Download Constructing Integrated Clinical Information Systems for Traditional and Nontraditional Users

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
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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
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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
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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.
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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
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11
-----------88
7
16
10
13
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15
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-----------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
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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.
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