Internet for Clinical Trials: Past, Present, and Future

Internet for Clinical Trials:Past, Present, and Future

Eugenio Santoro, MS, Enrico Nicolis, MS,Maria Grazia Franzosi, PhD, and Gianni Tognoni, MDDepartment of Cardiovascular Research, Istituto di Ricerche Farmacologiche Mario Negri,Milan, Italy

ABSTRACT: The Internet and World Wide Web have recently been introduced into the manage-ment of some aspects of large-scale clinical trials such as remote randomization anddata entry and the distribution of information on trial progress. Electronic mail andwebsites have also been used to enhance communication among people involved in aclinical trial. The Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocar-dico acuto (GISSI) used telecommunications and the Internet in some recent large-scaleclinical trials. GISSI constructed a website to keep the medical and cardiology communityinformed about the progress of its studies. Websites for clinical trials could play animportant role in the future, especially in international clinical trials. The website couldprovide information such as study material and study news and tools such as electronicforums on protocol application for use by investigators around the world. This articledescribes the GISSI experience and outlines an appropriate structure for a clinical trialwebsite. Controlled Clin Trials 1999;20:194–201. Elsevier Science Inc. 1999

KEY WORDS: Clinical trials, GISSI, Internet, myocardial infarction, web site

INTRODUCTION

The use of the Internet is growing rapidly in the medical field as is demon-strated by the increasing number of medical journals accessible on the Internetand the broadening access to medical information and organizations on theInternet [1].

The Internet and the World Wide Web have recently been introduced intothe management of some aspects of large-scale clinical trials such as the dissemi-nation of information on trial progress, randomization and monitoring pro-cesses, and remote data entry [2]. Electronic mail also allows a faster and cheapermeans of communication among people involved in the study. Clinical trialswebsites have also been utilized to distribute clinical information (protocols,main results, clinical implications) to the medical and scientific community.

Address reprint requests to: Eugenio Santoro, MS, Laboratory of Clinical Informatics and AppliedStatistics, Department of Cardiovascular Research, Istituto di Ricerche Farmacologiche Mario Negri, ViaEritrea, 62 Milan, Italy.

Received August 4, 1998; revised November 2, 1998; accepted August 10, 1998

Controlled Clinical Trials 19:194–201 (1999) Elsevier Science Inc. 1999 0197-2456/99/$–see front matter655 Avenue of the Americas, New York, NY 10010 PII S0197-2456(98)00060-9

Internet and Clinical Trials 195

Some examples are the Gruppo Italiano per lo Studio della Sopravvivenzanell’Infarto miocardico acuto (GISSI) website and the Alzheimer’s Disease Co-operative Study (ADCS) website [3] (see appendix).

This article describes how GISSI has used telecommunications and the In-ternet for its trials and discusses which information and tools should be takeninto consideration for the development of a clinical trial website.

THE GISSI EXPERIENCE

For the past 15 years, GISSI has been involved with several national and in-ternational multicenter clinical trials in myocardial infarction (GISSI-1, GISSI-2,GISSI-3, GISSI-Prevenzione, CORE, OASIS). During this period, telecommuni-cations technology has become available worldwide, enabling clinical trialsgroups to develop and make use of applications such as automated randomiza-tion systems and distributed clinical data management systems.

GISSI began using telecommunications technology with the GISSI-3 trial [4,5]. Of the 200 participating Italian centers, 100 were provided with a personalcomputer and a modem to allow telephone connection to the GISSI coordinatingcenter main computer. Because Internet connections in Italy in 1991 were notas widely available as they are today, a direct connection was established bytelephone. GISSI developed ad hoc communication software to allow investiga-tors to enroll and randomize patients in the trial and to receive computerizedreminders. The system, operating 24 hours a day without any central manualoperator, enabled GISSI-3 to recruit about 17,000 of the 20,000 total patientsand to disseminate over 1000 reports for a total of 15 megabytes of information.

Randomization software checked input for range and logical errors andverified trial eligibility criteria. An automatic randomization algorithm basedon a modified biased coin method was used to allocate the study treatments.The system was subsequently successfully used in some European countriesin the CORE trial [6, 7] and in Italy in the GISSI-Prevenzione trial.

Development of this system (including telecommunications, data entry, datachecking, and data security software) took about 2 months for each trial. Themain difficulty in implementation was development of ad hoc communicationssoftware, as a standard protocol (such as the TCP/IP protocol) was not availableat that time. Other continuing difficulties related to local problems such as softwareand modem installation. We began using electronic mail in clinical trials in1994 with the CORE trial. The main aim was to improve and speed communica-tion among the European coordinating center at GISSI, the project office inCanada, the sponsor in the United Kingdom, and the contract research organiza-tion in France responsible for trial monitoring. Status reports on trial progressin the European centers were automatically created and e-mailed biweekly tothe members of the above committees, and scheduled e-mail transmissionswere used to periodically update the central database at the project office.

