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INTRODUCTION:

Clinical research is an important and growing industry

in pharmaceutical sciences as well as in all other biomedical areas. Clinical research covers the conduct of very rigorous randomized clinical trials to prospective cohort studies to retrospective cohort and case control studies. The result of accumulating research today is illustrated in the growing concept of evidence-based medicine, which attempts to coordinate and organize published research regarding a particular research question to provide a definitive answer based on the accumulated science. The emergence of the internet as a medium for conducting research provides an opportunity for investigators to expand, enhance, and potentially redefine the way clinical research is conducted. An early focus of using the internet for clinical research is in enhancing the clinical trials process. The reason for this interest is the current high cost of clinical trials and the inefficiencies that exist in the conduct of complex processes. The main problem that exists in current clinical trials conduct is the decentralization, or distributed, implementation of processes that are problematic to monitor and manage during the trial. The Web offers the advantages of both centralization of all study information and coordination of multiple clinical trials processes, providing real-time information for all clinical trial constituents.^1-3

The major benefits of Web-based clinical trials can be summarized in the three S's—Site, Sponsor, and Safety. This paper will focus on the benefits of Web-based research for clinical trials and other clinical research designs, and its implications for evidence-based medicine.

CLINICAL TRIALS:

Site Benefits

Web-based clinical trials can provide numerous benefits to the investigative sites. Site benefits include a less stringent

computing environment, enhanced training, improved monitoring, faster compensation, and reduced administration. In the past, sites required a proprietary hardware and software computing system provided by the sponsor to participate in a clinical trial. The investigator staff

required training in the use of the computer system and had

to make it fit into the practice. Today, all a site requires is its own contemporary Personal computer (PC) with Internet access. The result is a reduced computing cost for the sponsor and a simpler, more user-friendly system that fits into the office infrastructure. Training becomes focused on Good Clinical Practice (GCP), informed consent, and the study protocol rather than on the computer system. Study training can be conducted online at the convenience of the

investigator, at home or the office, at night or on the weekend, as desired. Further, electronic documentation of successful training can be provided to the sponsor and any regulatory body.

Monitoring is a high cost and time requirement in completion of a clinical trial, and involves extensive interaction by a Clinical Research Associate (CRA) reviewing all work performed at each investigative site. Web-based clinical trials offer the opportunity for remote real-time monitoring, in which the CRA is documenting site activity almost as it occurs. Any problems in trial conduct or slow enrollment can be detected and resolved quickly, avoiding serious problems resulting from the lack of early detection. Documenting site compensation at any time can be easily established through an online report available for the site and sponsor to review. At the end of a payment period, payment can be made electronically to the site, avoiding the delays and disagreements about compensation owed that occurs in many clinical trials.

Site administration can be greatly reduced in a Web- based clinical trial. The scientific protocol, informed consent material, and case report forms (CRFs) can all be supplied over the Web. The protocol can be linked to each data element on each CRF, providing needed information about the data element. A paper copy of the protocol may never be needed for the trial conduct. Randomization to study product can also be completed in seconds with the use of Web-based systems, reducing the time and effort to complete and reducing errors. Study product management can also be provided electronically over the Web, with delivery of study product managed from a central facility. Providing randomization and study product management electronically to an investigative site eliminates a heavy administrative time commitment from site responsibility and eliminates the need for any monitoring of these activities.

One major area of early use of the internet for clinical trials is in enhancing electronic data capture (EDC). Pharmaceutical clinical trials have historically been paper based-that is, clinical data are first written down on paper. Historically, the paper forms were sent to a central data entry site for computerization. After computerization, data were checked, and queries regarding any questionable data elements were sent to the site investigator either to justify or to correct. In the mid-1980s, with the advent of the PC for research, EDC began to develop where collected paper-based data were computerized at the investigator site. Computerized data were then transmitted to the sponsor for the query process to begin. Both the centralized data processing and EDC systems had many flaws, due to the lack of oversight of the original data collection at the site, which has led to the excessive monitoring commitment in clinical trials.

Since the mid-'1980s, some dental clinical trials, especially in studies measuring gingivitis, plaque, and bleeding have been conducted with the use of "electronic source documents" (ESD), in which data are collected directly into a computer by a research assistant in the dental clinic as information is obtained from the investigator directly from the subject. The concept of ESD is new to the pharmaceutical industry and remains a goal for them to achieve. In contrast, ESD has been standard operating procedure in some dental clinical trials for two decades.

