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DATA MANAGEMENT BRIEFINGS

IN PHARMACEUTICAL
RESEARCH & DEVELOPMENT

Editorial
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Michelle Grayson

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Contents

DATA MANAGEMENT
IN PHARMACEUTICAL
RESEARCH & DEVELOPMENT
Foreword

Embracing New Challenges

Clinical Development – The New Opportunity 4
Jonathan Palmer 1 and Nicholas Giannasi , PhD 2
1. Business Development Lead, Clinical Solutions, Europe, Middle East and Africa (EMEA), Oracle, and
2. Senior Business Development Director, Life Sciences, EMEA, Oracle

Introduction

Putting the ‘e’ in R&D 5

Michelle Grayson
Managing Editor, Medical Communications, Touch Briefings

Optimising eClinical

Large-scale Electronic Data Capture – When Size Is Not the Only Issue 7
Nicolas Schaltenbrand , PhD
Senior Director, Global Data Management, Quintiles

Electronic Safety Data Management – The Dawn of a New Era, but Are We
Awake to the Consequences? 10
Barry Burnstead
Director of Project Management, i3 Statprobe International

Data Integration – Business Requirements and Implications for Data Standards 12

Sharon Marmaras
Director, Clinical Trial Support and Life Sciences Data Hub (LSH) Business Project Leader, Boehringer Ingelheim

The Convergence of Healthcare and Clinical Research Standards 14

Pierre-Yves Lastic , PhD
Senior Director, Standards Management & Data Privacy, sanofi aventis R&D

Scaling Up Clinical Research by Expansion of Electronic Infrastructure 17

Peter J van der Spek
Professor and Head, Department of Bioinformatics, Erasmus University Medical Centre

Clinical Trials Abroad – ‘Back in the USSR’ 20

Vladimir V Novakovskiy , MD , PhD
Vice President of Regulatory Affairs and Quality Assurance, Congenix LLC

DATA MANAGEMENT IN PHARMACEUTICAL RESEARCH & DEVELOPMENT 3

Foreword_edit.qxp 6/6/07 3:37 pm Page 4

Foreword

Embracing New Challenges

Clinical Development – The New Opportunity
a report by
J o n a t h a n P a l m e r 1 and N i c h o l a s G i a n n a s i , P h D 2

1. Business Development Lead, Clinical Solutions, Europe, Middle East and Africa (EMEA), Oracle, and
2. Senior Business Development Director, Life Sciences, EMEA, Oracle

The clinical development industry is entering a new era of change and
opportunity. It faces an increasing array of drivers from the commercial,
regulatory, safety and patient sectors, the like of which have never been
seen before. Billion-dollar development costs are dwarfed by multi-billion-
dollar safety withdrawals, such as that of Vioxx by Merck & Co., which
erased US$25 billion from the company’s market value overnight. In
parallel, patients are becoming more informed, and are consequently
demanding therapies that can stretch the budgets of their health providers.
In response to these pressures, the industry is embracing new techniques
and technologies at a rate of change not seen for many years. Clinical
trial timelines are under scrutiny, meaning that companies must seek new
technologies and new territories; maturing data standards are changing
the way in which data are collected, stored and analysed; realtime clinical
trial adverse event reporting is being considered against rapid electronic
data capture (EDC) adoption; and translational medicine is helping to
convert basic research to patient-focused therapies. Across the entire
value chain there is the realisation that those companies that best exploit
and mine their data as an asset, rather than just collecting and collating
it, will be the winners in the race to market dominance.
Oracle has been involved in providing solutions for the life science and
healthcare markets for more than 20 years. Our suite of six applications
for clinical trials and pharmacovigilance is used by more than 300
companies globally. The full spectrum of our solutions in discovery,
clinical development, supply chain and sales and marketing is widely used
Jonathan Palmer is Business Development Lead for Oracle’s
Clinical and Pharmacovigilance Solutions across Europe, the
Middle East and Africa. He has 17 years of clinical
experience. He began his career as a statistical programmer,
then moved through the rapid growth of the contract
research organisation (CRO) industry, ultimately being
responsible for clinical solutions and support at Parexel. He
has had numerous roles at Oracle and IBM, helping life
science organisations realise benefits from implementing
new clinical technologies.
Nicholas Giannasi, PhD, is Senior Business Development
Director, Life Sciences at Oracle, responsible for the Life
Sciences business in Europe, the Middle East and Africa. Before
joining Oracle in 2006, Dr Giannasi was at GE Healthcare, a
US$15 billion unit of General Electric, where he was Head of
the Informatics Business and Director of Business Development
& Licensing Discovery Systems, as well as being a Member of
the GE Healthcare Strategic Marketing Executive. He led a
global team for Sales, Marketing, Support and Research and
Development. His career also includes success at a number of
smaller bioinformatic companies; he was co-founder of a
start-up biotech company and an advisor to investment
funds. Dr Giannasi holds a PhD in Population Genetics and a
first-class Bachelor degree.
across the industry, including by all of the top 20 global pharmaceutical
companies and top five clinical research organisations.
As the world’s leading enterprise software company, Oracle combines
leading-edge technologies with domain expertise to build market-leading
industry applications. Our Healthcare and Life Sciences Application
Engineering team is embracing new architectural approaches such as
service-oriented architectures to facilitate integration of ever-flexing
business processes and expanding virtual project teams.
With these challenges in mind, we have gathered a collection of experts
to provide some thought-provoking commentary and guidance on
emerging opportunities:
• Nicholas Schaltenbrand, Quintiles, illustrates how the industry is finally
moving from endless EDC pilots into mainstream global deployment.
• Barry Burnstead, i3 Statprobe, considers breaking down the historical
boundaries between safety and clinical data management to propose
more wide-scale usage of EDC as a platform for reporting serious
adverse events during a clinical trial.
• Sharon Marmaras, Boehringer Ingelheim (BI), describes BI’s initiative
to optimise clinical integration and reporting through a new
integration platform.
• Pierre-Yves Lastic, sanofi aventis, provides an overview of the latest
data standards initiatives between the Clinical Data Interchange
Standards Consortium (CDISC) and Health Level 7 (HL7) to aid
convergence of clinical trial and healthcare data.
• Peter van der Spek, Erasmus University Medical Centre, gives an
insight into the architecture of an enterprise platform to enable and
exploit translational medicine advances.
• Vladimir Novakovskiy, Congenix, illustrates the growing opportunities
to use broad patient populations and clinical services in Eastern
Europe.
We are extremely grateful to our authors for their contributions and
insights, and trust you will find their views stimulating and enlightening.
Oracle’s vision is to embrace these emerging approaches and maximise
benefit to all by providing an integrated platform of solutions for life
sciences and healthcare organisations to enable collaborative research
and, ultimately, drive better patient care.
We look forward to your feedback and to working in collaboration soon. ■

4 © TOUCH BRIEFINGS 2007

Intro_edit.qxp 4/6/07 5:25 pm Page 5

Introduction

Putting the ‘e’ in R&D

a report by
Michelle Grayson

Managing Editor, Medical Communications, Touch Briefings

eClinical is no longer just a buzz-word, but a business and scientific reality.
An eClinical trial is defined by the Clinical Data Interchange Standards
Consortium (CDISC) as a study “in which primarily electronic processes are
used to plan, collect (acquire), access, exchange and archive data required for
conduct, management, analysis, and reporting of the trial”. Electronic data
capture (EDC) is one element of this, and the adoption of this technology to
drive forward drug research is gaining pace, championed by the
pharmaceutical industry, primary healthcare providers and regulators. The
next step, or ‘eClinical Phase II’, is to move from a data-capture-centric world
to one of data exploitation and exploration. All stakeholders have a vision of
technology convergence that will provide efficiencies in drug development,
greater patient safety and improvements in patient care. Although still in its
early stages, eClinical has the power to transform pharmaceutical research
and development, and the continuing evolution of technology will help to
advance convergence across the value chain.
Technological development continues apace, fuelled by Moore’s law –
making more power available more cheaply and in a smaller package.
Many different areas of modern living are in some way affected or
enhanced by electronic help, and the life sciences are no exception. “As
the biopharma industry grapples to cope with a variety of major
challenges confronting it – from expiring patents to adverse events to
stagnating pipelines – it must continually search for better and more
efficient technologies to speed the flow of drugs into and through clinical
trials. The cost of drug development is likely to soar to a staggering
US$2 billion per IND [investigational new drug] by 2010 unless new
technologies and strategies can turn things around,” observes Kevin
Davies, PhD, Editor in Chief of Bio-IT World.
However, for every one advance there are at least two new questions that
need to be answered. EDC means that pharma are now swimming in
deep pools of information; the next big challenge is to efficiently store
and make sense of it all.
Industry Acceptance
Last year, Cambridge Healthtech Institute (CHI) conducted a survey on the
practices, views and plans of 55 pharma directors and vice presidents –
many of whom were from top 20 firms – concerning a variety of
technologies that have an impact on clinical trials now and in the future.
According to the CHI data, half of respondents believed that EDC,
particularly electronic case report forms (eCRFs), is in routine use today
(see Figure 1). A further 28% thought EDC would be endemic by 2008.
Survey respondents indicated that advances such as the use of clinical
biomarkers and offshoring of clinical trials are in mainstream use today.
Adaptive design is still a year off, and microdosing (‘phase 0’) will not
become routine until 2010.

Figure 1: When Do You Expect the Following Clinical Technologies and Practices to be Routinely Integrated Into Clinical Trials Across
Most Applicable Therapeutic Areas at Your Company?

