Comprehensive Phase I-IV
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FounderRebar Interactive New Orleans, LA
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4 APPLIED CLINICAL TRIALS appliedclinicaltrialsonline.com
CONTENTS
June/July 2016
O U R M I S S I O N
Applied Clinical Trials is the authoritative, peer-reviewed resource and thought leader for the global community that designs,
initiates, manages, conducts, and monitors clinical trials. Industry professionals learn effective and efficient solutions
to strategic and tactical challenges within the tightly regulated, highly competitive pharma ceutical environment.
A P P L I E D C L I N I C A L T R I A L SVOLUME 25, NUMBER 6/7
COMMENTARY
VIEW FROM BRUSSELS
10 New Focus on Antimicrobial
Resistance Could Benefit R&D
Peter O’Donnell
CLINICAL TRIAL INSIGHTS
16 Emphasizing ‘Solutions’
in eClinical Tools for Sites
Kenneth A. Getz
A CLOSING THOUGHT
50 Role of Regulators Critical
in eSource Data Integration
Jules Mitchel
CLINICAL TRIALS COMMUNITY
6 APPLIED CLINICAL TRIALS ONLINE
8 NEWS
DIA EXHIBITOR PROFILES
40 DIA EXHIBITOR PROFILES
MARKETPLACE
49 CLASSIFIED
SUBJECT RECRUITMENT
26 Engagement Shift: Informed
Consent in the Digital Era
Jeffrey Litwin, MD
Why electronic informed consent is
key to supporting today’s patient-
centric push in clinical trials.
TRIAL MONITORING
34 Quality Remote Monitoring:
The Tools of the Game
Penelope Manasco, MD
Outlining those technologies best
able to raise the data and process
quality of risk-based monitoring.
COVER STORY
18 Bring Your Own Device for Trial Outcome AssessmentBill Byrom, Jeff Lee, Kara Dennis, Matthew Noble, Marie McCarthy, Willie Muehlhausen
Survey uncovers the challenges, myths, and potential
useful strategies associated with BYOD adoption. LO
OPS
7/G
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6 APPLIED CLINICAL TRIALS appliedclinicaltrialsonline.com June/July 2016
WEB CONTENTS
appliedclinicaltrialsonline.comwww.linkedin.com/groups/Applied-Clinical-Trials-2949042/about
twitter.com/clin_trials
Site-owned IT infrastructures and technol-
ogies allow investigators to develop sim-
ple mobile applications (implemented via
“bring your own device” [BYOD]) to remotely
conduct patient visits and engage patients.
Furthermore, such infrastructures allow
the study site to collect behavioral and en-
gagement analytics to identify major depres-
sive disorder (MDD) patients posing study
risks (i.e., lack of engagement, risk of attrition,
etc.), and enables site staff to intervene with
high-risk patients, reducing dropout (more
trial data), acting on non-adherence (better
compliance), and bringing the trial to the pa-
tient (patient centricity).
Sponsors can certainly develop this type
of technology and implement it study-wide.
However, it is important for sponsors to
consider how such technologies will fit into
study site infrastructures, and which clini-
cal IT systems the technology will need to
integrate into (i.e., CTMS in case of site-staff
change), which can be costly and inefficient.
Another hurdle involves protecting patient
privacy, and supplying patients with the op-
tion to use a study-given device.
Leveraging a site-owned IT infrastructure
has its benefits, as deploying such infra-
structures address privacy concerns, and up-
dates are made by site staff in case of staff
turnover, preventing operational delays and
discrepancies.
N O T E W O R T H Y
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Source: Association of Clinical Research
Organizations survey, May 2016
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8 APPLIED CLINICAL TRIALS appliedclinicaltrialsonline.com June/July 2016
NEWS
V I E W F R O M W A S H I N G T O N
FDA’s breakthrough drug initiative is
much more successful than ever an-
ticipated, attracting hundreds of ap-
plications and speeding dozens of life-
saving and important new therapies to
patients. More than 45 new drugs and
biologics with the breakthrough therapy
(BT) designation have come to market
since the program was established in
2012, many benefitting from special as-
sistance from FDA experts.
Even more notable is that the pro-
gram actually appears to be accelerat-
ing clinical development of promising
therapies—as opposed to just speeding
up the agency’s approval process. An
analysis by Friends of Cancer Research
(FOCR) finds that pre-market develop-
ment time for breakthrough-designated
drugs is 2.2 years shorter than for those
without the BT imprimatur (see http://
bit.ly/1qWj585). These gains arise from
more streamlined clinical testing pro-
tocols negotiated early in development
by FDA reviewers and sponsors; a single
arm trial with fairly few patients may
suffice if treatment effect appears very
large. But the BT program involves a
lot of work for FDA: the agency has
vetted more than 300 breakthrough des-
ignation requests (BTDRs) and granted
BT status to about one-third of these
therapies.
Targeting assistance
The program’s success also has created
some confusion in the healthcare com-
munity about the significance of drugs
receiving BT status. More than half of
physicians believe that BTs have been
proven safe and effective in random-
ized trials, according to a recent study
in the Journal of the American Medical As-
sociation (April 12, 2016), and consumers
have high expectations for new drugs
described as “breakthroughs,” says an-
other JAMA article (September 2015).
FDA seeks to address these overly op-
timistic expectations for BTs by clarifying
its terms and improving BT program op-
erations. Although these drugs may “look
really good” in early trials, many may
“fail to deliver on the promise” initially
shown, explained Richard Moscicki, dep-
uty director of the Center for Drug Evalu-
ation and Research (CDER) in a recent
posting (see http://1.usa.gov/1TBcuGY).
He noted that BT drugs must treat seri-
ous conditions and present evidence of
their potential for providing “substantial
improvement” over available therapies, a
term that FDA is looking to define more
clearly. While a head-to-head compari-
son of a new drug to standard of care
may be ideal for documenting results,
evidence that a BT reduces progression
of disease may suffice when more exten-
sive data is not available.
To be able to provide assistance to
sponsors of true BTs, FDA also seeks to
limit the volume of inappropriate BTDR
requests. A new “preliminary BTDR ad-
vice” request process asks sponsors to
file a short form with basic information
on its BT candidate, namely whether
the indication is serious and life-threat-
ening, other available drugs, and early
clinical evidence (trial design, end-
points, number of subjects enrolled).
The relevant FDA review division will
discuss the request in a teleconference
and offer nonbinding advice on whether
to file the full BTDR at that time.
Patient concerns
Meanwhile, BT therapy development is
leading to more “seamless” clinical re-
search programs, particularly for oncology
treatments. Instead of three distinct clini-
cal trial phases, FDA is encouraging stud-
ies that can rapidly enroll patients based
on preliminary evidence of effectiveness.
Some patient advocates, though, have ob-
jected that such approaches increase risks
to patients. FDA officials commented in a
recent journal article that well-designed
protocols, clear rationales for expanding
patient cohorts, and updated informed
consent can address these issues. FDA
also proposes to limit the seamless trial
model to drugs receiving the BT designa-
tion and thus more intensive oversight
and communication with agency experts
through product development (see http://
bit.ly/24Ooe0w).
Another concern is whether expe-
dited development programs can fully
incorporate patient experience in clinical
trials. Although sponsors increasingly
are tapping patient groups for input on
study design and key endpoints, acceler-
ated studies may conclude before they
can collect and assess patient-reported
outcomes and other measures. One ap-
proach supported by FDA leaders is to
encourage more standing clinical trials
able to investigate innovative therapies
more efficiently by reducing the need to
identify sites, recruit patients, negotiate
research agreements, and enlist CROs
for every new promising treatment.
FDA and the research community also
are examining whether expedited devel-
opment programs can efficiently evalu-
ate combination therapies and diagnos-
tics needed to identify patients likely
to benefit from a personalized break-
through medicine. Patient advocates
led by FOCR have proposed that FDA
establish a “virtual” Oncology Center of
Excellence that would better coordinate
scientists and reviewers in separate FDA
Centers to achieve a more integrated ap-
proach to regulating combination cancer
therapies. FDA has offered strategies
that will improve the ability of its Office
of Combination Products to accomplish
similar goals, but may be willing to de-
vise a pilot program to test this new
“disease-oriented” regulatory approach.
— Jill Wechsler
‘Breakthrough’ Program Generates Optimism — and Concerns
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10 APPLIED CLINICAL TRIALS appliedclinicaltrialsonline.com June/July 2016
To see more View From Brussels articles, visit
appliedclinicaltrialsonline.com
NEWS
V I E W F R O M B R U S S E L S
Antimicrobial resistance is hitting the
world headlines at present for several
very good reasons—and the clinical
trial community in particular may
benefit from all this new attention to an
old problem.
The problem of resistance is almost as
old as antibiotics, since it is in the nature
of microbes that they adapt and evolve.
But the new attention is a response not
only to the increasingly familiar and
terrifying predictions of the risks of the
coming decades, or to the release in May
of the long-awaited O’Neill report “Tackling
drug-resistant infections globally” (see
http://bit.ly/1ToZXcw), or to the reflections
at the World Health Assembly at the
end of May on its “Global action plan on
antimicrobial resistance” (see http://bit.
ly/1TF2Tlg), or the discussions among
world leaders at the G7 summit in Japan.
The real driver is the painful awareness
that only a trickle of new antibiotics are
emerging to compensate for the erosion
of the existing arsenal (even the last-
resort carbapenems), and that the world’s
entire R&D pipeline contains less than 50
candidate products.
The momentum now gathering at the
international level to tackle the threats
more effectively is throwing what may
prove to be some welcome light into some
of the corners of clinical trial regulation
that have until now been too esoteric and
obscure to capture public interest.
One of the main points that the O’Neill
report makes is that antibiotic research
and development is hindered by regulatory
challenges—which it follows up with a fact
that is well known in the world of clinical
trials, but not so well known in the wider
world: “The greatest cost associated with
new antibiotic development is that of
running clinical trials—particularly during
the later stages of testing.”
O’Neill goes on to remark that on
average more than 80% of the costs of
bringing an antibiotic to market are
related to clinical trials. It is right, the
report concedes, that testing and approval
processes should be robust to prevent
unsafe or ineffective drugs coming to
market, but it then explains —in a way that
is capable of changing public perception—
that antibiotics face particular challenges,
and that those have contributed to the
progressive decline of R&D efforts.
As an example, it cites the cases of
antibiotics that are intended for use as
back-up defences for current generics to
which resistance is rising. These need,
in principle, to demonstrate clinical
“superiority” versus the existing treatment,
it points out, and “identifying and enrolling
large enough groups of patients with drug-
resistant infections can be a technical
and logistical challenge.” Furthermore,
companies and health technology
assessment agencies must consider how
to establish fair assessments of value for
money and cost-effectiveness for new
products approved via adapted non-
inferiority trial processes.
Its recommendation is to form clinical
trial networks for antibiotics, not only to
reduce the time taken to get each trial up
and running, but also to speed up the trials
themselves and reduce costs. “Sharing
‘control arms’ between trials, the overall
size of each trial could be reduced by more
than 40%,” O’Neill speculates, adding that
regulators could also benefit from all trials
undertaken using the same protocol.
The report complements the efforts by
the US FDA, the Japanese Pharmaceutical
and Medical Devices Agency, and the
EMA in Europe for their alertness to these
concerns and the steps they have taken to
address them. But, it goes on, “more can
be done to support antibiotic development
by improving the regulatory process.”
Because, the report points out, “even
when regulators manage to harmonize
and simplify requirements for developers
to bring new antibiotics to the market
that are effective for those patients with
a resistant infection, there remains a
separate challenge, which is the question
of how to price these antibiotics.” The
demands from healthcare providers and
price-setting authorities for robust clinical
evidence of the value of new drugs against
comparators are legitimate, the report
says—so “there is no escaping relatively
large clinical trials.”
One way of reducing these costs,
argues O’Neill, is for regulator y
agencies to work more closely together
to improve the global harmonization of
regulatory pathways for new antibiotics,
and explore the possibilities for mutual
recognition of regulatory approval across
multiple jurisdictions. If pharmaceutical
companies, regulators, and healthcare
system leaders cooperate, they could set
up national and regional “clinical trial
networks” for antibiotics, to streamline the
clinical trial process and reduce the costs
and duration of antibiotic development.
O’Neill is chipping away in a very public
fashion at some of the barriers that have
for years bedevilled drug development–
and not just in the field of antibiotics. The
current alarm over the risks of exhaustion
of the antibacterial armamentarium
is giving more exposure to some of the
underlying challenges of drug innovation
that have long remained remote from
public attention.
— Peter O’Donnell
Antibiotic-Resistance Focus Could Benefit Clinical Trials
New attention on ways to tackle this age-old scourge is building in Europe and beyond
If your current electronic data capture (EDC) platform always seems to toss
hurdles in your path, it’s time to switch lanes.
At Merge, an IBM Company, we're used to customers switching to our EDC for
new studies. But lately, we've noticed that more and more researchers are
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every clinical trial is a time trial—and that an EDC that slows progress to the
finish line is an EDC that’s not worth its weight in gold (or even silver or bronze,
for that matter).
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12 APPLIED CLINICAL TRIALS appliedclinicaltrialsonline.com June/July 2016
NEWS
D A T A A N A LY S I S
G L O B A L R E P O R T
EFGCP Renews Campaign on Older People in Research
The European Forum for Good Clinical
Practice (EFGCP) is stepping up its ef-
forts to involve more older people in
clinical research by focusing on two central
questions: What can be done about it?
What are the problems and the solutions?
There’s an urgent need to obtain bet-
ter evidence for future treatment of older
people (i.e., over 75) and for providing
them with optimal care, according to Flo-
rian von Raison, MD, and Laurence Hu-
gonot-Diener, MD, the co-chairpersons of
the EFGCP’s Geriatrics Medicine Working
Party in Brussels.
