YOUR PEER-REVIEWED GUIDE TO GLOBAL CLINICAL TRIALS ...files.alfresco.mjh.group/alfresco_images/pharma/2014/08/20/9121fd74-cb... · 1992–2011 ACT20 Year of rSe v i c e Volume 20,

YOUR PEER-REVIEWED GUIDE TO GLOBAL CLINICAL TRIALS MANAGEMENT appliedclinicaltrialsonline.com

1992–2011

ACT

2020Year of Servi c

e

Volume 20, Number 2 February 2011

INSID

E

Hispanics

Underrepresented

in Trials

➤ INFORMATION TECHNOLOGY

A Risk-Based Approach for Computer Systems Validation

➤ SITES

Trial Monitoring: Source Document Verifi cation

➤ REGULATORY

FDA’s Guidance on Patient-Reported Outcomes

Also in this issue

■ FDA’s Oversight Capabilities Increased

■ Influenza Warning Issued

■ Cloud Computing: A Reality?

■ Guidance Says Focus on the Patient

Complete contents pages 6

Volu

me 2

0 N

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In

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Site

s • R

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1

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A P P L I E D C L I N I C A L T R I A L S

COMMENTARY

10 From the EditorCROs Show Biosimilar Strength

Lisa Henderson

20 View from WashingtonChanges at FDA and Challenges on Capitol Hill

Jill Wechsler

24 View from BrusselsH1N1 Influenza: Not to be Sneezed at

Peter O’Donnell

28 Technology ViewpointAre We Ready to Fly into the Cloud?

Wayne Kubick

58 A Closing ThoughtThe Patient Matters: Thanks FDA

Jean Paty

CLINICAL TRIALS COMMUNITY

14 News

52 Business and People Update

54 Calendar of Events

MARKETPLACE

56 Showcase

57 Marketplace

55 Advertiser Index

VOLUME 20, NUMBER 2

SITES

38 Targeting Source Document Verification

Sandra Hines

Targeted SDV provides data valida-

tion by comparing trial data with

primary health records.

REGULATORY

44 The FDA’s Guidance on PRO

Jane Speight and Shalleen Barendse

This guidance has both raised the

stakes and improved the odds of

securing label claims based on PROs.

COVER STORY

32 New Approach to System ValidationRichard Von Culin

Considerations in implementing a risk-based framework for computer

systems validation.

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A P P L I E D C L I N I C A L T R I A L SEditorial Advisory Board

The expertise of Editorial Advisory Board members is essential to the

credibility and integrity of Applied Clinical Trials. These clinical trials experts

share with the editors the wisdom gained through their experience in many

areas of drug development. EAB members review manuscripts, suggest top-

ics for coverage, and advise the editors on industry issues. All manuscripts

must first be submitted to the Editor-in-Chief, Applied Clinical Trials, 485

Route 1 South, Building F, First Floor, Iselin, NJ 08830 USA.

Kiran Avancha, PhD, RPhClinical Research PharmacistUniversity of Miami Hospital and Clinics/Sylvester Comprehensive Cancer CenterMiami, FL

Aaron F. Bartlone, MSVice President& Head of Global QualityUCBBrussels, Belgium

Maarten Beekman, MDVice President, Medical & Regulatory AffairsAstraZeneca Zoetermeer, Netherlands

Paul Bleicher, MD, PhDChief Medical OfficerHumedicaBoston, MA

Timothy Callahan, PhDChief Scientific OfficerBiomedical SystemsSaint Louis, MO

Jo Collier, MBChB, FFPMMedical DirectorClinical Science and PharmacokineticsQuotient ClinicalNottingham, UK

Francis P. CrawleyExecutive DirectorGood Clinical PracticeAlliance–EuropeKessel-Lo, Belgium

Domenico Criscuolo, MD, PhD, FFPMChief Executive OfficerGenovaxColleretto Giacosa, Italy

Edward Stewart Geary, MDVice President& Global Safety OfficerEisai Co., Ltd.Tokyo, Japan

Uwe Gudat, MDMedical DirectorOffice of Chief Medical OfficerMerck SeronoGeneva, Switzerland

Felix Khin-Maung-GyiPharmD, MBA, CIPChief Executive OfficerChesapeake Research Review, Inc.Columbia, MD

Michael R. Hamrell, PhD, RACPresidentMORIAH ConsultantsYorba Linda, CA

Erica J. Heath, CIP, MBAPresidentEthical and Independent Review Services, LLCSan Anselmo, CA

Tim M. Jaeger, MD, PhD, MBAHead of Commercial Operations EMEA & LATAMSwisslab LIS SolutionsRoche Diagnostics Ltd./Swisslab GmbHBerlin, Germany

Brian J. Koziol, PhDDirector, Project Management& Strategic OperationsAmgen Inc.Thousand Oaks, CA

Patricia E. Koziol, PhDPresidentPEK Associates, Inc.Holmdel, NJ

Jeffrey S. Litwin, MDExecutive Vice President & Chief Medical OfficerERTPhiladelphia, PA

Somesh Nigam, PhDVice PresidentHealthcare InformaticsMedical Devices & DiagnosticsJohnson & JohnsonNew Brunswick, NJ

Timothy Pratt, PhD, MBAPrincipalCRUCIAL Clinical/Business ConsultantsMinneapolis, MN

Stanley C. RogersExecutive Vice PresidentSMHW Associates, LLCLawrenceville, NJ

Richard Rubin, MDDirectorThe Vermont Clinical Study CenterBurlington, VT

Stephen Senn, PhDProfessor of StatisticsDepartment of StatisticsThe University of GlasgowGlasgow, UK

Johanna Schenk, MD, FFPMSenior Partner& Managing DirectorPharmaProjekthaus GmbH & Co. KGFrankfurt, Germany

Albert J. Siemens, PhDChairmanNovella Clinical Inc.Research Triangle Park, NC

Thomas Sudhop, MDDirector and ProfessorFederal Institute for Drugsand Medical DevicesBonn, Germany

John R. Vogel, PhDDrug Development ConsultantJohn R. Vogel Associates, Inc.Kihei, HI

Glen de VriesPresident Medidata Solutions WorldwideNew York, NY

www.appliedclinicaltrialsonline.com


Lisa Henderson

Editor-in-Chief

email: [email protected]

www.appliedclinicaltrialsonline.com

From the Editor

Parexel made this announcement

in short advance of JP Morgan’s

Healthcare Conference. At the

conference, it was reported that both

Amgen and Biogen made comments

about biosimilar activity. Amgen would

consider biosimilars particularly in

emerging markets like Asia and South

America, with a specific biosimilar

strategy to be announced at its April

investor meeting. George Scangos,

Biogen CEO, also noted it was in a

prime position to develop biosimilars

because of its manufacturing and

expertise in biologics.

In December, I interviewed

two executives at PharmaNet

Consulting, another CRO offering

biosimilar services to the sponsor

community. Those interviews are

available in part as a podcast at www.

appliedclinicaltrialsonline.com/

biosimilarspodcast and in a news article

on page 16 of this issue.

The interview centered around FDA’s

November meeting on biosimilars.

The FDA has no formal guidance for

biosimilar development and William

Egan, PhD, Vice President, described

this meeting primarily as a listening

exercise. Egan, who is a 28-year FDA

veteran himself, isn’t alarmed that the

FDA doesn’t have a formal guidance yet

in place to address biosimilars. Rather,

both he and Jeffrey Freitag, MD, Senior

Vice President, put forth that being

familiar with the actions FDA has made

to date will help guide sponsors on the

regulatory pathway.

“In the absence of guidelines,

biosimilar development can go

forward,” Egan said. “But [the FDA]

may issue guidelines. It ’s likely there

will be some guidelines, probably

along the lines of the guidelines when

the FDA began their formal process

of comparability in 1996 about how

manufacturers could demonstrate

comparability. They were general in

nature.”

Biosimilars meanwhile have a

regulatory pathway in the EU. These

have been proven for the three

“traditional” classes of biologics—

growth hormones, epoteins, and

recombinant insulins. Therefore,

there is a wealth of clinical safety data

that could be used to back up a US

submission. Freitag noted that using

EU safety data is a possibility.

The Merck/Parexel agreement

proves Freitag’s statement that

manufacturers are not going to wait for

a formal guidance. When opportunity

comes knocking, it will be up to the

sponsors and CROs to communicate

early on with FDA to ensure their

regulatory plan is copasetic.

Biosimilars are the generic equivalent of biologics, large

molecule compounds that include living cells, or recombinant

DNA. Biologics are typically the domain of the biotechnology

companies, and more so now with traditional pharma. In recent years,

with the economy gutting their financials, the increasing growth of

biologics as therapeutic agents, and the first of blockbuster biologics

coming off patent, CROs have come forward on their historic

strengths to address biosimilar development. Last month, Parexel

and Merck announced their alliance; Parexel will bring regulatory and

clinical development planning to Merck BioVentures, which has a goal

of five potential products in late-stage clinical trials by 2012.

Without a stated FDA guidance on biosimilars, regulatory strength may be helpful on the biosimilar development program.

CROs Show Biosimilar Strength

Consolidateddato

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appliedclinicaltrialsonline.com

N O T E W O R T H Y

Go to:


to access these exclusive stories

and other featured content.

@trialsonlineApplied Clinical Trials has joined

the legions of Twitterati and those

who tweet. Follow us to get daily

alerts on broad topics of interest

@trialsonline.

Investigator PortalsRodd Schlerf, FDA and USDA

Markets Manager, ARX, and

Michael Ayers, Associate Director,

Information Technology, PPD,

discuss digital signatures, secu-

rity, investigator portals and

more in the webcast “Enhancing

Clinical Operations with Digital

Signatures.” According to a poll

taken during the webcast, 25%

of respondents currently use an

investigator portal.

Latino/Hispanic Recruitment In our online news section, recruit-

ment company MMG announced

a forum with Hispanic and Latino

healthcare community leaders.

The goal? To improve understand-

ing of the research barriers faced

by this population. Assistant

Editor Kayda Norman offers an

article on this issue, and a blog on

outreach to this population.

The Most Influential in Healthcare?In an informal website survey asking this question, respondents overwhelmingly

chose government organizations. A glimpse at our sister site, PharmExec.com,

reveals responses to the same question proclaimed their top three stakeholders

as payers 38%, regulators 24%, and government organizations 17%.

Risk evaluation and mitigation

strategies (REMS), have been

a requirement since 2007. In an

online exclusive article, Lawrence Gry-

lack, MD, Principal Consultant, Par-

exel Consulting, updates the current

status and provides insight into REMS

for sponsors. The following excerpt

comes from his article “Regulatory

Update on Risk Evaluation and Mitiga-

tion Strategies (REMS)”:

One hundred and fifty REMS have

been approved as of October 13, 2010.

These have been for products that

were the focus of both New Drug Ap-

plications (NDAs) as well as Biologic

License Applicat ions (BL As). Ap -

proximately two-thirds of the approved

REMS contain only a medication guide.

The remainder required additional com-

ponents such as elements to assure safe

use (ETASU), a communication plan,

and an implementation system. Less

than 25% of the REMS have a communi-

cation plan as the primary element, and

less than 10% have the ETASU as the

primary element. Despite these other

elements being required, rarely was

a medication guide not required. As-

sociated with the FDAAA legislation,

approximately 300 post-marketing re-

quirements have been issued. In addi-

tion, approximately 40 label changes

have been recommended. T hese

have typically been recommended for

classes of products. REMS may also

be modified, and between 10% and 15%

have undergone revision.

Based on the experience to date,

the FDA has recognized that it still

faces ongoing challenges in terms of

meeting its goals in the REMS arena.

Although the FDA is bound by the

statutory requirements that exist with

regard to REMS, evolution of process

and policy is still ongoing.

0%

Governmentorganizations

Medical insurers

Payers

Regulators

Patients

Physicians

20%10% 30% 40% 50% 60%

15%

54%

8%

8%

8%

8%

Who do you think will become the most influential healthcarestakeholders in the next few years?

Source: appliedclinicaltrialsonline.com survey, 12/22/2010-1/20/2011

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News

T H E R A P E U T I C C O R N E R

G L O B A L N E W S

In mid-January, a combined

Data Safety and Monitoring

Board (DSMB) halted one of

two Phase III trials of Merck’s

investigational anti-clotting drug

vorapaxar because of increased risk

of bleeding—specifically intracranial

hemorrhage—in subjects with a

history of stroke.

The TRACER study was being

conducted by Duke Clinical Research

Institute. It was fully enrolled in June

2010 and included 13,000 subjects

with non-ST-segment-elevation acute

coronary syndrome. TRA-2P, or TIMI

50 as the trial was also known, was

fully enrolled in November 2009 and

included 26,500 subjects who had

previously experienced a heart attack.

The study was being conducted by

Brigham and Women’s Hospital.

The DSMB instructed TRACER

investigators to discontinue the study

drug in subjects and begin close-out

activities. For TRA-2P, investigators

were told to discontinue the study

drug in those who experienced a

stroke prior to entering or during

the course of the study. They could

continue the study drug in those who

entered the trial with a history of a

previous heart attack or peripheral

arterial disease, an estimated 75% of

the subjects.

The clintrials.gov identifier for

the TRACER trial is NCT00527943,

and NCT00526474 for TRA-2P.

Peter Kim, PhD, President of Merck

Research Laboratories, emphasized

in a conference call that the goal of

vorapaxar was to find “an antiplatelet

agent that we could add on top of

standard of care.” Vorapaxar is one

of the company’s key programs in

Phase III, and it had anticipated

filing for approval this year. While

financials were not discussed, at an

estimated cost of $26,000 per subject

in Phase III trials, this represents

a $338 million hit to the company’s

bottom line.

The number of patients participat-

ing in clinical research in the

state healthcare sector, the

National Health Service (NHS), took

a significant leap forward in England

during 2010, according to new data

released by the National Institute for

Clinical Research’s (NIHR) Clinical

Research Network.

The figures show that more than

500,000 people participated in NIHR

Clinical Research Network studies

last year, compared with 300,000

in 2009. The institute was set up by

the Department of Health to reduce

the red tape around setting up clini-

cal studies. It also aims to identify

patients to participate in studies and

to cover additional costs such as re-

search nurses and imaging examina-

tions so that research activities do not

drain NHS resources.

“We are working to raise the level of

patient awareness about clinical stud-

ies, so that people start to ask their

doctor about participating in a research

study as part of their care,” noted Jona-

than Sheffield, MD, Chief Executive of

the NIHR’s Clinical Research Network.

“Today’s figures suggest that all of this

activity is gathering momentum.”

In the past, research activity was

focused on the big teaching hospitals,

but by supporting research posts and

costs in a wider range of hospitals, it

has been possible to cast the net wider,

and more patients now have access to

clinical studies, he said.

Participation in clinical research

is written into the NHS constitution

and operating framework, but Shef-

field thinks that more groundwork is

needed to ensure that all parts of the

NHS embrace the research culture.

“The NHS has been asked to make

efficiency savings over the next four

years. That means understanding

which treatments work best for pa-

tients, so we can focus resources in

these areas,” he added. “We need the

level of research activity to continue

to grow, so we can determine the very

best healthcare solutions, and help the

NHS to shape its service for the future.”

Sheffield took up his current post

on October 1, 2010, having previously

served on the institute’s advisory

board, which works with the Depart-

ment of Health on the strategic devel-

opment of the NIHR. He was formerly

medical director at the University Hos-

pitals Bristol NHS Foundation Trust.

