Are you starting a clinical trial or about to start one? If so, read this article first published in the June 2011 issue of the peer-reviewed journal ,The Monitor. The article discusses challenges in how trials are started today and explore a new wave of cloud-based technologies, which will forever reshape how studies are started around the world.

1. Peer reviewed Daniel Manak | Jae Chung, MBA, CPA | Sherry Reuter, BSN, MSHS
S o l u t i o n S - B a S e d
Study Startup 2.0
Reinventing How Clinical Trials Begin
t e c h n o l o g y
A nyone who has ever participated in clinical study startup for drugs,
devices, or biologics knows that it is a tedious, labor-intensive, and
frustrating process that often fails to meet timelines.1 Methods used to com-
plete startup tasks remain largely paper-based and are often inefficient and
slow.2,3
This scenario leaves much room for improvement, and this article ex-
This article explores plores state-of-the-art approaches to bringing about the desired goal of
completing startup tasks more efficiently, reducing the number of clinical
state-of-the-art trials that do not complete on time and within budget. Specifically, the fo-
cus here is on best practices and new technologies for streamlining startup
approaches to bringing processes. The technologies are based on cloud computing, a dynamically
about the desired goal scalable method of providing software to the end-user from a web-based
server to deliver applications on demand.
of completing startup Utilizing shared virtualized resources, these user-friendly programs can
simplify document exchange and decrease repetitive tasks while provid-
tasks more efficiently, ing up-to-the minute transparency to all stakeholders involved in startup.
Sponsor-site relations improve, leading to greater buy-in by sites and con-
reducing the number of tract research organizations (CROs) and greater motivation to perform. The
sponsor that is functioning in a financially and time-squeezed environment
clinical trials that do not may realize dramatic time and cost savings as tasks are completed and
complete on time and tracked in an organized and simplified manner, allowing studies to proceed
on schedule.
within budget.
Startup 1.0: The Process
Clinical study startup is the multistep practice of selecting and preparing
investigative sites for initiation. It is a collaboration of stakeholders: spon-
sor, CRO, site, institutional review board (IRB) or ethics committee (EC),
and a variety of outsourced providers. It consists of exchanging numerous
documents, communication, and budget and contract negotiations, which
involve:
●● Distribution, collection, and evaluation of pretrial questionnaire
●● Regulatory document completion and IRB/EC approval
●● Negotiation of contracts and budgets
●● Scheduling and performing site evaluation visits
●● Conducting investigator meetings/site training
●● Provision of supplies and test article
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2. The work begins with site identification, factored heavily in study delays, with they can be found, and what types
an increasingly global function, and contract and budget negotiation cited of sites will be able to access, recruit,
continues until all selected sites are as the most frequent cause at 49%, fol- and enroll them. An ideal site profile
initiated. lowed by patient recruitment and other should be used in accordance with the
Each component of startup has sev- routine tasks (see Figure 2).4 Research protocol to guide every step of site se-
eral steps, often tracked using multiple suggests that sponsors stand to lose lection; otherwise, sites are likely to be
spreadsheets created and accessed by between $600,000 and $8 million each chosen that will not perform well.
various partners. Generally, these cre- day product development is stalled;5 so Next, the sponsor or CRO compiles
ate inefficiencies because the methods startup processes that drag on cut into a list of potential sites that meet the
are not standardized across functions the bottom line in a very direct way. unique criteria defined in the ideal site
or centralized for easy access; so they There is a lot at stake in startup, profile, perhaps beginning by identify-
tend to be reinvented for each study. which is why continuing with the sta- ing sites with which they have previ-
A view of startup appears in Figure 1. tus quo is not a sustainable business ous experience. Other sources of sites
The figure is not meant to be inclu- practice. A better option is to employ include online directories, referrals
sive of all guidelines from the Inter- standards and process changes for site from trusted sources, social network-
national Conference on Harmonization selection, complemented by technol- ing sites, site networks, site manage-
(ICH), but can serve as a framework for ogy to bring about startup improve- ment organizations, and physician lists
understanding startup complexity. ments that will extend into other stages (typically by specialty) from profes-
Given the nature of the startup pro- of development.6 Some technologies sional medical associations. Additional
cess, it is not surprising that the cur- designed for startup use cloud com- site selection tips include:
rent system breeds delays. A LinkedIn puting, which is described in Figure 3.