“There is only weak evidence-based
guidance coming from often poor and in-
sufficient clinical research, and this vulner-
able population is often underrepresented
in research and the development of drugs,”
they noted in a statement issued in ad-
vance of the late September workshop on
the topic, to be held in Nice, France. “If
study participants do not represent the
average patient in daily practice, the con-
sequence is that many medical decisions
for older people are extrapolated from
clinical trial data derived from younger
population.”
Drugs are often prescribed to older pa-
tients with very little idea of efficacy, dos-
age, or adverse effects, they believe. Global
evaluation of their needs and frailties‚
including co-morbidity, polypharmacy,
disability, and cognitive impairment, is
necessary in order to reduce the risk of a
drug’s inappropriate use and to evaluate
the chances of benefit, the risks of harm,
and the cost-effectiveness of treatments.
Three years on from the EFGCP’s pub-
lication of detailed guidelines on older
people and research, the organizers are
keen for everybody to take a fresh look at
this subject. Raison thinks several key ar-
eas of ethical concern in geriatrics remain:
t� Different reaction to medicines from
other adults
t� Issues of information and consent
t� The involvement of family and careers
t� Appropriate age-relevant formulations
t� Differences in pharmacokinetics and
pharmacodynamics
t� Ethical issues around technology.
The EFGCP workshop will take place
on September 27 at the Institut Claude
Pompidou in Nice, and is being organized
in partnership with Innovation Alzheimer.
— Philip Ward
In January 2014, the FDA presented a
webinar “Promoting eSource Data Cap-
ture,” to explain its Final Guidance on
Electronic Source Data in Clinical In-
vestigations. In a slide, the FDA said the
worst case for source data capture is
“transcription of data from paper or elec-
tronic sources to the eCRF.” The reason
being that there was no intervening pa-
per step needed, less confusion on what
is source and the decreased likelihood of
data errors.
In April of this year, we conducted a
survey with SCORR Marketing to evaluate
the paperless trial. In this survey, of 143
respondents, 25% said 0%-10% of their
data collection in clinical trials was pa-
perless. The next highest was 22%, who
said that greater than 75% of their trials
were paperless. And 15% said between
51% and 75% were paperless. So the ma-
jority fall in the middle of paperless pro-
cesses, leaving room for greater adoption
in the coming years.
In fact, the majority of respon-
dents—27%—said that in the next three
years, 75% to 99%
of the processes
for clinical trials
would be paper-
le ss . With the
plethora of new
technologies sur-
rounding data ag-
gregation, mining,
and analytics in
all critical areas of
study conduct, we
can only see that
our respondents
are correct in their
view.
For more infor-
mation, download
SCORR’s free report at http://www.scorr-
marketing.com/resources/paperless-clin-
ical-trials-survey-report
— Lisa Henderson
Paperless Processes on the Way Out?
Source: Applied Clinical Trials and SCORR Marketing Paperless Clinical
Trials survey, April 2016.
More efficient
data collection
100
120
80
60
40
20
0
Greater ease
searching for
and finding
documents
n = 143
104100
8985
73
Increased
data quality
Improved
document
quality
Reduced need
for data entry
Agree that Paperless Processes Helped Realize the Following
Data-Related Goals
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14 APPLIED CLINICAL TRIALS appliedclinicaltrialsonline.com June/July 2016
NEWS
I N F O R M A T I O N T E C H N O L O G Y
C L I N I C A L S A F E T Y M O N I T O R I N G
Now that the era of digital health is
upon us in the U.S. and other coun-
tries, it’s time for a fresh look at how
we collect research data. What if we
could make a great leap forward by com-
pletely changing our approach through
electronic health record (EHR) eSource?
Would we dare to try?
“Source” is the initial recording of
data for a clinical study. When the
original recording is on digital media
rather than paper, it’s “eSource.” Clini-
cal trials have used eSource for years
in ECG readings, lab results, and other
measurements. The FDA eSource Guid-
ance describes different ways to trans-
mit eSource data (from direct capture,
devices, transcription, EHRs, or patient-
reported outcome instruments) to an
electronic case report form (eCRF) sys-
tem, and several approaches have been
proposed for trying to feed EHR data
into our existing EDC-based processes.
Last year the FDA even asked for dem-
onstration projects to explore such ap-
proaches.
But a more recent draft Guidance
on Use of EHR Data in Clinical Inves-
tigations offers another take entirely
with explicit goals to “facilitate the use
of EHR data in clinical investigations”
and to “promote the interoperability of
EHRs” with clinical research systems.
The guidance recognizes that the ONC
Health IT Certification Program can in-
dicate the readiness of EHRs to support
research. And ONC’s Advancing Care
Information initiative relies heavily on
leveraging application program inter-
faces (APIs) to make health data more
timely and accessible to patients and
caregivers.
This is where HL7’s FHIR platform
standard comes in:
t� ')*3�T�%BUB� "DDFTT� 'SBNFXPSL�XJMM�
provide a universal API to EHR systems
that can be used to populate much of a
casebook in a clinical database.
t�5IF�4NBSU�PO�')*3�TQFDJGJDBUJPO�EFN�
onstrates how patients can grant re-
searchers access to their data through
electronic informed consent, as well
as input outcome data through smart-
phones and browsers—data that can be
directed to an EHR or a trusted third-
party cloud-based research repository
simply by selecting the appropriate tar-
get FHIR server.
t�4JODF�&)3�EBUB� JT�F4PVSDF � ')*3�DBO�
also provide authorized access to re-
mote study monitors.
t� "OE� TJODF� ')*3� DBO�VQEBUF� BT�XFMM�
as read data, it can also support the
processing of data clarification transac-
tions, thus making it possible to syn-
chronize EHR records with clinical da-
tabases, improving transparency and
traceability for both monitors and regu-
latory inspectors.
t� ')*3�NBLFT� JU�QPTTJCMF� GPS� SFHVMBUPSZ�
reviewers to delve into the full EHR da-
tabase to explore, for example, serious
adverse events, in more depth than was
ever possible before.
In the future, it may not be necessary
to have an eCRF system in the middle
of the process. That would enable using
the EHR data directly to feed our analy-
sis so that all health data could poten-
tially be reused as research data.
— Wayne Kubick, is Chief Technology Of-
ficer, Health Level Seven International, and a
member of Applied Clinical Trials’ Editorial
Advisory Board
EHR eSource: Sword of Change?
In December 2015, the ICH updated its
E14 Guideline Q&A to define an alterna-
tive path for identifying the cardiac safety
issue of QT prolongation in non-cardiac
drugs. This is the most fundamental revi-
sion to the Q&A of “The Clinical Evaluation
of QT/QTc Interval Prolongation and Proar-
rhythmic Potential for Non-Antiarrhythmic
Drugs” since its implementation in 2005.
This alternative path—call it “concentra-
tion effect modeling”—relies on intensive,
high quality ECG analysis and the use of
exposure response modeling to determine
the extent of QTc prolongation. Proof of its
validation is FDA’s acceptance of this ap-
proach in lieu of a TQT study earlier in 2015.
Applied Clinical Trials spoke with Norman
Stockbridge, MD, PhD, Director of the Divi-
sion of Cardiovascular and Renal Products
in CDER’s Office of New Drugs, about this
development. Stockbridge noted that it has
always been a known that TQT studies are
inefficient. He said, “It led to sponsors do-
ing a separate study instead of piggyback-
ing onto an existing study. Then because it
was a special study, it was only conducted
late in development. Also, the previous
by-time-point analysis doesn’t use all the
information; it just uses the information
where the QT interval is the worst.”
However, getting to a new approach
that also had an acceptable confidence
level for the older TQT approach, took time
In the end, Stockbridge says, FDA asked
for a trial that formally compared the two
approaches. The Cardiac Safety Research
Consortium (CSRC) and IQPharma mem-
bers initiated the IQ-CRSC study, of which
the FDA was heavily involved in the design.
For more information, download the
free report at http://bit.ly/1TtPERI
— Lisa Henderson
Critical Update to Cardiac Safety Assessments
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16 APPLIED CLINICAL TRIALS appliedclinicaltrialsonline.com June/July 2016
CLINICAL TRIAL INSIGHTS
To see more Clinical Trial Insights articles, visit
appliedclinicaltrialsonline.com
On average, investigative sites
are managing a dozen different
systems provided by sponsors,
contract research organizations
(CROs), and vendors to collect and
capture clinical study data. These
systems—a mix of mature and nascent
tools—are not integrated, they are
incompatible, they are increasing
investigative site workload, and,
according to principal investigators
and study coordinators, they are
cont r ibu t ing to s tudy conduc t
inefficiencies and lower productivity.
A new CenterWatch study shows
that investigative sites are being
inundated with a growing number
of eClinical technologies. The large
number of disparate and incompatible
solutions has left many sites feeling
that they are, at best, an afterthought
in the design of eClinical technology
functions and uses.
The survey was conducted online
between January and March 2016 in
collaboration with the Association
of Clinical Research Professionals
(ACRP). In addition to the large
average number of systems used,
investigative sites report routinely
using an average of 10 software
appl i ca t ions s imul taneous ly to
manage their clinical studies, each
requiring unique login instructions
and training.
Increased burden and potential
for errors
Despite the best o f intent ions,
technology solutions implemented
at investigative sites frequently have
the opposite effect to which they
were intended: the solutions create
additional work since information
from patient visits and laboratory
tests must be transcribed from paper
or electronic sources manually into
study software.
Technology solutions implementation
and ongoing support also largely
falls on study staff. As the number
of solutions has grown, particularly
interactive and mobile technologies
used by patients, study staff must
frequently act as the “Help Desk” while
communicating with a large number
of third-party vendors for technical
assistance.
The majority—80%—of investigative
sites report using electronic data
capture (EDC) and electronic case
report form (eCRF) technologies.
More than half of sites report using
interactive voice and web response
systems, (IVRS/IWRS), clinical web
portals, safety and adverse event
reporting technology, and clinical
trial management system (CTMS) and
electronic patient reported outcome
(ePRO) systems. Other technologies
employed less often include learning
management systems (LMS), electronic
trial master files (eTMF), and ePRO
platforms that use a patient’s own
smartphone or tablet.
Although EDC was widely adopted
more than a decade ago, investigators
and study coordinators continue to
record patient study-visit information
on paper and then re-enter the source
data into electronic data capture
and management systems. Patient
information stored in the site’s own
CTMS or electronic medical record
(EMR) software is typically printed
out and manually transcribed into
clinical trial software systems. Since
various systems seldom have the
ability to integrate, patient data often
must be entered into several different
electronic systems—such as EDC,
IVRS/IWRS, ePRO or an investigator
portal—for the same study.
eClinical solutions also appear
to be complicating procedures and
poor interoperability requires using
antiquated and new technologies
simultaneously. Laboratory reports,
for example, are sent to investigators
for rev iew ei ther by fax—which
requires sites to maintain facsimile
machines and traditional landlines—
or through Internet por ta ls . In
turn, study staff typically needs to
manually enter information from the
reports, along with evidence that they
have been reviewed by the principal
invest igator , into EDC or other
software systems.
Study coordinators also report that
electronic systems require continual
monitoring to locate copies of new
laboratory reports, such as results
from electrocardiogram (ECG) tests.
Further compounding the challenge,
investigative site staff must juggle
the use of disparate solutions while
under tight deadlines.
The need to transcribe source
documents and patient information
into electronic systems not-only
duplicates effort, it also increases
Kenneth A. Getz
MBA, is the Director of
Sponsored Research at
the Tufts CSDD and
Chairman of CISCRP, both
in Boston, MA, e-mail:
Emphasizing ‘Solutions’ in eClinical Tools for Sites
Work burden and performance hurt by technology incompatibility and limited utility
appliedclinicaltrialsonline.com APPLIED CLINICAL TRIALS 17June/July 2016
CLINICAL TRIAL INSIGHTS
the possibility of transcription errors.
And many sites report interacting
with a large number of third-party
solutions providers who often fail to
identify themselves and the specific
solution that they are supporting and
upgrading.
Study staff must devote additional
time to ensure that these vendor
solicitations are legitimate. Responding
to fraudulent technology vendor
solicitations could have disastrous
consequences.
A sea of login and training
requirements
In every eClinical solutions category—
EDC, eCRF, CTMS, and Internet
portals, for example—investigative
sites must manage software from
multiple vendors. These systems
each require a unique username
and password, which typically must
be changed every three months for
security reasons. Nearly three-fourths
(74%) of study staf f report that
keeping track of multiple usernames
and passwords is a top challenge.
High-volume investigative sites
report routinely maintaining login
information for at least 40 or 50
systems. Study staff use a variety
o f met ho d s — s ome pro g r e s s ive
(use of secure sof t ware), some
very rudimentary (notebooks and
paper forms)—to remember login
instructions and passwords. Many
large sites have dedicated sta f f
to oversee the management and
protection of passwords and a process
for changing and updating them.
S i t e s e x p r e s s c o n s i d e r a b l e
frustration over technology solutions
training requirements. Four-out-of-10
investigative sites surveyed indicate
that too much technology training
is required. And an overwhelming
majority (95%) of sites believes that
training contains repetitive elements.
Most sites report that sponsors and
CROs typically force sites to repeat
training activity despite the clinical
study staff having experience and
prior training on certain technology
solutions.
Unmet site technology needs: A
major opportunity
As sponsors and CROs look to
more firmly establish themselves as
partners-of-choice with investigative
s i tes , the re i s much room fo r
improvement.
Sponsors, CROs, and eClinical
solution providers continue to develop
and implement point-based solutions
that bombard and over -burden
investigative sites. The CenterWatch
study points to the urgent need to
rethink this top-down approach and
to build investigative site operating
experience and requirements in
at the outset. Investigative sites
want technology systems that are
interoperable and that demonstrate a
deeper understanding of site and study
workflow.
More than a quarter (28%) of sites
surveyed want the biopharma industry
to adopt a single common technology
platform. Investigative sites also
want sponsor organizations and
CROs to reduce redundant training
requirements by accepting proof of
prior training.
