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CONSTRUCTING INTEGRATED CLINICAL INFORMATION SYSTEMS FOR TRADITIONAL AND NONTRADITIONAL USERS Martin J. Rosenberg, PhD, MAJARO INFOSYSTEMS, INC. ABSTRACT As can be imagined from the magnitude of information that must be collected, computer systems have long been a part of the drug development process. We call a computer system for the collection, retrieval, and analysis of clinical trial information, a Clinical Information System or CIS. The three functions comprising the current concept of a Clinical Information System are shown in Figure 1. Physicians who conduct clinical trials of new drugs transmit the raw data to the sponsor on case report forms (CRFs) which are then entered into a database management system (DBMS). The data from the DBMS is transferred to a data analysis package for statistical analysis and computer generation of tables and graphs which are then incorporated into reports which become part of the NDA. Although a variety of products are used by the U.S. pharmaceutical industry for data entry. storage, and retrieval, SAS has long been the standard software used for statistical analysis, report generation, and production of summary tables and graphs. Increasingly, pharmaceutical companies are attempting to enhance productivity by expanding the scope of their clinical information systems to embrace non-traditional users such as: investigators, in-house clinical staff, and FDA reviewers. As these systems become commonplace, companies are confronted with the prospect of having up to five different computer systems, each with incompatible data structures: a remote data entry system; a database management system for traditional data entry; a clinical data review system for use by in-house clinical staff; a statistical analysis system; and a computer assisted NDA review system (CANDA). This paper describes the emerging features of Version 6 SAS software, including enhancements such as screen control language, host windowing environments, mUlti-vendor architecture, multiple engine architecture, indexing, SAS/ACCESS software, and PROC SOL; and explores their role as a connectivity tool in constructing remote data entry, CANDA, and clinical data review systems in order to develop an integrated approach to clinical information systems. The development of CLiNACCESSTM, a clinical data review system designed to exploit these new features, is discussed. CLINICAL INFORMATION SYSTEMS Figure 1: Current CIS Before a new drug can be introduced into the marketplace, pharmaceutical firms must undertake a lengthy research process which can frequently last five or more years. The company collects information about the safety of the drug in both animals and humans; its efficacy in the diseases to be treated; the stability of the drug (how long it can the remain on the shelf without degrading); pharmacokinetics of the drug, i.e., how it is metabolized in humans; and the abil~y of the company to manufacture the drug in production quantities. In an effort to better manage the volume of information and to reduce the length of time required to introduce a drug in the United States, the Food and Drug Administration, in conjunction with the pharmaceutical industry, has been experimenting with ways of using computer technology to facilitate the NDA review process. Such a computer system is called a Computer Assisted NDA Review system or CANDA. Participants in the CANDA experiments have 1027 reported that similar systems would be of use not only by FDA reviewers, but by the medical staff of We designate pharmaceutical corporations. systems for use by the medical staff to monitor ongoing clinical trials, Clinical Data Review Systems. Simultaneously, there has been much interest in computer systems that permit the investigator to enter data and the sponsor to remotely monitor the trial. The intent of such systems is to collect more timely and accurate information. We call such systems Remote Data Entry and Monitoring systems orREDEM. structure (with the attendant risk of inconsistencies between the databases) and must either train the staff in the operation 01 multiple systems or maintain separate staffs for each technology. Consequently, it would be desirable to integrate these five functions. Since SAS software is already in common use throughout the pharmaceutical industry, this paper explores the emerging capabilities of Version 6 of the SAS system and the role they can play in producing the integrated CIS of tomorrow. With the introduction of these three new classes of users (investigators, in-house medical staff, and FDA reviewers) future clinical information systems will resemble Figure 2. Not every study will require all the facilities of the future CIS's. In particular, REDEM is likely to be used in selected studies only. However, pharmaceutical firms will