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International Clinical Trials
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ICT: We’ve heard you say that data acquired throughout the
clinical research process must be complementary to clinical care goals.
However, CROs are sometimes perceived as caring more about the
technology being used to acquire the data than the actual data. Why is
that?
Dr Michael Murphy: Given the business models of
CROs, it is a common misperception that the incorporation of new
technology into trial operations occurs simply in service to novelty, or
in an effort to achieve service differentiation. However, novel data
acquisition processes are predicated on an ability to enable the
clinical research procedure and maximise the efficiency and value-added
activity of CRO staff. There is a strong regulatory endorsement for the
use of a variety of platforms in data acquisition, as it provides
consistency and reliability and permits innovative approaches to trial
design and analyses; additionally, these advances are foundational for
participating in various permutations of risk-based monitoring.
New
technology that is incorporated within a thoughtful and programmed
approach by a CRO facilitates the drug development process (such as
study start-up activities or electronic source documents); enables
innovative trial designs (like adaptive studies); changes the point of
data collection for many types of trials (for example, from clinics to
the home); and – most importantly – increases the time available for
professional contributions from CRO staff.
The pharmaceutical
industry has been slow to take up electronic solutions, despite their
revolutionary potential. Many believe the sector is nearing a tipping
point – do you agree?
It is said that the art of
interventional clinical research is the ability to responsibly evaluate
small molecules, biologics and devices inherently unpredictable in terms
of safety and efficacy, in the hopes of transforming therapy.
Appropriately, the clinical trial process is one that attempts to
mitigate risk – a sentiment that extends into the use of technology,
making the cautious uptake of various electronic solutions a prudent
business and clinical decision. Nevertheless, incremental changes in
regulatory guidance and technology have converged with the need for
efficient and informative study designs, creating an imperative to
re-examine the procedure.
Various regulatory agencies have
introduced draft guidelines to remove uncertainty, and shape the
direction of technology and the methods for application in the clinical
trial process. These include the methods of oversight through risk-based
monitoring, the use of electronic source data, and the ability to
provide regulatory submissions using standardised study data. Where data
acquisition platforms are not patient-facing, rules of engagement seem
codified and less controversial, and adoption has been swift. For
example, a cloud-based system for data warehousing is readily suited to
business documents. In contrast, similar solutions for patientfacing
assessments are approached more cautiously and predicated on first
addressing reliability, necessity and utility for generating evidentiary
standards for safety and efficacy. An ability to use technology
intelligently in either observational or interventional research
represents a challenge that the industry now fully embraces.
Which
technologies do you think will have the biggest impact on clinical
research and commercialisation activities over the next 10 years? What
do you predict to be the next big development?
In 1949, it
was predicted that computers might have, in the not-too-distant future,
fewer than 1,000 vacuum tubes and weigh only 1.5 tonnes (1). Forecasting
the evolution of technology – and more importantly, how that technology
might be applied within the study process – is best entertained
cautiously. What can be said, however, is that innovations in how new
technology is used – as much as the technology itself – constitute the
largest single factor in a technology’s eventual incorporation into the
clinical trial procedure.
For example, most longitudinal studies
have data acquisition procedures demarcated temporally by visit
structures. Customarily, these visits occur in a clinic setting, spaced
at intervals – balancing the need to address hypotheses with the
inconvenience and cost of obtaining the information. What if you could
gather data intermittently, or on a continuous basis in the patient’s
home and across different types of activity – particularly for
physiologicallybased assessments (glucose or cardiac monitors connected
to smartphones, for instance)? In essence, adopt processes in clinical
trial design which acknowledge that the beauty in music (clinical
research) is as much contained in the pauses between the notes (the
visit structure) as in the individual notes (the site visits).
And
if that technology was in place, what are the methods that could be
employed of assuring meaningful patient compliance, controlling for
environmental confounders, to assure the data could be analysed in a
fashion that would be informative? Technology and the management of
technology that enables this harmony will create beautiful music – and
deliver a huge impact on the industry.
In so many ways, the next
‘big development’ is not in reference to the tool; it is in reference
to the methods of using the tool to provide an opportunity for change
and differentiation.
How important is it to be able to share
data acquired during a trial among patient participants and other
collaborators, and what impact can this have on study outcomes?