Today electronic mail is the standard communication tool for our ongoingtrials, although it is currently limited to communication among members ofthe main committees. As Internet access becomes more widely available world-wide, e-mail communication will be extended to clinical investigators.

196 E. Santoro, et al.

Figure 1 Home page of the GISSI website (http://www.irfmn.mnegri.it/other/cardio/gissi01.htm)

THE GISSI WEBSITE

In 1996 GISSI developed a website (see Figure 1 and the appendix). Themain aim was to keep the medical and cardiology community (Italian andinternational) informed of progress achieved in the cardiovascular field. TheGISSI website anticipated some features recently provided by the Cardio-Vascu-lar Clinical Trials Forum [8] (see appendix). A registry of cardiovascular clinicaltrials (limited at present to the GISSI trials) is available and provides a summaryof the aims, study design, protocol, main results, and literature references. Alist of the main publications by GISSI (over 100, ranging from GISSI-1 to theGISSI-Prevenzione trials) is also available, including links to on-line papers (ifalready published by the journal in an electronic version). The website linksto the electronic version of the GISSI newsletter which includes news on theprogress of the GISSI trials (recruitment, meeting minutes, and general communica-tion from the Steering and Scientific Committees) and on other similar cardiovascu-lar trials (Figure 2). The electronic version of the newsletter also includes extensivehyperlinks to allow the reader to view related information.

The GISSI website also links to Cardio.Care, an index of relevant websitesin cardiology [1]. The index includes a number of useful links classified bytopic and including electronic journals, images databases, educational sites,guidelines, mailing lists, newsgroups, and main medical associations (Cardio.Care: Internet resources in cardiology; see the appendix).


Figure 2 Example of the GISSI newsletter, “Il Cuore del GISSI” (“The Heart of GISSI,”available only in Italian). The figure illustrates an article that appeared in thenewsletter dated July 1996, which included the main results of the 4S, CARE,and WOSCOPS trials. Another article in the same newsletter illustrated therepercussions of these results on the GISSI-Prevenzione trial.

PLANNING A TRIAL WEBSITE

Although some registries of ongoing clinical trials such Cardio-VascularClinical Trials Forum and CenterWatch are available on the Internet (see theappendix), we see at least two reasons why a trialists’ group should plan awebsite for a specific clinical trial. The first is to provide a place on the Internetwhere the medical and scientific community can find detailed information onthe ongoing clinical trial or on similar trials conducted in the past by the samegroup. The second is to provide people involved in the trial (investigators,monitors, sponsors, and committee members) with a powerful means of com-munication and, eventually, with tools to decentralize trial activities such asrandomization and data entry. The information stored in the website shouldbe structured as hypertext to facilitate browsing. We have identified some areasthat a clinical trial website should cover.

General Information

One section on the website should cover general medical information, includ-ing a summary of the background, aim, and design of the ongoing trial as wellas the main results of similar trials or hyperlinks to the websites where they


are published. Publication of the complete protocol may provide more informa-tion (see on-line PPP trial protocol in the appendix) but is sometimes notpossible because the protocol may include confidential information. A directoryof investigators, committees, sponsors, and monitors (and their e-mail ad-dresses) could also help to improve communication. For international trials,the distribution of participating centers by country and a directory of regionalcoordinators should also be considered.

Trial Update

The trial update section should include information concerning the trialstatus. At least two kinds of reports could be provided: a center-based summaryand a regional and overall summary of the trial. The first provides centers withuseful administrative information such as a list of randomized patients, theirfollow-up schedules, a list of patients lost to follow-up, case report forms, andqueries that are still outstanding. Even if this information could be sent byelectronic mail, a central archive would allow users to search for past reports.The second type of report would allow users access to a number of statisticsuseful in planning future trial strategies. Information could include, for exam-ple, the number of randomized patients (stratified by center, region, or country),statistics on data and center quality, and preliminary epidemiologic data. Be-cause only a restricted group of people should access this information (forexample, the project office and committee members), security should be imple-mented to identify and allow access only to authorized users.

News

The news section should include the latest news of the trial. Examples ofinformation to be included in this section are the trial newsletter and anyinteresting information or communication about the trial (such as meetingsand presentations) or concerning the clinical conditions considered in the trial(such as the progress of similar trials) but not included in the newsletter.Frequently Asked Questions (or Commonly Asked Questions) on the applica-tion of the trial protocol, although generally part of the newsletter, could alsobe included. This would allow investigators real-time access to questions andanswers that arise during the trial. A search engine could also be implementedto facilitate retrieval of information.

