Computers In Clinical Development; Computer Aided Drug Development (CADD)

1. COMPUTERS IN CLINICAL
DEVELOPMENT
[CLINICAL DATA COLLECTION & CLINICAL DATA
MANAGEMENT]
Presented by:
NAVEEN BALAJI
2nd Semester M.Pharm
Department of Pharmaceutics
Sree Siddaganga college of pharmacy
Tumkur.
Under the guidance of:
K.P.HEMALATHA,M.Pharm,
Assistant Professor
Department of Pharmaceutics
Sree Siddaganga college of pharmacy
Tumkur.

2. • Clinical trial data collection and management is organized into eleven major sections:
1) Introduction,
2) Data collection versus management,
3) Communication in clinical trial data collection and management,
4) Pure paper-based data collection and management systems,
5) Electronic-based data collection and management systems,
6) Hybrid data collection and management systems,
7) Acquiring e-clinical software from vendors,
8) Processes before data collection,
9) Processes during data collection,
10) processes after data collection,
11) Final comments

3. (1) Introduction :-
• Clinical trial data management involves a set of processes that must be executed
successfully to turn out reliable clinical, control, and administrative data to a
central location such as a coordinating center, a data center, or a resource
center. In the literature, these processes are lumped together under the name
clinical data management or clinical trial data management.
• These aspects are accomplished and coordinated through a set of communication
tools, a central ingredient of any clinical trial, used to develop a data collection
and management system.

4. • With the ongoing and rapid advancement in computer hardware and software
technology, and the wide range of newly available commercial databases,
proprietary software vendors, design tools, and security applications---clinical
trial data collection and management have become widely attainable, much
easier, less time consuming, more reliable, more secure, and more scalable
than ever.
• Although these attributes assure a greater confidence in the results of clinical
trials, new challenges have arisen with this technological advancement, which
must be addressed. Some of these are cost, learning curve, shifting
responsibilities, and dealing with unforeseeable events.

5. • Figure illustrates the integration of the communication aspect before
data collection begins, during data collection, during data
management, and after data collection.

6. The two major, and distinct, computer applications in conducting clinical trials are
data collection and data management.
 Each of these applications has a distinct role in clinical trials. For that reason, the
term “clinical trial data collection and management” will be used. This does
not imply that these two aspects are independent of each other. Although each one
can be accomplished as a separate system, they should be integrated, thus the
term “data collection and management system” is used.
 Another aspect that is also integrated in each of these two aspects is data
security.
 Data security tools and procedures are necessary during data collection and data
management.
(2) DATA COLLECTION VERSUS DATA MANAGEMENT :-

7.  Data Collection
 Data collection in clinical trials consists of the processes of collecting
reliable clinical, control, and administrative data from the trial’s
participating sites with agreed-upon methods and procedures to record the
collected data and send them to a central location.
 Data Management
 The official definition given by the Data Management Association (DAMA) is
“The development and execution of architectures, policies, practices and
procedures that properly manage the full data lifecycle needs of an
enterprise” .
 A layperson’s definition of data management is, “The process of
accumulating collected data into a master database in a central location
while ensuring their security, validity, and completeness by generating
quality assurance reports to monitor the progress of the trial”.

8. (3) COMMUNICATION :-
 Communication is the process of sending information from one location to
another or from one person to another by means that enable the sender to
send the information to the intended recipient and the intended recipient to
receive, retrieve, and interpret the information.
 Planning, conducting, and ultimately reporting the results of a clinical trial
require that trial personnel be connected throughout the duration of the trial
to ensure successful completion.

9. (i) Direct Contact Meetings :-
 Once a trial is approved, the principal investigator (PI) meets with the
appropriate coordinating center staffs, they include- the biostatistician,
computer programmer, and project manager, to review and finalize the drafted
data collection forms and their data points before they are sent to the form
designer for production.
 The programmer at the coordinating center meets with the biostatistician to get
answers to questions regarding the trial’s protocol and to set up a
development plan, assign tasks, and resolve problems.

