Steve Wilson, DrPH (Biostatistics) Deputy Director, Division of Biometrics II, CDER, FDA
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The internet as a means of recruitment, electronic data capture,
monitoring, patient education and data management – a regulatory
perspectiveSteve Wilson, DrPH (Biostatistics)
Deputy Director, Division of Biometrics II, CDER, FDA
Session 2: Regulatory Updates and Clinical The 4th Kitasato University-Harvard School of Public
Health Symposium on
Advanced and Global Drug Development Techniques:Emerging Trends, Technology Updates, and Novel
Paradigms15:50 – 18:50, Tuesday, October 28, 2003
ANA Hotel Tokyo
Disclaimer
Views expressed in this presentation are those of the speaker and not, necessarily, of the Food and Drug Administration.
Acknowledgements
• Frances Cook, CDER/FDA• Rebecca Kush, CDISC• Randy Levin, CDER/FDA• Edward Nevius, CDER/FDA• Robert T. O’Neill, CDER/FDA
Outline• Internet Applications for Today’s Clinical
Trial– Recruitment– Monitoring– Patient Education– Electronic Data Capture– Data Management
• A Regulatory Perspective on Data Quality • Internet Applications for Tomorrow’s
Clinical Trial – the “eClinical Trial”• The Key Role of Data Standards• Concluding Comments
Today’s Clinical Trial• Phase 3, confirmatory study -- large,
complex experiment (this is Science!)• Difficult to plan and implement –
protocol-driven, yet unpredictable• Expensive (Phase 3, confirmatory
clinical trials)• Many people involved – many “players”• May be conducted in a number of
locations/countries
Today’s Clinical Trial• Mostly paper-based (90%?)– large paper
burden• Must be concerned about regulatory
aspects• Based on established “Good Practice”
norms• Conservative – reluctance to adopt new
technology• Communication is important• Data Quality is important• Did I say Expensive?
Today’s Clinical Trial• However, there is growing pressure to
do it better!• We need to be more efficient!• We need to overcome our dependence
on paper!• Unprecedented attention from
regulatory parties (ICH, FDA’s Strategic Plan)
• More proof – my participation in this meeting
Today’s Clinical Trial
Site/Trial PreparationSites;Trial Sponsor; IRB
Protocol DevelopmentPI or Trial Sponsor
Research HypothesisPI or Trial Sponsor
Subject Recruitment Sites & CRO
Trial Management&Data Management
Trial Sponsor; Sites
Data AnalysisReporting of Results
Trial Sponsor
Data CollectionSites
Patient EducationSites
Regulatory SubmissionTrial Sponsor to Agency
Adapted from
Internet Applications for Today’s Clinical Trial
Sponsors and vendors have recognized the value of the internet for:
• Patient Recruitment• Monitoring• Patient Education• Electronic Data Capture• Data Management
Why the Internet?• Growing popularity/accessibility• Many uses
– Business – Personal
• Still a number of concerns– Privacy/security– Data integrity– Bandwidth
• Developing new technology -- issues with adoption (generation gap)
Patient Recruitment• Competition for participants• Sometimes difficult to find patients -- specific
inclusion and exclusion criteria (screening)• Sometimes difficult to enroll • Multi-center, international studies• Evidence requirements (e.g., heterogeneity)• With it’s ability to reach a large population of
potential subjects, the internet is a natural, important tool for recruitment for a number of trials
• Large number of websites have been developed
Patient Recruitment & the Internet
www.clinicaltrials.gov
Data Monitoring• Quality of the data from clinical trials is the
responsibility of the sponsor• US regulation requires that the sponsor
monitor clinical trials• No standards – each sponsor determines
how they are going to monitor each trial• Process ensures that data are consistent
with source data – often many transcriptions, hidden-effects, etc.
• Multi-center trials labor-, cost- and paper- intensive (manpower, travel, communication, etc.)
Data Monitoring
Observation Source Document
Transcription CaseReportForms
Verification by Monitor
Monitoring Paper
Data Monitoring & the Internet
• Growing number of vendor and in-house sponsor applications
• Great potential for gain in efficiency, but slow to realize and accommodate
• Need for better description of process, metrics and “use cases”
• Need to work on GDMPs (Good Data Monitoring Practices) in order to develop more consistent technology solutions
• There is a potential that standards for collection of “operational data” will enhance solutions
Patient Education• Patients are an important • For the experiment to work – participants must
be motivated and informed (drop-outs and issues with missing data may affect the interpretability of trial results) – better trial design!
• It is important that patients understand and follow protocol instructions
• Need for communication with investigator• Ethical responsibility – connection to IRB• With the growing dependence on the internet
for medical advice, this is another natural for the internet – an open field for innovation in applications to clinical trials
Patient Education & the Internet
http://www.nlm.nih.gov/medlineplus/druginformation.html
Electronic Data Capture (EDC)
• Long history of systems to capture and transmit data electronically (e.g., “remote data entry”)
• Large number of sponsor/vendor solutions• To be successful – need attention to sites,
“eSource” data, standards, regulatory data quality/privacy conformance, trusted third parties, more technology, etc.
• Tremendous potential for efficiency and quality improvements
eSource Data
• Source data (as described by ICH) captured initially into a permanent record.
• Note: “Permanent” implies that any changes made to the electronic data are recorded via a “protected” audit trail.
