Barriers to entry for implementing an Internet-based clinical trial (IBCT; a.k.a. electronic data capture, or EDC) were described by Kelly and Oldham,

  and very early on, it became clear what were the obvious advantages and potential impact of IBCTs in drug development. Just a few years later, the emerging roles of Internet technologies for data collection in clinical trials and how IBCTs can and should be effective in collecting clinical data were presented.

  The article predicted the eventual common use of IBCTs in the pharmaceutical industry. Richardson

  provided specific details on how to plan and execute an IBCT. Prove

  described in detail how Bayer AG had set up and executed a remote site monitoring (RSM) program using a customized laptop.  

In a recent survey, 14 pharmaceutical companies were interviewed to determine the best practice requirements for clinical data management and biostatistics.

  Among the key metrics were: the rate of case report form (CRF) pages entered and processed, last patient visit to final CRF lock in-house, number of queries generated, and last patient-last visit (LPLV) to database lock. Bart

  reported that by using EDC systems, clinical research costs could be reduced by up to 20% due to a reduction in queries, overall reduction in the duration of the clinical trial, and the time to database lock. Hyde

  described that one of the benefits of EDC systems is that at the time of data entry, real-time edit checks can be fired to alert for missing and inconsistent data. These edit checks save time and money, and improve the quality of the data compared to the paper query system.  

General attributes of EDC have been summarized in a series of publications.

  Time and money are saved by eliminating the need to print and ship CRFs and perform double key entry. When using EDC, double key entry is eliminated because the site enters data directly from the source documents. Because the clinical site personnel enter the data, there are no illegible fields and no one needs to interpret abbreviations or symbols. Costs for query management are also reduced, as there is a marked reduction in the number of queries as well as the time it takes to resolve a query. If a value is out of range, an edit check will prompt the user to check the value at the time of data entry. The role of the CRA has changed with EDC.

  The CRA has taken over some of the roles of data management and in part now acts as a quality auditor.  

While it is clear that there are many theoretical advantages of an IBCT over a paper-based clinical trial, there is a paucity of data on the efficiencies of: data entry, in-field monitoring, and in-house form review prior to database lock. The present case study uses data derived from an ongoing IBCT using Target e*CRF®  in order to evaluate efficiencies of data entry, field monitoring, and in-house data review. 

The data for this case study were derived from an open-label, randomized, multicenter IBCT for the treatment of prostate cancer. Approximately 170 patients participated in this multi-year study. The results represent data collected only during the first year of the study. The goal of the current analysis is to evaluate the efficiencies of IBCTs using metrics derived directly from the IBCT database. 

Four forms were selected for analysis: Visit Date, Demographics, Concomitant Medications, and Adverse Events. The roles described below are illustrated and will vary between companies. The analysis evaluated the following: 

1. Number of forms that required no modification after initial data entry.

 This metric represents the quality of data entry by the clinical study site. 

2. The time from initial data entry by the clinical study site to the time data are modified.

 This metric represents both the time that data management or the CRA identifies a monitoring issue and generates a query, as well as how quickly the clinical study site resolves a query. 

3. The time from data modification to in-field data review by the CRA.

 This metric represents the time between query resolution to the time of final source document review by the CRA. At final source document review, the form is designated as "reviewed" by the monitor and the site cannot enter data without the form being electronically opened by the CRA. This metric will vary based on the frequency of monitoring as well as the quality of the monitoring. 

4. The time from in-field data review to in-house form review (form "lock").

 This metric represents the time between final source document review by the CRA and final acceptance of the form data by the clinical data manager. At this point, the form is designated as "locked" by the clinical data manager and the site cannot enter data without the form being electronically opened by the clinical data manager. Once all forms are locked in-house and all off-line SAS batch validations have been resolved, the patient record can be locked by the data manager. 

 Table 1 summarizes the efficiencies of data entry by the site and efficiencies of in-field monitoring by the CRA. In terms of efficiencies of data entry, 85.9% of all forms did not require any data modification. As expected, Visit Date and Demographics had the fewest changes. The vast majority of the Visit Date (99.3%) and Demographic (96%) forms required no data modifications. In contrast, and as expected, fewer Con Med and Adverse Event forms required no data modifications (71% and 70.2%, respectively). The difference in results between the Visit Date and Demographics forms and the Con Med and Adverse Event forms is that visit dates and demographic data are static and do not change over time, while medication and adverse event data often require updates as new data become available during the course of the clinical trial. Also, the latter two forms are more complex and spelling errors are common.  

Table 1. Cumulative frequency (days) from the date of initial data entry to last form modified by the study site. 			

Table 1 also displays the percentage of forms that were modified within 30, 60, and 90 days of data entry. In general, 76%–99.5% of all forms had their final modification within 30 days of data entry. Having such a high percentage of "clean" forms early in the study cycle allows the CRA to perform source document verification in a very efficient manner.  

 Table 2 summarizes the efficiencies in data cleaning by measuring the time between final data entry by the clinical study site and in-field source document verification by the CRA. These results will vary based on the frequency of monitoring as well as the quality of the monitoring.  

Table 2. Cumulative frequency (days) from the day the form was last modified to CRA review.			

In terms of efficiencies of monitoring, 10.1% of all forms were reviewed on the same day the data were modified. What this means is that immediately after the study coordinator modified data (e.g., in response to a query) the monitor was able to review the form. Simultaneous data modification and review occurred 3.7% of the time for Visit Date, 5.4% for Demographics, 30.1% for Con Med, and 17.4% for Adverse Events. 

In terms of monitoring efficiencies, the percentage of forms that were reviewed within 30, 60, and 90 days of data entry are also displayed in Table 2. In general, 69%–83% of all forms were reviewed by the CRA in the field within 60 days of data entry or final form modification. 

