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Volume 24 Number 10/11 October/November 2015

ALSO IN THIS ISSUE:

■ Informed Consent Changes in Works

■ Europe’s Embrace of New Science

■ Alzheimer’s and Patient Safety

TRIAL DESIGN

GENE TRANSFER: KEY CHALLENGES

THERAPY MASKING ASSESSMENT

SAFETY REPORTING

DEATH WAIVERS FALL SHORT

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appliedclinicaltrialsonline.com APPLIED CLINICAL TRIALS 3October/November 2015

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4 APPLIED CLINICAL TRIALS appliedclinicaltrialsonline.com October/November 2015

CONTENTS

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 24, NUMBER 10/11

COMMENTARY

VIEW FROM BRUSSELS

12 Europe Ups Focus On Syncing Science with Trials

Peter O’Donnell

CLINICAL TRIAL INSIGHTS

16 eClinical Adoption On Rise, But What About Performance?

Kenneth A. Getz

A CLOSING THOUGHT

46 Designing Alzheimer’s Trials With Patient Safety at Forefront

John Hubbard, PhD

CLINICAL TRIALS COMMUNITY

6 APPLIED CLINICAL TRIALS ONLINE

8 NEWS

MARKETPLACE

45 CLASSIFIED

TRIAL DESIGN

24 Evaluating the Effects of Therapy Masking

Barbara A. Ricker, Katherine M.

Seymour, Alexander R. Arslan,

April Slee, Ruth McBride,

Jeffrey L. Probstfield, MD

Using a specific trial, the importance

of assessing the success of

therapy masking is examined.

SAFETY REPORTING

34 Death Waivers an Incomplete Picture of Drug Safety

Margarita Mare, MD, Lisa

Carlson, Maxim Belotserkovskiy,

MD, Nickolai Usachev, MD

Examining the practical significance

of reporting patient deaths due

to main disease progression.

SUBJECT ENGAGEMENT

38 Satisfaction of Healthy Subjects in Phase I Trials

Sherilyn Adcock, PhD, John Sramek,

Kurt Hauptmann, Hong Ding,

Keith Fern, Neal R. Cutler, MD

Survey applies rigorous analysis to

provide a rare formal look at volunteer

satisfaction in early setting.

COVER STORY

18 Human Gene Transfer Studies:

What Clinicians Should Know

Chris Jenkins, PhD, Lindsay McNair, MD

Exploring the key challenges unique to gene transfer clinical trials in

such areas as oversight, safety monitoring, and informed consent. REB

IM

AG

ES

/G

ETTY IM

AG

ES

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WEB CONTENTS

appliedclinicaltrialsonline.comwww.linkedin.com/groups/Applied-Clinical-Trials-2949042/about

twitter.com/clin_trials

Clinical trial recruitment and enrollment has

presented its challenges in many ways. For

Quintiles’ Phase I Unit in Kansas, clinical trial

recruitment was a matter of process and strat-

egy that it improved with innovation and mo-

bile health (mHealth) technology applications.

Quintiles’ Phase I Unit exhibits a similar op-

erational infrastructure as a study site; it initi-

ates many studies, seeks out patients, and en-

rolls them in clinical trials. Moreover, this unit

has established a digital community of engaged

patients that receive information about new

studies, generating between 12,000 to 17,000

visitors per month. In addition, the unit regu-

larly executes advertising campaigns, including

radio ads, emails, and social media campaigns

to landing pages that generate several thou-

sand monthly interest referrals with a nearly

75% pass-through rate.

Due to the high amount of simultaneously

running studies, the Phase I Unit was faced with

competing clinical trials, which affected equiva-

lent patient recruitment rates across all studies;

“the studies started cannibalizing each other,”

said Benjamin Sieve, Clinical Trial Marketing

Coordinator at Quintiles. The Phase I Unit ob-

served that some studies were enrolling very

rapidly, leading to waitlisted patients, whereas

other studies were enrolling at lower rates. Fac-

tors associated with study design which af-

fected enrollment included study duration, time

commitment, and patient stipend amounts.

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WebcastsFrom our OnDemand Webcasts archive,

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Register for free at: http://bit.ly/1L35p3x

eLearning

Has Your Company

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NEWS

After years of delay, there’s renewed

action to update the “Common Rule,”

which protects human subjects in-

volved in research regulated or funded

by the federal government. Although

clinical trials to support market ap-

proval of new drugs and medical prod-

ucts are governed by FDA regulations,

changes in the Common Rule promise

to shape policies for conducting clinical

trials throughout the research commu-

nity. Once the Common Rule revisions

are finalized, FDA will examine where it

needs to revise its regulatory provisions

to accommodate certain changes, ex-

plains an FDA official. In the meantime,

says David Forster, chief compliance of-

ficer for the WIRB-Copernicus Group,

proposed changes in institutional review

board (IRB) practices and in formats and

procedures for obtaining informed con-

sent will begin to affect all sponsors and

investigators.

The 500-page proposed rule (pub-

lished in the Federal Register, vol. 80,

no. 173, Sept. 8, 2015) aims to stream-

line requirements that add to the cost

and complexity of clinical research. This

latest revision from the Department of

Health and Human Services (HHS) and

15 other federal agencies builds on an

initial proposal issued in 2011, which

drew thousands of comments and then

dropped out of sight.

The new proposal continues to pro-

mote the use of a single IRB for multi-

site studies and offers significant

changes in informed consent processes,

with an eye to making consent forms

shorter, more understandable and more

transparent. Sponsors would have to

publicly post consent forms as a way to

encourage development of more concise

formats that provide relevant details for

participants and avoid burying important

information in “unduly long documents.”

More controversial is the requirement

to obtain individual consent for the fu-

ture use of biospecimens such as blood

samples. This change reflects the emer-

gence of genomic technologies able to

identify the donor of even de-identified

specimens. To head off strong objec-

tions, the policy will not be retroactive

and offers a three-year implementation

period.

A parallel goal of the reformers is to

reduce oversight of low-risk studies. The

Common Rule would not apply to ac-

tivities such as oral histories and pub-

lic health surveillance, and continuing

review by IRBs would be dropped for

certain projects involving no more than

minimal risk. There’s much to comment

on, and those are due by December 7.

Meanwhile, FDA will continue to up-

date its good clinical practice (GCP)

policies, as seen in a draft guidance is-

sued in July 2014 that outlines extensive

changes to informed consent procedures

and policies for clinical investigators,

sponsors, and IRBs; the stated aim was

to revise FDA rules to conform more with

the changes to the Common Rule pro-

posed in 2011, and another draft now

may be warranted. FDA also published

draft guidance in March 2015 explaining

how sponsors and investigators should

use electronic systems to obtain in-

formed consent.

Changes in informed consent policies

also will come from the Clinical Trials

Transformation Initiative (CTTI) at Duke

University as part of its broader program

for modernizing FDA clinical research

policies. And the 21st Century Cures

legislation before Congress supports

the use of central IRBs for government-

funded multi-site studies.

Review reforms?

Efforts to increase transparency in FDA

research policies also may be shaped

by recent analyses of the application

review process and how effectively FDA

determines the need for more or less

data for market approvals. One way to

help patients understand the risks and

benefits of new medicines, according

to some FDA analysts, is to make pub-

lic FDA Complete Response Letters

(CRLs). Only sponsors—and not FDA—

can disclose such “commercially confi-

dential” information on why the agency

turns down an application, but many

company statements regarding CRLs

differ from what is actually in a letter,

according to Peter Lurie, FDA associate

commissioner for public health strategy

and analysis, and his staff. Their review

of the content of some 61 CRLs issued

by the Center for Drug Evaluation and

Research (CDER) from August 2008 to

June 2013 (published June 2015 in the

British Medical Journal) finds that many

press releases from sponsors about

those CRLs contain incomplete or er-

roneous statements.

On the too-fast-or-too-slow review

issue, a surprising critique in Forbes

magazine (August 20, 2015) charges

FDA with approving just about every

application sent in, providing a “rubber

stamp” approach and not being suf-

ficiently selective. Taking a different

tack, two MIT economists urge FDA

to be more flexible in approving more

risky therapies for serious illnesses,

but more cautious with treatments for

common conditions (see “Is the FDA Too

Conservative or Too Aggressive?” by Vahid

Montazerhodjat and Andrew Lo, Aug.

19, 2015, http://papers.ssrn.com/sol3/

papers.cfm?abstract_id=2641547 ). The

rise of breakthrough drugs and expe-

dited review programs largely address

such concerns, as well as questions

raised by other analysts as to why some

CDER review divisions approve applica-

tions faster than others.

— Jill Wechsler

Changes Ahead for Informed Consent, IRBs, Transparency

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NEWS

G L O B A L R E P O R T

Closer collaboration between aca-

demia and industry in the design and

execution of clinical trials is vital to

produce the best results, delegates were

told at the European Society of Cardiol-

ogy (ESC) annual meeting, held in Lon-

don last month.

Industry-funded trials have many ex-

cellent features and have convincingly

demonstrated the benefit of many medi-

cines, but challenges to the external and

internal validity of pure industry trials

must be addressed more effectively, ac-

cording to Marc S. Sabatine, MD, Chair-

man of the Thrombolysis in Myocardial

Infarction (TIMI) Study Group and a Pro-

fessor of Medicine at Harvard Medical

School, Boston. Government and profes-

sional society funding can fill important

gaps in this area, he said during a spe-

cial ESC lecture on pressures and con-

flicts in industry-sponsored trials.

Problems and delays tend not to oc-

cur in Phase III trials because they are

extremely well-resourced, Sabatine ex-

plained. In general, a careful central re-

view of endpoints and safety takes place,

case report forms are comprehensive, and

there is a large sample size, number of

events, and statistical power. Therefore,

usually these trials are completed rapidly.

“Acceptance of a new drug depends

on clear and compelling evidence of

helping patients,” says Sabatine, add-

ing that pharmaceutical companies are

very good at reading Phase II trial data

because their future survival depends on

selecting the right compounds to take

through to Phase III studies. “There is

intense scrutiny of every piece of data,

which is picked over and checked.”

When it comes to the questions being

asked in a trial, a practical challenge is

to retain a focus on commercial value,

particularly when the end of a com-

pound’s patent life approaches. Trials

organizers must think about indications

early on, later turning to government

and academic society funding, Sabatine

recommends. Furthermore, some Phase

IV studies offer nominal assurance in a

specific disease or patient subgroup, but

are not well-powered, in which case the

solution is to be more discerning about

how to use such trial data.

In the control arm of a study, two

challenges are dealing with the sub-

optimal comparator and the need to

avoid head-to-head comparisons against

roughly similarly active controls. Pos-

sible solutions are to partner with aca-

demic clinical trialists and to see gov-

ernment and academic society funding.

Often, there is a pressure for rapid

selection of dose, leading to reliance on

imperfect surrogates. Sabatine’s solu-

tion is for greater investment of time and

resources in Phase II trials in order to op-

timize the likelihood of positive results.

Also, to avoid multiple doses in Phase III

studies, guidance from academic trialists

and support from regulators for analyses

of trials testing multiple doses can help,

he says.

To achieve composite outcomes, in-

clusion of “softer” components is an

appealing option, but the answer is to

focus on harder outcomes, Sabatine

contends. When amalgamating direc-

tionally opposite components into a sin-

gle composite, it is advisable to present

data on efficacy and safety separately

and then analyze the benefits and risks.

To keep patients on a study drug and

guarantee follow-up, thereby maximizing

trial quality, sponsors should make sure

those individuals directly interacting

with and guiding sites understand and

appreciate the importance of metrics for

trial integrity, Sabatine pointed out.

Heart of the matter

Session moderator Kim Fox, Professor

of Clinical Cardiology and Head of the

National Heart and Lung Institute at

Imperial College London, says the major

problem for trial organizers in cardiology

is that the outcome in cases of stable

coronary disease is so good now that it

becomes impossible to test a drug for

mortality because so many patients are

required and it is necessary to add softer

composite endpoints like admission for

stable angina and revascularization.

“In some senses, we are a victim of our

own success for getting the event rates

down,” Sabatine noted. “We need to ac-

cept that we will use these composites,

but then we need to look at them very

carefully.”

An overall goal should be to conduct

trials that give a definitive answer for

all-cause mortality, but provided there

is no hazard for non-cardiovascular (CV)

mortality; Sabatine does not insist that a

particular trial shows a reduction for all-

cause mortality.

“As long as it’s neutral for non-CV mor-

tality, I then like to see a reduction in

CV mortality,” he says. “If there’s only a

reduction in MI (myocardial infarction)

and stroke and the trial doesn’t impact

CV mortality, I’m still OK with that. I’m a

cardiologist, and I want to decrease the

number of patients having heart attacks

and strokes.”

— Philip Ward

Top Investigator Lays out Strategy for Avoiding Conflicts

Marc S. Sabatine


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NEWS

To see more View From Brussels articles, visit

appliedclinicaltrialsonline.com

What has been obvious to strate-

gists—and to most readers of

this publication—for a long time

is now becoming evident to a

wider population in Europe: the classic

methods for evaluating new medicines

are being overtaken by science. In other

words, new thinking is needed on clini-

cal trials.

So the autumn is seeing a wave of

European initiatives to explore just how

things ought to change.

In late September, the subject is high

on the agenda of the European Society

for Medical Oncology (ESMO)-European

CanCer Organization (ECCO) Congress

in Vienna, and one of the first into the

fray is the European Alliance for Per-

sonalized Medicine (EAPM), one of the

most vocal advocates of change. EAPM

is holding an event under the banner of

“modernizing clinical trials for the ben-

efit of Europe’s patients,” with the aim

of promoting consensus on the policy

initiatives that the oncology community

should focus on for the next two years.

Mark Lawler of Queen’s University

Belfast and Anastassia Negrouk from

the European Organization for Research

and Treatment of Cancer (EORTC) will

be among those calling for new thinking

across the range of trials, biobanks, and

data sharing. The group has already been

energetic in promoting understanding

among members of the European Parlia-

ment and other legislators of how one-

time informed consent be handled to

ensure that the patient understands the

benefits and risks of conducting future

research based on archived samples, or

how access to clinical trials can be han-

dled to prioritize the evaluation of tech-

nologies that have the highest potential

for clinical utility and avoid exhausting

valuable samples unnecessarily. It has

also been working on exploring stan-

dards that could ensure multiple clinical

trials addressing the same questions are

comparable, both from a clinical and

analytical perspective.

Among the suggestions the group is

now canvassing are the idea of setting

the efficacy bars much higher than at

present at the start of trials, and the

development of a well-defined biomarker

strategy embedded in the clinical trial

process, with regulatory review and im-

plementation based on best interna-

tional practices.

