Overall CDM Process

ICRI
Introduction
 CDM is consistently being recognized as a
primary part of clinical development team & in
some instances leads this team!
Evolution

 CDM has evolved from a data entry process into a

diverse process
 “to provide clean data in a useable format in a timely
manner”
 “provide a database fit for use”
 “ensuring data are clean & database is ready to lock”
 Now CDM manages
 entry of CRF data
 merging of non-CRF data
 systems & processes designed to identify bad data
 generate & track CRFs & queries
 determine protocol violators
 interact with site personnel to resolve data issues
CDM as a Science
 Factors contributing to CDM as a subject
 New technologies
 Growth predictions
 Globalization
 Need for a supporting infrastructure
 Role of CDM in overall drug development
organization is continuing to evolve
 Relationships with other organizations are
continuing to be defined & developed
 CDM is a very visible & strong organization now
 Considered as an integral, respected, highly valued
member of clinical development team
Importance of CDM
CDM is a vital vehicle in Clinical Trials to
ensure integrity & quality of data being
transferred from trial subjects to a database
system
 To provide consistent, accurate, & valid
clinical data
 To support accuracy of final conclusions &
report
 GCP Guidelines
 All clinical research data should be recorded, handled, & stored in a way
that allows its accurate reporting, interpretation & verification. (ICH GCP
2.10, 4.9, 5.5, 5.14 & ICH E9 3.6 & 5.8)
 Systems with procedures that assure quality of every aspect of research
should be implemented. (GCP 2.13)
 Quality assurance & quality control systems with written standard
operating procedures should be implemented & maintained to ensure
that research are conducted & data are generated, documented &
recorded, & reported in compliance with protocol, GCP & applicable
regulatory requirements. (GCP 5.1.1)
GCP Guidelines

 If data are transformed during processing, it should always be

possible to compare original data & observations with processed
data (ICH GCP 5.5.4)
 Sponsor should use an unambiguous subject identification
number or code that allows identification of all data reported for
each subject. (ICH GCP 5.5.5)
 Protocol amendments that necessitate a change in design of
CRF, subject diaries, study worksheets, research database &
other key aspects of CDM processes need to be controlled. (ICH
E9 2.1.2)
 Common standards should be adopted for a number of features
of research such as dictionaries of medical terms, definition &
timing of main measurements, handling of protocol deviations.
(ICH E9 2.1.1)
 Clinical Data Management
 CDM refers to management of data capture &
data flow processes in conduct of a clinical
research
 It begins with design of data capture instrument
& data collection, continues with data QC
procedures to assure quality of all aspects of
process, & ends with database finalization
Objectives of CDM

To ensure:
 That collected data is complete & accurate so
that results are correct
 That trial database is complete & accurate, & a
true representation of what took place in trial
 That trial database is sufficiently clean to
support statistical analysis, & its subsequent
presentation & interpretation
Clinical Development Process

Data Collection Financial

and Management Management

Site Trial
Management Management

Clinical
Regulatory
Program
Submission
Management

Site Pharmaco-
Systems vigilance

Source:Bio-IT 2004
Clinical Development Process

Data Financial
Processing Mgmt
Drug
Protocol Investigator
Coding & Vendor
Authoring Payments
Mgmt
Lab Contract
Load Mgmt
Site Schedule
Planning Mgmt
Site Site Resource
Recruitment Mgmt Monitoring
Mgmt
Site & Drug Process
Logistics Metrics
Reg Site
Planning & Selection
Tracking
Stats & Trial Portfolio
eSubmit
Reporting Benchmark Mgmt
Doc Trial
Mgmt Simulation
Site
Regulatory
Payments
Reporting
& Reports
Patient Site & Lab Saftey
Recruitment Comm’s Coding
Mgmt
Patient Medical
Scheduling Information Source:Bio-IT 2004
Multidisciplinary Team

1. Clinical Investigator • Regulatory affairs

2. Site coordinator • Clinical Data
3. Pharmacologist Management
4. Trialist/Methodologist • Clinical Safety
Surveillance Associate
5. Biostatistician
(SSA)
6. Lab Coordinator
• IT
7. Reference lab
• IT/IS personnel
8. Project manager
• Trial pharmacist
9. Clinical Research
• Clinical supply
Manager/Associate
• Auditor/Compliance
10. Monitor
 CDM Process
Subject