 Rapid source document review also allowed for rapid in-house review of the data (Table 3). The analysis showed that 9.8% of all forms were reviewed by the in-house data reviewers on the same day of CRA review. What this means is that immediately after the CRA verified the source documents, the in-house data reviewer (clinical data manager) was able to "close" the form. Simultaneous form review by the CRA and clinical data manager occurred 9.7% of the time for Visit Date, 3.7% for Demographics, 11.8% for Con Med, and 10.4% for Adverse Events.  

Table 3. Cumulative frequency (days) from the date of CRA review to in-house form review.			

Table 3 also displays the percentage of forms that were reviewed by the clinical data manager within 30, 60, and 90 days of review by the CRA. In general, 88%–97% of all forms were reviewed by the clinical data manager within 60 days of form review by the CRA. 

This rapid data review also allowed for rapid lock of individual patient data by data management. 

In recent years, with advances in EDC technology and IBCTs, the pharmaceutical industry has made dramatic advances in the area of clinical data management. By using EDC, data entry has been streamlined, data management has become more efficient, and the quality of the data has improved. 

The current study allows for the evaluation of some of the preferred metrics described by Fitzmartin.

  The data illustrate that there are clear advantages of IBCTs in terms of data entry, source document verification, and data cleanup and management. The types of metrics presented in this article can provide a benchmark to evaluate the operational efficiencies of IBCTs during long-term studies. There is little question that IBCTs can reduce clinical trial costs and improve quality as systems mature and meet the needs of clinical research, data management, and project management. 

In contrast to an IBCT, when performing a paper-based clinical trial it is not uncommon for a CRA to discover that the site was not properly prepared for the visit and has not completely filled out the CRFs. The reason for this is that the CRA has no bird's eye view of the data until he/she actually arrives at the study site. Only then does the CRA look at the CRF data and verify that the data entered into the paper CRF match the data in the patient record (source document). The CRA also attempts to reconcile missing, out-of-range, and inconsistent data. As a result, during the monitoring visit the CRA and study coordinator devote more time to resolving issues regarding careless transcription errors, out-of-range data, and missing data than to protocol compliance issues. With EDC, a lot of these issues are resolved prior to the monitoring visit. 

One of the main challenges for an IBCT, as well as for a paper-based clinical trial, is to get the clinical study site to enter the data into the CRF in a timely manner. However, once the data are entered, there are major advantages of IBCTs over paper-based trials. With a little effort, any delay in entry/review can be caught up at the end of the trial, enabling database lock one–two days after the last data are available. Often, this only depends on the time it takes to complete the last monitoring visit. This workflow is a major improvement over a paper CRF-based clinical trial, where it can take months to perform final data verification by data management. 

The main advantage of an IBCT is the automatic feedback system (i.e., online edit checks), which addresses the most basic errors at the time of data entry (e.g., missing, out of range, and inconsistent data). In paper CRF-based clinical trials, this reconciliation occurs well into the study when data management runs the validation checks after double-key data entry has been completed. In an IBCT, the CRAs are much more knowledgeable about the status of the trial prior to the monitoring visit. From the home office, the CRA can identify and instruct the study coordinator to address missing and  illogical data, spelling errors, and incorrect terminologies/acronyms. If there are missing or out-of-range data, the CRA has the explanation, in electronic format, prior to the visit. During the monitoring visit, there is no need for the CRA to make inquiries as to why data are missing, out of range, or inconsistent, since these issues have already been resolved via the edit/logic check and query processes prior to the visit.  The CRA can also be authorized to "review" the form electronically to prevent the site from changing data after source document verification is completed. This "review" feature further ensures data integrity. 

 1. M.A. Kelly and J. Oldham, "The Internet and Randomised Controlled Trials," 

International Journal of Medical Informatics

 2. J. Kuchenbecker, H.B. Dick, K. Schmitz, W. Behrens-Baumann, "Use of Internet Technologies for Data Acquisition in Large Clinical Trials," 

 3. A. Richardson, "Planning and Running the e-Clinical Trial," 

 4. J. Prove, "Challenges and Solutions for the Use of Remote Study Monitoring in a Transcontinental Project," 

 5. R.D. Fitzmartin, "A Survey of Industry Best Practice Metrics in Clinical Data Management and Biostatistics," 

 6. B. Thomas, "Comparison of Electronic Data Capture with Paper Data Collection—Is There Really an Advantage?" 

 7. A.W. Hyde, "The Changing Face of Electronic Data Capture: From Remote Data Entry to Direct Data Capture," 

 8. J. Mitchel, J. You, A. Lau, Y.J. Kim, "Paper Versus Web: A Tale of Three Trials," 

 9. J. Mitchel, J. You, A. Lau, Y.J. Kim, L. Cheng, S. Fein, R. Nardi, "Clinical Trial Data Integrity. Using Internet-Based Remote Data Entry to Collect Reliable Data," 

10. J. Mitchel, J. You, Y.J. Kim, A. Lau, B. Levinson, S. Lynch, P. O'Connor, "Internet-Based Clinical Trials—Practical Considerations," 

Pharmaceutical Development and Regulations,

11. J. Mitchel, C. Ernst, S. Cappi, W. Beasley, A. Lau, Y.J. Kim,  J. You, "Implementing Internet-based Clinical Trials," 

12. J. Mitchel, C. Ernst, S. Cappi, W. Beasley, A. Lau, Y. J. Kim, J. You "Meeting the Challenges of Internet-based Clinical Trials," 

13. J. Mitchel, E. Jurewicz, K. Flynn-Fuchs, E. Sharpe, G. Park, "The Role of CRAs in the Development and Implementation of Internet-Based Clinical Trial Applications: New Career Opportunities," 

, MS, is senior director of applications development and data management, 

, BS, is associate director of application development, and 

, BS, JD, is manager of regulatory affairs with Target Health, Inc., 261 Madison Avenue, 24th Floor, New York, NY 10016, (212) 681-2100, fax (212) 681-2105, email: 

 is datamatician and clinical data manager and 

, MBA, MSc, is executive director, biometrics, with Ferring Pharmaceuticals International, Copenhagen, Denmark.