Within
the clinical trial setting, much attention is focused on the
technological aspects of data acquisition and assurances of regulatory
compliance. Historically, the flow of information is one-way: from the
patient to the clinician; to the database for analyses; and, apart from
rare exceptions, the process is fully blinded to treatment group
assignment. Utilisation of technology to inform trial design prior to
study inception, or to communicate information to patients following
study completion, suggests possibilities that have not been fully
exploited.
Prior to protocol initiation, for example, social
media might be used to solicit ideas regarding protocol design before it
is finalised, in order to enhance patient accrual and retention.
Understanding the realities of patient management and the experience of
the illness from the perspective of family and patients assists in the
resolution of conflicting data needs in the study design process. In
contrast, during study conduct, technology promoting online conversation
could jeopardise the integrity of the study. Anecdotes from subjects
may imply adverse events, lack of efficacy or inconvenience, negatively
impacting trial participation. These unstructured conversations, which
can prove invaluable in the design phase of a project, may also
inappropriately and inaccurately influence how symptoms are reported
during the trial, distorting the implications derived from the resulting
database.
Following product registration, quantitative study
designs for quality improvement research could benefit from technology
permitting distribution of information in a widespread fashion to
patients receiving therapy in an adaptive process uniquely suited to
that type of research. For example, stepped wedge designs sequentially
roll out interventions to clinicians, doctors or organisations to
monitor the impact of innovative therapy adoption, while time series
designs are useful in evaluating whether a quality improvement
initiative has an effect in comparison to the secular trend relevant to
this particular indication. In these settings, reciprocal exchanges of
information between patients, sponsors and providers might facilitate
the use of adaptive strategies determining the content and format of
information most likely to influence patient and doctor behaviour.
The
utility of sharing data, as well as information derived from those
data, with study participants varies by phase of development (before,
during and after product evaluation), and the methods by which that
information is structured.
You’re saying that data
acquisition through the use of novel technology can facilitate
patient-centric and site-oriented research. How do we make that happen?
Clinical
research data are derived from doctor/patient interactions, in which
the process of those interactions – including the collected information –
are determined by the design of the protocol. Technology that is
transparent to those interactions, while also satisfying reliability,
sensitivity, various aspects of validity and attribution, can be
transformative. However, the skills required to participate in that
process, particularly by site-facing CRO staff, are clinical. They arise
from an appreciation of patient management issues and site dynamics
occurring in clinical research against a backdrop of clinical care. This
is particularly important for therapy with breakthrough characteristics
targeting unique patient phenotypes, which are commonly encountered in
the current research setting. CROs that highlight the importance of
clinical acumen through credentialing and training programmes provide a
differentiated business model – one which emphasises that technology
exists in service to clinical research.
What is the role of
the clinical research assistant (CRA) in that regard? Do you have any
recommendations to help them succeed in their roles?
CRAs
are specialists in applied clinical research. Emerging technology
increasingly permits the CRA and other operational staff to ‘live in the
data stream’, while simultaneously enabling monitors to spend more time
reviewing critical study-related issues, assessing protocol compliance,
monitoring for patient safety, and gaining more insights regarding the
impact of novel interventions on patient care. With the introduction of
facilitative technology, the ultimate expression of the art thus becomes
site management, analytics and monitoring data for medical
meaningfulness, as well as integrity. A therapeutically focused,
tech-savvy CRO will assist its CRAs in developing these skills by using
technology that enhances the benefits that accrue, by allowing staff to
remain therapeutically focused.
Therapeutic focus – coupled with
enabling technology – helps each CRA gain a deeper understanding of the
disease management process, the rationale for therapeutic
interventions, and a diverse mosaic of assessments specific to each
therapeutic indication that demands informed monitoring. With this
perspective, cost savings that come from enhanced technology become a
secondary consideration, and value-added monitoring services with a
strong clinical orientation by a CRA will be the real differentiator for
the CRO. Emerging technology increasingly permits the CRA and other
operational staff to ‘live in the data stream’, while simultaneously
enabling monitors to spend more time reviewing critical study-related
issues, assessing protocol compliance, monitoring for patient safety,
and gaining more insights regarding the impact of novel interventions on
patient care
Reference
1. Popular Mechanics, 1949
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