Percentage agree
60

50

40

30

20 Biomarkers
EDC (eCRF)
10 Adaptive design
Offshoring
0 Microdosing
Now 2008 2010 2012
Year

EDC = electronic data capture; eCRF = electronic case report form; Microdosing = ‘phase 0’.
Source: Insight Pharma Reports, March 2006. Contact: Mike Goodman, Editor-in-Chief, mgoodman@healthtech.com

© TOUCH BRIEFINGS 2007 5

Intro_edit.qxp 4/6/07 3:43 pm Page 6

Optimising eClinical

Figure 2: Please Rank the Top Three Technologies in Which Your Company Will Invest Over the Next 12 Months

Weighted number of votes

70

60

50

40

30

20

10 3rd Choice
2nd Choice
0 1st Choice
CTMS EDC Data Legacy eSub Virtual RFIDs
mining data patient

Future technologies
CTMS = clinical trials management system; EDC = electronic data capture, including electronic diaries and case report forms; data mining includes extraction and reporting tools; legacy data =
integration thereof, both structured and unstructured; eSub = structured electronic submissions; virtual patients = computational models; RFIDs – radio frequency identification tags to manage
the clinical supply chain.
Source: Insight Pharma Reports, March 2006. Contact: Mike Goodman, Editor-in-chief, mgoodman@healthtech.com

Offshoring, most notably in the Asia-Pacific region, can save costs –
particularly in expensive phase III trials. There are other advantages in
terms of access to diverse and treatment-naïve patients (elaborated in the
Novakovskiy article), but with all advances there are new issues to
overcome such as legal and intellectual property (IP) problems,
understanding different national regulatory environments and standards
of care, training study personnel and coping with ethical issues.
Tellingly, more than three-quarters of CHI’s respondents had already
implemented EDC in clinical trials, or were planning to by 2009. EDC
equipment such as eCRFs and eDiaries were also popular tools in which
pharma will likely invest (see Figure 2).
Davies from Bio-IT World elaborates: “The arrival of technologies such as
EDC have had a great impact in this regard (speeding up clinical trials), in
large part because every day saved in clinical trials could translate to
US$1 million or more in drug development cost savings. But EDC is not a
solution unto itself. The integration of EDC allows other disruptive
technologies, notably adaptive trial designs, to become much more
commonly adopted across the leading pharmas.”
Putting Into Practice
There is a huge gulf between saying and doing, and implementing the
eClinical vision takes more effort and planning than simply flicking a switch.
For instance, CDISC recommends that certain issues be considered during
a technology selection process, including, among others: the hosting
environment – in-house or externally hosted; user acceptance, promoting
flexibility and accessibility; user support, again whether provided in-house
or by a third party; regulatory requirements, e.g. 21 CFR 11; cost; and
support for the standards (see the Lastic article for more information).
Partly for these reasons, companies are cautious of implementing new
technologies, with the result that the drug development industry has been
a “slow-adopter” of new technology, says Dr Ron Fitzmartin, President-elect
of the Drug Information Association (DIA) and Vice President of Informatics
and Knowledge Management at Daiichi Sankyo Pharma Development.
As an illustration, he points out that the US Food and Drug Administration’s
(FDA) Critical Path Initiative and the European Medicines Agency’s (EMEA)
Roadmap both mention the slow uptake by pharmas of technologies that
have the potential to “move clinical trials to a different level”. Two of the
EDC is not a solution unto itself.
The integration of EDC allows other
disruptive technologies, notably
adaptive trial designs, to become
much more commonly adopted...
main initiatives in the Critical Path are the use of biomarkers and adaptive trial
designs, neither of which can be realised without technology. “The FIREBIRD
initiative and the adoption of CDISC standards are just two examples that
show that the FDA wants to become an ‘eFDA’,” Fitzmartin adds.
According to Fitzmartin, better drug development comes from improved
processes, which can be optimised by technology, but not controlled by
it. “The core competency of pharma development is pharmaceutical
development, not information technology. So, pharma need to
understand and leverage technology, but not to build it ab initio,” he
opines. The bottom line is that, with Moore’s law dictating pace of
change, “pharma must be able to deploy new technology in six months
or fewer, otherwise the technology will have moved on”. ■

6 DATA MANAGEMENT IN PHARMACEUTICAL RESEARCH & DEVELOPMENT

Schaltenbrand_edit.qxp 4/6/07 5:03 pm Page 7
Large-scale Electronic Data Capture – When Size Is Not the Only Issue
a report by
Nicolas Schaltenbrand, PhD
Senior Director, Global Data Management, Quintiles
The rationale for switching from paper-based to eClinical trials is clear, as
readers of this report are, no doubt, already aware. Using an electronic
data capture (EDC) solution brings cost-efficient improvements in quality
of data and a huge reduction in database closure time. However, the
difficulties in making the transfer from paper to EDC on a large scale
should not be underestimated. Pilot studies carried out in the last five
years identified major areas where such large-scale clinical trials may
encounter problems, in particular IT, planning and the reworking of data
management processes.
While the general pace of progress since 2001 has ensured that
software issues and shortcomings in strategic planning have largely
resolved themselves, managing the wholesale procedural change in
the switch from paper to eClinical continues to offer challenges. New
One of the main criteria that must be
considered by a sponsor company
when selecting an EDC solution is
its ability to integrate with existing
in-house systems…
processes must be controlled and integrated with those of the sponsor
organisation, on-site equipment needs to be delivered to site and
installed and investigators must be trained and given access to
software support.
Globally, paper-based systems still predominate – only 35% of studies
currently use EDC. Bringing the other 65% into the eClinical fold
depends on the ability of contract research organisations (CROs) to
answer logistical and organisational problems and provide the sponsor
organisation with a turbulence-free migration.
Integrated Approach – Hybrid Solution
One of the main criteria that must be considered by a sponsor company
when selecting an EDC solution is its ability to integrate with existing
in-house systems once the clinical trial process has finished and the
database has closed or ‘locked’. As the majority of global players in the
pharmaceutical industry have evolved their own systems – often
predating the eClinical revolution – the degree of compatibility between
the existing and incoming system will be critical.
With time-frames for clinical trials spanning decades, an EDC solution
must also be able to anticipate the arrival of new versions or systems. As
© TOUCH BRIEFINGS 2007
Optimising eClinical
such, the CRO must provide a solution that meets current industry and
company-specific requirements, but that is also standardised enough to
allow migration or upgrading to a new solution for the next generation.
Issues Associated with Large-scale EDC
The most obvious difficulty to overcome is the sheer size of the project
that needs to be dealt with. Certain therapeutic areas require large and
complex clinical trials with long study duration and a global range of site
locations. These studies include a huge volume of concomitant
medication and potential adverse events, and in some cases can last for
many years. In areas such as oncology, long-term patient follow-up can
last anywhere between five and 10 years.
Studies of this size generate vast quantities of laboratory data that need
to be processed and analysed. Any CRO running a trial like this needs to
create a single database that consolidates all the constituent datasets –
laboratory, coded and randomisation data – into a single central
information repository that can be accessed at any time from any place
for the duration of the study.
Process and Organisational Change
The large-scale deployment of EDC involves substantial re-engineering of
the sponsor’s existing clinical data management system (CDMS). The
complexity of this operation should be duly factored in at the planning
stage of the trial, as experience has shown this undertaking to be
particularly time-intensive.
Clinical trials require that accurate records be kept of the case report form
(CRF) – which frequently extends to more than 100 pages per patient –
and of the number of visits made by the patient. It is also vital that the
data are consistent between visits. In addition, the coded terms used to
describe all conditions and adverse events must be monitored to ensure
they tally with the global library.
Nicolas Schaltenbrand, PhD, is Senior Director of Global
Data Management at Quintiles. He has 17 years of
experience in the pharmaceutical industry and clinical
research environment. Prior to joining Quintiles, Nicolas
spent five years in applied research managing the design
and development of data mining techniques in the
biomedical field. Following that, he performed various roles
in the pharmaceutical industry and contract research
organisations (CROs). He joined Quintiles in 1998 as
Director of Data Management, where he is in charge of the
organisation and management of all aspects of data from
clinical studies at the Strasbourg office. In 2007, after the
completion of a Masters degree in Business Administration,
Nicolas took responsibility for the whole of Quintiles France
as General Manager.
7
Schaltenbrand_edit.qxp 4/6/07 5:04 pm Page 8
Optimising eClinical
Figure 1: Example of Processes Necessary for a Large-scale EDC Project
EDC Clinical Study
Site Assessment
Order/delivery Site Provisioned Equipment
Support & Helpdesk
Hosting Study
Set-up
User
eCRF Design Acceptance
Test
Paper Process
April July Sep
It is not only hardware and software that need to be considered. The
shift from paper- to web-based trials is accompanied by training
requirements for all users. Bringing investigators and other personnel
up to speed in processing information via EDC represents a top priority
for both the CRO and the client organisation.
The early years of training in EDC implementation generated higher
costs than are common now, as users three to four years ago were
much less accustomed to web-based data management. As well as
being cheaper, the learning curve is now less steep because
investigators have become more familiar with EDC systems.
Nevertheless, training of personnel is intrinsic to any long-term study,
and retraining on a yearly basis is necessary to ensure that
competencies are maintained. CROs need to consider establishing a
dedicated training group to give specific software-related training and
technical support to the investigators.
There are considerable logistical challenges in providing the
infrastructure for global deployment of EDC. In the large-scale projects
discussed here – where an EDC solution is rolled out across perhaps
A dedicated and multilingual call centre
is essential to ensure the coherence
and smooth function of an EDC
solution on a global scale.
45 different countries – the compatibility of logistics becomes critical.
The tasks of providing on-site equipment and establishing Internet
access in regions poorly equipped in IT infrastructure are tricky and any
CRO undertaking this kind of operation should be prepared at least for
connectivity difficulties, even if the general picture for global
connectivity is rapidly improving.
8 DATA MANAGEMENT IN PHARMACEUTICAL RESEARCH & DEVELOPMENT
Monitor
Training
Investing Site Switch to EDC Solution
Training
Oct Jan June June
Go live
Such issues are where prior experience becomes vital in order to
understand and negotiate around potential problems, for example with
import or customs departments or perhaps with security of data or
Internet connection. A dedicated and multilingual call centre is essential
to ensure the coherence and smooth function of an EDC solution on a
global scale. Such a facility needs to be fully versed in software and
connectivity issues and able to offer support in the event that the system
experiences difficulties.
Case Study
Quintiles is one CRO with vast experience of tackling large-scale EDC
challenges. This particular case study was a large phase III trial,
comprising the study of 12,000 patients in 35 countries over a three-
year duration.
Like many large-scale EDC trials, the sponsor of this trial required a
customised solution that smoothed the migration between paper and
eClinical. The resulting hybrid solution was able to accommodate both
mechanisms for data capture – starting with paper and moving to
EDC – while allowing the speed of migration to EDC to be staggered
from site to site, albeit within the same organisation. As part of the
service, Quintiles provided the site assessment and all the computing
equipment, set up the help desk, trained the investigators and
established an electronic CRF and data cleaning process (see Figure 1).
The IT requirements for this project presented logistical challenges typical
of large-scale EDC studies. Laptop supply and Internet connectivity had to
be provided to sites in 35 countries and standard computer images were
built into the solution to facilitate database navigation and
communication between users.
Specific to this project was a particularly high provisioning rate: 40% of
sites required computers and 20% needed Internet connection to be
set up. This, coupled with poor IT infrastructure or governmental
obstruction in some countries, led to significant delays in providing
Internet access to particular sites. Similar delays were also experienced
with the customs service of certain countries in the delivery of on-site
Schaltenbrand_edit.qxp 6/6/07 3:45 pm Page 9

Large-scale Electronic Data Capture – When Size Is Not the Only Issue

Figure 2: Sample of Problems Encountered by Users Figure 3: Study Portal

(From Helpdesk Log)

User account 45%

Software 5%

OC RDC 16%

Hardware 4%

General 10%

Connectivity 20%

equipment. As part of the provisioning, Quintiles provided a
multilingual helpdesk, available 24 hours a day and seven days a week,
to support EDC software and connectivity. The volume and type of calls
received provided valuable feedback for Quintiles on the range of issues
that users encountered (see Figure 2).
To resolve the software, connectivity and user account issues identified
in this trial, Quintiles also set up a study web portal designed to
complement the helpdesk and allow the end-user to submit account
available to users, who could also access performance metrics and a
study contact database that included all the people connected with
the EDC solution.
On a more functional level, the study web portal allowed users to review
patient listings prior to the patients’ arrival at a hospital or medical centre.
Thus, staff were able to anticipate and prepare in advance of a visit. Last
but not least, the study web portal gave easy access to patient profiles
for use in medical review (see Figure 3).