*To whom all correspondence should be addressed.

Articles

Feature Article

This case study shows how Internet-based clinical trials improve data entry, monitoring, and management.

Impact of IBCTs on Clinical Trial Efficiency

The way in which devices are regulated in the EU is very different from the way they are regulated in the United States, especially in terms of the clinical data required for premarket approval. This has introduced significant differences in time-to-market approval for the United States versus the EU, particularly in the case of high-risk Class III and Class IIb implantable devices. 

As a result, some U.S. physicians have experienced one- to three-year delays in access to certain important technical innovations such as drug eluting stents compared to their European colleagues.

  This article will explain why these timelines can differ so extensively by examining the clinical data requirements for market approval in the two systems.  

Medical devices are regulated in the European Union by three EC Directives.

  The main directive, which covers the vast majority of medical devices from surgical gloves to life sustaining implantable devices such as heart valves, is the Medical Devices Directive (MDD). The MDD is supplemented by an older directive on active implantable medical devices and a newer directive on in vitro medical devices. These three EC directives have been enacted ("transposed") into the national laws of each EU Member State, resulting in a legislative framework comprised of literally dozens of medical device laws. 

The medical device directives are known as "New Approach" directives. This means that medical devices bearing a CE marking can circulate freely throughout the EU without any barriers. Examples of other products regulated by "New Approach" directives include pressure vessels, toys, and personal protective equipment. 

The underlying principle of the "New Approach" is as follows. Each of the medical device directives contains a legislative list of "Essential Requirements" that must be met by any product falling within its scope. In the MDD, the list of Essential Requirements can be broken down into two groups: 1) a set of general requirements for safety and performance that applies to all devices, and 2) a list of specific technical requirements with regard to design and manufacturing that may or may not apply depending on the nature of the device. For example, the technical requirement for electrical safety would not apply to a urinary catheter. 

Compliance with the technical requirements is generally demonstrated by using the relevant European Harmonized technical standard. The need for clinical data in the CE marking process arises from the general requirements for demonstrating safety and performance.  

A key aspect of medical device regulation in the EU is that the responsibility for ensuring that devices meet the Essential Requirements lies with the manufacturer. For low risk devices (Class I) such as a tongue depressor or colostomy bag, the manufacturer is allowed to self declare conformity with the Essential Requirements. For medium- to high-risk devices (Class IIa, IIb, III), the manufacturer must call on a third party to assess conformity. To some degree, the manufacturer may choose among methods for "conformity assessment" of the device and/or manufacturing system. The end result is certificates of conformity that enable the manufacturer to apply a "CE marking" to the product. 

Another major aspect of the CE marking process is that, unlike pharmaceutical products, the medical device "conformity assessment" is not conducted by a regulatory agency for drugs and devices (i.e., a Member State Competent Authority or a central authority such as the EMEA). The CE marking system relies heavily on "Notified Bodies" to implement regulatory control over medical devices. 

The majority of Notified Bodies are independent commercial organizations that are designated, monitored, and audited by the relevant Member States via the national Competent Authorities. Currently, there are more than 50 active Notified Bodies within the EU. A company is free to choose any Notified Body to cover the particular class of device under review. After approval, postmarket surveillance functions are the responsibility of a member state via the Competent Authority. 

What clinical data is required by the EU medical device regulations? How does this differ from U.S. FDA requirements? As previously mentioned, the need for clinical data in the CE marking process arises from the requirement to demonstrate that a device is safe, that it performs as intended by the manufacturer, and that any risks are acceptable when weighed against the benefits of the device. The term "clinical data" within the meaning of the EC Directives is a broad concept that includes everything from bench testing to clinical trials in human subjects. As stated in the MDD, the clinical data used for CE marking may be in one of two forms: 					

either a compilation of the relevant scientific literature currently available on the intended purpose of the device and the techniques employed, together with, if appropriate, a report containing a critical evaluation of the compilation

the results and conclusions of a specifically designed clinical investigation.

The first option, also referred to as the "literature route," is commonly used by manufacturers for the CE marking of low- to medium-risk devices (Class I, IIa and IIb) for which safety and performance can be adequately demonstrated by a combination of nonclinical data (i.e., bench testing and animal testing) and clinical data that already exists on the device (published or unpublished) or by analogy with published data generated on an equivalent device. 

Even when it is clear that the "clinical data" should come from a prospective clinical investigation, specific guidance on the criteria to be used is limited. While some guidance specific to medical devices is available, in general it concerns good clinical practices and clinical trials methodology.

  Specific requirements for clinical evaluation of most devices are not available in the guidance. In the absence of such specific requirements, the manufacturer must decide which data are sufficient for CE marking (i.e., number of subjects, type of study design, primary and secondary endpoints, type and schedule of assessments, minimum patient follow-up period, etc.). The Notified Body may be consulted with prior to initiating the clinical trial to verify whether or not the protocol is designed to yield adequate data for CE marking. 

As a basic principle, the objective of a CE marking trial is to demonstrate safety and performance. Therefore, the majority of these trials are nonrandomized, single arm, feasibility studies involving less than 100 patients for which the primary objective is to demonstrate safety. In our experience, CE marking protocols rarely include a study hypothesis and a statistical calculation of sample size even though this is a requirement of the European Standard.