10.  The protocol, the Manual Of Operations (MOP), drug-dispensing procedures,
and any other important issues are presented, using various presentation
packages such as MS PowerPoint through a projection device.
(ii)Telephone :-
The telephone is still one of the primary means of communication for clinical trial
personnel for the transmission of digital data from one location to another.
 Various software packages have been developed for this purpose. Using a voice
modem connected to a telephone, a user on a local computer can connect to
another remote computer that has a modem connected to a telephone and
download or upload data files.
 The telephone is also utilized in the development of interactive voice response
(IVR) systems that support touch-tone or speech recognition responses.
 IVR systems have been developed for subject randomization, drug assignment,
and survey data collection.

11. (iii) Fax :-
With fax technology, documents can easily be transmitted to trial participants
either from hard copies with a fax machine or as an electronic file directly from a
computer.
 Fax technology is also used to fax data collection forms as an image to a
computer equipped with OMR or OCR software that can receive the image,
interpret recorded data, flag bad entries, and add the data to a centralized
database.

12. (iv) E-Mail :-
 It is used as stand-alone software or integrated within a data collection and
management system.
 With e-mail, text messages and attachment files can be sent to the trial’s
personnel instantaneously. When integrated in a data collection and
management system, it can be programmed to send messages automatically.
 E-mail as a communication tools has a number of drawbacks,
 (i) it is vulnerable to being intercepted,
 (ii) intended recipients may not access their e-mail on a timely basis,
 (iii) there is the possibility of sending files inadvertently to the wrong
recipient.

13. (v) Web Sites :-
 clinical trials information is disseminated among the various individuals and
collaborating organizations running and monitoring these trials via websites.
 A trial’s website provides trial personnel an easy, secure, real-time access to
information that includes operational issues, clinical procedures, data collection
forms, data management, system manuals, training documents, phone
directories, contact lists, calendars, reference documents, policies, protocol,
MOPs, meeting agendas, and meeting minutes.
(vi) File Transfer Protocol :-
File transfer protocol (FTP) technology is a data communication tool that allows
sending, accessing, and sharing files quickly and easily through a secure
environment. The user logs onto the FTP site with a valid account name and a valid
password. This method allows participants to share data files instantly.

14. (vii) Video-conferencing :-
 In a videoconference, two or more people in different locations can see and hear
each other at the same time, sometimes even sharing computer applications for
collaboration.
 The visual communication provides a feeling of direct contact that enhances
understanding and helps participants feel connected to each other.

16. (4) PURE PAPER-BASED SYSTEMS :-
They are still being used by many contract research organizations (CROs) either
because of financial constraints or because they deal with small clinical trials that
do not justify that investment.
 Suitability and Hardware/Software Requirements
 Their advantages are that no computer hardware or software is needed
because data are recorded manually on paper forms that are transferred to the
centralized location in batches.
 A major drawback is that participating sites do not have real-time access to
their data. However, both hardware and software are needed at the centralized
location for the data management system. The most commonly used platforms
include Open VMS, Unix, or PC, and one of the most widely used software
packages is SAS®

17. Design and Implementation :-
Pure paper-based data collection systems use paper forms that can be designed
with any graphical or word processing software such as Adobe PageMaker,
Microsoft Word, or MS PowerPoint.
Forms consisting of records of 80 columns long are standard, but they can be
longer. A header is repeated for every record that contains identifying
information.
These identifiers must contain sufficient information to uniquely identify each
line or record of data entered into the database. Each collectable data element
exists in a specific record of a specific form and can be further identified by the
column or space number(s) within the record.

18. Managing Data
Pure paper-based data collection require large data editing overhead.
Personnel at the central location must perform visual inspections of forms &
compare them & visually inspect for completion and legibility, log the received
forms, and send the received forms that pass visual inspections to data entry staff.
The data entry staff enters the data into electronic text files with Double key data
entry software. Then these files are released to the trial data management
programmer.
The trial programmer develops customized programs to read the text files,
perform data checking for accuracy and consistency, rectify data errors, and add
edited data to the master database.