One benefit of Web-based clinical trial conduct is in advancing EDC toward ESD and in enhancing regulatory aspects of 21 CFR Part 11, FDA rules on electronic records and electronic signatures. Dental research has experience with ESD, and regulatory issues are not as critical in many dental clinical trials, so the internet has not yet been seen as an essential tool for enhancing dental clinical data capture. However, dental clinical trials will benefit from the coordination of multiple clinical trials processes described here and the improvement in subject safety that can result from Web-based research. More information is available on the coordination of multiple clinical trials processes and on an example of a large international Web-based clinical trial taking advantage of these process changes through technology. The overall result of Web-based clinical trials is that investigators spend more time in the conduct of dental medicine and science, and less time in administration and bureaucracy. The result is that more practicing dentists can participate in research and will bring more "real world" subjects to clinical research. As the Web-based model for clinical research improves research participation, more dentists will be interested in participating in cutting-edge research as a new source of income and an opportunity for

their patients to benefit from research participation.^{1, 2, 4}

Sponsor Benefits

Benefits to the sponsor include real-time management

reports on screening rates and failures, study enrollment rates, and study follow up rates. This real-time study monitoring leads to improved subject recruitment and follow-up, reduced site efforts in randomization and study treatment management processes, improved Adverse Event (AE) management, improved efficiency of study monitoring, and better fiscal management of the trial. The result for the sponsor is improved efficiency, accuracy, and subject safety.^{3, 4}

Safety Benefits

Subject safety is enhanced through Web-based activities of

the Institutional Review Board (IRB) to approve and monitor investigative sites for a clinical trial. In a Web- based study, the IRB can electronically approve a site's participation, and also electronically remove its permission to participate. Safety is further enhanced through more efficient processes to inform all needed safety officials of serious Adverse Events (AEs). A serious AE entered into the Web based system can automatically trigger an e-mail to study safety officials. The result is an enhanced process to

provide needed documentation for the serious AE, and to monitor the AE process through notification of the appropriate regulatory group. The result is better protection of subject safety, a major focus in contemporary clinical trials.²

OBSERVATIONAL RESEARCH:

The internet also provides the opportunity for industry

and government-funded research to expand cohort studies and surveys directly to practicing pharmacy practices and their patients. The Internet provides the opportunity for the collection of important information directly from medical practitioner and their patients, providing the benefits of increased efficiency and accuracy of data collection in a more real world environment than the current model for clinical research. The opportunities for globalization of data collection efficiently in standardized protocols can greatly enhance evidence-based medicine.

Cohort studies, both prospective and retrospective, are less rigorous than clinical trials. However, they offer the opportunity for the collection of greater amounts of information in a more natural and realistic environment. More real-world medical practitioners with their typical patient pools provide answers to research questions that in some ways are more realistic than answers provided by clinical trials. The Internet offers the opportunity for outcomes information to be collected from a wide range of sources worldwide in a systematic and centralized manner, enhancing the information and more efficiently, accurately, and quickly providing new valuable research answers.³

EVIDENCE-BASED MEDICINE:

Meta-analysis is a statistical tool used by investigators

to bring information together from multiple clinical trials in an attempt to determine the overall relative efficacy and safety of a product. The use of meta- analysis has been extended for observational studies as well, but this use has been controversial. Also, other issues regarding meta analysis have arisen.^{5, 6}One limitation of evidence-based medicine is the reliance on a set of published papers, with the information brought together years after the research was conducted.

The internet allows contemporary research to be conducted in hundreds or thousands of medical practices worldwide, and provides each individual practitioner with his or her results. In addition, information can be brought together in a central site by Web-based approaches so that information can be compiled for different regions of the world, different ethnic groups, by gender, age, treatment type, and any host of possibilities. The results should be to produce more useful information to answer research questions by using more contemporary information from a large

number of practices geographically dispersed and with patients receiving real-world treatments.^7-9

LIMITATIONS TO WEB-BASED RESEARCH: Several limitations have been discussed regarding use of the internet for research. One concern is the lack of internet access in many medical practices, either because the practice has not taken advantage of internet availability, or because the internet may not be accessible (especially in international sites). Today, most Indian medical practices either have internet access or certainly can access it for a low monthly cost. Even in international sites, internet access is rapidly expanding and certainly will not be a limitation in a few years. A second expressed concern regards internet reliability. An argument is made that if the Internet is not available; research will suffer and cannot be conducted. The reality is that the Internet has proved to be a very reliable workhorse as users document their daily access. Of course, the Internet will have some periods of loss of connectivity, but this problem is no more serious than current problems when PC hard disks fail or other PC problems render the PC inoperable for some period of time.