study conducted in 2010 questioned ●● developing a customized pretrial
205 clinical trial professionals about questionnaire based on charac-
Improving the Process
their views of the startup process;3 41% teristics of the ideal site;
responded that it was “lengthy, manual, A critical element of startup is site se- ●● reviewing responses to the ques-
and inefficient,” while 30% reported lection. Finding reliable, performing tionnaires; and
that it was “OK, but could use improve- sites begins with sponsors and CROs ●● performing site evaluation visits,
ment.” In a 2009 CenterWatch survey developing a detailed plan to define focusing on the principal inves-
of investigative sites, startup activities the target patient population, where tigator’s (PI’s) interest in the
Figure 1 The Complex Process of Clinical Study Startup
Study offered
Initial contact YES Site review of pretrial YES to PI
Confidentiality Perform Start regulatory
by pharma, biotech, questionnaire and
agreement prestudy visit Accepted document collection
or device sponsor protocol requirements
NO NO
• PI declines study
PI not interested PI not interested • Sponsor does not select PI/site
Budget Budget and Contracts Final;
negotiations may need final contracts to
submit to IRB/EC
Contract Submit to IRB/EC:
negotiations • IRB/EC application
• CVs/Licenses of personnel
• Protocol Approval
IRB/EC • Informed consent form with site information
submission prep • HIPAA authorization (U.S.)
Regulatory • Final contracts (country dependent)
documents
complete Submit to regulatory agency(s) Site
Regulatory/Good Clinical evaluation
• FDA Form 1572
Practices document prep visit and/or
• Curriculum vitae, medical license of PI
• Financial disclosure (U.S. and EU if necessary) investigator
meeting
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34 Monitor June 2011

3. Figure 2 Factors Most Often Causing Study Delays (n=950) it should focus on honest discussion
about the targeted population and the
49% site’s ability to recruit and perform the
trial successfully.
41% Statistics indicate that the industry
continues to do a poor job with recruit-
ment, as evidenced by these dismal
26% 26% facts:
25%
●● 70% of investigative sites are
more than one month behind
in enrollment, and only 7% of
sites report meeting enrollment
timelines.4
Contract and Patient Protocol design Legal review IRB review and ●● A major pharmaceutical com-
budget negotiation recruitment and and refinement approval pany reported that between 2000
and approval enrollment and 2006, 26% of sites recruited
80% of participants; 11% of sites
Source: CenterWatch Survey of Investigative Sites in the U.S. (2009) recruited one subject; and for
oncology studies, 37% of sites
recruited no subjects.8
study and realistic assessment tionnaire. When there is little scru-
of the site’s ability to conduct it tiny of what is written on the ques- Recent research highlights the sav-
successfully. tionnaire, the phenomenon known as ings that can be realized by planning
Lasagna’s Law comes into play; this and implementing improved processes
Unfortunately, all too often sites law captures the notion that investiga- for this basic clinical trial activity.9
are chosen that lack the ability and/ tive sites frequently overestimate the The research makes the assumption
or motivation to conduct the trial suc- number of subjects they will be able that if 65,000 investigator sites are
cessfully. This happens for several to enroll.7 Second, there is often in- initiated annually, and the cost of ini-
reasons. First, timelines are almost al- adequate communication between the tiating each one were $20,000, even a
ways extremely short, so there is rarely sponsor and the PI as to the types of 1% reduction in nonperforming sites
time to properly identify sites beyond challenges he or she foresees with the would save the industry $13 million.
a cursory review of the pretrial ques- protocol. Third, the site evaluation vis- By identifying nonperforming sites,
fewer sites would be needed, and more
subjects would be enrolled at each of
Figure 3 What is Cloud Computing? the remaining sites.