The traditional paper-based process
and electronic data collection via
Internet can all be implemented within
a single database where all information
can be viewed in parallel by multiple
team members.
Summary
The benefits of deploying a fully integrated paper and EDC solution as
described above are clear-cut. The traditional paper-based process and
electronic data collection via Internet can all be implemented within a
single database where all information can be viewed in parallel by
multiple team members. Furthermore, a central point of access to all
patient listings and study documents is available via the web study
portal. The hybrid system obviates the risk of paper loss – all images are
available online – improves the cleaning process and provides easy
access for data review.

We have reached a tipping point in the deployment of EDC. More than

one-third of trials now use EDC, and the next two to three years will see
requests and password resets via email. The study web portal also rapid expansion across the rest of the sector. It is vital that CROs
served as a second point of access to information on the clinical trials. understand the issues and take the needs of the sponsors into account in
General study documents – such as protocol and eCRFs – were made order to ease the migration from paper to eClinical. ■

ASP Quick-start Services for Oracle Life Sciences Suite

Hosting • Site Assessment and Provisioning • Helpdesk • Support

DATA MANAGEMENT IN PHARMACEUTICAL RESEARCH & DEVELOPMENT 9

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Optimising eClinical
Electronic Safety Data Management – The Dawn of a New Era, but Are We
Awake to the Consequences?
a report by
Barry Burnstead
Director of Project Management, i3 Statprobe International
The enthusiasm of both the pharmaceutical industry and regulatory
authorities to adopt new technologies such as electronic data capture
(EDC) systems and electronic patient diaries is a powerful reason to
change the established practices of collecting safety data. This article
examines the pressures and opportunities for safety data management in
the brave new world of eClinical development. Specifically, it will address
the question: ‘Will single-source serious adverse event (SAE) data
collection via EDC become the industry norm?’
Safety data on pharmaceutical products are collected during clinical
testing and continue to be collected after the product is on the market.
Each pharmaceutical company needs a pharmacovigilance department to
record all SAEs, while the team undertaking clinical testing will
concentrate on all AEs that occur during their trials. Traditionally, clinical
trial results were recorded on paper in a case report form (CRF), to be
collected weeks later. This process was not fast enough for the
pharmacovigilance team, who need to report deaths within seven days of
their being recorded and SAEs within 15 days. Thus, there was a
separate, fax-based system for reporting SAEs for pharmacovigilance
purposes, and management of safety data was effectively performed by
two operations in parallel, albeit with contrasting objectives.
For many years these two operations co-existed harmoniously, inasmuch
as pharmacovigilance and clinical data management barely
acknowledged each other’s existence. This dual system required that the
common SAE data in the two databases be tediously reconciled – a
sobering reminder that the industry had created two sources and
independent procedures to handle the SAE information from a clinical
trial. Nevertheless, it appeared to work.
Barry Burnstead is the Director of Project Management in
the international division of i3 Statprobe, Phase Forward. He
has worked in the pharmaceutical industry for over 30 years,
beginning at Beecham Pharmaceuticals, working initially ‘at
the bench’ before establishing a Statistics and Data
Management Department to support worldwide early-phase
clinical trials. He remained at the company following its
merger with SmithKline French. Since leaving, Barry has
been involved in the contract research organisation (CRO)
business, even co-founding his own CRO in Germany. In
August 1999, he joined Domain Pharma as a Senior
Business Consultant, expanding his role to cover the global
implementation of safety systems for five major companies
and, after Phase Forward acquired Domain, becoming global
Head of Programme Management. Mr Burnstead is also an
active member of the Drug Information Association (DIA)
and recently received a Lifetime Membership Award in
recognition of his contributions. He is also a member of the
European Clinical Data Interchange Standards Consortium
(CDISC) co-ordinating committee.
10
So what has changed? The drive to accelerate data acquisition and
improve data management led to the development of new technology.
EDC was one result, and it has taken more than a decade to become
established. However, recognition of its wider impact has been even more
pedestrian: pharmacovigilance operations have continued with their paper
and fax solution for acquiring SAE data. What has become clear, however,
is the fact that clinical data management operations using EDC are
potentially receiving notification of an SAE before pharmacovigilance, and
with better quality and transmission success rate than the faxing
procedure. It has therefore dawned on the safety departments that they
are vulnerable to becoming non-compliant with regulatory reporting time-
frames while remaining blissfully unaware of this.
Yet nothing that is being implemented is revolutionary. An automated
e-mail alert whenever an SAE is reported via EDC might effectively
address the compliance concern, but it fails to eliminate redundancy and
obviate the generation of conflicting data. Continuous SAE reconciliation,
automated SAE reconciliation and e-mail alerts are laudable responses to
the advent of EDC. However, the present situation cries out for more
courageous intervention and radical process improvement.
One Source Fits All
Herald the arrival of single-source SAE information. The safety mavericks
among us have recognised how the functionality of EDC can be as
beneficial to the collection of our own SAE data as it is for clinical trial
information. For example:
• the quality of SAE data can be enhanced by use of instantaneous
dynamic data checks, which can send out an alert when data lie out
of plausible ranges;
• data can be transferred into the safety database within 24 hours,
enabling the more complex checks developed for the safety database
to be run sooner and for queries to be presented back to the site at
the start of the next working day;
• the tedious task of SAE reconciliation is eliminated and, along with it,
any queries that are presented back to the site weeks or sometimes
months after the event, which all too frequently compromise rather
than enhance data quality; and
• as it is a new communication medium, EDC can ensure that important
safety information – and advice on how to report it – can be conveyed
to the whole investigator community if necessary.
Above all, the most eye-catching benefit is the fact that data are collected
once only. Nevertheless, there is a distinct lack of enthusiasm to embrace
EDC from the pharmacovigilance world, despite the fact that it is a more
efficient means of capturing information at the investigator site. Perhaps
there is a political or cultural divide between the two operations?
© TOUCH BRIEFINGS 2007
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Electronic Safety Data Management – The Dawn of a New Era, but Are We Awake to the Consequences?
Figure 1: Single Sourcing of SAE Data
Routine EDC
checking process
1. Transfer an E2B
Report file equivalent
SITE EDC Safety
SAE Database 2. Query transfer Database
Query
resolution 3. Query resolution
ODM XML
file
eSubmission
of ICSR
Ultimately a paperless
process from site to
regulatory submission
Opportunity knocks for the ‘pharmacovigilantes’. One company going for
first-mover advantage is GlaxoSmithKline (GSK). Speaking at the Drug
Information Association (DIA) EuroMeeting (26–28 March 2007 in Vienna,
Austria), GSK’s Director of the Case Management Group announced that
for the company’s research operation, capture of SAE information via EDC
has moved from pilot mode into production. This means that GSK has had
to refine its business practices for capturing all safety information required,
both for expedited reporting and for inclusion within the clinical report.
Pharmacovigilance gained responsibility for the safety data area within
EDC, and could specify the data to be transferred to the safety database.
Working rules have been established and political sensitivities addressed,
but have not been allowed to dictate. The benefits of dynamic on-line
checking of SAE data are emphasised. True single-sourcing of SAE data
eliminates reconciliation and ensures that no conflicting information is
submitted to the competent authorities and the European Agency for
the Evaluation of Medicinal Products (EMEA). The process is illustrated in
Figure 1. GSK is to be congratulated on achieving a harmonious business
solution that will deliver increased efficiency.
Reading the Signals
All of this effort, both technical and political, can be justified on the
grounds of efficiency in SAE data collection, yet further associated benefits
exist. There is a lot of pressure on drug developers to cut costs, and one of
the ways in which this can be done is to ensure that ineffective, poor or
dangerous drugs are identified as early in the development cycle as possible
to prevent any more time or money being lavished on them. This has
focused attention on the clinical trials (CT) database. Collecting all SAE
information via EDC and then loading it into a catch-all clinical data
management system (CDMS) will actually lead to an enrichment of the
content of the CT database. An aggregated CT database would hold all the
data associated with the investigational medicinal product (IMP) and would
therefore be used for running algorithms to detect early safety signals. In
fact, this environment could ultimately support continuous signal detection.
The benefits of a single-source electronic safety data collection system do
not end there. There is a further, less obvious regulatory perspective. For
several years now, the US Food and Drug Administration (FDA) has asked
to have access to the raw clinical data for clinical study evaluation
purposes. In the paper world this was simply a case of providing access
to the CRFs. So well established was this process that the first response
to EDC was simply to translate the requirements directly and recreate the
DATA MANAGEMENT IN PHARMACEUTICAL RESEARCH & DEVELOPMENT
CRF as a pdf file. Current activity is focused on CDISC’s study data
tabulation model (SDTM), which is a recognised format for submitting
electronic information to the FDA, and effectively replaces the CRF
listings. One should recognise that the FDA is the only agency requiring
the raw clinical data and hence the only agency to take a specific interest
in this particular CDISC model.
Watching the Detectives
In a new move (March 2007), the FDA’s Center for Drug Evaluation and
Research (CDER) and Center for Biologics Evaluation and Research (CBER)
have launched a search for five partners to participate in an operational
data model (ODM) XML transfer pilot. ODM was developed as a means
of transferring complete databases, with the key being that it is platform-
independent. This request essentially confirms the FDA’s interest in
metadata and audit trails, covering all the SAE information in the
database and any changes that have been made to it. One might
speculate on the motives behind the FDA’s interest: why would it wish to
view all these data? Perhaps the FDA wishes to:
• import the whole of the study data into its new database, Janus;
• inspect audit trails to assess consistency and objectiveness; and
• ultimately be reassured of the authenticity of the data.
What are the ramifications of this request? Access to the source data
offers the assessors greater confidence about any SAEs and their
collection than is currently supplied via the pharmacovigilance route. This
is because the data in an ODM file will expose quite different information
than an E2B file. For example, a user might change the Medical Dictionary
for Regulatory Activities (MedDRA) coding of an SAE, and this change will
be recorded in the audit trail and be immediately available to the
assessor. Such changes can now be assessed for consistency and absence
of bias, which are very difficult to detect in individual case summary
reports and product safety update reports.
Other important pieces of information are the date stamps, which will
provide unequivocal evidence of when these data were received in
the sponsor database. This places pressure on pharmacovigilance
departments to ensure they report within the statutory timeframes. One
can speculate on motive and paranoia sets in, but a sponsor ultimately
wishes to submit quality data that cannot be challenged.
Whatever the purposes and consequences of an ODM XML file may be,
it raises the spectre of data consistency and a need for pharmacovigilance
to be aware of new information on an SAE provided in ODM of which
they may have been blissfully unaware. One can speculate on the
consequences of authorities uncovering conflicting data on an SAE
occurring within a trial, but it is reasonable to assume that confidence is
undermined and the likelihood of an audit is increased.
Personally, I see the FDA’s interest in ODM XML as bringing further
pressure upon the pharmaceutical industry to adopt single sourcing of
SAE information. EDC offers the best medium for this. The pot of gold at
the end of the rainbow is the promise of casting SAE reconciliation into
the history books forever. The electronic era has placed the two
independent processes for SAE data collection under the spotlight, and
to answer the opening question: yes, single-source SAE data collection is
the obvious solution. Dual SAE data recording will be judged to have
become a luxury that drug development can no longer afford. ■
11
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Optimising eClinical
Data Integration – Business Requirements and Implications for Data Standards
a report by
Sharon Marmaras
Director, Clinical Trial Support and Life Sciences Data Hub (LSH) Business Project Leader, Boehringer Ingelheim
The integration, analysis and reporting of data collected in clinical
trials is one of the critical paths in drug development. Challenges
arrive from integrating data from multiple sources. Furthermore, the
analysis of this data must be controlled and must deliver reproducible
results. Data from clinical trials are captured, cleaned, processed,
reported and archived using appropriate computerised tools. These
tools support various aspects of the research process, such as trial
design, data entry, source document tracking, data cleaning, analysis
and reporting.
Problems arise when multiple data sources need to be shared. Often,
problems linked to sharing data between different systems are
addressed by several one-to-one links between the various systems. This
results in considerable maintenance effort and version dependencies.
Typically, data transformation and reporting programs are developed by
copying files from a file system, which are then edited, possibly trial by
trial. Managing version control and the testing cycle is a major challenge
in such an environment. Accordingly, integrating data across the
systems is time-consuming. Because data are dispersed, end-users
cannot access crucial information without the involvement of a
technically skilled person. Such delays during regulatory submission
preparation are very costly.
Boehringer Ingelheim (BI) currently uses Oracle Clinical (OC) as its
clinical data management system (CDMS) to perform clinical data
management functions. Data in OC are depicted in a relational
structure, which does not implicitly support reporting, but does allow
flexible study set-up and data entry. However, in OC it is difficult to
handle cross-trial data and to perform the sophisticated data
transformations required for statistical analysis. Reporting and analysis
are currently supported by an SAS-based system developed in-house,
CARE (Clinical data Analysis and Reporting Environment). CARE was
developed to reduce global programming effort within BI, by providing
a standard environment for generating the tables, listings and figures
for clinical trial reports. CARE promotes a harmonised SAS environment
across the corporation, through standardised OC database structures,
SAS data libraries, a library of standard SAS programs and the use of an
SAS-based report appendices generator (RAGe) to apply headers,
footers and a table of contents to the SAS output. Using CARE, data
managers and statisticians create their own tables, listings and figures
for the reporting and analysis of clinical data. The analysed data are
then collated and published using Documentum®.
The Life Sciences Data Hub
BI needed a solution where data could be loaded by end-users from a
variety of sources (e.g. OC, SAS), where programs and reports could be
built from a library of re-usable standards, and all authorised users could
12
easily access the data they required. In addition, the automation of some
of the process would be an extra benefit.
To achieve this, BI wanted to establish a unified environment for
clinical data building, analysis and reporting at a global, cross-trial and
individual trial level – effectively, a central global repository for data,
which would integrate data from multiple sources and help to move
BI’s processes in the direction in which the industry is headed in terms
of eClinical development.
BI put out a set of user requirements that the company felt were
essential from the system and put up several requests for proposals to
different groups. BI’s main considerations were for a central global
repository that allowed users to be able to work in a secure location. BI
also wanted to integrate SAS (the skill-set of the organisation) to
promote the use of standards and reusability by use of library functions.
BI also wanted its medical personnel to be able to review data easily with
a user-friendly interface – the current data management system is often
considered too complicated for non-technical personnel. The new system
also needed to support regulatory requirements such as US Food and
Drug Administration (FDA) 21 CFR part 11 compliance. Other key
requirements identified by BI included:
• enabling a configurable workflow, e.g. to support users in the
validation of programs;