He is also a member of the Department

of Health Cancer Task Force, and was

chair of the Regional Modernization

Cancer Task Force. —Philip Ward

State Cash Fuels Growth in England

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News

N E W S

In early November, the Food and

Drug Administration held a two-day

public meeting to gather input from

a variety of industry stakeholders to

determine the future of a regulatory

pathway for biosimilar development in

the United States. Later in the month,

the European Medicines Agency issued

its draft guideline on immunogenicity

assessment of monoclonal antibodies

intended for in vivo clinical use,

available at www.ema.europa.eu/docs/

en_GB/document_library/Scientific_

guideline/2010/11/WC500099362.pdf.

In a recent interview with Applied

Clinical Trials, Jeffrey Freitag, MD,

Senior Vice President of PharmaNet,

offered his thoughts on the future of

biosimilar development in the United

States, as well as how the EU’s more

advanced regulatory pathway impacts

this side of the pond.

“The big unknown is really what’s

on the horizon and that is the mono-

clonal antibodies. Blockbuster mono-

clonal antibodies primarily in the

cancer arena and rheumatology are

going to be coming off or already are

off patent,” said Frietag. In a related

statement released by PharmaNet, he

stated that for the FDA moving for-

ward, immunogenicity or patient safety

will “emerge as the key issue and that

carefully designed clinical trials will

be crucial in this process.”

At the FDA meeting, Freitag said

that some presentations keyed in

to “very interesting” concepts of

trial designs. “I think that is what is

likely going to be required as we go

forward—especially with monoclo-

nal antibodies—is innovative trial

designs. And that can take many fac-

ets,” said Freitag.

He believes it will require the co-

operation between clinical developers

and the

regulatory

agencies

to come up

and approve

these innova-

tive designs.

Those novel

designs

could take

the following

forms: use of

surrogate endpoints; shortened time

intervals for approval with follow-on

later after approval, for example as in

oncology drugs; innovative statistical

methodologies; and others. Freitag

said “something is going to need to be

considered if you want to avoid hav-

ing to do many, many hundreds, if not

thousands of patients in an equivalence

design clinical trial.”

To date, Europe has approved 14

biosimilars with no significant safety

issues reported (save for one that was

a follow-on biologic called Eprex, an

epoetin alfa to treat anemia, which suf-

fered from a significant safety issue in

France). The biosimilar developments

that have been reviewed in Europe

include three classes—human growth

hormones, epoetins, and recombinant

insulins. Freitag noted that these

drugs have been fairly safe and that

was supported by the audience when

the FDA asked if there were any is-

sues they should be alerted to and

no one responded. “Meaning that the

European experience has been a posi-

tive one,” Freitag said. “And that the

follow-up to that was would the FDA

consider letting data from Europe

carry the weight of the necessary ap-

proval process for US submissions. So

I think that remains out there as poten-

tial consideration.”

Freitag emphasized that the FDA

is not going to follow the European

Guidelines, per se. However, because

there has been several years of use of

biosimilars in the EU, with exhaustive

review and without safety issues, it

might make sense to not reinvent the

wheel and allow some use of the clini-

cal data in the United States.

Sponsors desiring a formal biosimi-

lar guidance from the FDA will go

forward without, as Freitag noted in

the podcast interview available on the

Applied Clinical Trials website. With a

growth hormone already approved in

the United States, as well as the July

2010 FDA approval of a low-weight mo-

lecular heparin (enoxaparin), there are

pathways to approval.

In fact, according to Freitag, the

enoxaparin approval may offer an

inkling of where the FDA and Europe

differ. “Enoxaparin was approved in

the United States earlier this year

based on preclinical data and Phase I

data and no late phase clinical trials.

Europe would suggest, based on their

guidelines that late-stage trials will be

necessary. In fact, Europe has more or

less stated, even though they have de-

veloped a guideline for low molecular

weight heparin, they feel it is very un-

likely that a biosimilar for low-weight

molecular heparin…could be approved

in Europe just because of the difficul-

ties in demonstrating biosimilarity.”

What does this mean to the clini-

cal trial community? Obviously, says

Freitag that there wouldn’t be inappro-

priate short cuts taken in clinical de-

velopment. However, clinical trials will

be impacted by taking European data

into consideration, as well as innova-

tive trial designs and ethical concerns

surrounding any patient population.

—Lisa Henderson

Biosimilars in the US & EU Regulatory Pathways

Jeffrey Freitag, MD

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data from an oncology study.

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N EW S

News

According to the US Census Bu-

reau, Hispanics constitute the

nation’s largest ethnic or race

minority. In contrast, Hispanics make

up only 1 percent of clinical trial par-

ticipants. Ella Grach, MD, Executive

Medical Director at Wake Research As-

sociates, explains that part of the reason

the Hispanic population is underrep-

resented in trials is a lack of education

about clinical research.

“A lot of minority populations…don’t

know enough about clinical research so

they think they’re going to be used as a

guinea pig and really try to stay away,”

Grach said. “So step number one, you

have to educate the population. In order

to educate the population, you need to

know how to reach out.”

Minority representation is of dire

concern to researchers because

various ethnic groups have different

reactions to pharmaceuticals. There-

fore a diverse trial population allows

researchers to study potential side ef-

fects in a more realistic way. Without

minority participation in clinical trials,

whole populations are left vulnerable to

unforeseen side effects.

“The leading causes of death in the

Hispanic population is cardiovascu-

lar diseases and cancer,” Grach said.

“There are so many trials right now that

this population would benefit from, and

pharmaceutical companies would bene-

fit by having that ethnic variety enrolled

in clinical trials. I think that we need to

fill that gap.”

While some may believe that reach-

ing out to a different community might

be as simple as handing out brochures

translated in another language, cultural

barriers often stand in the way.

To better understand the Hispanic

population, Wake Research Associates,

a multi-center clinical research site,

completed a training course provided

by Blaire Borthayre, CEO of Hispanic

Marketing Resources. Borthayre’s

training helps companies reach out to

the Hispanic population by teaching

clinical research sites about differences

in cultural behaviors. To improve the re-

lationship between minority participants

and clinical research companies, the

course works on building trust between

the two parties.

“I do not work with businesses who

seek only to have their materials trans-

lated into Spanish,” said Borthayre.

“Motivations and concerns regarding

clinical trials are very different for the

Hispanic immigrant and those issues

are simply not addressed by most

clinical sites.”

Borthayre’s course is mandatory for

recruiters and clinical research coor-

dinators at Wake Research Associates.

The course, based off of information

from focus groups and surveys, is

taught either in person or through we-

binars. Before Borthayre teaches the

course, she does an initial interview

to find out what the company does and

what topics students want to cover.

Borthayre then prepares her webinar

based on this interview.

A retention exam is given at the end

of the course, and a certificate is is-

sued based on the results. In addition,

Borthayre is also available to come on

site where the company can ask ques-

tions and seek her opinion on ideas

and advertisements.

The course, which focuses on the

needs of the foreign born Hispanic, is

particularly useful for those living in

an area where the Hispanic population

is fairly new.

“Our situation is unique,” Grach said.

“I have a good friend in Miami where

there are a lot of (Hispanic) populations

there. (The population is) people who

have lived there and also newcomers, so

it’s a good mix. The course is probably

not important for researchers in Miami.”

This course is especially relevant

to Wake Research, located in Raleigh,

North Carolina, where 75 to 80 percent

of the Hispanic populations are “new-

comers,” according to Grach.

Grach told Applied Clinical Trials that

the immigration community itself could

be broken down into various segments.

For instance, someone who came to the

United States 20 years ago might be clas-

sified as a segment 4, whereas someone

who came to the country a few years ago

would be considered segment 1.

“(Borthayre) said (segment 1) is the

most vulnerable population you need

to learn how to deal with. I learned a

lot of useful information and I insisted

that I wanted to take that course my-

self,” Grach said.

Although the staff at Wake Re-

search took the course only a month

and a half ago, they have started to see

positive results.

“We’ve already seen changes. We’ve

learned some minor things. We never

knew Hispanics are the number one

population in the United States us-

ing cell phones, so that was good…to

know how to communicate with them,”

Grach said.

Grach plans on continuing to use

Borthaye’s services in the future,

as she seems to view learning about

Hispanic culture as an ongoing pro-

cess, rather than an isolated, one-time

event. “I’m planning on staying in

touch with her and continuing to use

her services because I don’t think we

are there yet,” Grach said.

To learn more about the course visit

www.hispanicmarketingresources.com.

—Kayda Norman

Hispanics Remain Minority in Clinical Trials

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appliedclinicaltrialsonline.com APPLIED CLINICAL TRIALS 19February 2011

L E T T E R S T O T H E E D I T O R

D A T A A N A LY S I S

It was not a surprise to read the re-

sults of the Applied Clinical Trials

2010 Salary & Satisfaction Survey,

especially with regard to increased

workload. Two things we have noticed

in the communications sector is more

outsourcing of PR and marketing

work as internal staffs are gutted and

more poorly written pieces announc-

ing trials results are released.

The latter is most troubling, as

newswires are full of corrections to er-

ror-ridden press releases. Most of the

media contacts on these releases are

C-level executives with titles unrelated

to communications-oriented roles,

which tells me that overworked owners

of small-to-mid-sized firms are trying

to handle the communications function

themselves. The legal repercussions

of publishing misleading or incorrect

information aside, having scientists

do PR or marketing without proper

training, experience, or oversight can

be devastating for a company’s reputa-

tion and brand. Unfortunately, this is

a trend we will continue to see until

economic factors begin leading to in-

creased staffing.

David D. Menzies

President

Menzies Consulting, Inc.

Asia, Latin American, and East-

ern Europe are increasingly at-

tractive geographies in which to

conduct clinical research. The data in

GrantPlan® shows that overhead rates

in many countries are increasing, as

illustrated by China and India. Accord-

ing to ClinicalTrials.gov, GrantPlan

subscribers conduct over 76 percent of

all clinical trials.

Drug development professionals al-

ready know that successful investiga-

tors and sites often seek to command

a premium in any discussion over

clinical trial agreement negotiations.

Similarly, when multiple studies in the

same indication are looking to enlist

investigators, individual sites are of-

ten in a stronger position to command

a price premium. We see much the

same phenomenon at work in geogra-

phies newer to clinical research. They

offer large naïve patient pools, well

trained physicians, and potentially

lower costs.

For instance, recent data shows that

China and India are experiencing sus-

tained growth in the number of clini-

cal sites involved in commercial clini-

cal trial activity. Unlike in the United

States, the vast majority of clinical

research in China and India is done

in hospitals, rather than private prac-

tice. The demand for clinical research

services is growing in the institutions,

while the supply is clearly limited.

Many of these institutions in China

and India are putting in substantial

effort to better understand their clini-

cal trials’ indirect costs. These are all

the costs that are necessary to sustain

the infrastructure for the conduct of

clinical research, but which cannot be

directly charged to any specific proj-

ect. Supply and demand also helps to

explain the increase in overhead rates.

These institutions are in demand.

Institutions can charge these rates be-

cause someone will pay them.

—TTC (for more information, contact

[email protected]).

Rates Increase Abroad Due to High Demand

Salary & Satisfaction Survey

0

10

12

14

16

18

20

2007

14%

15%

2008

14% 14%

2009

18% 18%

2010

18%

17%

China

India

Source: TTC

Average institutional overhead rates in China and India.


To see more View from Washington articles, visit


View from Washington

Jill Wechsler

is the Washington editor

of Applied Clinical Trials,

(301) 656-4634

[email protected]

Changes at FDA and Challenges on Capitol HillCongress readies probes of FDA practices, while FDA seeks transparency and organizational changes.

One of the last acts of Congress

in 2010 was to approve sweep-

ing food safety legislation.

The new law provides the

Food and Drug Administration with

more authority to recall and monitor

food products, boosts its inspection

force, and strengthens its capacity to

halt unsafe imports. This may be the

last time for a while that the legislators

bolster FDA’s oversight capabilities

or authorize added resources. With

Republicans taking over the House last

month and increasing their clout in

the Senate, Congressional leaders are

contemplating broad federal budget cuts

and much more aggressive oversight of

administration health policy and regula-

tory programs. FDA is a prime target as

agency critics move to examine an ap-

parent slow-down in new drug approvals

and the agency’s difficulties in keeping

violative products off the market. It’s not

clear that Congress will even provide

the $1.4 billion over five years to hire

some 2,000 additional FDA inspectors

for the new food safety program.

Similar legislation to strengthen

drug safety, moreover, is not likely

to move forward in the near future.

House Democrats have proposed a bill

giving FDA additional enforcement

tools over drugs and biologics, includ-

ing mandatory recall authority, stiffer

civil and criminal penalties and author-

ity to subpoena records related to drug

violations. But there’s not likely to be

any action on the measure before 2012

when Congress will face a deadline for

renewing prescription drug user fees.

Probing FDAMeanwhile, new Republican commit-

tee chairmen in the House are prepar-

ing for extensive oversight hearings

on administration healthcare policy

and regulatory initiatives. The head

of the House Committee on Oversight

and Government Reform, Darrell Issa

(R-Calif.), has called FDA a “broken

bureaucracy” and put the agency on

his priority investigation list. Issa was

highly critical of FDA officials and

pharma executives at hearings before

the committee last year on delays in

drug recalls by Johnson & Johnson’s

McNeil unit. Now as panel chairman,

he plans to hold FDA officials account-

able for such regulatory lapses. In

December, Issa sent FDA Commis-

sioner Hamburg a letter questioning

FDA oversight of a J&J contract manu-

facturer and of pharma contracting

practices in general. FDA’s Office of

Criminal Investigations also may draw

scrutiny following strong criticism of

its operations from Congress’ Govern-

ment Accountability Office (GAO).

Similarly, House Energy and Com-

merce Committee chairman Fred Up-

ton (R-Mich.) is preparing to scrutinize

the administration’s health reform

legislation, along with “job-killing

regulations” that block technological

innovation and wasteful programs that

warrant budget cuts. FDA approval

programs and research policies are fod-

der for the E&C Health subcommittee,

headed by Rep. Joe Pitts (R-Pa.) and

Mike Burgess (R-Tex.). In addition, the

E&C subcommittee on oversight and

investigations may continue the panel’s

probe into FDA’s failure to adequately

monitor foreign drug production and

clinical research operations.

FDA’s progress in creating an ap-

proval pathway for biosimilars is an-

other issue of great concern to legisla-

tors from both sides of the aisle. E&C

members who crafted the reform pro-

vision and several Senators involved

in the legislation have sent letters to

Hamburg clarifying the 12-year data

exclusivity provision. The law does not

provide for 12 years market exclusivity,

they emphasized, and is designed to

prevent sponsors from obtaining addi-

tional “next generation” patents based

on minor product changes.

Changes at FDAAt last year’s House hearings on J&J’s

manufacturing problems, FDA was

represented by Principal Deputy Com-

missioner Joshua Sharfstein, who won

plaudits for his command of the issues

and knowledge of FDA operations.

Now someone else at FDA will have to

fill the hot seat at Congressional hear-

ings, following Sharfstein’s surprise

departure from the agency last month.

Sharfstein was lured away by an offer

to head Maryland’s health department,

a move that capitalizes on his public

health roots as Baltimore’s health

commissioner. In shifting to the state

agency, Sharfstein will manage a $7

billion budget and will be involved with

implementing the many health reform

policies that require state involvement,

such as Medicaid expansion and forma-

tion of new health insurance exchanges.

At FDA, Sharfstein helped engineer

a get-tough compliance policy designed

to curb perceptions that FDA was too

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View from Washington

cozy with industry. The stronger en-

forcement stance has produced more

warning letters citing manufactur-

ing, marketing, and clinical research

violations, as well as more criminal

investigations of industry. Sharfstein

also was involved in strengthening

FDA’s medical device approval process,

a high-profile exercise that remains

ongoing, and he was a strong advocate

for drug safety and tight curbs on the

use of more risky medicines, such as

the GlaxoSmithKline’s diabetes drug

Avandia (rosiglitazone).