A few words about metrics are in
Cloud computing refers to a web-based method of providing software to the end-user, order. Sponsors and CROs charged with
similar to the way consumers access applications or “apps” on their BlackBerries, site selection should keep metrics such
iPhones, or Droids. Desired applications are delivered on demand from a web-based
as the following on site performance,
server with shared virtualized resources. With this format, cloud computing enables the
ramping up or scaling down of computing resources as workload dictates. because they can offer an indication of
site potential:
Importantly, with cloud computing, there is no need for local software installation by
either the client or end-user. The only requirement is a device with a web browser and
●● Time to screening of first subject
an Internet connection, meaning that the desired software can be used from virtually
●● Number of subjects enrolled
anywhere.
compared to the number the site
This setup provides an important cost-saving advantage, because with technology forecasted
changing at warp speed, users can immediately access the latest functionality without ●● Number of subjects completed
purchasing additional hardware or having to update older software applications. Neither
●● Reasons for subjects withdrawing
is there a need for onsite training for users or support. Support is provided by the
software provider, and user interfaces are intuitive. Technical support is provided by the from the study
software provider, but typically tips and tricks, wizards, and training videos are embed- ●● Number of protocol deviations or
ded within the software itself. violations
●● Accurate document turnaround
Source: Whatis.com times
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4. ●● Time to completion of case report widely being adopted by sponsors and on a permissioned basis, providing
forms (CRFs) CROs for other aspects of clinical trial a visible measure of performance.
●● Number of data queries management do not necessarily focus This information enables the team to
on startup, either. A broad review of quickly identify sources of slowdowns
The evaluation of sponsor and CRO market solutions is beyond the scope or other issues needing attention.
performance in startup is as important of this article, but a cloud computing The cloud-based startup functions
as the evaluation of site metrics. For platform is discussed as a compelling include:
example, a site is not responsible for a alternative.
delay caused by the turnaround time a ●● streamlining the startup work-
sponsor takes with documents such as flow to save time and money;
Applying the Cloud to Startup
contracts or budgets. ●● collaborating with internal and
Successful startup relies on highly external partners from a single
organized project management pro- dashboard;
Technology and Startup
cesses and the ability to quickly ●● optimizing the organization and
Bringing new technology to startup exchange documents among stake- exchange of documents with
can be an important complement to holders. A cloud-based system enables security;
improving the current way startup is fast and secure document exchange ●● maintaining version control of
documents;
The evaluation of sponsor and CRO performance in ●● providing real-time and trans-
parent startup status to the entire
startup is as important as the evaluation of site metrics. study team;
●● being audit ready; and
conducted. As electronic data cap- and generates an audit trail. The sys- ●● utilizing valuable metrics gath-
ture (EDC) and clinical trial manage- tem can be configured to generate real- ered for post-study analysis and
ment system (CTMS) products, which time reports and status alerts and bring future planning.
manage operational and administra- them to the attention of the correct
tive clinical trial activities, have been team members regarding the next step The importance of this technology
adopted, new technological options in the process. There is also a level of extends beyond its ability to improve
are needed to optimize startup opera- transparency in the cloud that cannot and accelerate a single trial. Investing
tions. Continuing to cling to paper or be realized otherwise; that is, through- in organization and improved method-
spreadsheets is not likely to achieve out the startup process, all members of ology can have a positive impact on
the kinds of improvements needed to the study team can track and evaluate current as well as future trial opera-
conform to increasingly compressed processes and tasks instantaneously, tions, and this benefit can extend
timelines or facilitate the exchange of
documents.
