Title: Informatics for Clinical and Translational Research Daniel R' Masys, MD Professor and Chair Departme
1Informatics for Clinical and Translational
Research Daniel R. Masys, MDProfessor and
ChairDepartment of Biomedical InformaticsProfess
or of MedicineVanderbilt University School of
Medicine
2Session Outline
- Goals for this session
- Size and scope of clinical research ie., why this
topic is important - Role of informatics in clinical and translational
research - Informatics-related topics in the design and
execution of clinical research studies - Regulatory context Good Clinical Practice
standards and 21 CFR 11 - Design of forms and databases
- Data security and HIPAA compliance
- Specialized technologies
- Putting it all together
3Premise and Goals for this session
- This week is a teach the teachers session for
change agents - You might want (or be asked) to teach some of the
material covered here - The topics touched upon during this session are
taught in a 20 credit hour Masters course, and
all PowerPoint, readings, quizzes and course
outlines are available for your use. - This session is a sampler of topics from the
course
4Full Course website http//dbmichair.mc.vanderbil
t.edu/courses/crestdata/
Educational objectives Session outlines Readings P
owerPoint flies
5Widely used text Second Edition 2007
6Clinical Research as an activity
- Fundamental to translation of basic research to
medically useful interventions - Big business est. 95 B spent annually in U.S.
in biomedical research/drug and device testing - Academic centers lag behind commercial clinical
trials organizations in knowledge and skills
related to efficient and high quality clinical
research. - Academic center market share of clinical trials
now est. at 20, was 80 in 1990 - Generally inferior performance with respect to
error rates, missing data, timeliness of
submission
7National Context
- NIH Roadmap and Clinical Translational Science
Awards (CTSA) envision networks of clinical
researchers - FDA rules now being applied to NIH sponsored
research - Clinical research training has historically
included biostatistics and trial design, but
little regarding informatics and data management
8Barriers to Research
- Administrative bottlenecks
- Poor integration of translational resources
- Delay in the completion of clinical studies
- Difficulties in human subject recruitment
- Little investment in methodologic research
- Insufficient bi-directional information flow
- Increasingly complex resources needed
- Inadequate models of human disease
- Reduced financial margins
- Difficulty recruiting, training, mentoring
scientists
9CTSA A roadmap initiative
It is the responsibility of those of us involved
in todays biomedical research enterprise to
translate the remarkable scientific innovations
we are witnessing into health gains for the
nation.
10NIH CTSAs Home for Clinical and Translational
Science
Clinical Research Ethics
Trial Design
Advanced Degree-Granting Programs
Biomedical Informatics
CTSA HOME
Industry
Participant Community Involvement
Clinical Resources
Biostatistics
Regulatory Support
11Re-engineering Clinical Research
Interdisciplinary Research Innovator Award
Public-Private Partnerships
Bench
Bedside
Practice
Building Blocks and Pathways Molecular
Libraries Bioinformatics Computational
Biology Nanomedicine
Integrated Research Networks Clinical Research
Informatics NIH Clinical Research
Associates Clinical outcomes Harmonization Trainin
g
Translational Research Initiatives
12Role of Informatics in Clinical and
Translational Research
- Structured observation and structured record
keeping are the essence of science - Primary differentiation between routine clinical
care and research is how processes are controlled
(ie., protocol-driven) and information is managed
to make it useful for analysis
13Classical Data Management Flow for Clinical
Research
14Research Data Management Goals
- Create processes and systems that result in
research data that is - Accurate
- Complete
- Timely
- Verifiable
- Secure
- Available for analysis
15Regulatory ContextGood Clinical Practiceand21
CFR 11Electronic Records Signatures
16Regulatory Context Good Clinical Practice
standards
- General and uniform set of principles for
conducting clinical research - Two themes
- Respecting rights of participants
- Conducting research so that data is accurate and
verifiable - Required by FDA but a good (higher) standard for
NIH and other sponsored research
17http//www.fda.gov/oc/gcp/
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19GCP Standards address...