Hamburg is using Sharfstein’s

departure as an opportunity to re-

examine the agency’s top management

structure. Previous commissioners

have tried various organizational mod-

els, with multiple deputy commission-

ers and chiefs of staff, and Hamburg

may move away from the one-deputy

arrangement. Counselor to the com-

missioner John Taylor is filling Sharf-

stein’s shoes while Hamburg weighs

her options, and he is likely to assume

a more visible role at the agency in the

future. Taylor has had a long career

at FDA in legal, enforcement, and

regulatory affairs positions under sev-

eral FDA commissioners during both

Democratic and Republican adminis-

trations. He rose to be Associate Com-

missioner for Regulatory Affairs from

2002 to 2005 and then served brief

stints at Abbott Laboratories and with

the Biotechnology Industry Organiza-

tion. Taylor returned to FDA in 2009

to be Hamburg’s top legal advisor,

and the commissioner might very well

prefer to have a seasoned enforcement

official represent the agency before

Congressional committees probing

regulatory and safety issues.

More transparencyOne of Sharfstein’s last official acts at

FDA was to unveil the third phase of

the agency’s transparency initiative,

a program he headed as chair of its

Transparency Task Force. Launched

in June 2009, the initiative has cre-

ated an FDA Basics web page that

presents broad information on agency

operations and public health policies.

Another innovation is the FDA-TRACK

program, which provides the public

with measures of the performance and

accomplishments of multiple agency

offices and regulatory activities.

This latest segment of the project

aims to provide sponsors with useful

information on FDA policies and pro-

Sharfstein is leaving FDA without resolving the most contentious disclosure proposals under review by the transparency task force.

Clinical trials professionals

across the globeare reading

Applied Clinical Trials

Applied Clinical Trials magazine is the first global information resource

about the process of managing clinical trials. Pharmaceutical, contract

research organizations, laboratory, regulatory, clinical research and

academic professionals across the globe acknowledge Applied

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be immediately applied to daily work.

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cedures. Most of the proposals raise

few concerns: FDA will post more in-

formation on key staffers and meeting

presentations, and will provide a system

to answer industry questions quickly. To

improve the drug application review pro-

cess, FDA will clarify standard operating

procedures for staff meetings with spon-

sors about applications, the types of no-

tifications provided to sponsors, such as

those for mid-cycle review meetings, and

how it informs sponsors whether the re-

view of an application is on track to meet

the target action date. A related initiative

is to explain the agency’s system for

developing new guidances and regula-

tions. Still under review are several more

complex draft policies, such as whether

to set specific timelines for guidance

development and how to handle sponsor

requests to appeal agency decisions.

More significant for industry is FDA’s

rejection of two other proposals. The

agency decided it will not issue binding

advisory opinions on the legality of com-

pany marketing and communications

activities, as sought by industry and

similar to practices by the HHS Inspec-

tor General and the Federal Trade Com-

mission. FDA says that it will continue

to provide advice on whether pharma-

ceutical promotional pieces meet regula-

tory standards, but retains the right to

change its opinion later on.

FDA also won’t commit to notifying

companies in advance of publicly dis-

closing information about the safety of a

regulated product. The agency will try

to discuss emerging quality problems

with the manufacturer, and the Center

for Drug Evaluation and Research still

aims to notify sponsors at least 24 hours

in advance of plans to post drug safety

information. But FDA retains the right

to post information about a safety issue

before consulting with the company if

necessary to protect public health.

Moreover, Sharfstein is leaving FDA

without resolving the most contentious

disclosure proposals under review by

the transparency task force. A May

2010 report on phase two of the initia-

tive sought comments on proposals to

make public a broad range of confiden-

tial regulatory information, such as

when a manufacturer files an investiga-

tional application and whether such an

application is put on hold, withdrawn

or terminated [see Applied Clinical

Trials, “View from Washington,” July

2010]. FDA also is considering whether

to disclose when a company submits a

market application for a new drug, bio-

logic, generic drug, or medical device,

and if such applications later are with-

drawn or abandoned. Most controver-

sial is whether to make public refuse-

to-file or complete response letters.

Those issues raise “very interest-

ing legal issues” as well as additional

resource requirements, Sharfstein ex-

plained at his last FDA media briefing.

Agency teams are assessing dozens of

comments on these proposals, but a res-

olution is not expected anytime soon. ❏

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To see more View from Brussels articles, visit


View from Brussels

Peter O’Donnell

is a freelance journalist

who specializes in

European health affairs

and is based in Brussels,

Belgium.

H1N1 Influenza: Not to be Sneezed at

Renewed pandemic fears draw criticism of industry and regulators for exaggerating the risks.

A new mid-January influenza

warning from the European

Region of the World Health

Organization (WHO) has

cast a new light on the ongoing contro-

versy in Europe over the authorities’

response to the H1N1 outbreak.

Influenza activity is increasing,

said WHO, most notably in Northwest

Europe, with pandemic (H1N1) 2009

not only among the most prevalent vi-

ruses, but also associated with most of

the severe and fatal cases reported in

some countries.

This reality may take some of the

wind out of the sails of the harshest

critics of Europe’s actions to date. As

this column commented last October,

both in the Council of Europe and in

the European Parliament, accusations

have been repeatedly leveled at regula-

tors and at industry for exaggerating

the risks, and for resorting too uncriti-

cally to medication, regardless both of

real need and of potential side effects.

Last year a report for the Council of

Europe blamed European Union agen-

cies, WHO, and national governments

for wasting large sums of public money,

and for “unjustified scares and fears

about the health risks faced by the Eu-

ropean public.” It spoke of “overwhelm-

ing evidence that the seriousness of

the pandemic was vastly overrated by

WHO,” resulting in distorted health

priorities, and “grave shortcomings” in

decision-making. Central to the criti-

cisms were suspicions that advice to

the authorities was biased in favor of

vaccination by scientists with links to

the drug firms that stood to benefit.

European parliament criticismsTo prove that not everything is new

in the new year, a draft report for

the European parliament’s health

committee, due for discussion early

this year, also makes sharp criticisms

of the EU’s performance in 2009-2010,

revisiting many of the allegations of

drug industry manipulation of the

regulatory system in pursuit of vaccine

sales. The report, and many of the still-

more hostile amendments that have

been tabled to it, also focuses heavily

on what it sees as an inadequate

approach to testing.

The tone is set by passages claim-

ing that most efficacy studies “have

been conducted by pharmaceutical

companies, meaning that no objective

proof has been provided of the efficacy

of influenza vaccines,” and that “differ-

ing recommendations made within the

EU” reveal “huge uncertainties sur-

rounding the evaluation of the H1N1

vaccines recommended.”

The evaluation of the management of

H1N1 influenza in the EU has been pre-

pared by French Green MEP Michèle

Rivasi, who has already made herself

conspicuous with her criticisms of the

pharma industry in other areas. The

debate in the parliament will attract

further attention, with attacks sched-

uled on “the EU’s lack of independence

and critical acumen in risk evaluation,”

“blind faith” in influenza vaccines, and

failing to take into account “scientific

data that contradict that belief.” Calls

will be made for screening proce-

dures for experts to be tightened up

to exclude pro-industry bias. There

will also be criticism of the way that

vaccine manufacturers’ purchase con-

tracts transferring part of the liability

for any side effects to the purchasing

countries; pressure will be exerted for

full liability for the quality, safety, and

effectiveness of a medicine to remain

entirely with the manufacturer.

Rivasi’s draft report makes the famil-

iar accusation that authorization deci-

sions are made in too much secrecy,

and it “reminds the EMA [European

Medicines Agency] of the regulatory

requirement to give access to all the

documents relating to clinical trials,

research protocols, and the undesir-

able effects of the medicinal products

evaluated by its experts, including the

vaccines and anti-viral drugs recom-

mended as a means of combating H1N1

influenza.” It also reiterates “linger-

ing uncertainties” about benefit-risk

profiles and urges a review of the EU’s

accelerated marketing authorization

procedures. One of the specific accusa-

tions is that “the stock ‘pandemic’ vac-

cines given to millions of people in Eu-

rope were the subject of extraordinary

‘facilitated’ authorization procedures,

based in fact on old studies and vaccine

formula produced at the time of the

H5N1 virus, which also dated from the

years 2005/2007.” The draft report also

claims that Zsuzsanna Jakob, a former

head of the European Center for Dis-

ease Control, said that “no vaccine had

ever been authorized on the basis of so

little scientific information.”

Some of the amendments proposed

go further, demanding examination of

“the influence exerted on the WHO and

the EU by lobbyists working on behalf

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View from Brussels

of international pharmaceuticals com-

panies,” and referring to “lawsuits in

various member states, alleging corrup-

tion and conspiracy on the part of civil

servants in relation to contracts signed

in summer 2009 between ministries of

public health and manufacturers.”

If these views go unchecked and

unchallenged, the outcome is likely

to be further political endorsement of

the need for changes in the current

healthcare system in the EU so as to

diminish the role of pharmaceuticals

and limit the influence of the industry.

Industry critics have been drawing

a contrast with increasing frequency

between “public health objectives” and

“a purely pharmacological approach,”

and if criticisms are unanswered, the

view will increasingly prevail. The re-

cent shifts toward greater disclosure of

drug data by the EMA are also likely to

be discounted as insufficient.

WHO reality checkAgainst this background, the January

statement from WHO Europe may

come as a salutary reality check.

It underlines that —as the WHO

Director-General stated in a post-

pandemic announcement in August

2010—“the pandemic (H1N1) 2009

virus was expected to continue to

circulate and cause local outbreaks

and epidemics, as well as severe

disease and deaths both in recognized

higher-risk groups and in previously

healthy people.”

It makes clear that on the available

evidence, groups identified during the

pandemic as at high risk for severe or fa-

tal illness remain at heightened risk, and

points out that most of the fatal cases

had not been vaccinated. Consequently,

it recommends that health ministries

ensure high rates of uptake of vaccine by

individuals who might be at risk of devel-

oping complications, in particular preg-

nant women and healthcare workers. It

is advising national authorities to start

or enhance awareness-raising activities

among individuals at risk for complica-

tions from influenza, emphasizing the

need to seek medical advice or care

early on. In addition, WHO says, gov-

ernments need to alert family doctors,

hospitals, and intensive care units to the

expected increase in influenza patients,

so that they can start triage and early

treatment of pneumonia patients, espe-

cially in resource-poor environments. It

urges clinicians to “start treatment for

influenza when they suspect the illness,

Not only has the EMA moved toward greater transparency, but its shift of position has even won applause from the European Ombudsman.

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without relying on rapid diagnostic tests

or waiting for laboratory confirmation.”

Access to drug informationOn the subject of better access

to drug information, not only has

the EMA moved toward greater

transparency, but its shift of position

has even won applause from one of

its most vigorous official critics, the

European Ombudsman.

During 2009, the ombudsman, Ni-

kiforos Diamandouros, who acts as a

watchdog of the public interest in the

European Union, sharply and repeat-

edly criticized the EMA’s reluctance to

provide more access to its documents

and called for major improvements.

Late last year, the EMA confirmed

that it was widening public access to

drug data through a new policy of “pro-

active disclosure of documents.” The

EMA said it was responding to increas-

ing public demand, and would work on

a presumption that documents would be

released once regulatory decisions had

been made. It said its aim was to permit

“stakeholders to understand the basis

for the agency’s scientific decision-mak-

ing and provide for the basis on which

patients and healthcare professionals

can have confidence in our opinions and

information relating to medicines.”

The new policy gives access to all

business-related documents unless

there is a need to respect arrangements

with non-EU regulators or international

organizations, or to protect the privacy

and integrity of a natural or legal person.

Documents submitted to the agency as

part of a marketing authorization appli-

cation, such as clinical trial reports, can

now also be released, provided the deci-

sion-making process for the application

in question is finalized, the EMA said.

There will be freer access to informa-

tion from clinical trials, allowing patient

groups and members of the public more

opportunities to scrutinize the results of

trials. Noel Wathion, one of the most se-

nior officials at the EMA, described the

move as a culture change.

Now Diamandouros has issued a

statement welcoming the EMA an-

nouncement. “I am greatly encour-

aged and applaud EMA’s constructive

approach to improving its transpar-

ency policy,” he said. He has repeat-

edly argued that the EMA’s work has

a direct impact on the health of Euro-

pean citizens and it is therefore crucial

that it should “give the widest possible

access to documents and pursue a

pro-active information policy for the

benefit of citizens.”

The new EMA arrangements do not

provide total access—yet. Safeguards

are built in for sensitive personal and

commercial data. The question that

concerns many in the clinical trials

community is that as criticisms of EU

health regulation mounts—as the

H1N1 debate exemplifies —pressure

may build for the safeguards to be pro-

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Technology Viewpoint

Are We Ready to Fly into the Cloud?Cloud computing is now becoming possible for pharmaceutical companies, but still faces challenges.

During my early days at a CRO,

our CEO would repeatedly

complain to me that IT

infrastructure should be just

as convenient, reliable, and easy to get

as electricity. You should just be able

to plug in, he’d say, and immediately

everything works, and you only pay

for what you use. Of course in those

days of PC LANs, modems, and

cranky MS-DOS applications, it did

little good for a weary CIO like me

to protest that his analogy wasn’t

realistic—that computers were used

for many discrete purposes with

different types of data, both standalone

and in networks, with every potential

opportunity for issues to arise. Instead,

we tried our best and took our lumps

when the inevitable failures and

breakdowns occurred from time to

time. But we were especially careful to

play to the CEO’s illusion by making

sure that his computer really did run

reliably with only e-mail and a couple

of simple applications, hoping he’d be

satisfied with that.

Today with ever more powerful,

networked computing devices on our

laps and in our palms, it really is begin-

ning to seem that computing is finally

inching closer to becoming a utility just

as my former CEO wanted. We expect

to just power on at will and have im-

mediate access to the Internet where

we can do almost anything we want

right away without worrying where

it comes from. At the business enter-

prise level this type of ready access to

computing resources, applications, and

information is commonly (though not

always accurately) referred to as cloud

computing. Cloud computing has been

notably highlighted in the Gartner

Group’s 2010 Hype Cycle Report1 as

being at the peak of inflated expecta-

tions, just leaning out into the trough of

disillusionment when overly-optimistic

expectations typically begin to disap-

point before eventually leveling out into

a steady upward slope of enlightenment

where it will realize its potential to

transform the way we use technology.

And what a transformative concept

it can eventually be where companies

rapidly expand their computing capa-

bilities on demand without significant

up front capital investment or an ex-

tensive data center and IT team. It’s

also more than that—it provides an

opportunity for increased collaboration

and unleashes innovation by removing

many of the constraints of traditional,

internalized IT environments. But

what exactly is it? Phil Wainewright

defines four essential components of

true cloud computing:2 an elastic, ab-

stracted architecture that allows you

to dynamically swap components; an

“as-a-service” infrastructure that pairs

virtualization with provisioning and

management; shared multi-tenancy

among all customers; and nearly limit-

less cloud scale.

Some pharmaceutical and biotech-

nology companies have already ad-

opted cloud computing for some com-

puter-intensive research tasks such as

bioinformatics, molecular modeling,

and proteomics. These applications

often follow narrower flavors referred

to as infrastructure as a service (IaaS)

which means having near immediate

access to processing and storage ser-

vices on demand, or platform as a ser-

vice (PaaS), which provides a hosted

environment for developing custom

applications. These types of uses are

likely to be particularly attractive to

start-ups, since they can avoid capital-

intensive investments on computing

infrastructure and just rent what they

need in the early stages of product

development. Cloud computing not

only reduces the initial investment,

but also reduces start-up times—cloud

services can be ready for use in a frac-

tion of the time it takes to build up all

the infrastructure internally. This is

equally important to large pharma,

which can be subject to bureaucratic

obstacles and interminable delays

when trying to add a server through

internal IT organizations.

