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International Clinical Trials
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Patient-centricity, crowdsourcing, data transparency and telemedicine –
these novel trial design elements hail a transformation of the drug
development model.
As investigators and participants in clinical trials, clinicians and
patients stand on the front line of drug development. They experience
first-hand the safety and efficacy of experimental treatments and
intuitively understand the suitability of a clinical trial for
generating useful data. These ‘users’ know the benefits and risks of
treatments and trial designs on a personal level, rather than acting as
passive observers – not just in terms of such factors as pharmacodynamic
parameters, but also in terms of the effectiveness of the trial’s data
generation and collection mechanisms.
In a clinical trial, clinicians and patients work with the drug
developer on a shared mission to determine the safety and effectiveness
of an experimental treatment. Yet clinical trial design consistently
prioritises the developer’s perceived knowledge requirements over the
user’s ability to meet them. Additionally, the developer’s needs may not
be the most relevant for assessing the utility of a treatment. Partly
as a result, the drug industry conducts a staggering number of complex
and costly clinical trials that fail to produce useful findings. On an
aggregate basis, according to the Tufts Center for the Study of Drug
Development, pharmaceutical and biotech companies’ spending on clinical
research grew by nine per cent each year from 2004 to 2008, reaching $35
billion – nearly twice the $18 billion spent in 2000. Yet productivity
has still been lagging (1).
The good news is that tools now exist for increasing the efficiency of
clinical trials. Novel trial design elements being integrated into a new
drug development model include patient-centricity, crowdsourcing, data
transparency and telemedicine. Each is playing a role in transforming
drug development and improving the efficiency of clinical trials.
Collectively, they promise to signifi cantly shorten the time and lessen
the cost of drug development, while also potentially increasing its
utility.
Patient-Centricity
The patient is becoming the driver of clinical innovation. This is true
partly because electronic patient reported outcome (ePRO) tools provide
investigators and developers with more timely data directly from the
patient than they’ve had before. And personalised medicine, which is
shifting the focus from large ‘anonymous’ clinical studies to much more
customised clinical research approaches, is another reason to increase
emphasis on patient-centricity (2).
But perhaps the most forceful driver is the patient community itself.
Patients have become “more proactive about all aspects of their care”,
according to the social networking site, PatientsLikeMe (3). In
addition, disease-specifi c portals like ThisIsMS have created
flourishing online communities for tens of thousands of patients.
Janet Woodcock, Director at the US FDA’s Center for Drug Evaluation and
Research, explained the agency’s perspective during a recent ECRI
conference on patient-centeredness in policy and practice (4): “there’s
been a societal shift from medically defined assessment of treatment to
patientassessed impact”. The FDA now references “patient centered drug
development” as a key objective. According to Woodcock, “patient groups
have often come to us, and they say they want to be on advisory
committees for drug development. But we think the time to establish the
standards for approval and [define what] should be taken into
consideration for any given disease should be earlier.”
Woodcock said that, through the FDA’s Patient Centered Drug Development
Initiative, the agency is attempting to develop better patient reported
outcome measures – those targeted to the disease, of course, but also
those that capture the “impacts of the treatment.” She noted, “for many
diseases, we may not have good existing measurement tools to quantify
impact on the patient.”
Woodcock also noted that capturing the impact of therapies needs to be
done early in the drug development process: “developers should be
thinking about this well before they have a candidate drug that they’re
studying.”
Patient-Centricity at Work
Consistent with societal changes, the availability of new technologies
and the FDA perspective voiced by Woodcock, the agency’s patient-centric
drug development initiative has moved past the goal-setting stage. In
fact, the concept is now being put into practice with a new company’s
prototype crowdsourcing web platform launched in January 2012, which
allows patients, physicians, researchers and other stakeholders to
contribute to the design of clinical studies.
The platform’s utility is initially being confirmed using generic
compounds that have extensive safety records. The ‘protocol builders’
enabling ‘the crowd’ to participate in the design of proof-of-concept
Phase 2 trials are currently accessible for the platform’s first three
candidates (the anti-hypertensive lisinopril, which is being repurposed
as a treatment for multiple sclerosis; sulodexide as a potential
treatment for peripheral vascular disease; and low-dose naltrexone as a
candidate treatment for inflammatory bowel disease). These three
projects are accepting ongoing collaborative input via the crowdsourcing
web platform.