• facilitating the import/export of data, together with associated
metadata and programs, to send to regulatory authorities and
contract research organisations (CROs); and
• providing archiving functions.
BI had originally contracted a company to build a customised system.
However, Oracle approached BI with a view to building a tier 1 product
in collaboration with a partner from the pharmaceutical industry. A
consortium was formed – the current partners being BI, Oracle and
IBM – and development began on the Life Sciences Data Hub (LSH) in
2000. The LSH is not intended to specify the standard reporting
programs, but to provide an interface for creating, maintaining and
running these programs. BI will develop standard programs in parallel.
Data Loading
To allow clinical data reporting in the LSH, the data needs to be made
available from the external source systems by loading them into the LSH.
Loading data is handled through predefined adapters. Adapters for OC,
Oracle tables, SAS datasets and ASCII files are shipped with LSH. Data
loading may be accomplished by physically copying data into LSH or by
just defining views onto the source system. There are two components to
© TOUCH BRIEFINGS 2007
Marmaras_edit3.qxp 5/6/07 12:04 pm Page 13
Data Integration – Business Requirements and Implications for Data Standards
loading data – the metadata that describe the structure of the data to be
loaded, and the actual data source supplying data to LSH. After loading
the clinical data, together with the metadata, into the LSH, they can be
further processed and transformed within the LSH to prepare analysis
datasets, to perform data building for reporting or to combine them
across trials to build a project database.
Programs in LSH are created to transform, analyse and report data. The
LSH’s interactive development environment (IDE) allows users to write
program logic (i.e. source code) for data transformation and reporting
programs in the IDE, and to save source code files in LSH for re-use.
Reporting Data
One of the primary goals of LSH is clinical data reporting, which is
accomplished with the use of report sets. Company standard templates
will be available for standard reports, such as clinical trial reports and
other internal review reports. At BI, programs for analysing and reporting
clinical data are developed in the SAS IDE in the same way as programs
for data transformations. For other reporting purposes, e.g.
administrative reporting, Oracle Reports might be used.
Visualisations provide easy and user-friendly access to data for data
visualisations and exploratory data snooping by non-programmers. The
LSH allows users to view data using tools such as Oracle Discoverer or
other commercially available review tools. BI intends to use a
visualisation tool as a review tool for clinical personnel during the
conduct of clinical development.
A validation life-cycle can be defined for all programs developed in LSH.
For example, a program may move through these statuses: under
development, ‘in test’ and in production. The validation life-cycle is
customisable and will be adapted to match BI’s development process. All
output is labelled with the validation status of the program that produced
it in order to make it obvious on which validation status an output is
based. All changes to data and metadata are audited.
The Benefits of Data Integration
After the first implementation phase to bring the LSH into production at
BI, we intend to integrate further BI systems into the LSH with the goal
of establishing an integrated reporting environment for a wide spectrum
of data generated in clinical development.
In terms of business benefits, having one central global data repository
will be the biggest benefit. As a global company, with clinical studies
running all over the world, data can be in several locations. With the LSH
we can put all data in one place, which gives BI the opportunity to reuse
programs, further facilitate the use of standards and reduce cost and time
for the development of programs.
The LSH will be able to pull data from the database that you may be
working in, together with data from multiple trials, which will enable
reporting on one substance or one indication. Furthermore, there is the
potential to integrate administrative trial data with clinical data or
integrate drug safety data with clinical data.
In essence, the LSH is one security concept, one central application.
Although the LSH has only been running in non-production mode since
March 2006, in terms of the maintenance effort it has definitely been
DATA MANAGEMENT IN PHARMACEUTICAL RESEARCH & DEVELOPMENT
easier for BI’s administrative people.
No major issues have been encountered with data integration. However,
the reporting components of the LSH still need additional refinement and
we are still working towards improving certain aspects of functionality
and the user interface. BI is working very closely with Oracle on
recommendations for improvements. In addition, Oracle plans the
development of an improved interface to Documentum, which will satisfy
the needs of the company.
While it is still too early to comment about real benefits – BI has yet to
run a pilot study on real data – several simulations, run for proof-of-
concept purposes, have demonstrated that the benefits that could be
realised include improved quality and speed of summary information,
facilitating the reuse of standards.
Visualisations provide easy and user-
friendly access to data for data
visualisations and exploratory data
snooping by non-programmers.
Essentially, the LSH has the potential to introduce significant
improvements in efficiency, which in turn can reduce time and cost for
drug development. The integration of multiple data sources also
increases the knowledge across the company. As a company BI has been
promoting standards for some time. As such, the LSH will provide the
opportunity to introduce a stricter standardisation of data.
Summary
BI envisages that the LSH will help to:
• increase the quality and speed of summary information available for
decision points;
• reduce the time and cost of the drug development process by
supporting the use of company standards and the sharing/re-use of
user programs;
• automate and facilitate company validation efforts;
• increase drug development knowledge by integrating multiple
company data sources;
• transform data to information;
• increase knowledge of our drugs.
LSH will close the gap between the collection and tracking of clinical data
and the submission of the analysed data to regulatory agencies, and
when the LSH is a part of the company’s reporting process, we expect to
see a significant improvement in efficiency. Currently, the learning curve
is fairly steep and that curve needs to be brought down, either through
improving the graphical user interface of the system or through the
development of training materials. Finally, BI plans to go into pilot phase,
with a live study, in September 2007. ■
Originally published in The eClinical Equation: Delivering the Vision,
Touch Briefings/IBM, 2006.
13
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Optimising eClinical
The Convergence of Healthcare and Clinical Research Standards
a report by
Pierre-Yves Lastic, PhD
Senior Director, Standards Management & Data Privacy, sanofi aventis R&D
Most individuals involved in the collection, validation, coding, transfer,
analysis, reporting and archiving of data from clinical trials are generally
aware of the existence of the standards developed by the Clinical Data
Interchange Standards Consortium (CDISC).1 In fact, most people
working in clinical research across the world use these standards on a
daily basis, or at least specifications derived from or inspired by them. It
is fair to say that the majority of these people are unaware of Health Level
Seven (HL7)2 standards. On the other hand, software developers working
on hospital information systems routinely implement HL7 specifications,
but know CDISC only from hearsay. However, there is a growing
community of healthcare and clinical research professionals working with
a foot in each world. If you are not yet among them, here are a few
answers to frequently asked questions.
Where Do HL7 and CDISC Come From?
HL7 is one of several standards-developing organisations (SDOs)
accredited by the American National Standards Institute for the
healthcare arena, and has just celebrated its 20th birthday. It was born at
a time when information systems used in healthcare were not linked with
each other. This meant that patients admitted to a hospital filled in paper
forms that clerks entered into the administration system. The patient
received a printout and took it to another department, where staff would
perform the examinations and write these results on other paper forms
that would eventually be entered in a different computer. A similar
process occurred at the pharmacy and involved yet another form, which
would be attached to all the forms from the hospital; the whole paper
stack would then be filed to the insurance company for reimbursement.
Similar systems still operate in many countries. Nevertheless, growing
healthcare costs have driven a huge optimisation effort and, as bytes are
easier to move than physical forms, electronic messages are progressively
replacing paper-carrying patients. HL7 plays an important role in this
process as it has defined sets of standardised messages to carry bits of
Pierre-Yves Lastic, PhD, is Senior Director of Standards
Management & Data Privacy at sanofi-aventis R&D. After
working for several years as an Assistant Professor at the
University of Bayreuth, he moved to the pharmaceutical
industry where he spent 17 years in different management
positions in the field of clinical research, leading clinical data
management, biostatistics, clinical operations and
information management, first with Ciba-Geigy
(Switzerland), then with Synthélabo, Sanofi-Synthélabo and
sanofi-aventis (France). Dr Lastic is a member of the Board
of Directors of the Clinical Data Interchange Standards
Consortium (CDISC) and of the International Pharmaceutical
Privacy Consortium (IPPC). He studied biology, computer
sciences and languages in France and Germany and holds a
PhD in biology from Bayreuth University, Germany.
14
administrative, financial and clinical information between independent
computer systems on a variety of hardware and software environments.
HL7 has also developed specifications for documents, leading the way
towards the implementation of electronic medical records. Above all,
during these 20 years of continuous improvement, HL7 has put in place
a standards development and maintenance methodology that can cope
with the extremely complex processes that are the norm in healthcare.
CDISC is only half as old as HL7. It started as a volunteer group within the
Drug Information Association (DIA) in 1997 and was incorporated in
1999. Most of the original CDISC members worked as statisticians, data
managers or programmers in biopharmaceutical companies, contract
research organisations or software providers, yet they faced a number of
similar business problems:
• agreeing about data exchange formats with development partners,
clinical research organisations and central laboratories, then spending
considerable amounts of time and resources to check and clean the
exchanged data;
• redefining internal data formats and database organisation with each
merger or acquisition;
• customising software systems to accommodate different data
models; and
• transforming and reorganising clinical study data from different
sources to be able to prepare integrated summaries of safety
and efficacy.
On the other side of the fence, the US Food and Drug Administration
(FDA) was confronted with the need to analyse data from thousands of
clinical trials, all formatted differently.
These different business cases led CDISC to develop several models: an
XML model called the operational data model (ODM) dealing with the
acquisition, validation, transfer and archival of clinical data; the LAB
model specifically for the exchange of data from central laboratories; a
submission data model (SDM; now called the submission data tabulation
model, SDTM) defining the format and organisation of raw data
submitted to the FDA for review and analysis; and an analysis data model
(ADaM) documenting the analysis process.
The Different Models
A partnership between HL7 and CDISC makes a lot of sense. HL7 can
provide proven methodology and know-how from the healthcare side,
while CDISC can contribute expertise in the clinical research domain.
© TOUCH BRIEFINGS 2007
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The Convergence of Healthcare and Clinical Research Standards
Therefore, together with the FDA, CDISC and HL7 created the Regulated
Clinical Research Information Management (RCRIM) technical
committee3 to provide a framework for common developments.
However, early attempts to harmonise HL7 and CDISC models faced
difficulties. To begin with, HL7 develops messages. By nature, a message
is transient: it contains a piece of information extracted from one place
to be delivered to another before disappearing. This is perfectly suitable
for personal medical records that consist of various documents such as
clinical examinations, laboratory results, X-rays, videos, etc. However, it
does not provide for easy access across patients or structured data
domains. CDISC, on the other hand, is built around well-defined clinical
trial protocols with strict data structures, and development is driven by
the need to use technology to improve the efficiency of the heavily
regulated clinical trial process.4
Of the CDISC models, ODM is designed to comply with good clinical
practice regulations – for example, audit trails and electronic signatures
are built in – while SDTM allows easy review and analysis across studies
and across patients – for example the ability to pool all adverse events
from several drugs of the same class, or verify the exposure of a certain
patient population to a drug across several studies.
The only CDISC model that was easily translated into an HL7 model was
the LAB model, because its primary use is the transfer of data from a
central laboratory to a clinical research database: in other words, a
message. Currently, the LAB model can be implemented in four different
ways: as a CDISC XML file, an ASCII flat file, an SAS data set or an HL7
v3.0 message.
Bringing Them All Together
The goal of information standardisation is the interoperability of
computer systems, i.e. the possibility for one computer system to
adequately process data from another system without human
intervention. The prerequisites for interoperability are known as ‘the four
pillars of interoperability’:5
1. a common reference information model;
2. unambiguously defined data types;
3. a robust mechanism to bind domain-specific terminologies; and
4. a formal top-down message development process.
Following this, a domain analysis model was developed for clinical
research that is compliant with the HL7 reference information model
(RIM). This clinical model, which eventually became the biomedical
research integrated domain group (BRIDG) model with the
participation of the US National Cancer Institute (NCI), supports the
first pillar of interoperability between hospital information systems
and systems used in clinical research and in regulatory agencies.
Data types used should follow or be translated into the HL7 v3.0
specifications.
Terminology is also an area that needs to be standardised. This is handled
by two HL7 technical committees (Vocabulary and Modelling &
Methodology), while the vocabulary itself is either drawn from existing
domain-specific terminologies – e.g. systemised nomenclature of human
medicine (SNOMED),6 logical observation identifiers, names and codes
(LOINC),7 digital imaging and communications in medicine (DICOM),8
DATA MANAGEMENT IN PHARMACEUTICAL RESEARCH & DEVELOPMENT
medical dictionary for regulatory activities (MedDRA),9 etc. – or
developed within the RCRIM Vocabulary Working Group using the
enterprise vocabulary services from the NCI.10 The entire development
process is supported by a number of HL7 v3.0 tools to assist developers
in building compliant interchange structures.
Given that CDISC and HL7 develop models and specifications, not
programs, putting all four pillars in place is only a signal for the software
development work to begin; there are still plenty of issues to be resolved.
This is common for all projects that aim to link electronic medical records
with clinical research systems.
Real-life Applications
The interconnection of patient hospital records and clinical research
systems faces many issues: privacy, security, non-matching patient
identification numbers, FDA regulatory compliance (e.g. 21 CFR part 11),
etc. These have been reviewed and analysed several times, as can be
found in the references.11,12
One of the most appealing solutions to these issues is the Single Source
Project,13 which aims to have a one-time collection of data that are
subsequently rendered into multiple formats/systems using CDISC and
HL7 standards. Single Source was tested in a CDISC proof-of-concept trial
Given that CDISC and HL7 develop
models and specifications, not
programs, putting all four pillars of
interoperability in place is only a
signal for the software development
work to begin…
that led to the co-development of a new methodology, or integration
profile, with the Integrating the Healthcare Enterprise (IHE) initiative.14
Called Retrieve Form for Data-capture (RFD), this profile enables any
electronic health record (EHR) to retrieve data-capture forms from many
external systems.
RFD was recently demonstrated at the Interoperability Showcase at the
Healthcare Information and Management Systems Society (HIMSS) 2007
Annual Meeting.15 Similarly, the US National Cancer Institute (NCI) and
Oracle collaborate on the electronic Data Collection Instrument (eDCI)
project to develop a method of transferring the definitions and
functionality of data capture forms from the data dictionary of a clinical
data management system into an EHR.16
The Single Source approach was also recently tested at the European
Hospital Georges Pompidou in Paris with promising results.17 Data were
shown to be imported into existing EHR and electronic data capture
(EDC) systems using HL7 and CDISC standards, and work continues on
semantic integration of both sides.
Looking Ahead
All of these pilot projects show that progress is being made. For example,
HL7 v3.0 and CDISC ODM have been stable for years; the BRIDG model
15
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Optimising eClinical

