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Vice President, Global Head of Pre-Clinical and Clinical QAUCB Pharma S.A.Chemin du Foriest, Belgium

Maarten Beekman, MD

Respiratory Medical Director, International RegionAstraZeneca Zoetermeer, Netherlands

Timothy Callahan, PhD

Chief Scientific OfficerBiomedical SystemsSaint Louis, MO

Anthony J. Costello

Chief Executive OfficerMytrus, Inc.San Francisco, CA

Domenico Criscuolo, MD, PhD, FFPM

Chief Executive OfficerGenovaxColleretto Giacosa, Italy

Srini Dagalur, PhD

Specialist Leader, Life Sciences Technology StrategyDeloitteParsippany, NJ

Edward Stewart Geary, MD

Chief Medical Officer & Vice PresidentEisai Co., Ltd.Tokyo, Japan

Ashok K. Ghone, PhD

VP, Global ServicesMakroCareNewark, NJ

Rahlyn Gossen

FounderRebar Interactive New Orleans, LA

Uwe Gudat, MD

Head of Safety, BiosimilarsMerck SeronoGeneva, Switzerland

Ira M. Katz

ConsultantInsigniamNarberth, PA

Wayne Kubick

Chief Technology Officer Health Level Seven InternationalChicago, IL

Darshan Kulkarni, PharmD, Esq

Principal AttorneyThe Kulkarni Law FirmPhiladelphia, PA

Michael R. Hamrell, PhD, RAC

PresidentMORIAH ConsultantsHuntington Beach, CA

Erica J. Heath, CIP, MBA

PresidentEthical and Independent Review Services, LLCSan Anselmo, CA

Patricia E. Koziol, PhD

PresidentPEK Associates, Inc.Holmdel, NJ

Jeffrey S. Litwin, MD

Chief Scientific and Strategic ConsultantERTPhiladelphia, PA

VIcky Parikh, MD, MPH

Executive DirectorMid-Atlantic Medical Research CentersHollywood, MD

Timothy Pratt, PhD, MBA

Senior Principal Medical Research ManagerNAMSAMinneapolis, MN

Stephen Senn, PhD

Head of Competence Center for Methodology and StatisticsCRP-SanteStrassen, Luxembourg

Johanna Schenk, MD, FFPM

Managing Director and Chief Operating OfficerPPH plus GmbH & Co. KGFrankfurt am Main, Germany

Philippa Marshall,

MB ChB, BSc, FFPM, FICR

1st Vice President, Global Therapeutic Head, General MedicinePPDLaren, The Netherlands

Thomas Sudhop, MD

Director and ProfessorFederal Institute for Drugsand Medical DevicesBonn, Germany

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

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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.

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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

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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.

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new studies. But lately, we've noticed that more and more researchers are

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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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your program, your investigators, your patients.

�� U.S. +1 910 338 4760

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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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To see more Clinical Trial Insights articles, visit


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:

[email protected]

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


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


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


Figure 2. Respondents attitudes toward various

device equivalence requirements (A) and other mea-

sures in the BYOD setting (B).

Device Equivalence Views

A

B


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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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.


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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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

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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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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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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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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


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

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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



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

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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

[email protected]

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


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

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associated with implementing biomarker testing in Immuno-

oncology trials

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Immuno-oncology clinical trials and the development of

companion diagnostics

For technical questions, please contact

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Register now

www.appliedclinicaltrialsonline.com/act/ immuno-oncology

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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,


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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

EMAIL

[email protected]

WEBSITE

www.gobio.com/research

NUMBER OF EMPLOYEES

1,200

DATE FOUNDED

1999

42 ADVERTISING June/July 2016


ICON plcBooth 617


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.


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

EMAIL

[email protected]

WEBSITE

www.iconplc.com

NUMBER OF EMPLOYEES

12,200

DATE FOUNDED

1990



OmniComm SystemsBooth 2201


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.


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

EMAIL

[email protected]

WEBSITE

www.omnicomm.com

NUMBER OF EMPLOYEES

121

DATE FOUNDED

1997



Mapi: Language ServicesBooth 1034


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

EMAIL

[email protected]

WEBSITE

mapigroup.com

NUMBER OF EMPLOYEES

800

DATE FOUNDED

1974



Mapi: Real World EvidenceBooth 1034


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


Yardley, PA 19067

TELEPHONE

859-223-4334

EMAIL

[email protected]

WEBSITE

mapigroup.com

NUMBER OF EMPLOYEES

800

DATE FOUNDED

1974



Mapi: Real World Strategy & AnalyticsBooth 1034


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


Yardley, PA 19067

TELEPHONE

859-223-4334

EMAIL

[email protected]

WEBSITE

mapigroup.com

NUMBER OF EMPLOYEES

800

DATE FOUNDED

1974



Mapi Research Trust Booth 1034


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


Yardley, PA 19067

TELEPHONE

859-223-4334

EMAIL

[email protected]

WEBSITE

mapigroup.com

NUMBER OF EMPLOYEES

800

DATE FOUNDED

1974



Mapi: Strategic Regulatory ServicesBooth 1034


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


Yardley, PA 19067

TELEPHONE

859-223-4334

EMAIL

[email protected]

WEBSITE

mapigroup.com

NUMBER OF EMPLOYEES

800

DATE FOUNDED

1974

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A CLOSING THOUGHT

To see more A Closing Thought articles, visit


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

than just a central laboratory with state-of-the-art facilities

and the capacity to support thousands of tests daily. You get

a dedicated team of project managers, research scientists

and service specialists who are ready, willing and able to align

with your processes and deadlines, so you get the personalized

service—and reliable outcomes—your unique trial deserves.

An experienced team that listens? That would be unique.

“Inspiring Hope” IdeathonTogether, let’s raise greater awareness of clinical trials

September 27–28, 2016

District Hall

Innovation District

Boston, MA

INC Research and CISCRP – collaborators

in raising awareness of clinical research – are

excited to co-host a ground-breaking event with

one aim: to develop innovative and effective new

ways to increase the awareness of clinical trials

amongst patients, healthcare professionals and

the general public.

Join us, be a competitor and be part of innovation

by visiting inspiring-hope-ideathon.com

your peer-reviewed guide to global clinical trials...

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