From its launch date in late January through to mid-June, the open
platform had attracted some 8,000 unique visitors. About 400 converted
to registered users. Roughly two thirds of these are patients. All
visitors – patients, healthcare professionals, and other interested
individuals – can offer trial design ideas, some of which may be ‘gold’
for these formative development programmes. For example, patients
participating in developing the MS protocol have proposed a novel
efficacy measure – improvement in mobility – that has not been commonly
used in MS trials.
To participate in the community effort, registered site users select the
development programme of interest, before completing a questionnaire
tailored to their expertise. Researchers, for example, are asked which
patient populations to study, while patients are asked about their
experiences with prior medications (5).
The Value of Crowdsourcing: Case Study
Linux
Perhaps the most widely known example of crowdsourcing is the
open-source computer operating system, Linux. Computer programmer
frustration with the inaccessibility and limitations of proprietary
operating systems in the 1980s and 1990s sparked the open software
movement, much as the cumulative effect of clinical trial failures is
now driving adoption of crowdsourcing in drug development.
Unlike drug developers, however, Linux’s creators had no open-source
development map to follow. First came the GNU project in the early
1980s. The GNU acronym stands for “GNU is not Unix,” which perhaps
reveals the mindset of those behind it. Their premise was that software
should have no restrictions against copying or modification, to yield
better and efficient computer programmes (10). This was the philosophy
used initially to develop programming tools and, eventually, the
crowdsourcing operating system of today that continues to be tweaked by
professional programmers to meet their requirements.
OpenClinica
In the drug development world, an example of crowdsourcing is the
OpenClinica Clinical Trial Management System for Electronic Data Capture
(EDC) Clinical Data Management (CDM). Since its release four years ago,
OpenClinica has spread to more than 100 countries and now boasts more
than 12,000 community members.
OpenClinica grew out of frustration with proprietary electronic data
capture (EDC) software (11). It is the product of internal and
community-developed open source software.
Crowdsourcing
As a side effect of the open-source approach to software development
environments such as Linux, crowdsourcing is now being applied to
numerous scientific disciplines and is becoming an effective tool for
drug development. In clinical development, crowdsourcing permits anyone,
in any location, to contribute to the design of clinical protocols by
reviewing the posted protocol and all relevant data that has been
collected to date, and adding their input to the evolving design. The
idea is to tap into the wisdom of the crowd by having a large number of
stakeholders address well-posed challenges. Expert curation separates
the ‘wheat’ from the ‘chaff.’ A spirit of collaborative improvement,
along with recognition by peers, catalyses further participation, as it
has already in the software development community.
A proven example of the power of crowdsourcing in medical research was
the recent elucidation of the crystal structure of retroviral protease
by a group of online ‘Foldit’ gamers. In 10 days, two winning groups
developed models that were close enough to the long-sought molecule to
enable scientists to describe the entire structure. (6). Players are now
applying the game technique to the more challenging work of protein
design. Using this approach, researchers have created an enzyme with
more than 18-fold higher activity than the original (7).
Rewarding participants for contributions is a necessary part of the
crowdsourcing drug development concept. The forms of reward will evolve,
but currently include professional development and industry networking
benefits. Eventually it may also involve prizes and direct financial
incentives.
Data Transparency
Data transparency feeds crowdsourcing – it’s an enticement for those who
can contribute unique perspectives because it builds trust and
credibility.
Such transparency is currently perceived to be in direct conflict with
the pharmaceutical industry’s longstanding protection of intellectual
property (IP). The transparency concept is a hard sell to companies that
have made substantial investment in discovery and development, and for
whom business success hinges on financial benefits generated from IP
protection. Examples of successful value creation via open innovation
and crowdsourcing in other industries (consumer products, for example)
are helping to alleviate fears of incumbents. Recent initiatives by some
pharmaceutical companies to pool drug discovery resources are
encouraging in this regard. In a similar vein, in May 2012, NIH’s
National Center for Advancing Translational Sciences (NCATS) announced a
major new initiative that matches drugs with interested researchers in
an open setting.
Another hurdle has been the unwillingness of most drug companies to
publish negative trial results. One reality of the pharmaceutical
industry is that companies are competing to develop drugs that treat the
same conditions. By publishing negative results, competitors might
create opportunities to retool their own studies or pursue a different
avenue of development. Nonetheless, calls for full disclosure of
clinical trial data, both negative and positive, are on the rise and
will provide further support for the transparency that is an integral
part of this new model.