increasingly expect to have these capabilities at their disposal. As such systems become commonplace, companies will be confronted with the prospect of having up to five different computer systems, each with incompatible data structures: a remote data entry and monitoring system; a database management system for traditional data entry; a clinical data review system for use by in-house clinical staff; a statistical analysis system; and a computer assisted NDA review system (CANDA). The introduction of separate, incompatible systems could adversely impact productivity. Companies must maintain duplicate databases for each ADVANTAGES FOR APPLICATIONS DEVELOPMENT The SAS system has always been a powerful product for data analysis and data presentation. The introduction of SAS/AF in Version 5 helped to extend that power to the non-traditional user. Version 6 further extends that power with greater ease of use, transparent access to data stored in a variety of data structures, and the addition of many desirable features associated with relational database management systems (RDBMS). These enhancements combine to transform SAS into a connectivity tool which spans databases, hardware, and software platforms. The Version 6 enhancements include: Screen Control language available in SAS/AF and SAS/FSP software. PROC PMENU which creates custom pull-down menus and dialog boxes, permitting a common user interface across all platforms. REMOTE DATA ENTRY AND MONITORING Support for host windowing environments such as Presentation Manager and DECwindows. (Support for Microsoft Windows is anticipated.) Use by investigators I PROC Sal which implements the emerging standard for fourth generation relational database query languages. DATA MANAGEMENT I STATISTICAL ANALYSIS I AUTOMATED TABLE AND GRAPH SAS/ACCESS software and Muttiple Engine Architecture which provide transparent access to databases such as Oracle, DB2, SOL/DS, and RdbNMS. CLINICAL DATA REVIEW Use by in-house medi cat staff SAS/CONNECT software distributed processing. GENERATION which facilitates Multi-Vendor Architecture, which perm~s applications to run on multiple hardware platforms. I CANDA Indexing of SAS datasets, which provides interactive applications with faster access to data. Use by fDA Reviewers Pigure 2: Future CIS 1028 Compressed SAS datasets, which can save disk storage space. used by the database administrator, to define the mapping between the host DBMS structure and SAS. Thereafter, access to the DBMS is transparent to the user. As shown in Figure 4, a SAS program that requires data sends a request to the engine supervisor, a portion of the SAS system. The engine supervisor selects the appropriate software engine to read the data, and the information is provided to the requesting program. No SAS dataset needs to be created. Screen Control language (SCl) serves two purposes. In SAS/FSP software, SCl performs sophisticated interactive edit checks during data In SAS/AF software, SCl is specifically entry. to create interactive full-screen designed applications. First available in Version 6.03, SCl has been enhanced in Version 6.06 to support a common user interface with pull down menus, dialog boxes, and other point and shoot tools. In particular, under the OS/2 Presentation Manager and DEC Windows, graphical user interfaces are supported, providing for the first time, the power of SAS software with the ease of use of a Macintosh like interface. SAS Application Requests Data ~----, I Another addition to Version 6.06 is Muhiple Engine Architecture. Multiple Engine Architecture provides the ability to use data stored in data structures other than a SAS dataset, for example data stored in another database management system (DBMS). Prior to Version 6.06, one had to extract data from a DBMS and create SAS datasets before the SAS system could use the data (Figure 3). This extra step of extracting data from a database and creating a SAS dataset can be a considerable obstacle to the non-traditional user. In addition, since the data is physically removed from the DBMS, as new data are added or corrections are made to the DBMS, the extracted data ceases to be current and must be re-extracted. I Engine Supervisor I I I Proper Engine l~----~ Figure 4: Multiple Engine Architecture Multi-vendor architecture refers to the ability of a SAS program written for one computer to be used on other computers. This is particularly important in the pharmaceutical industry where companies may use several types of computers, e.g. a corporate mainframe, a departmental mini-computer such as a VAX, and intelligent workstations or PC's. Because the CIS will have a common user interface across the hardware platforms, training costs can be minimized. Under multiple engine architecture, SAS applications will be able to run directly against other databases. A new procedure, PROC