				Furthermore, Notified Bodies tend to function in a closed manner that provides little visibility on criteria required for approval, which allows for variations in clinical data requirements despite the fact that guidance documents have been mandated by the Commission to ensure a "level playing field."			

The U.S. approval process for medical devices is very different, especially in terms of the scope and size of clinical trials required for high-risk devices. To receive approval to market a device in the EU, the manufacturer must demonstrate that the device is safe and that it performs in a manner consistent with the manufacturer's intended use. To receive approval to market a class III high-risk (and some class II) device in the United States, the manufacturer must demonstrate that the device is reasonably safe and effective. This typically requires a prospective, randomized controlled, adequately powered clinical trial involving hundreds of patients. 

This significant difference is illustrated by the example of distal protection systems used in interventional cardiology. The first such system to be developed was a specialized coronary guide wire with an expandable balloon at its tip (GuardWire from Percusurge, Inc., which was later acquired by Medtronic). During a coronary angioplasty or stenting procedure, the device is inserted via femoral arterial access and the balloon is inflated distal to the lesion. After the balloon is expanded, the lesion is treated. The purpose of the device is to block any dislodged arterial debris from embolizing. After the lesion is treated, any debris is evacuated by aspiration and the GuardWire is removed. 

In the EU, the GuardWire device was awarded CE marking by demonstrating safety and performance (i.e., the ability to aspirate material during the stenting procedure) in a 22-patient, single arm study.

  In the United States, this device was designated Class II. To demonstrate safety and effectiveness (defined as the ability to reduce complications associated with stenting of saphenous vein grafts) the FDA required an 800-patient, multicenter, randomized trial comparing distal protection to usual care (no protection).

As a result, the GuardWire was available in the EU at least two years before U.S. physicians had access to the technology. On the other hand, one may argue that this early access must be weighed against the absence of proven efficacy. 

Without careful trials evaluating efficacy, no legitimate medical judgement on the appropriate use of a medium- to highrisk medical device may be made. Unlike the United States, the EU approval process for medical devices does not incorporate such evaluations into its regulations. 

What could already be perceived by some as a shortcoming in the EU regulatory requirements is further exacerbated by the fact that: 1) "real" clinical data in the form of results from prospective clinical investigation is not mandatory for medical devices in Class IIb, even though they are relatively "high risk"; and 2) Notified Bodies are not on a level playing field in terms of their criteria for approval. 

There is a proposal currently to amend Annex X of the Medical Devices Directive to strengthen the language concerning clinical data requirements; however, the proposed changes will not fundamentally alter the spirit of the requirements, which remains the demonstration by the manufacturer of safety, performance, and acceptable risk/benefit ration. On the other hand, Notified Bodies will increasingly require effective postmarket surveillance in the form of postmarket clinical follow-up for certain types of devices.

1. A.V. Kaplan, D.S. Baim, J.J. Smith, D.A. Feigal, M. Simons, D. Jefferys, T.J. Fogarty, R.E. Kuntz, M.B. Leon, "Medical Device Development: From Prototype to Regulatory Approval," 

2. Council Directive 90/385/EEC of 20 June 1990 on the approximation of the laws of the Member States relating to active implantable medical equipment (AIMDD); Council Directive 93/42/EEC of 14 June 1993 concerning medical devices (MDD); Council Directive 98/79/EC of 27 October 1998 on in vitro diagnostic medical devices (IVDD). 

3. NB-MED/2.7/Rec.1: Co-ordination of Notified Bodies Medical Devices. Recommendation—Guidance on Clinicals. 

4. MEDDEV 2.7.1: European Commission—Guidelines on Medical Devices—Evaluation of Clinical Data: A Guide for Manufacturers and Notified Bodies. 

5. EN ISO 14155-1&2: Clinical Investigations of Medical Devices for Human Subjects. Part 1: General Requirements, Part 2: Clinical Investigation Plans. 

6. J.G. Webb, R.G. Carere, R. Virmani et al., "Retrieval and Analysis of Particulate Debris Following Saphenous Vein Graft Intervention," 

7. D.S. Baim, D. Wahr, B. George et al., "Randomized Trial of a Distal Embolic Protection Device During Percutaneous Intervention of Saphenous Vein Aorto-coronary Bypass Grafts, 

8. MEDDEV 2.12.2: European Commission—Guidelines on Post Market Clinical Follow-up (PMCF). 

, MS, is founder and president of MedPass International SAS, 95bis Boulevard Péreire, 75017 Paris, France, +33 (0)1 4212 8330, fax +33 (0)1 4053 8111, email: 

Less stringent requirements in the European Union result in faster medical device approval times.

Medical Device Development: U.S. and EU Differences

Research professionals who follow the United Kingdom's Department of Health guidelines when recruiting volunteers for clinical trials could find they have acquired personal liability for compensation claims from injured subjects. 

In 1991, the United Kingdom's Department of Health commendably stated that potential subjects in clinical trials must "be told in advance of all known risks and be made aware that there could also be unforeseen risks, and of the possible difficulties in obtaining compensation."

The words "possible difficulties in obtaining compensation" undoubtedly refer primarily to non-negligent harm. In the United Kingdom, courts will not award compensation for nonnegligent injury, unless a prior legally binding agreement provides for it. 

Non-negligent harm is a cost inherent in medical research. Trial sponsors and research professionals clearly are free to propose that the cost be borne by the injured subjects themselves. But as a matter of law, subjects must be told plainly what they are letting themselves in for. 

Despite this, the Department of Health, through its own Central Office for Research Ethics Committees (COREC), advocates the following words for use in information provided to potential patient volunteers: "[the sponsor] 

 [emphasis added] pay compensation for [non-negligent harm]. Any payment would be without legal commitment (please ask if you wish for more information on this)."