Then in early October, the annual

gathering of Europe’s great and good

at Gastein, a village in the Austrian

mountains, will pick up the reflections,

with a seminar on how patients will be

impacted by adaptive pathways and

breakthrough designations. “While the

long-awaited promise of personalized

medicine is finally arriving, the regula-

tory structures required for their evalu-

ation and reimbursement are still based

around the blockbuster models of the

last century,” proclaims the blurb for the

meeting. And senior figures including

Carole Longson from the National In-

stitute for Health and Care Excellence

(NICE), Gordon McVie of the European

Institute of Oncology, and Barbara Ker-

stiens of the European Commission’s

public health research department will

lead the discussion.

In late October, the next meeting

of the European Commission’s expert

group on safe and timely access to med-

icines for patients—another bizarrely

concocted European Union (EU) name

to permit the equally bizarre acronym

of STAMP (safe and timely access to

medicines for patients)—will resume

its reflections on real-world data and

registries, and pursue its exploration of

national schemes for early links between

marketing authorization applicants and

authorities to reinforce dialogue and

regulatory support for new medicines

addressing major public health needs. It

will also review possible modifications

of conditional marketing authorization

procedures in Europe that are now un-

der consideration.

All the while, the European Medicines

Agency’s (EMA) own pilot project on

adaptive pathways is humming along

quietly, sifting through the proposals

submitted by drugmakers as possible

test cases as the mechanisms are stud-

ied. So far, one of the lessons to emerge

is that companies need to be better

prepared to get involved with authori-

ties, but just when the pilot phase will

be completed and evaluated remains

clouded in uncertainty.

Further toward the end of the year,

the EU is expected to agree on broad

principles on personalized medicine

that will have significant implications for

clinical trials. Luxembourg, the country

currently holding the rotating presidency

Europe: At Last, the Hunt is On for Trials That Fit Science

Several initiatives are focused on integrating biomarkers and personalized medicine techniques into studies

Peter O’Donnell

is a freelance journalist who

specializes in European

health affairs and is based

in Brussels, Belgium.

V I E W F R O M B R U S S E L S



NEWS

V I E W F R O M B R U S S E L S

of the EU council of ministers, has been

working with diplomats and officials over

recent weeks to draft a plan, which it

says will be “patient-centered” but will

take account of the need for adaptations

in evidence-gathering and evaluation.

Meanwhile, another informal EU

group of individuals from national au-

thorities, academia, and industry have

circulated a paper of their own on per-

sonalized medicine, which gives a flavor

of how the debate in Europe is proceed-

ing. Entitled “Ten actions to stimulate

patient access to personalized medi-

cine in Europe,” this extends across the

entire range of adaptations it says are

needed in what it calls “a fast-moving

field.” It says “this new approach to

medicine will foster more collaborative

and interdisciplinary working methods

amongst health professionals, induce

the use of big data, and imply a change

for the regulatory framework,” and calls

for “disruptive change to the traditional

way of working and thinking.”

Not surprisingly, this study de-

votes much of its attention to trials. “A

key challenge for companies investing

in innovative personalized medicine is

to develop compelling evidence about

the added value of the personalized

approach in a timely and efficient way.

However, the current clinical develop-

ment paradigm and the traditional rather

rigid requirements for trial designs are

not adapted to the specific development

challenges,” it says. There will be “an in-

creased need to endorse and accept flex-

ible trial designs that are adapted to the

type of the diagnostic-therapy relation-

ship and allow the identification of opti-

mal combinations,” it adds.

In addition, “the collection of a stan-

dardized baseline biomarker data and

associated treatment, and treatment out-

comes in large national or supranational

databases will be essential to support

the future development and clinical use

of personalized medicine.” Databases

of this sort “would help the real-life po-

sitioning of treatments providing out-

comes in specific patient subgroups.”

Adaptive pathways “need to become

more established and formalized,” and

“it should finally be acknowledged” that

comprehensive evidence about benefit

and risk “is only going to be clear once

diagnostic tools and medicines are on

the market, based on real-life data. Evi-

dence generation is a continuum.” Inevi-

tably, “the lack of solid and complete evi-

dence at the time of market authorization

will require agreement on the application

of principles of risk management.”

To make all this possible, the study

insists, the full introduction of electronic

patient records containing all health-

related data of European citizens is

essential, not just for development of

innovations but to observe and guide

the appropriate use of innovative treat-

ments. But it complains that current

efforts to establish registries are still

insufficient, and “greater governance

is needed to speed up this process to-

wards full capacity health informatics

systems.”

Then in December, the EMA and

industry association Emerging Bio-

pharmaceutical Entreprises is holding

a conference on how to get emerging

medicines from laboratory to patient,

with a particular focus on how regulators

should respond to the challenges posed

by innovative medicines, and how regu-

lators and developers can work together

early in the development process.

Whether this process can move for-

ward fast enough and with sufficient

coherence to keep up with the pace of

change in product development is an-

other question. But at last, there is a

sense that pioneers are no longer voices

crying in the wilderness, but are shifting

wider perceptions that their messages

are now increasingly being integrated

into mainstream thinking.

At last, there is a sense

that R&D pioneers are

no longer voices crying in

the wilderness, but are

shifting wider perceptions

that their messages

are now increasingly

being integrated into

mainstream thinking.



NEWS

D A T A A N A LY S I S

C L I N I C A L S U R V E I L L A N C E

F ew topics occasion the lamentations of

clinical trial professionals more than

the topic of patient inclusion/exclusion

criteria in clinical protocols. ClinicalTrials.

gov represents an important public data

source to establish baseline numbers of

inclusion/exclusion criteria. A review of

these publicly available data shows that

there is a small increase in the number of

commercially funded Phase III inclusion/

exclusion criteria per trial, but nowhere

as dramatic as is sometimes portrayed in

industry press and industry conferences.

Every year, there is a statistically sig-

nificant 0.41 increase in inclusion/exclu-

sion criteria totals in commercially funded

Phase III studies. Although the increase is

not large, the mere size of the database

itself helps to make even mild changes

seem statistically significant. Two Med-

DRA therapeutic areas, renal and urinary

disorders as well as gastrointestinal disor-

ders, differ statistically significantly from

the overall trend, evidencing slight de-

clines in the total number of criteria.

Ñ Harold E. Glass, PhD

I nnovative surveillance tools and tech-

nologies have transformed the field of

drug safety into a more proactive, dy-

namic analytical process. As the field con-

tinues to grow, drug safety leaders, regula-

tory authorities, and healthcare providers

rely on active surveillance systems to ex-

pand knowledge of the medical products

we use and regulate. For example, the

FDA has mandatory surveillance systems

(AERs, VAERs, MAUDE, and MedWatch)

dedicated to furthering the science of

drug safety. Recently, new pilot programs,

such as the FDA Sentinel Project, use fed-

erally-held data sources to monitor public

health and safety of medicines.

Today, pharmacovigilance activities

are also being employed much earlier

by industry with risk/benefit analysis oc-

curing throughout a product’s develop-

ment. Safety research professionals have

increasing expertise in drug safety com-

pared to 20 years ago. This may be due

to the growth of subspecialties of surveil-

lance and risk evaluation of medicines,

including pharmacovigilance (PVG), risk

management (RM), risk evaluation and

mitigation strategies (REMS), and signal

detection or safety signal (SD).

Today, opportunities extend beyond

basic pharmacovigilance operation activi-

ties such as case processing and medical

coding. Since earlier safety planning has

become best practice and is more proac-

tive, company discussions often include

development of required pharmacovigi-

lance and risk management plans, inno-

vative safety systems activities in data

migration and data mining (i.e., database

express set-up and recoding), and a grow-

ing interest in better understanding sig-

nal detection strategies. Increased safety

measures have been taken by regulators

and industry researchers to ensure that

the benefits outweigh the risks in mar-

keted products, which, in turn, has led to

the development of new areas associated

with the REM-related risk management

activities.

MORE ONLINE: To read about these

new areas, as well as the key components

that make up strong sponsor and CRO

safety teams, view the full article here:

http://bit.ly/1LwA7kv.

Ñ Dr. Magalie Emile-Backer is a Drug Safety

and Pharmacovigilance Specialist at Technical

Resources International, Inc.

Inclusion/Exclusion Criteria Show Minimal Rise

Drug Safety Subspecialties Grow

Source: Department of Health Policy and Public Policy, University of the Sciences, Philadelphia,

PA.

Average Number of Inclusion/Exclusion Criteria per Study by Year


EVENT OVERVIEW:

Tremendous innovation in drug and device development is driven by small

and mid-sized research organizations. These organizations, however, face

greater resource and budget constraints than larger companies – present-

ing unique challenges across clinical development from processes and

training, to the adoption and use of key clinical trial technologies.

During this webcast, we will hear from three organizations – world-re-

nowned academic research organization and NCI consortium member

Dana-Farber / Harvard Cancer Center, leading biotech Ophthotech, and

innovative CRO Seaview Research. Each will present their challenges and

valuable lessons learned of how to leverage eClinical solutions to optimize

clinical trials while delivering high-quality data.

Who Should Attend:

• Small and mid-sized

biopharmaceutical and medical

device companies

• Small and mid-sized AROs and

CROs

• Regulatory agencies and health

authorities

• C-Suite

• Heads and VP/Director/Manager

level of:

o R&D

o clinical development

o clinical operations

o clinical data management

o IT

o safety/pharmacovigilance

o medical afairs

o informatics

o project management

o regulatory afairs

o R&D Finance

o Outsourcing/Procurement

ON-DEMAND WEBCASTOriginally aired October 14, 2015

Register for free at www.appliedclinicaltrialsonline.com/act/industry

Presenters will provide real-world, practical insight into:

· Key criteria to consider when conducting eClinical technology and

vendor evaluation and selection at smaller organizations, including

EDC, CDM, CTMS, and IRT

• Using eClinical technologies and standards to shorten trial timelines

with fewer resources, while still maintaining high data quality

• Important considerations around technology adoption and

implementation at small and mid-sized organizations, from both the

sponsor and site perspective

· How to get the most out of eClinical solutions and the capabilities

ofered by vendors and service providers

Marina H. Nillni, PMP

EDC Program Manager

Dana Farber / Harvard Cancer Center

Jefrey Nau

Vice President,

Clinical and Medical A7airs

Ophthotech

Richard Harris, BSE, MSME

IT Manager

Seaview Research

James Streeter

Global Vice President,

Life Sciences Product Strategy

Oracle Health Sciences

Sponsored by

Presented by

Presenters:

Moderator:

Lisa Henderson, Editorial Director, ACT

For questions contact Sara Barschdorf

at [email protected]

Industry Perspectives: Overcoming Clinical Trial Challenges at Small and Mid-Sized Research Organizations




To see more Clinical Trial Insights articles, visit


One can’t help but marvel at the

number of clinical trial technology

solutions providers exhibiting at

major conferences like the Drug

Information Association (DIA) annual

meeting or the Disruptive Innovations

conference. The advent of new and

potentially lower-cost technologies

improved access to capital, and better

access to scientific and operating data

has fueled a proliferation of vendors and

solutions categories. These categories

include mature solutions where

substantial vendor consolidation has

occurred, as well as nascent solutions that

have attracted a vast collective of players.

To name but a few of the solutions

categories: document exchange portals;

electronic data capture (EDC); electronic

case report forms (eCRFs); electronic

patient-reported outcomes (ePRO);

ePRO/electronic clinical outcomes

assessments (eCOA); electronic trial

master files (eTMFs); site-oriented

project management technologies;

randomizat ion and t r ia l supply

management /interactive response

technologies (RTSM/IRT); structured

content management (SCM); and

regulatory information management

(RIM). Taken all together, according to

a recent analyst report, the clinical trial

technology sector will generate total

global sales of $5 billion by 2018, nearly a

14% five-year annual growth rate.

Despite the expanding depth

and breadth of eClinical technology

solutions during the past two decades,

the drug development enterprise

continues to experience long cycle

times, more complex protocols, and

high levels of inefficiency. The average

clinical phase duration is 6.8 years, a

15% increase over levels observed 10

years ago. Only 11.3% of drugs that enter

clinical testing will be approved in the

U.S. and Europe, half the success rate

observed 15 years ago. In addition, the

total capitalized cost to develop a single

drug now exceeds $2.5 billion—nearly

a 9% annual increase over 2003 levels

when adjusted for inflation.

Given rising cost and high levels of risk

and inefficiency, pressure on sponsors

and contract research organizations

(CROs) to adopt technology solutions

that promise to streamline processes

and accelerate management decision-

making have intensified. Regulatory

agency support of technology solutions

adoption to improve efficiency has

also increased. But there have been

few reports published in the last

decade that monitor and inform

industry professionals on the usage

and adoption of eClinical technology

solutions. It seems that as the breadth

and depth of the arsenal of technology

solutions has expanded, our ability

to monitor usage and impact has

diminished.

In mid-2014, the Tufts Center for

the Study of Drug Development (Tufts

CSDD) collaborated with the Clinical

Data Interchange Standards Consortium

(CDISC) and 10 biopharmaceutical

companies, CROs, and eClinical

technology vendors to develop an online

survey to gather updated benchmark

data on technology solution usage.

This working group of participating

companies had planned to gather

study performance data to evaluate

the impact of various solutions. That

ambitious plan, however, was quickly

aborted—a very telling sign about the

ways that technology solutions are used

and managed within organizations. More

about that later.

Updated usage benchmarks

More than 550 companies completed the

online survey in late 2014. Of that total,

290 sponsor companies and 146 CROs

responded, representing a broad mix

of large global, mid-sized, and smaller

companies. Overall, the rate of adoption

of nearly all technology solutions was

higher among sponsor companies than

CROs, with only two exceptions (see

Figure 1 on facing page).

The top five most used technology

solutions are EDC, CTMS, RTSM/IRT,

and ePRO/eCOA. More than 90% of

sponsors and 87% of CROs report that

they are currently using EDC; two-thirds

of sponsors and nearly 60% of CROs

report regularly using CTMS. Usage

varied by study phase with Phase III

studies receiving the highest usage rates

of these four solutions categories.

Four out of 10 sponsors and CROs

report that they are now routinely using

eTMF and safety case management

systems. As expected, a relatively small

percentage of sponsors and CROs report

using newer solutions regularly, such as

RIM, patient portals, and SCM.

The cost of implementing technology

solut ions remains the pr ima r y

barrier to adoption. A similar result

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]

New Look at the Arsenal of Technology Solutions

Survey provides new benchmarks on e-solutions adoption, but actual impact data remains elusive




was shown in a 2007 survey of EDC

adoption. A strong majority, 80% of

sponsor companies and 70% of CROs,

cited the investment required as the

top constraint. Approximately half

of sponsors and CROs cited having

insufficient time to evaluate new

systems and the challenge of having

to maintain old and new systems

simultaneously as major barriers to

adoption. Nearly 60% of sponsors and

CROs noted that, in many cases, their

current processes and systems were

performing adequately and there was

limited incentive or a reasonable value

proposition to adopt something new.