ACCESS, is PROC Sal and indexing bring to SAS two important database management features for performing queries. Sal is the emerging standard for relational database query languages. The SAS implementation will permit queries of both SAS datasets and other database structures, through multiple engine architecture. Indexing is a common database management feature that can speed online queries. Finally, compressed datasets will reduce storage costs. Extract Program User Specifies variables SAS Dataset Created Add to these enhancements, the SAS system's already widely used facilities for data analysis and data presentation, and we see that SAS software is a unique environment in which to develop applications for the pharmaceutical industry. Data Used by SAS Application Figure 3: Extract Process 1029 FSEDIT S274.EFFICACY----~-------- _ _ _ _ _ _ _.... Conmand ===> Obs Screen STUDY #: 274 STUDY: Curitol in Chronic Disease CENTER: S.F. GENERAL 1 6 PATIENT IDENTIFICATION INITIALS 10 NUMBER MJR 274-061 VITAL SIGNS TEMPERATURE and RESPIRATION TEMPERATURE (Fl: 98.7 RESPIRATION: 14 SITTING BLOOD PRESSURE and PULSE Reading #1 119 I 79 Reading #2 120 I 80 Reading #3 121 I 81 Pulse: AVERAGE READING: 120 I 80 n GO TO: Previous screen ADVERSE EVENTS DATA: . Figure 5: Cross-field edits and computations can be performed during data entry included in the new dataset. All the standard variable attributes (format, informat, label, type, and length) are automatically defined. To provide flexibility while enforcing standardization, the label, informat, and format may be customized to the study, while the name, type, and length of the variable are fixed. CLiNAcCESSTM CUNACCESS is a Clinical Data Review System engineered to take advantage of the emerging features of SAS. Originally written in Version 5.18 SAS/AF software for use on IBM mainframes under either the MVS or VM/CMS operating systems (see Rosenberg 1989a and 1989b), CUNAcCESS has been ported to the PC under Version 6.03 SAS software. Designed for use by medical monitors, clinical research associates, managers and other non·traditional users on the clinical staff, CUNACCESS has the following capabilities: single or double-key data entry; viewing and querying of data; graphics; descriptive statistics; and report CUNAcCESS features an extensive generation. context sensitive help system and an on·line tutorial to aid the new or infrequent user. Screens can be customized to resemble case report forms, and powerful cross field edit checks and computations can be performed during data entry. For example, to increase accuracy, clinical trial protocols often require blood pressure to be measured three times at each reading and the average used as the response. As shown in Figure 5, the data entry operator can enter the three sets of blood pressures and the mean will be accurately computed and stored in the dataset, available for immediate analysis. Data entry can now be performed either in CRF or in table view. Additionally, in table view, multiple windows can be opened for either data entry or browsing. The windows can be resized or zoomed to fill the entire screen. The Database Administrator is additionally permitted to structure new datasets, paint data entry screens, and manage study libraries. A key feature of CUNAcCESS is its data dictionary which is called the Clinical Questions Catalog (CQC). The Clinical Questions Catalog ensures uniformity of variables across studies, facilitating the pooling of informmion. The CQC also simplifies the study definition process. To create a new dataset, the Database Administrator simply places an X in the selection field for any variable which is to be CUNAcCESS's strength continues to be the ease with which data can be accessed and manipulated. For example, the report shown in FiglJre 6 can be created by simply selected variables from a list. 1030 DATA LISTING FOR STUDY S274 DATASET IS LAB 10 101 YEEK 0 4 8 12 16 20 BILIRUBIN CALCIUM 0.6 0.8 0.9 0.6 0.8 0.6 9.5 9.8 10.1 10.1 9.7 9.6 101 102 N= SGPT 13 8 12 10 12 12 14 14 17 15 19 -----------92 N= 102 SGOT 13 -----------67 6 0 4 8 12 16 20 28 1.0 0.7 1.0 0.9 0.7 0.9 0.8 9.0 9.2 9 •.6 9.4 9.2 9.7 9.5 17 12 11 10 13 14 11 -----------88 7 16 10 13 11 15 17 14 -----------96 Apr; l 6, 1989 Figure 6: A Report Produced by CLINACCESS SUMMARY Vp.j( computers, and enterprise wide mainframes, all with a common user interface. As the role of the Clinical Information System expands to encompass non-traditional users such as investigators, medical monitors, CRA's, and FDA reviewers, pharmaceutical companies are faced with an increasingly complex web of technology. In an effort to simplify the process, we might look for ways to integrate the various CIS processes. One way to do this is to explore existing standards in an effort to expand their use and leverage the invest· ment already made in training