This formula is not straightforward. The clear legal commitment given in the first sentence is undone by the legal sleight of hand in the second. The Department of Health's 1991 policy statement calls for openness and full information, but its actions in 2006 are obscurantist. 

Surprisingly, at least in the United Kingdom, researchers often suppose that the law leaves ethical questions to the discretion of researchers. But they are wrong. The Department of Health's doublespeak, adopted in the United Kingdom by trial sponsors and widely allowed by Research Ethics Committees, is odious to UK law. 

 that in the UK, a patient's agreement to take part in a clinical trial is a legal contract, which consumer law requires to be expressed in "plain language."

Under UK consumer law, it is unlawful even to recommend a term for use in consumer contract documents if the term is not open and fair. The Department of Health has no power to set aside consumer law for itself; nor has it the power to absolve any other person from the duty to comply with the law. 

A potential subject who "wishes for more information" (on the Department of Health's fast-talking about non-negligent harm) is likely to ask the research professional who is about to counter-sign the consent form on behalf of the trial sponsor. Research professionals who venture to make reassuring comments may later find themselves personally responsible for their amateur legal advice. 

The United Kingdom's systematic disinforming of potential subjects in clinical trials probably has no parallel in the United States,

  but research professionals working in the United Kingdom may want to seek their own legal advice. For a legal time bomb is ticking.  

1. NHS Management Executive. HSG(91)5. Local Research Ethics Committees. Priority and Health Service Division (PHS4D) Department of Health, London (1991). 

2. Central Office for Research Ethics Committees. Guidelines for researchers. Consultation version 22 November 2005; para 19. What if there is a problem? 

www.corec.org.uk/applicants/help/docs/Guidance_on_Patient_Information_Sheets_and_Consent_Forms.doc

3. D.R. Laurence, "Patients in Clinical Trials Are Protected by Consumer Regulations," 

4. Office of Fair Trading. Unfair Terms in Contracts: What Is an Unfair Term?, 

www.oft.gov.uk/Consumer/Unfair+terms+in+contracts/what+are+unfair+terms.htm

5. M. Hochhauser, "Paying for Research Related Injuries in the US," 

A Closing Thought

A patient's agreement to take part in a clinical trial is a legal contract, which consumer law requires to be expressed in plain language.

No Plain English for UK Subjects

If you haven't looked for it, you may have missed the quiet revolution occurring on the Internet. The change in the Web, dubbed "Web 2.0," is likely to improve the value and usability of the Internet for consumers, and has major untapped potential for corporate and other business users.  

Web 2.0 is one of those elusive Web terms that is used to describe many disparate threads of change. However, there are some shared underlying principles of Web 2.0 companies and platforms, which we'll discuss later. 

For a definition of Web 2.0, we can turn to Wikipedia, the free encyclopedia that is itself a shining example of the potential for the new approach to the Web: 

"The term Web 2.0 refers to a second generation of services available on the World Wide Web that lets people collaborate and share information online. In contrast to the first generation, Web 2.0 gives users an experience closer to desktop applications than the traditional static Web pages...The concept may include blogs and wikis." 

To understand Web 2.0, we must appreciate its origins and roots. Some of you may not realize that there was even a Web 1.0, so it probably makes sense to start at the beginning. 

When the World Wide Web (WWW) was first defined, it consisted almost entirely of static Web pages that each contained hyperlinks. A destination Web presence might have been a university, institution or company with an interlinking series of pages. Web directories such as Yahoo were established to categorize and provide search functionality for these sites. Web 1.0 was an exciting frontier for the pioneer Web surfer, and one that was easily mastered. 

Once established, the WWW underwent almost continuous evolution, which was driven by the introduction of a variety of more dynamic technologies (Java, Shockwave and Flash, dynamic HTML, etc.). Web pages were dynamically created from a database, and the database could be customized for each user. For example, Yahoo evolved into My Yahoo for many users—a highly customized, dynamic portal of information and services that met the needs of each individual. 

This newer Web is referred to by some as Web 1.5 and encompasses much of the Web as we experience it today. Web 1.5 linked bricks and mortar with the Web, leading to a major shift in the way we get our news; buy our clothing, electronic "toys," and books; and obtain information. It was built on the framework of Web 1.0 but added a variety of tools and an evolving sense of style and design. 

Web 2.0 also builds upon the foundations of all that has come before it but takes some radical departures. The idea of tying together a group of disparate new Web applications and platforms was developed by two conference organizers (O'Reilly Media and MediaLive International) when brainstorming a conference concept. Web 2.0 was defined, more or less, by example: Companies that were old school (i.e., Web 1.0) and those that were new school (i.e., Web 2.0). 

Before identifying unifying concepts, let's look at a few examples of Web 2.0 concepts. 

). An astounding example of the power of the commons, Wikipedia serves as a gigantic and very current encyclopedia that is created and maintained by its users. In contrast to a Web 1.0 encyclopedia (Britannica Online, for example), Wikipedia is completely dependent on users to create, update, and provide quality control for the content of its articles. The technology itself is very simple, open source software, but the power of the Wikipedia is the vast database of very detailed information on almost any topic, far exceeding most online encyclopedias in terms of detail and, often, quality of information. 

Of course, since anybody can edit a Wikipedia article, some controversial topics can become battlegrounds for ideology. However, Wikipedia users are hopefully sophisticated enough to understand this and to take it into account when using the information. 

). The blogging revolution is in full force, powered by an enormous collection of dedicated people who create "Web logs" (otherwise known as blogs) on almost any topic, from politics to rock music. 