Cloud computing in a broader

sense—that includes hosted ap-

plications and software as a service

(SaaS)—is already in widespread use

among pharmaceuticals, as evidenced

by the hosted services for EDC stud-

ies, safety products, and even data

warehouses and analysis environments

in some cases. Is this really cloud

computing, or is it just a rebranding of

something we’ve been doing all along?

When a company sets up a VPN or

other secure link to a hosting environ-

ment to run a specific application,

they’re not really plugging into a cloud.

Rather, they’re just stretching a very

long extension cord to an outlet in an-

other location. And when we’re talking

about regulated applications and pro-

tected research information, we usu-

ally have to tunnel through corporate


Technology Viewpoint

firewalls to access a variety of complex

and often cumbersome products on

individual servers with separate data-

bases, each with their own complica-

tions, pitfalls, and nuances.

To fully realize the potential trans-

formative power of the cloud, we have

to separate our needs for computa-

tional power, storage, software ap-

plications and, above all, information.

While we already have examples of

accessing external data centers, we

have few cases where our principal

sources of information reside in the

cloud. Though much of the work

done in clinical development is really

common across all companies, there

are many individual commercial and

custom applications used in perform-

ing this work. Many companies still

feel their specific business needs

and processes require a custom solu-

tion—whether in the form of bespoke

applications that predominated in

the last century, or in highly custom-

ized commercial applications today

that take on a unique f lavor for each

individual customer. Many of these

companies are reluctant to share a

common standard application for re-

search and development applications,

even if they do use products like

salesforce.com for other purposes.

This stubborn mindset is slowly

changing as applications become

more easily configurable and open,

and as more and more companies

converge around mainstream solu-

tions, but there’s still an inherent re-

sistance in many companies to adopt

the same standards and tools as

everyone else. There’s still a sense of

competitive advantage by having an

individual solution optimized for your

own use that seems to better protect

your intellectual property.

Yet in the cloud, it should be pos-

sible to offer common applications

to many users, and to capitalize on

service-oriented architectures to give

individual customers the flexibility

to adapt to variations in business pro-

cesses.3 If this is done in the cloud, a

single connection can be available to

all while reducing the effort to indi-

vidually integrate each system at each

customer site.

Fear of letting go is just one

of many psychological barriers.

When the term “cloud computing”

is broached an outcry of security

concerns is likely to erupt—even

for those who already use external

hosting providers. Yet in most cases

service providers can actually provide

a higher degree of auditable security

and disaster recovery for far less

effort than most internal IT depart-

ments—it’s their primary business. A

risk assessment and mitigation plan

(possibly based on lessons learned in

other industries such as finance and

e-commerce) is essential—both to

ensure the necessary precautions are

already in place and to build internal

confidence that it’s even feasible to

proceed in the first place.

Then there are the typical regula-

tory concerns. Are cloud computing

providers really capable of conforming

to Part 11, HIPAA, GCP and the many

other regulatory-required or inspired

internal precautions we follow with our

computing infrastructures? Well, those

who are active in the industry must

be —assuming they’re experienced

and have had their offerings verified

by audit.

The ultimate hang-up is our need

to hoard our critical information as-

sets—our data. Data are what R&D

is all about. Even in the case of infor-

mation we all collect—such as safety

data—we’re understandably reluctant

to have it leave our internal storage

vaults except when we have to—much

less transfer custody to an external

provider who is also managing infor-

mation for our competitors. Why such

reluctance in an age when we supply

our credit card number to multiple ven-

dors and perform most of our banking

and financial transactions online?

Maybe it is time to seriously con-

sider the vision of having all relevant

information to clinical research in one

place where it could be simultaneously

accessed by the provider (site), the

sponsor research team, and the regula-

tory authority. This wouldn’t mean it’s

out of control, only that it’s managed

by a central utility provider who gives

us the permissions we need to manage

our own info—and to grant access to

others such as partners during devel-

opment, regulators during review, and

anyone else as the need arises. In fact,

regulatory agencies are a critical influ-

ence over the attitude for adopting the

cloud for regulated data—the lack of

clear-cut regulatory positions can be a

serious disincentive to adoption. Then

again, they could lead the way as they

transition to a new set of information

technologies themselves.

One direct benefit of such an envi-

ronment would be to minimize redun-

dancy and the number of transforma-

tions required. Under this approach,

multiple companies would contribute

to a data bank, potentially earning

interest on deposits and paying fees

on withdrawals. Each company would

have control over their accounts, trans-

ferring only what was necessary when

needed. Behind the scenes it all would

be in a finite set of common environ-

ments. Who knows what future capa-

bilities or efficiencies might ensue?

We need simple and convenient data

sharing across functions, companies,

partners, and stakeholders.

So are we ready yet to fly into the

cloud? Maybe not quite yet. But we

should be planning our itinerary now.❏

References1. “Gartner’s 2010 Hype Cycle Special

Report Evaluates Maturity of 1,800 Tech-

nologies,” www.gartner.com/it/page.

jsp?id=1447613.

2. Phil Wainewright, “Defining the True

Meaning of Cloud,” www.zdnet.com/

blog/saas/defining-the-true-meaning-of-

cloud/1160?pg=1.

3. Phil Wainewright, “Seeking the True

Meaning of SaaS,” www.zdnet.com/

blog/saas/seeking-the-true-meaning-of-

saas/251?tag=mantle_skin;content.

D I A 2 0 1 1 Convergence of Science, Medicine, and Health

47th Annual Meeting | June 19-23, 2011 | McCormick Place | Chicago, IL

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IT

PEERREVIEWED

New Approach to System Validation

Considerations in implementing a risk-based framework for computer systems validation.

Richard Von Culin

ADAM GAULT/GETTY IMAGES

One of the trends I have no-

ticed as a computer system

auditor is that the r isk-

based approach has been

extremely slow and is not

widely adopted. The industry seems to be

facing several challenges regarding im-

plementing a risk-based approach with computer

system validation. One thing to consider here

is that people take calculated risks every day

just getting to their place of work. Risk taking is

simply making a decision given the information

available. This implies not all of the information

may be available when the decision is made.

ConsistencyOne of the interesting aspects of computer vali-

dation is every company has a slightly different

methodology for documenting their validation

efforts. In fact, the only consistency between

the various documentation sets is inconsistency.

Basically, every company is generating the same

overall validation documentation. The difficulty

with the documentation is it never looks the

same because some documents are split and

some are merged. In addition, test cases are dif-

ferent, and user requirements may vary. Even

though the process is similar, each company has

adopted their own unique documentation style.

Some of these documentation differences appear

to have been driven by the industry.

Sponsor auditorsPart of the difficulty with the documenta-

tion is related to how the industry veri-

fies vendor activities related to electronic

information. Time and time again, many

companies’ state there are inconsisten-

cies with the many different auditors.

This may not seem like a major concern but what

is acceptable for one sponsor auditor becomes

unacceptable for another. This statement most

likely holds true for regulatory inspectors as

well. The audit process is not perfect, but if the

industry cannot agree on what validation is and

what is acceptable then there is no way anyone

will adopt a risk-based approach.

RequirementsThe foundation for validating any computer

system is the user requirements.1, 2, 3 Writing

user requirements is very difficult because of-

ten people may not understand how the system

should work. As a result, the requirements be-

come cluttered and often evolve in the form of

scope creep as the system is being developed.

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Evolving requirements is not typical within the pharma-

ceutical industry, but have been observed during audits

where software organizations are using faster software

development methodologies. Often, people think the soft-

ware tool will cure all ailments in the process once in

place. However, historically, many software projects fail to

meet their expectations.4

The result of the user requirement battle is an unend-

ing epic. The important thing to take into consideration

is how accurate are the user requirements if people do

not know what they really need? Often, requirements are

not based on what is needed. Instead, people write user

requirements based on what they want. Taking this into

consideration is very important because user require-

ments often have a lot of unneeded features. These un-

needed features bias the user requirements. Implement-

ing a good risk-based approach should target removing

the biased user requirements from the validation testing

if appropriate.

Well-documented processAlthough there are a lot of difficulties within the software

development lifecycle and monitoring the process, many

of these difficulties can be avoided with well written stan-

dard operating procedures (SOPs). SOPs are important for

defining what documents are required during the software

lifecycle.3 In addition, SOPs should be written guiding the

organization through the software validation process while

also managing system changes over time. Often, there are

gaps between the written process in the SOP and what is

actually being performed in practice.

Risk approachAnother difficulty stems from the FDA guidance issued in

February 2003 on the risk-based approach.5 The guidance

presented the opportunity to reduce validation documenta-

tion but did not offer any suggestions on how to implement

a compliant risk-based approach. In addition, the FDA also

restricted the interpretation of 21 CFR, Part 11.6 The result

for the past few years has been very few citations against

Part 11. The difficulty here is organizations do not under-

stand how the agency will react to a risk-based validation.

Who is going to take this risk in order to see how their ap-

proach will hold up in an inspection?

In order to be able to reduce the validation effort, one

must evaluate the user requirements and make decisions

as to what requirement will be tested and what require-

ment will not. This is not as easy as it appears because

there is a lot to lose in the event the risk-based approach

is unacceptable in the eyes of an inspector. There are

many different methodologies like hazard analysis and

critical control points (HACCP), failure modes and ef-

fects analysis (FMEA), and functional risk assessment

(FRA) to choose from but these are all very time consum-

ing.7 These methods also require some working knowl-

edge of the system, which may be vague if a new system

is being considered.

Another difficulty working with risk-based frameworks

is the amount of documentation required to demonstrate

the risk-based methodology was followed. Why implement

a risk-based approach if it will take the same amount of

time and effort as it would to just validate in its entirety?

This is a valid argument and one I have heard during spon-

sor audits. Taking this factor into consideration, any risk-

based approach must be documentation lean, eliminate

unneeded requirements, and be fast.

Framework for a risk-based approachThe proposed framework consists of two separate phases.

The first phase takes into consideration the risk of the

entire system and the second phase reviews risk at the

requirement level. One thing to note here is it is crucial

to have completed accurate user requirements for a risk-

based approach.7 The framework is designed to reduce the

amount of documentation required for a validation effort

based on the overall system risk. A simple example would

rate the overall system risk as high, medium, or low. Arbi-

trarily, the corresponding validation could be 90 percent,

80 percent, or 70 percent of the user requirements based on

the overall risk. Of course, the percentages as well as the

risk categories are flexible depending on how conservative

the organization chooses to be.

Using an approach mentioned above requires some

flexibility be built in when writing a procedure. This is

important because it is difficult for an organization to

pull out the perfect amount of requirements every time a

system is validated. When the procedure is written, the

validation expectations can be written as a range. For ex-

ample, high risk may be from 88 to 92 percent of the user

requirements to be tested. Each requirement is selected

by assessing risk using the second part of the defined

framework. Another way to add flexibility is to allow the

validation plan and validation summary to address dif-

ferences in the validation approach. Furthermore, if the

overall risk assessment is very different from the require-

ments analysis then an error could have been made in the

overall risk or more requirements need to be removed or

added to the validation effort in order to be aligned with

the procedure.

To reduce the validation effort, evaluate what requirement will be tested and what requirement will not.

Announcing the

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©2011 Outcome Sciences, Inc. (d/b/a Outcome). All rights reserved.


IT

Overall Risk Assessment

Requirement Risk Safety/Efficacy Risk

H M L

Business/Compliance Risk

H HH MH LH

M HM MM LM

L HL ML LL

Source: Richard Von Culin

Table 2. Matrix representing how each requirement could be quickly evaluated for risk.

To reduce documentation and ef-

fort for the system level approach,

the easiest way to determine system

risk is by identifying various factors.

Some of the questions could be:

• Experience with the system?

• Type of system implementation—

new, major upgrade, minor upgrade?

• Audit results?

• Potential impact to personal safety?

• How are the results going to be

used?

• Is the system going to support GxP

work?

• Probability of losing critical data?

• Probability of corrupting data?

• Probability of detecting the error?

• Potential financial impact or busi-

ness risk?

These are only examples of what

an organization may consider impor-

tant risk factors. Each risk should

be categorized and then weighted by

importance. One example of a weight-

ing system could be assigning a value

of five for high risk, three for medium

risk, and one for low risk. Using a cal-

culation, the overall system risk could

be determined based on the factors’

importance and criticality. A critical

system, like a clinical trial database

application, could be rated as medium

risk as shown in Table 1.

Based on the overall risk assess-

ment, the second step is used to sys-

tematically eliminate the non-essen-

tial user requirements. This can be

done by simply amending the current user requirements

by adding two additional columns for determining risk. As

shown in Table 2, examples of risk categories could be busi-

ness/GxP compliance and patient safety/product efficacy.

Each requirement should be evaluated by ranking the risk

high, medium, or low. The overall result will become a grid

where risk can be assessed.

In the case of a high risk system, only the LL require-

ments would be excluded from the system validation in

order to test approximately 90 percent of the user require-

ments. Once again, the values are flexible in order to meet

the various needs of different organizations. Rating each

requirement should be performed by a team of various

interdepartmental representations.7 In addition, the risk

ranking should be performed toward the end of the user

requirement gathering phase.

In addition to only testing the most important require-

ments, the business team implementing the system should

also look at the entire software development life cycle. If

the vendor audit goes well, do not look to repeat what has

already been tested for you by the vendor. In addition, there

seems to be a lot of overlap between integration testing

and user acceptance testing. In fact, many organizations

have started to adopt an integrated approach where they

are combining the integration and user acceptance into a

single test effort.

AuditabilityAny risk-based approach must be documented in a stan-

dard operating procedure. The framework should be de-

fined in a standard operating procedure in order to be

able to consistently execute the risk-based approach over

Clinical Trial Database Risk Assessment

Question Response Risk Weight

Experience with the system? 10 Years Low 1

Type of implementation (New, major

upgrade, minor upgrade)?Major High 5

Audit results? Low Risk Low 1

Potential impact to personal safety? Yes Med 3

How are the results going to be used? Submission High 5

Is the system going to support GxP work? Yes High 5

Probability of losing critical data? Low Low 1

Probability of corrupting data? Low Low 1

Probability of detecting the error? Low Low 1

Potential financial impact or business risk? High High 5

Average 2.8

Source: Richard Von Culin

Table 1. Risk factors are coded low, medium, or high.


time. In addition, the procedure also provides a reference

for auditors. The reference allows auditors the ability to

read how the risk-based method is performed and then

verify the process has been followed by reviewing the

documentation. It is important to remember the intent of a

risk-based approach is not to cut corners but to apply a sci-

entific rationale as to what truly needs to be tested.

Paradigm shiftEssentially, implementing a risk-based approach is go-

ing to require a change in how the industry monitors and

documents computer system validation. In the event there

is a disagreement during an audit, the auditor should cite

against the risk-based procedure and not against the un-

derlying data in the system. However, if the system is not

tested adequately, resulting in potential data integrity is-

sues, then the audit finding should go against the underly-

ing data as well as the documented risk-based process. As

long as the system maintains the integrity of the data, the

corrective action should be geared more toward correct-

ing the SOP to adjust the required amount of testing as

well as to perform additional system testing. This is an im-

portant point—the company taking the risk should be the

expert in understanding the system and underlying data.

