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International Clinical Trials
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As cloud computing, digital identities and cost concerns all apply
pressure to clinical research, eClinical providers look to respond with
solutions that are agile and affordable.
The clinical research community is on the brink of unprecedented
advances in medical science, but at the same time research productivity
is steadily eroding. Recent data show that studies are becoming more
complex, taking longer, and retaining fewer patients, while only 16 per
cent of the drugs entering the clinical pipeline are likely to gain FDA
approval (1,2).
eClinical systems are at the forefront of strategies to reverse the
erosion of research productivity. The FDA has impelled conversion to
eClinical systems with a draft guidance on eSource documentation that
essentially supports moving all clinical data into a single, massive
system with an audit trial (3). While the guidance is new, the
advantages of such an approach have been discussed among drug developers
for the last 25 years.
Despite its theoretical advantages, the promise of large eClinical
systems has not been matched by real-world performance. After more than
two decades of trial and error with integrated eClinical systems, the
research community has identified several common pitfalls and is moving
towards new solutions for effective, flexible and affordable eClinical
systems.
Bene fit for All Users
A frequent frustration for eClinical sponsors has been the push-back
from study site members, many of whom have resisted the transition from
paper-based to digital systems. Why would study sites prefer to push
paper when the whole world is going digital? The answer lies in how –
and for whom – eClinical systems have been developed.
In the traditional ‘waterfall’ approach to system development, user
requirements are created by clinical trial analysts, functional
requirements are drafted by the IT department, and systems are built and
tested by those creating them. Adherence to this approach ensures that
software can be validated in a quality regime per regulatory
requirements. An approach such as this produces eClinical systems that
function well and provide study managers with the data and reports they
want. However too often, these systems do not meet the needs of study
sites for simple, intuitive tools. Instead, study sites have encountered
eClinical systems that are complex, training-intensive and difficult to
access. When such systems create more, not less, work than the paper
alternatives, resistance by study sites is predictable.
eClinical providers have responded with a new generation of systems
designed with end-user needs evaluated at the beginning, middle and end
of system development. This solution may seem simple, but requires
constant advocacy for study site users, so that their needs are not
subordinated to the ever-present demands of IT and study management.
Flexible Use
eClinical systems can make clinical activities more efficient and
accurate, but that doesn’t mean they make sense for every trial, such as
small Phase 1 trials that can be effectively managed using paper, email
and phone calls. At the other end of the spectrum, Phase 3 global
trials can involve upwards of 200 study sites, and Phase 4 safety
monitoring trials can span five years or more. Clearly, this is not a
one-size-fits-all area of enterprise, and the challenge is to determine
what level of eClinical automation produces value in various study
settings.
Determining eClinical value can be highly technical and include
valuations of queries, invalidated data and other sources of
inefficiency in clinical trials. It may be more practical for study
managers simply to focus on areas of study operations that are known to
be the sources of error, major components of the planned trial, and
amenable to quality improvement using eClinical solutions.
The cost of eClinical systems must also be taken into account, including
allocated/committed, variable direct and variable indirect costs. The
latter includes lead time to ramp-up eClinical systems, training time
for users, and the potential need for parallel paper-based systems.
Value-based assessments may not be practical to conduct for each study. A
more sensible approach is to develop a standard tool that computes
value based on study variables and suggest an optimal mix of eClinical
support. Alternately, study sponsors can assign trials to three or more
levels of scale and complexity, and apply a standard mix of eClinical
resources within each level.
Modular Design
Early visionaries of eClinical sought the development of large
integrated systems that support a full array of clinical trial
operations, spanning CTMS, EDC, RTSM (IVR/IWR,) ePRO, document
management and more. The hope was that large integrated systems would
yield sundry benefits, including fast and accurate data transfer across
functional areas, combined metrics and sophisticated performance
reports. However, with experience, it has become apparent that such
large-scale systems are inherently complex and expensive, with long lead
times to develop, and a mixed record for delivery.
In response to this, many eClinical providers have shifted to the
development of systems that are modular and interoperable. Modular
design involves development of separate functional modules for CTMS, EDC
and others that can stand alone or work with each other, allowing study
sponsors to easily adjust the mix of eClinical systems to study needs.
Major eClinical providers such as BioClinica, Medidata and Parexel now
offer ‘suites’ of eClinical products, available as a menu of
applications built on a common framework.
