Clinical Study Design Process

 

Read the following article which describes a proposed clinical study design process. Please locate Figure 1. In the file that is attached to this.

The assignment requires designing a process management diagram from the Value Creation Hierarchy perspective.

Describe the roles and responsibilites of each involved organization (Sponsor, Principal Investigator, and Health Care Provider) in the clinical trial design process.

Describe the role of the Information and communication technology in the proposed clinical trial model

Map the activities conducted by each organization

Provide rationale for each stage of the process
Data Management

PHOTOGfiAPHV COMSTOCK, tVtWIKt

ILLUSTHATION STEPHEN DUD ASH

P. Fazi. L. Collada Ali, D. Luzi, F.L. Ricci. L.D. Serbanati. and M. Vignetti

A Proposed Clinical Trial Model:

Analyzing the CT Process
This new model standardizes data
exchange between the various
stages of a research study.

O

ver the past 15 years, methodology
and ethics have become important
issues in the design and conduct of
multicenter clinical trials. Nowadays.
clinical research embraces very different disciplines, such as information lechnology.
regulatory affairs, quality assurance, and economics, and it is associated with a complex regulatory
framework. ‘Vhe recent EU Clinical Trials Directive
has added even more to this complex framework.
All of this makes clinical research a more complicated process, and this translates into a difficult
planning phase, increased trial time, increased
costs, and additional energy.’-^
Generally, the start up of a clinical trial requires
a new design, and once the trial is completed the
entire process used in the design is discarded.
There is no system currently available that can

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manage the activities of clinical trials based on the
interoperability of each single task. A detailed
model of the entire CT process would allow for controlling the process in all its phases, in particular:
• Writing the protocol coherently and consistently
so that it supports the collaborative work of the
writing committee members
• Facilitating and coordinating the setup of the
trial in the various participating centers
• Supporting the critical phases of the process,
such as the eligibility, drug supply, severe
adverse events (SAE), etc.
• Monitoring the setup, particularly the quality of
clinical data and timely collection of case report
forms (CRFs)
• Supporting the evaluation and diffusion of clinical trial results.
There appears to be a strong demand for integrating research and systems in a way that supports the whole clinical trial process.^ Such an
approach can foster interoperability between CT
software applications, making system reengineering and maintenance easier. For this reason, we
propose a clinical trial model that provides a more
detailed analysis of the entire CT process to better
understand the number of procedures carried out
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during the trial.” Our approach is based on a holistic view of
CTs. We are developing a comprehensive conceptual model of
(he CT process independent of the possible information and
communication technology (ICO solutions applied to the
process automation.

In our CT model, each subprocess
has different objectives and is
enacted in different environments,
governed by specific rules.

Aim of the project
In order to develop a standard model and a common terminology. GIMEMA (The Italian Group for Haematological Diseases
of Adults) together with the Italian CNR (National Research
Council) have developed thefirstversion of a detailed model of
the entire CT process that locuses attention on:
• activities that compose the CT process
• rules that govern its functioning
• data needed to synchronize CT activities carried out by the
different actors involved (e.g.. sponsor, investigators, data
managers).
From the analysis of this model, it will be possible to:
• verify the pillars of the ti’ial and. thus, identify the different
types of support that ICT can offer in this field (e.g., applications for communication between and within centers,
CRF and serious adverse event (SAE) management, and
toots for execution monitoring)
• help and support the writing of a consistent protocol that
describes the entire process in a detailed, comprehensive,
and coherent way for all actors involved in the performance
of the trial
• determine which parts of the process are independent from
the type of trial and which ones vary, thus helping to
achieve a standardized protocol text.

The clinical trial model
We propose to model trials as a highly organized process that
is composed of subprocesses.” We have identified three main
subprocesses. Each subprocess has different objectives and
is enacted in different environments, carried out by its own
agents, supplied with needed resources, and governed by specific ruies. The three main subprocesses are:
• The clinical trial management process (CTMP), which
includes activities related to the setup, coordination, and
monitoring of the CT participating centers, and the final
evaluation of trial results. This process is carried out by the
sponsor.
• The statistical units management process (SUMP), which
includes activities related to the management ofthe trial in
the participating centers. In our approach to trials, a statistical unit indicates an instance of an enrolled patient. The
process described in the protocol is executed in each center and performed on each enrolled patient.
• The patient health care delivery management process
(PM). which relates to the diagnostic and therapeutic activities necessary to treat an enrolled patient, following the
instructions defined in the protocol. Hiis process is carried
out within the clinical ward (CW).
Figure 1 describes the relationship between the three
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process types. As soon as the clinical protocol is developed by
the writing committee and approved by the scientific and ethics
committees, the sponsor opens participating centers to enrollment. This is why in the figure the CTMF triggers the SUMP
for each participating center, hi each center enviromnent, for
each enrolled patient a PM process instance is created. This
means that at a certain point in the SUMP there are as many
PM instances as the number of enrolled patients in treatment.
For the SUMP, these instances represent statistical units that
will be evaluated during the analysis of the clinical trial results.

