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AN INTEGRATED APPROACH TO COMPUTER SYSTEMS FOR NDA PREPARATION AND PRESENTATION Martin J. Rosenberg, PhD, MAJARO INFOSYSTEMS, INC. ABSTRACT 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 date 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). in order to look for toxic effects in man. As evidence of safety is accumulated, dosages are increased to therapeutiC levels. In Phase II, the drug is tried for the first time in human volunteers with the targeted disease. Sample sizes are small, and information is gathered concerning the appropriate dose and regimen to use to obtain a therapeutic effect. Once sufficient Information is gathered and hypotheses about the drug's efficacy in various indications have been formulated, large scale Phase III testing in human volunteers begins. The research process can take five or more years. Throughout the process additionai information is gathered concerning the safety of the drug in both humans and animals; the stability 01 the drug (how long it can remain on the sheff without degrading); the pharmacokinetics of the drug, I.e., how it is metabolized in humans; and the ability of the company This papar describes the emerging features of SAS software, including Version 6 enhancements such as screen control language, multi-vendor architecture, muhiple engine architecture, 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. to manufacture the drug in production quantities. When all the required research is completed, the drug company submits its information to the FDA and makes a formal request for permission to market the drug In specified diseases. This registration process is known as a New Drug Application or NDA in the United States. An NDA Is frequently between 200 and 400 volumes long Of more than one hundred thousand pages. Although information from many scientific disciplines is presented, frequently the largest single portion of the NDA is the clinical section. The FDA then reviews the NDA and can take three actions: approve the drug for all or some of the Indications; not approve the drug; or request more Information be gathered. The review process frequently takes another two or more years. THE DRUG APPROVAL PROCESS The pharmaceutical and biotechnology industries are unique in that before they can bring a product to market, they must first obtain government approval. The process of obtaining government approval is a long and complicated one. In the United States, the company must first use the proposed drug in animals to show that there are no gross toxic effects. With this knowledge, the sponsoring company can obtain an IND (Investigational New Drug) from the Food and Drug Administration (FDA). An IND permits the sponsor to ship the drug across interstate lines and to use It experimentaity in humans. Although the details are different, the drug approval process is conceptually the same in other countries. Experimental information is gathered according to the requirements of the particular country until sufficient information Is gathered to submit the drug for approval to a governmental regulatory agency. Once an IND is obtained, the three pre-marketing phases of clinical research begin. Phase I starts by using small single doses in heahhy human volunteers 786 CLINICAL INFORMATION SYSTEMS such systems Remote Data Entry and Monitoring systems or REDEM. As can be imagined from the magnHudeof 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 and retrieval of clinical trial information, a Clinical Information System or CIS. The current concept of a Oinical Information System is 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 analysls package for statistical analysis and computer generation of tables and graphs which are then incorporated into reports which become part of the NDA. Although no atandard DBMS has emerged in the U.S. pharmaceutical industry, SAS has long been the standard software used for statistical analysis, report generation, and production of summary tables and graphs. With the introduction of these three new classes of users Qnvestigators, in· house medical stafl, 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 wHh the prospect of having up to five different computer systems, each with incompatible data structures: a remote data entry and monitoring sys· tem; 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 productiWy. Companies must maintain duplicate databases for each structure (with the attendant risk of inconsistencies between the databases) and must either train the staff in the operation of· mu~iple systems or maintain separate stalls for each technology. DBMS I STATISTICAL ANALYSIS REMOTE DATA ENTRY AND MOIi(ro'UNG I Use by lrwestigatQrs