computer in clinical development, computer adided drug delivery

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COMPUTERS IN CLINICAL
DEVELOPMENT
Sujitha Mary
M Pharm
Pharmaceutics
St Joseph College of Pharmacy

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 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.
 The development of comprehensive and reliable data collection and management systems is
fundamental for conducting successful clinical trials.
 It is thus extremely important that close attention be given to the development of these systems
in terms of their design and the hardware and software selections made.
 New developments in computer hardware and software technology have made clinical trial
data collection and management timely, effective, and reliable, the cornerstones for conducting
a successful clinical trial.

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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.
The integration of the communication aspect before data collection begins, during data collection,
during data management, and after data collection involves:
1) Before Data Collection
2) Data Collection
3) Data Management
4) After Data Collection

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Electronic Based Systems:
Electronic-based data collection and management systems have revolutionized data collection and
management. The advantages of such systems over the traditional pure paper-based data collection
and management systems include their ability to
 Provide cleaner data faster, thus significantly reducing query rates and eliminating double data
entry,
 Provide up-to-date interim progress reports in a timely fashion, and
 Dramatically reduce the time from last patient visit to final database lock out.

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These advantages provide for quick access of up-to-date data for feedback to the appropriate
stakeholders which allows them to make timely critical decisions and enables them to easily
monitor protocol compliance, enrollment rates, and performance metrics of participating sites. It
involves:
1) Centralized Systems
2) Distributed Systems
3) Wireless Systems
4) PDF-Based System
5) Web-Based Systems
6) Direct Systems

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Acquiring Proprietary E-Clinical Software:
1) The New Trend:
 Contract research organizations (CROs) may choose to acquire one of the many already
established and well-developed proprietary 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 tend to be comprised of integrated components using various technologies that
allow flexibility in the methods of data entry, data submission, and data management.

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2) 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 ClinPlus® Data Management (CPDM) by DZS Software
Solutions, Inc.

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Processes before Data Collection:
All processes for data collection and management are defined, addressed, and accomplished before
data collection begins. These processes include determining the type of the data collection and
management systems, developing the systems, defining procedures for subject recruitment,
registration, screening, randomization, and treatment dispensing. It involves:
1) Choosing a Data Collection and Management System
2) Hardware and Software Selection

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Processes During Data Collection:
1) 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.
Monitoring clinical trials is usually accomplished by generating various customized routines
that generate monitoring reports.

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2) Treatment Dispensing:
Treatment Dispensing Clinical trials that involve drug dispensing or device assignment require a
robust mechanism for distributing the drugs or devices to the participating sites and ensuring that
the correct drug regimens or devices are assigned to the correct subjects based on their
randomization numbers. Computers play a very vital role in making sure that this is done in a
timely manner and accurately to enable the pharmacy coordinating center to track the distribution
status at each participating site. This also enables accounting what has been dispensed and what
has been returned.

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3) 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. For example, there is always the possibility for a subject to move from one
participating site to another. If the subject is willing to continue to be followed at the new site,
his/her records must be transferred from the old to the new participating site. The processes
needed to accomplish this depend on the type of the data collection and management system.

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4) 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.

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Process after Data Collection:
1) 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.
2) 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.

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3) Data Archiving:
After the data collection phase of a clinical trial is completed and its collected data are analyzed,
collected data are archived centrally, usually at the coordinating center, for future reference. The
data archive method depends on the data collection system. In paper-based data collection
system, the physical paper forms may need to be archived for a specified period of time.
4) Data Sharing:
Computers facilitate data sharing among researchers. The Internet provides an effective method
for designing and implementing data repositories of completed clinical trials. The repository
software may be designed to classify users as follows. Administrative users have full access to the
repository.

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Final Comments:
In summary, advancement of IT has had a great impact on the conduct of clinical trials. A
discussion was held during the Society for Clinical Data Management’s (SCDM) Spring Forum
in Atlanta, GA, March 13–15, 2005, that examined the role of technology and standards in the
future clinical data management. The participants articulated that “CDM will be dramatically
transformed by new uses of technology, and by the emergence of industry wide standards.”
Others anticipated a more “gradual impact.” The complete list of the discussion results have
been reported elsewhere.

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Regulations of Computer Systems:
 The Federal Drug Administration (FDA) describes the biopharmaceutical industries as “self-
regulated,” retaining for itself the responsibility of assuring and checking on that self-
regulatory process.
 When manufacturing processes were primitive, unclean, and uncontrolled, the FDA issued the
“Good Manufacturing Practices” and eventually the “Good Laboratory Practices,” “Good
Clinical Practices,” and “Good Tissue Practices.” Together these Practices provide standards
for the industry operations.
 The United States Federal Regulation identified as 21 CFR Part 11 focuses on electronic
records.

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 While emphasizing the approval and long-term review of those records with guidance regarding
electronic record archiving and electronic signature approval, the regulation incorporated
standards for system validation and all previous guidance related to computer systems.
 Currently, Part 11 serves as a guideline for industry control of all computer systems and as a
requirement for high-risk systems directly affecting human health and safety.
 Responsibility for classifying and defending a system as falling outside the high-risk requirement
circle falls on the regulated organization.