allows data to be shared between the patient-care and research worlds;
and IHE facilitates the move from standards specifications to practical
solutions. The question now is, will we soon be feeding clinical trial
databases from hospital records?
There is no simple answer to that question. It will certainly take 10 or
even 20 years before we are able to run a multinational, multicentre
clinical trial in which the clinical trial database is populated by the
information systems of the hundreds of hospitals in all the different
countries involved. That would require all these systems to be HL7 RIM-
compliant, which cannot be achieved quickly. Many efforts are being
made to harmonise laws and regulations internationally, but it is a
lengthy process. Even within the EU, national interpretations of the same
directives are often a barrier to efficient clinical trials. When it comes to
accessing patient records from hospitals and general practitioners, a
possible solution seems even further away.
However, there are some areas where practical solutions are only a few
years away:
• For many years, clinical pharmacology units have used their own
proprietary systems to manage the clinical data of volunteers. The
implementation of HL7/CDISC-compliant standards could lower the
costs of a phase I trial by 20–30% by eliminating the source-data
verification steps and thus reducing the number of monitoring visits.
• In oncology, organisations such as the NCI or the European Organisation
for Research and Treatment of Cancer18 sponsor hundreds of clinical
trials that are run in their hospital networks. Such organisations will be
leading hospital-research interoperability within a few years.
• The development of biomarkers that, like medical images, will need
to be shared between hospitals, sponsors and regulatory reviewers
will also be a strong driver for this kind of interoperability.
In conclusion, given that EDC in clinical trials took 15 years to take off,
one can expect that healthcare-research interoperability will need a
generation to establish itself. Nevertheless, this process has already
started and will be a hot topic for the decade to come. ■