The LinkedIn survey referred to ear-
Figure 4 Managing Startup Activities (n=205)
lier revealed that more than 53% of
respondents were using Excel spread- 53.2%
sheets to track their startup progress,
and 6% were using paper (see Figure 4).3
Spreadsheets may be standalone
or part of a patchwork solution with
a database, reporting software, and
possibly a webportal platform. These
homegrown efforts often require a lev-
el of information technology support 15.6%
13.6%
that is beyond the capacity of many 11.2%
in-house resources. As a result, com- 6.3%
panies may struggle to keep up with
the latest updates, and may be unable
Excel Sharepoint Internal Third-party Paper-based
to establish and staff a Help Desk. Ad- homegrown solution
ditionally, these systems rarely address software
the specific needs of startup. Simi-
larly, off-the-shelf solutions that are Source: LinkedIn Survey 2010
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36 Monitor June 2011

5. across multiple product and therapeu- table 1 Sampling of Electronic Submissions
tic lines.
FDA EMA
Ultimately, a well-designed cloud-
based system will wield a so-called Electronic Common 1/1/2008 – all electronic 1/1/2010 – all electronic
Technical Document submissions to Center for submissions must use eCTD
“network effect”—a term borrowed
(eCTD) Drug Evaluation and Research for Centralized Procedure
from adoption of the telephone and, (CDER) must use eCTD
more recently, from social network-
PIM Labeling Standard N/A Timeline for going live for
ing. A network effect refers to the fact
Centralized Procedure to be
that a technological tool becomes more determined; PIM is in pilot
valuable as more people use it.10 For mode
example, smartphones are increasingly Structured Product 10/31/2005 – all labeling N/A
valued as more people use them and Labeling (SPL) submission must be in SPL
rely on them for an ever-expanding format
range of functionality. If one considers Source: FDA, EMA
where the cellphone was 20 years ago
and where the smartphone is today, As shown in Table 1, some of the to comply with FDA-based 21 Code of
the technology has advanced beyond submissions leaning toward or requir- Federal Regulations (CFR) Part 11, the
making phone calls. Various uses are ing electronic formatting include the Electronic Records; Electronic Signa-
widespread, including texting, online electronic common technical docu- tures rule.17 According to the rule, elec-
banking, travel planning, shopping, ment,11,12 the Structured Product Label- tronic records and electronic signa-
e-mailing, and, in the near future, ing standard in the U.S.,13 and the Prod- tures can, under specified conditions,
clinical trial management. This range uct Information Management (PIM) be accepted as their paper equivalent.
of functionality establishes a virtual labeling standard in pilot-mode in Electronic records can be created in
community. Applying this methodol- Europe.14,15 Also, in 2006, FDA opened “closed” or “open” systems. As defined
ogy to startup, as more stakeholders the Electronic Submissions Gateway in the rule, a closed system refers to
adopt cloud-based technology, will (ESG), a central transmission point for an environment in which systems
inch it toward becoming the norm, sending information electronically to access is controlled by persons who
creating an even larger base of users its final destination within the agency. are responsible for the content of elec-
as they join the bandwagon. Currently, ESG is migrating to a new tronic records on the system. An open
data center.16 system refers to an environment in
A cloud-based system A second driver toward the cloud is which system access is not controlled
the fact that solutions can be designed by persons who are responsible for
enables fast and secure
document exchange and table 2 Challenges of Cloud Computing for Sites
Challenge Mitigation Strategy
generates an audit trail.
Provide reliable service Design for reliability and build in backup
Sites using cloud computing cannot Systems must either be up or covered by backup
afford to have interruptions in their systems at all times (industry standard = 99.9%
Drivers Toward the Cloud service—ever uptime)
For stakeholders still uncertain about • Ensure automatic nightly backups that are
encrypted
taking that first step toward the cloud,
• Redundant power systems for backup power
there are several key drivers pushing supply
the market in that direction. First, reg-
Security Utilize equipment and systems designed for
ulatory agencies, such as the U.S. Food
Sites have zero tolerance for maximum security
and Drug Administration (FDA) and the unauthorized access of user data; Secure data centers with 24-hour manned secu-
European Medicines Agency (EMA), data must be safe, backed up, and rity, video surveillance, and buildings engineered
have started requiring electronic sub- recoverable at all times for local seismic, storm, and flood risks
missions using highly structured for- Interoperability with other systems Interoperability is possible through file format,
mats, so they can be transmitted over It is common for sites to have multi- data sharing, and data integration
the Internet and read electronically. ple systems to run an entire process; File format for study startup data should be for-
The goal of these initiatives is to reduce data must be able to be easily shared matted in XML, which can be generated from any
paper, improve data quality, cut costs, across multiple systems number of source applications and received and
and speed review of information. processed by CTMS and EDC products
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6. the content of electronic records on Acknowledgment 12. European Medicines Agency. December 2008.
