Case Report Form (CRF) Design Made Easy: An Evaluation of Clinical Data Acquisition Standards Harmonization (CDASH) in Use

The standardized formats of clinical research data have been developed and established by the Clinical Data Interchange Standards Consortium (CDISC), which is addressing standardization in order to support the acquisition, exchange, submission, and archive of clinical data from individual trials and their metadata [1]. CDISC has developed the Clinical Data Acquisition Standards Harmonization (CDASH), which is a standard for data collection [2-4]. Data reliability, integrity, and exchangeability for clinical research depend greatly on having accurate and uniform definitions of the data items to be collected and the design of case report forms (CRF). The use of CDASH is very helpful for standardizing the items and data formats in a CRF for any trial across different research institutions.


Introduction
The standardized formats of clinical research data have been developed and established by the Clinical Data Interchange Standards Consortium (CDISC), which is addressing standardization in order to support the acquisition, exchange, submission, and archive of clinical data from individual trials and their metadata [1]. CDISC has developed the Clinical Data Acquisition Standards Harmonization (CDASH), which is a standard for data collection [2][3][4]. Data reliability, integrity, and exchangeability for clinical research depend greatly on having accurate and uniform definitions of the data items to be collected and the design of case report forms (CRF). The use of CDASH is very helpful for standardizing the items and data formats in a CRF for any trial across different research institutions.
Although CDASH is considered as a breakthrough to control the quality of CRFs, its implementation has scarcely been reported for actual clinical trials and its practicality has not been sufficiently discussed. Therefore, we present a report of using CDASH to design a CRF, an evaluation of its usefulness, and a discussion of our experience and findings.

Methodology
In this study, a medical student, with no experience of clinical trials, was given the task of designing a CRF using CDASH in order to evaluate its usefulness. The process of the study, which was implemented by only one student, is composed of 3 stages; training, production, and evaluation.
First, in the training stage, the student went through a training process to learn about clinical trials, CRF and CDASH. An experienced clinical data manager (CDM) lectured the student about clinical trials, how CRF and CDASH work in clinical trials, and how to use each standard. The training course was held for 2-3 hours, every 2 weeks, for 2 months. After finishing the course, the student read 3 manuals for self-study: CDASH Standard [2], CDASH User Guide [3] and Library of Example CRFs [4].
Next, in the production stage, the student was given the protocol and independently designed the CRF. The applied protocol was of a colorectal cancer clinical trial conducted in the University of Tsukuba Hospital and the Tsukuba Medical Center Hospital. This study was an open-label, single arm, therapeutic exploratory, phase I study. In total, 100 patients with colorectal cancer will be recruited from the University of Tsukuba Hospital and the Tsukuba Medical Center Hospital, and enrolled into the study if they meet the eligibility criteria. Ethical approvals were obtained from the Research ethics committees at the two centers. Patients enrolled in this study will receive daily *Corresponding author: Satoshi Ueno, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba Ibaraki 305-8575, Japan, Tel: +81-29-853-3415; Fax: +81-29-853-3258; E-mail: satoshi.ueno@md.tsukuba.ac.jp clinical practice, be collected clinical data (demographics, medical history, laboratory examinations, previous/concomitant medications and imaging test). This study aims to evaluate the immunosuppressive function in colorectal cancer patients. No particular criteria were used when choosing the protocol, because CDASH describes the basic data collection fields for 18 general domains such as 'Demographics' and 'Adverse Events', which are common to almost all protocols. A Principal Investigator (PI) in the trial and the CDM decided the data items of CRF. After the student received the data items from the CDM, the student searched CDASH for the appropriate parts to explain each data item and mapped the variables to the CRF. The data items defined in the protocol are listed in Table 1. When the items were not defined in CDASH, Study Data Tabulation Model (SDTM) standards were used instead [5]. For more detailed process of CRF design, see Appendix 1.
Finally, in the evaluation stage, the CDM evaluated the CRF designed by the student. The variables mapped in the CRF were compared with those defined in CDASH. To evaluate the performance of the designed CRF, we analyzed its concordance with CDASH. When the CDISC-defined part of the variable was identical, the item was counted as concordant. For detailed concept of this definition, see Appendix 2.

Results
The data items defined in the protocol, the domain of the data items, and the named variables by the student are listed in Table 1. A total of 52 data items were defined in the protocol. All the items were correctly categorized into 9 domains (Common Identifier Variables, Disposition, Demographics, Inclusion/Exclusion Criteria Not Met, Laboratory Test Results, Prior/Concomitant Medications, Substance Use, Tumor Identification and Tumor Results) and were accurately reflected in the CRF. Of the items, 30 were found in the CDASH manual and the remaining 22 were not; for these items categorized in domains 'Tumor Identification' and 'Tumor Results', we referred to SDTM. All the 52 items were named by the student according to CDASH or SDTM. However, of 52 items, 6 items categorized in the 'Inclusion/Exclusion Criteria Not Met' domain were incorrectly named. Excluding this domain, the concordance proportions of the other 8 domains were 100% ( What was the term for the listed oral chemotherapy taken?

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Limitations
There are two limitations in this study. First, the limitation of this study is it did not meet Tier 2 of the 2 levels of conformance to CDASH. Tier 1 evaluates the conformance at the CRF level and Tier 2 evaluates at the operational level [2,3]. We met only the Tier 1 level of conformance, because we did not apply the designed CRF to actual data collection. Second, because this is a case report, it is necessary to increase the number of subjects in experiment to obtain generalizable result.

Conclusion
Through our study we have confirmed that CDASH standard is useful to design CRFs, especially to design general domains such as 'Demographics' and 'Adverse Event'. It is also easy for researchers who do not have much experience in clinical trials to use the CDASH standard.

Declaration of Conflicting Interests
The Authors declare that there is no conflict of interest.