Electronic source data promises to
play a particularly important role in
driving study conduct efficiency. With
eSource, data obtained during each
study visit or during participation
can be entered directly, eliminating
the need for duplicate data entry into
EDC systems. And interest in eSource
is gaining momentum since the FDA
issued guidance in 2013 encouraging
its use.
Sponsors are increasingly looking
for technologies to gather more data
to support real-time monitoring of
clinical study progress and enrollment
performance. The adoption of new
technology solutions will no doubt
continue.
B a s e d o n i n v e s t i g a t i v e s i t e
feedback, however, the most useful
and valuable technology solutions are
not those that introduce disparate
functionality. They are those that
reflect a deep understanding of site
workflow, that are interoperable and
that integrate with other systems and
processes. Ultimately, technology
s o l u t i o n s t h a t o p t i m i z e s i t e
performance are the ones poised to
deliver on the promise of speed and
efficiency while meeting the priority
objective of supporting higher levels of
study volunteer engagement.
Source: CenterWatch-ACRP, 2016; N=252 global investigative sites
Investigative Site Ratings of Select Technology Solutions
18 APPLIED CLINICAL TRIALS appliedclinicaltrialsonline.com June/July 201618 APPLIED CLINICAL TRIALS appliedclinicaltrialsonline.com
PEER
REVIEW
CLINICAL TECHNOLOGY
Bring Your Own Device for Trial Outcome Assessment Bill Byrom, Jeff Lee, Kara Dennis, Matthew Noble, Marie McCarthy,
Willie Muehlhausen
Using patients’ own mobile devices to col-
lect self-reported outcomes data (referred
to as electronic patient-reported outcome
[ePRO] or electronic clinical outcome as-
sessment [eCOA]) is an industry hot topic.
Limited use of “Bring Your Own Device,” or BYOD,
in regulatory studies to date is mainly due to in-
dustry concerns spanning two areas. The first is a
concern that different device sizes and operating
systems might affect the measurement properties
of a PRO instrument. When employing eCOA on
a single device type, the measurement properties
can be assessed fully by usability testing, cogni-
tive debrief, or quantitative equivalence studies.
In a BYOD setting, performing validation studies
to cover all possible device types and sizes would
be impossible. The second area is concern around
the technical and practical aspects of using a
patient’s own hardware. Concerns, for example,
include the effect of a subject changing their de-
vice mid-study, upgrading their operating system,
or having insufficient storage space available to
store eCOA data due to other apps, data, pictures,
and music.
Between August and October 2015, we con-
ducted a research survey to identify and assess
the perceived barriers and challenges with the
use of BYOD for eCOA in clinical trials. Our aim is
to provide information helpful in devising future
strategies for BYOD adoption, and to help identify
popular perceived challenges that perhaps are
more myth than reality. In preparing the survey
questions, we supplemented our own knowledge
of commonly considered challenges and issues
with information gathered during telephone inter-
views of five respected industry eCOA experts.
Survey respondents
Ninety-eight individuals accessed our survey
which was promoted primarily through LinkedIn
connections and groups. Of these, 19 individu-
als answered only the first question, a mandatory
question measuring employment type, but did not
answer any of the BYOD-specific questions. We
excluded these respondents, leaving a sample of
79 respondents, and assume that the individuals
answering only the initial question did so to pro-
ceed but then realized that they would be unable
or unwilling to answer the technical questions that
followed.
Of the 79 respondents, 14 (18%) were employed
at biopharmaceutical companies, 18 (23%) at con-
tract research organizations (CROs), and 27 at
eCOA vendors (34%) (see Figure 1 on page 20). For
confidentiality reasons we do not report the in-
dividual organizations represented, but note that
in all categories companies ranged from large to
small organizations, and each contained a number
of household names. The four respondents in the
“Other” category included a patient advocate em-
ployed by a number of charities, a psychometrics
expert, and two individuals from research institu-
tions.
In all cases, responses collected represented
personal views and not necessarily those of the
respondents’ employing organizations.
Survey uncovers the challenges, myths, and potential useful strategies associated with BYOD adoption.
We found no upside to silos, territories, handoffs, roadblocks, walls, fences, gaps or sidetracks. So we eliminated them.
Shortening the distance from lab to life.TM
First and foremost, we are focused on constantly evolving and pioneering best practices across all disciplines, streamlining procedures, removing hurdles and reducing opportunities for errors, false starts and wasted time or money. Our thinking is simple: a smoother process is a better process—and sometimes even a faster one.
Maybe that’s why we have helped to develop or commercialize 81% of all Novel New Drugs approved by the FDA over the past fi ve years. Or maybe our clients just like working with us.
inVentivHealth.com
20 APPLIED CLINICAL TRIALS appliedclinicaltrialsonline.com June/July 2016
CLINICAL TECHNOLOGY
Attitudes toward equivalence requirements
While the challenge of proving equivalence across multiple
device types seems to dominate the public discussion re-
garding BYOD, our respondents seemed significantly less
deterred by the equivalence challenge:
t� Overall, 44% agreed or strongly agreed that equivalence
should be demonstrated on all possible devices used in a
BYOD study (see Figure 2).
t� Only 30% of respondents disagreed or strongly disagreed
that demonstration of equivalence on a single device was
acceptable if access using devices of a smaller screen size
or resolution could be prevented.
t� In addition, 68% of respondents agreed or strongly agreed
that showing equivalence only on a single device would be
acceptable if the strategy was agreed a priori with the regu-
latory bodies.
t� Few saw distinction between primary and secondary
data—only 22% agreeing or strongly agreeing that demon-
strating equivalence on a single device was necessary only
if the data represented secondary endpoints.
t� Seventeen percent of the respondents disagreed or
strongly disagreed that no further equivalence testing
would be needed if a similar equivalence study had already
been conducted and reported.
Few respondents disagreed that scale author agreement
would be necessary if using an existing instrument in a BYOD
setting—only 17% and 5% disagreeing and strongly disagree-
ing, respectively (Figure 2b on page 21). The majority of re-
spondents agreed or strongly agreed that ensuring minimum
screen size would be sufficient for valid implementation of a
visual analogue scale (41% and 27%, respectively), and that
differences in font sizes between devices was unimportant
(44% and 26%, respectively).
There was some evidence of trends indicating differing
strength of agreement based on the employment type of the
respondents, although the sample was not considered large
enough to assess this formally. In comparison to CROs and
eCOA vendors, biopharmaceutical company respondents
generally saw a greater need for equivalence demonstration
across all device types, with 72% agreeing or strongly agree-
ing, compared to 48% among CRO respondents and 34%
among eCOA vendor respondents. That said, these sponsor
respondents were supportive that equivalence demonstration
on a single device was acceptable if usage could be limited
to devices of at least that screen resolution and size (79% of
sponsor respondents agreed or strongly agreed, compared to
67% and 35% for eCOA vendors and CROs, respectively).
Concern over perceived BYOD practical or technical
challenges or issues
Of the 21 perceived practical/technical challenges and issues
associated with BYOD use for eCOA that we considered, few
appeared of significant concern to the respondents in this
Source: Byrom et al.
Figure 1. The breakdown of survey respondents by
discipline/classification.
Range of Respondents
Source: Byrom et al.
Figure 2. Respondents attitudes toward various
device equivalence requirements (A) and other mea-
sures in the BYOD setting (B).
Device Equivalence Views
A
B
appliedclinicaltrialsonline.com APPLIED CLINICAL TRIALS 21June/July 2016
CLINICAL TECHNOLOGY
survey (see Figure 3 on page 22). Over 75% of respondents
identified they were “not at all concerned” or “a little con-
cerned” about the following perceived challenges:
t� The subject could delete the app during the study.
t� The subject may fail to download an updated version.
t� The subject may upgrade their device operating system.
t� The subject may not be permitted to use their device at
work.
t� There may be insufficient free storage capacity on the de-
vice.
t� The subject may become distracted by other things on the
device during ePRO completion.
t� Some personal identifiable data may need to be collected
t� Data on the device could be accessed by a hacker.
t� It may be complicated to compensate subjects due to dif-
ferences in individual data plans.
t� Patient setup and training may be more complicated for
site staff.
t� It may be more difficult to identify that the app is working
correctly on the subject’s own device.
t� Logging into the app in addition to their device may be in-
convenient for the subject.
Fifty-three percent of respondents were “not at all con-
cerned” or “a little concerned” that the subject may be able
to turn off in-app notifications, such
as diary reminders, using their phone
settings.
There was little concern about sub-
jects changing their phone during
a study. Seventy-four percent of re-
spondents were “not at all concerned”
or “a little concerned” about subjects
changing device mid-study, 67% that
subjects may discontinue their con-
tract, and 71% that subjects may lose
their device during the study.
Respondents were generally not
greatly concerned about perceived se-
curity issues with using subjects’ own
devices. Sixty-seven percent (67%)
were “not at all concerned” or “a little
concerned” that eCOA data could be
accessed by other apps on the sub-
ject’s device, and 83% that data could
be accessed by a hacker.
Almost 20% of respondents were
very concerned or extremely con-
cerned that subjects without a suit-
able device would be ineligible to
participate in the study. Thirty-two
percent of respondents indicated they
were very concerned or extremely
concerned that a subject’s device may
not pair with a Bluetooth device if used in the study, with
59% “not at all concerned” or “a little concerned.”
There was moderate concern around training and support
of study participants. Twenty-seven percent were very con-
cerned or extremely concerned about the potential training
burden on sites in a BYOD study, with 33% of respondents
expressing the same degree of concern that site staff may be
unable to troubleshoot more technical problems associated
with using an eCOA app over multiple device types.
Again, while the numbers per group prohibited formal
analysis, we noted some possible trends that may indicate dif-
fering strength of concern over certain perceived issues based
on the employment type of the respondents. In comparison
to CROs and eCOA vendors, biopharmaceutical company re-
spondents generally appeared more concerned about subjects
deleting their ePRO app during the study, subjects discontinu-
ing their device contract during the study, subjects losing their
device, data being accessible to other apps on the subject’s
device or being accessed by a hacker, and the subject’s device
being unable to be paired with a provided Bluetooth device.
Discussion
When it comes to demonstrating measurement equivalence
across all devices in BYOD settings, over half of the respon-
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22 APPLIED CLINICAL TRIALS appliedclinicaltrialsonline.com June/July 2016
CLINICAL TECHNOLOGY
dents in our survey neither agreed nor strongly agreed that
testing was required on all possible devices; and over half
agreed or strongly agreed that demonstrating equivalence on
a single device was acceptable if all subjects could be guar-
anteed to use a device of at least that minimum screen reso-
lution and size. Would that strength of feeling translate into
the use of BYOD to deliver eCOA instruments in a regulatory
study today? Perhaps, but maybe that’s unlikely. However, as
we see more and more evidence that electronic devices of all
shapes and sizes do not adversely affect the measurement
properties of eCOA instruments across different study con-
texts and patient populations, this position may relax.
There are already positive signals that measurement
equivalence across modalities is less problematic than pre-
viously thought, especially if ePRO design best practices are
employed (see the C-Path institute’s ePRO consortium white
paper for example).1 One of these signals is the growing evi-
dence of paper and electronic equivalence. One might argue
that the magnitude of change is far greater from paper to an
electronic device, than from device to device. A recent meta-
analysis by Muehlhausen and colleagues provides strong
evidence of the equivalence of paper and electronic over
multiple instruments, patient populations and electronic
media.2 This study also included two studies in which the
equivalence of two electronic formats was assessed. If pa-
tients respond consistently with PRO instruments, whether
in paper or electronic form, then it seems a reasonable infer-
ence that the subtle changes across different mobile phones
should not present an equivalence challenge.
This isn’t the first meta-analysis we’ve seen exploring this
topic. Gwaltney and colleagues published a meta-analysis of
46 equivalence studies conducted up to 2006.3 This analysis
reported a pooled correlation of paper to electronic scores of
0.90 with a 95% confidence interval from 0.87 to 0.92. This is
above the correlation threshold of 0.75 or 0.8 considered to
represent acceptable reliability.
Muehlhausen et al.’s meta-analysis considered new equiva-
lence studies published from 2007 to 2013. Significantly, these
studies were reported after the publication of the ISPOR ePRO
Task Force recommendations on the design and analysis of
equivalence studies and many, therefore, adhered to the task
force recommendations. This new meta-analysis included 72
equivalence studies from 23 different patient groups and in-
cluded a wide range of electronic modalities including PC, tab-
let, handheld device/smartphone, and interactive voice response
system (IVRS). Their conclusions were in line with Gwaltney and
colleagues—a pooled correlation of 0.875 (CI: 0.867-0.884).
These two important studies provide extensive evidence that
paper and electronically administered PROs are equivalent—
across many different PRO instruments, patient populations,
and electronic modes of administration. While none of these
studies were conducted in a BYOD setting, it seems that device
type does not affect equivalence to paper—so we might gain
encouragement that device-to-device differences are likely to
be similarly insignificant in affecting the way in which patients
respond to ePRO instruments if the design of the questionnaire
follows the ePRO Consortium white paper design guidelines.1
Should measurement equivalence concerns be assigned
to the category of myth? We argue that the body of evidence
collected to date strongly suggests this. The above pieces of
work, and others actively being conducted, provide a positive
signal on the way to greater acceptance of BYOD as a valid
approach that protects eCOA instruments’ measurement
properties when applied appropriately.
As we have seen in our survey, however, perceived issues
and challenges with BYOD for eCOA are not confined to con-
siderations of measurement equivalence. There are perceived
practical and technical concerns with the use of a subject’s
own mobile device to collect submission data.
Some of these concerns are tangible situations that could
happen in a clinical trial. Subjects, with full control over
the contents and operation of their mobile device, could
indeed delete the eCOA app, prevent notifications appear-
ing on their home screen outside the app, may upgrade their
operating system during a study or change their device or
Some perceived issues and challenges
can likely be dismissed as myth—at
least in the sense that they do not apply
specially to BYOD, but apply equally to
other approaches to PRO collection.
Source: Byrom et al.