Interoperable Systems
The prime attraction of a single, massive eClinical system is that a
consistent data set can be used across various functions, streamlining
data management, reducing errors and improving study quality and
efficiency. Similar benefits can be achieved with separate, yet
interoperable eClinical systems that work seamlessly with each other to
exchange data and harmonise activities. Interoperability goes
hand-in-hand with modular and hosted solutions, and virtually every
major eClinical provider professes to be interoperable. But despite
lofty claims and many legitimate advances, most drug developers today
utilise a patchwork of unconnected eClinical systems, sometimes from the
same vendor.
Data standards are the foundation of eClinical interoperability, and
CDISC, the Clinical Data Interchange Standards Consortium, was formed in
1997 “to develop and support global, platform-independent data
standards that enable information system interoperability”. CDISC has
promulgated several data standards, notably SDTM and CDASH, which have
gained traction with study sponsors, especially in recent years (4).
However, true CDISC-based interoperability among eClinical providers has
remained elusive, with the most common barriers cited as lack of
understanding of standards, high cost, domains not covering sufficient
data, and lack of regulatory guidance (5).
Similar initiatives include the Metrics Champion Consortium, which has
pursued standardised metrics to improve clinical trial performance, and
the SAFE Biopharma Association, which has developed a digital identity
and signature standard to support transformation to a fully electronic
environment for clinical research. Similar to CDISC, these standards
have generated successful pilots and expanding membership, but practical
barriers remain and achieving interoperability among eClinical systems
is a continuing challenge (6,7).
A general trial portal can complement other eClinical platforms and
serve as a starting point for interoperability. General trial portals
include features such as training and communications centres, as well as
study documents and resources. A trial portal can also accept data
feeds from other eClinical platforms and post key study metrics from
multiple systems on a common dashboard, providing study team members
with a current, consolidated view of study status. The ePortal can
support single sign-on (SSO) to other eClinical platforms, providing end
users at study sites with a more convenient way to access and comply
with all study systems. A trial ePortal can serve as a conduit for data
streams from multiple eClinical platforms, and potentially convert
heterogeneous data feeds into a standardised, unified data set. In this
way, a general trial portal can serve as a foundational contributor to
an eTrial master file.
Hosted Services
The IT departments of large biopharmaceutical companies have
traditionally preferred to operate eClinical systems from servers
installed within their company networks. This penchant for control
reflects the heightened pressures placed on biopharma companies for
security, privacy and regulatory compliance. Technology has evolved,
however, so that hosted eClinical systems, such as Software-as-a-
Service (SaaS), offer several advantages over installed systems. Hosted
services by definition do not require on-site installment and are
already functionally validated, so they are faster and less expensive to
ramp up. It’s also easier and less costly to maintain systems that are
hosted by the eClinical providers who developed them. And, of course,
hosted eClinical systems do not require customers to purchase and
operate a multitude of servers.
eClinical providers have strived to win the confidence of study sponsors
with hosted services that are highly compliant and secure. To gain
ground, hosted eClinical systems must be flexible enough to support a
wide range of study designs. To deploy quickly, systems must support
rapid provisioning, with pre-built forms and import functions, and
systems must be easy to populate with study information such as study
documents, third-party data, branding, training modules and study
communications.
The next phase in study sponsors off-loading eClinical duties to
vendors, and this year’s hottest trend in IT is cloud-based computing,
using third-party providers of data processing, storage and software.
Using efficient, large-scale IT resources can yield benefits in cost and
flexibility, and the cloud approach also facilitates centralising data,
managing access, and sharing data among collaborating parties. These
aspects are convergent with modular design, interoperable systems and
digital identities, as discussed. Additionally, the assemblage of very
large data sets into a central, coherent environment has profound
implications for data analytics that could identify trends and
efficiencies, transforming clinical trials. Cloud computing is also
compatible with another end goal of eClinical systems: creation of an
electronic Trial Master File, or eTMF.
Another recent innovation in eClincial systems is the selfservice SaaS
platform. The eClinical provider Merge has introduced a ready-to-use
platform that supports a menu of comprehensive eClinical functions (8).
After training on the system, study managers can access a web interface
to mix and match services, configure their workflow, and populate these
platforms. The unique aspect is that customers use the platform ‘as is’,
with no additional programming by the vendor.
