যারা ক্লিনিকাল ট্রায়াল রিসার্চে আগ্রহী, পড়ে দেখতে পারেন। শুভ কামনা রইলো সবার জন্য।

Conducting Clinical Trial over Internet, Perspective for Future

Md.Qaumrul Islam Ph.D

Abstract

Due to its access to vast segments of the population and its technological capabilities, the Internet has tremendous appeal as a vehicle for conducting randomized controlled clinical trials (RCTs) [1- 4]. Rapidly recruit individuals over the Internet into an online randomized controlled clinical trial will ease the tenure, money spent, effective data validation efficient trial operation [5]. The main advantages of conducting clinical trial online are automated data validation and standardization, fast data transfer independent of geographical distance, user feedback, synchronization of protocol updates and automatic data formatting facilitating statistical analyses. However, Safety and Expertise are the area need to explore in the future to establish the wide range of acceptability of online clinical trial, might would cover a lions share of traditional clinical trial operation.

Introduction

Human drug development is a dynamic process that keeps pace with the recent advances within the pharmaceutical analytical labs, combined with a precise understanding of the integrated pharmacokinetic-pharmacodynamic-pharmacogenomic drug profile. New drugs are a great need for many clinical conditions but, unfortunately, development costs are rising and the number of drugs receiving marketing approval has fallen. Further, drug development is a long, complex and expensive activity. It typically involves a total cost around US$ 800 million per marketed drug and is spread over 10-15 years [7]. A study published in 2006 estimates that costs vary from around 500 million to 2,000 million dollars depending on the therapy or the developing firm [8]. The situation has become so serious that the FDA published the document 'critical path', highlighting the problems in drug development and encouraging novel approaches to be incorporated into the current drug development paradigm [9].
The clinical research can be defined as pharmaceutical research intended to produce knowledge valuable for understanding human disease, preventing and treating illness, and promoting health. These definitions express a close association of studies involving interaction with patients; evaluate clinical products through data over populations. Clinical research is currently challenged in several ways as well as facing huge demand of robust budget. Many exciting opportunities are coming from advances in biology and technology, such as functional imaging, information technology, changes in the health system and most importantly the attitude of the participating subjects. Also being challenged by roaring financial incurs of conductance and patient care regulations on academic medical-center revenues. Which otherwise interpret shortage of time and questioned the resources used at trial level. Clinical trials are, of course, necessary, but they come with a staggering price tag. On average, pharma companies are spending anywhere between $100 and $800 million per drug candidate. Given this climate, drug companies are looking for cost-saving measures. Sure, pharma companies bring in a lot of money, but they also have to spend a huge chunk of it, too.
CMSInfo, Chesam, UK, reports that national spending on clinical trials in the United States was nearly $24 billion in 2005. Results are forthcoming, but the research institute expects this number to rise to $25.6 billion in 2006 and $32.1 billion in 2011—growing at an average rate of 4.6% per year. The number of clinical trials performed in 2005 was 8,386. BCC Research, Wellesley, Mass., predicts this number will reach almost 10,000 by 2006. At a growth rate of 5.8%, the number of clinical trials performed in 2011 will reach more than 13,000. Research companies are predicting huge growth in this market, but it is clear that life science companies need to find a way to decrease these costs if the industry is to fund all those trials.

The Cost of Clinical Trials

There are two types of costs associated with a trial [10].
Patient care costs and Research costs
Patient care costs: These are costs associated with providing medical goods and services to each patient. Usual care costs include doctor visits, hospital stays, clinical laboratory tests, x-rays, and any other medical costs that occur regardless of whether a patient is participating in a clinical trial or receiving standard treatment.
Research costs: Research costs are costs that are associated with clinical trial participation, such as data collection and management, research physician and nurse time, analysis of results, and tests performed purely for research purposes.
Also Trials require expenditures that aren't always obvious. Include:
Copying
Long distance telephone calls
Overnight shipping
Faxes
Materials (paper, folders, gloves, etc.)
Long-term record storage
Specialty equipment
Recruiting
Screening