Telemedicine and IT
The Drug Development 2.0 model – allowing patient/ doctor-centricity
through crowdsourcing and open data sharing – can be turbo-charged with
telemedicine and information technologies. Consistent use of remote
diagnostic techniques, and data transmission via computer, mobile
devices and satellite links, make possible virtual clinical trials that
are patient-centric in contrast to the traditional site-centric model
with its costly, recruitment-limiting requirement of multiple clinic
visits.
Telemedicine permits subject participation from home. In addition,
in-home monitoring of trial participants may yield an improvement in
data quality by minimising researcher bias and yielding more uniform
data (8).
A wealth of newly developed mobile diagnostic devices promises data of
at least equal quality to those obtained in-clinic. The fact that
industry leader Pfizer initiated an all-electronic trial is testimony to
the practical reality of this approach, even though the study finished
early due to patient enrolment issues. Pfizer’s Head of Clinical
Innovation, Craig Lipset, has promoted an “app store of tools from
telemedicine, which can help expand health IT connectivity.” He said he
views the use of telemedicine apps in clinical trials, which permit
patient progress reports via smartphones and computers, as “a
repurposing rather than inventing” (9).
Conclusion
Modern technology has provided several tools that support open
innovation, crowdsourcing and decentralised data gathering – the
infrastructure of Drug Development 2.0. When used in a patient-centric
context, these tools will help transform clinical trials and make drug
development a more successful and sustainable business model for the
pharmaceutical industry.
References
- Getz KA, Sizing up the clinical research market, Applied Clinical
Trials, 1 March 2010, http://www.
appliedclinicaltrialsonline.com/appliedclinicaltrials/article/
articleDetail.jsp?id=660749
- TranslationalMedicineOntology Internet Site, Translational
Medicine Ontology: A Patient-Centric Ontology for Drug Development and
Clinical Practice, http://code.google.com/p/
translationalmedicineontology, accessed 20th March 2012
- Williams DS, The value of openness, The PatientsLikeMe Blog,
available at http://blog.patientslikeme.com/2007/12/13/thevalue-
of-openness, accessed 20th March 2012
- Woodcock J, An FDA perspective on the critical role that patients
play in the lifecycle of medical products, ECRI Institute 18th Annual
Conference: Patient-Centeredness in Policy and Practice transcript,
pp15, 29th November 2011, available at www.ecri.
org/Documents/2011_TA_Conf/Transcripts/ECRI_Institute_2011_
Conference_Session_8.pdf, accessed 20 March 2012
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new-york/2012/02/23/transparency-launches-as-linux-of-drugdevelopment/,
accessed 20th March 2012.
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March 2012, http://transparencyls.com/?q=node/12
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protein, Scientific American, 22nd January 2012, http://www.scientifi
camerican.com/article. cfm?id=victory-for-crowdsourced-biomolecule2
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costs, MedCity News, 1st February 2012, available at www.
medcitynews.com/2012/02/4-ways-to-shake-up-the-clinicaltrial-
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accessed 20th March 2012
- Hasan R, History of Linux: New baby in [sic] the horizon,
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2012
- Open Source Clinical Trial Software? Cool!, OpenClinica, available
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20th March 2012
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ArticleStandard/Article/detail/660749, accessed 20 March 2012
- www.scientificamerican.com/article.cfm?id=victory-forcrowdsourced-
biomolecule2#comments%20and%20presents%20
the%20challenge%20with%20colorful%20blocks.%20
problems%20that%20would%20otherwise, accessed 20th March 2012
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Tomasz Sablinski, MD, PhD, is Co-Founder and CEO at Transparency Life
Sciences (TLS). He is also Head of Development and Managing Director at
Celtic Therapeutics Development. Tomasz has more than 30 years’
experience in healthcare and clinical research, as a practicing surgeon,
basic researcher, and has worked as an executive in a major
pharmaceutical company and a virtual drug development enterprise. He
co-founded TLS in 2010, recognising the feasibility and great potential
for an enhanced drug development process that prioritises stakeholder
participation, the open sharing of widespread drug development
expertise, internet-enabled communications, and computer and
telemedicine technologies. |
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