Clinical trial databases are a

crucial investment in clinical

research

Part 2 - Design and Development of Case

Report Forms (CRFs)

Speakers: M.Duvenhage
K. Laras
S. Erari
12 Oct 2018
 Case Report Forms (CRFs)
• Study protocol is arguably the most important
document used during a clinical study, CRFs are
of vital importance
• CRFs are the most frequently used tools for
data collection
• A well-structured CRF simplifies database
design
• Study data quality relies on the quality of the
tools (CRFs) used to collect the data
 Poorly managed CRF development
Common risk and consequences
Increase the time of CRF creation
Delayed on clinical database creation and go-live
Collection of redundant data
Miss collection of relevant data (i.e. question on CRF not precise
enough, may lead into wrong direction)
Increase number of queries (increase data cleaning timelines)
Create strain on internal resources due to iterative review circles
Increase of the likelihood of database changes and unlock
Increase downstream impact on programming such as remapping of
variables
 Minimum Standards
• Design CRFs to collect the data specified by the
protocol
• Document the process for CRF design,
development, approval, and version control
• Document training of team on the protocol, CRF
completion instructions and data submittal
process
• CRFs based on rating instruments must be
properly licensed
• Ensure CRFs are available at the clinical site prior
to enrollment of subjects
 Best Practices
• Establish and maintain a library of standard forms to include:
– CRFs
– CRF completion instructions
– Subject diary cards
• Multidisciplinary team to provide input into the CRF design & review
(data management, biostatisticians, and clinical operations)
• Design CRFs with study safety and efficacy endpoints in mind
• Keep the CRF’s questions, prompts, and instructions clear, concise
• Comply with CDISC CDASH standards
• Design the CRF to follow the data flow of person completing the CRF
• Avoid referential and redundant data points
• Use carbonless copy paper (NCR) paper to ensure exact replicas of
CRFs
 Design and Development Process
(continue)
• First step into translating the protocol into data
• Multidisciplinary approach to designing and developing
CRFs
• Input from entire study team
• Design CRFs to collect the data specified by the protocol
• If you collect it, you need to enter it, clean it, analyze and report it
• CRF design should be taken into consideration before
the protocol is finalized
• If Protocol and CRFs are designed concurrently, the
quality of both the protocol and the CRFs can be
improved through continuous collaboration between
these teams
 Design and Development Process
(continue)
• CRFs should not collect data that ultimately will
not be used for analysis
• Extraneous data can adversely affect overall
data quality by drawing the attention of site
personnel away from key variables
• All data must be attributable to a subject
• All CRFs should also contain a provision for
investigator signature
 Design and Development Process
(continue)
• Data collected on CRFs will be consolidated for statistical
analysis, therefore use standard data structures
• Ensure biostatistician review of CRF’s primary and secondary
endpoints
• Consider developing standardized protocol templates, CRFs,
database structures, validation procedures, and reporting
tables.
• Consider CRF approval, CRF change management and
version control
• Training on CRF completion and CRF submission to data
coordination center
• Distribution of CRFs to sites – prior to first subject enrolled
 CRF Development Process
Draft CRF from Protocol

Diverse review team

CRF Review meeting
Provide comments to CRF designer
Implement all comments
CRF Designer Apply version control even on
draft version
Might require additional
review cycles

CRF Review Provide sufficient printing

Team specifications to CRF print
vendor

CRF Designer Ensure CRF is approved and

version control is applied.
Distribute to sites

CRF Book

Site(s)
 CRF development – Clarity and ease of
use
A number of factors contribute to ensuring a CRF is easily
understood and used:

• CRF layout,
• Section and concise question wording,
• Coding,
• Use of minimal text field responses,
• Avoid redundant data collection

CRF should be designed with the entire study

team in mind; All CRF data should be attributable to a subject
 CRF development – General
considerations
Consistency of CRF
– Formats, text font, size, question alignment, document
neatness
CRF whitespace
– Is there enough OR too much?
Page layout
– Portrait or Landscape
Page number
– Use consistently. Either use or don’t use at all.
– CRF book – ensure that numbers make sense when
repeating pages into different visits
 CRF development – General
considerations
Section headers
– Differentiate data modules on CRF
– Separate data into groups that are logically related e.g.
Demographics, Vital Signs, Medical History, Physical Examination,
Adverse Events, etc.

Log forms (e.g. Adverse Events, Medical History, Concomitant

medication)
– Add page numbers positions – important to identify missing
pages
– Consider how to identify the last page
 CRF development – General
considerations
Avoid splitting data modules across pages
– Exceptions may include questionnaires that are too long to fit on
the same page.

Questions should be clear / specific

– There should be no doubt what is expected
– Avoid “negative” phrased questions.
– Indicate if one response is expected vs. multiple responses
– If questions are to be skipped due to a specific answer, indicate
the skipping pattern clearly on CRF
 CRF development – General
considerations
Avoid graphics on CRF
– How will this data be captured / analyzed

Use of indicator questions – Yes/No

Repeat CRF modules consistently across different visits

– Vital Signs, Physical examination
– Ensures sections are the same to avoid confusion (e.g. item
order)
 CRF development – General
considerations
Don’t collect fields that can be derived
– Age, BMI, Adverse event durations
– Rather collect date of birth, height & weight, Adverse event start
and stop date that is used to calculate the derived values.

