Basics of Case Report Form Designing in Clinical Research
Basics of Case Report Form Designing in Clinical Research
Basics of Case Report Form Designing in Clinical Research
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Shantala Bellary,
Binny Krishnankutty1, Basics of case report form designing in
clinical research
M. S. Latha
Ab stract Case report form (CRF) is a specialized document in clinical research. It should be study protocol
driven, robust in content and have material to collect the study specific data. Though paper
CRFs are still used largely, use of electronic CRFs (eCRFS) are gaining popularity due to the
advantages they offer such as improved data quality, online discrepancy management and faster
database lock etc. Main objectives behind CRF development are preserving and maintaining
quality and integrity of data. CRF design should be standardized to address the needs of all users
such as investigator, site coordinator, study monitor, data entry personnel, medical coder and
statistician. Data should be organized in a format that facilitates and simplifies data analysis.
Collection of large amount of data will result in wasted resources in collecting and processing it
and in many circumstances, will not be utilized for analysis. Apart from that, standard guidelines
should be followed while designing the CRF. CRF completion manual should be provided to
the site personnel to promote accurate data entry by them. These measures will result in reduced
query generations and improved data integrity. It is recommended to establish and maintain a
library of templates of standard CRF modules as they are time saving and cost-effective. This
article is an attempt to describe the methods of CRF designing in clinical research and discusses
the challenges encountered in this process.
Key words: Case report form, completion guidelines, case report form design, electronic case
report form, standard templates
protocol development, but may result in many versions, and hence, clean data is obtained much quickly, resulting
and hence needs to be version controlled. Timing of the in timely database lock, faster regulatory submission, and
design process will also play an important role as both the subsequent approval.
approaches have pros and cons.
Designing a paper CRF is a tedious job that could
It is increasingly recognized that the design of the CRF (paper result in data errors and wrong conclusions, requiring
form/electronic form) is a key quality step in ensuring the meticulous attention to minimize duplication of CRF
data required by the protocol, regulatory compliance and/or pages. Chances of error during data transfer from the
safety needs/comments, study-specific hypothesis attributes, source document to paper CRF are common. Moreover,
site work flow, and cross-checking of data items within a for studies with large sample size if traditional method
form or across different forms are addressed.[3] The CRF of data collection through paper CRFs is opted, then
used in clinical research reduces messy clinical realities to manual data cleaning may be a major concern. However,
round integers and categorical answers.[4] this method may not require user training and system
validation as in the case of EDC systems, where such
This article is an attempt to describe the methods of CRF things are essential before implementing it. Despite their
designing in clinical research, discusses the challenges many advantages, eCRFs have not been accepted widely.
encountered and measures to be taken to prevent the Main reasons behind this are lack of available on-site
occurrence of issues in its development. technology, investigators’ lack of motivation, complexity
of installation, and maintenance of the software and
high investment cost.
PAPER CASE REPORT FORM VERSUS
ELECTRONIC CASE REPORT FORM
STANDARD CASE REPORT FORM DESIGN
There are two types of CRFs used in clinical research,
that is, traditional paper CRF and improvised electronic Designing a CRF is an art that should to be based on
CRF (eCRF). Paper CRF is the traditional way of data scientific practices and the design should be implemented
capture and a better option if studies are small or vary in keeping the end-user (the one who enters data in the
design, whereas eCRFs are considered if studies are large CRF) in mind. While designing, all important sections
with similar designs.[5] of the CRF should be included with care; always it is
worth to remember that insufficient/inaccurate data
In the current global scenario, eCRFs are preferred over collection would prove expensive during analysis. Hence,
paper CRFs as they are less time-consuming, and also it is advisable to have a standard operating procedure for
encourage the sponsor/pharmaceutical company to carry CRF preparation and to follow best practices of CRF
out large multicentric studies at the same time due to the designing.
ease of administration. It is designed in such a way that data
entry can be done with zero/minimal errors. Moreover, Primary objective of CRF designing is to gather complete
the regulatory authorities are readily accepting submissions and accurate data by avoiding duplication and facilitating
in which validated electronic data capture (EDC) systems transcription of data from source documents onto
are used.[6] the CRF. CRF should be designed with the primary
safety and efficacy endpoints as the main goal of data
While designing an eCRF, repetitive data such as collection.[6] Ideally, it should be well-structured, easy to
protocol ID, site code, subject ID, and patient initials complete without much assistance and should collect data
will be generated by the system automatically from the of the highest quality. Always minimum amount of data
first page to all others, thus ensuring no duplication of needed to answer the study hypotheses should be collected
CRF pages. avoiding collection of elaborate, unimportant information.