Blogging software sites allow an unsophisticated user to set up an aesthetically pleasing blog in minutes and begin publishing on a topic of their choice almost immediately. The result has created citizen journalists, armchair political pundits, scientific commentators, and movie critics who are widely read and followed. 

Each blog "advertises" other blogs by linking references to them, creating a huge interwoven tapestry of information that is completely separate from traditional information and media. The Web 1.0 equivalent of the blog was the personal Web page—a drastically different and static concept. The whole "blogosphere" can be searched through sites such as Technorati (http://

). Web 2.0 emphasizes community and the power of the commons. A powerful example of this is LinkedIn, a Web community composed of professionals who wish to network. 

When you join LinkedIn, you create a public profile that lists your previous positions and companies. When you invite friends to join, they become permanent "first degree" links to you. If they are already a member of the community, you become linked to their contacts through them. 

The real value of LinkedIn is that it allows a user to search for and contact many people with whom they have no other connection. The site allows you to identify a chain of people who can connect you with the person you want to contact. A user can send a message through this chain that is passed along from person to person until it gets to the individual they want to contact. Remarkably, the concept works very effectively. The power of LinkedIn is in the community it creates. 

You are likely already familiar with aspects of Web 2.0 applications, which have been included on some Web sites for many years. For example, the ability to write and publish a book review on 

 is a Web 2.0 concept, as is the ability for any user to rate the review. Similarly, the rating system used for buyers and sellers on Ebay is classic Web 2.0. 

Interestingly, Web 2.0 concepts aren't restricted to the Web. Tim O'Reilly of the O'Reilly Network that developed the Web 2.0 concept points out that iTunes and TIVO are two examples of Web 2.0 applications, both integrating aspects of the Web with devices. 

While the community aspects of iTunes and TIVO aren't significant, their devices use the Web to provide the user with a service (music downloads and television program recording, respectively) through a seamless experience of a device interacting with a large database. 

In my formulation, the organizing principles of Web 2.0 are: 					

A service-oriented, "lite" architecture. Web 2.0 applications are more a platform than a stand-alone application, and often use a simple interface with sophisticated functionality. Judicious use of newer technologies (e.g., AJAX) gives the user a richer experience, more like a desktop application (e.g., Google Maps).

Data-oriented collaboration. Most Web 2.0 applications are centered around a substantial database, often created, developed or vastly improved by its users.

Organization of content through nonhierarchical methods. Unlike traditional structured directories, content in Web 2.0 applications can be searched and organized upon retrieval, or can be "tagged" by other users, providing a communal and dynamic organizational structure.

Community building and user interaction. When a user interacts with a Web 2.0 application, they often create a presence within the community (e.g., LinkedIn), which becomes a center for further interactions, collaborations, and community building.

The user as contributor. In many Web 2.0 settings, the user becomes a participant in the building of the platform. This may be as a contributor (Wikipedia, blogging), content reviewer (eBay reputation ratings), or even as a software tester (many Web 2.0 applications frequently change and add functions in a "beta" mode). While some applications require explicit participation, others "repurpose" individual activities such as content tagging for community use.

Web 2.0 isn't just about fun sites; it is being put to work in corporate settings, even within the pharmaceutical industry. A company called TrueTrials appears to be putting together a Web 2.0-like service and community in which both sites and sponsors can participate. Investigative sites establish a presence and allow sponsors to contribute to their reputation by rating their performance in clinical trials. Through this rating system, the company can create a valuable database of rated sites for sponsors and provide new opportunities for highly rated sites. 

Web 2.0 has been around for a few years and is based on technology and concepts that have existed since the bursting of the first dotcom bubble. Some predict that the value and activities created with Web 2.0 may be greater than the initial Internet revolution. The value that Web 2.0 brings to clinical trials and technology will depend mostly on the creativity, imagination, and participation of you—the end user. 

MD, PhD, is the founder and chairman of Phase Forward, 880 Winter Street, Waltham, MA 02451, (888) 703-1122, 

Technology Viewpoint

From blogs to social networks, the newest Web is redefining the way we use technology.

Web 2.0 Revolution: Power to the People

When adverse events arise as dramatically as in the clinical trial that went so wrong earlier this year in the United Kingdom, the reporting of what happened presents few conundrums. In fact in that case, the reporting was conducted largely through the mass media, over and above any communication between sponsor, investigator, and regulatory authority.  

But most trials, fortunately, do not achieve such spectacular notoriety, and the decisions over what adverse reactions are to be reported, and how, are usually a more discreet matter—often calling for refined judgements by everyone involved in the trial. The European Union has recently issued some advice to help in this decision-making process. 

This takes the form of a lengthy document entitled "Detailed guidance on the collection, verification and presentation of adverse event/reaction reports, together with decoding procedures for unexpected serious adverse reactions" (http://

). It should help in interpreting the reporting requirements that are imposed on sponsors and investigators by EU rules on clinical trials (see sidebar), and ease some of the ambiguity that arises in on-the-ground situations. 			

In the most general terms, the sponsor is responsible for the ongoing safety evaluation of the investigational medicinal product, and consequently for promptly notifying all concerned investigators, the Ethics Committee (EC), and competent authority of each concerned member state of findings that could adversely affect the health of subjects, impact on the conduct of the trial or alter the competent authority's authorization to continue the trial.  

It is also the sponsor's responsibility to arrange the systems and written standard operating procedures to ensure quality standards are observed in every step of the case documentation, data collection, validation, evaluation, archiving, and reporting. 

More specifically, on the recording and evaluation of adverse events, the guidance says that individual adverse events should be evaluated by the investigator in relation to seriousness and the causality between the trial product and/or concomitant therapy and the adverse event, and where appropriate, reported to the sponsor for further evaluation with respect to seriousness, causality, and expectedness. The sponsor has to retain detailed records of all adverse events reported by investigators and submit them on request to any competent authority where the clinical trial is being conducted. 