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Review of 21 CFR Part 11:
 One of the great values of computer systems lies in their flexibility Through targeted programming, the
same computer using the same language code can be used for a variety of different functions.
 Because of the complexity of computer hardware and software and because of the intricacy of a risk
assessment, the FDA has to all intents and purposes adopted an indirect regulatory posture.
 The effectiveness of a QA-related independent Part 11 audit is dependent on the checklist or audit plan
utilized.
 Presented is a model checklist divided into two parts a general checklist of 21 CFR Part 11
requirements and a 21 CFR Part 11 software evaluation checklist for closed systems that do not use
biometrics.

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General Checklist—21 CFR Part 11:
Subpart B—Electronic Records
11.10 Controls for Closed Systems
11.10(a) Procedures and controls shall include validation of systems to ensure accuracy,
reliability etc.
11.10(b) Procedures and controls shall include the ability to generate accurate and complete copies of
records in both human readable and electronic form suitable for inspection, review, and copying by the
agency.
11.10(c) Procedures and controls shall include protection of records to enable their accurate and ready
retrieval throughout the records retention period.
11.10(d) Procedures and controls shall include limiting system access to authorized individuals.

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11.10(e) Procedures and controls shall include use of secure, computer generated time-stamped
audit trails to independently record the date and time of operator entries and actions that create,
modify, or delete electronic records.
11.10(f) Procedures and controls shall include use of operational system checks to assure integrity
of data.
11.10(g) Procedures and controls shall include use of authority checks to ensure that only
authorized individuals can use the system, electronically sign a record,
11.10(h) Procedures and controls shall include use of device (e.g., terminal) checks to determine, as
appropriate, the validity of the source of data input or of data transport.

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11.50 Signature Manifestations
11.50 Signed electronic records shall contain information associated with the signing that
clearly indicates the following:
 The printed name of the signer.
 The date and time when the signature was executed and
 The version of the document signed (or indication that the document was locked once
signed).

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11.70 Signature/Record Linking
11.70 Electronic signatures and handwritten signatures executed to electronic records shall be
linked to their respective electronic records to ensure that the signatures cannot be excised,
copied, or otherwise transferred to falsify an electronic record by ordinary means.

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Subpart C—Electronic Signatures
11.100 General Requirements
11.10 Controls for Closed Systems
11.100(a) Each electronic signature shall be unique to one individual and shall not be reused by, or
reassigned to, anyone else.

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11.200 Electronic Signature Components and Controls
11.200(a)(1) Electronic signatures shall employ at least two distinct components such as an
identification code and password.
11.200(a)(2) Electronic signatures shall be used only by their genuine owners.
11.200(a)(3) Electronic signatures shall be administered and executed to ensure that attempted use of
an individual’s electronic signature by anyone other than its genuine owner requires collaboration of
two or more individuals.

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11.300 Controls for Identification Codes/Passwords
11.300(a) Identification codes/passwords controls shall include maintaining the uniqueness of
each combined identification code and password.
11.300(b) Identification codes/passwords controls shall include ensuring that identification code
and password issuances are periodically checked, recalled, or revised.
11.300(d) Identification codes/passwords controls shall include use of transaction safeguards to
prevent unauthorized use of passwords and/or identification codes, and to detect and report in an
immediate and urgent manner.
11.300(e) Identification codes/passwords controls shall include initial and periodic testing of
devices that bear or generate identification code or password information.

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21 CFR Part 11 Software Evaluation Checklist for Closed Systems that do not
use Biometrics
Only those sections of 21 CFR Part 11 that describe technical controls required for 21 CFR Part 11
compliance of closed systems are included in this checklist (Table 26.1). Sections that describe only
procedural controls [11.10(i), (j), (k); 11.100(b), (c); 11.300(c)] that cannot be implemented by a
software product or additional controls for open system (11.30) are not included. Procedural controls
can only be exercised during the implementation of a 21 CFR Part 11-compliant system of which the
software is a component.

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Summary:
The United States Food and Drug Administration issued 21 CFR Part 11, the requirement for the use of
electronic signatures and archives after a lengthy period of FDA concern about the reliability, quality,
and control of computer systems the emergence and evolution of requirements for system validation;
and increasing industry reliance on computers in laboratory, manufacturing, and clinical environments.
Further emerging concerns about the relative cost and benefit of Part 11 led to its recall and revision,
incorporating a risk assessment to focus the regulation on areas of greatest risk to health and safety.

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To ensure 21 CFR Part 11 compliance an organization should:
 Adopt a multitier protocol or operating procedure, detailing the evidence to be provided in
support of high-, medium-, and low-risk systems or subsystems.
 Adopt an audit checklist; identify the key issues of Part 11 compliance.
 Conduct a Risk Assessment; utilizing dimensions of probability (likelihood of future
occurrence and/or incident of past occurrence) and severity (risk to human health and
safety) to classify all reasonable system dangers or missed performances.

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Conclusion:
1) Clinical trial processes involves set of processes which is expensive and time consuming.
The development of computers and reliable data collection in clinical trials helps to reduce
time and also supports to use less number of participants.
2) New developments in computer hardware and software technology have made clinical trial
data collection and management timely and effective and also with help of computers PMS
in clinical trials can be done quickly.
3) Regulation of computer systems in part 11 serves as a guideline for industry control of all
computer systems and as a requirement for high-risk systems directly affecting human
health and safety.
4) It also helps to conduct a risk assessment utilizing dimensions of probability and severity
to classify all reasonable system dangers or missed performances.

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References:
1) Ekins Sean, Computer Applications in Pharmaceutical Research and Development, A
John Wiley & Sons Inc. Publications USA, p: 593- 639.
2) https://academic.oup.com>article-pdf
3) https:// www.wiley.com>en-us>Comput..