standardized structures and formats by sponsors. To
facilitate meta-analysis across multiple studies, the legacy data that
reside at FDA need to be transformed into a uniform standard structure
that is CDISC/SDTM compliant. This paper describes the process
used to convert and harmonize clinical data from 29 different studies
over 7 sponsors into SDTM domains. This project used SAS tools to
convert legacy data from submitted pediatric studies to the
standardized CDISC SDTM format for cross study analysis and
research.
Copyright © 2007, SAS Institute Inc. All rights reserved.
Copyright © 2007, SAS Institute Inc. All rights reserved.
• Submission Standards
• Protocol Representation
• Critical Path Initiative
WHO International Clinical
Trial Registry Platform
• Liaison Status to ISO/TAG215
Terminology
• Submitted CDISC Standard
as New Work Item
BRIDG
• Protocol Representation w/
elements mapped to EudraCT
• Discussing all CDISC projects
PhRMA
EFPIA
• Shared Information
• Business Case
• CDASH
• IA Project
• eSubmissions
NIH / DCRI
C
D
A
S
H
Data Collection Stds
(FDA Critical Path)
• Integration Profile
CV/ TB Data Stds
Copyright © 2007, SAS Institute Inc. All rights reserved.
• Healthcare Link Demo
Copyright © 2007, SAS Institute Inc. All rights reserved.