The companies responding to our

survey showed mixed experience and

perceptions regarding the integration

of eClinical systems. Nearly one in four

(37%) sponsor and CRO companies

reported that they have already

integrated some of their systems or

are currently working on integrating

systems. About one-third (29%) of

companies were uncertain about

what integration steps had been

implemented or were underway. Nearly

one-third of sponsors (31%) and four

out of 10 (37%) CROs report having

integrated both front-end and back-end

systems, whereas one-in-five (21%) have

purchased prebuilt integrated systems.

Looking over a short term time

horizon, sponsors and CROs report

concerns about accommodating a

number of new technology developments.

Two areas in particular were the most

cited: 88% of companies said that they

are looking to accommodate patients’

own devices (e.g., smart phones and

other mobile devices) in clinical trials.

And 80% of respondents noted that

they are anticipating and evaluating the

use of validated wearable devices and

the collection of real-time patient data.

A small number of companies also

acknowledged the growing importance of

management data to support predictive

analytics.

Benchmarks, but not impact

The results of this important study

provide useful new benchmarks on

technology solutions adoption. Sponsor

and CRO companies are currently using

EDC, CTMS, RTSM/IRT, and ePRO/eCOA

extensively and actively. These findings

are not surprising given that EDC and

CTMS are relatively mature systems

categories, and they have become widely

viewed as common solutions. Use of

RTSM/IRT within clinical supply and

logistics functions is also relatively high

and speaks to the growing need for more

sophisticated controls as trials have

become increasingly dispersed. Use

of ePRO tools is also relatively high for

registration and post-marketing studies.

Use of investigator and patient portals,

however, are only beginning to resonate.

Technology solutions integration

appears to be occurring on a more

limited basis than expected. Many factors

are likely constraining integration efforts,

including high costs, implementation and

compatibility challenges, and insufficient

use of data standards.

The difficulty in gathering data

characterizing the impact of technology

solutions on performance, efficiency,

and drug development economics

is disappointing. Our working group

struggled on so many levels to derive

a methodology that would cleanly and

reasonably measure impact. The group

concluded that there is too much noise

from disparate practices to be mitigated.

And most participating companies can

neither access nor collect a sufficient

amount of performance data to make this

exercise feasible.

The real-world practice of technology

solutions usage within and between

companies makes it par ticularly

challenging to gather performance and

management metrics. Company use

of technology solutions is typically

inconsistent as organizations juggle the

use of legacy, new, and pilot solutions

simultaneously. Clinical teams and

contract service providers also play a role

in dictating the technology solutions that

will be used on a given study.

There is no doubt that next year, and

in the years thereafter, we will continue

to see a proliferation of technology

solutions targeting specific areas within

the drug development continuum of

activity. In addition to monitoring and

updating adoption trends, hopefully, we

will ultimately find ways to reasonably and

credibly quantify return on technology

solution investment. Source: TCSDD-CDISC online survey of 290 sponsor and 146 CRO companies; 2014.

91%87%

69%

68%

64%

50% 52%

39%

47%

36%

44%41%

33% 32%

50%

45%

28% 25%23%

18%13%14% 13%

15%12%

10%

Sponsors CROs

CTMS

RTSM/IRT

ePRO/eCOA

Safety Case Management

eTMF

Sponsor Porta

l

Investigator (S

ite Porta

l)

Patient R

ecruitm

ent Tools

RIM Syste

m

Patient E

ngagement Tools

Patient P

ortal

SCMEDC

Current Use of eClinical Trial Technology Solutions



TRIAL DESIGN

18 APPLIED CLINICAL TRIALS appliedclinicaltrialsonline.com

PEER

REVIEW

Human Gene Transfer Studies:

What Clinicians Should KnowChris Jenkins, PhD, Lindsay McNair, MD

Human gene transfer (HGT) is defined as the

transfer of genetic material (DNA or RNA)

into a person. This experimental technique

is being studied to see whether it could treat

certain health problems by “compensating

for defective genes, prompting the body to make a

potentially therapeutic substance, or triggering the

immune system to fight disease.”1 There are a num-

ber of different techniques for introducing the re-

combinant or synthetic DNA into the body, including

both ex-vivo (outside the body) and in-vivo (inside the

body) integration into the human genome (see Fig-

ure 1 on page 20). HGT research is sometimes called

“gene therapy” research, although many researchers

and ethicists prefer not to use the term “therapy” to

refer to products which are still investigational. HGT

research is now being tested in a wide number of

therapeutic indications (see Figure 2 on page 21).

The first clinical trial of an HGT product was initi-

ated in 1989, and the number of new trials started

to grow quickly over the next 10 years (see Figure 3

on page 22). The field of gene transfer research was

set back in 1999, after the death of 18-year-old Jesse

Gelsinger in a trial at the University of Pennsylvania.

Gelsinger suffered from ornithine transcarbamylase

deficiency, an X-linked genetic disease of the liver.

The symptoms include an inability to metabolize

ammonia, which is a byproduct of protein break-

down. The disease is usually fatal at birth. But Gel-

singer had not inherited the disease; in his case, it

was apparently the result of a spontaneous genetic

mutation. Some of his cells were normal, enabling

him to survive on medication and a restricted diet.

On September 13, 1999, Gelsinger was injected with

an adenoviral vector carrying a corrected gene as

part of a clinical trial to assess the safety of the gene

transfer product. He died four days later, apparently

having suffered a massive immune response trig-

gered by the use of the viral vector used to transport

the gene into his cells, leading to multiple organ

failure and brain death. A number of concerns were

subsequently raised about this clinical trial, regard-

ing the adequacy of the consent process, his full

awareness of the potential risks, and the conflict of

interests of the investigator who had created and

patented the gene transfer product. The resulting

concerns about the field of gene transfer research

slowed growth in the number of studies initiated

(Figure 3) and, consequently, slowed progress in this

area of research for several years.

Between 1989 and the beginning of 2015, approxi-

mately 2,000 trials have begun. About 195 companies

have gene transfer products in clinical development

at this time,2 and many of them are working with con-

tract research organizations (CROs) on the design and

conduct of studies in these clinical programs.

How is human gene transfer research

different from small molecule drug

development?

In many ways, the design and conduct of clinical tri-

als of HGT products are similar to those evaluating

small molecule drugs or non-HGT biologic products.

But there are some important differences to consider

in the planning of HGT clinical development pro-

grams and individual studies.

Exploring the key challenges unique to gene transfer clinical trials.


TECHNOLOGY IS ONLY

AS SMART AS THE

THINKING BEHIND IT.

An innovative approach. One that infuses clinical

research expertise from across our organization

into the designs of our Informatics solutions.

And an eClinical platform, Perceptive MyTrials,®

that brings them together in powerful new ways.

So you can do more with your data—at every step.

Find out why all top 15 biopharmaceutical

companies use our solutions. Watch our video

at proof.PAREXEL.com/informatics

© 2015 PAREXEL International Corp. All rights reserved.



TRIAL DESIGN

Regulatory oversight

In the U.S., many HGT products have been developed with sup-

port from the National Institutes of Health (NIH). This support

may have been to an academic institution at which the product

was first created or researched, or in some cases provided di-

rectly to the biopharma sponsor. The provision of this funding

provides a mechanism for NIH oversight of this HGT research.

Even if the funding period has ended, the NIH Office of Biotech-

nology Activities maintains authority over the development of

the product. Once one dollar of NIH funding is attached to the

product (which may include the technology platform on which

the product was based), the NIH oversight attaches as well.

Knowing exactly when the NIH oversight applies can be tricky.

If the funding was given to the biopharma sponsor, the NIH over-

sight applies to all the clinical sites in the study run by that spon-

sor. If there is NIH funding for recombinant DNA research at an

institution that is one of the clinical sites, NIH oversight applies

to all recombinant DNA research done at that institution even if

the research is using a different product or the funding is given to

a different investigator at the institution. NIH oversight may also

apply to clinical study sites in countries outside the U.S., unless

that country has equivalent policies and protections for the use of

recombinant DNA products. Therefore, NIH oversight may apply

to all, some, or none of the clinical sites in any multi-center clini-

cal study, and expert advice may be necessary to be certain of the

appropriate regulatory obligations.

The specific requirements of the NIH oversight are provided

in the NIH Guidelines for Research Involving Recombinant or

Synthetic Nucleic Acid Molecules3 (commonly referred to as the

“NIH Guidelines”). The NIH Guidelines is a dynamic document

that is periodically updated with the science and understanding

of recombinant and synthetic nucleic acid molecule research. In

1990, a new section was added to the NIH Guidelines, Appendix

M, which describes points to consider in the design and submis-

sion of HGT trials, including the standards and procedures to

which investigators must adhere.

The NIH Guidelines also describe the role of the NIH Re-

combinant Advisory Committee (RAC). The RAC makes recom-

mendations on research involving the use of recombinant DNA

and on developments in recombinant DNA technology. Gene

transfer trials using recombinant DNA fall under NIH oversight

and require registration and potential convened review through

the RAC. The RAC’s role is to conduct risk assessment reviews

of the protocols for HGT products, if it considers a specific risk

assessment is necessary. The RAC applies the NIH Guidelines

standards for investigators and institutions to ensure the safe

handling and containment of gene therapies. As more viral

vector delivery systems are becoming standard and the risks

are better understood, the RAC frequently declines to review

research using these more common systems and only convenes

to review novel systems.

Involvement of IBC

In addition to providing risk classification information for spe-

cific biologic compounds, the NIH Guidelines outline require-

ments for institutional oversight of gene transfer research and

for the constitution and conduct of institutional biosafety com-

mittees (IBCs). While the role of an institutional review board

(IRB) in human subject research is to protect the rights and

welfare of the study participant, the IBC’s role is to protect

those around the study participant; the research team, the

participant’s family and contacts, and the public. Although the

IRB regulations allow the use of a “central” IRB (an independent

IRB, not based at the research institution), the IBC must be a

local committee; that is, committee members must be at or

near the institution at which the research will be conducted,

although the administration and management of the IBC can

be “centralized.” The IBC reviews not only the protocol, but also

the clinical site’s physical qualifications, including the policies

and procedures for the safe and appropriate storage, handling,

and administration of the gene transfer product, based on the

product’s biosafety risk level. If a clinical site has not conducted

any HGT research before, and does not conduct non-clinical

research with recombinant DNA products, this may mean that

an IBC needs to be created to review the protocol at the clinical

site to maintain compliance with the NIH Guidelines. Like IRB

approval, IBC approval must be obtained before any clinical trial

of HGT research can be initiated, and approval must be main-

tained through periodic review during the study.

The institution’s IBC has oversight of the practices and op-

erating procedures governing the lifecycle of the product at the

dosing institution. The IBC will review the standard operating

procedures for these processes. These include receipt of the

product, storage of the product on site in appropriately labeled

Source: Kaji E, Leiden J. Gene and Stem Cell Therapies. JAMA.

2001;285(5):545-550

Figure 1. In-vivo and ex-vivo techniques of human

gene transfer.

Therapeutic Gene

Biopsy

Liver

Implantation

Gene Delivery Catheter

In Vitro Expansion

GrowthFactors

Genetically Altered Cells

Gene Therapy Vector

Therapeutic Gene

Donor Cells

Ex Vivo

Gene Transduction

In Vivo

Gene Transduction

Gene Therapy Vector

Plasmid

Adenovirus

Retrovirus

Adeno-associated

Lentivirus

Virus

DNA Integration



TRIAL DESIGN

biohazard freezers and liquid nitrogen containers, and trans-

port from storage to the dosing preparation areas. The IBC will

review the physical manipulations involved in product prepara-

tion and determine whether personal protective equipment for

research staff (e.g., masks, eye shields), or engineering controls

such as preparing injections inside a biosafety cabinet, are

indicated. The IBC will also review the product administration

process (e.g., injection, infusion, etc.).

This oversight is in addition to the FDA regulations for the

development of biologic products. FDA has also created a num-

ber of guidances and FAQs related to the development of HGT

products.4 The European Medicines Agency (EMA) has drafted

guidance for the development of HGT products as well.5

Site selection and preparation

One of the most challenging areas for sponsors and CROs is

how to evaluate a site for potential participation in an HGT

trial. Most sponsors and CROs are unaware of the role that

NIH has with regards to HGT trials in the U.S., along with the

standards and guidelines for initiating gene transfer trials. Many

institutions also have local standards which are beyond the NIH

Guidelines which they consider to be “best practice.”6,7

The NIH Guidelines and the requirements of the Centers for

Disease Control (CDC)8 require the IBC to assess a clinical site

to a biosafety level which is based on the risk assessment of the

biological agent (and is different from the adverse event profile

of the investigational product). No standard definitions of bio-

safety levels have been generated for clinical settings, so IBCs

default to applying the biosafety level definitions developed for

Source: The Journal of Gene Medicine, 2015, John Wiley & Sons Ltd.

Figure 2. Indications addressed by gene therapy

clinical trials.

Cancer diseases 64.2% (n=1376)

Monogenic diseases 9.2% (n=196)

Infectious diseases 8% (n=172)

Cardiovascular diseases 7.8% (n=168)

Neurological diseases 1.8% (n=39)

Ocular diseases 1.5% (n=33)

Infammatory diseases 0.7% (n=14)Other diseases 1.9% (n=41)

Gene marking 2.3% (n=50)

Healthy volunteers 2.6% (n=52)

Gene Therapy Focus

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TRIAL DESIGN

laboratory work. For most gene transfer products, the IBC will

require the clinical site to conform to Biosafety Level 2 require-

ments. These include requirements such as having eyewash sta-

tions available in case of splashing or eye exposure, bare floors

(no carpet) that can be cleaned in case of spills, and enclosed

spaces (as opposed to an open floor plan) that can be closed

off for decontamination in the event of an accidental product

release (broken or dropped vial, etc.).

The process of evaluating sites for participation in a HGT study

has to look not only at the usual requirements for any clinical

trial (experience, resources, potential subject population, basic

facilities) but at their ability to meet or to become prepared to

meet the additional standards required by the biosafety level as-

sessment, additional safety controls, and IBC review process. If

the site has never participated in an HGT study before, they may

need to develop and document new procedures, and to train all

their staff who will be involved in the study.

Endpoint selection

While basic guidelines for the selection of efficacy assess-

ments in specific therapeutic areas should be followed, the

timing of efficacy assessments may need to be modified in

studies of HGT products. In many diseases, the treatment goal

for an HGT product is not management of symptoms or delay

of the progression of disease but, particularly in the case of

genetic diseases, life-long continuation and function of the

newly-added genetic sequence. Therefore, assessment of the

efficacy endpoint should be evaluation with an appropriate du-

ration of follow-up, which may even persist into post-marketing

requirements.

Safety monitoring

There are novel considerations in the safety assessment of an

HGT product. Some of the potential safety effects may need to

be assessed in specific non-clinical studies, but they may also

have implications for safety monitoring in the human studies.