People should start to think about big reductions in

documentation. A radical thought to reducing docu-

mentation might be: Can the critical GxP system only

require 80 percent or even less of the requirements to

be tested? I do not think the industry is ready for this

but if you consider the 80 -20 rule and the bias in the

user requirements, anything could be possible. One ex-

ample would be: 20 percent of the user requirements are

system wants, as opposed to true needs, where people

request the bell and whistle components. Do we really

need to test all of the bells and whistles people would

like to have? This is a challenge because there are a lot

of requirements in a user specification not critical to the

overall business process.

Improved audit results and efficienciesI have reviewed the variety of findings I have cited through

the years for non-compliance. The interesting point about

the various citations is they seem to target errors made

in the documentation and are not always reflective of the

business process. If someone implements a risk-based ap-

proach where on average 10 percent of the requirements

are not tested then the overall audit results should improve

by 10 percent. This, of course, would require the documen-

tation be improved as well. The overall theory is if there is

less documentation to review then there should be fewer

citations during an audit.

The cost of validating a system has been estimated at ap-

proximately 50 percent to 100 percent of the software total

cost.8 Minimizing the effort by eliminating non-essential

testing could have significant impact on an organization.

Freeing up the time and resources comprising the addi-

tional validation cost estimation could allow organizations

to move quicker into new and innovative technologies

within the clinical field.

References1. Food and Drug Administration, General Principles of Software

Validation, Docket HFA-305, 1-24, 2002, www.fda.gov/down-

loads/RegulatoryInformation/Guidances/ucm126955.pdf.

2. Robert D. McDowall, Validation of Chromatography Data Systems

Meeting Business and Regulatory Requirements. (RSC Publish-

ing, Cambridge, 2005).

3. Timothy Stein, The Computer System Risk Management and Vali-

dation Life Cycle. (Paton Press, Chico, 2006).

4. B. Kaplan, K.D. Harris-Salamone, “Health IT Success and Fail-

ure: Recommendations from Literature and an AMIA Work-

shop,” Journal of the American Medical Informatics Association,

16 (3) 291-299 (2009).

5. Food and Drug Administration, Center for Drug Evaluation and

Research, Part 11, Electronic Records; Electronic Signatures —

Scope and Application. Guidance for Industry (FDA, Rockville,

MD, 2003).

6. Food and Drug Administration, CFR/ICH GCP Reference Guide

contains the FDA Code of Federal Regulations, Good Clinical Prac-

tice parts 11, 50, 54, 56, 58, 312, and 314, plus ICH Guidelines,

Good Clinical Practice (E6), Clinical Safety Data Management

(E2A), and the European Union Clinical Trials Directive (p. Part

314), Barnett International (2003).

7. R. McDowall, “Practical and Effective Risk Management for

Computerized System Validation,” Quality Assurance Journal, 9

(3) 196-227 (2005).

8. D. Ade, “Software Validation Goes a Long Way,” PharmaAsia,

2006, www.pharmaasia.com/print.asp?id=7044.

Richard Von Culin is Manager, Promotional Services Systems

at Boehringer Ingelheim, 900 Ridgebury Rd, Ridgefield, CT

06877, e-mail: [email protected].


Sites

PEERREVIEWED

Targeting Source Document Verification

Targeted SDV provides data validation by comparing trial data with primary health records.

Sandra Hines

PHOTO 24/GETTY IMAGES

Monitoring of clinical tri-

als is a federally man-

dated responsibil ity of

trial sponsors and a core

of fering of contract re -

search organizations (CROs) that is cru-

cial to the validity of clinical research.

Source document verification (SDV)—the com-

parison of reported trial data with information

from primary health records of trial subjects—is

an important component of trial monitoring in-

tended to ensure the integrity of trial data. Spon-

sors and project managers should develop SDV

strategies for each trial that comply with regula-

tory requirements and accommodate the size,

complexity, design, and purpose of the trial.

One hundred percent SDV, the comparison

of each data point on every case report form

(CRF) to subject medical records, may not be

appropriate for most large, multi -center tri -

als. Targeted SDV—the verification of critical

trial data, including study endpoints—has the

potential to improve safety oversight, data qual-

ity, regulatory compliance, protocol adherence,

and overall trial validity while reducing costs

and the time to database lock for large, multi-

center trials.

Regulatory requirements and SDVThe Guidance on Good Clinical Pract ices

(GCP), developed by the International Confer-

ence on Harmonization (ICH), requires that trial

monitors have access to and can review

source documents. This guidance, ICH

E6, has been adopted by both the Food

and Drug Administration (FDA) in the

US Code of Federal Regulations (CFR)

under Title 21 and by the European

Union (EU) as part of the EU directive

on clinical trials. Guidance ICH E6 and

the regulatory authorities that have adopted it,

refer to source documents (i.e., primary health

records, in the sections on investigators, spon-

sors, trial protocols, and essential documents).

According to the E6 guidance, source docu-

ments must be kept in good order and investi-

gators must make source documents available

to the sponsor and monitors working on be-

half of the sponsor. Investigators are respon-

sible for ensuring that the data reported on

CRFs is consistent with source documents,1

and the sponsor is responsible for ensuring

that each subject has provided written consent

to direct access to his or her medical records.2

Sponsors must also ensure that the trial proto-

col or other written agreement specifies that

investigator(s)/institution(s) will allow trial-

related monitoring3 and that the monitors verify

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Sites

the source documents are accurate, complete, up-to-date,

and maintained.4

Source documents are used to achieve two explicit regu-

latory objectives: to document the existence of the subjects

and to substantiate the integrity of trial data.5 Both objec-

tives depend on effective SDV by monitors. The most effec-

tive strategies for SDV depend on the particulars of each

clinical trial. While 100 percent SDV is not required by

law, industry standards maintain 100 percent SDV as the

most straightforward approach to regulatory compliance.

However, the FDA guidelines for monitoring clinical trials

states, “…the monitor should compare a representative

number of subject records and other supporting documents

to the investigator’s report...”6

FDA guidelines explicitly refer to a representative num-

ber of subject records, not all subject records. The Depart-

ment of Health and the Medical Research Council in the

United Kingdom announced, “verifiable…does not imply

that every item of data recorded must be supported by a

source document or checked.”7 The number of subjects, the

experience of the clinical site, the clinical endpoints, and

the nature of ancillary data are several of the factors that

should be considered when developing a strategy and pro-

tocol for a project-specific SDV plan.

Effective targeted SDVUnder several conditions, targeted SDV may be more ap-

propriate and effective than 100 percent SDV for large,

multi-center trials. Targeted SDV prioritizes critical data

and uses random sampling methods to select data for

SDV during an on-site monitoring visit. Trials with many

sites, and a large volume of data per site, may require a

combination of targeted SDV and extensive statistical

monitoring of data as it accrues to ensure the quality of

the data generated.

A report on diversifying monitoring methods states,

“central monitoring of data using statistical techniques may

help to identify departures from expected patterns which

might suggest incorrect procedures, or even data fraud,

thereby identifying sites that require further investiga-

tion.”8 The internal data review processes that routinely

lead to individual data queries can employ rigorous statisti-

Under several conditions, targeted SDV may be more appropriate and effective than 100 percent SDV for large, multi-center trials.

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cal methods to investigate overall quality and integrity of

the entire trial data set and subsets of trial data.

Trials employing highly experienced clinical sites, sites

that have previously demonstrated the ability to recruit and

retain subjects, to effectively train on-site trial staff, and

to report complete and accurate data, are also appropri-

ate candidates for targeted SDV strategies. Finally, there

should be no statistical difference between verified and

unverified data9 and there should be a low error rate on the

CRFs if a targeted SDV strategy is in use.

Fixed fields approach to targeted SDV reviews all en-

tries in specific CRF data fields that pertain to primary

and secondary clinical endpoints and all unexpected ad-

verse events (AEs). This approach includes 100 percent

SDV for all fields for the first one or two subjects enrolled

at each site to assess data quality and potential staf f

training deficiencies. When employing fixed field SDV,

discrepancy tracking can be utilized to signal the need

for remediation at a particular site. For example, discrep-

ancy tracking may reveal specific errors requiring an

on-site visit by the monitor that results in a temporary

suspension of targeted SDV and a deployment of 100 per-

cent SDV for all CRF fields. Retraining of the site staff is

often the answer in addition to closer extended monitor-

ing of the site for remediation and the resumption of the

targeted SDV protocol.

Random field selection, another approach to targeted

SDV, utilizes random statistical sampling to select CFR

fields for SDV during a site visit. Inclusion/exclusion cri-

teria, informed consent forms, and all serious AEs are

subject to 100 percent SDV, as are all CFR data fields for

the first one or two patients enrolled. As with fixed field

SDV, discrepancy tracking can lead to remediation at a site

including the temporary or permanent deployment of 100

percent SDV for all CRF fields.

The following are some examples of the techniques com-

monly used to produce a random sample. They can range

from a simple pre-specified or fixed approach to a more

complex strategy depending on the goals of the study.

An example of a pre-specified/fixed sampling would

be selecting one subject from the first five enrolled, then

another from the next five enrolled, and so on. This can

be considered the easiest of sampling techniques, and of

course there are pros and cons to consider. For example,

selecting subject numbers 1, 6, 11 is preferential to select-

ing subjects 5, 10, 15 as the later does not give the reviewer

an opportunity to identify data issues early on, and for the

obvious reason that not all sites will reach their group-

ing’s upper limit. This approach can be applied at the site

or whole-study level. When applying this technique in a

whole-study approach, you run the risk of not seeing the

low-enrolling sites, and focusing more on a higher-enroll-

ing site than is intended.

There are more complex strategies that can mitigate

the shortcomings of the simpler sampling techniques. A

complex strategy will take more effort to administrate,

however, the result is a more evenly distributed sampling.

For example, and in the context of a site-level sampling,

one could select the first subject at each site, then one

from the second through fifth, one from sixth through

10th, and so on until all subjects (except the first from

each site) have had an equal chance of being selected.

Subjects that were not selected in any round of sampling

can be grouped for further sampling until your SDV target

percentage is reached.

Implementing targeted SDVBoth approaches to targeted SDV require several com-

mon conditions for successful implementation. The trial

must have clear and focused objectives, along with valid

endpoints, for targeted SDV to work. This focus will help

project managers establish criterion that will allow them

to identify and prioritize critical data. A well designed

CRF (paper or electronic) and sufficient site staff train-

ing will increase procedural standardization and reduce

error rates. The monitoring plan should include a de-

tailed SDV protocol with a site remediation plan. Finally,

centralized statistical monitoring and rigorous internal

data review can be used to monitor many important pa-

rameters, including statistical differences between veri-

fied and unverified data and unusual patterns in data at

individual study sites.

Implementation of an effective targeted SDV strategy

is not without its challenges. The essential element is the

acceptance by leadership of a cultural shift in completion

of this operational task. The most senior leadership must

be willing to strongly support the strategy by taking a

visible role in the communication of the new expecta-

tions. Stakeholders should be involved in the develop-

ment of project specific targeted SDV plans and in rolling

them out to the staff.

Performance indicators regarding the project specific

SDV plans should be tied to objective management. The

multidisciplinary team—statisticians, data managers,

clinical project leaders, and medical monitors—must

be in agreement with the strategy to make it success-

ful. The change will have to be broad, and it will have

to be managed, especially in an organization that has

always performed 100 percent monitoring of every field.

When employing fixed field SDV, discrepancy tracking can be utilized to signal the need for remediation at a particular site.


Sites

Implementation of project specific targeted SDV strate-

gies may involve changing necessary standard operating

procedures (SOPs) that imply 100 percent monitoring

expectations.

A clear training strategy will help overcome the inexperi-

ence and reluctance to work in a new paradigm that goes

against the detailed nature of the staff. Training will be

better received and taken more seriously by the staff if it

involves representative champions from senior leadership.

Education of the internal team should include the protocol

specifics; justification for a reduced SDV plan; and review

of edit checks and address errors attributed to reduced

SDV strategy, as opposed to errors that would occur in a

fully monitored study.

Resistance needs to be managed at every level on an on-

going basis. We suggest creating a frequently asked ques-

tion list created at the critical stakeholder level. It is essen-

tial that the leadership be able to explain the rationale and

demonstrate the benefits of targeted SDV that outweigh the

perceived oversight of data.

Improved trial monitoring with targeted SDVTargeted SDV strategies may lead to improved perfor-

mance in clinical studies on many counts. Trial monitor-

ing is both important and multi-faceted. As outlined by

the ICH in its E6 Guidance on GCP, monitoring is em-

ployed to verify:

• Adherence to trial protocol, GCP, regulatory require-

ments

• Accuracy, quality, and integrity of trial data

• Subject well-being and to protect subject rights10

The time demands of 100 percent SDV may compromise

other important monitoring functions that require on-site

visits. In an informal, 2006 survey, monitors working in the

field responded that, on average, they spent 46% of their on-

site time performing SDV, 13% of that time performing reg-

ulatory review, 11% on drug accountability, and 5% on com-

munications with the principal investigators.11 With nearly

half the on-site time spent on SDV, other important moni-

toring functions such as adverse event follow-up, protocol

adherence, GCP assessment, and drug accountability may

The time demands of 100 percent SDV may compromise other important monitoring functions that require on-site visits.

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not receive the attention they need. The validity of clinical

studies are as dependent on GCP and strict adherence to

protocol as they are to the identification of individual errors

and inconsistencies in reported trial data.

The ICH E6 guidance on GCP during the conduct of a

clinical trial does not mandate 100 percent SDV and the

FDA guideline on GCP explicitly calls for the review of a

representative number of subject records. The validity of

trial data need not be compromised by employing targeted

SDV; in fact, some researchers persuasively argue that for

large data sets from large trials 100 percent SDV is not only

costly, it is less effective than more statistical approaches.8

In the future, the increasing availability of electronic

source documents (see the recent draft FDA guidance

on electronic source documentation in clinical investiga-

tions) will allow much of the SDV activity to be automated

and performed remotely.12 While access to and review of

source documents is critical to ensuring the existence and

informed consent of each trial subject, targeted SDV is an

effective, if not superior approach to data verification and

validation in trials with large data sets.

References 1. Food and Drug Administration, ICH E6 Good Clinical Practice

Consolidated Guidance, section 4.9.2

(FDA Rockville, MD, 1996).

2. Food and Drug Administration, ICH

E6 Good Clinical Practice Consoli-

dated Guidance, section 5.15.2 (FDA

Rockville, MD, 1996).



dated Guidance section, 6.10 (FDA




dated Guidance, section 5.18.4 (k)

(FDA Rockville, MD, 1996).



dated Guidance, section 8.3.13, (FDA


6. Food and Drug Administration, Guid-

ance for Industry; Guidelines for the

Monitoring of Clinical Investigations

(FDA, Rockville, MD, 1998).

7. Medical Research Council and the

Department of Health, Joint Project

to Codify Good Practices in Publicly

Funded UK Clinical Trials with Medi-

cines—Draft Workstream 4: Trial

Management and Monitoring: Moni-

toring Procedures (2004).

8. C. Baigent, F. E. Harrell, M. Buyse, R. J. Emberson, and D.G.

Altman, “Ensuring Trial Validity by Data Quality Assurance

and Diversification of Monitoring Methods,” Clinical Trials, 5

(1) 49-55 (2008).

9. B. Maruszewski, F, Laour-Gayet, J. L. Monro, B.E. Keogh, Z.

Tobota, and A. Kansy, “An Attempt at Data Verification in the

EACTS Congenital Database,” European Journal of Cardio-

Thoracic Surgery, 2 (5) 400-406 (2005).

10. Food and Drug Administration, ICH E6 Good Clinical Prac-

tice Consolidated Guidance, section 5.18.1 (FDA Rockville, MD,

1996).

