Describes the advantages and disadvantages of using the Internet to conduct a clinical trial.

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The Internet and Clinical Trials: Background, Online Resources, Examples and Issues

James Paul1,2, MSc, MD; Rachael Seib1,2, MA; Todd Prescott1,2, BSc

1Department of Anesthesia, Hamilton Health Sciences, Hamilton, ON, Canada
2Department of Anesthesia, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada

Corresponding Author:
James Paul, MSc, MD

Department of Anesthesia
Hamilton Health Sciences
Hamilton General Site
237 Barton St East
Hamilton, ON L8L 2X2
Canada
Phone: +1 905 527 4322 ext 46698
Fax: +1 905 577 8023
Email: james_paul [at] sympatico.ca

ABSTRACT
Both the Internet and clinical trials were significant developments in
the latter half of the twentieth century: the Internet revolutionized
global communications and the randomized controlled trial provided a
means to conduct an unbiased comparison of two or more treatments. Large
multicenter trials are often burdened with an extensive development
time and considerable expense, as well as significant challenges in
obtaining, backing up and analyzing large amounts of data. Alongside the
increasing complexities of the modern clinical trial has grown the
power of the Internet to improve communications, centralize and secure
data as well as to distribute information. As more and more clinical
trials are required to coordinate multiple trial processes in real time,
centers are turning to the Internet for the tools to manage the
components of a clinical trial, either in whole or in part, to produce
lower costs and faster results. This paper reviews the historical
development of the Internet and the randomized controlled trial,
describes the Internet resources available that can be used in a
clinical trial, reviews some examples of online trials and describes the
advantages and disadvantages of using the Internet to conduct a
clinical trial. We also extract the characteristics of the 5 largest
clinical trials conducted using the Internet to date, which together
enrolled over 26000 patients.
(J Med Internet Res 2005;7(1):e5)
doi:10.2196/jmir.7.1.e5

KEYWORDS

Clinical trials; randomized controlled trial; Internet

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Introduction
Both the Internet and clinical trials were significant developments in
the latter half of the 20th century: the Internet revolutionized global
communications and the randomized controlled trial (RCT) provided a
means to conduct an unbiased comparison of two or more treatments. This
paper reviews the historical development of the Internet and the
randomized controlled trial, describes the Internet resources available
that can be used in a clinical trial, reviews some examples of online
trials and describes the advantages and disadvantages of using the
Internet to conduct a clinical trial.

Historical Aspects of the Internet and Clinical Trials
Origins of the Internet
The Internet was born in the 1960s and its applications were initially
limited by the military uses for which it was originally conceived. The
original “Internet” consisted of a cooperative network of four
university computers in the United States (Stanford Research Institute;
University of California, Los Angeles [UCLA]; University of California,
Santa Barbara; and University of Utah) [1]. The development of a
protocol for information distribution in 1990 by Tim Berners-Lee paved
the way for the emergence on the Internet of applications with broader
public appeal [2]. Fifteen years after its inception, the World Wide Web
has become a nearly indispensable tool in education, government,
business, news media and, most important for the purposes of this paper,
medicine and research [3]. Originally designed as an emergency
communications network, the medium evolved from a communications tool
for academics and the military to a medium used for education,
government, business, news media, entertainment, medicine, and research.
The Internet has grown at a phenomenal rate; with over 100 thousand
domains or hosts in 1993 it currently has over 250 million [4]. It is
the first unrestricted uncensored broadcast medium, and under ideal
circumstances (namely, the right location, low traffic volumes and the
right service provider), it can be very cost-effective, because unlike
the telephone system, there is no charge for long-distance service.