- Responsibilities of participating sites
- Responsibilities of coordinating centers for
multisite trials - Quality Assurance methods for data
- Audits
- Reporting to regulatory agencies
20GCP Principles of Data Management
- All data should be independently verifiable
- Normally done by comparison with locally kept
medical records in interventional trials - Structured approach to record keeping
- Physical structure tabbed participant folders
with dividers for different classes of
information - Logical structure database designs and tracking
systems
21GCP Principles of Data Management
- Research records are separately maintained from
healthcare-related records - Source document place where observation first
recorded - Source document verification comparison of Case
Report Forms (CRFs) with source documents - corollary CRFs are not usually considered source
documents
22GCP standards example Paper Case Report Forms
- Follow instructions
- Write legibly
- Originals normally go to Coordinating Center
copies local - No marginalia (literally outside the box)
- Forms designed so that all variables have a
current value (may be code for Pending, Missing,
Missed) - Correct units of measurement (best included with
value as separate field)
23GCP standards for Case Report Forms, contd
- Proper methods of correction
- Line through incorrect value (value still
visible) - Correct value added
- Correction initialed
- White-out is always red in an auditors eyes - no
correction fluids or erasures - Check forms for completeness prior to submission
- Double check and verify ID info on CRF
- Submit on time
2421 CFR 11Electronic Records Signatures
- Applies (only) to data submitted to FDA in
support of drug device applications - Address issues related to paperless data
management systems where there is no source
document for verification - Subpart C relates to digital signatures
- Full compliance requires formal software
validation testing and certification - To date, has paradoxically impeded rather than
advanced use of electronic research data
management systems
25Forms Design
26General Forms Design Principles
- Have definitions of all data to be collected in
hand before starting the study - Avoids unnecesary forms revisions that often
confuse Clinical Research Associates (CRAs),
participants, and creates statistical
complexities - Avoids fishing expedition approach to iterative
protocol modification
27Forms Design
- Think of forms as chronologically ordered data
containers - Define container size and content on the basis of
who, when, where - Who fills out the form
- When the data becomes available in the course of
the study - Where the data will be collected
28General Forms Principles, contd
- Design forms for ease of use
- this can be difficult since same form often
serves different user groups - Strive to be clear and unambiguous
- only achievable when others review the forms
- Create forms that make it more likely to do the
right thing than to make mistakes - amount of training required is an indicator
- Get draft forms early enough in the planning of
the trial that they can be pilot tested prior to
study launch
29Forms Design principles, contd
- Format should anticipate three purposes
- Data acquisition (recording on paper forms or
entering data into electronic forms) - Data entry from paper to computer
- Data retrieval (inspection, QA, inference)
30Forms Design principles, contd
- Top three considerations
- Consistency, consistency, consistency
- Includes consistency of overall layout, and
consistency of coding - Use standardized form header for referential
integrity items - Study ID
- Participant ID
- Event ID and/or Date
- Site ID
- Consider systems approach to ID data barcoded
labels or barcoded unique forms
31Web browser (thin client) electronic forms for
data entry and retrieval
- Strengths
- Deploy to any location on the Internet
- Platform independent (sort of be careful and
test all software on all potential clients) - No software to install or license on users
machines - Weaknesses
- Less efficient (compact interface)
- Fewer controls available
- Limited repertoire of widgets (buttons, lists,
etc.) - Slower
- Dependent upon Internet connectivity
32Specialized Software
33Specialized Software for Clinical Trials
- Registration
- Randomization
- Participant tracking
- Site communications
- Transaction or batch upload of local data to
coordinating center - Websites for protocols, forms, administrative info
34Specialized Software for Clinical Trials, contd
- Performance measures
- Site actual vs. projected accrual
- Data completeness
- Data accuracy
- Data timeliness
- Usually displayed as trends over time
- Performance measures should include reference
values for performance at all sites combined
35Data Acquisition Technologies
36Data acquisition TechnologiesKeyboard Data Entry
- Average keystroke error rates will be 0.1 to 1,
depending upon data type - Improve accuracy over baseline by
- Double entry and file comparison (gold standard
but inefficient and expensive) - Special technologies for referential integrity
items (e.g., barcode visit and participant ID) - Event-driven auditing and source document
verification of scientifically important
variables
37Data acquisition TechnologiesDouble keying