Information flow
In our approach, modeling a process means to identify the
main participants involved, the needs of participants with
regard to what procedures need to be carried out, the objects
used (resources) and delivered (results) by the process, and
the rules that constrain the execution process. Generally, two
processes may be synchronized on certain events or objects:
One process (the consumer) will not start because it has to
wait for an event or object produced by the other process (the
producer). Some of the subprocesses are simultaneous and
their interaction may be triggered when specific clauses/conFigure 1 . Process types in the clinical trial process.

Organization:
Sponsor

AgerUi:
cr Coordinator
Statistical Units

Data Center

Organization:
Investigator Center

Cliief Investigator

CRF Data Collector

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Data Management
ditions are produced because of the occurrence of certain
information/documents or specific events.
Figure 2 shows the information flow between the trial
processes and specifies the different types of information
exchanged (e.g., data, resources, commands/directives,

I

The CT master file contains, among
other documents, the protocol and
CRF templates.

woridlows/process specifications, etc.). This information is
contained in at least one of the following three highly structured documents:
• ITie CT master file
• The CRF database
• Tlie patient’s Health Care Record (HCR).
The CT master file. This file contains the information necessary to set up and perform the entire CT. The whole CT
process can be divided into three sequential macro phases:
preparatory, execution, and evaluation. In the preparatory
phase (which is represented by the CTMP in Figure 1), the
focus is on planning and specifying what needs to be done in
the following phases. In the first phase, one of the main tasks
is the development of a CT masterfile.The CT masterfilecontains, among other documents, the protocol (i.e., the document that describes the trial’s objective (s), design, methodology, statistical considerations, and organization) and the CRF
templates (i.e.. a document designed to record all of the protoFigure 2. Data flow of the clinical trial.

CT Enviromncnt

Workflow, Process
Specification

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col required information to be reported to the sponsor on
each trial subject). After defining the contents of the CT masterfile,two processes can start: database creation and writing
of the operating procedures manual. The start-up experimentation process can begin only when the previous three
processes are concluded.
The CRF. The CRF database gathers the CRF from all
patients. A compiled single CRI'” form describes the patient’s
health status in each well-defined phase of the CT execution; the
whole CRF also reports the changes in the patient’s health status
occurring during the CT. Analyzing the type and number of compiled CRF forms makes it possible to monitor the CT execution.
The patient’s HCR. The HCR is the official repository of the
clinical information related to a patient in a given CW. It contains both the information on the therapeutic approach and
changes in the patient’s health status. Data needed to fill in
the CRF are extracted from the HCR, and the quality of the
CRF data is verified through the HCR.
Application of the model
The model is defined by a formal language (UML), which
describes the process from three different points of view:
functional, structural, and behavioral.” Each view highlights a
specific aspect of the trial (e.g., the fiow of activities, the data
structures, and the interaction between the various activities
involved in the process).
We used the model to outline areas where ICT can improve
and optimize the whole process. In particular, the model has
been used to:
• Design an information system, which
helps the protocol writing and guarantees
its completeness and coherence as well as
the extraction of information necessary to
automate single activities of the trial
• Formalize the rules that govern the
exchange of data in the CT process, which
enables interoperability between the various ICT systems managing the single activities of the process
• Define a procedure that guarantees the
quality of the CT process related to all its
activities.
The protocol is a planning document for
the whole CT, where all activities of the
process are taken into account. The functional view of our model is an excellent
guide to protocol development. This view
also includes data necessary to perform
each single activity in the CT process, which
has allowed us to define a structural fi-amework that guides the text editing and controls its consistency. The framework has
been specified by an XML scheme, which
facilitates search functionalities within a
database of protocols, re-use of single parts
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Data Management
contained in the text, and interoperability with other systems.
We implemented a system, WITH (Write on Internet clinical
Trials in Haematology) that helps the CT writing committee
monitor the different phases of the writing process, re-use
parts/sections already written belonging to previously developed protocols, and promote the text coherence obtained
through the management of XML tags as well as a related data
dictionary.
Another important aspect of the process, which has been
emphasized by the model, is the exchange of information
between various activities. The structural view of the model
allowed us to define an XML format of the exchanged messages, guaranteeing the interoperability between the parts of
the system. In our case, the achievement of interoperability
also makes it possible to develop and test autonomously single modules of the system, which can be gradually implemented and easily updated to standards such as HL7 (Health
I^vel 7) and the CDISC Operational Data Model.«.’*The use of
standards guarantees the provision of seamless and automatic
connections from one software to another, regardless of platforms, applications, or programming languages.
Since our model provides a reference framework for al!
CTs. it can help achieve the uniformity of protocol quality
evaluation. Moreover, having a controlled system that governs all single steps regarding the conduction of a given trial
can guarantee that the main regulatory issues are respected.
As a result, a standard good practice can be developed that