Figure 3. The concern levels of 21 perceived practi-
cal/technical challenges and issues associated with
BYOD use for electronic clinical outcome assessment.
BYOD Concerns
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24 APPLIED CLINICAL TRIALS appliedclinicaltrialsonline.com June/July 2016
CLINICAL TECHNOLOGY
mobile contract during a trial. Can these risks be mitigated
and what is their potential impact on the measurement of
the PRO? Certainly some could be limited through training,
and additional information from system-based monitoring
of the app can help to present issues for patient follow-up by
sites. This might include regular receipt of information on the
device operating system and version of the app being used
to identify when changes have occurred, and flagging when
push notification tokens indicate that notifications have been
disabled on the patient’s device.
However, eliminating the possibility of the user upgrad-
ing his or her device or turning off notifications in a BYOD
setting will be hard to eliminate completely. Do these risks
outweigh the potential advantages of BYOD? We argue the
potential benefits of BYOD are greater than these concerns.
While the cost of provisioning mobile devices in current trials
is high, we do not believe that BYOD will necessarily result in
significant cost savings. Some provisioning may be needed
to enable inclusion of patients without compatible hardware,
and provisioning savings may be balanced by a higher sup-
port cost when patients use their own mobile devices to op-
erate study eCOA solutions.
It is hoped, however, that BYOD brings with it greater
patient convenience and centricity—enabling subjects to
utilize their own smartphone to maintain their symptom
diaries and instrument entries using the device they already
carry with them and refer to over the course of each day. With
BYOD, subjects will use a device they are familiar with and
know how to use. They will also not be required to carry and
keep charged a separate device solely for the purposes of
their eCOA entries. Previous patient preference studies have
shown that the majority of patients prefer to have a single
device, and this can only benefit PRO convenience, comple-
tion, and compliance.
Some perceived issues and challenges, however, can likely
be dismissed as myth—at least in the sense that they do not
apply specially to BYOD and in fact apply equally to other
approaches to PRO collection. Subjects can equally lose a
provisioned device or paper diary as opposed to their own
mobile device, and subjects may be equally unable to use a
study device as opposed to a personal device in a working
environment. In an unsupervised setting, subjects may be
equally distracted by their own smartphone while complet-
ing a paper diary or a diary on a dedicated study device; and
the same requirements for collection of personal identifiable
data apply to both BYOD and provisioned device studies.
Other issues fall into the category of surmountable tech-
nical considerations, which should be addressed by good
mobile app design. Security, for example, while an important
concern, has not limited the prevalence of online and mobile
banking services. There is no reason why we cannot learn
from the application of technology solutions in other indus-
tries to gain confidence and develop solutions that are ap-
propriate for healthcare and clinical trials. While the banking
industry has the benefit of large investment, leveraging their
R&D may be less expensive, and online banking has already
had an impact on user behavior and acceptance of online so-
lutions to manage sensitive information.
Conclusion
We believe that the time for BYOD is upon us. With that we
see greater potential to apply eCOA to study protocols where
paper data collection remains quite popular despite its well-
known limitations. As an industry, we should continue to
investigate the use of BYOD and share our findings, positive
and negative, so that as a collective we can provide sufficient
evidence to turn the tide.
FDA recently requested public input from a broad group of
stakeholders on the scope and direction of the use of tech-
nologies and innovative methods in the conduct of clinical
investigations.4 This docket includes a specific question for
comment: “What are the challenges presented when data are
collected using the Bring Your Own Device (BYOD) model?”
This is a positive signal from the regulators that we welcome
and one that can only help to ultimately provide better un-
derstanding of FDAs position and any gaps in evidence re-
quired to make BYOD a fully endorsed approach.
References
1. C-PATH Institute ePRO Consortium (2014). Best Practices for Elec-
tronic Implementation of Patient-Reported Outcome Response
Scale Options. http://c-path.org/wp-content/uploads/2014/05/Best-
PracticesForElectronicImplementationOfPROResponseScaleOp-
tions.pdf
2. Muehlhausen W. et al. (2015). Equivalence of electronic and paper
administration of patient-reported outcome measures: a system-
atic review and meta-analysis of studies conducted between 2007
and 2013. Health and Quality of Life Outcomes; 13: 167-187. http://hqlo.
biomedcentral.com/articles/10.1186/s12955-015-0362-x
3. Gwaltney C. et al. (2008). Equivalence of Electronic and Paper-and-
Pencil Administration of Patient-Reported Outcome Measures: A
Meta-Analytic Review. Value in Health; 11: 322-333.
4. Federal Register (2015). Using Technologies and Innovative
Methods to Conduct Food and Drug Administration-Regu-
lated Clinical Investigations of Investigational Drugs; Estab-
lishment of a Public Docket. https://www.federalregister.gov/
articles/2015/10/29/2015-27581/using-technologies-and-innova-
tive-methods-to-conduct-food-and-drug-administration-regu-
lated-clinical
Bill Byrom is Senior Director, Product Innovation, ICON Clinical
Research Ltd.; Jeff Lee is CEO, mProve Health; Kara Dennis is VP,
Chief of Staff, Medidata Solutions; Matthew Noble is Senior Director,
Product Management, Medidata Solutions; Marie McCarthy is Director
of Product Innovation, ICON Clinical Research; Willie Muehlhausen is
Vice President, Head of Innovation, ICON Clinical Research
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26 APPLIED CLINICAL TRIALS appliedclinicaltrialsonline.com June/July 201626 APPLIED CLINICAL TRIALS appliedclinicaltrialsonline.com
PEER
REVIEW
SUBJECT RECRUITMENT
Engagement Shift: Informed Consent in the Digital EraJeffrey Litwin, MD
Prior to a patient’s enrollment in a clinical
trial, the prospective participant is often
handed a document that is 15 to 25 pages
long. Known as the informed consent form
(ICF), the document is largely comprised of
a combination of medical terminology and “le-
galese” that even members of the pharmaceutical
community would have difficulty comprehending
in full. To further complicate matters, important
information on the benefits, and risks of the clini-
cal trial experience that patients are about to un-
dergo is often only a small part of the document.
This practice is outdated and is not consistent
with current calls for increased patient engage-
ment in the clinical trial process.
For many clinicians, informed consent is
thought of as a signature on a document, but it
should be a process that leads to greater under-
standing of what lies ahead for patients participat-
ing in a clinical trial. Though it took our indus-
try 20 years to embrace electronic data capture
(EDC), and at least 10 years to embrace electronic
reported outcomes/electronic clinical outcome
assessments (ePRO/eCOA), both now play an in-
creasingly crucial role in new drug development.
Electronic trial master files (eTMF) are also mak-
ing significant gains. Still, even though “patient
centricity” has become the new buzzword, our
industry has not yet implemented an electronic
informed consent (eIC) process that would benefit
our patient partners in clinical trials.
The FDA published guidance on informed con-
sent in 20141 and followed up with guidance on
eIC in 2015.2 The guidance document defines eIC
as using electronic systems and processes that
may employ multiple electronic media to convey
information related to the study and to obtain and
document informed consent. The general prin-
ciples of each are similar to the following recom-
mendations for obtaining patient agreement:
t� Description of the clinical investigation
t� Risks and discomforts of treatment
t� Benefits of treatments
t� Alternative procedures or treatments
t� Confidentiality
t� Compensation and medical treatment in the
event of injury
t� Contact information for questions
t� Patient understanding that participation is vol-
untary
t� The total number of patients in the study
In addition to the above, the patient should
understand what will happen if the study, or their
participation in the study, is terminated either
involuntarily or voluntarily, and the patient must
be made aware that new, unanticipated adverse
events may occur during the course of the trial.
Importantly, proof of comprehension is not a
requirement. Consequently, information about
whether the patient truly understands what they
have signed can be sparse. This should be of great
concern as informed consent is, by its intent, es-
tablished to ensure that the patient is both freely
participating in a process and making an informed
decision based on a complete understanding of
the benefits, risks and alternatives.
Why electronic informed consent is key to supporting today’s patient-centric mantra in clinical trials.
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28 APPLIED CLINICAL TRIALS appliedclinicaltrialsonline.com June/July 2016
SUBJECT RECRUITMENT
How effective is the current paper process?
Although the current adoption rate for eIC has been slow both
in clinical trials and in hospitals, there have been several studies
conducted in medical centers proving the value of computer-
assisted learning and consent that date back over 20 years.
Many studies have shown that most patients are unable
to recall or do not understand most of the information that is
presented to them in the informed consent process. In 2009,
Finch et al. presented 100 patients scheduled for transurethral
prostatectomies. When the patients were interviewed three
hours after consent was obtained, less than 50% of them could
accurately recall the risks or potential complications.3 In another
study, only 18% of guardians who provided consent for surgery
in pediatric patients could recall the specifics of the procedure
two to four weeks after the surgery.4 Krupp et al. showed that
65% of patients who consented for neurosurgery were unable to
remember more than two of six major risks associated with their
surgery only two hours after informed consent was obtained.5
In 2007, an article published in the American Heart Journal re-
vealed that among 633 patients who were to undergo coronary
artery bypass grafting or percutaneous coronary interventions,
there was poor agreement between what patients expected as
symptom benefits versus what they were told by their physi-
cians. On the important outcome of mortality, there was no
correlation between what physicians and patients expected
because patients believed there would be an improvement in
survival even when physicians did not describe this as a benefit.6
Cassileth et al.7 had 200 cancer patients complete a test of
their recall within one day of signing consent forms for chemo-
therapy, radiation therapy, or surgery. Only 60% understood the
purpose and nature of the procedure, and only 55% correctly
listed even one major risk or complication. Further, a mere 40%
of the patients stated that they had read the form “carefully.”
Although most thought that consent forms were necessary, com-
prehensible, and contained worthwhile information, the legalis-
tic connotations of the forms appeared to lead to cursory reading
and inadequate recall. In general, most believed that consent
forms were primarily meant to “protect the physician’s rights.”7
Although these studies were conducted in a healthcare in-
stead of a pharmaceutical clinical trial environment, it is reason-
able to assume that the patients in each environment would be
similar. Of greater concern is that a typical informed consent for
a hospital procedure is generally one to three pages, but many
clinical trial ICFs are 20 or more pages. Naturally, this signifi-
cantly increases the problem of comprehension and retention.
In 2013, The Center for Information and Study on Clinical
Research Participation (CISCRP) conducted a Perception and
Insights Study that included 724 patients who had participated
in clinical trials. Those that participated in North America were
at least somewhat satisfied that their questions were answered
with the current process—85% of the time. However, approxi-
mately 33% of patients outside North America were dissatisfied
in regard to the answering of their questions. Importantly, as an
indicator of what is to come in the future, 28% of respondents
ages 18 to 34 were not satisfied that their questions were an-
swered. Younger generations are used to receiving a lot more
information than their elders. As they continue to age, we can
expect that the level of dissatisfaction with the current process
will grow exponentially.
The same CISCRP study also measured the impact of dis-
satisfaction with the informed consent process on patient
retention. The results of the study (see Table 1) showed that
patients who were not satisfied with or did not understand the
informed consent process were much more likely to drop out of
a trial than those that were satisfied with the process. As patient
recruitment becomes more difficult and costly, it is essential to
retain those patients that have entered a trial. There is a sub-
stantial cost when a patient is lost after passing through the
screening process, and the cost is even greater if they have also
started treatment and undergone a significant amount of test-
ing. Additionally, there is no potential benefit in regard to prov-
ing the primary endpoints needed for drug approval.
What is the impact of the patient’s native language?
The importance of language on patient understanding of in-
formed consent is often overlooked, especially if English is not
Informed Consent Process: Retention Impact
OVERALL DROPPED OUT, N=260 COMPLETED, N=1,326
It was “Somewhat/Very Difficult” to understand the ICF 19% 35% 16%
After reading the ICF, the purpose of the study was “Not Very/Not
at all Clear”*5% 14% 2%
“Not Very/Not at all Satisfied” questions were answered during
IC review*4% 12% 1%
I did not understand parts of the study after ICF review* 12% 21% 11%
*Dropped Out vs. Completed significantly different at P<0.05
Table 1. The results of a CISCRP study measuring the effects of dissatisfaction with the informed consent process on
patient retention.
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30 APPLIED CLINICAL TRIALS appliedclinicaltrialsonline.com June/July 2016
SUBJECT RECRUITMENT
the patient’s native language and he or she is in an English
speaking country. Patients who have a poor understanding of
English are less likely to receive adequate informed consent. For
example, when the charts of 74 Spanish- and Chinese-speaking
patients who underwent thoracentesis, paracentesis, or lumbar
puncture at a hospital with well-trained interpreters in Spanish
and Chinese were compared with those of 74 English speakers,
only 28% of foreign language-speaking patients had well docu-
mented informed consent, versus 53% of the English speakers.8
The value of video educational tools
Trials of video educational tools have shown greater patient
understanding. For example, a randomized controlled trial of an
informational video for women considering laparoscopic tubal
ligation showed that women who watched the video, in addi-
tion to standard consent procedures, demonstrated 56% higher
knowledge scores than women who were engaged in standard
consent procedures alone (p<0.001).8 In another example, Eng-
lish- and Spanish-speaking patients receiving intravenous con-
trast for computed tomography who viewed a video in their pre-
ferred language showed 20% higher knowledge and 10% higher
satisfaction scores than those who did not watch the video.
In 2013, Rowbotham et al.9 completed a research study with
a presentation of the same information using paper versus an
iPad device. Among patients (n = 55), iPad subjects had signifi-
cantly higher test scores than standard paper consent subjects
(mean correct = 75% vs 58%, p < .001). The total time spent
reviewing the paper consent was 13.2 minutes, significantly less
than the average of 22.7 minutes total on the three components
to be reviewed using the iPad (introductory video, interactive
quiz, consent form).
What is the electronic informed consent process?
Electronic informed consent can be obtained at clinical sites via
a computer or tablet (preferred) or can be obtained over the web
as long as the user provides sufficient information that the per-
son signing the document is actually the patient. If the informa-
tion for consent is obtained via the web and the patient still has
questions, the site clinician needs to have a procedure in place
to ensure that the patient’s questions are answered before the
form is signed.