Origins of the Randomized Controlled Trial
A clinical trial can be defined as any form of planned experiment
involving patients [5]. The goal of a trial is to discover or verify the
safety and effectiveness of interventions designed to promote wellness
and prevent, diagnose, treat and provide prognosis information about
disease [6]. The essence of a trial is comparison [7]. The comparison is
between a group of patients who receivedtreatment with the intervention
in question and a group of patients who receivedplacebo or another
standard treatment. The modern clinical trial has evolved to include
several features in order to provide reliable and valid results. A good
trial addresses a specific clinical question for which there is
equipoise (an uncertainty as to whether any of the treatments is to be
preferred over the others). It uses a predefined patient population, a
well-defined intervention in comparison with an appropriate control,
predefined outcomes, and a methodology that involves getting informed
consent from participants. Further, a trial involves appropriate
blinding, randomization, and analysis. The inclusion of a control group,
as opposed to historical data, is to ensure that any observed
differences are due to the treatment under investigation and not another
prognostic factor [5]. The purpose of randomization is to balance the
treatment groups for both known and unknown prognostic factors such that
any observed differences in outcome are more likely to be due to
differences between the treatments in question [8]. Hence, randomization
helps to prevent patient selection bias. The purpose of blinding
(patients, investigators, and analysts) is to prevent outcome assessment
bias.

‎

[view this figure] Figure 1. Cumulative number of randomized control
trials (RCTs) versus online RCTs (based on Medline and Old Medline
searches from 1950) on a logarithmic scale over time

Although many examples of clinical investigation can be found throughout
the history of medicine, the RCT emerged in the mid-20th century as the
most powerful and scientifically sound way to establish the efficacy
and safety of medications [9]. Statistician Ronald Fisher introduced the
practice of randomization (randomly assigning study participants to one
or more treatment groups) in horticultural research in 1926 [6]. An
epidemiologist, Austin Bradford Hill, is generally given credit for the
first randomized trial involving humans in 1948 [7]. This trial,
conducted by the Medical Research Council in the United Kingdom,
addressed the question of whether streptomycintherapy and bed rest was
more effective than bed rest alone in treating patients with pulmonary
tuberculosis. In the past few decades the RCT has been increasingly used
as a method to evaluate medical interventions. The Cochrane Controlled
Trials Register (CCTR) is a bibliography of controlled trials generated
from hand searching the world’s medical journals and as of the year 2004
it identified over 415 thousand trials [10]. A recent search of the
PubMed database of the National Library of Medicine in the United States
yielded 65886 controlled clinical trials and 32760 of these were
randomized controlled trials. This represents published trials since the
mid-1960s [11]. Figure 1 illustrates the growth of RCTs. The increasing
pace of RCT research is reflected by the fact that it took 21 years
(1948-1969) for the first 1000 trials to be conducted yet thousands of
trials were conducted in 2004 alone.

The Complexity of Modern Clinical Trials
An RCT is conceptually simple, but to plan a protocol for a study,
obtain funding, recruit patients, conduct the trial, and analyze the
data collected require considerable resources. The initial clinical
trials evaluating antibiotic therapy for communicable diseases had the
advantage of large treatment effects–Hill’s trial on streptomycin
therapy demonstrated a 74% risk reduction for mortality [12]. Today,
most interventions investigated in superiority trials are expected to
have a more modest benefit, perhaps a 10% to 20% risk reduction for an
important outcome [6]. In order to investigate these more modest
treatment effects it is necessary for modern trials to be carefully
designed so that both systematic and random error are minimized, as
differences of this magnitude cannot be detected reliably against a
background noise of chance or other influences. Systematic error is
minimized with a well-designed protocol that avoids bias, and random
error is avoided by studying a large enough sample size [13]. Sample
size is of particular importance in the conduct of equivalence trials.
Equivalence trials, in contrast to superiority trials, are designed to
establish no difference in efficacy between two interventions. However,
in order to show equal efficacy, equivalence trials usually will require
a 10% larger sample size in comparison with conventional superiority
trials [14]. In order to achieve a sufficient sample size in a
reasonable time, many trials recruit patients from multiple centers
across several geographical entities (eg, cities, countries) [6]. These
multicenter trials require infrastructure which is accomplished with a
central coordinating center that usually handles the recruitment of
study centers, the randomization of patients, any necessary laboratory
analysis of patient samples, data collection, data analysis, and quality
control [15].

Internet Resources Applied to the Clinical Trial
Although the complexity of modern clinical trials is unlikely to change
in the future, using Internet resources may reduce the expense and
development time of a clinical trial. The Internet has many features
that are useful in the conduct of a clinical trial. For instance,
funding information and tools for developing a trial protocol are
available online; and the processes of patient registration,
randomization, data collection, analysis, and publication can all be
accomplished with online resources. The Internet is also an ideal
vehicle for the dissemination of information, and in this respect may
facilitate the ease and rapidity with which the findings of a trial are
translated into clinical practice. Table 1 summarizes a selection of
Internet resources for conducting a clinical trial.

