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.
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.
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) [
A clinical trial can be defined as any form of planned experiment involving patients [
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 [
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 [
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.
A well-designed RCT begins with the identification of a medically important question [
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 [
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 [
There are many reasons for a multicenter clinical trial to have a website [
Summary of Internet resources for clinical trials
|
|
|
|
Canadian Institutes of Health Research |
|
US National Institutes of Health |
|
UK Medical Research Council |
|
Bibliographic Databases | |
National Library of Medicine - Medline |
|
The Cochrane Collaboration – The Cochrane Library |
|
Elsevier Science – Bibliographic Databases |
|
|
|
National Institutes of Health – ClinicalTrials.gov |
|
Current Controlled Trials - |
|
Veritas Medicine Inc. |
|
Centerwatch Clinical Trials Listing Service |
|
|
|
Directory of Randomization Services |
|
Randomization.com |
|
Paradigm |
|
|
|
Simple Interactive Statistical Analysis – SISA |
|
Statpages.net |
|
|
|
Free Medical Journals |
|
Directory of Open Access Journals |
|
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 [
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 [
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 [
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 [
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 [
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
HTML Web pages by themselves are static text documents that cannot accept data input [
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 [
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 [
After collection, data can be analyzed using online statistical tools. Simple Interactive Statistical Analysis (SISA) is one example of such Web service [
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 [
The underlying network protocol (TCP/IP) on the Internet contains no security layer [
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 [
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 [
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 [
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, [
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 [
Examples of clinical trials conducted using the Internet
|
|
|
|
|
|||||
|
Lower Pole Renal Calculi | Urology | 2004 | [ |
|||||
|
Growth Restriction Intervention Trial (GRIT) | Obstetrics | 1996 |
[ |
|||||
|
International Verapamil SR/Trandolapril Study (INVEST) | Cardiology | 1997 |
[ |
|||||
|
Osteoarthritis of the Knee: Trial of Glucosamine | Orthopedics | 2000 |
[ |
|||||
|
Intraoperative Anti-infective Prophylaxis | Ophthalmology | 2001 |
[ |
|||||
|
|
|
|
|
|
||||
Study centers | 21 centers in North America | 69 centers in 13 European countries | 862 centers in 14 countries | Single center | Various centers in Germany | ||||
Methodology | Multicenter randomized controlled trial | Multicenter randomized controlled trial | Multicenter randomized controlled trial | Double blind randomized controlled trial | Multicenter controlled trial | ||||
Population | Adults with lower pole renal calculi | Primary physician uncertain whether a growth restricted baby should be delivered or not | Adults with coronary artery disease and hypertension | Adult patients with osteoarthritis of the knee. | Adult patients undergoing elective cataract surgery | ||||
Sample size | 112 | 548 | 22576 | 205 | 4000 to date | ||||
Intervention | Shock wave lithotripsy, percutaneous nephrolithotomy and retrograde ureteroscopic stone manipulation | Early delivery versus delayed delivery | Antihypertensive therapy with verapamil versus atenolol/hydrocholorothiazide | Glucosamine versus placebo | Irrigation with gentamicin versus regular irrigation | ||||
Outcomes | Stone removal | Perinatal mortality and developmental quotient at 2 years | Adverse outcomes: all-cause mortality, nonfatal MI, or nonfatal stroke | WOMAC pain scores | Postoperative endopthalmitis | ||||
|
|||||||||
Online protocol | • |
• | • | • | |||||
Online registration | • | • | • | • | |||||
Online randomization | • | • | • | • | |||||
Online data collection | • | • | • | • | • | ||||
Email communication | • | • | • | • | |||||
Data server Fifrewall | • | • | |||||||
Confidential website | • | • | • | • | • | ||||
User IDs / passwords | • | • | • | • | |||||
Encrypted transmission | • | • | |||||||
Other | Website requires a 6-digit code assigned by an RSA SecurID key fob | No patient identifying data sent online, but by more secure means | Online ordering of study medications | Automated reminder emails and personalized schedules | No patient identifying data sent online |
* The year that the trial was started.
† “•” Denotes that the feature was present in the trial. If the “•” is absent, the feature was not present or was not documented in the protocol.
The numerous issues with online clinical trials are summarized in
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 [
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.
Advantages and disadvantages of using the Internet to conduct clinical trials
|
|
|
Communication | • Email and website notices make exchange of information less expensive, faster and easier | • Online communications are not as secure as more traditional means (telephone, fax and mail) |
Feasibility | • No need for special hardware or software at participating centers |
• Risk of selection bias if all study centers are required to have Internet access |
Training | • Online training resources allow for easily accessible and flexible programs for investigators | • Online training may not be as effective as a live educator |
Patient recruitment | • Cost-effective broadcast medium to advertise a study to potential participants and study centers |
• Some patients and study centers may decline involvement because of concerns over the security of online data |
Randomization | • Eliminates the need and expense of a 24-hour call-in center for registration and randomization. |
•It is harder to locate a computer terminal than a telephone at the point of patient contact |
Data collection | • Enables real-time data validation |
• Data input could be slowed down during times of peak Internet use when access to the Web server is slowed |
Monitoring | • Study monitors have real-time access to all aspects of the trial activity | • With less frequent in-person site monitoring some problems may take much longer to be identified |
Safety | • Internal Review Board (IRB) has real-time access to adverse events | |
Security | • Sensitive patient data is centralized in one location which simplifies security management | • Online data can be intercepted during transmission or accessed from the database server if security measures are not sufficient |
Study personnel | • Fewer data entry personnel required |
• Requires experienced computer professionals to set up and maintain an online clinical trial system |
Administration | • Reduction or elimination of paper reporting |
• Because of the expense of developing an online trial system it may not be feasible for smaller 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.
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.
None declared.
Cochrane Controlled Trials Register
Food and Drug Administration
Hypertext Markup Language
Randomized Controlled Trial
Simple Interactive Statistical Analysis
Secure Socket Layer
Extensible Markup Language