Colliding with this self-service approach is the need to match the
workflow of individual studies. Wide variability among companies,
departments and study designs all serve to undermine the use of
templated workflows. To match study operations, either a self-service
eClinical system must be highly flexible, or study designs must conform
to eClinical functions. Indeed, some eClinical thought leaders believe
that for the next phase of eClinical to succeed, studies must be
designed around eClinical systems, and that process change is needed to
revolutionise the conduct of clinical trials (9,10).
A ffordability
The consensus view is that the costs of drug development have spiralled
to a tipping point, elevating the issue of affordability for eClinical
systems. Most major biopharmaceutical companies are restructuring their
research programmes into smaller decentralised units, and diverting a
larger share of research capital into partnerships, alliances and
stand-along acquisitions. The smaller buyers of eClinical systems
generally operate in a more constrained funding environment, and are
likely to prefer systems that are flexible, agile and most importantly,
affordable.
eClinical system affordability is a challenge that must be met on
several fronts. Cloud computing can play a part, lowering IT resource
costs by an estimated 25 per cent (11). Another tactic is to build
eClinical systems for reuse so they yield value over multiple instances.
This calls for disciplined study design and use of templated systems
that require minimal work to use for the next study (8). Quality
compliance, validation and documentation are costly, and eClinical
systems must be designed for use without a major cycle of re-validation
for each next study. Drug developers need to resist the temptation to
make design changes to eClinical platforms and avoid layering on
non-core ‘wish list’ functionality. Consistency and affordability go
hand-in-hand. The final frontiers of affordability are the design of
clinical trials and the definition of workflows, both with efficiency of
study systems in mind. As cost becomes more of a driver in drug
development, the idea that studies should be designed around systems,
and not vice versa, is likely to gain traction.
Conclusion
We live in a period of unprecedented, rapid change. Mobile devices,
apps, texting, search engines and social media are but a few of the
technologies that have transformed modern life in just a handful of
years. In clinical research, cloud computing, digital identities and
cost pressures are among the transformative forces looming on the
horizon. eClinical systems must not only be ready for forces we see
coming, but for unforeseen change as well, because the event horizon is
only a few years hence. The iPad, first sold in April 2010, has become
the most rapidly adopted device in history, and is now a prevalent
digital device in clinical settings. Many eClinical developers are
scrambling to develop solutions that work not only with the iPad, but
the iPhone, Android, and other mobile devices and operating systems.
These mobile technologies have one thing in common: a few years ago, no
one saw them coming.
Most importantly, eClinical systems must address research productivity
and play a role in yielding more market success from the $65 billion
spent annually on biopharma R&D. To achieve that, eClinical systems
must be designed for affordability and provide the foundation for a
process change towards more efficient, successful trials. Clinical
trials themselves may need to be re-designed around efficient use of
eClinical systems, as part of a new, more productive R&D paradigm.
References
- Tufts Center for the Study of Drug Development, Impact Report:
Growing protocol design complexity stresses investigators, volunteers,
10, January/February 2008
- Tufts Center for the Study of Drug Development, Impact Report:
Large pharma success rate for drugs entering clinical trials in 1993-04:
16%,11, (4), July/August 2009
- US Food and Drug Administration, Guidance for Industry: Electronic
Source Documentation in Clinical Investigations, December 2010
- CDISC Website, Mission and Principles, www.cdisc.org/missionand- principles
- CDISC Journal, CDISC: Adoption Trends, Benefits and Addressing Barriers, Friggle W, Li F, Labout S, Kush R, October 2011
- AstraZeneca, AstraZeneca Implementation of SAFE Digital Signatures, 25 February 2007
- Metrics Champion Consortium, Inc, AstraZeneca and ERT Case Study:
Utilizing a Multi-Phased Approach to MCC ECG Performance Metrics
Implementation, 2008
- Merge Healthcare Incorporated, Merge Announces Release of eClinical OS Platform at DIA Conference, Press release, 25 June 2012
- Nick Lucus, MD, Foresight, an INC Research Publication, An Honest
Look at the eClinical Process: What Can We Learn from Best Practices
Outside the Industry? 1,(5), February 2009
- David M Connelly, Touch Briefings, The Challenges of Data Capture and Data Management – a CRO Perspective, 2007
- Pharmaceutical Technology.com, Ahead in the cloud – a new home for clinical trial data, 31 January 2012
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