personnel and incorporating the technology. IBM Similarly, multiple engine architecture permits the same application to run against data stored in SAS datasets or in database management systems such In addition to minimizing as Oracle or DB2. application development, this can facilitate the transition from one DBMS to another or the sharing of information between divisions that use different databases. Mernatively, the addition of PROC SOL, indexing, data compression, and other database management tools may make storage of data in SAS datasets sufficiently powerful for many companies. SAS software is the de facto standard in the pharmaceutical industry for performing statistical analyses and presenting the results in graphical or tabular forms. Once data is in machine readable form, most of the subsequent processing is typically performed in SAS. Consequently, it is reasonable to examine whether SAS can play an expanded role in the CIS. As the concept of distributed data processing proliferates, applications developed in SAS software will offer the ability to simultaneously access data stored on multiple computers and database systems. For these reasons, the SAS system was chosen as the development platform for the CLiNAcCESS™ clinical data review system, which is deSigned to provide monitors, CRA's, and other non-traditional users wtth access to the information stored in clinical databases. CLiNAcCESS provides: single or double-key data entry; viewing and querying of data; graphics; descriptive statistics; and report generation. Many of the ideas of this paper have Mhough initially a statistical package, much of the recent development of SAS has been to add features commonly associated with relational database management systems and fourth generation languages. Version 6 of the SAS system, offers the potential to develop applications which can be run on personal workstations, department 1031 ACKNOWLEDGEMENTS already been incorporated into CLiNAcCESS and others are currently under development. CLiNAcCESS is available on IBM mainframes running Version 5.18 of the SAS system under MVS or VM/CMS; and on IBM PC compatibles running Version 5.18 of the SAS system under MS-DOS. Support for ·other hardware platforms and operating systems is anticipated. CUNAcCESS is a trademark of MAJARO INFoSVSTEMS, INc., Mountain View, CA, USA. All CUNAcCESS screens shown are Copyrighted (C) 1988,1989 by MAJARO INFOSVSTEMS, INC. and are used by permission. SAS, SAS/AF, SAS/FSP, and SAS/ACCESS are the registered trademarks of SAS Institute Inc., Cary, NC. SAS/CONNECT is a trademark of SAS Institute Inc., Cary, NC. For a number of years now, we've witnessed the evolution of SAS software into a product with greater interactivity and data management capabilities. Version 6 is a major step in that evolution. Companies that start now to exploit these new capabilities through systems such as CLiNAcCESS, have the potential of realizing substantial advantages over their competitors in terms of reducing the cost and time needed to bring a new drug to the market. DEC, DECwindows, VAX, VMS, and RdbNMS are trademarks of Digital Equipment Corporation. Macintosh is a registered trademark of Apple Computer Inc. IBM is a registered trademark and DB2, SQljDS, OS/2, and Presentation Manager are trademarks of International Business Machines Corporation. Oracle is a registered trademark of Oracle Corporation. MS-DOS and Microsoft are registered trademarks of Microsoft Corporation. UNIX is a registered trademark of AT&T. REFERENCES Rosenberg, Martin J. (1989a). An Integrated Approach to Computer Systems for NDA Preparation and Presentation. Proceedings of the Fourteenth Annual SAS Users Group International Conference. SAS Institute Inc., Cary, NC. pp. 786792. Rosenberg, Martin J. (1989b). Integrated Clinical Information Systems for Traditional and NonTraditional Users. Proceedings of the Second Annual MAJARO INFOSVSTEMS INc. provides statistical and information management services to the pharmaceutical, biotechnology, and food products industries, and specializes in extending computer technology to non-traditional users. Regional Conference of the NorthEast SAS Users Group. SAS Institute Inc., Cary, NC. pp. 21-28. Using the SAS Rosenberg, Martin J. (1988). System to Facilitate Clinical Trials Research and NDA Approval. Proceedings of the Thirteenth Annual SAS Users Group International Conference. SAS Institute Inc., Cary, NC. pp. 550-556. For further information regarding this paper, please contact: Martin J. Rosenberg, Ph.D. MAJARO INFOSVSTEMS, INc. 99 East Middlefield Road Sune 31 Mountain View, CA 94043 tel. (415) 961-8432 (415) 961-9260 Wallace, Emily P. (1989). Database Interfaces Under the Version 6 Engine Architecture. Proceedings of the Fourteenth Annual SAS Users Group International Conference. SAS Institute Inc., Cary, NC. pp.347-349. 1032