AUTOMATED TABLE AND GRAPH GENERATION I I Figure 1: Current CIS I DBMS T I I STATISTICAL In an effort to better manage the volume of information and to reduce the length of time required to introduce a drug in the UnHed States, the Food and Drug Administration, in conjunction wHh the pharmaceutical industry, has been experimenting with ways of using computer· technology to .fac~Hate the NDA review process. Such a computer system is called a Computer Assisted NDA Review system or CANDA. Participants in the CANDA experiments have reported that similar systems would be of use not only by FDA reviewers, but by the medical stafl of pharmaceutical corporations. We designate systems for use by medical stafl to monttor ongoing clinical trials, Clinical Data Review Systems. Simuttaneously, there has been much interest in computer systems that permtt the investigator to enter data and the sponsor to remotely monHor the trial. The Intent of such systems is to collect mare timely and accurate information. We call MALYSIS CLINICAL DATA REVIEW I Use by in~house AUTOMATEO medical staff TABLE AIID GRAPH GENERATlCM I CA>OA ~ Use by fDA Reviewers Figure 2: Future CIS Consequently, it would be desirable to integrate these fllle functions. Since SAS software is already in common use throughout the pharmaceutical industry, this paper explores the emerging capabilities of SAS and the role they can play in producing the integrated CIS of tomorrow. The remainder of this 787 paper explores three areas: the use of the current release 01 SAS on mainframes; the new features of Version 6.03 of SAS; and the features and architecture of future Version 6 releases. CuNAcCESS'S strength is the ease with which data can be accessed and manipulated. For example, Figures 4-8 illustrate the process of creating a report. In Figure 4, the user specifies the study and dataset for the report. If the user is unsure of the dataset, he or she can check a box and a list of available datasets appears (Figure 5). In Figure 6, the user selects whether all variables are to be displayed in the report or only selected variables. In this case the user has decided to select which variabies will be included in the report. Note also that CUNAccESS has selected the variables 10 and WEEK for automatic display. These variables will be used to clarify the report In Figure 7, the user selects which variables will appear in the report by placing an X next to each variable to be included. To print sums in the report, the user additionally checks the sum column. Figure 8 shows the finished report. The data is automatically displayed by identifying variables, in this case the patient id and the week of the visit. CUNAcCESS'M CuNACCESS Version 5 is a Clinical Data Review System designed for use by medical monitors, cfinical research associates, managers and other nontradttionai users on the clinical staff. Written using Version 5.18 SAS{AF software,. CUNACCESS has the follOWing capabilities: single or double-key data entry; viewing and querying of data; graphics; descriptive statistics; and report generation. CUNAccESS features an extensive context sensitive help system and an online tutorial 10 aid the new or infrequent user. Figure 3 shows the main CUNAccESS menu. Users select one of the options by entering its number on the ·Select Option" line and preSSing enter. The Database Administrator is addttionally permitted to structure new datasels, 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, lacn;tating the pooling of information. 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 included In the new dataset All the standard variable attributes (format, inform at, label, type, and length) are automatically defined. To provide f1exiblltty 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. ClinACCeS$ DATA LIST REPORT 5274 study- X_ Check (I) here w press enter to see a list ef datasets fer the above study. +-----------------------------------------------------------+ HEloP DATA L.IST +------------------ 2 View" dataset 6 wri tun reports 7 l.i'HU'n 'to use 4 Graphics STOOY AND OATASET MAtlE -------~---------+ study- Cl iMcceas 8 bit Cl inAccesll Libname: S274 _KEYS p" HELP m CONTual£ ~EPtlRT 5274 +----------------------------------------------------------+ levtl 1 (Main Menu) CANCEL Figure 4: Selecting a Study and Dataset COImIand ==> 5. Descriptive statistics ". PF1 ('till) 1 Enter data dataset MASS LAB MV_RX etHED ENTER to select Figure 3: The ClinAccess Main Menu Figure 5: A List of Datasets is Displayed 788 OATA UST REPOiI.T nATA I.ISTING ,Oft SMY $274 DATASET IS LAB CcmMnd ===> +------------------------------------------------------------+ I STU>Y ftNO DATmT flAME: 5274.I.AB I +------------- _VARiABLES AUTCMATICAlLY OISPLA't£O ._----------+ I ,....'" ID ,., I +I··a;;;.;;~·;,;;;;;··· OTH. . . . . . . .lES TO ""PUT ················+1 _ Display all other variable$ in the -dataset. X_ select other variables to display from a list. r···················- 01'''''''' TITLES ---- ••••••••••••••••• . j HELP Pf4 03tasets PFS Variables Pf6 PF3 CANcel SUI'PIlT 81LIRUBIN CALCIUM 0.' 