The process should begin with a secure login by the site staff
or by the patient if consent will be obtained remotely. User
groups should be defined, by role, to determine their access to
information. The patient can then watch videos that will explain
the clinical trial process and contain the elements described
earlier that should be required of the informed consent process.
During or after the video segment, patients may be asked ques-
tions to assess their retention of the information imparted. To
reinforce the learning process, any incorrect answers a patient
may provide should be visually corrected on screen, showing
them the correct answer. Once the video and assessment ques-
Paper vs. Electronic Informed Consent
PAPER INFORMED CONSENT ELECTRONIC INFORMED CONSENT
Patient-site interaction
Patient is given a form to sign and site
personnel are responsible for ensuring that
patient understands the ICF and answers all
questions
Patient engages in an interactive process with
videos, retention questions, and dictionary
definitions. Site personnel answer questions
that are prompted by the patient within the
software application. Patient’s retention of
information is documented
Patient comprehensionLimited due to extent of documents and
medical and legal terminology
Enhanced due to video assistance in native
language and layman’s terms
Multiple languagesStudies show that many paper translations are
not up to par
Video augmentation of the process with high
quality translations
Fraud protection Complete reliance on the paper documentComplete audit trail showing when all parties
signed the document
IRB and EC reviewMultiple circulating paper copies varying by
IRB/EC and by country
Standardized process with web portal for
review
Site consistency Process varies considerably from site to site Standardized process at all sites
Storage, access, and site monitoring Cumbersome review of charts and paperAll forms and data are easily accessible via a
secure web portal
Version c ontrol and new signatures for
protocol amendments
Poorly done with paper, with a significant
number of patients not receiving updated
safety information
Strict version control with notifications to
sites and patients when a form is updated and
requires a signature
Source: Litwin
Table 2. Comparing the advantages of electronic informed consent approaches over paper across several categories.
EVENT OVERVIEW:
This webcast will discuss the implications of the recent ICH guidelines,
incorporating key considerations for trial sponsors and CROs trying
to operationalize these new requirements into their processes
and risk-based strategies. In addition to process adjustments and
optimization, this webinar will explore the crucial role technology
will play in successfully executing trials in a more transparent,
collaborative, and data-driven paradigm.
■ Explore the ICH E6 (R2) guideline and its implications for sponsors
and CROs
■ Increased investigator oversight and responsibility
■ Increased Sponsor oversight and responsibility of sites and vendors
■ Risk Based Quality Management System and Risk Based Monitoring
■ Learn how emerging technologies can enable successful
implementation of risk-based quality management and oversight
■ Hear about how other companies have successfully begun the
process of incorporating risk-based processes and approaches to
their clinical trial operations
Who Should Attend:
■ Clinical Operations teams for Sponsors and CRO’s
■ Data management
■ Clinical Operations
■ Study Managers
■ Biostats
■ CRA’s
For questions, contact Daniel Graves at [email protected]
Sponsored by
Presented by
Presenters
GARETH ADAMS
Founder
Syniad Consulting
BRION REGAN
Product Manager
ERT Insights Cloud
Moderator
LISA HENDERSON
Editorial Director
Applied Clinical Trials
Key Learning Objectives:
■ Explore the ICH E6 (R2) guideline and its
implications for sponsors and CROs
■ Learn how Risk Based Monitoring is one
component of a risk-based approach to
clinical trials management
■ Learn how emerging technologies
can enable successful implementation
of risk-based strategies for planning,
conduct, and oversight of clinical trials
ON-DEMAND WEBCAST Originally aired May 12, 2016
Register for free at www.appliedclinicaltrialsonline.com/act/goldstandard
ICH E6 (R2)Process and Technology Considerations for the New Risk Based Gold Standard
32 APPLIED CLINICAL TRIALS appliedclinicaltrialsonline.com June/July 2016
SUBJECT RECRUITMENT
tions are complete, the patient will then have access to a digital
screen copy of the ICF for review.
Tablets provide an additional opportunity to use built-in dic-
tionary functionality on the device to allow patients to look up
definitions of terms used within the ICF. Patients can note and
record any questions they have to discuss with the investigator.
The patient or site should be able to print the consent form at
any time. Upon completion of the process, a digital signature can
be obtained for the patient and/or guardian, the investigator, and
a witness. The entire process will be entered in an audit trail.
Why use electronic informed consent versus paper?
The eICF process allows for improved patient engagement and
understanding from the outset of the clinical trial process. The
interaction with the site is enhanced by using a system that
enables patients to self-educate in their native language and
prompts them to ask questions. At the same time, institutional
review board (IRB) and independent ethics committee (IEC)
review is enhanced by allowing them to review the script of the
patient video alongside the ICF via a web-based portal.
Sponsors can monitor regulatory issues by viewing a com-
plete audit trail, which will show precisely when patients viewed
the information, how long they took to review the video and the
ICF, what additional questions they had, and their degree of re-
tention of the information given. This process also allows for ad-
justments to the videos and/or ICF if a large number of patients
are unable to answer certain assessment questions correctly.
These benefits just mentioned and others are outlined in Table
2 (see page 30).
Challenges to the adoption of eIC
As has been the case with most new technology, the greatest
challenges to adoption are inertia and cost. As paper has served
the purpose of obtaining consent, and it is viewed as easy and
inexpensive, the challenge is convincing sponsors that there is
a significant enough benefit to outweigh the additional expense
and learning curve of adopting a new technology. This can be
difficult as the costs of paper processes are often not well quan-
tified. Studies with few patients and multiple languages can
result in considerable additional cost primarily due to the fees
for translation and voice-over of the videos produced. Larger
studies with fewer languages can be much more cost efficient.
Several pharmaceutical sponsors view the eIC as part of their
patient recruitment process, especially for rare diseases where a
consistent well-scripted message can lead to increased enroll-
ment as well as retention. In these cases, cost justification is
easier with the value proposition becoming part of the decision-
making process of the clinical team.
Finally, there is still concern about IRB and, particularly, EC
adoption of the educational videos and the eICF forms. There
are individual reviewers who are still not completely comfort-
able with this process but, in general, we have found most
IRBs and ECs to be very receptive, as they recognize that this
method is well controlled and that the message received by
patients is standardized.
Conclusions
Patient engagement in clinical trials should start at the begin-
ning and continue throughout. The best way to start a process
that is patient-centric is to ensure that the patient is fully aware
of what her or she is signing up for. Many studies conducted in
the healthcare and clinical trial setting have shown that we are
currently falling short when it comes to providing our patients
with the information they need to truly give informed consent.
Providing patients with video educational tools and retention
aids that explain information in layman’s terms and in their na-
tive language improves both patient recall and comprehension.
eICF has been used worldwide and is accepted by IRBs and
ECs, but the overall adoption rate has been slow. The regulatory
safeguards for documentation and re-consenting, the ease of use
for ICF approval on a local level, and the benefits to the patient
will hopefully move the ICF from being one of the last remaining
bastions of the paper process into the modern digital era.
References
1. Informed Consent Information Sheet, Guidance for IRBs, Clinical
Investigators, and Sponsors July 2014, http://www.fda.gov/downloads/
RegulatoryInformation/Guidances/UCM405006.pdf
2. Use of Electronic Informed Consent in Clinical Investigations Ques-
tions and Answers Guidance for Industry, March 2015; http://www.
fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/
guidances/ucm436811.pdf
3. Finch WJ, Rochester MA, Mills RD. A randomized trial of conventional
versus BAUS procedure-specific consent forms for transurethral resec-
tion of prostate. Ann R Coll Surg Engl. 2009;91(3):232–8.
4. Lashley M, Talley W, Lands LC, et al. Informed proxy consent: com-
munication between pediatric surgeons and surrogates about surgery.
Pediatrics. 2000;105(3 Pt 1):591–7.
5. Krupp W, Spanehl O, Laubach W, et al. Informed consent in neu-
rosurgery: patients’ recall of preoperative discussion. Acta Neurochir.
2000;142(3):233–8. discussion 8-9
6. Whittle J, Conigliaro J, Good CB, et al. Understanding of the benefits
of coronary revascularization procedures among patients who are
offered such procedures. Am Heart J. 2007;154(4):662–8
7. Cassileth BR, Zupkis RV, Sutton-Smith K, et al. Informed consent —
why are its goals imperfectly realized? N Engl J Med. 1980;302(16):896–
900.
8. Schenker Y, Wang F, Selig SJ, et al. The impact of language barriers on
documentation of informed consent at a hospital with on-site inter-
preter services. J Gen Intern Med. 2007;22 Suppl 2:294–9.
9. Rowbotham MC, Astin J, Greene K, Cummings SR (2013) Interactive
Informed Consent: Randomized Comparison with Paper Consents.
PLoS ONE 8(3): e58603. doi:10.1371/journal.pone.0058603
Jeffrey Litwin, MD, is a co-founder of Patient Genesis; email: jeffrey.litwin@
patientgenesis.com
Live webinar:Wednesday, May 4, 2016
11:00 AM EDT (8:00 AM PDT)
Learn more about
Keeping pace with immuno-oncology
research breakthroughs and
'-+�0)#0�'"#,2'Ȗ!�2'-,
Event overview The excitement surrounding immuno-oncology is being driven
by results seen in the clinic. New treatments can potentially
be made more efficacious using NGS technology that would
accelerate biomarker identification and bring down costs for
research subject screening and safety monitoring. Among
these technologies is RNA-Seq, a flexible sequencing assay
that enables multiple applications with one assay from a single
sample. In this webinar, we’ll summarize the clinical relevance
of RNA-Seq, when and how to use expression profiling
economically, some common challenges and associated
remedies.
Key learning objectives
+����"����'������)�� ����!���$�#�$#��������"�&�#�$�����"���'�
insights to keep pace with today’s rapid advance of therapeutic
breakthroughs
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direct measurement of functionally relevant molecular
processes
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immuno-oncology
For technical questions, please contact
Daniel Graves at [email protected]
Register now
www.appliedclinicaltrialsonline.com/act/ biomarker
Copyright ©2016 Q2 Solutions. All rights reserved.
Contact us
Toll free: 1 855.277.9929
Direct: +1 919.998.7000
International: +44 (0) 1506 814000
Website: www.Q2LabSolutions.com
Follow us on
Sponsored by
Presented by
Presenters:
UBM moderator:
Adrian Benjamin
Commercial Development Manager,
Oncology
Illumina
Kimberly Robasky, PhD
Associate Director, Lead Scientist,
Bioinformatics and Clinical Systems
Product Manager, Genomics, Q2 Solutions
Lisa Henderson
Editorial Director
Applied Clinical Trials
34 APPLIED CLINICAL TRIALS appliedclinicaltrialsonline.com June/July 201634 APPLIED CLINICAL TRIALS appliedclinicaltrialsonline.com
PEER
REVIEW
TRIAL MONITORING
Quality Remote Monitoring: The Tools of the Game Penelope Manasco, MD
Acritical aspect of risk-based monitoring
(RBM) is rapid access to a site’s clinical
data. In 2013, industry median values from
2009-2012 Phase II and III clinical trials (see
Figure 1 on facing page) showed that the
median time from electronic case report (eCRF)
entry to data manager query opened was 59 to 89
days. This is even more extraordinary when one
considers that the median time from subject visit
to query close (all queries including automatically
generated queries) ranged from 30 to 36 days.1
These findings emphasize that direct data en-
try, either into the electronic data capture (EDC)
or eSource systems, provides significant value in
overseeing study conduct quality. Mitchel et al.2
reported on their experience implementing direct
data entry (DDE) and RBM in a clinical trial of 18
investigative sites in the U.S. and Canada study-
ing 180 research subjects. In that trial, 92% of the
data was entered within one day of the subject
visit and 98% within eight days. Data review was
also faster with 50% of the data reviewed within 13
hours of data entry. Source data verification (SDV)
was completed at the site for approximately 20%
of the data within the EDC. There were changes on
0.8% of the pages, with the majority in three areas:
concomitant medications, medical history, and
clinical laboratory results.
The evidence above, coupled with the find-
ing that SDV was not an adequate approach to
ensure trial quality,3 illustrates the importance of
technology and process changes that should be
implemented to enhance remote trial oversight
as envisioned by the FDA,4 European Medicines
Agency (EMA),5 and International Conference on
Harmonization (ICH) guidance6 documents on
RBM and quality management. The following tech-
nology solutions can provide significant benefits
to implementing RBM and remote trial manage-
ment.
Technology solutions
EDC and eSource
Direct data entry can be accomplished though
web-based EDC solutions and tablets. It is imper-
ative that sites have adequate Internet access to
use tablets for direct data entry. Sites benefit from
eliminating transcription of documents. Moni-
tors and data managers also benefit from having
immediate access to the data. Questions that
document good clinical practice (GCP) compli-
ance can be incorporated into the EDC or eSource.
These fields (e.g., detailing timing for vital signs,
informed consent processes) enable monitors to
conduct source data review remotely. Many data
managers may not be familiar with the additional
questions the monitor will want to have docu-
mented, so cross-functional input into the EDC
is needed during design. Tablet setup and testing
ensures tablets work as needed by the site. The
initiation visit should include site training on how
to use the tablets to collect all data, including
source data.
eSource tablets are specifically designed to
collect data directly at the time of a subject visit
(DDE), rather than having the data entered onto
Outlining those technologies best able to raise the data and process quality of risk-based monitoring.
TRIAL MONITORING
paper and transcribed into an EDC system. These systems
also meet the FDA guidance and ICH GCP draft guidance
(4.9.0) requiring the principles of ALCOA (Attributable, Leg-
ible, Contemporaneous, Original, and Accurate) for all data
and records. Some focus on providing a “look and feel” like
a paper chart. eSource tablets may not be as robust in data
exporting and data query capabilities as EDC systems, which
can also be used for direct data entry. In addition, allowing
sites to enter data anywhere on the electronic chart requires
that they be reviewed frequently to assure there are not
entries that would indicate a safety or protocol compliance
issue. Understanding what queries are possible and what
queries require manual entry is important for the data and
monitoring team. Often, the clinical team will assume a cer-
tain query will be generated by the data collection system,
when that may not be the case.