19. (5) Electronic-based systems :-
The hallmark of the electronic-based data collection and management systems is the
elimination of paper data collection forms. Instead of recording data on paper forms,
data collectors enter data directly into a computer system.
The advantages of such systems over the traditional pure paper-based data collection
and management systems include their ability to,
(1)Provide cleaner data faster, thus significantly reducing query rates and eliminating
double data entry.
(2)Provide up-to-date interim progress reports in a timely fashion,
(3)dramatically reduces the Time.
()Analysis has underlined the value of Electronic Data Capture (EDC) as a cost- and
time-saving approach in modern clinical research.

20. Centralized systems
• Centralized systems reside at a central location and are accessed through a local
area network (LAN), a wide area network (WAN), or a virtual private network
(VPN).
• The user logs into the system with valid user id and password. This system
enables direct entry of the data into a centralized database.
• Remote data entry does not necessarily require the purchase of any computer
hardware and software for the participating sites because the system is centralized
and participating sites can use existing computers to access it.

21. Distributed systems
In distributed systems, each participating site must be equipped with a
desktop or a laptop computer loaded with the distributed data collection
system software to collect and enter data locally.
 In addition, each site is provided with necessary storage devices such as
tapes, zip diskettes, and cds and printers.
Collected data are transferred periodically to the central location as files
saved on storage devices, via phone modems, by FTP, or through wireless
communications, where they are managed by a centralized data management
system.

22. Various software packages are available to transfer data from the
participating Sites to the central location.
One example of this software is PCAnywhere from semantic,
which allows for downloading and uploading data from the
participating sites in addition to remote control sessions.
System updates may be needed to fix a glitch, incorporate protocol
amendments, respond to changes in business rules, add, change, or
disable reports, forms, or variables, correct misspelled or incorrect
variable labels, correct variables’ displayed unit of measurement,
modify reference ranges, and add or modify existing consistency
checks.

24. Wireless systems
The use of wireless computer systems has gain popularity in data collection for
clinical trials. They have been used as a substitute for normal paper-based
patient diaries to increase data quality and shorten the time needed to close
the database.
In comparison to laptops and desktops, hand-held computers have much
smaller screens. They have limited memory space and computational
capability. For these reasons they cannot be used to enter large amounts of
text data or perform sophisticated edit checks.
They are prone to loss or damage, but they have an advantage over laptops
and desktops in their ease of mobility.

25. Pdf-based systems :-
This method of data collection uses Portable Document Format (PDF) forms.
This approach is flexible and inexpensive.
A number of commercial software packages such as adobe acrobat, latext, and
Microsoft word and free software such as python and R are used to create the
PDF forms.
Paper copies of the PDF forms may be used as an intermediate data collection.
Electronic versions are completed at each site with adobe reader software.
Completed forms are submitted on a CD or faxed as extended markup
language data files to the coordinating center.

26. Web-based systems :-
web-based data collection and management systems have become
the choice of many CROs because of their capability for collecting
clinical trial data in real time and disseminating critical clinical
trial information to the participating sites and various oversight
committees .
Many languages are used to develop web-based data collection and
management systems, The most common of the tag-based
languages is Macromedia ColdFusion Markup Language (CFML)
using macromedia coldfusion studio or dreamweaver ultradev.

27. • The most common script-based languages include Active Server Pages (ASP)
from MS, which runs on Microsoft internet information server (IIS), and
java server pages (JSP) from sun microsystems. Perl language has also been
used to generate dynamic e-forms on the fly.
• Web-based data collection and management systems provide a mechanism for
remote data entry, where entered data are added to a centralized database once the
submit button is pressed. They can be designed to automate the various aspects of
clinical trials such as eligibility evaluation, data collection, and tracking
specimens.
• They play an important role in facilitating the conduct of international clinical
trials.