Online Resources for Developing a Trial Protocol
A well-designed RCT begins with the identification of a medically
important question [16]. Before undertaking a new trial it is important
to know what research has been done on the question in the past. To
identify previous trials and systematic reviews, the Internet can be
used to search online databases. Medline, EMBASE, and the Cochrane
Library are online resources that can be used to quickly identify both
systematic reviews and clinical trials [17]. Medline can be accessed
free of charge using PubMed, but both EMBASE and the Cochrane Library
require registration and an access fee [10-12]. Once relevant citations
are found, most of the full text articles can be obtained by accessing
the journal’s home page. Members of academic institutions can often
access electronic journals free of charge from their homes or offices by
accessing websites via a proxy server, most often the institution’s
library home page [18]. Ongoing and some completed trials can be located
from online trial registries in both the United States and Europe
[19,20]. Online searches are useful in identifying published studies but
researchers interested in exhaustive searches on a subject will have to
supplement them with conventional hand searching of relevant article
reference lists and by contacting experts in the area [21].

Once a research question is formulated and the literature in the field
is reviewed, the Internet has tools to aid with the task of protocol
development. The US National Cancer Institute maintains a website that
has suggested templates for phase I – III studies, guidelines for
dealing with various patient groups, as well as guidelines for
formulating informed consent documents [22]. The University of
California, San Francisco, School of Medicine maintains a website
devoted to clinical research tools [23]. The site includes templates for
study subject screening and data collection, data and safety
monitoring, financial tracking, study budget, and checklists for
protocol feasibility and study management. If the local expertise is not
available to help with the development of the trial protocol, companies
advertising online offer experienced teams of medical experts,
biostatisticians, and clinical research specialists to help clients
design clinical trials [24]. One of the key steps in the generation of a
trial protocol is calculating the required sample size; online tools
exist to perform this calculation [25].

Online Funding Information
A difficult hurdle is obtaining funding to conducta clinical trial. The
Canadian Institute for Health Research, the National Institutes of
Health in the United States, and the Medical Research Council in the
United Kingdom maintain websites that contain advice to applicants and
online submission forms for specific grants [26-28].

Study Website and Communication Amongst Trial Personnel
There are many reasons for a multicenter clinical trial to have a
website [29]. A study website can be used for the following tasks:
providing information to potential participants, study subjects, and
investigators; listing contact information; and centralizing data
handling for patient registration, randomization and data collection.
Detailed information about the trial can be displayed, and the entire
protocol (apart from any confidential aspects) can be made available. A
secure (password protected) section of the website can be used as a
powerful means of communication for trial personnel (investigators,
monitors, sponsors and committee members). Today electronic mail is the
standard for communication amongst members of a trial group; it is
faster than conventional mail, cheaper than using long-distance
telephone service, and provides an archive record of the communications.
A directory on the website of the investigators, committees, sponsors,
and monitors with their email addresses can help improve communications.
A directory of participating centers and regional coordinators would
also be helpful. A news section of the website can provide a progress
report concerning the trial status and advertise upcoming meetings. A
”Frequently Asked Questions” section can provide investigators with
answers to common questions regarding the study protocol, and a download
page can be a means of distributing study materials (protocol, case
report forms, informed consent forms) to participating study centers.

‎

[view this table] Table 1. Summary of Internet resources for clinical trials

Online Recruitment of Patients
The Internet also plays an increasing role for informing the general
public about ongoing trials that are recruiting patients. Prior to the
emergence of the Internet most patients were recruited for clinical
trials through their physicians or perhaps through mass media
advertising [30]. This system depends on individual physicians keeping
up-to-date with a large range of clinical trials–an impossible task.
The US Food and Drug Modernization Act of 1997 required the Department
of Health and Human Services to establish a registry of clinical trials
for both the government and the private sector [31]. As a result a new
trial registry was launched and the home page banner reads “linking
patients to medical research.”[19] The site was launched in February
2000 and currently contains approximately 11300 clinical studies
sponsored by the National Institutes of Health, other US government
agencies, and the pharmaceutical industry in over 90 countries. People
who access the site can find trials by searching by disease condition or
funding source. The website also provides information for people
considering participating in a trial, including basic information on
clinical trials. Several other commercial websites have been launched
with the business idea of linking patients with clinical trials [32-34].
It is important for potential participants to be cautious because
financial incentives used to recruit patients may interfere with ethical
informed consent [30].