Since many HGT products create an immune response, im-

munogenicity should be assessed in non-clinical studies and

considered in the selection of the population and in the safety

monitoring plans. This is especially important in pediatric or

elderly populations, who may have different immune responses

compared to adults, based on whether or not they have had

prior exposure to, or vaccination with, the viral vector being

used. Instructions for the assessment of safety monitoring

should specifically include the assessment of infusion-related

reactions, infections, and inflammatory responses, and im-

mune-mediated adverse events.

When live viral vectors are used in the product, clinical trial

eligibility criteria should contain an assessment of immuno-

suppression, including the presence of immunosuppressive

illnesses (HIV infection, etc.) or concomitant use of immuno-

suppressive medications. After administration of the product,

“shedding” of the virus is also possible. Shedding refers to the

potential for the participant to whom the product has been ad-

ministered to continue to secrete the virus in their bodily fluids.

This can include direct leakage of the virus from the injection

site after administration, when the skin puncture is still open or

through a lesion that forms at the site. Viral shedding creates a

safety issue not just for the participant, but creates the potential

for infection of family, friends, and even casual contacts. The po-

tential for shedding should be assessed in non-clinical studies,

but human shedding studies may also be performed to assess

this risk. Protocols may need to specify the use of waterproof,

occlusive dressings over injection sites and/or the resulting le-

sions, rather than use of gauze or other common bandages.

Human DNA contains many sequences that turn the transla-

tion of other DNA sections on and off. When DNA is introduced

into the research participant with the use of a viral vector, the

DNA can be incorporated into the DNA of the participant’s cell,

but the precise location of that integration cannot be controlled.

It is possible that the new DNA can be incorporated into a lo-

cation which accidentally turns on a tumor-promoter gene (or

turns off a tumor suppressor), which is called “insertional onco-

genesis.” Non-clinical studies to assess tumorogenicity may be

Source: The Journal of Gene Medicine, 2015, John Wiley & Sons Ltd.

Figure 3. The number of gene therapy clinical stud-

ies skyrocketed from 1989-1999, and has remained

fairly steady since.

Number of Gene Therapy Clinical Trials

Approved Worldwide 1989 - 2014

2014

2013

2012

2011

2010

2009

2008

2007

2006

2005

2004

2003

2002

2001

2000

1999

1998

1997

1996

1995

1994

1993

1992

1991

1990

1989

Unknown

104

120

101

87

92

81

120

90

117

112

101

85

98

108

96

116

68

82

51

67

38

37

14

8

2

1

146

Trial Activity by Year



TRIAL DESIGN

conducted, but long-term follow-up for secondary cancers may

also be necessary in clinical trials.

Some HGT products are introduced into specific tissues

rather than being administered systemically; for example, ad-

ministration of a gene transfer product using an adenovirus vec-

tor into the eye for the treatment of macular degeneration. 9,10,11 In

such cases, safety monitoring should also watch for the distribu-

tion of viral vector beyond the intended tissues.

Informed consent

The NIH Guidelines provide guidance on four topics in addition

to the standard required elements of informed consent that are

considered necessary to include in trials of HGT products. While

IBCs will review the informed consent document to see if these

issues are addressed, they do not “approve” consent docu-

ments; they will provide feedback to the researcher, sponsor or

the appropriate IRB if they feel that these elements are not ad-

equately addressed. The topics are:

• Reproductive Considerations — When existing data are inad-

equate to rule out the possibility of inadvertent germline

alteration that could be passed on to offspring, participants

should be informed that the consequences to unborn chil-

dren are unknown.

• Long-term Follow-up with rDNA — Prospective participants

should be aware that they will be expected to participate in

long-term follow up that extends beyond the active phase of

the study. Investigators should explain the rationale for long-

term follow up and describe the specific follow-up activities

planned, including the desire to collect information about

any new cancers, blood disorders, autoimmune diseases, and

neurologic disorders encountered.

• Request for Autopsy — The request to be allowed to perform

an autopsy in case of the participant’s death is an aspect of

long-term follow up that is unique to gene transfer, since it

is still such a new area of research. It is requested because

autopsies can yield important information that may enable

a better understanding about the long-term effects of gene

transfer intervention.

• Interest of the Media and Others — This issue was added shortly

after the Gelsinger case, when it was thought necessary to

warn participants that there may be public interest in their

trial and participation. While generally considered much less

necessary now, this item has not been removed from the

guidance.

Summary

The number of HGT products in development is increasing,

and the number of these clinical trials is increasing. As this

trend continues, more clinical research professionals within

biopharma sponsors and CROs, who may be well-versed in the

details of drug and/or biologic development, may find it neces-

sary to be aware of the specifics of the design and conduct of

HGT studies. This will be necessary to ensure that these trials

are conducted with regulatory compliance, scientific rigor, and

the best protection for the participants as well as the research-

ers and the public.

This paper has provided only a brief summary of some of the

key challenges unique to gene transfer clinical trials. The field

is constantly changing as regulatory bodies develop and evolve

frameworks that will impact the conduct of these types of trials.

As these products pass through proof-of-concept assessments,

gain financial support, and progress into later-stage clinical tri-

als, it is important that clinical research professionals keep up

with the additional challenges of successfully conducting these

trials.

References

1. NIH Backgrounder on Gene Transfer; http://www.nih.gov/news/pr/

nov2002/genetransferbackgrounder.htm. Accessed 8 July 2015.

2. Jain Biotech Gene Therapy – technologies, markets and companies.

http://pharmabiotech.ch/reports/genetherapy/. Accessed 8 July 2015.

3. NIH Guidelines for Research Involving Recombinant or Synthetic

Nucleic Acid Molecules. http://osp.od.nih.gov/sites/default/files/

NIH_Guidelines_0.pdf. Accessed 8 July 2015.

4. FDA Cellular and Gene Therapy Guidances; Cellular and Gene Ther-

apy Guidance Documents. http://www.fda.gov/BiologicsBloodVac-

cines/GuidanceComplianceRegulatoryInformation/Guidances/Cel-

lularandGeneTherapy/. Accessed 8 July 2015.

5. Guideline on the Quality, Non-clinical and Clinical Aspects of Gene

Therapy Medicinal Products. EMA/CAT/80183/2014, draft, March

2015.

6. Jenkins, CL. Biological Materials Oversight in the United States.

Health Care Compliance Professionals Handbook. 2014. http://

www.hcca-info.org/Products/Books.aspx.

7. Jenkins, CL. Trends in United States Biological Materials Oversight

and Institutional Biosafety Committees. Journal of Research Administra-

tion. Volume XLV, Number 1. Spring 2014. http://srainternational.org/

publications/journal/volume-xlv-number-1.

8. U.S. Department of Health and Human Services, Centers for Dis-

ease Control and Prevention, & National Institutes of Health. (2007).

Biosafety in Microbiological and Biomedical Laboratories (5th ed.).

L. C. Chosewood and D. E. Wilson (Eds.). Washington, DC: U.S. Gov-

ernment Printing Office. Available at: www.cdc.gov/od/ohs/biosfty/

bmbl5/bmbl5toc.htm.

9. Spark Therapeutics. https://www.clinicaltrials.gov/ct2/show/NCT02

341807?term=spark+therapeutics&rank=1. Accessed 10 July 2015.

10. Avalanche Biotechnologies. https://www.clinicaltrials.gov/ct2/show/

NCT01494805?term=raav+sflt&rank=1 Accessed 10 July 2015.

11. Applied Genetics Technology Corporation (AGTC). https://www.

clinicaltrials.gov/ct2/show/NCT02416622?term=AGTC&rank=1.

Accessed 10 July 2015.

Chris Jenkins, PhD, MPH, BRP, CHMM, is Senior Vice President of

Biosafety and Gene Therapy, WIRB-Copernicus Group, email: cjenkins@

wcgclinical.com; Lindsay McNair, MD, MPH, MSB, is Chief Medical

Officer, WIRB-Copernicus Group, email: [email protected].

ES683028_ACT1015_023.pgs 10.01.2015 17:57 ADV black


TRIAL DESIGN


PEER

REVIEW

Evaluating the Effects of Therapy MaskingBarbara A. Ricker, Katherine M. Seymour, Alexander R. Arslan, April

Slee, Ruth McBride, Jeffrey L. Probstfield, MD

An important criterion for a well-conducted

clinical trial is minimization of bias in end-

point assessment. When possible, treat-

ment assignments should be masked (or

“blinded”) so the assignment is unknown

to both the study participants and healthcare pro-

fessionals treating the participants. Strategies for

masking studies range from very elaborate, such

as sham surgeries,1,2 to the most common, which

is simply providing a placebo pill that is visually

identical to the active drug. While masking is a

common strategy to reduce bias in randomized

clinical trials (RCT), assessment of the adequacy

of the treatment mask is seldom evaluated. Schultz

reported that trials that were not double-blind

yielded larger effects with odds ratios exaggerated

by as much as 17%.3

The 2001 CONSORT Statement4 and the Inter-

national Committee of Journal Editors5 both rec-

ommend disclosure of the methods used to blind

therapy. The 2001 CONSORT Statement suggested

clinical trials assess the strength of blinding, but

made very few recommendations regarding how

this should be accomplished. The updated 2010

CONSORT Statement6 recognized the difficulty of

assessment of blinding, and the dubious nature

of common assessment techniques. The theo-

retical measure of an adequate blind would have

participants, healthcare providers, and outcome

assessors able to correctly guess study assign-

ment no more frequently than by chance alone.

The 2010 CONSORT Statement describes inter-

pretational and measurement difficulties causing

concern about the usefulness of testing blinding,

but they suggest detailing how trials are blinded

and precisely who was blinded. Bang7 argues that

“…empirical (quantitative) evidence is almost al-

ways superior to ignorance in any decision-making

process and understanding/characterizing scien-

tific phenomena.” Preservation of the blind has

well-recognized importance for endpoints poten-

tially influenced by patient perception, such as re-

lapse in alcoholism or assessment of post-surgical

pain.1,2,8

However, it is not inconceivable that patient

knowledge of assignment could result in differen-

tial treatment and study visit compliance, which

might introduce bias even in the case of events

that are considered more objective. James8 argued

that reanalysis of data should be conducted when

the blind is compromised. In summary, there is

consensus within the research community that

blinding is important and should be evaluated, but

no consensus about how to undertake a practical

assessment of whether a specific strategy within a

specific trial was adequate.

When the active treatment has a distinctive

side effect, masking the active treatment against a

placebo can be difficult. Niacin, in doses sufficient

to affect lipid metabolism (> 1,000 mg), causes a

noticeable flush and, frequently, itching. This side

effect can be mitigated by taking 325 mg of aspirin

approximately 30 minutes before taking the niacin.

And, proprietary formulations of extended release

products, such as that used in AIM-HIGH (Nias-

pan™, AbbVie Inc.) can also decrease the flush-

Using a specific trial, the importance of assessing the success of therapy masking is examined.


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Clinical Trial Design and Analysis to Improve Assay Sensitivity

Clinical Trial Design and Analysis to Improve Assay Sensitivity



TRIAL DESIGN

ing response. Several earlier studies involving niacin used a

placebo “spiked” with 50 mg of immediate-release crystalline

niacin, an amount sufficient to induce flushing, but insuf-

ficient to have an effect on lipids. In the ADMIT study,9 50 mg

of free niacin was added to the placebo. In another study con-

ducted by Brown10 testing simvastatin or antioxidant vitamins;

(niacin) or the combination of the two to prevent coronary

disease, the placebo tablets also were spiked with niacin. The

technique used in the Brown study was successfully repeated

by Garg13 and by Zhao.14 Zhao reported flushing of any severity

in 30% of the simvastatin and niacin treated groups and 23%

in the simvastatin-placebo group (p =0.35). In the ARBITER 2

study,15 the placebo did not contain any active niacin. At the

conclusion of the study, the reported side effect of skin flush-

ing was significantly higher in the niacin treated group than

the placebo group (69.2% vs. 12.7% P<0.001), pointing to the

difficulty in blinding participants and caregivers when testing

a drug such as niacin.

We examined the relative success of masking therapy in

the Atherothrombosis Intervention in Metabolic Syndrome

with Low HDL/high triglycerides Impact on Global Health

Outcomes (AIM-HIGH) trial, a randomized controlled clinical

trial testing statin + “spiked” placebo versus statin + extended

release niacin. The well-known flushing side effect of niacin

was described to participants during the informed consent

process, so participants in either arm who experienced flush-

ing might suspect that their flushing was caused by niacin.

Overview of AIM-HIGH

The design and results of AIM-HIGH have been described

elsewhere,16,17 AIM-HIGH was a randomized, double-blind trial

to assess the effect of extended release niacin (Niaspan™,

AbbVie Inc.) on the rate of important cardiovascular events

(time to first occurrence of coronary artery disease death,

non-fatal myocardial infarction, hospitalization for acute

coronary syndrome, ischemic stroke, or symptom-driven coro-

nary or cerebral revascularization) compared to placebo in

participants with a history of cardiovascular disease, low HDL

and high triglycerides. All participants were treated (open

label) with a statin with the possible addition of ezetimibe to

achieve a target LDL-C of 40 to 80 mg/dL.

During the planning phase of AIM-HIGH, the investigators

recognized the difficulties of blinding caregivers and partici-

pants to niacin therapy because of the distinctive side effect

profile associated with high doses of niacin: extreme flush-

ing and itching. The extended-release formulation of niacin

chosen for the trial was designed to minimize the symptoms

associated with high doses of niacin; however, the package

label warns of these symptoms and the trial included an open

label run-in period to gradually increase the dose from 500

mg/day to 2,000 mg/day to determine whether the participant

would be able to tolerate the medication. During open-label

run-in, all trial participants were educated about these poten-

tial side effects and ways to minimize the flushing expected

with niacin. Participants who tolerated at least 1,500 mg per

day of Niaspan were randomized to continue with the drug or

to take a matching placebo. In an attempt to mask physicians,

research coordinators, and participants, placebo tablets were

manufactured to contain 50 mg of immediate release (crystal-

line) niacin. This small amount of niacin has been shown to

be sub-therapeutic for modifying lipids, but sufficient to in-

duce a flushing response. At baseline, participants were asked

about their prior experience with niacin or niacin products

Assessing study drug masking

The study was stopped at the recommendation of the Data

and Safety Monitoring Board (DSMB) prior to its planned

completion because of a demonstrated lack of efficacy of

niacin on the primary outcome.17 At the close-out visit, par-

ticipants were asked to make their best guess regarding the

therapy they were assigned, with the choices being: “Active

Niaspan,” “Placebo,” and “No Idea.” Research coordinators

were also asked to guess their participants’ treatment, and

were offered the same choices. Physicians were not included

There is consensus within the research

community that blinding is important,

but no consensus about how to

undertake a practical assessment

of whether a specific strategy within

a specific trial was adequate.