Avoid collecting redundant data

– Increase data entry, validation effort
– Inconsistency between data items – result in queries

Consistent date fields across entire CRF

– dd/MMM/yyyy vs. mm/dd/yyyy vs. dd/mm/yyyy
– Human readable – dd/MMM/yyyy (e.g. 08/NOV/2017) – CDASH
format
 CRF development – General
considerations
Appropriate use of units on CRF

Standard CRF header

– Include protocol title, subject number, standard visit number /
names, visit date, repeating log page numbers
– Subject initials – does this add value
 Paper CRF
• CRF is poorly designed, organized, or printed, there is a
greater potential for missing, or incorrect data
• CRF pages should be printed single sided
• Appropriate font and size
• Each CRF page should be clearly linked to the correct
site, subject, visit and follow-up interval
• Correct usage of CRF page numbers
• Use proper date format (e.g., mm/dd/yyyy,
dd/MMM/yy) should be clearly stated. Preferance for
CDASH DISC format ddMMMyyyy
• Time should be collected using 24hour clock (HH:MM)
 eCRF
• Provide functionality that helps to avoid potential
problems that can occur with paper CRFs (e.g.
dates use a pop-up calendar)
• Grouping of sites/subjects together thus avoid
assigning incorrect site/subject numbers.
• Edit checks programmed within the eCRF
application validate the data at the point of entry
• Capability to tab through fields in a prescribed
sequence, avoiding the potential for missed data
 Patient Reported Outcomes (PRO)
• Data directly reported by subjects is known as patient
reported outcomes (PRO).
• Used to quantify subjects’ subjective experiences (e.g.
pain intensity, quality of life)
• Completed by subjects themselves (instead of trained
study personnel)
• Wording of questions and instructions on a CRF
collecting PRO data should be clear and understandable
• Translate into local language
• PRO data can also be collected with a variety of
electronic tools commonly referred to as ePRO
Paper Diary Cards (PRO) Challenges
• Have high error rate (up to 80%)
• Illegible diary cards > Data entry
errors
• Participants back-fill diary cards (recollection
bias)
• Inability to query data
• Data not instantaneous /
Not directly link medication event
• Dataflow not automated
• Inability to effectively (timely)
intervene in poor adherence

Up to 80% of paper diary cards contain significant errors (Quinn et

al., 2000)
 CRF Review and Quality Process
• Review against the protocol to ensure all protocol-
specified data are captured
• Various team members may be involved in CRF
design (statistical, clinical, safety monitoring, regulatory)
• Certain types of CRFs (e.g., translations) may require
specialized input
• CRFs translated into multiple languages should be
carefully reviewed (e.g. back-translations)
• Reviewed prior to printing by preparing a prototype
using the same paper size
• eCRF should undergo User Acceptance Testing (UAT) by
team members / sites responsible for data entry.
CRF Review Group Exercise
CRF Review Group Exercise (Answers)
CRF Review Group Exercise (Answers)
CRF Review Group Exercise (Answers)
CRF Review Group Exercise (Answers)
 CRF Development Standards
• Clinical Data Interchange Standards Consortium (CDISC)
• Suite of standards supports medical research of any type from protocol
through analysis and reporting of results
• Dec 2014: FDA published binding guidance regarding the submission of
study data in standardized formats, which are available on the FDA
Study Data Standards Resources page
• Requires submissions to be submitted in an electronic format specified
by the FDA beginning 24 months (i.e. Dec 2016) from the issuance of
guidance (studies with a start date 24 months after the publication)

• Clinical Data Acquisition Standards Harmonization (CDASH)

• Basic standards for the collection of data in a clinical trial (Case Report
Form)
• CDASH 2.0 released on 25 Sep 2017
• CDASH User guide contains library of CRF Examples
• https://www.cdisc.org/standards/foundational/cdash
CDASH Example
VS Domain
 CRF Completion Guidelines
• CRFs should include clearly stated instructions
• May have associated CRF completion
guidelines
• Instructions regarding completion and
acceptable methods of correcting or changing
the CRF
• Paper-based CRFs typically use printed CRF
completion guidelines
• EDC systems may use on-line help screens
CRF Change Control and Versioning
• Appropriate authorization should be obtained for
CRF changes
• Relevant personnel should be consulted
• CRF changes should be clearly documented
• CRF should contain a clearly identified version
number
• Document the reasons for CRF changes
• If updated during an ongoing study, ensure all sites
use the latest CRF version
 Data Privacy
• CRFs must also avoid collecting data that could
lead to direct or indirect identification of the
subject
• Subject should be assigned a unique code to be
used for identification of that subject within
the study
• For example - do not collect: subject names,
home or work addresses, telephone number.
 CRF Printing – Best Practices
• Select and qualify your CRF printing vendor
• Distribute all study materials such as CRFs,
pocket cards, study schedule posters, pre-
printed return envelopes, and study contact
information simultaneously
• Obtain a prototype of the CRF book from the
CRF printing vendor
• Setup a vendor evaluation program throughout
the vendor relationship
 CRF Printing - Specifications
• Final print-ready electronic CRF files
• Type of binder, binder color, width, number of inside pockets,
cover text or art, and spine label.
• Specify the packaging instructions and include a packing list
• List of tabs (different visits)
• Company logo and text for the spine label
• If the printer is shipping to the sites, a list of sites and their
mailing addresses
• Specifications for printing the barcode (if applicable)
• Tentative timetable for sending the final-master copy to the
printer, final printing run, and deadline for releasing CRFs to
sites.
• Vendor should provide a complete prototype of the CRF book
for review and approval
Questions