Online Patient Registration and Informed Consent
Once a patient indicates interest in participating in a particular
trial, he is then screened for eligibility, and provided with the
information necessary for informed consent and a consent form for
signature. The necessary data for enrollment into the study is then
collected. A study website can provide detailed information about the
clinical trial presented in terms which the general public can
understand. An online questionnaire canscreen for potential
participants, and eligible patients, who elect to participate, canbe
directed to the enrollment page and consent forms, made available for
downloading from the website. This paradigm necessitates that potential
participants have access to the Internet and that they be reasonably
familiar with computers. To access the Internet, potential participants
would require a personal computer, a Web browser, and access to the
Internet via an Internet service provider [35]. Given these
requirements, this method of patient recruitment could lead to selection
bias. Surveys conducted on the demographics of Internet users show that
the average user is young, white, employed, well-educated, with a
higher social-economic status, and suburban [36]. Those who lack the
resources for online access (for example, those with a disability that
prevents access, or those who are socially disconnected or lack
knowledge about Internet access points in the community) would be less
likely to use the Internet and would therefore be underrepresented;
whereas professionals working in the computer or telecommunications
industries would likely be overrepresented.

Traditionally, study participants have signed consent documents by hand,
but new legislation in both the United States and Canada has given
legal weight to digital signatures for the purpose of facilitating
electronic commerce [37,38]. A digital signature is a unique string that
special software creates by applying a mathematical function and an
encryption key to a message or file [39]. The unique string confirms
both the file author’s identity and the maintenance of the integrity of
the file during its transmission. If accepted as ethical and legal for
clinical trials, digital signatures would save the step of mailing
hand-signed consent forms to the coordinating center. Regardless of the
method used to obtain consent, it is important that the study
participants are appropriately informed of the potential risks and
benefits of the trial intervention, and of their rights regarding their
electronic information. It is necessary to offer patients the option of
not having their information handled electronically (for those that
refuse)and to give them the option to request removal of their
electronic information from the electronic environment [40]. In terms of
informed consent, an argument couldbe made that all eligible patients
should speak to a study representative (in person or on the phone) in
order to ensure that the complexity of the study and confidentiality
issues are clearly communicated and understood prior to proceeding with
registration into the clinical trial. In-person contact with all trial
participants wouldhelp with verification of the baseline data collection
and help guard against people who might attempt to pose as a patient
for mischievous reasons.

Online Randomization
The method of dividing subjects into groups is called random allocation
or randomization and is necessary to ensure that any baseline
differences between groups are due to chance alone [41]. This prevents
selection bias and ensures validity of certain statistical tests.
Several methods of randomizing have been used over the years, including
coins, dice, cards, lots, spinning wheels, random number tables, and
random number generators on computers. For multicenter trials a central
coordinating center often serves as the randomization center and
participating centers access the randomization allocation by a 24-hour
phone service. As an alternative to this service, which can be
expensive, there are several online randomization programs (some free of
charge and some commercial) that can generate random allocations [42].
Randomization.com is a cost-free online randomization program that
generates simple lists of allocations that can then be printed [43].
Paradigm is a Web-based randomization package developed by the
Netherlands Cancer Institute and the UK Medical Research Council; it is
free of charge and guides through studies interactively [44].

Online Data Collection
Remote data entry to a central database is one of the more useful
promises of conducting a clinical trial using the Internet. A
single-center clinical trial can have data entry decentralized by having
a two-tier (client-server) network system that involvesindividual
application instances (thick clients) running on remote computers
connected to a central database server [45].