Groups Behind the CT Model
The Italian Group for Haematological Diseases
of Adults (GIMEMA)
Defines and manages clinical trials involving more
than 100 Italian centers, mainly for acute leukemia.
GIMEMA operates throughout a Data Center in
Rome, which prepares/reviews clinical trial protocols
and case report forms, manages and analyzes study
results data, and cooperates with researchers for scientific reports writing.
The ttalian National Research Council (Consiglio
Nazionale delle Ricerche; CNR)
A national public body with the assignment of carrying out, promoting, diffusing, and emphasizing
research activities in main knowledge fields and its
applications in scientific, technological, economical,
and social development of the country.
“Politehnica” University of Bucharest (UPB)
Offers degrees in many engineering fields. Students
may enroll in several types of undergraduate and
graduate programs. Besides this basic program, the
faculty also offers the advance studies program,
which consists of one additional year after completing the engineering diploma courses and a PhD program. The university also includes a Faculty of Engineering Sciences in Foreign Languages.

guides the stakeholders (physicians, investigators, sponsors,
etc.) during the CT process.
Conclusion
The process model we are studying is the starting point for
defining standards related to the use of ICT in CTs. In fact,
this model identifies how data (messages) between the various activities should be exchanged. “Diese messages need lo
be standardized in order to achieve semantic interoperability
for the automation of the entire clinical research process. Al a
higher level, the CT model enables organizational interoperability by defining a virtual community ol’ organizations playing roles as CF coordinator, participant center, etc.
References
1. D.L Rubin. J.H. Gennari, S. Srinivas et at.. “Tool Support for
Authoring Eligibility Criteria for Cancer Trials.” AMIA Symposium
1999. available at http://www.aniia.org/pubs/syiiip()sia/D()05fi09.
PDE
2. J. Unutzer. Y. Choi. IA Cook, S. Oishi, “Clinical Computing: A Webbased Data Management System lo Improve Care for Depression in
a Multicenter Clinical Trial,” Psychiatric Services June 2002).
3. Verny and I. Klingmann. “A 6-Moiilh Process for Planning Multinational Clinical Trials.” Applied Clinical Trials. 58-61 (February
4. Standardizing Information Flow In Clinical Trial Protocols. Panel
organizer: John Gennari. available at http://www.amia.org/pubs/
symposia/D200541.PDF (2000).
5. L. Collada Ali, P. Fazi. D. Luzi, F.L. Ricci. L.D. Serbanati, M.
ViEnetti. “Toward a Model of Clinical Trials.” in Biological and
Medical Data Analysis, 5th Internationa! Symposium. ISBMDA
2004, Barcelona, Spain. November 2004, Lecture Notes in Computer Science (Berlin: Springer-Verlag. 2004).
6. J. Rumbaugb. 1, Jactibson, G. Booch, Tfte Unified Modeling Language Reference Manual (Addison Wesley, 1999).
7. P Fazi. D. Luzi, M. Manco. FL. Ricci, G. Toffali. M. Vlgnetti.
“WITH: A System to Write Clinical Trials Using XML and
RDBMS,” AMIA Symposium 2002, 240-244.
8. bttp://vrtvw.bl7.ca/.
9. D. Iberson-Hurst, ‘Tbe CDISC Operational Data Model: Ready to
RoW” Applied Clinical Trials Qu\y 2004).

R Fazi, MD, L Collada All, ^project manager, and M. Vignettl,
MD, are with the The Italian Group for Haematological
Diseases of Adults (GIMEMA), Dip. di Bioteehnologie
Cellurali ed Ematotogia, Vniversita degli Studi di Roma “La
Sapienza,” Via Benevento, 6. 00161 Rome, Italy, +(39) 06
441 639 828, fax + (39) 06 440 2516 639 828, email:
collada_ali@bce.uniromaLit. D. Luzi is a researcher and
F.L. Ricci is a researcher with The Italian National Research
Council (IRPPS-CNR), Rome, Italy. L.D. Serbanati is a
professor with UPB- “Politehnica” (University of Bucharest),
Bucharest, Romania.
*To whom all correspondence should be addressed.

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