The major issue in moving to Web-based methods involves a willingness to change the paradigm from paper-based methods to electronic source documents in clinical trials. The pharmaceutical industry has been slower to make the move. The reason is likely due to the greater volume and complexity of the collected data in pharmaceutical clinical trials and the greater regulatory scrutiny. The Internet appears to be the first technology that allows pharmaceutical clinical trials to change their processes from manually driven, inefficient, and decentralized to a quite efficient electronically managed centralized collection of information, and coordinated with other clinical trials processes. As Web- based processes transform the conduct of clinical research, we will see a shift from research conducted at "research mills" with the use of subjects recruited specifically for research to more "real-world" medical practices with more typical patients as research subjects. The result will be a more realistic evaluation of study products, medical practices, and consumer attitudes and preferences.

Probably the single greatest disadvantage to Web-based research has been lack of mobility of current computers, mostly constrained to a single location with wired access to the internet. Wireless technologies have made rapid advances and can allow for portability of a laptop computer anywhere within many medical practices. This final piece of the puzzle will greatly expand all types of research activities within a medical practice, and should dramatically influence the new way that research will be conducted in the future.^{1, 2}

FUTURE:

The tremendous explosion of genetic and gene therapy

research will substantially increase the need for research methods that can manage the vast amount of new data that will emerge. Much effort is being expended in bone- regeneration and bone-growth genetically based products, and in gene therapy procedures for restoring salivation in xerostomic patients and in head and neck cancer patients who have had extensive radiation therapy. Research is also proceeding in gene products in immunology and restoring salivation. The issues in these areas are complex regarding the potential need for new study designs and certainly for improved systems to collect and manage the emerging data more efficiently and accurately. All of this research is conducted in a heavily regulated environment, which is enhanced through the use of electronic source documents and portable lightweight Web-connected computers to provide the efficiency and accuracy required for the research to be successful. The Internet provides an opportunity for enhanced research needs in the area of genetics and gene therapy.1, 2, 7, 9

SUMMARY:

The Web is a tool that can support important process changes to enhance clinical research. The Web is the first tool that supports development of technology allowing for the centralization of all clinical research information and

coordination of multiple processes in a clinical research study. The result over the next few years should be improvements in the efficiency, accuracy, and subject safety of clinical trials. A second improvement should be in

observational research, being conducted worldwide in typical medical practices with real-world patients. The results should be much more information, and more realistic use of medical practices, leading to more and better

information. The overall result—provided that a series of barriers can be overcome—can be tremendous growth in valid evidence-based medicine, further enhancing medical research in the 21st century.

REFERENCES:

1. Marks RG, Conlon M and Ruberg SJ. Paradigm shifts in clinical trials enabled by Information technology. Stat Med.2001; 20: 2683-2696.

2. Marks RG et al. Enhancing clinical trials on the Internet: lessons from INVEST.Clin.Card.2001; 24: 17-23.

3. McKee M et al. Interpreting the evidence: choosing between randomized and non randomized studies.BMJ.1999; 319:312315.

4. Pepine CJ et al. Rationale and design of the International Verapamil SR/trandolapril study (INVEST): an Internet-based randomized trial in coronary artery disease patients with hypertension. J. Am. Coll. Cardiol.1998; 32: 1228-1237.

5. Editorial. Meta-analysis and the meta-epidemiology of clinical research. BMJ.1997; 315: 617-619.

6. Smith GD and Egger M. Meta-analysis: unresolved issues and future developments.BMJ.1998; 316:221-225.

7. Altman DG. Practical statistics for medical research. Chapman and Hall, London. V1991.

8. Armitage P and Berry G. Statistical methods in medical research. Blackwell Science, Oxford.1994

9. Lilienfeld DE and Stolley PD. Foundations of epidemiology. Oxford University Press, New York. 1994

Received on 27.03.2008 Modified on 22.04.2008

Research J. Pharm. and Tech. 1(3): July-Sept. 2008; Page 120-123