In a multicenter trial, participating centers can be geographically
separated by great distances across several cities and countries, making
the traditional local area network unfeasible. A thin-client (less
bandwidth intensive) Internet-based solution canbe used to connect study
centers from all over the world. An Internet data entry solution has
Web-browsers – thin clients running on remote computers with the
application itself running in a central Web enterprise application
server. The three tiers (client/investigator, Web application server,
and database server) of an online trial system are illustrated in Figure
2. With this system the following processes occur: browser
requests/submits data from/to the Web application server; the Web
application server in turn executes incoming business logic and
submits/requests data to/from the database server; the database server
saves the submitted data and sends the requested data to the Web
application server; and the Web application server then executes the
outgoing business logic in the application, formats the resulting data
into HTML,and sends it back to the browser as a Web page. With this Web
system the traditional case report forms are translated into electronic
forms in HTML [46].

HTML Web pages by themselves are static text documents that cannot
accept data input [47]. It is necessary to incorporate an additional
enterprise application between the Web server and the database server in
order to facilitate data collection, increase the efficiency of
database requests and offer additional functionality for interactive
real-time data validation [46]. Real-time data validation (see below)
can reduce transcription errors and avoids missing data; the data thus
collected should be of higher quality. The step of double keying the
data for quality assurance becomes redundant [48]. This additional
functionality can be incorporated by running Java or .Net code in the
application server, which allows for interactive behavior with each data
field [46,49]. Java is a computer programming language developed by Sun
Microsystems that allows small-application programs to be downloaded
from a server to a client along with the data that each program
processes [50]. More commonly Java writes server-side enterprise
applications that interact with Web browsers and other enterprise
applications through pure HTML and Extensible Markup Language (XML) over
the Internet and corporate intranet, and XML Web services (small,
discrete, building-block applications that connect to each other).
Microsoft .NET is a set of Microsoft software technologies for software
integration through the use of XML Web services as well as to other
larger applications—via the Internet [51].

‎

[view this figure] Figure 2. Example of a 3-tier architecture in an online clinical trial system

XML is designed to improve the functionality of the Web by providing
more flexible and adaptable information identification. It is called
extensible because it is not a fixed format as is HTML (a single,
predefined markup language). Instead XML is actually a metalanguage (a
language for describing other languages) for designing customized markup
languages for limitless types of documents [52].

Online Data Validation
Clinical data comes directly from the patient, the medical record, or a
laboratory test. In traditional paper-based clinical trials, data is
recorded on paper case report formsand then transcribed into a computer.
Electronic data collection through the Internet has a number of
advantages including real-time data validation, time savings due to
fewer steps in data collection, and reduced handling and storage costs
due to the near-elimination of paper source documents. Real-time
validation could alert a researcher to an invalid entry even as he is
viewing the original data source. For example, a researcher recording
systolic blood pressure (in mmHg) and entering a value of 1400 couldbe
prompted immediately of an invalid entry, allowing for immediate
correction. The disadvantage of this electronic approach is that the US
Food and Drug Administration requires validation of clinical data from
each trail and it is not clear how this can be done with electronic
systems. In the past the computer hardware for mobile data collection
was insufficient, and study data monitors have been reluctant to embrace
a fully electronic data collection model [53].

Online Data Analysis
After collection, data can be analyzed using online statistical tools.
Simple Interactive Statistical Analysis (SISA) is one example of such
Web service [25]. This Java program allows users to do statistical
analysis directly on the Internet. Users select one of the procedure
names, fill in a form, and click a button for immediate data analysis.
Another website contains hundreds of links to free-of-charge online
statistics books, tutorials, downloadable software, and related
resources; immediate analysis of the results is available to the
investigator [54].

Security Issues
Security is a central issue when considering the Internet for sensitive
information exchange. Both patients and study investigators need to be
confident that the data entered on electronic forms and in email
communications will not be intercepted by a sniffer. A sniffer is
software that monitors network traffic and it is analogous to a
telephone tap [48]. The database server itself needs to be protected
from intrusion from unauthorized Internet users and from unauthorized
intranet users (clients connected to the local area network) [39].
Lastly, the system needs to guard against spoofing (the practice of
someone pretending to be someone else) [48]. Malicious Internet users
could enter fictitious patient information and invalidate the trial
results. Essentially, a secure Internet clinical trial system should
ensure confidentiality (information is only disclosed to users
authorized to access it), integrity (information is only entered or
modified by users authorized to do so), and availability (information
and other resources can be accessed only by authorized users) [55].