“Site level” data is available from clinical trial manage-
ment systems (CTMS). However, CTMS systems don’t include
The evidence is indicative for new
processes for data review, and
different monitoring strategies
beyond on-site monitoring, such
as remote, centralized, or RBM.
Source: Manasco
Figure 1. The median time from electronic case
eCRF entry to data manager query opened was 59 to
89 days.
Data Cleaning Cycle Time Efficiency
Sub
ject
Vis
it t
o Q
uery
Clo
sed
eC
RF E
ntr
y t
o D
M Q
uery
Op
en
ed38.0
36.0
34.0
32.0
30.0
28.0
26.0
24.0
22.0
20.0
2009
Subject Visit to Query Closed
eCRF Entry to Data Manager Query Opened
2010 2011 2012
100.0
90.0
80.0
70.0
60.0
50.0
40.0
30.0
The Direct-Data-Entry Payoff
SMARTER TESTING STRATEGIES THAT OPTIMIZE CLINICAL PROTOCOL DEVELOPMENT
UNITED STATES | EUROPE | SINGAPORE | CHINA | INDIA | AUSTR ALIAwww.acmglobal lab.com
Find Out More by Visiting Us at DIA 2016 52nd Annual Meeting | Booth # 1010
36 APPLIED CLINICAL TRIALS appliedclinicaltrialsonline.com June/July 2016
TRIAL MONITORING
Remote review of informed consent
forms is not required in RBM, but the
review of critical documents for subject
safety and GCP compliance is a critical
component of quality management.
all the data needed to manage sites remotely. EDC systems
can be set up to collect key site data. Risk assessments, is-
sue management, investigational product receipt, training
records, monitoring reports (with sign off), and site delega-
tion logs can be provided from EDC. This provides greater
flexibility and delivers key data for reporting and oversight of
trial conduct.
IVR/IWR
Interactive voice response/interactive web response (IVR/
IWR) outputs can be integrated into EDC or eSource systems
using a web services interface. By integrating the data into
the EDC, and having the data come directly from the IVR/
IWR, fewer changes are needed during reconciliation because
the data are not entered separately into two different sys-
tems, yielding a faster time to database lock. It also allows
the sites to continue working in a single system rather than
having to switch systems and transcribe data—which contrib-
utes to data errors.
When IVR/IWR is integrated, it is important for the project
manager to plan time for integration testing and to assure
both systems are ready simultaneously to facilitate integra-
tion testing during user acceptance testing.
SAE reporting
When electronic systems are used for data collection (EDC
or eSource), no separate manual process is needed for faxing
information to the company for manual entry into a separate
database, which is the usual practice. A more efficient and
effective use of resources is to have the serious adverse event
(SAE) data entered into the EDC/eSource system by the site,
then transferred to the safety database, if present. All ques-
tions about the episode should be generated as queries in
the EDC system so it contains the most current and complete
SAE data.
When data are integrated throughout the clinical trial, with
the EDC containing the most current version of SAEs, there is
less time needed for SAE reconciliation, resulting in a shorter
time to database lock. In addition, there will be a common
understanding of the SAE by all team members.
ePRO, eDiaries, and eConsent
The FDA released guidance on the use of patient reported
outcomes in 2009.6 That guidance specified the need to
have data collected from subjects at protocol-specified
times. Since this cannot be documented using paper
diaries (which are subject to “parking lot syndrome” or
completion of all diaries immediately before a study visit),
there has been a significant move to electronic systems.
When ePRO data from subjects are integrated into the
EDC, it is easier for sites to evaluate data and identify any
errors with completion when the site sees the subject in
the clinic than when the data are in separate databases.
RBM requires the comprehensive review of subject data
and confirmation that investigator assessments align with
patient-reported outcomes.
eConsent/informed consent form (ICF) errors routinely
rank as one of the top five findings during site audits. The
complexity of the informed consent process (e.g., multiple
consents required for the study and sub studies, such as
genetic testing), the frequency of amendments, the number
of different languages required, and the number of organi-
zations managing the trial all increase the likelihood of in-
formed consent errors.
eConsent systems are an excellent option for large tri-
als that require the use of multiple languages because the
translations can be incorporated directly into the eCon-
sent system. This simplifies the process of informed con-
sent review, particularly when there are amendments to
the protocol. The systems that provide eConsent can also
provide educational materials to help the research subject
better understand the process. An audit trail confirms who
signed the document and when. Ideally, on the same date
the subject signs the informed consent, it is transferred to
the EDC system.
This step eliminates the risk for transcription errors. Costs
increase when the ICF requires multiple amendments. The
benefit is that there is a greater likelihood that the correct
version of the ICF has been provided for the site to use be-
cause they are loaded and delivered from a central system,
which has been through a validation process.
An alternative to using an electronic system for reviewing
ICF is to generate a certified copy of the signed ICF, upload
it into the site’s eISF, and review it remotely shortly after the
subject visit. This assures you have an executed ICF(s) for
each research subject.
Medical coding is traditionally the domain of data man-
agement. It is usually performed infrequently during the trial.
As part of the within-site and cross-site review, it is valuable
to look at the AEs by system, organ, and class (SOC) as part
of the review. Simply looking at the rate of AEs across sub-
jects within a site and across sites, may not identify impor-
tant safety issues—a key requirement of RBM.
eISF and eTMF
The electronic investigator site files (eISF) and electronic trial
master files (eTMF) are very important additions needed to
TRIAL MONITORING
fully implement RBM. Many early adopters already have an
eTMF, but companies gain great advantages to trial oversight
by also incorporating an eISF.
A key component of trial conduct and GCP is the manage-
ment and oversight of all documentation. The new ICH draft
guidance on GCP provides two key requirements that are ad-
dressed with an eISF.
t� Any copy used to replace an original must fulfill the re-
quirements of a certified copy.
t� The investigator/institution should have control of all es-
sential documents and records generated by the investiga-
tor/institution before, during, and after the trial.
An eISF replaces the site’s regulatory binder. The eISF
provides benefits as follows:
t� It eliminates the need for having duplicate documents in
both the investigator site file and the TMF. The files (eTMF
and eISF) are managed together and following the trial, all
relevant documents from the eISF (minus any documents
with personal health information [PHI]) are merged into
the eTMF for final archiving.
t� Access control assures that documents containing PHI are
seen only by the research site and monitor—not by other
users who should not have access to this information.
t� Certified copies are easily generated.
t� Sites have access to all documents from anywhere; not just
the site location.
t� No storage space required during the trial and only mini-
mal storage required after completion.
t� All documents for each site (including informed consents)
are complete and available for review.
t� Review of informed consents and other key documents oc-
cur rapidly without requiring an onsite visit.
t� Document or file audits are performed remotely in a frac-
tion of the time with significant cost savings.
Key requirements for the eISF include assuring inves-
tigative sites have access to their entire file, granular ac-
cess control to protect PHI, audit trails, version control,
electronic signatures that meet the 21 CFR Part 11 require-
ments, and customized archiving so the site’s archive con-
tains subject documents, but the sponsor organization
archive does not.
Cost does not have to be an issue with adoption. A variety
of solutions exist; some are very cost effective, allow users to
set up the file structure and workflow, and can be launched
in days. Other solutions have more customized, automated,
workflow and take much longer to implement.
The ever-increasing volume of clinical data — including laboratory data —
represents a substantial resource that can provide a foundation for the improved
understanding of disease presentation, response to therapy and health care
delivery processes. Data mining supports these goals by discovering, unraveling
and, in some cases, anticipating similarities and relationships between data
elements in large datasets.
In this webinar, we’ll discuss:
■ Next-generation data management tools and services and how they are
changing how researchers are able
to interpret intricate data and make
better informed decisions
■ How a versatile biovisualization
platform can enable effective data
mining and ease of interpretation
■ Biovisualization as a viable way to
free up in-house staff to work on
development and research rather
than data analysis
Sponsored by Presented by
Key Learning Objectives:
■ Learn how by visualizing clinical trial data in
diverse ways, clearly and simply, researchers
can better identify important trends in study
results
■ Discover how customizable figures provide
a wealth of insights, which facilitate time-
and cost-saving decisions, particularly in
areas such as medical and investigator site
monitoring
■ Understand the benefits of real-time data
analysis and interpretation
Who Should Attend
■ Pharmaceutical and biotech companies.
■ Anyone whose job responsibility includes
data analysis and interpretation with the goal
of maximizing the results of a clinical trial.
For questions, contact Daniel Graves at
ON-DEMAND WEBCAST | Originally aired May 26, 2016
Register for free at www.appliedclinicaltrialsonline.com/act/biovisualization
Presenter:Hermioni Zouridis, PhDSenior Scientist,
Scientific Operations
LabConnect
Moderator: Lisa Henderson Editorial Director, ACT
BIOVISUALIZATIONEffective Mining and Interpretation of Laboratory Results Data
38 APPLIED CLINICAL TRIALS appliedclinicaltrialsonline.com June/July 2016
TRIAL MONITORING
Data repositories/reports/data visualizations
Reporting and data visualizations are vital components in
successfully implementing RBM. Barnes et al. published an
in-depth discussion of the technology requirements for sys-
tems used to aggregate and analyze data and metrics on site
and staff performance for RBM oversight.7 In their discussion,
the complexity of managing multiple data sources and tech-
nology systems (e.g., EDC, labs, eInformed consent, IVR/IWR,
CTMS, payments, eTMF) was highlighted and the need for
systems that integrate and aggregate the data. They further
provided user requirements for reporting and visualization, a
critical component to RBM.
One additional, very important requirement for data re-
positories is needed—ad hoc reporting. While standard visu-
alizations of key risk indicators with thresholds is important,
there is a critical need to be able to develop oversight reports
for protocol-specific risks identified during the risk assess-
ment and categorization activity.
A crucial component of the monitor’s role in quality
oversight is evaluating the research subject’s appropriate-
ness for the study and safety oversight at the site level.
Data visualization tools can enable faster identification
of issues that would be difficult to see if a monitor had
to “flip” across multiple pages within the CRF and across
multiple systems.
For example, it would be important to see that the sub-
ject’s reported AE of anemia pre-dated treatment with the
study drug. This knowledge allows the monitor to query the
AE to see if the anemia worsened and to have the anemia re-
ported as medical history. The graphical patient profiles can
be built to interface with many different inputs (e.g., central
ECG reading, ePRO vs. investigator reports, etc.). It is impera-
tive that all data sources are represented in the reports, in-
cluding metadata, not just the EDC data for analysis.
Many life sciences companies have a data repository for
analysis of datasets, but the data used is often converted to
study data tabulation model (SDTM) for analysis, which is
problematic for real-time data review. SDTM conversion for
submission of data to regulatory authorities involves data
manipulation, conversion, and merging of data into subfold-
ers. Much of this converted data, including metrics that are
not included in analysis datasets, are needed for quality
oversight reporting. Therefore, new reports may need to be
generated using the real-time data sets and metrics.
For some companies with fewer trials, using a data reposi-
tory with standard RBM and medical monitoring reporting
included may provide the most expeditious solution rather
than developing their own repository and reporting system.
Development of internal data repositories and reporting
tools requires significant resources for development and
validation as well as managing the process of regular data
imports from multiple systems. In addition, it is important
to have a system that will enable ad hoc reporting to allow
further evaluations if issues are identified. Having a system
to develop and manage study-specific issue logs with input
from multiple team members is another key requirement of
technologies used for risk identification and analysis.
Conclusion
Many of the approaches that we recommend are not required
for RBM, but all of the tools discussed make the review of
critical data and processes better—which is a key component
of RBM. While eSource is not required for RBM, it is a valu-
able tool because it eliminates the need for transcription,
enables immediate review of data (which is a component rec-
ommended in the RBM guidance), and aligns with the FDA
guidance on eSource and ICH draft GCP guidance.
Remote review of informed consent forms is not required
in RBM, but the review of critical documents for subject
safety and GCP compliance is a critical component of qual-
ity management. Being able to perform that review remotely
without waiting for onsite visits aligns with the FDA’s spirit of
rapid, focused review. Our recommendation is that by imple-
menting these tools, you enhance quality oversight and focus
efforts on the areas of highest risk: protocol compliance, GCP
compliance, investigational product management, and pa-
tient safety.
References
1. Are your data cleaning cycle times out of control? Blog.mdsol.com.
http://blog.mdsol.com/are-your-data-cleaning-cycle-times-out-of-
control/
2. Mitchel JT, Cho T, Gittleman DA, Markowitz JMS, Kim YJ, Choi J,
Hamrell MR, Carrara D, Nora SD. Time to Change the Clinical Trial
Monitoring Paradigm. Applied Clinical Trials. Jan. 17, 2014
3. Sheetz N, Wilson B, Benedict J, Huffman E, Lawton A, Travers M,
Nadolny P, Young S, Given K, Florin L. Evaluating Source Data Veri-
fication as a Quality Control Measure in Clinical Trials. Therapeutic
Innovation and Regulatory Science.48: 6: 671-680. November 2014
4. Oversight of Clinical Investigations: A Risk-Based Approach to
Monitoring. U.S. Department of HHS, FDA, August 2013 OMB Con-
trol No. 0910-0733.
5. Reflection Paper on Risk-Based Quality Management in Clini-
cal Trials. European Medicines Agency. 18 November 2013
EMA/269011/2013
6. Guidance for Industry: Patient Reported Outcome Measures: Use
in Medical Product Development to Support Labeling Claims. US
Department of HHS, U.S. FDA, December 2009. http://www.fda.gov/
downloads/Drugs/Guidances/UCM193282.pdf
7. Barnes S, Katta N, Sanford N, Staigers T, Verish T, Technology Con-
siderations to Enable the Risk-Based Monitoring Methodology.