28. Direct systems
• In this approach most of the required clinical data are acquired directly from
existing patient record systems such as MRI machines, ECG, EEG,
laboratories, and other measurement equipments.
• This approach eliminates the need for paper transcription and re-entry to
another system.
• It promises error-free and resource-efficient data capture, which allows early
locking of the database and therefore potentially earlier product launch.

29. (6) HYBRID SYSTEMS :-
Hybrid systems are those systems that employ various strategies to collect data. In such
systems, data may be collected on paper forms as patient self administered questionnaires,
while additional data may be downloaded from centralized databases. where data
coordinators enters them directly into a centralized data management system.
The data coordinator visually checks received forms as in pure paper-based DMS. However,
forms are not entered by Double-key High-speed Data Entry.
Instead, they are entered directly into a customized data management system through
computerized screens. A second data coordinator reviews the fully marked entered forms
and compares the entries against the paper forms, flagging any discrepancies. The first data
coordinator checks and rectifies these discrepancies. Range and consistence errors flagged
upon entry are reported to the SCs for rectification as monthly error reports.

30. Paper data collection with centralized batch data entry
In this approach data are collected on paper forms. Completed forms are
mailed to the coordinating center, where they go through visual inspections.
Forms that pass the visual inspections are sent to the data entry department,
where they are entered with High-speed Double-key Data Entry.
It appears to be superior to the paper data collection with centralized
interactive data entry. It is not time consuming because data are entered with
High-speed Double-key Data Entry, which expedites processing of received
forms and thus the accumulation of the master database.
Major advantage is that only one person is needed to run the system.

31. Paper data collection with direct data transfer to Centralized DMS
Another approach is the use of facsimile (fax) transmission to a dedicated
computer equipped with software such teleform® that can be customized to fit
the needs of the clinical trial.
Scannable forms are designed With specialized software and distributed to the
participating sites to complete. SCs are equipped with fax machines to fax the
completed forms to the central location.
Another approach is the use of scanners to scan completed forms, using
specialized software to create an image of the paper forms and read their data
fields into a database. Completed forms may be scanned at the local sites, and
The resulted electronic data are sent to a central location or are scanned
centrally.

32. Integration of distributed systems with remote servers over the internet
In web-based application models that use web browsers to display information
Sent by the application server.it has important limitations
(1)All participating sites must have an internet connection;
(2) the internet connection makes it less portable;
(3) it creates difficult issues of data validation and data integrity; and
(4) there can be browser incompatibilities. Existing distributed systems can be
modified into web-enabled Systems.
()In this approach, the distributed application installed on the client PC at each of
the participating sites communicates with a remote server over the internet. This
approach is inherently faster because only data and integrity check records need
to be transmitted via the web, and the bulk of processing is performed locally, not
on the server.

33. (7) ACQUIRING PROPRIETARY E-CLINICAL SOFTWARE :-
THE NEW TREND
Contract research organizations (cros) may choose to acquire one of the established data
collection and management systems known as e-clinical software from various vendors in the
field as an alternative to developing their own systems in-house.
These systems allow flexibility in the methods of data entry, data submission, and data
management. They can support paper-based and interactive data collection.
Data submission can be done through fax technology or through the internet. Data
management aspects such as error reporting and correction depend on the type of the system.
Some vendors indicate that their products comply with FDA regulations for computerized
systems, including 21 CFR part 11.

34. E-clinical software examples
Searching google.Com for “e-clinical” provides
many vendors.
Some of these are oracle clinical v4i® from oracle
corporation ,datalabsxc® from datalabs, inc.,
trialmaster® from omnicomm systems, and clin-
plus® data management (CPDM) by DZS
software solutions, inc.

