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?