Source: Ricker et al.

Figure 1. Odds ratio associated with correct

guesses by participants. Odds ratio greater than 1

indicates more likely to guess correctly.

Effect of covariates on correctness of Participant guesses

Flushing (vs. No fushing)

Itching (vs.no itching)

Nausea (vs.no nausea)

Gl symptoms (vs. no Gl symptoms)

Changes in eyesight (vs. no changes)

Gout (vs. no gout)

Prior Niacin use (vs. no prior use)

Gender (women vs. men)

0.5

OR LCL UCL p-value

1.50

1.59 1.30 1.90

1.290.861.05

1.16

1.23 1.01 1.51 0.043

1.21 1.01 1.46

1.69

1.201.74

1.101.36

0.94

0.043

0.005

0.623

0.97 1.37 0.103

<.001

0.627

1.12 2.00 0.006

1.5 2.52 31

Covariate Impact: Participants



TRIAL DESIGN

in the questionnaires because the research coordinators con-

ducted the majority of visits, spending the most time with the

participants. The blind was not intentionally broken for any

participants or research coordinators during the trial.

Statistical methods

The primary objective was to compare the results of partici-

pant and research coordinator treatment guesses compared

to actual treatment assignment. The null hypothesis was that

guesses are correct 50% of the time (as expected by chance),

versus the two-sided alternative hypothesis that the percent-

age of correct guesses is significantly different than 50%.

P-values and confidence intervals are based on the exact bi-

nomial distribution for participant guesses and from weighted

linear regression for the percentage of correct guesses by clin-

ical site. A correct guess was defined as guessing active Nias-

pan when the participant had been randomized to Niaspan or

guessing placebo when the participant had been randomized

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Participant Guesses

NIASPAN PLACEBO TOTAL

Number

randomized1,718 1,696 3,414

Number of

respondents1,577 1,583 3,160

Guessed Niaspan 949 (60.2%) 876 (55.3%) 1,825 (57.8%)

Guessed Placebo 121 (7.7%) 167 (10.5%) 288 (9.1%)

No Idea 507 (32.1%) 540 (34.1%) 1,047 (33.1%)


Table 1. Participant guesses for treatment arm.

Research-Coordinator Guesses

NIASPAN PLACEBO TOTAL

Number of

respondents1,609 1,608 3,217

Guessed Niaspan 599 (37.2%) 516 (32.1%) 1,115 (34.7%)

Guessed Placebo 251 (15.6%) 302 (18.8%) 553 (17.2%)

No Idea 759 (47.2%) 790 (49.1%) 1,549 (48.2%)


Table 2. Research-coordinator guesses for treatment

arm.



TRIAL DESIGN

to placebo. The proportion of correct guesses was defined to

be the number who guessed correctly divided by the number

of guesses among those who responded.

Secondary analyses included calculation and comparison

of two blinding indices7,8 and determining whether there was

evidence that the presence of side effects, prior niacin use,

and gender were associated with correct guesses. Logistic re-

gression models used were to determine whether side effects,

gender, and prior niacin use were associated with correct

guesses.

For research coordinators, odds ratios were computed

using generalized estimating equations to account for cor-

relation within the site. We assumed one coordinator at each

site completed all the close-out visit forms for participants at

their site. We assumed that guesses from the same research

coordinator for different participants could be correlated, but

that guesses regarding participants from different sites were

independent.

Two blinding indices (BI) were calculated.7,8 These two

indices were chosen because they interpret the “No Idea”

responses differently. The James BI is a variant of the kappa

statistic, ranging from 0, indicating complete unblinding, to

1, indicating complete blinding. Therefore, it is a measure of

the disagreement between random assignment and treatment

guess. The basic assumption is that the “No Idea” responses

are most indicative of the success of blinding and assigns a

weight of 1 for these responses. A weight of 0 is assigned to

correct responses, as these indicate unblinding. The variance

of the James index is computed using the jackknife procedure.

The Bang BI can be used to assess studies with more than

two treatment groups or more complex study designs. The

Bang BI yields the proportion of correct guesses in each treat-

ment group beyond what would be expected by chance. It

assigns less weight to the “No Idea” responses, and is more

sensitive to the value of the other responses. The Bang index

ranges from -1, indicating that all responses were wrong to +1

indicating that all responses were correct (complete unblind-

ing). A Bang index of 0 indicates random guessing. The Bang

index and confidence interval are computed for each treat-

ment group. The variance of the Bang index is computed us-

ing exact methods based on a trinomial distribution.

Analyses and graphs were performed using SAS version 9.2

(Carry, NC). Unless otherwise specified, all confidence inter-

vals and p-values are two-sided.

Results

Responses were available from 3,160 of 3,414 participants, 1,577

randomized to active Niaspan and 1,583 to placebo. Overall,

1,116 (35%, 95% CI: 34, 37%, p < 0.001 for comparison to 50% null

hypothesis) correctly guessed their treatment assignment, while

997 (32%) guessed incorrectly and 1,047 (33%) chose “No Idea”

(see Table 1 on page 27). For participants randomized to Nias-

pan, 60% guessed correctly and for participants randomized to

placebo, 10.5% guessed correctly. Of the 3,217 guesses from the

research coordinators, 901 (28%, 95% CI: 24%, 32%, p < 0.001)

guessed correctly and 767 (24%) guessed incorrectly. The major-

ity of answers from research coordinators, 1549 (48%), were “No

Idea” (see Table 2 on page 27).

Flushing was reported by 91% of placebo participants and

88% of Niacin participants. Within the placebo group, 57% of

participants reporting flushing guessed active Niacin compared

to 34% without flushing (p <0.0001). Twenty percent of placebo

participants with no flushing correctly guessed placebo, com-

pared to 10% who experienced flushing (p=0.0003). Within the

active Niacin group, 62% of participants reporting flushing cor-

rectly guessed active Niacin, compared to 41% without flushing

(p < 0.0001). The presence or absence of the expected side effects

of flushing and itching was significantly associated with correct

guesses of therapy by the participant (p < 0.01, see Figure 1 on

page 26). Nausea, GI symptoms, changes in eyesight, and gout

may have an effect on correct guesses, but comparisons did not

reach nominal significance. Experience with niacin prior to AIM-

HIGH was significantly associated with correct guesses among

participants, p=0.005. Gender had no effect on whether the

participant correctly guessed the treatment assignment. When

AIM-HIGH points out the importance

of assessing the blind soon

after randomization to avoid any

potential issues with early stopping

should such be dictated.Source: Ricker et al.

Figure 2. Odds ratio associated with correct

guesses by research coordinators. Odds ratio greater

than 1 indicates more likely to guess correctly.

Effect of covariates on correctness of research coordinator guesses

OR LCL UCL p-value

1.25 0.94 1.68 0.125

1.36 1.12 1.65 0.005

1.07 0.86 1.32 0.559

1.18 1.00 1.39 0.069

0.90 0.73 1.10 0.312

1.01 0.85 1.20 0.908

1.07 0.86 1.32 0.555

0.90 0.73 1.11 0.324

Flushing (vs. No fushing)

Itching (vs.no itching)

Nausea (vs.no nausea)

Gl symptoms (vs. no Gl symptoms)

Changes in eyesight (vs. no changes)

Gout (vs. no gout)

Prior Niacin use (vs. no prior use)

Gender (women vs. men)

0.5 1.5 2.52 31

Covariate Impact: Research Coordinators


Sponsored by Presented by

EVENT OVERVIEW:

Endpoint and event adjudication brings scientifc rigor to a

complex trial and is frequently requested by regulatory authori-

ties. The use of adjudication committees is becoming common-

place across many indications and study phases and frequently

involves imaging endpoints. Most often, these are trials with

cardiovascular or composite endpoints. Successful adjudication

requires careful and early planning from all key stakeholders

in the process. In this presentation, you will learn how to run a

successful clinical endpoint committee (CEC), mitigate risks to

adjudication and put the best processes in place to save time

and costs.

In the presentation, we will also:

• Examine who the stakeholders in the adjudication process

are, and why early planning is important.

• Identify some of the common pitfalls to good adjudication.

Lessons learned from clinical trials will be provided.

• Discuss best practices to streamline process and ensure

quality outcome review for successful analysis and

submissions.

Who Should Attend:

You will beneft from this event if you

are a manager, associate director,

director or vice president from a bio/

pharmaceutical or CRO company with

responsibilities or involvement in the

following area(s):

• CEC Coordination

• Project Management

• Data Management

• Biometrics/Biostatistics

• Safety or Pharmacovigilance

• Medical Monitoring

• Clinical Monitoring

• Therapeutic Leadership

• Clinical Operations

For questions, contact

Sara Barschdorf at

[email protected]

ON-DEMAND WEBCAST (Originally aired Tuesday, Sept. 22, 2015)

Register for free at www.appliedclinicaltrialsonline.com/act/cec

Key Learning Objectives:

• To understand the importance of clear and well-de3ned

defnitions to successful adjudication and your trial

outcome.

• To describe clinical source data needed and e4ective ways

to collect this information.

• To develop strategies to mitigate the risk of changes late in

the trial.

Presenters:

Lisa Moore, PhD, RN

Senior Director,

Scienti3c A4airs

Chiltern

Richard H. Patt, MD

Principal and Cofounder

RadMD and BRITI

Moderator:

Lisa Henderson

Editorial Director

ACT

Clinical Endpoint Adjudication Strategies to Improve CEC Process Flow and Accurate Endpoint Review



TRIAL DESIGN

participants presented with itching, but not flushing, the re-

search coordinators more frequently guessed the correct therapy,

p=0.005 (see Figure 2 on page 28).

The James BI was 0.645 (95%CI 0.637, 0.663) for guesses

by the study participants and 0.722 (95%CI 0.707, 0.737) for

guesses by research coordinators. These values indicate suc-

cessful blinding for both groups, since the lower limit of the

95% confidence interval is greater than 0.5 (see Table 3).

The Bang BI for participants assigned to Niaspan was 0.53

(95%CI 0.49, 0.56) and -0.45 (95% -0.48, -0.41) for participants

assigned to placebo. For guesses by research coordinators,

the Bang index was 0.22 (95%CI 0.18, 0.25) for participants

assigned to niacin and -0.13 (95%CI -0.17, -0.099) for those

assigned to placebo. Responses by both participants and

research coordinators indicate moderate success in blinding

participants assigned to niacin and more incorrect responses

than expected by random guessing in participants assigned

to placebo.

There were 92 clinical sites in AIM-HIGH. Research coordi-

nators had been working on the study from three months to

5.75 years at the time that the study was stopped. Those who

had been with the study longer made correct guesses more

frequently than those who had joined the trial more recently

(mean duration with study for those guessing correctly, 4.07

years (95%CI 3.28, 3.43) and mean duration for those guessing

incorrectly 3.36 years, (95%CI 3.97, 4.17, p < 0.001).

Discussion

Overall, both participants and research coordinators cor-

rectly guessed treatment assignment less often than would be

predicted by chance, which we interpret as evidence that the

blind was satisfactory. More than 90% of participants guessed

they were taking the active drug, or had “No Idea” about which

treatment they received. The calculation of both Bang and

James BI’s support this observation. The presence of flush-

ing was associated with guessing active drug in both arms,

and the absence of flushing was associated with correctly

guessing placebo. Most patients reported flushing at least

once during the study. The majority of participants—those

assigned to Niaspan (60%) and those assigned to placebo

(55%)—believed that they were taking the active drug, though

substantial proportion (33% overall) had “No Idea” to which

drug they were assigned. The high percentage guessing active

treatment may be due to the spiked placebo dose of Niacin,

which has been shown to induce a flush12, but not affect lipids.

Alternatively, it could have been due to the participant’s de-

sire to be on the active treatment (wishful thinking).

In treatment-adjusted models, the presence of flushing and

itching were associated with correct identification of treat-

ment, though the number of participants guessing placebo

was quite low. Taken together, these findings suggest that

participants noticed side effects and may have used this in-

formation to guess treatment assignment, which underscores

the importance of efforts to blind participants and research

coordinators to a drug with known and pronounced side ef-

fects. In the absence of a definitive side effect, a difference

in the proportion of correct guesses by treatment may raise

concerns about blinding. However, the proportions of correct

guesses are expected to be different by treatment assignment

when a characteristic side effect of active treatment is simu-

lated in the placebo group, and neither of the blinding indices

we calculated were developed specifically for this situation.

The spiked placebo strategy leads participants in both

arms to believe they are taking active drug, though those as-

signed to active drug will guess correctly with this logic and

those assigned to placebo will guess incorrectly. The realized

results from AIM-HIGH support this theory—among par-

ticipants who guessed either placebo or niacin (i.e., those who

had some idea of what treatment they received) 86% overall

(84% and 89% in placebo and niacin) did guess active niacin.

Without the spiked placebo, the number of participants who

correctly guessed niacin might be similar to what we saw, but

The presence or absence of the

expected side effects of flushing

and itching was significantly

associated with correct guesses

of therapy by the participant.

Blinding Index: Bang

PARTICIPANTS

BANG BLINDING

INDEX

95% CONFIDENCE

INTERVAL

Assigned to Niaspan 0.53 [0.49, 0.56]

Assigned to Placebo -0.45 [-0.48, -0.41]

Research Coordinators

Guesses for Participants

Assigned to Niaspan0.22 [0.18, 0.25]

Guesses for Participants

Assigned to Placebo-0.13 [-0.17, -0.099]


Table 4. The Bang Blinding Index for guesses by partici-

pants and coordinators.

Blinding Index: James

JAMES

BLINDING INDEX

95% CONFIDENCE

INTERVAL

Participants 0.65 [0.64, 0.66]

Research Coordinators 0.72 [0.71, 0.74]


Table 3. The James Blinding Index for guesses by par-

ticipants and coordinators.

ES684301_ACT1015_030.pgs 10.02.2015 01:43 ADV blackyellowmagenta


TRIAL DESIGN

the number who correctly guessed placebo would likely have

been higher.

Clearly, the ideal for both participants and for the integ-

rity of the experiment is to eliminate differential side effects.

When this is not possible, and the risk to participants is low,

a technique such as this spiked placebo can strengthen the

design of a study by preserving the blinding. The appropriate

technique to retrospectively assess blinding in this setting is

an important topic for future research.

At the time that participants and research coordinators

were asked to guess therapy, the overall results of the trial

had been presented to them and announced in a press re-

lease by the sponsor. So, while the participants may have

hoped that they were on an effective therapy, the overall

results were null, that is extended release niacin showed no

benefit compared to placebo on the primary or any second-

ary endpoints. Some have recommended that assessing the

success of study masking should be done prior to announce-

ment of study results (Sackett, DL Letter to Editor, BMJ

328: 8May2004), since the study results may affect guesses.

AIM-HIGH was stopped prior to its planned conclusion by its

DSMB due to the observed lack of efficacy. This specific case

in AIM-HIGH points out the importance of assessing the blind

soon after randomization to avoid any potential issues with

early stopping should such be dictated.