Rapidly rising clinical trial costs worry researcher

The clinical trial expense for a drug candidate is rising like soaring year after year, alarming the drug companies that ultimately would harm the consumers and will discourage the investigators and academician.
From the 1980s to the 1990s, the clinical trial costs of drug development increased 5 times faster than preclinical costs, according to the Tuft Center for the Study of Drug Development. In 2003, some health economists in the United States estimated the average cost of bringing a drug to market at US$802 million. Estimates of typical research and development costs today are in the US$1.3 billion-to-US$1.7 billion range, though some health researchers dispute these numbers [11].
As patient and physician demand for clinical trials increases over the next several years, it will be necessary to remove several existing barriers to clinical trial enrollment. The Internet is a growing resource for both educating and recruiting patients for clinical trials. The possibility of conducting clinical trials entirely on line is an enticing but relatively unexplored medical application of the internet [5]
The Internet established a new era in world wide communications and the randomized controlled trial provided a means to conduct an unbiased comparison of two or more treatments. The penetrance of the internet in the population offers the possibility of rapid recruitment of participants, and technological advances enable instant collection of data in a secure and confidential manner [12].
These attributes could theoretically accelerate the evaluation of many compounds by cutting costs and reducing the duration of each study [1].
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 [13]. 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 [14]. As a perspective of future I would like to describe the available Internet resource so far developed, existing online tools for clinical trial operation, merits and demerits of conducting clinical trial through online.

Components need for Online Trial

Conducting clinical trial through online may require many components such as recruitment website, electronic data capture and validation, randomization module, security measures, providing informed consent entirely online. At this time it is still early to say the existing procedure of conducting clinical trial would unlikely to change in the very near future. But one should obviously say with the amenities of internet available so far meantime, might reduce the current expense ant tenure of clinical trial. Besides Now a Days, with the advent of Information Technology many features of Clinical Trial you cannot even think without internet such as finding grant information, potential investigative sites as well as investigators, communication with investigators and probable subjects, statistical analysis of data, sources of similar competitive trial and publication of study outcome.

Randomized Controlled Clinical Trial

Clinical trials are done to see whether a new drug or device is safe and effective for people to use. More broadly can be say, Clinical trials are research studies involving patients, which compare a new or different type of treatment involving medication with the standard treatment currently available (if there is one). Some clinical trials also look at possible ways to prevent illnesses, for example by testing new vaccines. No matter how promising a new drug or treatment may appear during tests in a laboratory, it must go through clinical trials maintaining rigorous regulations before its benefits and risks can really be known.
In many clinical trials, one group of patients will be given an experimental drug or treatment, while the control group is given either a standard treatment for the illness or a placebo.
A clinical study in which participants are randomly (i.e., by chance) assigned to either an experimental group or control group is termed as randomized controlled trial. The experimental group receives the new intervention and the control group receives a placebo or standard intervention. These groups are followed for the outcomes of interest.
Usually, clinical trials compare a new product or therapy to something else to see if it works as well or better to treat or prevent a disease or condition of patients. So the target of clinical trial is to maintain safety of patients as well to establish the effectiveness of tested drug. In order to achieve that comparison, is applied in clinical trial. The comparison between groups as mentioned above. In a blinded study, a participant may be randomly assigned to receive the test product, or an existing, approved therapy. In some studies, participants may be assigned to receive a placebo (a product with no therapeutic action that looks like the test product). 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 [15]. Hence, randomization helps to prevent patient selection bias. The purpose of blinding (patients, investigators, and analysts) is to prevent outcome assessment bias. Comparison with a placebo can be the fastest and surest way to demonstrate therapeutic effectiveness of new products.

Growing Concern of Today’s 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. Growing Complexity of Clinical Trials Increases Burden on Investigators and Volunteers, according to Tufts Center for the study of Drug Development [16]. More complex clinical trial protocols are demanding more of investigative site personnel and study volunteers, leading to longer clinical trials and increasing difficulty in recruiting and retaining patients, according to a new study recently completed by the Tufts Center for the Study of Drug Development.
"During the past years the number and diversity in the procedures of protocol, has been remarkably increased. A similar rise in the number of enrollment eligibility criteria and pages per case report form," said Ken Getz, a senior research fellow at the Tufts Center and lead investigator on the study. According to him "These protocol design changes are largely due to the nature of diseases currently under investigation and intensifying competition among drug developers."
Getz noted that the increasing complexity of protocol designs is contributing to the growing time, cost, and risk of drug development. "The rise in protocol complexity represents a significant challenge for drug developers," he said.
According to a Tuft Center study concerning the impact of gradual change in protocol design and its effect on Clinical Trial Outcome was manifested by the findings are as follows. The annual growth rate of unique procedures per protocol grew 6.5% between 1999 and 2005. Clinical trials tenure turning longer: between 1999-02 and 2003-06, total time from protocol design readiness to database lock rose from 460 to 780 days, or 69.6%. Volunteer enrollment rates dropped from 75% in 1999-02 to 59% in 2003-06, while volunteer retention rates declined from 69% to 48%. Which means the performance of individuals to accomplish clinical study has scope to improve a lot or do faster?