the system. In this instance, document EMEA implementation of electronic-only sub-
The authors wish to acknowledge Ann missions and mandatory eCTD submissions in
encryption and use of appropriate digi-
Neuer of Medical deScriptions, Gen Li, the Centralised Procedure: Statement of Intent.
tal signature standards are required to Available at www.emea.europa.eu/docs/en_GB
PhD, MBA, and Peter DiBiaso, MHSA,
ensure record authenticity, integrity, /document_library/Regulatory_and_procedural
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have appropriate backup, validation of
tributing to the research. 13. Draft Guidance for Industry and Reviewers
systems to ensure accuracy and reli-
on Structured Product Labeling Standard for
ability, as well as other controls. The Content of Labeling Technical Questions and
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Discovery & Development March 1(10): 32. Daniel Manak is senior director of business develop-
needed are cutting-edge solutions 7. Spilker B, Cramer JA. 1992. Patient Recruit- ment at goBalto. He has worked in pharmaceuticals, health-
that will enable end-users to perform ment in Clinical Trials. New York: Raven Press. care, and clinical research for more than 20 years. For this
the array of startup tasks quickly and 8. Gidron M. 2007. Cultivating clinical investiga- article, he provided oversight of collaborators, as well as
accurately. tors a challenge for Pfizer. Clinical Trials Advi- substantial contributions to research, design, and drafting
With the help of processes linked to sor 12: 3-4; available at www.fdanews.com and revising text, and gave final approval of the version to
/ext/files/CTA.pdf, accessed February 15, 2011. be published. He can be reached at dmanak@gobalto.com.
improved site selection, the availabil-
9. Li G. 2008. Site activation: the key to more
ity of cloud-based technology, and efficient clinical trials. PharmaExec.com, Jae Chung, MBA, CPA, is the founder and CeO
the resulting network effect, there is December 12; available at http://pharmexec of goBalto. Previously, he cofounded Celltrion, a leading
the potential to dramatically affect .findpharma.com/pharmexec/article/article biopharmaceutical supplier. For this article, he provided
Detail.jsp?id=571374&pageID=3, accessed substantial contributions to concept development, contrib-
the cost and timelines for clinical trial
January 11, 2011. uted to the drafting and revision of the text, and gave final
conduct. As the next generation of approval of the version to be published. He can be reached
10. Cox R, Larsen PT. 2010. Facebook’s power, and
tech-savvy workers enters the clini- its weakness. The New York Times, May 27;
at jchung@gobalto.com.
cal trials workforce, they will expect available at www.nytimes.com/2010/05/27 Sherry Reuter, BSN, MSHS, has more than 17
automation of tasks, similar to what /business/27views.html, accessed February 15, years of diverse experience in the clinical research industry,
has become standard practice in other 2011. having held positions in pharmaceutical and biotechnol-
industries. With the right tools, the 11. U.S. Food and Drug Administration. 2009. ogy firms, CrOs, and academia. She now is president of
eCTD Submission Waivers, June 18; available Sherry reuter & Associates, LLC, a consulting company
clinical research industry is poised to
at www.fda.gov/Drugs/DevelopmentApproval in the pharmaceutical arena. For this article, she provided
reap the same benefits other industries Process/FormsSubmissionRequirements/ substantial contributions to research, design, and drafting
have realized from optimizing their ElectronicSubmissions/ucm163186.htm, and revising the text, and gave final approval of the version
processes. accessed February 16, 2011. to be published. She can be reached at sreuter@gwu.edu.
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38 Monitor June 2011