For ordinal data, to ensure uniformity and clarity among
In eCRF, linking the data between two related pages of raters, adequate explanation should be provided adjacent
CRFs becomes easy and quick. They have built-in edit to the CRF fields. Capturing the same piece of data in
checks tagged to each data field as well as to the CRF as more than one place (duplication) on the CRF should also
a whole. Therefore, majority of data cleaning activities be avoided. In other words, CRF should collect data in
will take place during the completion of the eCRFs, thus sufficient detail without ambiguity and at the same time,
reducing the time and effort required by data management should avoid redundancy and avoid capture of unwanted
personnel. Instant query resolution reduces the time spent details. Hence, striking the perfect chords to ensure balance
on obtaining the clarification from the site/investigator between effective data collection and structuring the CRF
to support accurate data entry is essential. Collecting the enter the response and helps to differentiate it visually
data in the coded form whenever possible is ideal as it from the entry fields for other questions
facilitates data entry (at CRF and at the database levels) • Separate the columns with thick lines
and helps the statistician in data interpretation and analysis. • Provide bold and italicized instructions
• Minimize free text responses
Important part of the CRF is an informative header and • Position only specified density of questions on each
footer, which can be customized.[7] In general, the header page
includes protocol ID, site code, subject ID, and patient • Page numbering if necessary, should be consistent
initials. Whereas, the footer includes investigator’s signature, throughout
date of signature, version number, and page number. • Avoid using “check all that apply” as it forces
assumptions about the clinical data
In order to enhance easy reading/understanding and • Specify the unit of measurement
accurate data entry, an uncrowded CRF layout should • Indicate the number of decimal places to be recorded
be preferred. Placing too many details on the same • Use standard data format (e.g., dd/mm/yyyy)
page, makes the CRF look cluttered and makes data throughout the CRF
entry difficult, which eventually leads to increase in data • Use precoded answer sets such as yes/no, male/female,
discrepancies. method of administration of medicine, and severity of
adverse event (AE) (mild/moderate/severe) wherever
Case report form design should be standardized to possible
address the needs of all those who handle the data such as • Not to split modules/sections (a set of one or more
investigator, data manager, biostatistician, clinical research related groups of questions that pertain to a single
monitor/coordinator, database developer/programmer clinical study visit) like, for example, AE section should
and data entry personnel etc. An effective CRF design not be split and laid across pages such that information
would always be user friendly. Moreover, it should capture related to a single AE will have to be collected from
legible, consistent and valid data, thereby, reducing query different pages
generations.[7] While designing the CRFs, design standards • Use “no carbon required (NCR)” copies to ensure
should be adhered to for improving the quality of data exact replica of CRF
collected. Hence, data should be organized in a format that • Use instructions including page numbers where data
facilitates data analysis and makes it simplified. has to be entered (e.g., during a follow-up visit, the
investigator is supposed to record whether any AE
The following points are to be borne in mind while has occurred and if occurred, details of the AE has
designing a CRF: to be recorded in the AE module. Hence, the field
• Use of consistent formats, font style and font sizes corresponding to this question on the module for the
throughout the CRF booklet particular visit would be having the options “yes” or
• Selection of portrait versus landscape versus “no”. There should be an instruction “If ‘yes’, please
combination layouts provide the information in the AEs page (page no.
• Use of clear and concise questions, prompts, and XX)” as shown in Figure 1.
instructions
• Visual cues, such as boxes that clearly indicate place
and format of data to be recorded should be provided WELL DESIGNED CASE REPORT FORM
to the person recording the data as much as possible VERSUS POORLY DESIGNED CASE REPORT
• Using the option of “circling of answers” should be FORM
limited as it’s hard to interpret; instead check boxes
would be appropriate Table 1 provides the comparison between well-designed
• Clear guidance about skip patterns like what to skip and and poorly designed CRF. In case of poorly designed CRF,
what not to skip should be mentioned at appropriate by placing a single line for required response results in
places variations in the investigator’s responses from site to site.
• Skips (are instructions provided in the CRF page to On the other hand, separate lines and boxes are provided
maintain the connectivity between pages) should be in the well-designed form, which gives the visual cues about
kept to a minimum by the placement of questions to what is expected as a response and thereby, reduces the
avoid confusions unnecessary queries. Usually, boxes are used for entering
• Provide boxes or separate lines to hold the answers. This dates and the date format (i.e., DD/MM/YYYY) should
indirectly informs the data recorder where to write/ be consistent on all pages of CRF. Units and decimal points
ADVERSE EVENT In some places, answers are coded in order to simplify the
Did any adverse event occur after the last visit?—Indicator
data collection. When codes are used to obtain an answer
Question
Yes 1 No 2 for a question, consistency in codes should be maintained
throughout the CRF booklet and there should not be any
If “ Yes”, please provide the information in the adverse events (AE) page (page no. XX) and give
details below:–Skip variation in the answer for the same question.