11. C. Breslauer, “Could Source Document Verification Become a

Risk in a Fixed-Unit Price Environment?” Monitor, December,

2006, 43-47.

12. Food and Drug Administration, Guidance for Industry: Elec-

tronic Source Documentation in Clinical Investigations, (FDA

Rockville, MD, 2010), http://www.fda.gov/downloads/Drugs/

GuidanceComplianceRegulatoryInformation/Guidances/

UCM239052.pdf.

Sandra Hines (DiGiambattista) is Director of Clinical

Operations at ePharmaSolutions, 625 Ridge Pike, Building

E, Suite 402, Conshohocken, PA 19428, e-mail: shines@

epharmasolutions.com.

Assistant/Associate Professor Clinical Research and Leadership

Te George Washington University School of Medicine and Health Sciences, Department of Clinical Research and Leadership, announces a position for Assistant/Associate Professor to join our team of interdisciplinary health sciences educators. Tis position requires teaching across a broad curriculum that may include clinical research, regulatory affairs, and clinical leadership. Basic qualifications: Applicants must hold a doctorate degree, provide evidence of teaching expertise through course evaluations, and have demonstrated ability to perform scholarly research as evidenced by prior research and/or publications. Doctoral candidates will be considered for a conditional appointment at the rank of instructor and must complete all degree requirements by the end of the first academic year of appointment. Preferred qualifications: Preference will be given to applicants with strong research skills and a research agenda in the health sciences.

Successful candidates will be required to teach in the GW distance education programs. Tis is a 12-month, tenure track, faculty position.

Application Procedure: Please send curriculum vitae and the names, addresses, phone numbers, and email addresses of at least 3 professional references. Please include teaching evaluations. Applications and nominations should be sent to:

Joseph M. Bocchino, Ed.D.Chair, Department of Clinical Research and LeadershipTe George Washington University 900 23rd Street, NW, Suite 6174Washington DC, 20037

Only complete applications will be considered.

Review of applications began on January 5, 2011 and will continue until the position is filled. Te George Washington

University is an Equal Opportunity/Affirmative Action Employer and people of color are strongly encouraged to apply.


Regulatory

PEERREVIEWED

The FDA’s

Guidance

on PRO

This guidance has both raised the stakes and improved the odds of securing label claims based on PROs.

Jane Speight and Shalleen Barendse

WINSTON DAVIDIAN/GETTY IMAGES

The recent release of the US

Food and Drug Administration

(FDA) guidance on the use

of pat ient-reported outcome

(PRO) measures to support la-

beling claims (December 9, 2009)1 had

been eagerly anticipated since the pub-

lication of the draft guidance.2 In the past four

years, there was much speculation about the

meaning and implications of the FDA’s “cur-

rent thinking” about the development and use

of PRO measures.3 The draft guidance was de-

signed to offer a set of guiding principles to

those conducting and supporting industry-spon-

sored clinical trials, but it has undoubtedly gen-

erated wider interest and been more contentious

than originally intended. At a time when PROs

were more commonly referred to as psychologi-

cal outcomes (largely considered the remit of

health psychologists rather than of interest to

clinicians or industry) and were viewed with

more skepticism than today (in terms of their

importance, relevance, and scientific merit), the

draft guidance was designed to enable industry

to engage with the regulatory authority in a

dialogue about the appropriate use of PROs to

evaluate medicinal products. However, while

the draft guidance was largely welcomed as a

means of encouraging the adoption of scientific

standards, it generated more questions than an-

swers about the nature of PRO research and the

level of evidence required to demonstrate good

scientific practice.4-6

In the two years following the release

of the draft guidance, there was a reduc-

tion in the number of successful label

claims (compared with the preceding five

years),7 but the percentage of success-

ful PRO claims remained steady. This

seems to suggest that fewer applications

were made (perhaps due to the perceived

challenges inherent in meeting the recommen-

dations of the draft). Furthermore, successful

claims were largely symptom based, providing

compelling evidence of the difficulty (or per-

ceived difficulty) of securing a claim based on

more contentious (though, arguably, more pa-

tient-centered) concepts such as psychological

well-being, treatment satisfaction, or health-

related quality of life. Thus, while the draft guid-

ance raised the profile and value of PROs in the

industry, it also positioned many hurdles that

smaller pharmaceutical companies might strug-

gle to overcome. Preparation of a PRO evidence

dossier has cost implications at every stage:

planning; conduct of background studies such as

systematic reviews or qualitative studies; ques-

tionnaire design, validation, and translation; and

compilation of the evidence dossier itself. More-

over, access to outcomes research expertise (ei-

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Regulatory

ther in-house or externally), is essential to ensure that the

evidence dossier will stand up to the rigor of FDA scrutiny.

So, does the release of the final guidance mean that the

FDA is now placing its cards on the table, or is it just rais-

ing the stakes?

Why is the FDA interested in PROs?PROs are outcomes reported directly by patients by means

of a self-report questionnaire about aspects of their con-

dition or treatment. The FDA guidance, and the related

guidance from the European Medicines Agency (EMA),8 is

supportive of the use of PROs because:

• Patients provide a unique perspective on treatment effec-

tiveness: some outcomes are known only to the patient

and are not necessarily related to biomedical/objective

outcomes.

• Achievement of biomedical targets may have negative

implications for other aspects of life deemed to be impor-

tant to the individual: side effects are often a necessary

but unwanted implication of medicinal treatment. Life-

style may be severely restricted by a treatment but will

the patient tolerate this?

• They may be the only way to distinguish the benefits of

a new treatment: new treatments often produce similar

biomedical results to existing treatments, but may differ

in terms of patient experience (e.g., flexibility of lifestyle,

convenience, acceptability due to side effect profile).

Furthermore, patient preferences and priorities influ-

ence adherence to treatment. In the long term, the re-

ported clinical and cost-effectiveness of a drug may be-

come questionable if patients do not take it as prescribed.

In the draft guidance, the FDA provided examples of

the concepts included under the umbrella terminology

of PROs, including symptoms, activities of daily living,

health status, and quality of life (QoL). The updated guid-

ance no longer defines PROs in this manner, an omission

that can be interpreted in two ways. Either the FDA now

assumes that the term PRO is well-understood, requir-

ing no further explanation, or the FDA does not wish to

become embroiled in the debate regarding individual

concepts (which remain ill-defined and somewhat conten-

tious). In the glossary, the FDA continues to assert that

claims cannot be made on QoL per se (“a general concept

that implies an evaluation of the effect of all aspects of

l i fe”)1 but can be made on health-related or disease -

specific QoL, (i.e., “the patient’s general perception of the

effect of illness and treatment on physical, psychological,

and social aspects of life”).1 The guidance states “gener-

ally, findings measured by a well-defined and reliable PRO

instrument in appropriately designed investigations can

be used to support a claim in medicinal product labeling if

the claim is consistent with the instrument’s documented

measurement capability.”1

What are the main changes to the guidance?The delay in the release of the guidance has been due, in

no small part, to the number of concerns raised by the draft

guidance among key stakeholders. More than 50 individual

responses were received from stakeholders (academics,

health professionals, policy makers, professional organiza-

tions, and industry representatives). Thus, it is should be

no surprise that the focus and emphasis of the guidance

has shifted somewhat from the FDA’s original stance. As it

is beyond the remit of this article to provide a line-by-line

account of the changes between the draft and final guid-

ance, the following serves to highlight some key issues.

Overall focusThe guidance describes how the FDA “reviews and evalu-

ates existing, modified, or newly created PRO instruments

used to support claims in approved medical product la-

belling”1 and goes on to state that a PRO instrument is a

“means to capture PRO data used to measure treatment

benefit or risk in medical product clinical trials.”1 In these

short introductory statements, the FDA has made two im-

portant changes. First, the focus has moved from describ-

ing how the FDA evaluates “PRO instruments” to acknowl-

edging the different approaches that may be needed with

regard to reviewing the suitability of “existing, modified,

or newly created” instruments. Second, the guidance now

takes a more balanced perspective, acknowledging that

PRO data can be used to measure treatment risk (e.g., side

effects, inconvenience) as well as benefit; risk was not pre-

viously mentioned.

Endpoint models and conceptual frameworksFive years ago, the draft guidance introduced the language

of conceptual frameworks, which was met largely with

confusion in the industry and much speculation about its

meaning. Professional meetings have since been domi-

nated by presentations explaining this and related termi-

nology (“conceptual models” and “endpoint models”). The

new guidance begins with a discussion of the use of end-

point models, which serves to emphasize the importance of

matching chosen outcome measures to specific treatment

objectives, (i.e., defining “the role a PRO endpoint is in-

tended to play in the clinical trial).”1 The conceptual frame-

work of a PRO instrument “explicitly defines the concepts

measured by the instrument in a diagram that presents

a description of the relationships between items, domain

The delay in the release of the guidance has been due, in no small part, to the number of concerns raised by key stakeholders.

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Regulatory

(subconcepts), and concepts measured.”1 Diagrams and

further explanations are provided to improve clarity. End-

point models and conceptual frameworks may be relatively

new terminology but they are important tools to use and

represent good practice in ensuring the appropriate selec-

tion of PRO instruments.

Content validityContent validity is “the extent to which the instrument

measures the concept of interest.”1 This aspect of an in-

strument ’s properties is highlighted as fundamentally

important (it now has its own dedicated section) with the

following significant statement: “evidence of other types

of validity…or reliability…will not overcome problems

with content validity because we evaluate instrument ad-

equacy to measure the concept represented by the labeling

claim.”1 Sponsors are encouraged to support the adequacy

of content validity by documenting how items were gener-

ated. The guidance states that the FDA “cannot provide

recommendations for the number or size of the individual

patient interviews or focus groups for establishing content

validity…generally, the number of patients is not as critical

as interview quality and patient diversity,”1 confirming the

importance of sound qualitative research to inform instru-

ment design.

Importantly, the FDA acknowledges from the outset that

“PRO instrument development is an iterative process and

[they] recognize there is no single correct way to develop a

PRO instrument. Different strategies and methods can be

used to address FDA review issues.”1 Previously, the stan-

dards for instrument development suggested by the draft

guidance may have been very difficult to achieve, particu-

larly for those developed and validated pre-guidance. Now,

the FDA makes explicit that existing instruments with a

less than rigorous development history can be considered

if “new qualitative work similar to that conducted when

developing a new instrument can provide documentation of

content validity.”1

The guidance has expanded significantly in this area,

detailing how content validity can be demonstrated and

documented. The assessment of content validity includes

detailed examination not only of item generation and pa-

tient understanding of items and response options but

also the appropriateness (to the patient group) of: the

data collection method and administration mode; recall

period; and instrument format, instructions, and training.

The guidance also presents criteria against which content

validity and respondent and administrator burden will be

assessed. In relation to the recall period, the FDA contin-

ues to encourage the use of items with appropriately short

recall periods,1, noting that instruments that require recall

over a longer period (i.e., relying on memory) may threaten

content validity.

Measurement propertiesIn the draft guidance, it was not clear whether all listed

measurement properties were essential for each instru-

ment. For example, it may be appropriate in some cases to

assess predictive validity, while in other situations it may

not be feasible or relevant. The new guidance removes pre-

dictive validity, focusing specifically on content (discussed

above) and construct validity, which the FDA will review

in terms of convergent, discriminate, and known-groups

validity (all of which are appropriate to the validation of

any PRO instrument). In terms of reliability, the FDA

continues to value all three types (i.e., test-retest, internal

consistency, and inter-interviewer/inter-rater) but provides

greater clarity about the specific situations in which their

assessment may or may not be feasible (e.g., test-retest may

not be possible for “remitting and relapsing or episodic dis-

eases”).1 In particular, the guidance emphasizes the need

to demonstrate the instrument’s ability to detect change

and states that the FDA will want to examine “evidence that

a PRO instrument can identify differences in scores over

time in individuals or groups (similar to those in the clini-

cal trial) who have changed with respect to the measure-

ment concept.”1

Instrument modificationIncreasingly, instruments are modified before use ac-

cording to the needs of the new study, (e.g., transfer from

paper-and-pencil to electronic format such as PDA, tab-

let, or web) or to a new population (e.g., adolescents or a

new condition), or to a new language/culture. However,

an instrument’s development and measurement proper-

ties are specific to its original application. Previously, the

draft guidance stated that “the FDA intends to consider

a modified instrument as a different instrument from the

original and will consider measurement properties to be

version-specific.”2 This strict categorization suggested that

“additional validation” would almost certainly be required,

raising many concerns as to what would be considered

adequate and/or that very expensive and time-consuming

new studies would be needed. Responses to the draft guid-

ance indicated that minor modifications should not require

complete re-validation.

The new guidance provides a list of changes that may

require additional validation (e.g., changing an instrument

from paper to electronic format; changing the applica-

tion to a different setting, population, or condition) and

provides brief guidance to suggest that a small feasibility

study or a qualitative study may be needed to confirm the

instrument’s properties in the new population. In recent

years, task forces set up by the International Society for

Pharmacoeconomics and Outcomes Research (ISPOR)

have produced “good research practice” publications that

provide guidance on what constitutes sound scientific evi-

20

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Regulatory

dence (and may also be considered reasonable) in relation

to specific examples of modification.5,6,9

Proxy measuresImportantly, proxy-reported outcome measures (e.g., for pe-

diatric or cognitively/communication-impaired populations)

are now actively discouraged, when previously they were

considered a less than ideal option. This raises new chal-

lenges about the collection of “observer reports that include

only those events or behaviors that can be observed.”1

Interpretation of PRO dataPreviously, the draft guidance suggested that determina-

tion of the minimum important difference was key to the

interpretation of results. Yet, practical and consistent

methodologies for evaluating the minimum important

difference are not available and the various options often

produce conf licting ranges of what can be considered

“minimum.” The anchor-based approach often means, in

practice, that PRO scores are mapped onto clinically im-

portant changes in clinical outcomes to define a responder

on the PRO instrument. This may be relevant for some

symptom-based or health status measures but is inappro-

priate for other PROs such as emotional well-being (e.g.,

anxiety or depression) or health-related QoL, that are less

closely related to clinical endpoints. Consequently, the

previously recommended minimum important difference

has been replaced by the cumulative distribution func-

tion of responses to demonstrate treatment effect, or by

responder definition (which must be defined prior to the

start of Phase III studies).

PRO evidence dossierIn response to the draft guidance, stakeholders speculated

about the minimum evidence base and format for present-

ing supporting documentation about PRO instruments.

Speculation is no longer required, as the guidance provides

an appendix in which the contents of an evidence dossier are

made explicit. This is one of the most significant changes in

the guidance, which now provides practical advice about the

presentation of evidence that the FDA will expect to review.

ConclusionsThe FDA guidance provides a set of guiding principles to

assist industry sponsors in the appropriate selection, devel-

opment, validation, implementation, and analysis of PRO

instruments in clinical trial programs. The guidance has

changed in many ways (in response to the concerns and

issues raised by numerous stakeholders) to provide clearer

messages for researchers, which emphasize the sound

scientific principles by which PRO instruments should be

developed and implemented. The guidance offers a struc-

tured understanding of FDA standards for integrating PRO

effectiveness endpoints in clinical trials, particularly to sup-

port future labeling claims. Thus, by emphasizing good sci-

ence but also providing greater clarity about the evidence

required for FDA review, we believe that the FDA has

simultaneously raised the stakes and improved the odds of

securing label claims based on PROs.