All adverse events that the investigator or the sponsor judges as having a reasonable suspected causal relationship to a trial product qualify as adverse reactions. The causality assessment given by the investigator should not be downgraded by the sponsor, and in the event of disagreement between sponsor and investigator, the causality assessment from both should be provided with the report. 

Adverse reactions should be considered as unexpected if the nature, seriousness, severity or outcome of the reaction is not consistent with the trial product's reference information. The sponsor is to determine expectedness of an adverse reaction on the basis of the investigator's brochure or the summary of product characteristics—whichever is identified in the protocol as the reference document for the entire trial. 

One of the most delicate areas in reporting is how to handle SUSARs—suspected unexpected serious adverse reactions—particularly in view of the multiple scenarios in which the sponsor of a trial in Phase I–IV with at least one investigator site in the EU is obliged to report. Expedited reporting is required for all suspected adverse reactions related to an investigational medicinal product (defined here as "the tested investigational medicinal products and comparators") that occur in the trial, and that are both unexpected and serious. 

But the requirements are even more onerous. Reporting is also required for SUSARs that occur outside the concerned clinical trial, if the investigational medicinal product has a marketing authorization in a member state and the sponsor is the marketing authorization holder. Even where the sponsor is not the marketing authorization holder for the trial product, any SUSARs associated with it in another trial conducted by the same sponsor in a non-EU country must be reported. 

And for investigational products without a marketing authorization in any member state, the sponsor is obliged to provide expedited reporting of any SUSARs associated with it as soon as he/she becomes aware of them. This includes SUSARs that occur in another trial conducted by the same sponsor either in the EU or in Iceland, Norway or Liechtenstein (which are closely linked to the EU via their membership of the 28-nation European Economic Area); those that are identified by spontaneous reports or a publication; or those that are transmitted to the sponsor by another regulatory authority. 

Some safety issues also qualify for expedited reporting if they can alter the benefit–risk assessment of a trial product or lead to changes in product administration or trial conduct. Increases in the rate of occurrence of an expected serious adverse reaction or a qualitative change that is considered clinically important as well as SUSARs that occur after the patient has completed a clinical trial and are reported by the investigator to the sponsor are two such situations. Similarly, expedited reporting is required for new events related to the conduct of the trial or the development of the trial products if they are likely to affect the safety of the subjects. These would include a serious adverse event that could be associated with the trial procedures, a significant hazard to the subject population (for instance, lack of efficacy of a trial product used for the treatment of a life-threatening disease), a major safety finding from a newly completed animal study (such as carcinogenicity) or any safety motivated halt of a trial on the same product in another country by the same sponsor. 

It is the sponsor's job—and the sponsor's job alone—to report all this information to the competent authorities and to the EC concerned with the trial. The sponsor also has to inform all investigators about SUSARs that could adversely affect the safety of subjects. 

Expedited reporting is not, however, usually required for reactions that are serious but expected, or for nonserious adverse reactions, whether they are expected or not. It is also not necessary to report events that are considered unrelated to the trial product. 

The sponsor also has to report all SUSARs associated with a comparator product in the clinical trial, even if the product is authorized—not just to the authorities, but also to the marketing authorization holder. Since events associated with placebo will usually not satisfy the criteria for a serious adverse drug reaction—and therefore will not usually require expedited reporting—if SUSARs are associated with placebo because of, for instance, reaction to an excipient, reporting is recommended. 

Notification of SUSARs must occur as soon as possible. In the event of fatal or life-threatening SUSARs, it must be no later than seven calendar days after the sponsor becomes aware that the case merits expedited reporting, with a follow-up report submitted within a further eight calendar days. For nonfatal and nonlife-threatening SUSARs, the initial reporting deadline is 15 calendar days. 

Information on the final description and evaluation of an adverse reaction report may not be available within the required reporting time frames, but initial expedited reports should be submitted as soon as there is a suspected investigational medicinal product, an identifiable subject (such as a study subject code number), an adverse event assessed as serious and unexpected for which there is a reasonable suspected causal relationship, and an identifiable reporting source. If the information is incomplete when the initial report is made, the sponsor should seek all relevant information for an adequate analysis of causality and provide follow-up reports—with, in appropriate cases, long-term follow-up of a particular reaction. 

Usually, treatment codes in a blinded trial should be broken by the sponsor before reporting a SUSAR. Although it is advantageous to retain the blind for all patients prior to final study analysis, when a serious adverse event may be a serious adverse reaction—unexpected or not—that is judged reportable on an expedited basis, the blind should be broken just for specific patients by the sponsor, even if the investigator has not broken it. But as far as possible, the blind should be maintained for biometrics personnel responsible for data-analysis and interpretation of results at the study's conclusion. And investigators should unblind single cases in the course of a trial only if the safety of the trial subject demands it. 

It is recommended that in case of a blinded study, the case is assessed for seriousness, expectedness, and causal relationship, assuming that the tested investigational medicinal product caused the reaction. If the case appears to be a SUSAR, then the blinding should be broken. Then, if the product being administered is the tested product, the case would be reported as a SUSAR. If it is a comparator with a marketing authorization, and the adverse reaction is unexpected, then the SUSAR should be reported; otherwise, it is an expected serious adverse reaction and not reportable on an expedited basis. And if, after unblinding, SUSARs are associated with placebo, it is the sponsor's responsibility to report such cases. 