The underlying network protocol (TCP/IP) on the Internet contains no
security layer [49]. To address the issue of secure Internet
transmissions, Netscape designed a nonproprietary protocol for providing
data security between application protocols (such as http, telnet,
NNTP, or FTP) and TCP/IP [39]. The Secure Socket Layer (SSL) provides
data encryption, server authentication, and optional client
authentication for a TCP/IP connection. Encrypting a file changes it
from readable text to a series of numbers that only parties that have
the decryption key can interpret. The latest versions of Web browsers
support 128-bit encryption, translating to a code that is almost
impossible to break. A computer capable of 225 million instructions per
second would take a dedicated year of processor time to break such an
encryption code. Documents from secure servers can be identified from
the location (URL) field. The letter “s” is added to the protocol
(http:// becomes https://). Encryption is also available for email
communications, and this is usually (depending on the software used) can
be selected as an option in the preferences menu of the email
application.

After secure transmissionand storage, the data needs protection from
unauthorized access once it is stored on the central database server.
For this purpose firewalls – hardware and/or software that sits between
the database server and the Internet – are used [39]. Further, the
database server needs to be placed in a secure location so that
unauthorized users cannot access it.

With the confidentiality of the clinical data maintained by encrypted
transmissions and firewalls, the integrity of the data can be maintained
by user logins and passwords for data entry and editing [56]. More
sophisticated user authentication is possible using digital signatures.
Potential spoofers have to be screened out by the enrollment procedure.
This can be accomplished by communicating with the primary caregivers of
potential study participants.

Online Publication
Currently, most major medical journals are published online and
individual articles, including the title and abstract, can be browsed;
full text versions are often available for download.
Freemedicaljournals.com is a website that contains links to over 900
medical journals with full text articles free of charge [57]. Several
mainstream journals are included but some journals limit access to
articles that have been published for greater than six months to a year.
Open Access journals such as those listed in the Directory of Open
Access Journals (eg. BioMed Central [58] or the Journal of Medical
Internet Research) offer speedy peer review and rapid publication.
Article Processing Fees need to be paid from the authors’ research
institution or grant to cover the expenses for the peer review process
and the preparation for online publication. It is the main source of
income to recover publication costs for Open Access journals since the
articles can be viewed free of charge and no pay-per-view charges can be
imposed.

Examples of Online Trials
Prior to the wide availability of the Internet, the The Gruppo Italiano
per lo Studio della Sopravvivenza nell’Infarcto micocarico acuto
(GISSI-3) Trial used telecommunications technology in the administration
of the trial, [3,29]. Of the 200 participating Italian centers, 100
were provided with a computer and a modem to allow direct telephone
connection to the GISSI-3coordinating center’s main computer. Custom
software allowed for patient enrollment, randomization, and reminder
notices to the participating centers.

A Medline search of the with the search query “Internet and Clinical
Trials” reveals that the Internet is increasingly being used, in whole
or in part, to conduct clinical trials [40,59-73]. The 5 largest trials
are summarized in Table 2. As of today, all results, except those of the
ophthalmology trial which began in 2001, have been released. A large
number of patients participated in Internet-based clinical trials. In
these 5 trials alone over 26000 patients have been enrolled and
randomized [74]. The largest Internet trial is the INVEST cardiology
trial which investigated the adverse outcomes from different
antihypertensive therapies. This trial alone randomized over 22000
patients. Each trial used different components of Internet technology in
the administration of the studies. All 5 trials used a trial website, 4
published the protocol online, 4 allowed for online registration, 5
allowed for online data collection, and 4 used email to communicate
amongst investigators. Security was approached differently as well. Two
trials described using a data server firewall, 4 trials used
confidential website addresses to shield their sites from spammers, 4
trials used user IDs and passwords, 3 trials described using encrypted
transmissions, 2 trials did not send any patient identifying data
online, and 1 trial required a 6-digit numerical code to access the
website which was assigned by an RSASecurID key fob (RSA is a
cryptosystem named after its inventors Rivest, Shamir and Adleman). The
trials may have used other Internet technologies and security features
but the preceding details are those described in their methods.