Clearly, the submission of a PRO evidence dossier re-

quires a huge volume of supporting work. For some, the

language of the FDA guidance may be daunting and the

requirements may appear to present insurmountable chal-

lenges (to the point that some may be discouraged from

using PROs at all). However, this may be a good thing if it

precludes the unscientific practice of last-minute inclusion

of any vaguely relevant PRO instrument. If pharmaceutical

companies believe in the PRO claim to be made for their

compound, they need to proactively plan for it as early as

Phase I/II. The guidance emphasizes the need to formulate

a clear strategy for the inclusion of PROs in clinical trial

programs, just as for other clinical endpoints. Interestingly,

it is widely speculated that the FDA will soon be turning its

attention to the validity/reliability of clinician-reported out-

comes, a decision which may not be popular but certainly

promises to bring greater scientific rigor to outcomes that

are often regarded as more robust than PROs.

Most importantly, the guidance gives pre-eminence to

content validity when evaluating the suitability of a PRO

instrument and emphasizes the importance of specifying

the role of the PRO instrument among the range of trial/re-

search endpoints. Fundamentally, these are good scientific

practices that can and should be adopted by industry to

ensure that outcomes reported from the patient perspective

are both robust and meaningful.

References1. US Department of Health and Human Services FDA Center

for Drug Evaluation and Research, US Department of Health

and Human Services FDA Center for Biologics Evaluation and

Research, US Department of Health and Human Services FDA

Center for Devices and Radiological Health, “Guidance for

Industry: Patient-Reported Outcome Measures: Use in Medical

Product Development to Support Labeling Claims,” 2009, http://

www.fda.gov/downloads/Drugs/GuidanceComplianceRegula-

toryInformation/Guidances/UCM193282.pdf.

2. US Department of Health and Human Services FDA Center

for Drug Evaluation and Research, US Department of Health

and Human Services FDA Center for Biologics Evaluation

The guidance offers a structured understanding of FDA standards for integrating PRO effectiveness endpoints in clinical trials.


and Research, US Department of Health and Human Services

FDA Center for Devices and Radiological Health, “Guidance

for Industry: Patient Report Outcome Measures: Use in Clini-

cal Medical Product Development to Support Labeling Claims:

Draft Guidance,” HQLO 2006; 4 (79).

3. Alan Shields, Chad Gwaltney, Brian Tiplady, Jean Paty, and Saul

Shiffman, “Grasping the FDA’s PRO Guidance: What the Agency

Requires to Support the Selection of Patient-Reported Outcome

Instruments,” Applied Clinical Trials, August 2006, 69-72, 83.

4. Keith Wenzel, Bill Byrom, and David Stein, “Putting the “e”

in FDA’s Draft PRO Guidance,” Applied Clinical Trials, March

2007, supplement, 12-16.

5. S. J. Coons, C. J. Gwaltney, R. D. Hays, J. Lundy, J. Sloan, and

D. A. Revicki, et al, “Recommendations on Evidence Needed

to Support Measurement Equivalence Between Electronic and

Paper-Based Patient-Reported Outcome (PRO) Measures:

ISPOR ePRO Good Research Practices Task Force Report,”

Value in Health, 12 (4) 419-429, (2009).

6. M. Rothman, L. Burke, P. Erickson, N.K. Leidy, D. Patrick, and

C.D. Petrie, “Use of Existing Patient-Reported Outcome (PRO)

Instruments and Their Modification: the ISPOR Good Research

Practices for Evaluating and Documenting Content Validity for

the Use of Existing Instruments and Their Modification PRO-

Task Force Report,” Value in Health, 12 (8) 1075-1083 (2009).

7. M. Caron, M.P. Emery, P. Marquis, E. Piault, J. Scott, “Recent

Trends in the Inclusion of Patient-Reported Outcome (PRO)

Data in Approved Drugs Labeling by the FDA and EMEA,” PRO

Newsletter, (40) 2008.

8. Committee for Medicinal Products for Human Use, “Reflection

Paper on the Regulatory Guidance for the Use of Heath-Related

Quality of Life (Hrql) Measures in the Evaluation of Medicinal

Products,” 2005, http://www.emea.europa.eu/pdfs/human/

ewp/1393104en.pdf.

9. D. Wild, S. Eremenco, I. Mear, M. Martin, C. Houchin, M.

Gawlicki, et al., “Multinational Trials—Recommendations on

the Translations Required, Approaches to Using the Same Lan-

guage in Different Countries, and the Approaches to Support

Pooling the Data: The ISPOR Patient-Reported Outcomes Trans-

lation and Linguistic Validation Good Research Practices Task

Force Report,” Value in Health 12 (4) 430-440, (2009).

Jane Speight,* PhD, is Director of Research, e-mail: jane.

[email protected], and Shalleen Barendse, PhD, is

a Health Psychology Consultant at AHP Research, Brunel

Science Park, Kingston Lane, Uxbridge, UB8 3PQ.

*To whom all correspondence should be addressed.

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BUSINESS AND PEOPLE UPDATE

Community

People ◗ Clinical Trials of America

(Eugene, OR) has opened a

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◗ Bringing with him more

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clinical trial planning, Ron

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Global Head of Clinical Re-

porting at Novella Clinical (Re-

search Triangle Park, NC).

◗ ACM Global Central Lab

(Rochester, NY) has made

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with the additions of Angela

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Management and Clinical

Systems. The company has

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Clinical Trials Global Opera-

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◗ WorldCare Clinical (Bos-

ton, MA) has promoted

Richard Walovitch, PhD,

from Chief Medical Officer

to President, and Xiaozhou

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tion and 3D Imaging.

◗ With more than 20 years

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development industry, David

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YBS (York, UK) as Business

Development Manager.

◗ Premier Research Group

(Philadelphia, PA) has ap-

pointed Charlene Sanders,

MD, to the position of Vice

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tory Affairs and Pediatric

Strategic Consulting and

appointed Christopher Co-

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Officer.

◗ DaVita Clinical Research

Laboratory Services, SM

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has promoted Kevin J. Gou-

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Development.

◗ TranScrip Partners (Read-

ing, UK) has made several

additions to the company

including Julia Lloyd-Parks

and Mark Watling as senior

partners.

◗ PharmaNet Development

Group (Princeton, NJ) has

hired Chris Beaver, PhD, as

Director, Immunochem-

istry Services, as well as

Catherine Derasp, as Vice

President, Clinical Op-

erations, of the company’s

Phase I clinics.

◗ After working at Praxis

(Lake Forest, IL) since

2002, Kevin J. Wysocki has

accepted an invitation to be-

come a partner at the firm.

◗ PPD (Wilmington, NC)

has appointed Elena Logan

as Senior Vice President of

Global Central Labs.

◗ Lifetree Center for Neuro-

science Research (Salt Lake

City, UT) has appointed

Miroslav Bačkonja, MD, as

Medical Director.

◗ CTI Clinical Trial and Con-

sulting Services (Blue Ash,

OH) recently promoted

Ranjana Iyer to Clinical

Safety Scientist.

Alliances•The Society for Clinical

Data Management (Mil-

waukee, WI) and the Asso-

ciation of Clinical Research

Professionals (Alexandria,

VA) have formed a col-

laboration to improve their

support of professionals in

clinical research.

•Clearstone Central Labora-

tories (Toronto, Canada) has

formed a strategic partner-

ship with TNT (Amserdam,

The Netherlands) with the

aim to provide innovative

and cost-effective solutions

for customers.

•To expand the scale and

scope of its operations,

Maximax Pharmaceutical

Research (Troy, MI) has

launched a development

group embracing its global

strategic alliance with

four CRO’s in India, South

America, Russia, and Cen-

tral Europe.

•Octagon (Wayne, PA) and

ScenPro (Richardson, TX)

have formed a partnership

to support a FDA legacy

data conversion project that

will further the agency’s

ability to review and evalu-

ate data across studies.

•Kaizen Clinical Services

(Jackson, NJ), an oncology

focused contract research

organization, has joined

BioClinica’s (Newtown, PA)

Certified Partner Program.

•GlaxoSmithKline (London,

UK) has signed a multi-

year enterprise technology

agreement to deploy BioClin-

ica’s (Newtown, PA) Trident

Interactive Web Response

system across its Phase

I-IV clinical trials.

•Celerion (Lincoln, NE)

and BryanLGH Health System

(Lincoln, NE) announced

an alliance to provide a

dedicated wing at Bryan-

LGH Medical Center West

for early clinical studies

including Phase I and first-

in-human.

Richard Walovitch, PhDAngela PanzarellaRon KershnerKathy Hendricks


caption_name caption_name caption_name caption_name cap-tion_name caption_name caption_name caption_name caption_name caption_name caption_name caption_name caption_name caption_name caption_name caption_name

•Perceptive Informatics

(Boston, MA) has selected

TIBCO (Palo Alto, CA) soft-

ware to enhance its suite of

eClinical service offerings,

incorporating enterprise

infrastructure software,

TIBCO ActiveMatrix

BusinessWorks,™ as well

as TIBCO Enterprise Mes-

sage Service,™ into its

eClinical platform.

Awards•Jonathan Trethowan, Di-

rector of TRAC (Camborne,

UK), was named winner of

the Inspiration category at

the TOPRA Symposium in

London.

•ClinTec International

(Glasgow, UK) has been

ranked in the Deloitte UK

Technology Fast 50 & Fast

500 EMEA. The awards,

which are based on percent-

age revenue growth over a

five-year period, position

and recognize ClinTec as

number 46 in the top 50

fastest-growing technology

companies in the UK and

226 in the 500 fastest grow-

ing in Europe, the Middle

East, and Africa.

•Synteract (Carlsbad, CA)

CEO Ellen Morgan has been

awarded Most Admired

CEO of the Year honors in

the private large company

sector by San Diego Busi-

ness Journal.

Company News•In order to reach and

serve Hispanics more ef-

fectively, staff members at

Wake Research Associates

(Raleigh, NC) completed

a training course focused

on improving Hispanic par-

ticipation in clinical trials

through Blaire Borthayre,

CEO of Hispanic Market-

ing Resources.

•The Agency for Healthcare

Research and Quality (Rock-

ville, MD) has awarded

Outcome Sciences (Cam-

bridge, MA) a task order to

design and develop a new

Registry of Patient Regis-

tries database.

•Integrium (Tustin, CA) cel-

ebrated 12 years of develop-

ing and managing over 150

successful clinical trials for

clients, consistently beating

patient enrollment goals

and reducing costs.

•The University of Leicester’s

(Leicester, UK) Clinical Tri-

als Unit has signed a contract

for the installation of MACRO

version 4.1, the latest release

of InferMed’s electronic data

capture solution.

•BioClinica (Newtown,

PA) celebrated 20 years

of experience, leadership,

and growth, including the

launch of Trident IWR, new

release of optimizer, and

acquisition of TranSenda

International.

•Popsi Cube (Paris, France)

has opened a new facility in

Philadelphia, PA in order to

meet the growing demands

of the company’s North

American sponsors.

Products•Cmed Technology (New

Providence, NJ) has re-

leased Timaues 5, Cmed

Technology’s newest version

of its eClinical platform to

manage data from study

design through reporting

and Timaeus HotSpot, a por-

table, regulatory-compliant

eClinical suite that com-

bines the Timaeus platform

with the freedom and flex-

ibility of a WiFi hotspot.

•Celerion (Lincoln, NE)

has launched Labnotes,

a commercially available

electronic laboratory note-

book system to standardize

bioanalytical processes and

improve documentation con-

sistency for all studies.

•Chiltern International

(London, UK) announced

the launch of Chiltern

SAFE, a global trial master

file management solution

that facilitates remote man-

agement of documents.

•IntraLinks (New York, NY)

has released IntraLinks

for Study Management, a

secure, online platform for

managing and monitoring

all communication and activ-

ity with investigative sites

and other outside parties

during clinical trials.

•In order to improve patient

safety, the European Medi-

cines Agency (London, UK)

and the European Network

of Centers for Pharmaco-

epidemiology and Phar-

macovigilance (ENCePP)

have launched the ENCePP

E-Register of Studies, a

publicly accessible resource

for the consultation of phar-

macoepidemiological and

pharmacovigilance studies

conducted by academic

centers and other research

organizations.

•Almac (Craigavon, North-

ern Ireland) has added an

additional dedicated Late

Stage Customization Suite

to the company’s commer-

cial facilities.

•StudyManager (Seattle,

WA) has released Reveal

version 3.1, expanding the

recruitment, financial, and

reporting capabilities of its

clinical trial management

software for sites, universi-

ties, and hospitals.

•PharmaNet Development

Group (Princeton, NJ) has

launched two technology

platforms, Initiator™ and

PKS,™ that will provide

improvements in clinical

study timelines by accelerat-

ing data acquisition and the

processing of final client re-

ports in its Phase I clinics.

Jonathan Trethowan, Director of TRAC, a Cornish regulatory affairs company, won the Inspiration Award at the TOPRA Symposium held in London after being nominated by TRAC Regulatory Affairs Executive, Lisa Pascoe.


To have your event considered, contact Kayda Norman at [email protected] or (732) 346-3035.

>> For a comprehensive calendar of events see appliedclinicaltrialsonline.com

Calendar of Events

March2-4: Drug Development

Process—From Discovery

to Communication, Berlin,

Germany, Contact: CfPIE

3-4: Preparation of FDA

Submissions (INDs, NDAs,

BLAs, ANDAs, Post-Approval

Supplements) and Communi-

cating with the FDA, King of

Prussia, PA. Contact: CfPIE

6-9: SGO’s 2011 Annual

Meeting on Women’s Cancer,

Orlando, FL. Contact: ASCO

6-11: 46th Annual Arden

Conference: Pharmaceuti-

cal Development of Biolog-

ics, West Point, NY. Contact:

American Association of

Pharmaceutical Scientists, (703)

243-2800, www.aaps.org/

index.asp

7: Medical Devices: Demystify-

ing Regulation and Guidance,

Arlington, VA. Contact: PERI

7-8: Clinical Document

Management—A Trial-by-Trial

Approach to Compliance, Los

Angeles, CA. Contact: CfPIE

7-9: Good Clinical Practices

(GCPs), Berlin, Germany.

Contact: CfPIE

8-9: Applying Pharmacokinet-

ics and Pharmacodynamics

for Regulatory Submissions,


10-11: DIA/FDA Practices

for Regulatory Information

Synthesis of Randomized

Trials for Product Safety

Evaluation, Bethesda, MD.

Contact: DIA

14-15: Clinical Trial Design

for Medical Devices, King of

Prussia, PA. Contact: CfPIE

14-15: Basic Drug Develop-

ment, Arlington, VA.

Contact: PERI

14-15: Developing Specifica-

tions for Drug Substances and

Drug Products, Amsterdam, The

Netherlands. Contact: CfPA

14-16: EudraVigilance Train-

ing—Electronic Reporting of

ICSRs in the EEA, London, UK.

Contact: DIA

14-16: BIO-Europe Spring 2011,

Milan, Italy. Contact: Biotechnol-

ogy Industry Organization, (202)

962-9200, www.bio.org

14-18: Clinical Science

Courses, Philadelphia, PA.

Contact: SoCRA.

14-18: Clinical Science

Courses, San Francisco, CA.

Contact: SoCRA

15-16: IQ, OQ, PQ, Burlingame,

CA. Contact: CfPA

16-17: Clinical Data Quality

Summit, Arlington, VA.

Contact: DIA

21-22: The EU Clinical Trial

Directive, King of Prussia, PA.

Contact: CfPIE

21-22: INDs/NDAs/CTDs,

Amsterdam, The Netherlands.

Contact: CfPA

21-22: 3rd Annual Bio/Pharma-

ceutical Drug Safety Forum,

Philadelphia, PA. Contact: CBI

21-22: The Institute of Clinical

Research 32nd Annual Confer-

ence and Exhibition, Brighton,

UK. Contact: Institute of Clinical

Research, +44 1628 899755,

www.instituteofclinical

research.com

21-23: Analytical Methods

Validation for FDA Compli-

ance, New Brunswick, NJ.