Therapeutic Innovation and Regulatory Science, 2014, Vol 48(5) 536-545.
August 2014
Penelope Manasco, MD, is CEO of MANA RBM; email: Pmanasco@
manarbm.com
Live webinar:Wednesday, April 27, 2016
11:00 AM EDT
Presenters:
UBM moderator:
Lisa Henderson
Editorial Director, Applied Clinical Trials
Sponsored by
Presented by
Learn more about
From eligibility to exploratory: planning and implementing biomarker testing for Immuno-oncology trials
Event overview To harness power of Immuno-oncology, a deep understanding
of the intricate workings of the anti-tumor immune response is
required. With mechanisms still partially veiled and hypotheses
emerging from all angles, one thing is clear — Immuno-oncology
is complex and these trials have brought new challenges to all
corners of drug development, including clinical biomarker testing.
In this webinar, scientists from Q2 Solutions will highlight some
of the particular challenges associated with the diverse clinical
biomarker requirements of Immuno-oncology trials and discuss
how our laboratories have worked with Pharma clients to bring
key research tools — anatomic pathology, flow cytometry,
and genomics — into Immuno-oncology clinical trials and the
potential development of companion diagnostics.
Key learning objectives
*����"�����%$�$������������#������"�$�����#%���##����$�"#�
associated with implementing biomarker testing in Immuno-
oncology trials
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Immuno-oncology clinical trials and the development of
companion diagnostics
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Register now
www.appliedclinicaltrialsonline.com/act/ immuno-oncology
Copyright ©2016 Q2 Solutions. All rights reserved.
Contact us
Toll free: 1 855.277.9929
Direct: +1 919.998.7000
International: +44 (0) 1506 814000
Website: www.Q2LabSolutions.com
Follow us on
Linda Robbie, Ph.D.
Senior Director, Biomarkers and Global Translational
Science Laboratory
Radha Krishnan, MD
Chief Pathologist and Senior Medical Director
Patrick Hurban, Ph.D.
Senior Director and Global Head, Genomic
Development/Esoteric Assays
Alistair J. Watt, Ph.D
Director, Translational Science Laboratory, Europe
EDITORS
FROM THE
BioTelemetry Research .......................................41
Booth 905
ICON plc ...............................................................42
Booth 617
OmniComm Systems ...........................................43
Booth 2201
Mapi Group ..................................................... 44-48
Booth 1034
DIA 2016 Annual Meeting
June 26-30, Philadelphia, PA
Welcome to our ',$�([KLELWRU�3URÀ�OH�6HFWLRQ.
This year, the DIA hosts its annual meeting in
Philadelphia, where it will focus on its three pillars:
Develop, Innovate, Advance. Traditionally, the June/
July issue of Applied Clinical Trials is distributed at the
',$��ZKHUH�UHDGHUV�QHZ�DQG�VHDVRQHG�FDQ�À�QG�KHOSIXO�
articles about the clinical trials industry. This year, our
issue focuses on eSource and Data Integration.
We’d like to thank our advertisers and sponsors
who continue to support Applied Clinical Trials.
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we encourage you to take a moment to read the
information they have provided about their company
and services. We also encourage you to visit our
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additional news, interviews, and articles about DIA
2016 at www.appliedclinicaltrialsonline.com/dia2016.
Best Regards,
Editors,
Applied Clinical Trials
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BITOR
DIA
PROFILES
June/July 2016 ADVERTISING 41
Exhibitor Profi les, 52nd DIA Annual Meeting
BioTelemetry ResearchBooth 905
Corporate Description
As a division of BioTelemetry (Nasdaq: BEAT),
BioTelemetry Research is part of the world’s
largest cardiac data network—processing
200,000 million heartbeats, monitoring 50,000
patients, supporting 30,000 devices, and
provisioning 20,000 sites every month.
Major Products/Markets Served
BioTelemetry Research is an industry leader
in clinical trials testing services, monitoring,
data, and scientific consulting. Our compre-
hensive offerings provide global clients with
world-leading technology, data management,
and consulting services, streamlining the
clinical trials process, and ensuring optimal
research performance. Providing a full range
of centralized clinical trials testing modalities
for both safety and endpoint evaluation, our
core offerings include: cardiovascular moni-
toring, advanced imaging, and a respiratory
alliance.
Major Services
Providing a full range of centralized clini-
cal trials testing modalities for both safety
and endpoint evaluation. Our core offerings
include: global cardiovascular monitoring,
advanced imaging services, and respiratory
testing alliance for clinical trials. Discover
how BioTelemetry Research has enhanced
its imaging services with the recent acquisi-
tion of VirtualScopics, a leader in clinical trial
imaging solutions.
DIA Information
Visit BioTelemetry Research at booth #905 to
learn more about:
t� Our recent acquisition of VirtualScopics,
a leader in clinical trial imaging solutions.
t� EvriBeat — Dynamic Electrocardiography,
a powerful and efficient alternative to
Thorough QT studies.
t� How our comprehensive cardiac, respira-
tory, and advanced imaging capabilities
provide global clients with world-leading
technology, data management, and
consulting services to ensure optimal
research performance.BioTelemetry Research
1 Preserve Pkwy Suite 600
Rockville, MD 20852
TELEPHONE
301-214-7628
FAX
301-214-7601
WEBSITE
www.gobio.com/research
NUMBER OF EMPLOYEES
1,200
DATE FOUNDED
1999
42 ADVERTISING June/July 2016
Exhibitor Profi les, 52nd DIA Annual Meeting
ICON plcBooth 617
Corporate Description
ICON plc is a global provider of drug
development solutions and services to the
pharmaceutical, biotechnology, and medical
device industries. The company specializes
in the strategic development, management,
and analysis of programs that support clinical
development—from compound selection to
Phase I-IV clinical studies. With headquarters
in Dublin, Ireland, ICON currently operates
from 89 locations in 37 countries and has
approximately 12,200 employees. Further
information is available at www.iconplc.com.
Major Products/Markets Served
ICON provides innovative clinical develop-
ment solutions for Pharma, Biotech, Device,
& Diagnostics. Our full-service capabilities
include:
t� Clinical Research Services
t� Commercialization & Outcomes
t� Consulting Services
t� Early Phase Services
t� Laboratory Services
t� Site & Patient Recruitment
t� Resourcing & FSP Services
DIA Information
VIPs and Spokespersons attending:
t� Ramita Tandon, Executive Vice President,
Commercialization & Outcomes, ICON
t� Mike Minor, Senior Vice President, Global
Head Operations and Strategic Planning,
Peri-Approval and Observational Research,
ICON
Session: Tuesday, June 28, 10:30 am
Outsourcing: Assessing CRO Performance
and Challenges
t� Bill Byrom, PhD, Senior Director, Product
Innovation, ICON
Session: Tuesday, June 28, 4-5:15 pm
Leveraging Smartphone Sensors and Apple
Research Kit to Measure Health Outcomes
t� Otis Johnson, Vice President, Feasibility &
Clinical Information
Session: Wednesday, June 29, 4 pm
Creating Competent Clinical Research
Professionals Through Systematic Evidence
Review
New Products and Services launching:
Meet our expanded Commercialization &
Outcomes team and learn how we are help-
ing biopharmaceutical and medical device
developers to maximize the clinical and
economic value of their products in today’s
patient-centric healthcare environment.
Cocktail Receptions and Parties:
ICON is hosting a cocktail reception at the
XIX Restaurant, Hyatt at the Bellevue, Broad
& Walnut Street, Philadelphia, Monday, June
27, 7 pm to 10 pm, via invitation only. Please
contact [email protected].
ICON plc
South County Business Park Leopardstown, Dublin 18
Ireland
TELEPHONE
+353 (1) 291-2000
FAX
+353 (1) 291-2700
WEBSITE
www.iconplc.com
NUMBER OF EMPLOYEES
12,200
DATE FOUNDED
1990
June/July 2016 ADVERTISING 43
Exhibitor Profi les, 52nd DIA Annual Meeting
OmniComm SystemsBooth 2201
Corporate Description
As the EDC specialist, OmniComm under-
stands the power that an information-driven
clinical enterprise can bring to your
clinical research organization. OmniComm
is the only company that provides a choice
of best-of-breed EDC platforms that are
purpose-built for Early Phase, Late Phase,
Phase I-IV, device trials, and Investigator Initi-
ated studies. We provide the most advanced
open and interoperable EDC platforms.
Our innovative clinical cloud makes
insight-driven data-based critical decisions
possible, bringing medical therapies to
patients faster with lower risk and the reason
why four of five top CROs and seven of the
10 largest Phase I clinics run OmniComm
EDC technologies.
Major Products/Markets Served
OmniComm Systems, Inc. provides web-
based electronic data capture (“EDC”)
software and services that streamline the
clinical research process. Our products
include TrialMaster® EDC and TrialOne®
early phase clinic automation. TrialMaster
and TrialOne are designed to allow clinical
trial sponsors and investigative sites to eas-
ily and securely collect, validate, transmit,
and analyze clinical study data.
Our applications are 21 CFR Part 11
compliant solutions and are designed to
offer clinical trial sponsors the ability to con-
duct clinical trials under multiple platforms,
with significant flexibility, ease-of-use, and
with complete control over collected data.
Major Services
OmniComm Transformation Services
provides product-independent consulting
services across all aspects of clinical re-
search. Our experts have worked around the
globe with pharmaceutical and life sciences
organizations, delivering software, process,
and documentation solutions of the highest
quality. We have extensive knowledge in the
following areas that drive the medical and life
sciences professions:
t� Industry standards (e.g., CDISC, WHO, HL7)
t� Regulatory standards (e.g., ICH, 21 CFR
Part 11, HIPAA, etc.)
t� New paradigms, including Quality-by-De-
sign, Risk-Based Monitoring, and Patient-
Centered research
OmniComm
2101 W. Commercial Blvd Suite 3500
Fort Lauderdale, FL 33309
TELEPHONE
954-473-1254
WEBSITE
www.omnicomm.com
NUMBER OF EMPLOYEES
121
DATE FOUNDED
1997
44 ADVERTISING June/July 2016
Exhibitor Profi les, 52nd DIA Annual Meeting
Mapi: Language ServicesBooth 1034
Corporate Description
Mapi Language Services is the worldwide
leader in medical translation and Linguistic
Validation of COAs, with first-hand knowledge
of local languages and cultures, regula-
tions, and healthcare practices. We work in
close collaboration with developers, assur-
ing conceptual equivalence and international
harmonization of all language versions. Our
Language Services experience includes more
than 170 languages, as well as translation of
patient facing research materials on over 300
research programs a year for the last 20 years.
Mapi is the industry’s most trusted com-
pany, with more Clinical Outcomes research-
ers entrusting Mapi with exclusive translation
support than all other providers combined.
Mapi Language Services has the proven ca-
pability of providing a quality service through
a fully traceable process and the industry’s
most qualified linguists, assuring that our
customers’ medical translations are done to
global standards. We’re the first Language
Services provider to achieve ISO 17100 Cer-
tification on all Linguistic Validation & Medical
Translations processes globally.
Linguistic Validation
MAPI understands that if measures are to be
used across cultures, the items must not only
be translated well linguistically, but must also
be adapted culturally to maintain the content
validity of the instrument at a conceptual level
across different cultures.
This process aiming at the production of
appropriate translated language versions is
linguistic validation, a process that we were
the first to develop in a coherent manner. Our
initial work inspired the ISPOR guidelines.
Mapi is a pioneer in Linguistic Validation,
with over 40,000 translated versions of more
than 2500 COAs!
Only Mapi can deliver this level of
expertise:
t� Over 1,000 PRO linguistic experts in over
100 countries
t� More than 2,500 PRO instruments trans-
lated into over 170 languages
t� Editor of the Linguistic Validation Manual,
the reference in cross-cultural adaptation
t� The most trusted Linguistic Validation
expert by questionnaire authors, managing
exclusivity on over 250 instruments
Medical Translation
Our medical translation services draw
on our extensive linguistic experience to
customize solutions that meet your every
objective.
t� Over 300 international studies conducted
every year across over 100 countries
t� Significant breadth of coverage for all
therapeutic areas
By working in close collaboration with
the developers of the original instruments,
we can ensure conceptual equivalence and
international harmonization of all language
versions.
Mapi Group
1010 Stony Hill Rd Suite 315
Yardley, PA 19067
TELEPHONE
859-223-4334
WEBSITE
mapigroup.com
NUMBER OF EMPLOYEES
800
DATE FOUNDED
1974
June/July 2016 ADVERTISING 45
Exhibitor Profi les, 52nd DIA Annual Meeting
Mapi: Real World EvidenceBooth 1034
Corporate Description
Mapi is the leading Patient-Centered
Research company serving academia, life
science researchers, and the pharmaceutical
industry. Since 1974, Mapi has helped ensure
that the voice of the patient is heard through-
out the lifecycle of drug development and
commercialization. Mapi can help conduct
your post-approval studies on a global scale.
Mapi is the industry’s only company
exclusively dedicated to Patient-Centered
Real-World research. With over 40 years of
Peri and Post regulatory approval research
expertise, only Mapi can combine all the dis-
ciplines critical to the generation and synthe-
sis of Real World Evidence needed to support
regulatory requirements and support HTA &
Payer expectations.
Understanding Patient Groups
Our innovative methods provide actionable
insights into the unique needs and priorities
of specific patient groups. Our team includes
clinical practitioners, health educators, and
experts in human performance and instruc-
tional design, each bringing a unique per-
spective to the challenge of understanding the
patient experience and creating interventions
that improve engagement and adherence to
programs and treatments.
Patient-Centered Outcomes
Mapi takes a phased approach to Patient-
Centered Outcomes research. Our dedicated
full-time professionals devote themselves to
overcoming challenges throughout the life-
cycle of the drug and the disease (PhI – Post
Market), offering patient-centered services for
the entire development process.
t� Full insight from Strategy to Execution
t� All Stakeholders
t� Entire Lifecycle: Early Development to Real-
World Evidence
t� Cross-Cultural: Conceptual, Linguistic,
Metric Equivalence
Direct-To-Patient Contact
Our Direct-To-Patient Contact solutions are
built on Mapi’s four decades of global Clinical
Outcomes expertise, two decades of Real
World Evidence experience, and 25 years
of clinical cross-cultural language services
expertise.
