Legal, Regulatory, and Practical Issues to Consider When Adopting Decentralized Clinical Trials: Recommendations From the Clinical Trials Transformation Initiative
Vol.: XXXXXXXXXX
Therapeutic Innovation & Regulatory Science XXXXXXXXXX:779–787
https:
doi.org/10.1007/s XXXXXXXXXX
RESEARCH ARTICLE
Legal, Regulatory, and Practical Issues to Consider When Adopting
Decentralized Clinical Trials: Recommendations From the Clinical Trials
Transformation Initiative
Maria Apostolaros1 · David Babaian2 · Amy Corneli3,4 · Annemarie Fo
est3 · Ge
it Hamre5 · Jan Hewett6 ·
Laura Podolsky7 · Vaishali Popat8 · Penny Randall9
Received: 20 May 2019 / Accepted: 17 September 2019 / Published online: 9 December 2019
© The Author(s) 2019
Abstract
Background Traditional clinical trials are often expensive, inefficient, include selected populations, and can create significant
participant burden via travel and other logistical demands. Using new technologies and methodologies to promote a decen-
tralized approach has the potential to improve the efficiency of clinical trials. The Clinical Trials Transformation Initiative
(CTTI)—a public–private partnership to improve clinical trials—launched a multi-stakeholder Decentralized Clinical Trials
(DCTs) Project to provide recommendations on addressing the actual and perceived legal, regulatory, and practical challenges
with DCT design and conduct in the United States.
Methods Informed by qualitative group interviews and an expert meeting, CTTI engaged stakeholders to identify key chal-
lenges to implementing DCTs and possible solutions.
Results The CTTI DCT project team used the interview findings and expert feedback to develop recommendations that will
drive
oader use of DCTs.
Conclusions CTTI’s recommendations cover protocol design, use of telemedicine and mobile healthcare providers, medi-
cal product supply chain, investigator delegation and oversight, and safety monitoring considerations. By implementing
these recommendations, sponsors, contract research organizations, and others can help advance successful medical product
development using mobile technologies and methodologies in DCTs.
Keywords Mobile clinical trials · Mobile technology · Mobile medical applications · Mobile nursing · Participant-centric
trials · Telehealth
All authors are considered equal contributors.
* Annemarie Fo
est
annemarie.fo
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1 Pharmaceutical Research and Manufacturers of America
(PhRMA), 950 F Street NW, Suite 300, Washington,
DC 20004, USA
2 Adva
a Consulting, 1501 Fourth Ave, Suite 800, Seattle,
WA 98101, USA
3 Clinical Trials Transformation Initiative, 200 Mo
is St,
Durham, NC 27701, USA
4 Department of Population Health Sciences, Duke Clinical
Research Institute, 215 Mo
is St, Suite 210, Durham,
NC 27701, USA
5 Hamre Strategies LLC, 507 N Elizabeth St, Durham,
NC 27701, USA
6 Office of Compliance, Center for Drug Evaluation
and Research, Food and Drug Administration, New
Hampshire Ave, Building 51, Silver Spring, MD 20903, USA
7 Science 37, Inc., 12121 Bluff Creek Dr, Suite 100,
Los Angeles, CA 90094, USA
8 Center for Drug Evaluation and Research, Office of New
Drugs, Food and Drug Administration, New Hampshire Ave,
Building 22, Silver Spring, MD 20903, USA
9 IQVIA, 10188 Telesis Court, Suite 400, San Diego,
CA 92121, USA
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780 Therapeutic Innovation & Regulatory Science XXXXXXXXXX:779–787
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Introduction
Remote or decentralized clinical trials (DCTs) have gained
attention as technology, infrastructure, and knowledge have
developed to support their use. DCTs—defined as trials exe-
cuted through telemedicine, mobile/local healthcare provid-
ers (HCPs) and/or mobile technologies—are not bound by the
geographic limitations that affect traditional trials. Therefore,
they can recruit participants from anywhere, potentially result-
ing in accelerated enrollment and more diverse participants’
epresentative of the target population. Moreover, measure-
ments can be more frequent or even continuous because they
are not restricted by scheduled clinic visits.
A decentralized approach allows trial participants to take
part in clinical research from anywhere, with research activi-
ties better integrated into their daily routine. DCT approaches
may lessen participant burden (e.g., travel costs and time loss),
which may enhance retention and facilitate certain research
that may otherwise be unduly burdensome under traditional
clinical trial constructs [1].
Despite the potential benefits of DCTs, adoption has been
slow and variable. Some ba
iers may be immature digital
infrastructure, limited experience with the approach, and the
perception of regulatory ba
iers with implementing and using
data from DCTs.
Importantly, almost all states now have telemedicine laws
that allow for mobile medicine, which sponsors, CROs, and
other stakeholders can use to inform DCTs [2, 3]. However,
effort is needed to drive acceptance and implementation of
DCTs.
The Clinical Trials Transformation Initiative (CTTI; www.
ctti-clini caltr ials.org), a public–private partnership co-founded
y Duke University and the United States (US) Food and Drug
Administration (FDA), whose mission is to develop and drive
adoption of practices that will increase the quality and effi-
ciency of clinical trials, recognized an opportunity to encour-
age
oader use of DCTs. CTTI launched the Decentralized
Clinical Trials project, guided by the following objectives: (1)
identify perceived and actual legal, regulatory, and practical
a
iers to conducting DCTs and (2) identify opportunities to
clarify and inform policies that affect the implementation of
DCTs. This project is one of the several projects [4] developed
y CTTI to address challenges with planning and conducting
clinical trials using mobile technologies.