Online Resources for Developing a Trial Protocol

A well-designed RCT begins with the identification of a medically important question [17]. All start with a question that is then developed into a protocol. 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 [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 protocol is at the heart of every clinical trial. However, many existing clinical trial protocols contain problems such as incompleteness, ambiguity, and inconsistency [22]. Most of the errors are introduced during the protocol writing process, which is often inefficient.
In this context, online protocol trial template can be used to avoid discrepancies. One such example is NHS foundation trust web page.
A well-constructed protocol can ensure common understanding of the study objectives and procedures to be implemented, thereby improving quality and saving time and effort for those using it. However, the development of a protocol can consume significant company resources and time. Efforts are going on to improve the complexity such as Web based collaborative Protocol writing system as machine readable. Meantime many Institutions are maintaining online resources for standardizing and developing trial protocol more delicate way
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 [23]. The University of California, San Francisco, and School of Medicine maintains a website devoted to clinical research tools [24]. 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 [25]. 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 [26].

Study Website and Communication amongst Trial Personnel

There are many reasons for a multicenter clinical trial to have a website [27]. This web site provides clinical trial data, results and other information from of clinical trials. This website contains summaries of results of completed clinical trials. Results would publish whether or not they are favorable to Sponsor. With the advent of Internet clinical trial websites usefulness is manifold. All sorts of communication either secure, no secure when necessary, detailed directory of all involved whether man or establishment, study materials required, could be made available in website.By utilizing web based tools it becomes possible to organize the information in a much simpler way, clinical trial operation would be delicate, time consuming, less costly, orderly. It makes the works of IRB easier by reviewing the concerned website time to time typically in a Clinical Trial Website the following main sections can be found
1. Project Status
2. Study Design
3. Database Management
4. Statistical Analysis
5. Research Report
6. Reference resources

Online trial Technical aspects:

Online Recruitment of Patients and Informed Consent
The successful and efficient recruitment of both patients and investigators for clinical trials is an increasingly difficult challenge. The inability to recruit patients according to plan sometimes cause significant delays in the progress of clinical trials, which ultimately lead to greater incurred costs and lost potential sales. The opportunity cost of a single day's delay in clinical development can equal millions of dollars depending on the prospective product's market potential.
Now days. Internet plays an increasing role for informing the general public about ongoing trials that are recruiting patients. Besides provides information to Investigators for people considering participating in a trial. There are handful commercial websites installed with the business idea of linking patients with clinical trials [28-30]. One such example is Imaginis, Directory of online clinical trial listings and services. The following organizations maintain databases of online clinical trial resources.
http://cancertrials.nci.nih.gov/
http://www.clinicaltrials.gov/
http://www.tricare.mil/mybenefit/ProfileFilter.do
http://www.acurian.com/
http://www.americasdoctor.com/
http://www.amgentrials.com/
http://www.cancerconsultants.com/
http://www.centerwatch.com/
http://www.drugstudycentral.com/
http://www.emergingmed.com/
http://www.hopelink.com/
http://www.researchacrossamerica.com/
http://www.healthexchange.org/
http://www.trialpages.com/
http://www.veritasmedicine.com/
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 [31,32]. 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.

Online trial and regulatory aspects:

Online Randomization

A directory of randomization software and services for clinical trials, including both simple do-it-yourself software and 24 hour telephone randomization services. It is intended to help people planning and seeking funding for clinical trials.There are several online randomization programs such as Clinstat, Minim, Graph Pads Quick Calcs, EDGAR, Stata, KEYFINDER, Stats Direct, Research Randomizer, Adaptive Randomization, TENALEA etc. Telephone randomization services are lot. A few of them are York’s Trials Unit, Rho, Inc. Covance, Clin phone, ASCOPHARM, Clraic LLC etc.

Electronic Data Capture

The capture, management and submission of clinical trial data is a sizeable component of the clinical trial process, in terms of time and cost. The cost element is largely related to the length of time needed to capture, collect and compile information from clinical trials. To reduce both the time and cost of clinical data collection, management and submission, applications of information technology and is widely increasing. Remote data entry to a central database is one of the more useful promises of conducting a clinical trial using the Internet using Local Area Network. 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. Internet-based solution can be used to connect study centers from all over the world.