0.8 9.S 9.S 10.1 10.' 0.7 0." 0 4 8 12 1. 20 a.• 0.' 0.8 0.' 001 ~ +---.--------------------------------------------------------... Pfl \/EEK 102 Figure 6: The User Fills in Blanks on the Report Program Screen SGOT SOOT 13 14 14 17 15 19 8 12 10 12 12 13 -------_ .. _. '2 .... _------67 • 0 4 8 12 1. 20 28 1.0 0.7 1.0 0.9 OJ 9.0 9.' 9.' 9.4 9.2 0.0 0.8 9.' 17 12 11 1. 13 14 11 9.7 .--~--~.-~-- 102 1. 10 13 11 15 17 14 88 .~ .. -----~".-~-~ 7 April 6. -1989 Figure 8: The Completed Report CUNACCESS is an example of the kind of applications which can be developed. using Version 5 SAS software. Version 5 is available on IBM mainframes under both the MVS and VMlCMS operating systems; and on DEC VAX. Prime. and Data General minicomputers. The next. section describes the substantial enhancements . possible under Release 6.03 of SAS for MS'DOS and UNIX. VERSION 6.03 CAPABIUTIES Edit dataset: 5274.LA8 kreeo 1 COIIIDIInd =::=> "'" Version 6.03 of SAS is available on IBM compatible PC's under the MS·DOS operating system and on selected HP and Sun Microsystems computers under UNIX. In Version 6.03, major steps were laken to make applications more interactive and to increase the database management functions available. This was . accomplished by the addition of Screen Control Language (SCL) to SAS/AF and SAS/FSP. SCL is a true programming language specifically designed to create interective full"screen applications. The syntax of SCL is similar 10 that of the SAS DATA step so experienced SAS .programmers will quickly feel comfortable. 1 Type- an X in the DISPLAY coll.J1l'l or use 1, 2~ 3, _._ to specify the order displayed. IJ$., X to indiCf:te which variables to SlA'!. DISPLAY $tJ4 x ;; x x x ...... TYPE tAtCIUM NUM SGOT HUM SOPI GlUCOSE lR011 X x '""' BUN 8lLIRUBN ~eATNnl PF1 lIELP OESCRl?TION .UM .UM .... IO.O! IO.O! .UM .". Phosphorus Bitirubin Crefltinine pf7 I>rev- Vars pfR Next Val's PF3 SUBMIT A number of tools were added to make applications easier to use. For example, Figure 9 shows a pop·up window which can be used to select variables. The user positions the cursor on the variable(s) to be used Figure 7: Selecting Variables to Display and Sum 789 and presses enter, The need .to know and to type the variable names is eliminated, VIBl DATA AS REelIJIGUlAR tABLE CominBnd ..,,;r,. Dllltaset to be vi ewed: Datas9ls can also be linked with SCL. One thcrny problem in clinical data management is to display comments mada by investigators. A solution is to place the comments in a separate dataset. When viewing data, the user sees a note that a comment is available (Figure 11). The user responds ''I' for yes to indicate he wishes to view the comment and the comment is displayed (Figure 12). When finished, a single keyatroke returns the user to the dataset he was browsing. I DEMO.D£MOC study .dataset_1'tM'e This pr«edu.re permits you to vi C<lllllliH'ld -"'=:> are variables and rows are patie OptionaUy select ~ to 3 variab Pleascnooke 3 selectim'l(s). .- (lD vadables remain visibte as , I. • x)OO(X)( XX><XX>< .""""' xxxx><x Data $et: oaIO.tlEMOG , I. I. lOOOO(X lOOOO(X XX><l"'" XlOOOO( xxmx XXXXXX XXXXlO( xioooo< DATE ."'. 1 C""" IlEEK FSEDIT DEMO.DE 8 """ • • PHOS NUll NUll CALCIUM for dataset names VA. for- variable names ",be' .... •• .... • CllAR NUM PATIENT SCREENS SEARCHES LETTERS .ND Fum, LOCATE, KAME, RFlNO, SEARCH, STRING """. ADD • HUM SGOT 01. ''''1 TYPe .EX SIRTHOAY PATIENT 10 -----' Figure 9: Pop-up Window appears far selecting ID STUDY • Ii 151 Sex: Birthday: Age; OEHO.DEMOG DR(l' fORlCAl !'lOVE 088 SCROLL SHO\.I 1 1 TREAllIENT: Placebo Ka'. " Height: 111 Weight: 117.2: CARO IOVASCUlAR: Blood Pressure: 11. sys Pulse-; Any (:()QIIlIfflts? YES I 70 dies View cOImIents{Y/H) y 76 Figure 11: A screen contrallanguage program permits conunents to be easily viewed. (B)-------------, JMFORMAT Screen 01/28/66 PHYSICAL EXAM: Version 6.03 also added a number of ways to display information from several datasets simultaneously. Customized screens· resembling case report forms can be developed which display data from more than one dataset. for example demographics and adverse events. In table view, mufiiple windows can be opened. For example, in Figure 10 three datasets are viewed simufianeously: demographics, adverse events, and laboratory. The windows can be resized or zoomed to fiU the entire screen, FSPRINT: Obo DEMOGRAMlICS: variables COlOR MORE 214 stDIT