1. Clinical Data Interchange Standards Consortium,
http://www.cdisc.org
2. Health Level Seven, http://www.hl7.org
3. Regulated Clinical Research Information Management Technical
Committee,
http://www.hl7.org/Special/committees/rcrim/rcrim.htm
4. Clinical Data Interchange Standards Consortium, Electronic
Source Data Interchange (eSDI) Group, Leveraging the CDISC
Standards to facilitate the use of Electronic Source Data within
Clinical Trials, Version 1.0, 20 November 2006,
http://www.cdisc.org/eSDI/eSDI.pdf
5. Mead CN, Data Interchange Standards in Healthcare IT—
Computable Semantic Interoperability: Now Possible but Still
Difficult, Do We Really Need a Better Mousetrap?, J Healthc Inf
Manag, 2006;20(1),
http://www.himss.org/ASP/publications_jhim_issue.asp?issue=1
/1/2006
6. Systematized nomenclature of medicine,
http://www.snomed.org/
7. Logical Observation Identifiers Names and Codes,
http://www.regenstrief.org/medinformatics/loinc/
8. Digital Imaging and Communications in Medicine,
http://medical.nema.org/
9. Medical Dictionary for Regulatory Activities,
http://www.meddramsso.com/MSSOWeb/index.htm
10. National Cancer Institute Enterprise Vocabulary Services,
http://evs.nci.nih.gov/
11. Bleicher P, Integrating EHR with EDC: When Two Worlds
Collide, Applied Clinical Trials, 2 March 2006,
http://www.actmagazine.com/appliedclinicaltrials/article/articleD
etail.jsp?id=310798
12. Donovan H, EHR & EDC: Tomorrow’s Technology Today,
Applied Clinical Trials, 1 February 2007,
http://www.actmagazine.com/appliedclinicaltrials/article/articleD
etail.jsp?id=401624
13. The Single Source Project,
http://www.cdisc.org/single_source/about.html
14. Integrating Healthcare Enterprise (IHE), http://www.ihe.net/
15. Healthcare Information and Management Systems Society
(HIMSS) Annual Meeting,
http://www.himss07.org/general/handouts.aspx
16. Kacher D, eDCI Project Report, CDISC Interchange, Bethesda,
27 September 2006,
http://www.cdisc.org/publications/interchange2006/session6/Do
nKachercdisc_edci_report.pdf
17. El Fadly N, Bousquet C, Daniel C, Facing the semantic issues in
aligning HL7 CDA templates and CDISC ODM – An experiment
in cardio-vascular radiology, CDISC Interchange, Bethesda, 27
September 2006,
http://www.cdisc.org/publications/interchange2006/session6/Pie
rre-YvesLasticEHR-EDCintegrationatHEGP-pyl-
CDISCInterchange2006.pdf
18. European Organisation for Research and Treatment of Cancer,
http://www.eortc.be/

16 DATA MANAGEMENT IN PHARMACEUTICAL RESEARCH & DEVELOPMENT

VanderSpek_edit.qxp 4/6/07 4:58 pm Page 17
Scaling Up Clinical Research by Expansion of Electronic Infrastructure
a report by
Peter J van der Spek
Professor and Head, Department of Bioinformatics, Erasmus University Medical Centre
Erasmus University Medical Centre (MC) provides advanced medical care
for three million people in the south-western part of The Netherlands,
making it the largest centre of its kind in the country. Care is organised
in three clinical branches: the General Hospital, the Sophia Children’s
Hospital and the Daniel den Hoed Oncology Centre. Erasmus MC has
achieved excellence in many areas, including cardiovascular diseases,
oncology, paediatrics, genetics and cell biology, human reproduction,
endocrinology, microbiology and virology, immunology, hepatology and
(micro-)surgery. It is among the top research institutes in The Netherlands
and participates in several nationally and internationally recognised
biobank initiatives. Research activities range from fundamental
biomedical research, patient-related research and epidemiology to public
healthcare policy and management.
Over recent decades, progress in molecular biology, chemistry and
imaging technology has provided the life sciences and healthcare
sectors with the opportunity – and the challenge – to use
unprecedented volumes of data across the entire spectrum of clinical
activities. High-throughput sequencing, such as that used in the
Human Genome Project, has provided complete genetic sequences of
growing numbers of organisms. DNA chip (or microarray) technologies
are responsible for the growth of hundreds of thousands of gene
expression and single-nucleotide polymorphism (SNP) data points on a
daily basis. Advances in proteomics are now creating a similar flood of
data on the biology of proteins. Novel in vivo molecular imaging
techniques allow visualisation of the molecular pathways that
underpin the aetiology of cardiovascular disease, neurological
disorders and, last but not least, cancer. This all requires a state-of-the-
art information and communication technology (ICT) infrastructure. To
this end, Erasmus MC’s department of bioinformatics has selected
several institutes with which to work, including US-based Windber
Research Institute (WRI) and Walter Reed Army Medical Center and
London-based Imperial College for tissue banking and data
warehousing of clinical, molecular and imaging information.
Evidence-based Therapy
Today, most diseases are diagnosed after clinical symptoms start to
manifest. Therapy is considered successful if symptoms are reduced,
but, in general, current interventions and pharmaceuticals tend to deal
with diseases at too late a stage of development. In future, novel
diagnostic technologies will allow for earlier and much more
individualised detection and treatment, and probably even prevention
in certain cases. With pressures on the pharmaceutical industry to cut
costs, yet also replace blockbuster drugs coming off patent, and with
insurance companies trying to force hospitals to run more cost-effective
operations and reduce the cost of expensive drugs, this could be an
improvement for all concerned.
© TOUCH BRIEFINGS 2007
Optimising eClinical
Such changes will be driven by molecular diagnostic detection and a
greater understanding of biological changes at genetic and cellular
levels, which will enable therapy to target the cause of disease rather
than simply the symptoms. Biomarkers are molecular indicators that
have recently risen in importance as potential diagnostic tools. Tests can
be developed based on technologies such as proteomics,
transcriptomics and genetics to look for specific biomarkers that
support medical decision-making. For clinicians, biomarkers will play an
increasingly important role in diagnosing and tailoring a medication or
dose to that which is more likely to work for that patient’s particular
pathology. In addition, biomarkers can be used to rapidly detect
pharmacological effect, allowing new candidate drugs to demonstrate
efficacy more quickly in smaller trials. Evidence-based, personalised
therapy necessarily results in a rapid expansion of data, collected from
diagnosis, prognosis and prediction of treatment efficacy through to
administration of therapy.
The Data Explosion
Scientists in life sciences and clinical research have to deal with huge
datasets, which are then analysed and interpreted in the context of
data from internal biobanks, external sources of biomedical
knowledge and electronic medical records. These days, relating
clinical data to molecular biology data represents a critical part of
clinical research; however, this is a minefield of consent
documentation and privacy regulation. In order to make sense of the
landscape, Erasmus MC has developed computational tools and a
relational database architecture that provides shared functionality and
tools for sample acquisition, tracking, workflow management and
data analysis. While there is no universal way to integrate and analyse
biomolecular microarray or proteomics data, consistent and
reproducible methodologies are needed to analyse the vast
amounts of data obtained. Moreover, these methodologies need to
be cost-effective and also validated for clinical diagnostic decision-
making processes.
Peter J van der Spek is Professor and Head of the
Department of Bioinformatics at Erasmus University Medical
Centre (MC), one of the largest medical centres in The
Netherlands. He runs a neuroscience research programme
that provides the biological and technological basis for the
bioinformatics group at Erasmus MC, concentrating on the
way in which the genome as a whole contributes to the
evolution, development, structure and function of the brain.
Dr van der Spek has six years of pharmaceutical experience
from Akzo-Nobel and Johnson & Johnson and holds several
international academic appointments in Japan, Australia
and the US. He obtained his doctoral degree in 1995 in
the field of molecular carcinogenesis by cloning cancer
predisposition genes.
17
VanderSpek_edit.qxp 4/6/07 4:58 pm Page 18

Optimising eClinical

Storage and Database Development Figure 1: Secure ICT Framework to Permit the Integration of
To reach these demanding goals, Erasmus MC has set up a translational Disparate Data Using Validated Capabilities from Inforsense and
Oracle
medicine partnership with the WRI, which hosts one of the world’s
largest biobanks. The WRI biobank contains DNA and serum samples
Importer Encoded SNP
from US army soldiers and their family collected through six different (cached) data (cached)
Userspace export
report (cached)
medical centres across the US. Both Erasmus and WRI biobanks
SNP metadata Userspace export
co-develop on a similar Oracle-based framework. (cached) report 2 (cached)

Patient metadata Userspace export

Within this framework, programmers and analysts collaborate to (cached) report 3 (cached)

integrate clinical, histopathological, imaging, genomic, proteomic and

Virtual private
pharmacogenomic knowledge. This datamodel is based on Oracle 10g, database
which has bioinformatics functionalities and is used for storage and
integration to support high-throughput sample processing in both clinical LDAP user management
and research environments. Enhancements for Oracle 11 are jointly
developed for improved digital imaging and communications in medicine
(DICOM) support for medical images.

Erasmus MC is implementing a secure ICT framework to permit the Single sign-on

integration of disparate data using validated capabilities from Inforsense

and Oracle (as illustrated in Figure 1). Inforsense technology has been
Figure 2: 3-D Virtual Reality Centre used to Examine
successfully applied by the pharma industry as well as by academia,
(Molecular) Imaging Modalities
including the US National Cancer Institute. The research data warehouse
infrastructure project will create a platform where clinicians and scientists
from different institutions (both public and private) active in translational
medicine can work collaboratively with access to the decision support
engine’s knowledge extraction tools.

In hospitals, traditional workflows involve biologists/technicians

performing laboratory tests and then passing the results to the clinician for
use in medical decision-making, with little interaction between the two
groups. In part, it has been difficult to take advantage of this junction
because it requires an understanding that spans both domains. One way
to gain an overview of both the biomedical and clinical disciplines is to
visualise the information. Capturing and integrating multidisciplinary
knowledge, data, scripts and encoding calculations leads to knowledge
retention and best practices (e.g. good laboratory practice).