Electronic Data Proof

Clinical research data, patient data collected during the investigation of a new drug or medical device is collected by physicians, nurses, and research study coordinators in medical settings (offices, hospitals, universities) throughout the world. Historically, this information was collected on paper forms which were then sent to the research sponsor (e.g., a pharmaceutical company) for data entry into a database and subsequent statistical analysis environment. Which had a lot of shortcomings. The shortcomings can overcome through Electronic Data Capture instantly checking data during data entry, preventing some errors altogether and immediately prompting for resolution of other errors. Data could be transmitted rightly to sponsors, thereby improving the sponsor's ability to monitor the progress and status of the research study and its patients. With the advent of time Electronic Data Capture would progress, develop as per requirement against the current hardware deficit. The use of EDC systems in clinical trials in Canada is increasing a large proportion of clinical trials in Canada use some form of automated data capture system [33].

Data Safety

After collection, data can be analyzed using online statistical tools. Safety data have traditionally been summarized as tables and listings that are difficult to review and interpret. In today’s climate of heightened safety concerns, these formats are inadequate for quick and accurate interpretation and comprehension. Now day’s lot of software provides methods for the rigorous analysis of safety data. Analysis results and reports can be readily deployed for interactive review and for submission / reporting.
Statistical Analysis
Statistical analysis has Pre-defined Analysis and Interactive Analysis/Online Analysis two sections:
A. Pre-defined Analysis
B. Interactive Analysis/Online Analysis
Interactive Analysis is a menu driven system; users can define their own analyses by just point-clicking the menus through Internet. It is featured with Descriptive Analysis, Safety Analysis (Prior/Concurrent Medication, Vital Sign, Adverse Events and Laboratory Test), ANOVA Analysis, Pair wise Comparison, Survival Analysis and Graphic Analysis.
Regarding data capture, authentication, and safety elaborate citation can be found in the literature [34].

Accountability Concern

Clinical Trial conducting through Online is a Web interactive, point-click menu driven system. Anyone can use it. From user's point of view, only a Web browser is needed. Every time when a user clicks on a Web page and sends a request to Web Server, Web Server takes the request and communicates it through common gateway interface (CGI) to software System; the System process the request and sends the results back to Web Server, and Web Server sends the results back to the user. Finding the balance between increased access to information and privacy is very important.
Security poses a great threat while letting the clinical trial information online. Both patients and study investigators need to be confident that the data entered on electronic forms and in email communications will not be leaked out. The web server needs to be protected from intrusion from unauthorized users. 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) [35]. Most of the Clinical trial online maintained such security measures available so far. One example of secure system is Centralized Outbound Authentication System. Example of trial website is city of hope clinical trial online secure webpage of NCI. More sophisticated user authentication is possible using digital signatures.

Advantages and Disadvantages of Online Trials:
Advantages

The Advantage if Conducting Online is many Manifolds. Trials on Internet would reduce time and use time efficiently that will increase the quality. With Internet now, Clinical Trial is not only confined in an area only rather can be conducted globally at many different countries.
Another advantage is publishing Clinical Trial Result through Online Publication on Web sites with minimal costs which will reduce publication bias. One of the most important initiatives aimed at reducing publication bias is trial registration i.e., making details of study designs publicly available at the start of a study. One potential advantage of electronic publication coupled with trial registration is that study results can be linked to the original protocol,
The results have optimized time management, since it is easier to work in real time; data quality is improved, since intermediates are eliminated, and it facilitates communication amongst the different parties involved in the project [36].

Disadvantages

While communicating may feel insecure, Online data might be leak, Speed might slowed down during peak hour, Training staff online might not be effective as live, Possibilities of troubleshoot, require experienced computer professional, internet resources are anonymous and transient

Recommendations

From the above discussion it can be say several unique factors contribute to be successful elements of internet based trial. The Internet has the potential to enhance clinical trials such that multicenter trials are more manageable, less expensive, easier to administer, and less time-consuming. However, On the basis of current available online resource, the internet based trial method is most suitable when the intervention is safe, the medical disorder can be confirmed by remote means, and the outcome measures can be applied by using electronically transmissible technologies. Within these parameters, the internet trial method offers opportunities for studying treatments quickly and efficiently.
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. Further explorations of Online Amenities may be needed to determine enhanced security measures, to ensure reliability of online trail among participants.

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