These combined services establish Mapi
as the clear industry leader in supporting
patients or their caregivers, and offer proven
results for accelerated recruitment, increased
patient engagement, improved patient-report-
ed data quality, and minimized study burden
and attrition.
Patient Insights and Engagement
Mapi is focused on gaining an in-depth
understanding of the patient and the many
factors that influence their health behavior
and decision-making process. Our collabora-
tion with patients and caregivers means we
can help our clients better inform and engage
with their distinct populations. We bring the
patient’s perspective into all aspects and
phases of the development process, as well
as post commercialization.
Mapi Group
1010 Stony Hill Rd Suite 315
Yardley, PA 19067
TELEPHONE
859-223-4334
WEBSITE
mapigroup.com
NUMBER OF EMPLOYEES
800
DATE FOUNDED
1974
46 ADVERTISING June/July 2016
Exhibitor Profi les, 52nd DIA Annual Meeting
Mapi: Real World Strategy & AnalyticsBooth 1034
Corporate Description
Mapi is a full-service provider with expertise
in developing strategy and implementing
programs supporting Pharmaceutical,
Biotechnology, and Medical device
companies to:
t� Meet post-approval regulatory
requirements
t� Engage patients, prescribers, and
advocacy groups
t� Establish value for payers and
endorsement bodies
t� Communicate data to influence key
opinion leaders
Health Economic Outcomes Research (HEOR)
Our HEOR scientists and researchers have
established themselves at the forefront
of patient-centered outcomes, evidence
synthesis, and health economic evaluations,
gaining respect from academic, industry, and
regulatory players for the last four decades.
Strategic Market Access
Mapi helps you identify, demonstrate, and
confirm your product-value proposition from
discovery throughout the entire lifecycle.
Mapi supports your research and
development teams, as well as your
market access organization, determining
which key product and market attributes
will be needed to ensure the launch of a
differentiated product that will meet the
payers’ approval.
Epidemiology
Mapi prides itself on having the most
experienced professionals guide and support
our clients throughout the development of
your research program in epidemiology and
phamaco-epidemiology.
We help our clients determine what type
of information is needed and the most
efficient and effective ways to collect disease
occurrence, burden of illness, and healthcare
resource use to support our clients’ health-
economic modeling and health technology
reimbursement activities.
We collaborate with our clients to
strategically design peri- and post-approval
programs that satisfy FDA, EMA, and other
regulatory agency requirements for post-
marketing surveillance while simultaneously
supporting important clinical and commercial
interests of the company.
We will:
t� Review the overall regulatory submission
strategy and aid in defining an integrated
approach that provides regulatory liaison
support and interaction
t� Develop an integrated pharmacovigilance
and post-marketing requirement study
t� Strategically design post-marketing studies
that addresses product safety and other
company interests
t� Design and implement “bridging studies”
prior to product approval
t� Provide clinical, epidemiology, biostatistics,
and analytical support
Mapi Group
1010 Stony Hill Rd Suite 315
Yardley, PA 19067
TELEPHONE
859-223-4334
WEBSITE
mapigroup.com
NUMBER OF EMPLOYEES
800
DATE FOUNDED
1974
June/July 2016 ADVERTISING 47
Exhibitor Profi les, 52nd DIA Annual Meeting
Mapi Research Trust Booth 1034
Corporate Description
Mapi Research Trust is a non-profit organization
that promotes the use of Clinical Outcomes As-
sessments (COAs) in studies and encourages
exchanges in the Patient-Centered Outcomes
field between academics, pharmaceutical com-
panies, and international organizations.
Through our unique databases—PRO-
INSIGHT, PROQOLID, and PROLabels,
developed and constantly updated by
Mapi Research Trust research profession-
als—we not only exchange the latest health
outcomes information, but also create vital
links among those at every level of Patient-
Centered Outcomes studies. We maintain the
world’s largest library devoted exclusively to
Clinical Outcomes Assessments and make
its wealth of information available to those
who need it most.
t� Patient-Reported Outcomes (PROs)
t� Clinician-Reported Outcomes (ClinROs)
t� Observer-Reported Outcomes (ObsROs)
t� Performance Outcomes (PerfOs)
t� Regulatory Labeling Claims
t� Regulatory guidance on Clinical Outcome
Assessments
Whether you need practical information
or more advanced searches on COAs, the
Mapi Research Trust team is ready to make a
difference.
Author Collaboration
The Author Collaboration Unit provides authors
with the Trust’s unique expertise in copyright
protection, management, and promotion of
questionnaires and derivative works. Over 250
questionnaires are officially distributed by the
Trust on behalf of their authors. This ensures
copyright protection, maintains questionnaire
integrity, and enhances their visibility.
Questionnaire Copyright Services
The Mapi Research Trust team, supported by
an international network of external Intellectual
Property specialists, offers unique expertise in
the field of questionnaire copyright. We have
over two decades of experience in the man-
agement of questionnaires and their deriva-
tives, as well as related requests on copyrights
from authors and users.
We advise authors on both question-
naire pre-registration and registration, and
we conduct the online processes on their
behalf. Mapi Research Trust also provides
recommendations for the first publications
of the questionnaire to ensure that authors
keep the copyright on the questionnaires in
all circumstances.
Questionnaire Distribution Services
Academic researchers, academic research
groups, pharmaceutical companies, and other
authors have long turned to the Mapi Research
Trust for assistance with the management of
their questionnaires and derivative works.
We protect the authors’ copyrights and
ensure that an author’s requirements are
respected in terms of methodology of lin-
guistic and electronic versions validation by
establishing legal documents (collaboration
agreement, user agreement, etc.) that govern
the distribution process.
Mapi Group
1010 Stony Hill Rd Suite 315
Yardley, PA 19067
TELEPHONE
859-223-4334
WEBSITE
mapigroup.com
NUMBER OF EMPLOYEES
800
DATE FOUNDED
1974
48 ADVERTISING June/July 2016
Exhibitor Profi les, 52nd DIA Annual Meeting
Mapi: Strategic Regulatory ServicesBooth 1034
Corporate Description
Mapi’s full-service regulatory team works
with regulatory agencies in more than 60
countries. We support companies of all sizes
to manage both specific regulatory projects
and entire outsourced Regulatory Affairs and
Pharmacovigilance departments.
Let Mapi be Your Integrated Solution for
Regulatory Services
t�&YQFSUT�XIP�DMBSJGZ�BOE�OFHPUJBUF�UIF�SFHVMB-
tory path for pharmaceuticals and biologics
t�4QFDJBMJTUT�XIP�QSFQBSF�BOE�ýMF�TVCNJTTJPOT�
effectively
t�1SPCMFN�TPMWJOH�UIBU�BDIJFWFT�BOE�NBJO-
tains compliance at any stage of the product
lifecycle
US Regulatory Services
t�4USBUFHJD�SFHVMBUPSZ�DPOTVMUJOH
t� IND prep & Pre-IND to Pre-NDA
t� NDA, BLA & ANDA preparations and filing,
including CMC
t� Post-approval support
t� Agency liaison & negotiation
Canadian Regulatory Services
t�$MJOJDBM�USJBM�BQQMJDBUJPOT�$5"T�BOE�$BOB-
dian agent services
t�/FX�ESVH�BOE�CJPMPHJD�TVCNJTTJPOT�
/%4 �4/%4 �"/%4
t�%*/�BQQMJDBUJPOT�BOE�OPUJýBCMF�DIBOHFT
EU Regulatory Services
t� $MJOJDBM�USJBM�BQQMJDBUJPOT�$5"T �$5"�TVC-
stantial amendments
t� MAAs- CP, DCP, MRP, national applications
including renewals and variations in accor-
EBODF�XJUI�$5%�BOE�F$5%
t� Orphan medicinal product submissions
t� Post Marketing Maintenance
Quality Systems
t�4FU�VQ�BOE�DPNQMFNFOU�FYJTUJOH�2VBMJUZ�
4ZTUFNT
t� GMP Auditing and training for Drug Product
and API
t�($1�"VEJUJOH�PG�5.' �TJUFT �BOE��������������
dispensaries
t� Assist with Agency inspections, close-outs,
and responses
Medical Device Regulatory Services
t�1SF�NBSLFU�OPUJýDBUJPO�����L���1SF�
market approval — PMA
t� *OWFTUJHBUJPOBM�%FWJDF�&YFNQUJPO��*%&�GPS�
DMJOJDBM�TUVEJFT
t� $PNCJOBUJPO�QSPEVDU�ESVH�EFWJDF�TVCNJT-
sions
CMC Regulatory Services
t� Drug development plans to meet regulatory,
technical, and quality requirements at each
phase of the product lifecycle
t� Regulatory document content, consistency,
and gap remediation
t� Global or regionally-targeted dossiers
t� Compliance with country-specific regulatory
requirements
Pharmacovigilance and Risk Management
.BQJ�QSPWJEFT�B�þFYJCMF �HMPCBM������������������
pharmacovigilance service supporting
regulatory compliance and management of
patient safety issues. We offer a full suite of
pre- and post-marketing solutions through-
out the product lifecycle, from phase I-III
clinical trials to observational studies and all
aspects of the post-marketing environment.
0VS�FYQFSJFODFE�QIBSNBDPWJHJMBODF�QSPGFT-
TJPOBMT �MPDBUFE�JO�&VSPQF�BOE�/PSUI�"NFSJDB �
are accustomed to working across the global
regulatory environment.
Mapi Group
1010 Stony Hill Rd Suite 315
Yardley, PA 19067
TELEPHONE
859-223-4334
WEBSITE
mapigroup.com
NUMBER OF EMPLOYEES
800
DATE FOUNDED
1974
Search for the company name you see in each of the ads in this section for FREE INFORMATION!
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EQUIPMENT RENTAL
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with the DYNAMICS of
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Contact
Wayne K Blow
Sales Director
Applied Clinical Trials & Pharmaceutical Executive
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For more information, call Wright’s Media at 877.652.5295 or visit our
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Leverage branded content from Applied Clinical Trials to create a more
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50 APPLIED CLINICAL TRIALS appliedclinicaltrialsonline.com June/July 2016
A CLOSING THOUGHT
To see more A Closing Thought articles, visit
appliedclinicaltrialsonline.com
While the pharmaceutical industry has
always used and analyzed data from mul-
tiple sources, such as central laboratories,
ECG and diagnostic devices, MRIs, etc., the
“mobile apps” that are currently flooding the
market, if used in the clinical trial space, will
provide challenges to data quality as we deal
with the large volumes of data collected and
with the different operating systems and
hardware. Therefore, the current eSource
transformation is fraught with challenges
that must be overcome, including regulatory
compliance, cooperation, and acceptance by
the patients and clinical research sites, who
are the customers of our trials, and strict
approaches to validation of these electronic
tools. We must also separate the “toys from
the tools.” Just having a “neat app” won’t fly in
the regulated ecosystem we all must live in.
Fortunately, the regulators have beat us
to it. There are now FDA and EMA guidance
on eSource, eInformed consent, mobile de-
vices, and risk-based monitoring, with more
to come. In terms of data integration, there
are also active programs to integrate the
electronic medical record (EMR) with clinical
trial electronic data capture (EDC) systems,
and companies are starting to include the
use of FDA-approved mobile devices such as
glucometers, blood pressure monitors, and
ECG devices as part of their clinical trials.
It’s critical to involve regulators when the
use of these devices impacts the manage-
ment of subject safety and the evaluation of
primary and secondary endpoints. Also, as
potentially non-regulated devices are used
or regulated devices are used “off-label,” we
must be ever-vigilant on the software valida-
tion process, the impact of app performance
when used with various operating systems
and devices, as well as the impact of system
upgrades on the validated state of software.
As we collect continuous data, such as
ECG readings, number of steps taken during
wake time, or number of awakenings when
participating in a nocturia trial, the software
should have validated algorithms to summa-
rize the outcomes rather than requiring the
pharma or device company to do the analysis
from scratch. This will be one of the main
advantages of using FDA-cleared devices
presenting with validated software. For ex-
ample, the Vicor PD2i Analyzer is a software
algorithm for recording heart rate variability
(HRV) using the point correlation dimension
algorithm (PD2i). The intended use of the tool
is to display and analyze electrocardiographic
information and to measure HRV.
The following quality measures were ap-
plied to the development of the system and
given to FDA as part of the approval process:
t� Level of concern and hazard analysis
t� User requirements
t� Software requirement specification
t� Software design specification
t� IQ/OQ/PQ
t� Software release
This is an exciting time in drug and device
development, where the goal is to improve
processes and reduce the time to get safe
and effective drugs and devices to the pa-
tients who need them. However, we must
make sure that as we “do more with less”
(the words first coined by visionary Buckmin-
ster Fuller), we do not add more complexity
to an already complex system.
FDA defines electronic source (eSource) data as data initially recorded
in electronic format. Now that direct data entry (DDE) at the time of
the clinic visit, mobile devices, telemedicine, and remote monitor-
ing of clinical trials are all realities, and are no longer “pie-in-the-sky”
concepts, it is time for a transformational change in our processes as we
plan, design, and execute trials, as well as how we will collect, analyze,
and use the potentially huge amount of data coming off mobile devices.
Regulatory Considerations are Key in eSource Data Integration
We must separate the
“toys from the tools.”
Just having a “neat
app” won’t fly in the
regulated ecosystem
we all must live in.
Jules Mitchel, MBA, PhDPresident, Target Health Inc.
www.spectraclinicalresearch.com
© 2016 Fresenius Medical Care Holdings, Inc. All rights reserved. Spectra Clinical Research is a division of Spectra Laboratories, Inc.
When you partner with Spectra Clinical Research, you get more
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An experienced team that listens? That would be unique.
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