It should be noted that the results from AIM-HIGH were

based on a blinded central review of medical records docu-

menting the elements of the clinical endpoint, thus it is

unlikely that the trial results were affected by a prior notion

of study drug assignment on the part of the participant or re-

search coordinator.

The presence/absence of clinical symptoms (flushing/itch-

ing) after switching from open label Niaspan at maximally

tolerated dose at end of run-in to randomly assigned treat-

ment may have influenced the correctness of the participant’s

guess because the symptoms disappeared or decreased

significantly between open label and randomized treatment,

despite the small amount of immediate release niacin in the

placebo tablets. While this is a possibility, there is no data

currently to support this conclusion. Regardless, prior experi-

ence with niacin was associated with more accurate guesses.

Development of gouty symptoms and visual impairment

was relatively infrequent, and participants may not have asso-

ciated these symptoms with Niaspan. Finally, while gastroin-

testinal symptoms were relatively frequent, there were similar

proportions of these in the two treatment groups. Since par-

ticipants were on multiple drugs for cardiovascular prevention

and other indications, it is possible that such symptoms could

have been attributed to other medications or causes and did

not lead the participant to think that they were on one therapy

or another.

Because the James BI weights “No Idea” or “do not know”

more heavily than an incorrect guess, the 33% of participants

in AIM-HIGH who answered “do not know” affected this score.

In the null case where there are no “do not know” and the

guesses are random, the James BI is 0.5. For AIM-HIGH, the

James BI of 0.65 for participants and 0.72 for research coor-

dinator indicates successful blinding, since the lower limit of

the 95% confidence interval for the computed index is greater

than 0.5 (see Table 3).

The Bang BI de-emphasizes the “do not know” in favor

of a balanced proportion of correct vs. incorrect guesses.

The Bang BIs for AIM-HIGH indicate that the magnitude

of blinding was similar in the two treatment groups, but

in opposite directions. This observation is consistent with

the design objective to try to make placebo-assigned par-

ticipants unsure about whether or not they were taking

Niaspan. The positive Bang BI of 0.53 for the participants on

niacin indicates they were more frequently correct in their

guesses (see Table 4 on facing page). The placebo group’s

Bang BI was of about the same magnitude but negative,

-0.45, indicating relative opposite guessing, that is, guess-

ing that they were on active treatment when they were on

placebo. The research coordinators’ Bang BI’s were also

positive for active drug guesses and negative for placebo

guesses, but much closer to zero or random guessing than

for the participants’ Bang BI.

The intention in AIM-HIGH was for all participants and

related clinical staff to be unsure about the participant as-

signment. Bang admits that interpreting a BI of -1 can be

“subjective because this may represent complete blinding or

complete unblinding in the opposite direction.”7

The James BI may provide a more appropriate measure

for AIM-HIGH data because “spiking the placebo” was de-

signed to confuse participants. Participants and coordina-

tors guessed in similar proportions either incorrectly or “No

Idea.” By design, the Bang BI assumes a situation in which

participants have no idea what they received. Because of the

known side-effect profile associated with Niaspan, it cannot

be assumed that participants had no idea the study drug they

received.

In a systematic review of reports of randomized, placebo

controlled clinical trials, only 7% provided any data on the

success of therapy masking,18 and fewer gave any data assess-

ing the success of masking among both study participants

and outcome assessors. Fergusson et al recommend that the

Trials designed to mask therapy

assignment from participants and

treating healthcare professionals should

consider assessing the success of their

attempts to mask therapy in all cases.



TRIAL DESIGN

CONSORT statement be modified to require assessment of

blinding for all double-blind randomized trials.

Limitations

The proportion of participants who had “No Idea” which

therapy they were taking may have been a polite response

in the sense that the participant realized that remaining

blinded was desirable. The question was asked neutrally by

the research coordinators at the final in-clinic visit; we have

no way of assessing whether the participant was responding

honestly or not. Similarly, the research coordinator’s fully

realized the importance of blinding in a clinical trial and may

not have responded honestly. The response from over half

of the research coordinators as “No Idea” may reflect their

professional neutrality. There is no way to assess if research

coordinator’s guesses were influenced by the response of the

participants.

Conclusion

By “spiking” the placebo tablets with 50 mg of crystalline

niacin, the AIM-HIGH investigators hoped to blind the

participants to the study drug to which they were assigned

randomly. Blinding indices such as those proposed by

Bang and by James provide effective statistics to measure

the success of treatment masking in different situations.

We concluded that “spiking” the placebo was effective in

blinding a large percentage of participants to their assigned

treatment.

Trials designed to mask therapy assignment from partici-

pants and treating healthcare professionals should consider

assessing the success of their attempts to mask therapy in all

cases, and to do so before the trial results are known to either

clinical staff or participants.

References

1. Moseley JB, O’Malley K, Petersen NJ, et al. A controlled trial of

arthroscopic surgery for osteoarthritis of the knee. N Engl J Med

2002;347:81-88

2. Sihvonen R, Paavola M, Malmivaara A, Itälä A, Joukainen A, Nurmi

H, Kalske J, Järvinen TL; Finnish Degenerative Meniscal Lesion

Study (FIDELITY) Group. Arthroscopic partial meniscectomy versus

sham surgery for a degenerative meniscal tear. N Engl J Med. 2013

Dec 26;369(26):2515-24.

3. Shultz, KF, Chalmers, I, Hayes, RJ, Altman, DG. Empirical Evidence

of Bias. JAMA 1995; 273, 408-412.

4. Mohler, D, Schulz, KF, Altman, D CONSORT Group. The CONSORT

Statement: Revised Recommendations for Improving the Quality

of Reports of Parallel-Group Randomized Trials. JAMA 2001; 285:

1987-1991.

5. International Committee of Medical Journal Editors. Uniform

requirements for manuscripts submitted to biomedical journals.

Med Edu 1999; 33: 66-78.

6. Schultz, KF, Altman, DG, and Moher, D; CONSORT Group. CON-

SORT 2010 statement: updated guidelines for reporting parallel

group randomized trials. PLOS Med 2010; 7: e1000251.

7. Bang H, Flaherty SP, Kolahi J, Park J. Blinding assessment in clini-

cal trials: A review of statistical methods and a proposal of blind-

ing assessment protocol. Clin Res Regul Aff 2010; 27: 42-51.

8. James, K, Lee, K, Kraemer, H, Fuller, R. An Index for assessing blind-

ness in a multi-center clinical trial: disulfiram for alcohol cessation

– a VA cooperative Study. Stat Med,1996; 15: 1421-1434.

9. Montori, VM, Bhandari, M, Devereux PJ, Manns, BJ, Ghali WA,

Guyatt, GH. In the dark the reporting of blinding status in random-

ized controlled trials. J of Clin Epidemiol 2002; 55: 787-790.

10. Coliguiri, B. Participant expectancies in double-blind randomized

placebo-controlled trials: potential limitations to trial validity. Clin

Trials 2010;7: 246-255.

11. Egan, DA, Garg, R, Wilt, TJ, Pettinger, MB, et al for the ADMIT

Investigators. Rationale and design of the arterial disease mul-

tiple intervention trial (ADMIT) Pilot Study. Am J Cardiol 1999; 83:

569-575.

12. Brown BG, Zhao XQ, Chait A, et al. Simvastatin and niacin, antioxi-

dant vitamins, or the combination for the prevention of coronary

disease. N Engl J Med. 2001 345:1583-92.

13. Garg, R, Elam, MB, Crouse, JR, et al. Effective and safe modifica-

tion of multiple atherosclerotic risk factors in participants with

peripheral arterial disease. Am Heart J 2000; 140: 792-803.

14. Zhao XQ, Morse JS, Dowdy AA, et al. Safety and tolerability of simv-

astatin plus niacin in participants with coronary artery disease and

low high-density lipoprotein cholesterol (The HDL Atherosclerosis

Treatment Study). Am J Cardiol 2004; 93: 307-12.

15. Taylor, AJ, Sullenberger, LE, Hyun, JL, Lee, JK, Grace, KA. Arterial

Biology for the Investigation of the Treatment Effects of Reducing

Cholesterol (ARBITER)2. Circ 2004; 110:3512-3517.

16. The AIM-HIGH Investigators. The role of niacin in raising high-den-

sity lipoprotein cholesterol to reduce cardiovascular events in par-

ticipants with atherosclerotic cardiovascular disease and optimally

treated low-density lipoprotein cholesterol: rationale and study

design. Am Heart J 2011; 161; 4771.e2-477.e2.

17. The AIM-HIGH Investigators. Niacin in participants with low HDL

cholesterol levels receiving intensive statin therapy. NEJM 2011;

365: 2255-2267.

18. Fergusson D, Glass KC, Waring D, Shapiro S. Turning a blind eye:

the success of blinding reported in a random sample of random-

ized, placebo controlled trials. BMJ 2004; 328:432.

Barbara A. Ricker*, MPH, BSN, University of Washington,

email: [email protected]; Katherine M. Seymour, BA, University of

Washington; Alexander R. Arslan, BS, Axio Research LLC; April Slee,

MS, Axio Research LLC; Ruth McBride, ScB, Axio Research LLC;

Jeffrey L. Probstfield, MD, University of Washington

* To whom all correspondence should be addressed


Presenters:

Rajneesh Patil

Director, Clinical Development Productivity and

Quality, Quintiles

XiaoQiang Xue

Director, Predictive Operational Analytics, Quintiles

Moderator:

Lisa Henderson

Editorial Director, Applied Clinical Trials

Presented by:

Sponsored by:

For technical questions please contact

Sara Barschdorf at [email protected]

US Toll free: +1 866 267 4479 US Direct: +1 973 850 7571

Non US: +44 203 564 4649

Web: http://www.quintiles.com/services/riskbased-monitoring


Register now for free! www.quintiles.com/webinar

Using predictive and

advanced analytics to

enhance risk-based

monitoring

Learn more about

Executing clinical studies using risk-based Monitoring (RBM) methodologies is reducing risks in clinical development while improving patient safety and study quality.

New capabilities for advanced statistical monitoring and Predictive Analytics are enabling the identification of potential patient safety issues and actionable insight into clinical trial performance.

By attending this webinar you will understand the application of analytics to identify potential risks before they occur, and to target the right action at the right place at the right time. This is a major step forward in improving quality, safety and productivity in the next generation of RBM execution.

Key learning objectives

• Learn of new capabilities being used in risk-based

monitoring study execution

• Understand how you can improve site performance

with advanced statistical monitoring

• Optimize site performance and improve patient

safety using Advanced and Predictive Analytics

On-demand webinarOriginally aired September 3, 2015



SAFETY REPORTING


PEER

REVIEW

Death Waivers an Incomplete Picture of Drug SafetyMargarita Mare, MD, Lisa Carlson, Maxim Belotserkovskiy, MD, Nickolai

Usachev, MD

The current practice of waiver on immediate

reporting of cases of death due to the main

disease progression may jeopardize data qual-

ity from discrepancies in the overall number of

deaths registered and documented across the

reporting of a clinical trial. This article will describe

the practical aspects of reporting deaths due to the

main disease progression to ensure the data quality

of the drug development program.

The International Conference on Harmonisation

(ICH) E2A Guideline titled “Clinical Safety Data Man-

agement: Definitions and Standards for Expedited

Reporting”1 defines a serious adverse event (SAE) as

any untoward medical occurrence that at any dose

results in death, is life-threatening, requires inpatient

hospitalization or prolongation of existing hospital-

ization, results in persistent or significant disability/

incapacity, or is a congenital anomaly/birth defect.

SAEs are critically important for the identifica-

tion of safety problems that might be significant

enough to lead to important changes in the way the

medicinal product is developed (e.g., change in dose,

population, needed monitoring, consent forms).

Such reactions should be expeditiously reported

to regulatory authorities if they are suspected to be

related to the medicinal product and unexpected as

per the applicable product information.1

Reporting of death—an SAE in its most severe

form—is the No. 1 postulate of drug safety or phar-

macovigilance (PVG) as per ICH E2A. However, there

are a number of trials in which death of the study sub-

jects is an expected event and likely due to the main

disease progression (e.g., late stage of cancer, coma).

Reporting of disease-related mortality as single events

is generally uninformative, and neither contributes

meaningfully to the developing safety profile of an

investigational drug nor to human subject protection.

Thus, the sponsor and regulatory authority rather fre-

quently reach the agreement that such cases will be

aggregated and compared to cases in a control group

and submitted only if the event occurs more fre-

quently in the drug treatment group.2 Many times, the

study protocol or the investigator’s brochure identify

cases of death due to the main disease progression

as not requiring expedited reporting. Investigators will

not complete and submit an SAE report form for such

cases unless they are considered related to the study

treatment by the investigator.3,4

On the other hand, at the end of the trial, the

sponsor should summarize the study results in the

clinical study report (CSR). The CSR is the docu-

ment—above all other study information—that

should include all comprehensive information of

all SAEs (including all deaths) from each particular

clinical trial and is reported to regulatory authori-

Examining the practical significance of reporting patient deaths due to main disease progression.

Reporting of disease-related

mortality as single events is

generally uninformative, and

neither contributes meaningfully

to the developing safety profile

of an investigational drug nor

to human subject protection.



SAFETY REPORTING

ties by the study sponsor. In the ICH E3

Guideline for Industry titled “Structure

and Content of Clinical Study Reports,”5

section 12.3.2 states that “there should

be brief narratives describing each death,

each other serious adverse event, and

those of the other significant adverse

events that are judged to be of special

interest because of clinical importance.”

At this stage, if there was a waiver on

expedited reporting of deaths due to the

main disease progression, discrepancies

may occur, such as:

• Death is an SAE in accordance with

ICH E2A, and without any exception,

information about all cases of death

should be listed in the CSR (includ-

ing cases of death that do not require

immediate reporting as per the study

protocol or the investigator’s brochure).

However, not all cases of death have

been captured in the safety database,

as the cases of death due to the main

disease progression were not reported

within the trial expeditiously. We un-

derstand that our opponents may refer

to the statement “Events (of death) that

were clearly unrelated to the test drug/

investigational product may be omit-

ted or described very briefly” in sec-

tion 12.3.2 of ICH E3. Nevertheless, the

necessity to have all safety information

on hand can arise at any stage of the

investigational medicinal product life

cycle based on analysis of aggregated

data performed both for individual

studies (if there are enough events to

be informative) and across all stud-

ies.6 The larger sample size provides the

best chance of detecting safety signals.7

• Comparison of disease-related mor-

tality is performed during the interim

and/or final analysis of statistical data

derived from the clinical study data-

base. In circumstances where the mor-

tality rate in the study treatment group

is higher than in the control group,

the case would be considered a sus-

pected unexpected serious adverse

reaction (SUSAR) and investigational

new drug (IND) safety reports should

be prepared and submitted to regula-

tory authorities in narrative format for

aggregated data in an expedited way.