- Common best practice forms entered by two
different data entry operators - Computer generates difference (diff) file
- Third person (usually data manager with clinical
expertise) reviews and resolves differences - Increases personnel costs by factor of 2 - 2.5
over single entry plus sample-based auditing
38Data acquisition Technologies Barcoding
- Applications
- Referential integrity items identifiers for
participant, study, site, protocol, event/visit - Physical object tracking e.g., tissue specimens,
freezer inventory management systems - System-generated barcode labels
- Various barcode standards 3-of-9 generally used
for scientific applications - Produced by TrueType fonts or dedicated barcode
printers
39Data acquisition Technologies Barcoding, contd
- Barcode readers
- Keyboard wedge - wand or handheld scanner
plugged between keyboard and computer - Self-contained scanners with infrared or USB bulk
data upload (derived from warehouse inventory
systems)
40Barcodes and reading devices
Workstation accessories
Code 39 (3-of-9) with and without readable
text Note without text is not a security measure
and increases errors
Self-contained Reader unit
41Data acquisition Technologies Mark-sensing
Technologies
- Example Scantron (www.scantronforms.com)
- Strengths
- Mature technology
- Efficient for re-usable form scanning
- Weaknesses
- Low information density poor for most biomedical
uses - Susceptible to frame shift errors by users
- Requires forms printing
- Cost effective at level of 100K forms
42Mark sensing technologies
43Data acquisition Technologies POF Plain Old Fax
- Design issues
- Include signature or initials on faxable forms
- Strengths
- Widely used surrogate for paper
- Weaknesses
- Not considered a source document
- Legibility
- Requires additional effort to enter data into
computable form
44Data acquisition Technologies Fax Optical
Character Recognition
- Example Teleform (www.cardiff.com)
- Strengths
- Can substitute for data entry staff
- Includes design, recognition, and verification
functionality - 90 recognition accuracy depending upon data
type - Weaknesses
- Error rates equivalent to single entry, higher
than double entry - Cost vs. person hours becomes favorable only at
large numbers of forms (50-100K)
45Data acquisition Technologies Direct Computer
Entry by Participants
- Can use thin client (HTML forms) or thick
client ie., workstation forms (e.g., MS Access) - Strengths
- If well designed, eliminates data entry step
- Can add multimedia explanations and tutorials
- Can be more enjoyable for study participants than
paper forms - Weaknesses
- Requires basic computer skills (mouse /-
keyboard) - Requires literacy skills
- Requires staff assistance and verification
46Data acquisition Technologies Computer to
Computer Messaging
- Example import lab results from lab system
directly into research database for study
participants. - Strengths
- If well designed, eliminates data entry step
- Timeliness
- Accuracy
- Weaknesses
- Requires specialized computer programming
expertise - Requires standards for representing clinical data
(most widely used HL-7) - Requires willingness of systems managers at
source of data (e.g., medical center Information
Services) to allow data connections
47Data acquisition Technologies PDAs
- Example Pendragon software
- Strengths
- Portable, relatively low cost
- Nonprogrammer interfaces to MSAccess
- Weaknesses
- Limited screen size and navigation speed
- Not suitable for text entry
- Security lost or stolen PDA
48Data Archiving and Database design
49Commonly used data archiving and analysis software
- Single investigator, simple trial
- Spreadsheet (MS Excel)
- Beware using spreadsheets for HIPAA-regulated
data no audit trail capability - Workgroup-capable database management software
(MS Access, Filemaker Pro, 4th Dimension, MS
Visual FoxPro) - Data Center, multiple studies
- Enterprise relational database system
- Sybase, Oracle, MS SQL Server
- Dedicated statistical analysis packages
- SAS, BMDP, SPSS, S Plus, JMP
50Commonly used data archiving and analysis
software, contd
- Pharmaceutical companies - multiple drugs,
multiple sites, multiple studies, FDA audits - Dedicated clinical trials software (e.g., BBN
ClinTrials, Oracle Clinical)
51Sample data model for one-time administration of
a survey
one
Person (Participant) ParticipantID primary
key Last_name First_name Address City State Zip P
hone Fax E-mail MRN Birthdate SSN Gender Last_upda
te Update_by
one
Study_Data ParticipantID Date Answer1 Answer2 An
swer3 Answer4 Last_update Update_by
Best practices store Person table on removable
media with physical security OR store Person
encrypted by private key
52Simple clinical study with a variable number of
identical repeat visits
one
Person (Participant) ParticipantID Last_name Fi
rst_name Address City State Zip Phone Fax E-mail M
RN Birthdate SSN Gender Last_update Update_by
many
Study_Data ParticipantID VisitID VisitDate BPsys
tolic BPdiastolic Weight Sodium Potassium Chloride
Bicarb BUN Creatinine Last_update Update_by
Note In best pactice, primary key of Study_Data
is the combination of Participant ID and the
study visit, which defines a unique protocol
event. VisitDate is the calendar date that event
occurs.