Did any unscheduled visit happen
after the last visit? For example, yes/no answers are coded as 1 = yes and
AE page number AE serial number
(Please provide details on page no.
2 = no (preferred coding) as shown in Figure 4. If the
YY)–Skip codes are assigned in this order, the same order should be
Yes 1 No 2 practiced throughout the CRF. Nowhere in the same CRF
Yes 1 No 2
“1” should be coded for “no” and “2” should be coded
for “yes”.
Yes 1 No 2
Figure 1: A sample case report form (CRF) page. An adverse event Even the location of these codes on the CRF should be
page of CRF is depicted showing codes, and skips questions consistent; same is shown in Figure 4. Clear instructions
should be provided to the user where ever necessary;
Table 1: Illustrating a well-designed and poorly otherwise, it will have a significant impact on the data
designed data fields imparting the significance management activities like database designing, data
of visual cues to help the site personnel to cleaning, data validation, and data extraction due to poor
understand the format understanding of the site personnel about the expected
Poorly designed Well designed responses. It is advisable to use indicator questions wherever
Date of visit: Date of visit: / / needed to avoid assumptions about the data. Use indicator
(DD/MM/YYYY) questions in connection to a set of other questions, and the
Blood pressure: / Blood pressure: / response to the indicator question would decide on whether
(mmHg)
Pulse:
the associated set of questions needs to be answered or
Pulse: (beats/min)
Temperature: Temperature: . (°C)
not. For example, in an AE question group, an indicator
Respiration: Respiration: (/min) question could be, “Did any AE occur after the last visit?”
On statins Education
V isit 1 V isit 2 V isit 3
Date of Visit
Blood
RBS
Dip stick Y N ARB /A CE Y N ARB /A CE Y N ARB /A CE
parameter
Uro bilinogen
Bi lir ubin
Ketone
Blo od
Protein
Nitrite
Leuk ocytes
Specific gravity
Ph
Microalbumin
Seal
CONCOMITANT MEDICATION
Medication Indication Route Frequency Daily dose Date (DD/MM/YYYY)
[dose, unit]
DEMOGRAPHY
Height (cm) •
Weight (kg) •
Smoker Yes 1 No 2
standard CRF templates are inclusion criteria, exclusion user-friendliness. These challenges can be overcome by
criteria, demography, medical history, PE, AE, concomitant proper planning by a team of data management personnel,
medication and study outcome modules, whereas, the biostatisticians, clinicians, and medical writers. Objectives
modules which captures efficacy data are not unique. should be defined clearly before designing. Consistent
Their design varies from study to study depending on the design is a crucial aspect as it reduces the number of
protocol specifications. mistakes in data entry. It is of great advantage when using
them across various studies. Maintaining standard CRF
CASE REPORT FORM CONNECTIVITY/WELL templates would resolve this issue. Collection of extraneous
data is another issue and measures should be taken to avoid
REFERENCED CASE REPORT FORMS it, as processing this becomes tedious. In such instances,
ensuring accuracy and quality become major challenges.
Linking of CRF (paper CRF and eCRF) pages wherever
Attention should be paid to avoid duplication. Design the
necessary is known as CRF connectivity. Each CRF booklet
is assigned with unique subject ID and it is the duty of CRF to avoid referential and redundant data collection.
site personnel to make sure that same ID is entered on all For example, collecting calculated fields/derivable data
pages of CRF booklet. Consistently entered subject ID will should be avoided and to ensure that data collection is
help in tracking the missing CRF pages. The fields such as cost-effective. Designing user-friendly CRF to reduce data
protocol ID, site code, subject ID, and patient initials make entry errors is again a challenge. Simple/standard designs
database designing easier and helps linking CRF pages to the should be incorporated wherever possible.
study database. The fields like protocol ID and visit labels
are informative features as they provide brief descriptions User feedback mechanism should be built into the CRF
of the study and the schedule of assessments, respectively. design and maintenance process. Best practices should
The CRF version number is a critical field that prevents be applied to improve the data quality and save time with
an incorrect CRF page being used. All pages of the CRF CRF design. Providing CRF completion guideline aids in
booklet should be numbered in sequential order, which will minimizing the challenges in data capture and data entry.
help in identifying queries through data validation procedures
and manual reviews. Page numbering not only provides the CASE REPORT FORM COMPLETION
site personnel with a quick reference to specific pages, but
also helps to design the database in a structured manner.