CDISC/Centerwatch Survey:Belief in Strategic Importance of
EDC
82%77%
69%77%
67%
84%
0%
25%
50%
75%
100%
Reduce Cycle Time Improve Data Quality and Safety
Sponsors CROs Sites
Percent Agree
“EDC is a Major Strategic Initiative that will…”Source: CDISC-CenterWatch, 2002
Respondents, n=750, Pharma companies, n=211, Sites n=355, CROs, n=146
75.0%72.3%72.6% 70.6%
0%
25%
50%
75%
100%
All sites AMC IndependentSites
Non-ProfitClinics
Proportion of Patient Visits Still Using Paper CRF Forms Percent of Investigative Sites
Source: CDISC-CenterWatch, 2003
Top 5 Reasons for EDC Adoption Delays
1 Regulatory concerns 53.3%2 Lack of clear leader ECT/EDC application space 50.9%3 Cost or perceived cost 49.7%4 Inertia or concern with changing current process 49.4%5 Insufficient implementation of common data standards 48.5%
Bio
Ph
arm
aTech
Pro
vid
ers
CR
Os
1 Inertia or concern with changing current process 76.3%2 Resistance from internal users at sponsors 65.8%3 Cost or perceived cost 63.2%4 Resistance from management 60.5%5 Company is undecided as to importance of EDC 60.5%
1 Regulatory concerns 59.6%2 Inertia or concern with changing current process 56.9%3 Cost or perceived cost 54.5%4 Lack of clear leader ECT/EDC application space 50.9%5 Insufficient implementation of common data standards 50.4%
“Current market offerings for EDC have adequate functionality and meet current
needs for trials.”
31.5% 33.3%
67.6%
0%
25%
50%
75%
100%
BioPharma CRO Tech Provider
Per
cen
t A
gree
Source: CDISC-CenterWatch, 2002
EDC is Failing to offer Adequate Functionality…
Data Management• Large, expensive operation • Includes large number of operations,
from case report form (CRF) design to production of reports
• Large portion of the cost of a trial.• Software support (e.g., Oracle
Clinical, SAS)• Each sponsor develops own system• Described “Good Practice” – Society
for Clinical Data Management (SCDM)
Data Management
Observe Source Document
TranscribeCaseReportForms
Verification
EnterData
OperationalDatabase
EditChecks
Data Management
MorePaper
Data Management & the Internet
• Growing number of applications and enhancements to current systems using internet browser access to process
• XML offers potential for dramatic improvements
• CDISC ODM (Operational Data Model) provides a common path to describing systems
• To be successful – attention to sites, “eSource,” data standards, regulatory data quality/privacy conformance, trusted third parties, better technology, etc.
• Maturing -- large potential for improvement
A Regulatory Perspective on Data Quality
• GCP: Regulations and Guidance (ICH)• 21 CFR 11,1997• FDA Guidance on Computerized
Systems Used in Clinical Trials • Health Insurance Portability and
Accountability Act, HIPAA, 1996
A Regulatory Perspective on Data Quality
• ALCOA – Attributable– Legible– Contemporaneous– Original– Accurate
• We know what we do with paper, need to be comfortable that there are guarantees with electronic (example: corrections to CRF)
• Impasse -- Trusted Third Party Solution??
Internet Applications for Tomorrow’s Clinical Trial –
The “eClinical Trial”
Internet Applications for Tomorrow’s Clinical Trials –
The “eClinical Trial”
Site/Trial PreparationSites;Trial Sponsor; IRB
Protocol DevelopmentPI or Trial Sponsor
Research HypothesisPI or Trial Sponsor
Subject Recruitment Sites & CRO
Trial Management&Data Management
Trial Sponsor; Sites
Data AnalysisReporting of Results
Trial Sponsor
Data CollectionSites
Patient EducationSites
Regulatory SubmissionTrial Sponsor to Agency
Adapted from
eClinical
“A clinical trial in which primarily electronic processes are used to collect (acquire), access, exchange and archive data required for conduct, management, analysis and reporting of the trial.“
Ref.: Rebecca Kush, et al., eClinical Trials: Planning and Implementation, Thomson/Centerwatch, Boston, MA, 2003
Healthcare Delivery
Patient Information
Basic Clinical Research
Investigator-Sponsored
Data Acquisition, Analysis
Insurance Claims
Protocol-driven Clinical Trials
Biopharmaceutical Industry-SponsoredData Acquisition,
Analysis
Publications
RegulatoryDrug Approval
MedicalRecords
eClinical: A Global Healthcare Perspective
• Increase efficiencies of performing clinical trials• Facilitate ‘business’ processes among
investigators, pharma companies, CROs, vendors, laboratories
• Streamline data collection at investigator sites• Higher quality data due to consistency of
requirements• Allow software development against a common
standard• Provide long-term means for electronic data
archive• Facilitate FDA review of submissions• Improve links between healthcare delivery and
clinical research/trials
The Key Role of Data Standards
Data Sources
• Site CRFs •Laboratories
•Contract Research
Organizations•Development
Partners
OperationalDatabase
•Study Data•Audit Trail•Metadata
OperationalData
Interchange& Archive:ODM, LAB
Submission Data
•CRT/Domain Datasets•Analysis
Datasets•Metadata
SubmissionData
Interchange & Archive:SDM, ADaM
Scope of CDISC/HL7 Models
ODM = Operational Data Model SDM = Submission Data ModelLAB = Laboratory Data Model ADaM = Analysis Data Models
One harmonized CDISC/HL7standard/model
Concluding Comments• As illustrated by the development of
recruitment, electronic data capture, monitoring, patient education and data management applications, the internet is becoming an important feature of today’s clinical trial paradigm
• For the internet’s full potential of efficiency and quality improvement to be realized, there is a need for:– a more comprehensive appreciation of clinical
trial activities (i.e., the “eClinical” trial with a focus on the global healthcare enterprise)
– a commitment to data quality/regulatory requirements (and the potential role of TTPs?)
– universal attention (devotion?) to the development of standards (ICH/CDISC/HL7)
THANK YOU
wilsons@cder.fda.gov 301-827-5583
Any Questions?
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