Contact: CfPA

22-23: Implementing Good

Clinical Laboratory Practice,

Cambridge, UK. Contact:

BARQA

24-25: Advanced Site Manage-

ment: Finance and Produc-

tivity Enhanced Business

Practices for Clinical Research

Programs, Jersey City, NJ.

Contact: SoCRA

24-25: 3rd Annual Forum

on Payers on Personalized

Medicine, Washington DC.

Contact: CBI

24-25: 4th Annual Clinical Trial

Management Systems (CTMS),


24-25: Advanced Cancer

Course “International Clinical

Trials Workshop” (FLASCA),

Punta del Eeste, Uruguay.

Contact: ASCO

28-29: The 3rd Annual Digital

Pharma Europe, Ingelheim,

Germany. Contact: ExL Pharma

28-29: Cardiovascular Drug

and Device Development,


28-30: 23rd Annual EuroMeet-

ing, Geneva, Switzerland.

Contact: DIA

28-30: Pharmaceutical Process

Development, Amsterdam, The

Netherlands. Contact: CfPA

30-31: Prescription Drug

Labeling Regulations: US,

Canada, and EU, Arlington, VA.

Contact: PERI

30-April 1: 20th Annual

Partnerships in Clinical Trials,

Phoenix, AZ. Contact: Institute

for International Research, (888)

670-8200, www.iirusa.com

April4-5: Good Laboratory

Practices (GLP) for Pre-Clinical

Testing, King of Prussia, PA.

Contact: CfPIE

4-5: Global Regulatory Affairs:

An Overview of Drugs and

Biologics, Arlington, VA.

Contact: PERI

4-6: 2nd Annual Proactive

GCP Compliance, Westin

Arlington Gateway, VA.

Contact: ExL Pharma

5-6: Research Quality Assur-

ance for Good Laboratory

Practice, Cambridge, UK.

Contact: BARQA

5-7: Medical Device Regula-

tory Affairs, Denham, UK.

ASCO: American Society

of Clinical Oncology,

(571) 483-1300,

www.asco.org

BARQA: British Association

of Research Quality

Assurance, +44 1473 221411,

www.barqa.com

CBI: Center for Business

Intelligence, (781) 939-2400,

www.cbinet.com

CfPIE: Center for Professional

Innovation and Education, (610)

688-1708, www.cfpie.com

CfPA: Center for Professional

Advancement, (732) 238-1600,

www.cfpa.com

CHI: Cambridge Health

Institute, (781) 972-5400,

www.healthtech.com

DIA: Drug Information

Association, (215) 442-6100,

www.diahome.org

ExL Pharma: (212) 400-6240,

www.exlpharma.com

PERI: Pharmaceutical Education

and Research Institute, (703)

276-0178, www.peri.org

SMi: +44 20 7827 6000.

www.smi-online.co.uk

SoCRA: Society of Clinical

Research Associates, (800)

SoCRA92 or (215) 822-8644,

www.socra.org


APPLIED CLINICAL TRIALS (ISSN 1064-8542) is published monthly by Advanstar Communications Inc., 131 West 1st Street, Duluth, MN 55802-2065. Subscription rates: $70 for 1 year (12 issues), $120 for 2 years (24 issues) in the United States and possessions; $90 for 1 year, $140 for 2 years in Canada and Mexico; all other countries $130 for 1 year, $235 for 2 years. Single copies (prepaid only): $9 in the United States and possessions; $11 in all other countries. Add $6.50 per order for shipping and handling. Periodicals postage paid at Duluth, MN 55806 and additional mailing offices. POSTMASTER: Please send address changes to APPLIED CLINICAL TRIALS, P.O. Box 6115, Duluth, MN 55806-6115. PUBLICATIONS MAIL AGREEMENT NO. 40612608, Return Undeliverable Canadian Addresses to: Pitney Bowes, P. O. Box 25542, London, ON N6C 6B2, CANADA. Canadian G.S.T. number: R-124213133RT001.

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Requirements, King of Prussia,

PA. Contact: CfPIE

30-May 3: ACRP 2011 Global

Conference and Exhibition,

Seattle, WA. Contact: ACRP

May 2-3: Writing Effective

Standard Operating Proce-

dures and Other Process

Documents, Los Angeles, CA.

Contact: CfPIE

2-4: Biomarker World

Congress, Philadelphia, PA.

Contact: CHI

2-4: Global Pharmacovigilance

Training Course, Arlington, VA.

Contact: PERI

2-4: Cancer: Pathophysiology,

Current Therapies, Clinical

Trials and Drug Development,

Washington, DC. Contact: PERI

2-4: cGMP Quality Principles

for Pharmaceuticals, Biophar-

maceuticals, Biologics, and

Medical Devices, Los Angeles,

CA. Contact: CfPIE

Contact: The Organization

for Professionals in Regulatory

Affairs, +44 (0) 20 7510 2560,

www.topra.org




Contact: DIA

7-8: SoCRA Clinical Site Coordi-

nator/Manager Program for

Coordinators, Research Associ-

ates, Study Nurses, and Site

Managers Registration, Toronto,

Ontario. Contact: SoCRA

7-8: 2011 RAPS Horizons:

Regulatory and Beyond,

Vancouver, Canada.

Contact: Regulatory Affairs

Professionals Society,

(301) 770-2920, www.raps.org




Contact: DIA

11-15: 2011 PDA Annual

Meeting, San Antonio, TX.

Contact: Parenteral Drug

Association, (301) 656-5900,

www.pda.org

12-14: Bio-IT World Conference

and Expo, Boston, MA.

Contact: CHI

13: Biosimilars and Follow-

on Biologics, Arlington, VA.

Contact: PERI

13-15: Cardiovascular Safety

in Drug Development: State

of the Art Assessments,

Washington, DC. Contact: DIA

14-15: Writing Effective

Standard Operating Proce-

dures and Other Process

Documents, Berlin, Germany.

Contact: CfPIE

14-15: Protecting Human

Research Participants:

Legal, Ethical, and Practical

Considerations, San Diego, CA.

Contact: SoCRA

14-15: GCP Audits—Best

Practices for Ensuring

Compliance & Detecting

Fraud and Misconduct in

Clinical Trials, King of Prussia,

PA. Contact: CfPIE

14-15: Stability Programs

for Product Shelf Life—From

Development to Approval, King

of Prussia, PA. Contact: CfPIE

18-19: Clinical Trial Planning

and Management, Arlington,

VA. Contact: PERI

26-27: Future Medicines:

Translational Approaches in

Cancer Therapeutics, Irvine,

CA. Contact: CHI

26-27: Best Practices for

Facilities and Utilities

Design, Qualification and

Monitoring, King of Prussia,

PA. Contact: CfPIE

27-28: 6th Annual Forum on

Clinical Trial Registries and

Results Databases, Philadel-

phia, PA. Contact: CBI

27-28: 3rd Annual Bio/Pharma-

ceutical Drug Safety Forum,


27-29: Drug Development

Process—From Discovery to

Communication, Los Angeles,

CA, Contact: CfPIE

28-29: Pediatric Clinical Trial

Design—Ethics, Manage-

ment, and Regulatory

ALMAC Group . . . . . . . . . . . . . . . . . . . . . . 9

AtCor Medical . . . . . . . . . . . . . . . . . . . . . . 3

BIO International . . . . . . . . . . . . . . . . . . 39

Corporate Translations Inc . . . . . . . . . . . 33

DIA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31

ERT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60

ExL Pharma . . . . . . . . . . . . . . . . . . . . 15, 45

Gen Probe Life Sciences Ltd . . . . . . . . . . 42

George Washington University Medical Center . . . . . . . . . . . . . . . . . . 43

ICON Medical Imaging . . . . . . . . . . . . . . 17

IIR Partnerships . . . . . . . . . . . . . . . . . . . 49

INTERLAB Central Lab Services —Worldwide . . . . . . . . . . . . . . . . . 40, 51

invivodata . . . . . . . . . . . . . . . . . . . . . . . . 21

Marken . . . . . . . . . . . . . . . . . . . . . . . . 18ab

Medpace Inc. . . . . . . . . . . . . . . . . . . . . . 25

Oracle Health Sciences . . . . . . . . . . . . . . 59

Outcome . . . . . . . . . . . . . . . . . . . . . . . 5, 35

PAREXEL International . . . . . . . . . . . . . . . 2

Perceptive Informatics . . . . . . . . . 11, 26-27

PharmaNet . . . . . . . . . . . . . . . . . . . . . . . 23

QualityMetric . . . . . . . . . . . . . . . . . . . . . . 7

SAS Institute . . . . . . . . . . . . . . . . . . . . . . 13

WorldCare Clinical . . . . . . . . . . . . . . . . . 29

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Standard of Care in Study BudgetingSurvey reveals industry practices

surrounding standard of care and

insurance claims data.

Harold e. Glass

Pharmaceutical executives readily acknowledge that

their industry faces a number of broad challenges,

not the least of which are the escalating costs of de-

veloping new drugs and a weak public image.1 Both

issues intersect in one area of drug development:

clinical grants. Based upon an industry survey of people

working in clinical operations, and an analysis of grant pay-

ments from the perspective of standard of care (SOC), this

article argues that cost management and fair market value

can be far more effectively addressed than has been the prac-

tice to date.Clinical grants represent a major and growing cost of

developing new drugs. These rapidly increasing costs have

been extensively documented and analyzed, 2 and the re-

search suggests that clinical trials are the largest single area

of R&D operating expenses, with clinical investigator grants

representing the bulk of these costs. Many drug develop-

ment managers appreciate the need to control clinical trial

costs. One important, if underappreciated, approach involves

avoiding double payments for activities that would be nor-

mally covered by third-party payers (including Medicare and

Medicaid in the United States) as part of the standard care

that any patient would receive at that clinical research site,

whether or not that patient is part of a clinical trial. While

sites are ethically prohibited from enrolling a patient in a

clinical trial if that patient would not otherwise be treated

for the illness being studied, many of these patients would

be partially covered by third-party payers as part of the stan-

dard of medical care.Understanding the standard of medical care, however,

can be particularly dif f icult when studies involve mul-

tiple countries. At one end of the health continuum some

countries are moving toward national medical

treatment protocols—the UK’s National Health

Service is one example. While health care in

many countries has one dominant payer, few

countries have just one agency delivering almost

all their health care, as is the case in the UK. In

sharp contrast, the United States has multiple

payers and health care delivery organizations.

Such differences challenge clinical development

teams as they seek to establish medical standard

of care guidelines for clinical trial grant pay-

ments. In the United States, however, it is easier

to establish what constitutes standard of care

through the payment practices of third-party

payers.A second pharmaceutical industry challenge is

the changing relationship with physicians. After

intense scrutiny from both within and outside

the industry, pharmaceutical companies have

now developed more stringent guidelines about

what they can give to prescribing doctors. For

instance, new guidelines prohibit gifts of any sort,

restrict meals to those associated with actual

medical education, and prohibit industry em-

ployees from giving any other objects to medical

professionals. Some pharmaceutical industry observers are

also concerned about the financial relationship be-

tween investigators participating in clinical trials

and the companies sponsoring the trials. These

observers have questioned whether the grant

amount for a clinical trial reflects payment only for

work performed or whether the payment might be

an attempt to influence investigator behavior. In

these instances, the foremost concern is whether

investigators are being paid at fair market rates or

at inflated rates that might influence their behav-

ior. 3 While some published research links relative

grant payment levels with subsequent investigator

Sites

Your Peer-reviewed Guide to Global CliniCal trials ManaGeMent appliedclinicaltrialsonline.com

1992–2010

ACT

Year of Servi ce

Volume 19, Number 7 July 2010

InsId

e

Protecting Subjects:

The IRBs Next Steps

➤ SiteS

incorporating Standard

of Care in Study Budgets

Benefits of CtMS

at the investigative Site

Also in this issue

■ FDA Transparency Efforts to Impact Research

■ Survey Assesses Europe’s Clinical Trials Directive

■ Tapping into the Potential of Pharmacists

■ Biosimilars Make Headway in the U.S.

Complete contents on pages 6 & 8

EU LEGAL SERVICES

EU Legal Representative. All 27 EU countries

require an EU based legal entity for clinical trials.

Our UK based Chartered Accountants form a UK

legal entity in 48hrs. Low fees – prompt service.

www.TopazClinical.com


To see more A Closing Thought articles,

visit appliedclinicaltrialsonline.com

A Closing Thought

How? By releasing the final “Guidance

for Industry, Patient-Reported Outcome

Measures: Use in Medical Product Devel-

opment to Support Labeling Claims” (or

PRO guidance) in December 2009. FDA

had previously released the draft version

of this guidance in February 2006.

So, what’s the big deal? FDA releases

Guidance for Industry documents all the

time. This PRO guidance is different: it

has almost single-handedly driven our

industry to take note of the patient—to

listen, understand, and document the

patient’s perspective during medical

product development. The momentum

started building following the release of

the draft guidance in February 2006. In

the almost three years between draft and

final guidance, FDA regularly and actively

communicated its key message: listen to

the patient.

In the past year, following the release of

the final version of the guidance, signifi-

cant strides have been made toward focus-

ing on the patient during product develop-

ment. Concretely, what has happened?

The answer lies in how the specific rec-

ommendations in the guidance have had

an impact on product development strat-

egy. Here is how the story unfolded…

The guidance delineates FDA’s current

expectations for PRO instruments (that

capture data directly from the patient with

no interpretation by a clinical professional)

that will be used to support labeling lan-

guage in medical products. The recom-

mendations from FDA are based upon the

discipline of developing PRO instruments

in psychology and other areas—psycho-

metrics. There is nothing new or surpris-

ing in terms of what should be done to

develop and evaluate PRO instruments.

Pleasantly surprising is that the PRO

guidance has legitimized PROs, elevating

their importance in product development

planning. The mere fact that the FDA

finalized this guidance has given a clear

message to the industry that the patient

perspective is important enough to be a

formal part of the regulatory-based com-

munication of a product: the label. This

has led many pharmaceutical companies

to re-evaluate their hierarchy of end-

points. In the past year, we have seen over

a dozen pharmaceutical companies that

have elevated PROs to be alongside other

primary or key secondary biomarkers or

physician-assessment endpoints. Such

companies are seeking PRO-based labels

for their new products. They have worked

closely and collaboratively with FDA on

the PRO instruments that will support

these labels. These companies are taking

advantage of the opportunity to clearly

communicate the value of their product to

the people who matter most—patients.

The elevation of PROs in clinical pro-

grams to endpoints that will form the

basis of labeling claims has had a follow-

on effect within pharmaceuticals. When

an endpoint, or class of endpoints, is

regularly part of the label plan, or target

product profile, it starts to become part of

the strategic planning for pipelines within

a pharmaceutical company. Multiple phar-

maceutical companies have adopted PROs

as part of their product strategy within

and across portfolios. In fact, some of the

largest pharmaceutical companies have

now made consideration of PRO endpoints

as part of their documented process for

developing a product strategy. PROs are

strategic. The patient benefits.

Thank you, FDA.❏

Many of us involved in the biopharmaceutical and medical device

industry do not often consider regulators the cutting edge

folks—the people who lead the charge. Times have changed.

FDA has led the way in pushing us to focus on the patient.

The guidance has driven the industry to take

note of the patient—to listen, understand, and

document.

Jean Paty, PhDSenior Vice President invivodata, inc.www.invivodata.com

The Patient Matters: Thanks FDA

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