I.

PhactaX - A package for data management system and related web sites for conducting medical researches and clinical trials

PhactaX - 의학연구 및 임상시험 수행을 위한 자료관리시스템 및 관련 웹사이트 패키지

Okgu Kim*, Sun-Ha Kim†,††, Young-Shin Kim†, Hee-Jung Ahn†, Young Koh†,

Hyoung-Joo Lim†, Jin-Young Jang†, Ju Han Kim*,**, Byung Joo Park*,†,††

* Interdisciplinary Program in Bioinformatics, Seoul National University College of Natural Sciences

†Seoul National University Hospital Clinical Trial Center

††Departement of Preventive Medicine, Seoul National University College of Medicine

** Seoul National University Biomedical Informatics

Abstract: Medical research and clinical trial process includes the flow of data from investigational sites to the data management center for statistical analysis. Therefore data management has a key role due to its impact on the whole process of the research. To support data management of middle and small-size data management center, we have developed a data management system and web sites for adverse event vocabularies and common electronic case report forms, which we collectively call PhactaX.  The data management system, PhactaManager, provides a web interface for remote data entry with online data validity check support using XML based electronic case report form description language. PhactaDictionary, a web site managing adverse event vocabularies, includes MedDRA and COSTART for browsing and searching.  PhactaForm is a web site managing common data elements, sample case report forms, and questionnaire papers.  These three programs are integrated using Simple Object Access Protocol for remote procedure call and data exchange.  PhactaX is going to be distributed to the domestic pharmaceutical companies as well as research institutes conducting new drug development freely after internal tests.

Keyword: Medical research, Clinical trial, Data management system, Case report form, Adverse event

Introduction

Conventional paper based medical researches and clinical trials raised the following problems. Firstly, delay happens when delivering paper case report forms (CRFs) from the investigation sites to the central data management center. Secondly, storage space for the received paper CRFs by the center results in spacial and management burden. Thirdly, transcription by data enterers from the paper CRFs to clinical trial management system (CTMS) inevitably causes transcription errors, which needs double or triple entry.

There are remote entry enabled clinical trial management system available. Clintrial, Oracle Clinical, and TrialDB are CTMSs used for the management of data from medical researches and clinical trials. However, the two former systems are commercial and too expensive for smaller-size data management center and all of the systems are dependent on the database management system (DBMS) for the performance enhancement and functionality extension.

The dependency of CTMS on DBMS has the following problems. Firstly, DBMS technicians are needed to properly manage the database and have to learn CTMS also to manage data of medical research. Secondly, research coordinators and data managers, such as research nurses, have to understand the internal architecture of database to take advantage of the functionality provided by the CTMS as well as the DBMS.

We developed a package, called PhactaX, for middle and small-size data management center performing medical researches and clinical trials. PhactaX consists of three parts, PhactaManager, PhactaDictionary, and PhactaForm. PhactaManager is a data management system providing a web interface for remote data entry with online data validity check support using XML base electronic case report form description language. PhactaDictionary, a web site managing adverse event controlled vocabularies including MedDRA and COSTART for browsing and searching. PhactaForm is a web site managing common data elements (CDEs) and sample case report forms of clinical trials and questionnaire papers of epidemiological researches.

II.  PhactaManager

PhactaManager is a web site for entering, managing, and retrieving medical research and clinical trial data. Figure 1 shows the data entry page of the enter module.

It consists of four modules. They are administration module, design module, enter module, and retrieve module. Administration module manages the whole system. Access privilege on every parts of the system and user management menus are provided. A study designer first designs data management strategy using design module. He or she creates a study, creates several sections as needed in the study, and registers electronic case report form (eCRF) pages in the sections for actual data entry and online data validity checking. Data enterers enter data into the eCRF pages that were previously designed using design module by the study designer. Lastly, data retrievers, such as research coordinators or statistical analyzer, retrieve the data inside the system as an SAS or a Microsoft Excel file format.

Each eCRF page is described using XML based eCRF description language. PhactaDesigner is a Java standalone program for designing, validating, and previewing eCRF pages. Figure 2 shows PhactaDesigner with edit window for XML content typing and output window for checking the output messages printed by the XML parser, the XML validator, and the XSLT processor embedded in the program. After finishing designing eCRF pages, the study designer registers them into the design module of PhactaManager as described in the previous paragraph.

eCRF description language is based on XML defined using XML Schema. The language was designed using CRFs of clinical trials performed at Seoul National University Hospital Clinical Trial Center (SNUH CTC) since 1995 and has the following functionalities.