The individual cases that were ana-

lyzed should also be submitted at the

same time (e.g., completed FDA Form

3500A for each case).2,6 However, as al-

ready discussed, not all cases of death

were captured in the safety database

if information about deaths due to the

main disease progression were not

collected within the trial.

It is the responsibility of the study

sponsor to maintain the safety database

in order to monitor the safety of medici-

nal products and to detect any change

to their risk-benefit balance (including

all events of death); however, information

regarding deaths due to the main dis-

ease progression will not be comprehen-

sively captured in the safety database.

The lack of clarity and consistency in

reporting of deaths in clinical trials can

also lead to discordance in deaths docu-

mented across reports of a trial.8

As a contract research organization

(CRO) and safety provider, we have al-

ready faced situations several times

when it was very difficult to collect suf-

ficient information about the cases of

death due to the main disease progres-

sion that had not required the immedi-

ate reporting as per study protocol. Such

information should be collected before

the CSR finalization and sometimes after

the study database lock (i.e., probably

a long time after the occurrence). For

queries, the investigators had to recall

the information of patients who discon-

tinued months (sometimes years) ago,

which was rather time-consuming and

annoying for the investigators.

From our point of view, the follow-

ing steps are necessary to improve the

process of cooperation between the dif-

ferent parties responsible for collection,

evaluation, benefit/risk assessment, and

regulatory reporting of deaths due to the

When you’re passionate about what you do, it doesn’t feel like work.

At WCG, we’re more than an IRB; we’re a clinical services

organization. We’re passionate about protecting others, and

committed to optimizing the performance of clinical trials.

www.wcgclinical.com/careers.Join the team. Join the revolution.



SAFETY REPORTING

main disease progression that are not reported by the investiga-

tor in an expedited way:

• Cross-functional operation procedure on collection of such oc-

currences within clinical trials should be developed by any CRO

or the study sponsor (if they run clinical trials on their own).

• Safety management plan should match with, or contain a

reference to, safety data reconciliation guidelines. Both docu-

ments should be finalized before the first patient in.

• Data management team should provide PVG team with the

listings of deaths on a regular basis (e.g., monthly or quar-

terly). The PVG team should review the listings and reconcile

them with previously reported SAE cases of death on an on-

going basis.

• Additional information should be requested from the clinical/

site team for all cases of death that were not reported by the

investigators on an expedited basis to avoid delayed queries

after the end of the trial.

• Brief narratives are compiled for all cases of death either by

the PVG team or by medical writers in accordance with the

safety management plan.

Such simple steps can eliminate the possibility of losing data

pertaining to disease-related mortality and could significantly

improve the quality of CSRs and lifecycle documentation for the

investigational product.

Because the regulations require reporting certain adverse

events in the aggregate rather than as individual cases, it is

important for sponsors to plan the process of collection and

evaluation of such safety data in the very beginning of the inves-

tigational product life cycle. It is crucial to remember that brief

narratives describing each death should be provided in CSRs

and in IND safety reports in situations where the mortality rate

in the study treatment group is higher than in the control group.

For cases of death that are specifically defined in the protocol as

the study endpoints, and that are neither collected in the safety

database nor on the adverse event pages of the case report

form, it also could be useful to design an additional case report

form, so that the investigator could provide a brief narrative for

the case in the pre-specified format.

A participant death is a serious event in a clinical trial and

needs to be unambiguously reported either in IND or ag-

gregated safety reports. Waiver on immediate reporting of

cases of death due to the main disease progression can be

a challenge in situations where the process of collection and

evaluation of all cases of deaths was not carefully planned by

the study sponsor in the very beginning of the investigational

product life cycle.

Failure to report all cases of death in the safety database

leads to discrepancies in the number of deaths registered and

documented across reports (the development safety update

report, CSR) of a trial thereafter, affecting the quality of the

reports. Incomplete reporting of deaths may overemphasize

health benefits when benefits and harms of the investigational

medicinal product are summarized in the large sample size or

may influence the timelines of expedited reporting in circum-

stances where the mortality rate in the study treatment group is

higher than in the control group.

References

1. International Conference on Harmonisation. “Clinical Safety Data

Management: Definitions and Standards for Expedited Reporting.”

E2A, Step 4. October 1994. http://www.ich.org/fileadmin/Public_Web_

Site/ICH_Products/Guidelines/Efficacy/E2A/Step4/E2A_Guideline.pdf

2. United States Food and Drug Administration. “Final Rule: Investiga-

tional New Drug Safety Reporting Requirements for Human Drug and

Biological Products and Safety Reporting Requirements for Bioavail-

ability and Bioequivalence Studies in Humans.” 21 CFR Parts 312 and

320. October 2013. http://www.fda.gov/Drugs/DevelopmentApprov-

alProcess/HowDrugsareDevelopedandApproved/ApprovalApplica-

tions/InvestigationalNewDrugINDApplication/ucm226358.htm

3. European Parliament. “Approximation of the laws, regulations and

administrative provisions of the Member States relating to the imple-

mentation of good clinical practice in the conduct of clinical trials

on medicinal products for human use.” Directive 2001/20/EC. April

4, 2001. http://ec.europa.eu/health/files/eudralex/vol-1/dir_2001_20/

dir_2001_20_en.pdf

4. European Commission. “Detailed guidance on the collection, veri-

fication and presentation of adverse event/reaction reports arising

from clinical trials on medicinal products for human use (‘CT-3’).”

2011/C 172/01 Article 16(1). http://ec.europa.eu/health/files/eudralex/

vol-10/2011_c172_01/2011_c172_01_en.pdf

5. International Conference on Harmonisation. “Structure and Content

of Clinical Study Report.” E3, Step 4. November 1995. http://www.ich.

org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/

E3/E3_Guideline.pdf

6. United States Department of Health and Human Services, Food

and Drug Administration, Center for Drug Evaluation and Research

(CDER), and Center for Biologics Evaluation and Research (CBER).

“Guidance for Industry and Investigators: Safety Reporting Require-

ments for INDs and BA/BE studies.” December 2012. http://www.fda.

gov/downloads/drugs/guidancecomplianceregulatoryinformation/

guidances/ucm227351.pdf

7. International Conference on Harmonisation. “Statistical Principles for

Clinical Trials.” E9, Step 4. February 1998. http://www.ich.org/filead-

min/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E9/Step4/

E9_Guideline.pdf

8. Earley Amy, Joseph Lau, and Katrin Uhlig. “Haphazard report-

ing of deaths in clinical trials: a review of cases of ClinicalTrials.

gov records and matched publications–a cross-sectional study.”

BMJ Open 2013;3:e001963. Accessed June 1, 2015. doi:10.1136/bmjo-

pen-2012-001963.

Margarita Mare, MD, is Medical Officer/Pharmacovigilance Physician, PSI

CRO South Africa (Pty) Ltd. Lisa Carlson is Director, Medical Writing,

PSI Pharma Support America Inc. Maxim Belotserkovskiy, MD, is Senior

Director, Medical Affairs, PSI CRO Deutschland GmbH. Nickolai Usachev,

MD, is Manager, Pharmacovigilance Unit, PSI Pharma Support Intl.


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SUBJECT ENGAGEMENT


PEER

REVIEW

Satisfaction of Healthy Subjects in Phase I TrialsSherilyn Adcock, PhD, John Sramek, Kurt Hauptmann, Hong Ding, Keith

Fern, Neal R. Cutler, MD

Satisfaction surveys provide clinicians valu-

able insight into quality-of-care metrics.

However, in order for satisfaction surveys

to be most useful and yield meaningful

results that can improve patient outcomes

and well being, the responses must be truthful

and accurately reflect the respondent’s inherent

satisfaction. To achieve this goal, it is important

that the survey be constructed and administered

properly.1 Assessing the satisfaction of healthy

volunteers is important because of the vital role

they play in the drug development process via

assessment of safety of dose administration and

pharmacokinetic characterization of the absorp-

tion, metabolism, and distribution of compounds

in the body.

Satisfaction surveys have been used for de-

cades in healthcare for patients undergoing med-

ical procedures and to assess their experience

during hospital stays.2 Recently, the General Med-

ical Council (GMC) directive in the U.K. requires

clinicians to access the satisfaction of patients

with their performance, even in clinical trials.3

There are many standardized general satisfaction

surveys in healthcare with good validity and reli-

ability, including the Patient Satisfaction Ques-

tionnaire Short Form (PSQ-18)4, the Picker Patient

Experience Questionnaire (PPEQ-15)5, and the

consumer assessment health plans (CAHPS), al-

though many medical centers also generate their

own internal forms. Surveys can be self-reported,

administered by an interviewer, or given over the

phone or by computer. Patients’ evaluation of

their care allows direct feedback on healthcare

performance and suggests areas for improve-

ment.

Satisfaction surveys have also been employed

in late stage clinical trials, as well as in specific

patient populations and the elderly.6,7,8 In ad-

dition, satisfaction surveys have been used in

clinical studies to assess very narrow or specific

aspects of trial satisfaction.9,10 Satisfaction with

the informed consent process has also been

evaluated in both patient11 and caregiver12 popula-

tions. A literature search did not reveal similar

published data on healthy subject satisfaction in

an early phase, clinical trial setting. We have con-

ducted various informal satisfaction surveys for a

number of years in our facilities. This is the first

time we have examined the results using a more

rigorous methodology.

Method

The items on the survey had been created and

reviewed by five clinical trial experts to target

important domains relevant to satisfaction: Back-

ground Information, Informed Consent, Partici-

pation, Facilities, Participation in Other Clinical

Trials, and Overall Impression & Future Participa-

tion. After extensive review by these experts, a

number of items deemed to be nonessential were

removed, leaving the 16 items that were included

owing to their domain relevance (i.e., face valid-

ity) and internal reliability. Demographic data was

also anonymously collected from each subject and

included age, sex, gender, level of education, and

Survey applies rigorous analysis to provide a rare formal look at volunteer satisfaction in early setting.



SUBJECT ENGAGEMENT

employment status. These domain clusters are displayed in

Table 3 (see page 43).

Subjects were healthy participants in five bioequivalence

clinical trials at Worldwide Clinical Trials Drug Development

Solutions (WCT-DDS). These BE trials were similar in design,

consisting of two-period crossover studies, which required

one- to two-night stays for each period. Staff asked subjects

to voluntarily take the 16-question survey anonymously at

their last study visit. A standard satisfaction survey, consist-

ing of 16 questions (two of which were multi-part questions)

relevant to clinical trials, was administered to the partici-

pants (See Figure 1). The survey items were worded as ÒIÓ

statements to give the subjects ownership of their responses.

Each item allowed for a response on a seven-point graded

scale from 1 = strongly agree to 7 = strongly disagree, with a

neutral (4) option in the middle. In addition, some questions

assessed similar criterion in order to assess internal validity.

Relationship of item scores to demographic data was exam-

ined for significance by the Wilcoxin Mann-Whitney Test.

The local institutional review board (IRB) was noti-

fied regarding the survey development prior to planned

administration of the survey. The IRB commented that in-

Source: Adcock et al.

Figure 1. This standard 16-question satisfaction survey was administered to trial participants.

There are several statements and questions listed below. Please circle the one response that you believefts best with each statement.

Informed Consent

Participation

1Strongly

Agree

7StronglyDisagree

2Agree

3SlightlyAgree

4Neutral

5SlightlyDisagree

6Disagree

1Strongly

Agree

7StronglyDisagree

2Agree

3SlightlyAgree

4Neutral

5SlightlyDisagree

6Disagree

1Strongly

Agree

7StronglyDisagree

2Agree

3SlightlyAgree

4Neutral

5SlightlyDisagree

6Disagree

1Strongly

Agree

7StronglyDisagree

2Agree

3SlightlyAgree

4Neutral

5SlightlyDisagree

6Disagree

1Strongly

Agree

7StronglyDisagree

2Agree

3SlightlyAgree

4Neutral

5SlightlyDisagree

6Disagree

1Strongly

Agree

7StronglyDisagree

2Agree

3SlightlyAgree

4Neutral

5SlightlyDisagree

6Disagree

1Strongly

Agree

7StronglyDisagree

2Agree

3SlightlyAgree

4Neutral

5SlightlyDisagree

6Disagree

1Strongly

Agree

7StronglyDisagree

2Agree

3SlightlyAgree

4Neutral

5SlightlyDisagree

6Disagree

1Strongly

Agree

7StronglyDisagree

2Agree

3SlightlyAgree

4Neutral

5SlightlyDisagree

6Disagree

1Strongly

Agree

7StronglyDisagree

2Agree

3SlightlyAgree

4Neutral

5SlightlyDisagree

6Disagree

1Strongly

Agree

7StronglyDisagree

2Agree

3SlightlyAgree

4Neutral

5SlightlyDisagree

6Disagree

1Strongly

Agree

7StronglyDisagree

2Agree

3SlightlyAgree

4Neutral

5SlightlyDisagree

6Disagree

1Strongly

Agree

7StronglyDisagree

2Agree

3SlightlyAgree

4Neutral

5SlightlyDisagree

6Disagree

1Strongly

Agree

7StronglyDisagree

2Agree

3SlightlyAgree

4Neutral

5SlightlyDisagree

6Disagree

1Strongly

Agree

7StronglyDisagree

2Agree

3SlightlyAgree

4Neutral

5SlightlyDisagree

6Disagree

1Strongly

Agree

7StronglyDisagree

2Agree

3SlightlyAgree

4Neutral

5SlightlyDisagree

6Disagree

1.) I was provided with adequate time to read and ask questions about the informed consent form.

Facilities

Overall Impressions & Future Participation

9.) The facilities (exam rooms, recreation areas, patient rooms) were clean.

10.) I was provided with acceptable options to keep myself enterained during down time.

11.) The quality of the food was acceptable (consider for your response that many studies require a standardized diet).

12.) I was able to sleep well throughout the study (if applicable).

13.) I believe that I will participate in a future clinical drug trial.

14.) The stipend I received for participation in this study was an acceptable amount for the time involved and the type and number of procedures I completed.

15.) Overall, my participation in this study was a positive experience.

16.) Based on my experience during this trial, I would recommend a friend or family member to participate in a trial at Cedra.

2.) The informed consent form was confusing and diffcult to understand.

3.) Staff fully answered any questions I had about the informed consent form.

4.) I have a clear understanding of what a clinical trial is.

5.) I was treated respectfully during all study procedures.

6.) I was fully informed throughout the course of the trial about what was going to happen.

7.) I had confdence in the staff performing the procedures.

8.) My overall needs were met during my participation in this study.

Or I did not have any questions about the informed consent.