36. (8) PROCESSES BEFORE DATA COLLECTION :-
Choosing a data collection and management system :-
Depending on the size of the CRO and the nature of the trial, the
system may Be acquired in one of the following ways:
(1) developed in-house by the organization’s staff with off-the-shelf
commercial software,
(2) outsourced to Outside contractors,
(3) with open source/free software (OSS/FS), and
(4) purchased from e-clinical proprietary vendors.

37. Hardware and software selection
The type of system chosen determines the types of hardware and
software needed. It also determines the processes for acquiring the
necessary hardware and software.
The hardware selection may include desktops, laptops, printers,
scanners, fax machines, and storage devices.
The software selection includes the system development software,
the database management software, the data communication
software, the data conversion software, specialized proprietary
software, servers, and firewalls.

38. Form and System Design
• The success of any clinical research trial depends greatly on the
quality of its collected data. Collecting high-quality data begins
with developing well designed data collection forms.
• Well-designed forms simplify the data collection and management
processes.
• They greatly reduce the time and effort of data collection and
management and drastically simplify the data analysis phase.

39. System Validation
• Before a data collection and management system is implemented, it has
to be validated.
• For a newly developed application, the validation processes consist of
various layers of testing.
• The first layer is testing the components of the system as it is being
developed. This validation ensures that the programming segments of the
system are error free and work as expected.
• The next layer of validation takes place after the system is completed and
before it is put into production.

40. (9) PROCESSES DURING DATA COLLECTION :-
System Evaluation
evaluation ensures that the system is working as intended, and that the
end users understand it and are comfortable with it. It also provides
feedback from the end users to correct any glitches and enhance the
system.
Data quality assurance
From the moment data collection begins to the closing of the trial,
monitoring the progress of the trial is essential for maintaining its
integrity and successful completion. Various computer software and
programs have been developed for that purpose, to enable the trial staff
to be aware of every single development and indicate how to respond to
it throughout the trial.

41. Handling Unexpected Events
• Unexpected events may occur that need to be taken care of during the clinical trial. Some of
these events may require actions to be taken with regard to the data collection and
management system.
Data Transformation
• Various computer software and programs have been developed and used to simplify the
transformation, manipulation, and analysis of trial data, to speed up and increase the
accuracy of reporting the trial’s findings.
• If data are collected in a format other than that required by the analysis software, the data
must be transformed. There are several data conversion software packages that can be used
to transform the collected data from the original format to the analysis format.
• Examples of these include DBMSCopy and Stat/ Transfer.

42. (10) Processes after data collection :-
Data lockout
Relatively little has been written about the practicalities of the closeout of large,
multicenter clinical trials, but this aspect of trial conduct and design is important and
requires careful planning to be accomplished in a timely and orderly fashion.
Data retention
Data collected at each participating site must be stored in a read-only format at that site
for future reference. The institutional review board (IRB) at each participating site
requires that the site retain its local database after trial closeout.
Data retention can be achieved in various ways. However the method should ensure that
(1) participating sites are not be able to modify retained data;
(2) data are presented in a way that allows sites to easily locate any data form for any
subject at any trial visit; and
(3) the site PI is solely responsible for the retained data.

43. Data archiving
After the data collection phase of a clinical trial is completed and its
collected.
Datas are analyzed, collected data are archived centrally, usually at the
coordinating center, for future reference.
In paper-based data collection system, the physical paper forms may
need to be archived for a specified period of time. Scanning technology
allows for storing paper forms as images. The computerized database is
archived.
Data sharing
Computers facilitate data sharing among researchers. The internet
provides, an effective method for designing and implementing data
repositories of completed clinical trials.

44. (11) FINAL COMMENTS :-
• The advancement of IT has had a great impact on the conduct of clinical trials.
• In a discussion, the participants articulated that “CDM will be dramatically
transformed by new uses of technology, and by the emergence of industry
wide standards.”

45. Reference :-
• Computer Applications in Pharmaceutical Research and Development,
Sean Ekins, 2006, John Wiley & Sons,
Page no. 593 to 632.

46. THANK YOU