There are many potential ways in which the process of bringing diverse
molecular and clinical data together can go wrong; therefore, standards
are required for data acquisition. The bioinformatics department at
Erasmus MC plays a bridging role in these multidisciplinary interactions
and oversees the management of molecular and clinical data.
Clinical Decision-making
Erasmus MC has invested extensively in developing advanced
computational and laboratory/clinical information management
systems to collect, process, organise and visually present huge
amounts of relevant biomedical data. Translating basic research into a
form that has clinical utility requires a unifying IT platform that lets the
researchers themselves access, integrate and analyse information from
multiple data sources and make use of diverse tools to derive the
knowledge needed. Unfortunately, the IT infrastructures currently
used in academic hospitals are often inflexible and disparate – being
kept in ‘silos’ – thus hindering rather than helping such decision-
makers. Instead of providing support for dynamic and iterative thought
processes, most such ‘solutions’ end up either restricting innovation or
else rigidly dictating how users can develop their ideas and turn them
into practical solutions.
As well as focusing on their own data, researchers have to simultaneously
consider other sources of information such as from the scientific literature
and patent databases. Text-mining tools and Google Scholar, for
instance, can be helpful in understanding background information on
biomedical topics. Business intelligence tools provide the ideal framework
for placing scientific data in context, and there are various software tools
and enterprise solutions that can be used to mine data from gene/protein
databases for in silico biology applications, from the analysis of pathways
of disease and disease risk to protein–protein interaction studies.
Unravelling the genetic information encoded in the DNA of human cells
has led to a rapid progression in the understanding of the roles of our
genes in health and disease. Erasmus MC has made important
contributions to this field, and has multiple platforms for high-quality
gene and protein expression research, transgenic facilities and DNA
analysis capacity to study SNPs in population studies of more than

18 DATA MANAGEMENT IN PHARMACEUTICAL RESEARCH & DEVELOPMENT

VanderSpek_edit.qxp 4/6/07 4:59 pm Page 19
Scaling Up Clinical Research by Expansion of Electronic Infrastructure
25,000 individuals. Further progress now requires the introduction of
even more advanced IT that can cope with the enormous quantities of
data involved. Alongside delivering services and technology to all
medical disciplines in Erasmus MC, the department of bioinformatics
runs a research programme of its own, providing the biomedical and
technological basis for such activities. It concentrates on the way the
whole genome contributes to the evolution, development, structure and
function of the brain. It involves analysis of gene expression in brain
cells, combining genomics, proteomics, imaging and cytogenetic data to
identify genes associated with neurological disorders (see Figure 2).
Progressive Research
The research data warehouse helps scientists with their biomarker
discovery activities and enables them to easily access content from their
desktop and provide an integrated knowledge base for drug and disease
biomarkers. Erasmus MC currently implements an ‘-omics’ analytical
processing platform in which scientists are given support for statistical
methods and experimental design. To ensure that data are of the highest
quality possible, we are developing a standard operating procedure for
quality assessment. This will guarantee the best experimental accuracy
and reproducibility of expression microarrays, DNA SNP chip analyses and
proteomics and metabolomics data, whether the data are from Erasmus
MC or from our external collaborators.
For example, there are many methods that can differentiate between
diseased and/or treated patients. However, to ensure the analytical
validity of such a selection process requires proper estimation of
performance. A test that measures many analytes but with too few
patients can easily derive biomarkers that are not based on biology, but
that arise because of random variations. Many published studies
inadequately estimate future biomarker performance and fail to test
statistical significance using the class permutation test.
Bird’s-eye View of Erasmus MC
The city of Rotterdam selects and supports activities such as those described above through
its strategic Economic Vision 2020.
1. Valk PJ, Verhaak RG, Beijen MA, et al., Prognostically useful gene-expression profiles in acute myeloid leukemia, N Engl J Med, 2004;350(16):1617–28.
DATA MANAGEMENT IN PHARMACEUTICAL RESEARCH & DEVELOPMENT
Our aim is to develop an ensemble approach to optimise classification
within a patient cohort using existing methods such as linear
discriminates, support vector machines, random forest and neural
nets. Within this framework we plan to explore the relationship
between sample size, outcome, methods, validation and parameters
for optimal patient stratification. These methods are part of our
biobank and biomarker activities in collaboration with the Erasmus MC
department of haematology to develop novel superior molecular
diagnostic and prognostic solutions in the field of acute myeloid
leukaemia (AML). Novel and existing methods will be used to define
whether the gene expression pattern (e.g. known pathways, specific
areas of the genome or clusters from a cluster analysis) over the whole
group of genes is related to a clinical outcome.
In parallel, we explore the topological properties of transcriptional
network and apply different approaches to inferring causal associations
among genes by integrating genotypic and expression data – a
necessary first step in reconstructing pathways associated with complex
traits. Our aim is to demonstrate core functional modules making up
the transcriptional networks that are readily identified in these data and
that are coherent for several core biological processes associated with
disease traits.
Skyline Diagnostics has developed an AML gene signature1 that will be
used to diagnose AML subtypes. Crosslinks, an Erasmus MC spin-out
company, will develop a robust software platform that is compliant with
the FDA’s 21 CFR part 11 guidelines that regulate the security and
reliability of electronic data for the diagnosis of AML. This will provide
secure access to the diagnostic application, maintain an audit trail and
ensure high availability of the data from the diagnostic site to the data-
analysis and management centre.
Conclusion
With the flood of data across all biomedical disciplines in large multi-
disciplinary environments such as Erasmus MC, information visualisation
is emerging as a critical component of discovery, diagnostic care and
clinical decision-making processes.
Evidence-based, personalised treatment strategies require a new class of
visualisations that are capable of displaying various data types collected
from multidisciplinary knowledge and interactions between clinicians and
supporting staff. The ability to use visualisations to cross domains and
data types provides the ability to integrate analyses and support fast,
effective clinical decisions.
With the fast-growing amounts of raw data, information and
knowledge, the need for infrastructure grows exponentially. Clinical data
need to be coupled with electronic medical records, internal biobanks
and external public domain databases. This requires a secure, scalable
research data warehouse infrastructure that needs to be developed and
maintained. Creating awareness with government, healthcare authorities
and insurance companies is important since the biomedical informatics
field progresses rapidly; also, the average budget that hospitals have to
spend on ICT is around 3% of its total budget, in contrast to the banking
industry, which invests an impressive 11%. ■
19
Novakovskiy_edit.qxp 4/6/07 3:38 pm Page 20
Optimising eClinical
Clinical Trials Abroad – ‘Back in the USSR’
a report by
Vladimir V Novakovskiy, MD, PhD
Vice President of Regulatory Affairs and Quality Assurance, Congenix LLC
The drug development services industry constitutes a significant and
growing portion of all pharmaceutical and biotechnology drug
development activity. Sponsor companies in the life sciences industry
are continually striving for more efficient and cheaper ways to bring
compounds to market. Conducting work in countries outside the US
and Western Europe is one strategy to help reduce costs and is
becoming increasingly common, particularly for clinical trials. Here are
some illustrative facts:
• the total cost of bringing a new product to market is estimated to be
US$800–1,000 million;
• only one in five commercial products will generate a profit;
• the number of US Food and Drug and Drug Administration (FDA)-
sanctioned ‘offshore’ trials increased from 1,000 in 1991 to 7,000 in
2000; and
• the percentage of new drug application (NDA) submissions to the FDA
that include data generated from offshore trials has increased
dramatically over the last five years.
Of the various locations, Russia and ‘Russian-speaking’ countries are
particularly attractive to the sponsor companies. This is because of
Russia’s clinical trials authorisation (CTA) system and its healthcare
system, including the available investigators and subject population. This
last factor is perhaps the most important: the enormous enrolment
potential offers a solution to the competition for clinical trial patients in
North America and Western Europe.
Furthermore, Russia has a large number of big, highly specialised
hospitals that could have been specifically designed for clinical research.
These medical centres may have modest interiors, but this does not
preclude their clinicians from carrying out quality work.
Vladimir Novakovskiy, MD, PhD, is Vice President of
Regulatory Affairs and Quality Assurance at Congenix,
a contract research organisation (CRO) specialising in
conducting clinical trials in Russia and countries of the
Commonwealth of Independent States (CIS). Congenix
provides comprehensive solutions for the pharmaceutical
and life sciences industries using its own experience
combined with the advantages of ‘Russian-speaking’
countries. In his 10 years’ working in clinical research,
Dr Novakovskiy has served in a variety of positions in
CROs, starting with CRA at the Moscow office of Quintiles.
Dr Novakovskiy holds a medical degree from St Petersburg
Medical University. He also has a PhD in medicine,
specialising in recombinant cytokines.
20
Large-scale clinical trials have been conducted in Russia since 1989.
However, back then when interest first arose, regulators and the medical
research community were largely unaware of good clinical practice
(GCP) and clinical trials were not governed by any regulations – anyone
could do anything. There was the constitution of the USSR, which
protected the rights of patients, but that was it; ethics committees had
yet to be established. Things have changed drastically, and nowadays
there is a system of national regulations for drug development and
clinical research, with clinical trials being approved in a similar way to in
the West.
In 1999, the official text of the International Conference on
Harmonisation (ICH) GCP standards was published in Russian. In the
Russia has a large number of big,
highly specialised hospitals that
could have been specifically designed
for clinical research.
same year, the Russian-language version of the GCP standards – National
Standard OST 42-511-99, a close translation of ICH GCP – became a part
of national regulations on clinical research.
Nowadays, the legal basis to conduct clinical trials in Russia is governed
by the 1998 Federal Law on Drugs. The regulatory basis for conducting
clinical trials in Russia is the 2005 National Standard of the Russian
Federation 52379-2005 Good Clinical Practice, a translation of the GCP
E6 guideline. The Russian Ministry of Health and Social Development
also regulates the process by means of various Orders and Instructions,
all of which have been developed in correspondence with the law and
national standards.
The Federal Service for Supervision in the Sphere of Health Care and
Social Development has direct control in the field. This regulatory
body grants the CTA and reports to the Russian Ministry of Health and
Social Development.
Obtaining a CTA requires parallel favourable decisions from the federal
Ethics Committee and the Scientific Centre for the Evaluation of the
Products for Medicinal Use (a federal state institution, or FSI). In
general, it does not take more than 60 days to obtain a CTA after
submission, including import and export licences.
© TOUCH BRIEFINGS 2007
Novakovskiy_edit.qxp 4/6/07 3:38 pm Page 21

Clinical Trials Abroad – ‘Back in the USSR’

Table 1: Medical Resources in Selected patient enrolment continues to be so strong.