CRF

DCF
Investigator Monitor Statistician

Sample
CRF DCF NDA

Clinical
Lab Data
Results
Regulatory
Authority
Central Data Manager Clinician
Laboratory 21 Jan 2006
Role of DM in Clinical Research

DATA
MANAGEMENT

PROGRAMMING

BIOSTATISTICS
 Data Flow Chart
Set up database,
with built in range
checks for validating
data at the data entry stage
Log in CRFs received via
Courier or CRF images received
via telephone line
Final Data Quality
Audit plus statistical
quality control procedures
Database Lock
Create data entry forms
Program complex
(linked to database)
data edits separately
with formats similar to
those of CRF pages
Data Entry & Validation using Periodic Conversion of
built-in range checks on an database for applying data
ongoing basis edit checks
Interim Data Run edits on converted
Quality Audits data
Query Resolution &
Database Correction Review edit lists &
send queries to Sites after
manual review
Paper based data collection
sample or
analysis results
test data

Core Lab or
Events Committee
performs analysis

Clinical Data CRF

Patient Research Coordinator Monitor / CRA CRF/core lab data

enrolled in trial completes paper CRF Source Document mailed to
Verification Data Entry Group

Clinical Trials
Database
iterative query
resolution process
(paper faxed or
mailed)

Data queries issued Data Entry

and resolved Data Entry QA Data entered into
Database verified Clean data database
to CRFs

Biostatistician
Data Analysis
Electronic data collection
sample or
test data analysis results

Core Lab or
Event Committee
perform analysis

Clinical Data

Patient Research Coordinator CRF submitted

enrolled in trial completes electronic CRF electronically

Electronic
query resolution

Monitor CRA
Source Document Real-time review
Verification of data

Clean data

Clinical Trials
Biostatistician Database
Data Analysis
Acquisition or Collection of
Clinical Trial Data
 Data Capture Instrument
 CRF Design
 Paper forms (‘No Carbon Required’ :NCR)
 Remote Data Entry
 Electronic data transmission from Central lab
 Central web based system & Other technologies
Data Source & Data Definition
 Identify Data Source
 Study Sites
 Reference Lab
 ECG/RDE
 Data Definition
 Identify data required (data items, study variables)
 Define variables
 Source Data Verification (SDV)
 Edit Checks
Validation Processes
 Testing of Screen vs DB structure
 Validation of
 Range
 Date
 Format
 Coding
 field discrepancies
 Testing of
 second entry verification
 file comparison
 batch verification
 Design specifications of software
 Criteria for acceptance or rejection of software
 Results documentation
 Review & approval documents
Data Validation/Edit Check

 Consist of computer checks on data to assure validity

& accuracy of data
 Validate data against predetermined specifications
 Primarily used to check efficacy data unique to current
study
Validation Checks
 Range checks
 To identify inaccurate or invalid data & statistical outliers
 To ensure that data outside of permitted range are to be
clarified & verified

 Consistency checks
 To highlight area where data in database are
inconsistent
 Presence checks
 To ensure completeness of data
CRF Design
 Design CRF along with protocol to assure collection
of only data protocol specifies
 Guidelines to collect data through independent
means
 Design CRF with primary safety & efficacy endpoints
in mind as main goal of data collection
 Establish & maintain a library of standard forms
 CRF to be available for review at clinical site prior to
approval
 Use NCR paper or other means to assure exact
replicas of paper collection tools
CRF Development & Tracking
 CRF completion guideline is printed as parts of CRF
 Training sessions are conducted for investigators & SC
during study initiation meeting
 Receipt & Tracking of CRF
 Tracking process encompass verification of arrival date & its
acknowledgement & its progress through process
CRF Scanning