The EU guidance also covers many other aspects of reporting, ranging from the management of adverse events in trials with high morbidity and high mortality diseases through to the format and content of the annual safety report of a clinical trial and how to keep investigators informed. There is also a lengthy annex providing comments on the definitions and abbreviations used in relation to safety reporting. 

 is a freelance journalist who specializes in European health affairs and is based in Brussels, Belgium. 

View from Brussels

EU helps ease ambiguity of reporting process with recent published guidance.

ADR Reporting: A Clearer Explanation

The drug development process would rarely be described as being on rails, unless roller coasters were included in the metaphor. However, with integrated project team planning, good project management, and the right tools it is possible to guide the process within narrow boundaries or, remaining true to the metaphor, put it on rails. Key benefits of a well-guided project are efficiency and rapid progress.  

Managing drug development is a complex undertaking. The activities of an individual functional domain or department are often so complex that it is difficult to marry one department's intricate schedule with those of a different functional domain. For example, the chemists and product formulators not only isolate the active substance and create a usable dosage form, but they also provide technical reports for the chemistry, manufacturing and controls (CMC) section of an investigational new drug (IND) submission and manufacture the investigational product (IP) in time to have it available for clinical trials.  

On the other hand, toxicologists should not start long-term and expensive carcinogenicity trials until there are positive clinical results. Then again, they should not wait too long or these studies will be on the critical path and hold up the new drug application (NDA)/common technical document (CTD) filing for FDA approval. Figure 1 shows a general overview of how the domains of discovery, CMC, nonclinical, clinical, and regulatory integrate their drug development activities.  

Figure 1. The 12-year roadmap to drug regulatory approval.			

When considering the unique knowledge in each of the five major domains of drug development, one quickly realizes that it takes a magician to coordinate the independent functional activities into a coherent and usable timeline. Yet, that is what good project managers are supposed to do: magic. 

Drug development is generally a slow process. Entire careers may be spent on just a few drug development programs. Resident departmental experts rarely have the decades of experience necessary to intrinsically know how their work product dovetails with the requirements of other functional areas. Good project managers are schedule coaches, and they understand how departmental plans integrate into the overall project plan. Departmental leads or representatives who participate in the project team negotiate, but they eventually accept the coach's prioritization and overall integration of each departmental plan into one project plan. 

A competent coach starts with a plan. A complete, detailed, and integrated project plan is the best place to begin when focusing the valuable energies of functional departments. The plan should be started early. A project plan should be visible to the entire company as soon as discovery has a viable compound/lead or when a licensing agreement is being considered for an external compound. 

This article describes a fully integrated template of a project plan used to accelerate NDA-related activities, milestones, and deliverables for a New Chemical Entity (NCE) during an estimated 12-year development cycle. The project template utilizes a regulatory backbone based on the IND and CTD tables of content. 

The NCE project template covers the broadest possible array of development milestones. It was built in 13 modular sections, utilizing the five functional domains of Discovery, CMC, Nonclinical, Clinical, and Regulatory. The complete plan contains approximately 8400 tasks. The modularity enables rapid customization for varying projects. The 13 plan modules are: pharmacology discovery and efficacy proof of concept; project initiation; CMC development; nonclinical development; IND preparation; clinical development; CTD preparation; 120-day safety update; final labeling safety update; FDA approval and launch preparation; IND annual reports; CTD periodic updates; and product development and strategy. 

The NCE model assumes the compound to be a chemically synthesized IP. From a project planning perspective, biologicals, new indications (sNDA), and generics (ANDA) have differences that would justify a modified template, particularly in the Nonclinical module and commonly in the CMC and Clinical modules. Templates of those variants have also been developed; however, for simplicity, only an NCE example is illustrated. The putative disease for this template is one that can be studied for efficacy in a 60-day "on-study" window in Phase II and III studies. The estimated times used in the NCE project template are customized in case different assumptions need to be made by the project team, or if actual protocols become available with final estimates. 

Utilizing the Microsoft (MS) Project®  software application, the template takes full advantage of the software's native functionality to properly organize, track, and present a complicated list of operational tasks and timelines. The project timeline self-adjusts based on the project's actual progress. 

The project plan may be used in many different roles. It serves as a planning tool. It can be a benchmark of company or team performance. It can provide a template that acts as an expert system for how things should be done. It creates a forum for project team member interaction and communication. It may even provide a means for controlling development costs. 

There are always those in an R&D organization who resist being held to a plan. "My work is too dependent on factors outside my control" is a common perspective. Behavioral studies show that productivity dramatically improves if there is some expectation of a deadline.

  Even with the creativity required within a function such as discovery, the department can benefit from having a rough guideline of how long it is allowed to experiment with a molecule before the company expects to have a lead compound to transition into nonclinical and CMC development. It is difficult to operate efficiently in an environment where there are no expectations. 

Executives make better decisions when presented with realistic expectations. A project manager who begins a plan based on a complete and fully integrated template can help position senior management's expectations to minimize surprises. 

A 12-year development timeline is far too unwieldy for even the best manager to remember in detail. While creating a customized project plan de novo might be one option, it is more reasonable to use the knowledge embedded in a project plan template. For any IP, the project manager uses whatever information is available from the functional domains, blends it into the project plan template, and modifies it as required. This method provides a far better visualization of what might be required during the multiyear development process for an NCE. 

A project plan based on a fully integrated template can position senior management's expectations to minimize surprises.

Applied Clinical Trials-08-01-2006

Impact of IBCTs on Clinical Trial Efficiency

Medical Device Development: U.S. and EU Differences

No Plain English for UK Subjects

Web 2.0 Revolution: Power to the People

ADR Reporting: A Clearer Explanation

Drug Development on Rails

Collaborating for CT Systems Validation

Two Years Later: The Impact of the EU Directive

Grasping the FDA's PRO Guidance

FDA to Modernize BIMO Activities

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