Eastern European Countries
Many patients in Russia require specific treatments that are usually
Country Major Cities Physicians Medical Hospital Beds
beyond their reach. Participation in a clinical trial is a good opportunity
per 1,000 Universities per 1,000
for them to receive appropriate long-term treatment because it offers
Inhabitants Inhabitants
Czech Republic 1 3.4 5 8.6 free access to the best medical facilities, the best diagnostic methods,
Hungary 1 3.6 4 8.4 the best physicians and, potentially, the best medications.
Latvia 0 3.2 2 8.7
Lithuania 0 3.8 2 9.2 Typically, the treatment provided in clinical research is better than the
Russia 13 (9) 4.2 55 13.1 standard of care available through the national health services. The
(European part)
fact that trial protocol often calls for complete physical assessments
Slovak Republic 0 3.2 3 8
and personal interaction with the investigator may in itself be an
Ukraine 5 4.6 18 10.4
incentive to join a trial. Combined with the additional lure of Western
Source: The Informer newsletter, June 2003, Imform GmbH.
medicines and therapies, it is easy to see why the prospective patients
are excited to participate.
The Russian Medical System
Russia ranks highly among other Eastern European countries on the The only requirement of the patients is to be compliant, which they
availability of basic medical resources for conducting clinical trials (see consider more than acceptable. The high general level of education with
Table 1). no illiteracy means that most people understand the nature of research
and the need to follow treatment regimens. In addition, Russian people
At present, most clinical trial work is conducted in Moscow and
St Petersburg owing to their better infrastructures, larger populations
and the presence of major research centres in these two cities; well-
equipped academic sites located to the east – from the Ural Mountains
in Siberia to the Far East, which is rich in natural gas and oil resources – Recruitment rate is fast in Russia: on
remain largely underused. average 2–4 months ahead of sites in

The ‘Soviet’-structured centralised healthcare system in Russia and the

more developed parts of the world.
countries of the former USSR consists of large medical institutions, many
of which specialise in different therapeutic areas. These institutions, both
general and specific, have large patient pools from which to draw,
making enrolment in clinical trials very easy for the patient and rapid for exhibit a greater respect for authority compared with those in the West
the sponsor. and have a more settled way of life. This all leads to higher acceptance
rates, more disciplined patients, increased compliance with physician
Despite the fact that many medical procedures that in the West might be instructions, low drop-out rates and high follow-up rates.
performed in an outpatient setting require a stay in hospital in Russia, these
additional hospital costs do not add significantly to the trial expenses. Data Quality
Moreover, this additional level of attention is helpful in informing the Despite rumours and existing prejudice, Russia remains a solid and
subjects of their obligations and providing the opportunity to closely reliable arena for conducting clinical trials. Cases of fraud in general
monitor and instruct them early on, thus helping to facilitate compliance. have been found to be much less frequent than in the US. In addition,
the European Forum for GCP (EFGCP) supports initiatives for
The Russian People developing better conditions for clinical trials in and around Europe,
Russia is a country with access to experienced, motivated and compliant
Table 2: Summary of FDA Inspections Performed in Eastern
investigators, for several reasons. First, taking part in a global project European Countries between 1 January 1994 and 31 March 2002
gives them an opportunity to interact, directly or indirectly, with the
international medical community from which they were almost entirely Country Number of
excluded during the Soviet era. Second, Russian clinicians are Inspections Observations
scientifically curious; the pioneering essence of a new drug always NAI VAI OAI
Czech Republic 2 1 3 0
presents an additional incentive for them. Third, most investigators are
Croatia 2 0 4 0
eager to become familiar with new quality standards and
Hungary 6 2 8 0
methodological approaches. This is why the GCP concept is normally Poland 5 4 1 0
readily accepted by clinicians, even those with no prior practical Romania 1 1 0 0
experience with the guidelines. Russia 6 4 7 0
Slovenia 1 1 0 0
Recruitment rate is fast in Russia: on average 2–4 months ahead of Total 23 13 23 0
sites in more developed parts of the world. Patients in Russia are both NAI = no action indicated; VAI = voluntary action indicated (objectionable conditions found,
but justifying only local measures and not any further regulatory action; any correction is left
eager to participate and extremely compliant. Given the overall to the investigator to take voluntarily); OAI = official action indicated.
healthcare situation in Russia, it is not difficult to understand why Source: www.fda.gov

DATA MANAGEMENT IN PHARMACEUTICAL RESEARCH & DEVELOPMENT 21

Novakovskiy_edit.qxp 4/6/07 3:39 pm Page 22

Optimising eClinical

Figure 1: Companies Involved in Clinical Trials in Russia

80

60

55%

40 46%
42%
35% 37%
29%
20 25%
21%

10%
0
2000-2003 2004 2005

Local pharmaceutical and biotechnology companies

International pharmaceutical and biotechnology companies
Contract research organisations

Source: www.regmed.ru

and since 2000 has been supporting efforts in Russia to conduct trials
to world-quality standards, thus paving the way for today’s sponsors
from the research-based pharmaceutical industry to place their studies
in the region with confidence. FDA audit data suggest that data
quality in Russia is at least as good as that from other regions around
the world (see Table 2).
These days more than 100 foreign pharmaceutical companies are
accredited in Russia, mostly located in Moscow. The international
A CRO is able to pay much higher
wages than government-owned
medical institutions, and can
therefore select the best, most
highly experienced professionals.
companies that do not have representation in Russia still conduct clinical
trials there through third-party organisations. Many major contract
research organisations (CROs) have opened offices there, and there are
several local CROs, including Congenix, LLC (see Figure 1).
number of clinical trials approved between 2003 and 2004, which can be
attributed to the increase in the number of mergers in the worldwide
healthcare sector at that time. Post-integration companies focus on
internal reorganisation, thus we see an increase in the number of trials in
2005 as these new entities resume normal operations.
Driving the Growth in Clinical Trials
When clinical trials first came to Russia, foreign pharmaceutical
companies had no representatives in the country; therefore, they started
work through local groups of researchers. The first group was based in
the Research Institute of Cardiology in St Petersburg and the first CROs
began to appear around 1990.
There are currently around 10 domestic CROs in Russia, with Congenix
one of the most advanced. The main difference between Russian CROs
and CROs in other countries is that in Russia all clinical research associates
(CRAs) are medical doctors. A CRO is able to pay much higher wages than
government-owned medical institutions, and can therefore select the
best, most highly experienced professionals. Many CRAs speak fluent
English, which helps a great deal in communication between investigators
and sponsors in terms of monitoring, reporting and so on. Russian CRAs
are trained in GCP, and many are also members of international
professional organisations such as the Drug Information Association (DIA)
and the Association of Clinical Research Professionals (ACRP).

The number of clinical trials conducted in Russia has increased
considerably over the past 10 years, and this trend continues with on
average close to 100 new trials being approved every year. Interestingly,
the number of trials outsourced to specialised CROs is also growing,
allowing international companies to benefit from local resources,
intelligence and expertise (see Figure 2). There was a slight decline in the
The role that these groups played in shaping the clinical research market
in Russia cannot be underestimated. They translated GCP guidelines and
introduced them to regulators, medical professionals and the
community; they implemented the most reliable communication
technologies; they established data management systems; and they
implemented modern methods of statistical analysis. In short, they

22 DATA MANAGEMENT IN PHARMACEUTICAL RESEARCH & DEVELOPMENT

Novakovskiy_edit.qxp 6/6/07 3:41 pm Page 23

Clinical Trials Abroad – ‘Back in the USSR’

Figure 2: Number of International Clinical Trials Approved in Russia

250

200

150

100

50

0
1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005
(Q1–3)

Source: www.regmed.ru

created comprehensive standard operating procedures (SOPs) and active work of software producers such as Oracle in the Russian market
invented effective project management technology. is of fundamental importance.

Russian CROs provide the full spectrum of services, including regulatory
submissions, medical monitoring, project management, handling clinical
trial supplies, reporting, medical writing and so forth. However, only a
few of them can provide the data management and biostatistics services
in accordance with the highest international standards. Therefore, the
In summary, by outsourcing drug development activities to local Russian
CROs, pharmaceutical, biotechnology and generic drug companies can
reduce their fixed costs and investment in infrastructure and focus their
resources on sales and marketing, drug discovery and other areas in
which they can best differentiate themselves. ■

DATA MANAGEMENT IN PHARMACEUTICAL RESEARCH & DEVELOPMENT 23

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(Siebel Clinical)

Electronic Data Capture

(Oracle Remote Data Capture) Pharmacovigilance
Reporting & Call Centre
Clinical Data (Oracle Adverse Event
Management System Reporting System)
(Oracle Clinical)

Term Classification/Dictionary Management

(Oracle Thesaurus Management System)

Clinical Integration, Warehousing & Reporting

(Oracle Life Sciences Data Hub) Contacts

Clinical Business Development, Europe, Middle East & Africa

Jonathan Palmer
Clinical Solutions Director, EMEA
jonathan.palmer@oracle.com

Gilbert Bellachen
Clinical Solutions Director, EMEA
gilbert.bellachen@oracle.com

Life Science Solutions, Europe, Middle East & Africa

Nick Giannasi
Life Sciences Senior Director, EMEA
nick.giannasi@oracle.com

Clinical Business Development, North America

Michele Becci
Life Sciences Industry Director, North America
michele.becci@oracle.com

www.oracle.com/goto/lifesciences
Oracle_Cover.qxp 5/6/07 12:14 pm Page 1

BRIEFINGS

DATA MANAGEMENT Optimising eClinical

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Tel: +44 (0) 118 924 0000

www.oracle.com/goto/lifesciences
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BRIEFINGS

BRIEFINGS

Cardinal Tower
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Includes:
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Large-scale Electronic Data Capture
EDITORIAL Tel: +44 (0) 20 77452 5181
Fax: +44 (0) 20 77452 5050 SAE Reporting with EDC

SALES Tel: +44 (0) 20 7526 2347 Improving Clinical Trial Software
Fax: +44 (0) 20 7452 5606
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CDISC and HL7 Convergence

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E-mail: info@touchbriefings.com
www.touchbriefings.com Translational Medicine
www.oracle.com
www.touchbriefings.com Clinical Trials in Eastern Europe