Materials and Methods
Industry Interviews
Between October 25, 2016, and January 20, 2017, CTTI
conducted semi-structured group interviews with trial
sponsors to identify important legal and regulatory chal-
lenges they faced at that time in conducting DCTs, and their
potential solutions. CTTI chose to conduct group interviews
with multiple individuals from the same company to enable
a multi-faceted discussion during a single interview. A total
of 31 purposefully selected [5] representatives from seven
different pharmaceutical or biotechnology companies that
were cu
ently implementing or planning DCTs participated
in nine group interviews (2–7 representatives per group).
The Duke University Health System Institutional Review
Board (IRB) designated the interviews “exempt” from full
oard review.
For those companies that had experience in the use of
some remote clinical research components, representatives
described ba
iers faced and lessons learned. For those com-
panies that had less experience with remote components,
epresentatives described the types of considerations their
companies have discussed in preparation for conducting such
esearch in the future and ba
iers faced. All interviews were
audio recorded and transcribed ve
atim. For some topics, a
simple summary was produced describing representatives’
experiences. For other topics, data were analyzed using
applied thematic analysis [6]. Challenges and suggested
solutions that emerged from the interviews are described
in Table 1. Most of the challenges identified by representa-
tives cu
ently are still factors in the planning and conduct
of DCTs; a few, however, no longer represent considerable
challenges (see sections on Engage and Partner and on Tel-
emedicine State Licensing).
Expert Meeting
CTTI convened an expert meeting in July 2017 to discuss
the interview findings and experience of those practiced in
conducting DCTs. The 50 participants represented a variety
of stakeholders. Meeting participants possessed knowledge
of or experience with the perceived and actual legal and
egulatory challenges associated with designing or conduct-
ing DCTs. Key themes from the discussion included those
in Table 1. Meeting participants discussed evidence-based
solutions to inform the development of project recommen-
dations and resources to address legal and regulatory chal-
lenges cu
ently associated with DCTs [7].
Results
Recommendations
Based on key topics and themes that emerged from the quali-
tative interviews and multi-stakeholder expert meeting [8],
the CTTI developed consensus recommendations [9] around
6 DCT topics (Table 2):
http:
www.ctti-clinicaltrials.org
http:
www.ctti-clinicaltrials.org
781Therapeutic Innovation & Regulatory Science XXXXXXXXXX:779–787
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1. DCT approaches and trial design
2. Telemedicine state licensing issues
3. Drug supply chain
4. Mobile HCPs
5. Investigator delegation and oversight
6. Safety monitoring.
DCT Approaches and Protocol Design
Partially Decentralized/Hy
id Approaches
The design and implementation of DCTs need not be an
“all-or-nothing” approach. A fully decentralized approach
may not include a central physical trial site, but include
trial visits conducted via telemedicine or by mobile or
local HCPs and the use of mobile technologies to record
data. Partially decentralized or hy
id approaches combine
some of the above-mentioned features with more tradi-
tional approaches. These hy
id approaches may include
the following:
• a designated trial site at which specific trial-related
activities occur (e.g., chest X-rays) while allowing other
procedures (e.g., blood draws, treatment administration)
to be completed elsewhere,
• data collection both within and outside of the clinical
setting using mobile technologies, and/o
• trial participants and investigative site personnel interact-
ing both at a clinical site and via video or teleconferenc-
ing.
Table 1. Challenges and Suggested Solutions from the Interviews and Considerations from the Expert Meeting.
DCT decentralized clinical trial, HCP healthcare provider, IMP investigational medical products.
Interviews: Main Perceived Challenges
• Ensuring that protocol-defined activities are ca
ied out in a consistent manner throughout the study when relying on mobile HCPs, given the
potential for varying medical qualifications of these providers and/or inconsistencies in their knowledge of the protocol
• Remotely replicating the interactive part of the informed consent process, allowing investigators to gauge participant understanding and ensure
that participants are adequately informed
• Verifying trial participants’ identities and ensuring their privacy and confidentiality when research is completely remote
• Identifying how to monitor safety within the context of remote clinical research
• Planning for and implementing clinical research with telemedicine components may be difficult and time consuming due to inconsistent state
telemedicine laws
• Some states require a “supervising” physician be licensed to practice medicine in their state
• Some states do not allow direct shipment of IMP to trial participants
• Within states that allow the direct shipping of IMP to trial participants, IMP receipt and accountability is difficult because study sites are not
involved in tracking the details of when an IMP is received by a study participant
Interviews: Main Suggested Solutions
• Starting trial planning early:
• Engaging partners, collaborators, and stakeholders (including legal and regulatory) at the earliest stage of the clinical research trial planning
and design
• Reviewing and understanding individual state laws governing clinical trials, medical practice, distribution of IMP, and telemedicine
• Developing systems for tracking receipt and drug accountability in remote trials
• Enhancing cu
ent systems to include training and assessments for mobile HCPs
• Adjusting cu
ent systems to include remote safety monitoring and privacy and confidentiality procedures
• Using a problem-based design approach. For example, start with the design and build from that, rather than trying to add devices into an
already established protocol
• Using a participant-centered approach. For example, obtain participant feedback throughout trial design and implementation
• Delineating the delegation of investigator responsibilities in the context of remote clinical research
• Identifying physicians with medical licenses in multiple states
• Clarifying federal regulations and standardizing state laws:
• Clarifying guidance on the distribution, shipping, disposition, etc. of IMP within the context of remote clinical research
•