 CRF are scanned soon after receipt in CRF

Tracking System & archived electronically as
backup into an image database by designated
CDC
 Benefits:-
Effortless access to CRF images
It provides a single source for most up to date copy of
CRF
Ensures that original entries were not overwritten during
clinical CRF / data review
EDC Processes
 Develop e-CRFs along with Monitoring, Statistics,
Regulatory affairs, & Medical teams
 Ensure
 Collection of safety data
 User-friendly screens
 Flexibility of data entry
 Validation procedures
 Query management tools
 Audit trails
 Data transfers
 Integration of laboratory & other non-CFR data
Data Storage
 Backup copies to be taken frequently
 Paper documents should be scanned & electronically archived
 Database design specifications
 Raw data
 Audit trail
 Original study documents
 Procedural Variation Documentation
 Database Closure
 Site copies of data
 Final data - ASCII, SAS Transport, pdf, CDISC ODM Model
External Data
 Vendor-specific training
 Vendor Audit
 Data clarification process
 Utilize standards such as HL7, CDISC
 Data editing & verification procedures
 File formats
 Data transmission
 Database updates
 Data storage & archiving
Coding
 Auto-encoder

 Dictionaries

 Process for change in dictionary or version

 Same version to be used for combined
studies
 Training

 Process for submitting changes to

dictionaries
Data Dictionaries

 MedDRA
 An International Conference on Harmonization (ICH)
initiative, is a standardized dictionary of medical
terminology
 WHO: WHOART, drugs
 World Health Organization Adverse Reaction
Terminology
 ICD
 International Classification of Diseases
 FDA COSTART
 Coding Symbols for a Thesaurus of Adverse Reaction
Terms
Data Cleaning
 Purpose, characteristics & complexity of study
 Critical variables
 primary & secondary safety & efficacy
 subject identifiers
 Documentation of
 Procedures
 Guidelines
 working practices
 references
 Testing the process
Data Cleaning
 CRF completion/data entry instructions
 Timelines for
 data entry
 running data checks
 replicating data.
 Database quality criteria
 Quality control plan
Image Review (a pre-entry review)

 CRF image also known as working copy CRF is

reviewed for accuracy, completeness &
consistency of data
 Any queries or discrepancy identified during
Image Review were annotated
Look for problems with legibility, incorrectly
completed fields, missing data & scientifically
invalid or obviously inconsistent data
Data Review

 Clinicaldata review by designated medical

reviewer
 Ensure complex medical data are reviewed
& assessed to detect any clinical nuances
in data
Data Query

A query is raised when a discrepancy or an

inconsistency is noted or annotated during
image review & during computer edit-
check.
 Subsequent changes in data must be
supported by signed Data Clarification
Form (DCF) or authorized Data Handling
Convention
 Declaring Clean File

 Clean File for final database is declared

when all clean data have been transferred
 After declaring Clean File, editing on
database will only be allowed with proper
documentation
Data Closure
 All data have been received & processed
 All queries have been resolved
 External data are reconciled
 SAEs are reconciled
 Coding list review
 Review for logic & consistency
 Final review
 Quality audit of data
 Error rate
 Updating documents
Data Closure
 Blind Data Review
 After clean file is declared, blind data review prior to final
analysis
 Data Listing
 Generate hardcopy listing of data for clinical study report
 Data Transfer
 Transfer of data to another site
 Sponsor, Statistician, Regulatory, eg eSubmission
 Electronic data archive
Archiving
Electronic repository of
 Clinical data
 Metadata
 Administrative data
 Reference data
 CRF or eCRF images in PDF form
 Program files
 Validation records
 Regulatory documents
 Audit trail
 Data structures
 Edit checks
 Transfer specifications
QA
 Compliance of procedures to
 Regulations
 Written procedures
 Error rates for variables used in primary & secondary safety &
efficacy
 Monitor aggregate data
 Site audits
 Inspections (CRF-to-database)
 Data quality impact analysis
 Quality Policy
 Standardized or validated data collection & handling processes
 Error prevention
 Process monitoring
 QC
CRF to
Database
Edit Inspection
Data
Coding Checks
Double & Data
Data Review
Image Entry
System SDV by Review
Validation CRA
By
Clinical IT
The Quality of overall data is thus
increased because sooner a data
capture problem is detected &
corrected, higher quality of final data