D f M O . C O M M E N T S - - - - - - - - - - - - - : - - - , Coomand ="''''". Obs OOSACK Screen SEX PATIEUT 151 152 153 154 155 156 DATE Male Female Kale Femate Male female 11/26/85 04/22/66 03/14/86 05/12186 02103/86 021'25/86 CClIIIMI;NTS fOR STUDY 2.14 DIWG Placebo Cud tet Curito{ Placebo Placebo euritot 19 23 32 72 19 24 110 102 156 102, 112 110 70 56 100 72 70 64 PATla.T: FORK: DEKO.ADV_R)( ( 8 ) - - ~SPRINT: DEMO. tAB ( 8 ) - - - , EDJTHlG HELP PRINTING HSCROll VSCROll N "'¥NAME GO COlOR, DR.QP, fORMAT. INFORMAT, K Set the default- vertical scroll 151 KEY: DEMOG fORMIlATE: FSPRINT: Patient did not return for second ... isit. ()(SPLAY on PATIENT t:OMPLNf1 PATtENT JOINT ST I FfNESS 151 15. FREQUENCY OF URtNATl '" 151 153 STREP THROAT 154 155 SORE SPOT 15. BURfUNG ,<1 8fLCM KNEf INFWEHZA ,,8 ST(»\ACH ACIte 153 154 155 156 157 158 CALCIIJM • 9,6 0.' 10.1 9.' '.2 SOOT SGPT 22 11 12 9 11 I. 17 342 11/16/86 Vas out of town business trip. 11 • 12 12 8 Figure 10: Multiple datasets can be viewed simultaneously Figure 12: 790 A comment for the patient from Figure 11 FUTURE ENHANCEMENTS • FutLKe releases of Version 6 are designed to further increase the database management capabilities of SAS and lis utility as an applicallons development language. Release 6.06 is scheduled to include features that will be particularly useful in developing integrated systems, specifically: multi-vendor archttecture, multiple engine architecture, PROC SOL, and indexing. Proper Engine Figure 14: Multiple Engine Architecture Multiple engine architecture refers to the ab~ity to use data stored in data structures other than a SAS dataset, for example data stored in another database management system (DBMS). Currently, interfaces between SAS and a DBMS are constructed as in Figure 13. A program is used to identify the data available in the DBMS. The user selects the variables and/or records desired and these are extracted from the DBMS and restructured in the form of a SAS dataset. 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. Mufti-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 PC's. PROC SOL and indexing bring to SAS two important database management features for performing queries. SOL is the emerging standard for relational database query languages. The SAS implementation will permit queries of SAS datasets and with multiple engine architecture of other database structures. Indexing is a common database management feature that can speed on-line queries. SUMMARY 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 lOOk for existing standards and see if there are ways to expand their use and thus leverage our investment in the technology and personnel already trained to use the technology. User Specifies Variables SAS Dataset Created Data Used by SAS Application Figure 13: Current Extract Process SAS software is the de facto standard in the pharmaceutical industry for performing statistical analyses and presenting the resuHs in graphical or tabular forms. Once data is in machine readable form, most of the subsequent processing is typically parforrned in SAS. Consequently, it is reasonable to examine whether SAS can play an expanded role in the CIS• Under multiple engine architecture, SAS applications will be able to run directly against other databases as shown in Figure 14. When a SAS program requires data, a request is sent 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 and the entire process is transparent to the user. Aithough initially a statistical. package, much of the recent development of SAS has been to add features commonly associated w~h relational database 791 management systems and fourth generation languages. This paper has explored many of these existing and emerging features and has shown that SAS may be able to play a prominent role in developing integrated, powertul, yet easy to use systems. REFERENCES Rosenberg, Martin J. (1988). Using the SAS 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. ACKNOWLEDGEMENTS CU"ACCESS is a trademark of MAJARO INfOSVSTEMS, INC., Mountain Vrew, CA. All CUNACCESS screens shown are Copyrighted (C) 1988, 1989 by MAJARO INFOSYSTEMS, INC. and are used by permission. VNX is a trademark of Digital Equipment Corporation. SAS, SAS/AF, and SAS/FSP are the registered trademarks of SAS Institute Inc., Cary, NC, USA. MAJARO INFoSVSTEMS INC. provides statistical and infOrmatlon management services to the pharma· ceutical, biotechnology, and food products industries. and specializes in extending computer technology to non·traditional users. For further information regarding this paper, please contact: Martin J. Rosenberg. Ph.D. MAJARO INFOSVSTEMS, INC. 99 East Middlefield Road Su~e31 Mountain View, CA 94043 tel. (415)961·8432 (415)961·9260 792