Data element types including text, textarea, checkbox, integer number, real number, and date for data entering

Value domain specification for the online validity checking of the entered data

Static page description tags, such as static text, text alignment, table, and special characters

Figure . A screen shot of PhactaManager (accessible at http://manager.phactax.org). Module menus are located in the upper frame. Submenus of Enter module are located in the left frame. An actual eCRF page for data entering is seen with the MedDRA adverse event term searching window.

III. PhactaDictionary

Figure . A screen shot of PhactaDesigner. It is used for designing eCRF pages. Designers enter XML content according to the eCRF description language grammar in the edit window, validates the XML content, and see the HTML page transformed from the XML content as a preview (The HTML window is just under the edit window with the 'HTML' tab).

PhactaDictionary is a web site for browsing and searching adverse event terms. It includes MedDRA 5.0, 5.1, 8.0 and COSTART adverse event controlled vocabularies and has collectively about 200,000 terms. Figure 3 shows a snap shot of PhactaDictionary.

As performing medical researches and clinical trials, clinical investigators observe several adverse events including adverse drug reactions. They are forced to record every adverse event for the safety of subjects and for the safety evaluation of the hypothesized intervention. A systematic controlled vocabulary has to be used for comparison, classification, and analysis of adverse events. We chose MedDRA controlled vocabulary as the major one because it has been internationally adopted after International Conference on Harmonization (ICH) proposed. COSTART controlled vocabulary was also embraced for backward compatibility to the past medical research and clinical trial results.

In PhactaDictionary, users can browse the hierarchy and search terms of MedDRA and COSTART. PhactaDictionary also supports term search functionality through Simple Object Access Protocol (SOAP). PhactaManager uses it for adverse event term searching when users enter data.

IV.  PhactaForm

Figure . A snap shot of PhactaDictionary (available at http://dictionary.phactax.org). Users traverse the hierarchy and search terms of MedDRA and COSTART controlled vocabularies.

PhactaForm is a web site for managing CDEs and sample CRFs of clinical trials and questionnaire papers of epidemiological researches. Figure 4 shows a screen shot of PhactaForm.

Common data elements are the data elements that have the same value type and are commonly embedded in different clinical trial CRFs. As CDEs are embedded, data comparison among different clinical trial results for systematic review or meta analysis can be accomplished with little effort. Using CDEs are also beneficial when designing CRFs. Users can design eCRFs as a combination of CDEs with non-CDEs where CDEs are considered as building blocks.

As having performed clinical trials for new drug development of multi-national pharmaceutical companies, SNUH CTC has accumulated know-how about designing CRFs. Particularly, Division of Pharmacoepidemiology of SNUH CTC has performed and supported national multi-center clinical trials and epidemiological researches. The questionnaire papers developed by the division also valuable for planning epidemiological research. Therefore we disclose the forms used for clinical trials and medical researches to public using PhactaForm. Users can visit PhactaForm to take advantage of the registered forms.

Figure . A screen shot of PhactaForm (available at http://form.phactax.org). PhactaForm manages CDEs and CRFs of clinical trials, and questionnaire papers of epidemiological researches.

V.  Discussion

PhactaManager is under internal testing. The clinical trial data set, which come from the clinical trial we are currently coordinating, are used for entering, managing, and retrieving. After the internal test, we plan to licence PhactaManager to several clinical research centers and multi-center clinical trial groups contacting us for managing the data of their own researches.

We plan to embed more controlled vocabularies  in PhactaDictionary. International Classification of Disease is one of the candidates because it is one of the most popular standard controlled vocabulary for coding diseases for medical researches, especially epidemiological researches. As described above, PhactaManager supports adverse event term search functionality using SOAP functions provided by PhactaDictionary. Until now, we have spent considerable time to check the spell of adverse event terms clinical researchers wrote to encode as codes. As adverse event term search functionality gets used, we hope that the time to be spent for encoding of the adverse event terms will be much shorter than that of conventional encoding process.

The CDEs and CRFs of clinical trials and questionnaire papers of epidemiological researches are steadily registered into PhactaForm with the elaborate work of research nurses at SNUH CTC. We are modifying PhactaDesigner so that it communicates with PhactaForm to receive the XML content of a CDE directly using SOAP. Users do not have to visit PhactaForm to get the XML content of the CDE they want to embed in their new eCRFs.

Conclusively, PhactaX package will shorten the time for performing medical researches and clinical trials by providing PhactaManager for data management, PhactaDictionary for adverse event term searching and management, and PhactaForm for managing CDEs, CRFs, and questionnaire papers.

Acknowledgements

This research was performed with the support of the National Research Laboratory Project M10302000093-03J0000-04710 funded by Korean Ministry of Science and Technology.

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