‎

[view this table] Table 2. Examples of clinical trials conducted using the Internet

Advantages and Disadvantages of Online Trials
The numerous issues with online clinical trials are summarized in Table
3. Some advantages and disadvantages mentioned there are highlighted
below.

Advantages
The main advantage of online clinical trials is the ability to
centralize study information and coordinate multiple trial processes in
real time at a lower cost [75]. Multicentered trials are more manageable
because a system can be scaled easily to many study centers around the
world without special requirements for hardware or software. The only
requirement for each participating center is a computer with a Web
browser and Internet access. Site training, patient recruitment,
randomization, data collection, site monitoring and patient safety can
all be enhanced and simplified using a clinical trial system. Further
advantages include fewer personnel for trial administration, reduced or
neglible paper reporting, security and backup of the entire trial at a
single location, optional updating and distribution of trial protocol
and data collection forms from a single location, and simplified
dissemination of results.

Disadvantages
The key disadvantages of online trials are the real and perceived
security threats that may inhibit both patients and study centers from
participating. It is difficult to convince the average person of the
efficiency of the abstract security measures used in Internet trials
(firewalls, encrypted transmissions, password protection) compared with
the conventional security measures used in traditional trials (locked
file drawers). If participants are recruited through the Internet, this
may lead to selection bias. Given the anonymous and transient nature of
the Internet, it can be difficult for trial coordinators to assess the
suitability of Internet resources that are not directly associated with
well-known academic institutions. The transient and anonymous nature of
the Internet is illustrated by the practice of citing the date of access
for electronic resources and by the fact that many documents on the
Internet do not have a documented author. If a trial relies on a
third-party Internet resource, there is always the possibility that the
third-party website ceases to exist prior to the completion of the
study, leaving the coordinators to find an alternative resource to
complete the trial. For example, finding another randomization site in
the midst of a trial, which takesinto account previously allocated
patients, would be problematic.

‎

[view this table] Table 3. Advantages and disadvantages of using the Internet to conduct clinical trials

Other disadvantages of an online system includes system performance,
lack of live support personnel, and the setup cost. The speed of the
online system can be slowed significantly during peak Internet traffic
and this can prolong every step of a study, from registration to data
entry. The lack of a 24-hour call-in center can lead to the loss of some
patients because some study centers may not be able to use online help
to solve their difficulties with the study protocol or the registration
and randomization steps. To set up and maintain an online clinical trial
system requires experienced computer professionals. This might be too
expensive for smaller trials where the administration budget is modest.

Conclusions
Clinical trials often involve investigations of interventions of modest
benefit that require multiple study centers in order to recruit a
sufficient sample size in a reasonable time. The Internet can be used to
administer these multicenter trials. Online resources are available to
aid with each step of the study, including protocol development,
identification of funding opportunities, recruitment, registration,
randomization, data collection, analysis, publication and
communications. The Internet has the potential to enhance clinical
trials such that multicentered trials are more manageable, less
expensive, easier to administer, and less time-consuming. The biggest
threats to online trials are the security risks of electronic data
collection, transmission, and storage. Online security measures exist
but it is not clear that these are sufficient to reassure most potential
study participants. We can look forward to evolving Internet technology
which will bring enhanced security measures, thereby adding to the
general public’s comfort with electronic data.

Conflicts of Interest
None declared.

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‎
Abbreviations
CCTR: Cochrane Controlled Trials Register
FDA: Food and Drug Administration
HTML: Hypertext Markup Language
RCT: Randomized Controlled Trial
SISA: Simple Interactive Statistical Analysis
SSL: Secure Socket Layer
XML: Extensible Markup Language

Edited by G. Eysenbach; submitted 17.01.05; peer-reviewed by R Marks;
comments to author 16.02.05; revised version received 07.03.05; accepted
09.03.05; published 16.03.05

Please cite as:
Paul J, Seib R, Prescott T
The Internet and Clinical Trials: Background, Online Resources, Examples and Issues
J Med Internet Res 2005;7(1):e5
URL: http://www.jmir.org/2005/1/e5/
doi: 10.2196/jmir.7.1.e5
PMID: 15829477

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© James Paul, Rachael Seib, Todd Prescott. Originally published in the
Journal of Medical Internet Research (http://www.jmir.org), 16.3.2005.
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