Satisfaction Survey



SUBJECT ENGAGEMENT

formed consent was not required for the activity. Subjects

were recruited by posted notices and also by staff. Subjects

who volunteered to participate in the survey were directed

into a private area by a staff member on their last visit of the

study in groups of 5-10 subjects at a time, and filled out the

survey questionnaire in privacy. Subjects were verbally told

that their responses were anonymous and would not affect

future participation in trials. Following their completion of

the survey, they sealed the survey in an envelope and handed

it back to a staff member. To keep it anonymous, they were

asked not to write their name or any identifying information

on the survey. Subjects were not compensated for participat-

ing in this survey.

Results

Between 90% to 95% of subjects asked to participate, did so,

with 181 healthy subjects completing the survey (97 male, 80

female, four non-identified; ages 18–55 years). This sample

had a mean age of 33.84 years, had a male-to-female ratio of

1.2125, and was 72.4% White, with 55.25% self-identifying as

Hispanic or Latino. Most subjects were 30 years of age and

older (107), non-married (111), college-educated (92), and not

currently employed (92).

In general, subjects were satisfied with their participation

in the study, with an overall mean score of 2.26 (Std Dev =

0.68) on the satisfaction survey (1 being most satisfied and 7

being least satisfied). Fourteen questions had a mean score

between 1 and 3, and only two questions had a mean score

between 3 and 4 (see Table 1). The highest reported mean

satisfaction scores related to subjects being given adequate

time to read and understand the informed consent (1.46) and

being clearly explained what a clinical trial is (1.36). The low-

est reported mean satisfaction scores related to the sleeping

conditions (3.51), food quality (4.00), and finding the informed

consent difficult to understand (1.85); note the lower number

for this latter item represents increased difficulty in under-

standing.

An analysis of the total mean survey score versus demo-

graphic group (See Table 2 on page 42), showed that subjects

with college education reported significantly lower satisfac-

tion (p<0.01) with the study overall compared to non-college

educated subjects.

When the analysis of demographic group versus satisfac-

tion scores was broken down further to look at individual

survey questions, a number of significant findings emerged.

Hispanic subjects found the consent form significantly more

confusing than non-Hispanic subjects (p<0.05). College edu-

cated subjects were significantly less likely to participate in

a future clinical trial than non-college educated subjects

(p<0.05), and also to have significantly less satisfaction with

sleeping conditions (p<0.01) and stipend amount (p<0.01)

than non-college educated subjects. Subjects under 30 years

of age were found to have significantly less confidence in the

study staff (p<0.05) than subjects 30 years or older, to report

they were significantly less satisfied with the respect given to

them by the study staff (p<0.05), and to report significantly

less satisfaction with sleeping conditions than subjects 30

years of age or older (p<0.01).

The internal consistency of the satisfaction survey was de-

termined by calculating the Cronbach’s alpha coefficient. The

resulting score of 0.839 indicated an acceptable lower bound

for the reliability coefficient as this is much greater than the

value of 0.70 as suggested by the literature.13

Discussion

Determining healthy subject satisfaction in early clinical tri-

als is an often overlooked but essential component of the

drug development process. Healthy subjects make up the

backbone of early phase clinical research, and their satisfac-

tion with trial processes and procedures is essential in order

to secure their continued involvement. Phase I trials are often

vital for determining proper dosing levels for later stage trials

and measuring adverse events. They can also provide invalu-

able insight on a compound’s efficacy potential, shape the

Determining healthy subject satisfaction

in early clinical trials is an often

overlooked but essential component

of the drug development process.

Mean Scorecard

SURVEY QUESTION N MEAN STD DEV

1 181 1.46 0.87

2 181 1.85 1.25

3 108 1.63 0.90

4 181 1.36 0.81

5 181 2.09 1.31

6 181 1.93 1.18

7 180 2.37 1.14

8 164 1.85 0.92

9 181 2.52 1.60

10 180 2.45 1.40

11 180 4.00 2.01

12 175 3.51 1.80

13 180 1.91 1.15

14 180 2.75 1.38

15 179 2.18 0.95

16 180 2.14 1.17

Overall Score 2.26 0.68


Table 1. Mean score for each survey question.


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SUBJECT ENGAGEMENT

design of later stage trials, or save money by terminating pro-

grams involving dangerous or non-efficacious compounds.

And unlike Phase II, III, and IV trials that involve patients,

healthy subjects in early phase trials typically do not have a

direct, vested interest in the outcome of the trial relating to

their health. Therefore, their overall satisfaction is of utmost

importance. It makes little sense why research on this metric

has been sorely lacking, especially considering the abun-

dance of literature evaluating patient satisfaction in clinical

trials.

Some Phase I sites collect satisfaction data from subjects

who participate, but only use this data internally. To our

knowledge, this is the first published satisfaction survey

administered to healthy normal volunteers who have par-

ticipated in Phase I studies. Our survey instrument dem-

onstrated good face validity and internal consistency. The

chosen method of survey administration guaranteed subject

anonymity, increasing the likelihood of getting truthful re-

sponses. This is supported by literature demonstrating that

a survey’s responses may be influenced by the presence of

an interviewer or an authority figure. One study showed that

oncology patients who were interviewed directly by a person

about quality-of-life issues showed inflated scores compared

to patients who self-administered the same questionnaires,

suggesting the presence of the interviewer has a direct effect

on survey scores.14

Likewise, another study compared three modes of admin-

istration (telephone, face-to-face, and self-administration) of

a commonly utilized health-related quality-of-life measure in

veterans, and found that face-to-face administration provided

a more optimistic picture of health than self-administration,

suggesting an acquiescence bias toward the interviewer’s

perceived predisposition.1 There is a body of literature sup-

porting the tendency of subjects to acquiesce to the per-

ceived will of authority figures.15,16,17 Removal of an interviewer

and the assurance of anonymity allowed us to minimize this

acquiescence effect in our survey and obtain more honest as-

sessments of subject satisfaction.

Survey items were worded as “I” statements to give the

subjects ownership of their responses. In addition, some

questions assessed similar criterion in order to assess

internal validity. Design input was collected from five clini-

cal trial experts, as well as recommendations from the

literature, to capture satisfaction in the most essential

trial elements and provide a high level of consistency. The

participation rate was high, estimated by the WCT clinic to

be greater than 90% of persons who were approached. One

potential drawback is that subjects who were discontinued

Unlike Phase II-IV trials that involve

patients, healthy subjects in early

phase trials typically do not have a

direct, vested interest in the outcome

of the trial relating to their health.

Therefore, their overall satisfaction

is of utmost importance.

Demographic Breakdown

GROUP MEAN SCORE (ALL 16 ITEMS) STD DEV (ALL 16 ITEMS) P- VALUE SIGNIFICANCE

30 Years of Age and Older 2.22 0.07 0.19

Under 30 Years of Age 2.37 0.09 0.19

Male 2.21 0.07 0.24

Female 2.33 0.08 0.24

Non-White 2.23 0.12 0.91

White 2.24 0.06 0.91

Non-Hispanic 2.18 0.09 0.19

Hispanic 2.33 0.07 0.19

Non-Married 2.26 0.07 0.77

Married 2.29 0.08 0.77

Not College Educated 2.11 0.08 0.01 p <0.01

College-Educated 2.39 0.07 0.01 p <0.01

Not currently Employed 2.29 0.07 0.65

Currently Employed 2.24 0.07 0.65


Table 2. The total mean survey score versus demographic group.



SUBJECT ENGAGEMENT

quote_ quote_ quote_ quote_

quote_ quote_ quote_ quote_ quote_

quote_ quote_ quote_ quote_ quote_

quote_ quote_ quote_ quote_

or withdrew from the study early were not captured by our

design. However, the estimated number of subjects who

withdraw early from BE studies is small, about 3% in our

experience. Additionally, our survey was only administered

to subjects who participated in BE studies. Future surveys

should be conducted with subjects who participate in other

types of Phase I studies, such as safety/tolerance and QTc

studies, as the satisfaction rate for these often longer and

more demanding studies may be different from what we

found in BE studies.

Although we found a number of significant findings when

comparing demographic variables to satisfaction scores,

none of these appear to be of meaningful clinical signifi-

cance, as all were less than one-point difference on our rat-

ing scale. For example, our significant finding that Hispanic

subjects found the consent more confusing than non-His-

panic subjects was only reflected in a difference of less than

half of one point (0.47) in the rating scale. We also found that

subjects in general found the consent form confusing and

difficult to understand; however, given that these BE consent

forms were around 13 pages in length and contained numer-

ous details about study design, adverse events, etc., this may

not be surprising and may be unavoidable. Fortunately, sub-

jects highly agreed that they were given enough time to prop-

erly review and ask questions about the informed consent.

Based on their responses in this survey, subjects were

generally satisfied with all aspects of their participation, and

the mean/SD scores did not indicate a ceiling effect on the

survey instrument. Even survey items with lower satisfaction

results (food and sleep) were still rated as “neutral” and not

negative. Lower satisfaction with food may result from study

dietary requirements, while lower satisfaction with sleep may

result from poor mattresses and the use of a dormitory set-

ting. Subsequent to this survey, the clinic made strides to

improve the food service, and upgraded the quality of mat-

tresses. Significant findings relating levels of satisfaction to

various demographic variables suggest that further study is

warranted.

References

1. Weinberger, M., et al., “Are health-related quality-of-life measures

affected by the mode of administration?” J Clin Epidemiol, 1996.

49(2): p. 135-40.

2. Al-Abri, R. and A. Al-Balushi, “Patient satisfaction survey as

a tool towards quality improvement.” Oman Med J, 2014. 29(1):

p. 3-7.

3. Campbell, J.L., et al., “Assessing the professional performance of

UK doctors: an evaluation of the utility of the General Medical

Council patient and colleague questionnaires.” Qual Saf Health Care,

2008. 17(3): p. 187-93.

Key Satisfaction Domains

DOMAIN CLUSTER ITEMS SURVEY ITEMS

1. Informed Consent 4

I was provided with adequate time to read and ask questions about the informed consent form.

The informed consent form was confusing and difficult to understand.

Staff fully answered any questions I had about the informed consent form.

I have a clear understanding of what a clinical trial is.

2. Participation 6

I was treated respectfully during all study procedures.

I was fully informed throughout the course of the trial about what was going to happen.

I had confidence in the staff performing the procedures.

The staff handled my problem(s) in a timely manner.

I feel that I was treated to the best of the staff’s ability.

My overall needs were met during my participation in this study.

3. Facilities 4

The facilities (exam rooms, recreation areas, patient rooms) were clean.

I was provided with acceptable options to keep myself entertained during down time.

The quality of the food was acceptable (consider for your response that many studies require a standard-

ized diet).

I was able to sleep well throughout the study (if applicable).

4. Participation in Other

Clinical Trials2

The total number of clinical trials I have participated in is ____.

If I participated in a clinical trial at another facility (not WCT-DDS), my experience there compared to WCT-

DDS was _______.

5. Overall Impression

and Future Participation 4

I believe that I will participate in a future clinical drug trial.

The stipend I received for participation in this study was an acceptable amount for the time involved and

the type and number of procedures I completed.

Overall, my participation in this study was a positive experience.

Based on my experience during this trial, I would recommend a friend or family member to participate in a

trial at WCT-DDS (here).


Table 3. Domain cluster groupings of survey items.



SUBJECT ENGAGEMENT

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12. Chappuy, H., et al., “Parental comprehension and satisfaction in

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Sherilyn Adcock, PhD; John Sramek, PharmD; Kurt Hauptmann,

MS; Hong Ding, MS; Keith Fern, MBA; Neal R. Cutler, MD, all of

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A CLOSING THOUGHT

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Improvements in technology, an increased

understanding of disease mechanisms, and

enhanced clinical trial processes and systems

are bringing new tools and resources with the

potential to help researchers develop safe

and effective drugs for this indication.

In the era of personalized medicine, imag-

ing and cerebrospinal fluid (CSF) biomarkers

play an increasingly pivotal role in AD tri-

als. The development and widespread use of

positron emission tomography (PET) tracers

enable clinicians and investigators to detect

and measure key targets, including amyloid

plaques and tau tangles, hallmarks of neuro-

degenerative disease. CSF biomarker assays

are being developed with the goal of identify-

ing and diagnosing patient cohorts in the ear-

liest stages of AD, prior to structural changes

in the brain and cognitive defects.

Biomarker approaches help direct tailored

treatment options to patients most likely to

respond, minimizing risk for patients unlikely

to benefit from treatment. Moreover, the abil-

ity to image the brain of AD patients during

the course of treatment provides a critical

tool for detecting and monitoring amyloid-

related imaging abnormalities (ARIA), includ-

ing edema and microhemorrhages, often

observed with immunotherapies targeting

amyloid plaques. Early detection of ARIA in

patients, combined with appropriate monitor-

ing and management, is important for reduc-

ing patient risk during the course of a trial.

Treating patients in the earlier stages of

disease translates to treating a significantly

younger population (on the order of decades),

potentially decreasing the likelihood for cer-

tain adverse events and complications. Strati-

fication of patient populations also increases

the likelihood of observing disease-modifying

activity, which may otherwise be obscured by

overlapping patient populations in various

stages of disease.

With over 500 open clinical trials for AD

looking to enroll thousands of patients, one

of the largest obstacles to developing new

and safe treatments is patient recruitment.

Many AD trial participants are over the age

of 65, may be undergoing treatment for other

diseases (e.g. cardiovascular disease, meta-

bolic disease), and may not meet inclusion

criteria designed to ensure participant safety.

Furthermore, the use of biomarkers for AD

diagnoses may result in more stringent inclu-

sion criteria for a trial.

Today’s trials require specialized recruit-

ment-retention strategies to enroll suitable

patients, keep them safely in the trial, and

minimize loss to follow up. To satisfy enroll-

ment needs, specialized industry services

aimed at ensuring the safety of patients over

the duration of long, complex trials are be-

coming more popular among sponsors.

Concerted patient-centric practices aligned

with personalized medicine, biomarker use,

and patient recruitment have already trans-

formed the design of AD clinical trials. These

efforts will continue to grow and ultimately

contribute to the approval of the first disease-

modifying therapy for this widespread disease.

Drug safety is an especially challenging issue in emerging treatments

for Alzheimer’s disease (AD), requiring pharmaceutical and biotechnol-

ogy companies to refocus clinical trial design using patient-centric

approaches that mitigate risk and manage adverse events. Current

research indicates that AD is a complex disease with a long progression

from early onset to the manifestation of clinical symptoms. Moreover,

physicians can struggle with the clinical diagnosis of AD versus related de-

mentias. Taken together, drug sponsors face the task of enrolling diverse

patient populations, which they must carefully enrich and monitor through-

out lengthy clinical trials.

Developing New Alzheimer’s Drugs With a Focus on Patient Safety

Biomarker approaches

help direct tailored

treatment options to

patients most likely to

respond, minimizing risk

for patients unlikely to

benefit from treatment.

John Hubbard, PhD, FCP

President and CEO, BioClinica


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