Data Handling

Patient randomization and registration and remote data entry are two addi-tional components of a clinical data management system that the website couldinclude. Web-based randomization systems allow investigators to enroll pa-tients in the trial 24 hours a day. Randomization systems have already beensuccessfully used by trialists in cancer studies [9]. Interactive voice responsesystems for randomization allow limited interaction between the user and theserver systems. Randomization systems developed using distributed micro-computers and modems allowed more interaction between the investigator


and the central system. Web-based systems, however, utilize a true client-server technology that allows client software running on the investigator’scomputer to provide a friendly interface for data collection while the serversoftware processes data and selects treatment allocation. Data checking is per-formed centrally by the server software or, in more recent applications, at theclient site using JavaScript applications. Patient-oriented systems have beendeveloped to speed the enrollment process. An example is the system usedby the Collaborative Longitudinal Evaluation Keratoconus (CLEK) study, anobservational study that allowed keratoconus patients to self-recruit directlyvia the Web [10] (see appendix).

A recent application of the Internet in clinical trials is remote data entry.Several web-based systems were presented recently at the meeting of the Societyfor Clinical Trials [11, 12]. Using such systems, data are directly entered by theinvestigator and submitted to the coordinating center through the website.HTML and JavaScript are generally used to develop forms and to check databefore transfer to the coordinating center. Data stored at the coordinating centerdatabase may also be retrieved using a browser with security tools to allowonly authorized users access to the data. Although still a new web application,in the near future this technology will most likely transform the data collec-tion process.

Other Options

Logistic issues such as the supply and distribution of study material (proto-col, case report forms, and informed consent forms) could be handled on theWeb. A clinical trial website could allow an investigator to request studymaterial [3] or to download it directly from the server to the client computer[2]. Suggestions for analyses and research ideas from the investigators outliningthe hypothesis to be tested, the populations to be selected, and the variablesto be considered might also be communicated using the website, especiallywhen the trial is a geographically dispersed collaboration. Results from thesesubanalyses could be published on the website, partially or completely, inparticular when the results are not intended to be published in a journal.Newsgroups and mailing lists may be hosted to include comments from investi-gators and discussion among the study group. A list of links to the websitesof medical interest related to the ongoing trial would provide a useful search-ing tool.

CONCLUSION

In the future, the Internet and clinical trial websites could transform theway a clinical trial is conducted; however, in order to achieve this goal eachparticipating center must have adequate access to the Internet. At present thisis a major hurdle, especially in some developing countries, but also in thosedeveloped countries where direct internet connection from hospitals and medi-cal centers is still uncommon.

Security remains a problem, even if firewalls and encryption algorithmshave been successfully used to limit the risk of access by unauthorized users[13]. At present, other problems, such as the lack of a common standard for


client software, the availability of personnel training, server-caused delays indata transmission, and resistance to paperless record-keeping methods, repre-sent further obstacles to a wide use of the Internet in clinical trials. Nevertheless,experts predict that within a few years, as the technology is refined, theseproblems will be solved [14]. At that point, clinical data capture through theInternet will be widespread and electronic mail will be commonly used andintegrated with new tools such as videoconferencing and telephone on theInternet thus improving interactive communication among all those involvedin a trial.

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Ital Cardiol 1996;26:775–792.

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4. Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico. GISSI-3:effects of lisinopril and transdermal glyceryl trinitrate singly and together on 6-weekmortality and ventricular function after acute myocardial infarction. Lancet 1994;343:1115–1122.

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6. Collaborative Organization for RheothRx Evaluation (CORE). Effects of RheothRxon mortality, morbidity, left ventricular function and infarct size in patients withacute myocardial infarction. Circulation 1997;96:192–201.

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8. Julian D. The Cardio-Vascular Clinical Trials Forum. Cardio-Vasc Clin Trials 1997;introductory issue: 1–2.

9. Kiuchi T, Ohashi Y, Konishi M, et al. A World Wide Web-based user interface fora data management system for use in multi-institutional clinical trials: developmentand experimental operation of an automated patient registration and random alloca-tion system. Control Clin Trials 1996;17:476–493.

10. Zadnik K, Bullimore MA, Barr JT, et al. Collaborative Longitudinal Evaluation inKeratoconus (CLEK) Study: recruitment for a large-scale clinical study via the In-ternet. Control Clin Trials 1996;17:45S.

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APPENDIXWebsites quoted in this article include the following:

GISSIhttp://www.irfmn.mnegri.it/cardiocareAlzheimer’s Disease Cooperative Study (ADCS)http://www-adcs.ucsd.eduCardio.Care—Internet resources in cardiologyhttp://www.irfmn.mnegri.it/cardiocareCardio-Vascular Clinical Trials Forumhttp://www.cardiosource.comCenterWatch Clinical Trials Listinghttp://www.centerwatch.comProgetto Prevenzione Primaria (PPP) trial—On-line protocolhttp://www.csermeg.it/ppp.htmCollaborative Longitudinal Evaluation of Keratoconus-CLEK Studyhttp://www.optometry.ohio-state.edu/clek

Documents

Internet for Clinical Trials: Past, Present, and Future