53Clinical study with a baseline evaluation
followed by variable number of identical repeat
visits
one
Baseline ParticipantID VisitDate DataItem1 DataI
tem2 DataItem3 Last_update Update_by
Person (Participant) ParticipantID Last_name Fi
rst_name Address City State Zip Phone Fax E-mail M
RN Birthdate SSN Gender Last_update Update_by
one
many
Follow_Up ParticipantID VisitID VisitDate BPsyst
olic BPdiastolic Weight Sodium Potassium Chloride
Bicarb BUN Creatinine Last_update Update_by
54Data Security
55 Information Security Elements
- Availability - when and where needed
- Authentication -a person or system is who they
purport to be (preceded by Identification) - Access Control - only authorized persons, for
authorized uses - Confidentiality - no unauthorized information
disclosure - Integrity - Information content not alterable
except under authorized circumstances - Attribution/non-repudiation - actions taken are
reliably traceable
56Research Records Security,General Principles
- Physical Security
- Locked file storage for physical files
- Programmable locks best
- Change combination on a regular basis (common
practice twice a year) - Person-identifiable data
- Keep separate from other study data
- Consider additional protections such as two
person access requirements
57Research Records Security, contd
- Electronic Security
- No workstations viewable from public areas
- Password-protected login
- Screensaver timeouts
- Separate login and password for database access
- Store demographics data separately and encrypted
if feasible - Regular backups and offsite backup storage
58Research Records Security, contd
- Network Security
- Safest but least useful disconnect workstations
with research data from network - Keep all workstations and servers patched with
latest security updates - Run antivirus software on all machines
- Consider firewall computer to protect Internet
access point, and/or workstation firewall software
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60Security Rule Basic Concepts
- Applies security principles well established in
other industries - Like Privacy Rule, affects Covered Entities that
create, store, use or disclose Protected Health
Information (PHI) - Unlike the Privacy Rule, affects only PHI in
electronic format (not oral or paper-based) - Like the Privacy Rule, written for health care
research not the principal focus - Scalable burden relative to size and complexity
of organization
61Three Categories of Standards
- Administrative safeguards
- Policies and procedures to prevent, detect,
contain and correct information security
violations - Physical Safeguards
- IT equipment and media protections
- Technical Safeguards
- Controls (mostly software) for access,
information integrity, audit trails -
62Administrative Safeguards
- Required
- Risk Analysis
- Risk Management Plan
- Sanctions Policy
- Information System Activity Review (audits)
- Security Incident Response Reporting
- Data Backup Plan
- Disaster Recovery Plan
- Emergency Mode Operations
- Periodic Evaluations of Standards Compliance
63Physical Safeguards
- Required
- Workstation Use Analysis
- Workstation Security
- Disposal of media
- deletion of PHI prior to disposal, or
- Secure disposal so data nonrecoverable
- Media Reuse
- Deletion of PHI prior to re-use
64Technical Safeguards
- Required
- Unique User Identification
- No shared logins
- Emergency access procedures
- Audit controls
- Logs of who created, edited or viewed PHI
- Person and/or Entity Authentication
- No systems without access control
65If a research project maintains e-PHI
- Responsible group must designate a Security
Officer who has responsibility for implementing
HIPAA-compliant policies and procedures for
research use of e-PHI - Must do and document a risk analysis
- Must create risk management plan based on the
risk analysis - Must create and keep current a HIPAA Security
Rule compliance document that includes
description of how 17 Required elements are met,
and decisions regarding Addressable elements
66Widespread current research practices that dont
meet the standard
- Research workgroups that create or use PHI in
electronic format but have no written security
procedures, policies or training - Workstations with no login security (e.g.,
Windows98) - Data management and analysis applications used to
store PHI that have no ability to generate audit
trails - E.g., Excel spreadsheets with PHI in them
67Using the Internetfor Clinical Research
68Internet Functionality for Clinical Research
- E-mail
- Avoid putting HIPAA PHI in e-mail
- Study participant recruitment
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70Internet Functionality for Clinical Research,
contd
- E-mail
- Avoid putting PHI in e-mail
- Study participant recruitment
- Private FTP site as drop box for study related
file communications - encrypt files if they contain PHI
- Data submission and reporting
- Multi-site coordination and administration
71Approved Internet Technologies relevant to
Clinical Research
1containing person-identifiable i.e., HIPAA PHI
2 must be encrypted to HCFA/CMS std
72Sample Project administration website for
multi-center study
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74Putting it All TogetherResearch Data Management
- An artful selection of physical and electronic
management methods - Signed informed consent documents
- Paper forms
- Regulatory and project management binders
- Data models and databases
- Data acquisition and display technologies
- Communications technologies for project
management as well as data management
75Attributes of Successful Data Management
- Attention to detail
- Explicit structure and process
- Robust designs
- Anticipate failures, lapses and mistakes
- Design systems that identify and correct them
- Mechanisms for verification
- Well documented
76Lessons Learned about Data Management in Clinical
and Translational Research
- Effective data management is a continuous
process, not a point in time analysis - Historically, health care organizations and
providers have invested suboptimally in
information systems and this provides an uneven
infrastructure for clinical research - In health care organizations, data management and
information systems implementation is 20
technology and 80 sociology (R. Gardner) plan
accordingly
77Research Data Trends
- Data Tsunamis
- Genome, proteome, regulome,new forms of imaging
- High dimensionality variables gtgt subjects
78Premise and Goals for this session
- This week is a teach the teachers session for
change agents - You might want (or be asked) to teach some of the
material covered here - The topics touched upon during this session are
taught in a 20 credit hour Masters course, and
all PowerPoint, readings, quizzes and course
outlines are available for your use. - This session is a sampler of topics from the
course
79Educational objectives Session outlines Readings P
owerPoint flies
Full Course website http//dbmichair.mc.vanderbil
t.edu/courses/crestdata/
80(No Transcript)
81Please submit online evaluations
82Questions?