GUIDELINES
Especially, in case of eCRF, retrieving of CRFs becomes
A CRF completion guideline is a document to assist the
challenging if proper programming is not carried out. CRF
investigator to complete the CRF in a step by step manner
connectivity is crucial when statistical analysis plan (SAP) is
and is drafted concurrently in line with the CRF and
complex and these fields will be of help in statistical analysis.
protocol. Figure 5 shows sample page of CRF completion
guideline. There is no standard template for CRF completion
CHALLENGES IN CASE REPORT FORM guidelines as it is study specific. It should be prepared in
DESIGNING such a way that it enables the site personnel to complete
the CRFs with ease and legibility. CRF completion manual
Commonly encountered challenges in CRF designing are should provide clear instructions to site personnel for
consistency in the design, collection of precise data and accurate completion of CRFs along with clear expectations
General Guidelines
• Entries in the CRF to be made using preferably Black ink ballpoint pen
• Ensure all entries are accurate, legible to others and verifiable with the source data
• In caseof correction
• Unknown: UNK or UK
• Not Done: ND
• Not Applicable: NA.
• In questions where some of the possible options listed has/have to be selected, it should be
Ticked (as shown below) .
Male Female
Gender
including proper instructions on handling unknown of the CRF, it is advisable to print instructions on the page
data. For example, if exact date is unknown, then use a facing the CRF page (back side of the previous page) as the
preferred notation in the place of missing value (i.e., UK/ investigator can easily take instructions and simultaneously
UNK/2012). The language used should be simple with clear fill the CRF page. CRF completion guidelines document
instructions, concise, and easy to understand. should have version control and amendments should be
done as and when required.
Case report form completion guidelines document, while
bridging the gap between the study protocol and the data
collection process, explains the activities involved in CRF CONCLUSION
completion, correction, signing, and data handling.[7] It
provides unambiguous instructions on CRF completion Case report form design is the initial step in translating the
in all practical scenarios. For example, if data were protocol into standard questionnaires and is paramount to
wrongly entered and the site personnel wants to correct a successful clinical trial. Standard CRF should be designed
it, the instruction provided would be to strike-through in such a way that it helps the collection of consistent and
the incorrect data with a single line, put the initials (of valid data, ultimately resulting in submission of data to
the person who makes the change) with date and to write regulatory authorities and its acceptance. Regardless of
the correct entry in the margin against the corresponding the time and effort spent conducting the trial, the correct
line. Similarly, instructions will be provided for each data data points (response to a CRF question/data is entered)
entry field on each page in the CRF booklet. This helps to must be collected; otherwise, a meaningful analysis may
ensure completion of all required data fields and enhances not be possible. Therefore, a sound SAP should be used
the data flow.[7] CRF completion guidelines could be a as a tool to develop and judge the adequacy of the CRF,
separate document or could be a part of the CRF booklet which should be available to guide on what data points need
giving page by page instructions. If it is included as part to be captured on the CRF. To avoid future amendments,
it is important to have design principles in mind well in 4. Latimer P. Case report form insanity. J Clin Res Best Pract 2008;4.
Available from: h p://www.firstclinical.com/journal/2008/0805_
advance before CRF designing is initiated. These standard
Insanity.pdf. [Last accessed on 2013 Jun 17].
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for data acquisition. Pract 2011;7. Available from: h p://www.firstclinical.com/
journal/2011/1110_Data_Management.pdf. [Last accessed on
2013 Jun 17].
ACKNOWLEDGMENT 6. [No authors listed]. Good Clinical Data Management Practices.
Belgium: Society for Clinical Data Management; 2009. Available
from: h p://www.swaggerinfosolutions.pro/sridevi/New%20
We would like to acknowledge the technical support offered by Folder/ICRI/GCDMP_complete_OCT2009.pdf. [Last accessed on
Mr. Vinoth T. and Mr. Sagi Subbaraju that has helped us during 2013 Jun 17].
the preparation of this article. 7. Moon KK. Techniques for designing case report forms in clinical
trials. ScianNews 2006;9:1-7. Available from: h p://www.mycro.ca/
media/1533/sciannews91b.pdf.
REFERENCES 8. Clinical Data Interchange Standards Consortium (CDISC). CDASH
Core and Domain Teams. Clinical Data Acquisition Standards
1. Nahm M, Shepherd J, Buzenberg A, Rostami R, Corcoran A, Harmonization (CDASH). Austin, TX: Clinical Data Interchange
McCall J, et al. Design and implementation of an institutional case Standards Consortium; 2008. Available from: h p://www.cdisc.org/
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2. [No authors listed]. ICH Guidance E6: Good Clinical Practice: cdash_std_1_0_2008_10_01.pdf. [Last accessed on 2013 Jun 11].
Consolidated guideline. US HHS, US FDA, CDER, CBER, 1996.
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How to cite this article: Bellary S, Krishnankutty B, Latha MS. Basics
ucm073122.pdf. [Last accessed on 2013 Jun 11].
of case report form designing in clinical research. Perspect Clin Res
3. Lu Z, Su J. Clinical data management: Current status, challenges,
2014;5:159-66.
and future directions from industry perspectives. Open Access J Clin
Trials 2010;2:93-105. Source of Support: Nil. Conflict of Interest: None declared.
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