The interest in exploiting the Internet and its associated technologies to revolutionize the conduct of clinical trials continues to be discussed at length in journals and at conferences.

 Although increasing numbers of clinical trials are being commissioned and performed as e-studies, the general take-up is still low when compared with traditional methods. Estimates suggest that approximately 5-10% of all clinical trial data are collected and managed currently as e-trials.

Figure 1. Standardized framework for the implementation and operation of an e-clinical trial.	

Key earlier, practical reasons given for not undertaking a study using e-clinical trial methods have been addressed and solved. Thus, e-trial-enabled software from various vendors is now readily available, and the regulatory issues, mainly concerned with subject confidentiality, have been addressed.

 Various authors and speakers have demonstrated that e-trials can bring value to a study.

 The improvements that may be seen are usually in speed (and availability) of data collection and collation, increased data accuracy (fewer clinical data queries), and benefit of the availability of the immediate communications infrastructure.	

Why, therefore, is the uptake of these approaches still so relatively low? A number of factors may be inhibiting a more rapid uptake. First, e-trials require a fundamentally different approach to both the design and procedural aspects of a study when compared with traditional methods. This is often organizationally difficult to achieve quickly, and the difficulty may be exacerbated if previous commitments to other technologies over, for example, a five-year cycle have been made. E-trials are often presented as too expensive because of the higher up-front costs associated with design and implementation. And the real or imagined risk of committing "my study" to these methods also suppresses uptake. An external factor of significance is that investigational sites may not have the will or the skill to use these methods, and sponsors are unwilling to invest in the extra training costs required.	

The very wide range of areas where e-approaches can add value often further complicates these issues. For example, the study design can benefit (by using sequential statistical designs), the research data collection can benefit (by  using an electronic case report form [e-CRF]), the management of study sites can benefit (with documents online, direct online monitor reporting), the drug supply chain can benefit (using online requests and batch confirmation), and subject medical monitoring can be improved (by earlier adverse event and laboratory data alerts). The value of using an e-trial approach can then easily be lost in the complexity of integrating so many specific areas where value can be added. Finally, it is now well understood that the introduction of new systems without parallel process changes will not guarantee operational improvement.	

This article presents a standardized model to help with reviewing in part or whole any function that could benefit from "e-ization." The key objectives of each element of the model are presented, together with a discussion of key practical factors that will lead to success in implementing and running the e-clinical trial.	

In order to enable any clinical trial function (whether it be a specific part, the whole trial, or the trial plus all the support functions) to benefit from e-ization, it is essential to have a common framework for developing, reviewing, and testing each required operational element or the system as a whole.				

Figure 1 presents such a standardized framework, one that can be used to review and develop an e-clinical trial. The model consists of seven top-level interacting elements:	

The first three elements represent the key implementation and support functions that an e-clinical trial requires, while the last four elements represent the e-trial project processes. For any project each element must be reviewed, put in place (if necessary), and its products and procedures validated. 	

In the figure, the links between the elements represent a requirement by one element for a product of another element. Links can be uni- or bidirectional. Orange lines show elements requiring products of the validated processes element; green lines show elements requiring products of human resources and qualified staff elements; blue lines show elements requiring products of design and build, production configuration, production processing, and close and archive elements; and purple lines show production processing elements requiring repeated use of those processes.		

Table 1  Involvement of different operational groups in e-clinical trial implementation and operations	

The model is of value in developing and operating e-clinical trials for the following reasons. First, it can be applied at the micro and macro levels without modification and used to support small or large projects. Second, the output from any element is a product (not a link between processes), and therefore does not require procedures to be explicitly stated. Procedures emerge from the requirement that one element in the framework requires a product from another element before it can proceed, and that the creation of the product must be controlled by procedures. Third, the model recognizes the need to provide properly project-qualified staff to the e-trial, and these staff must meet both basic qualification criteria and be available to work on the project. Thus, a box around all seven elements can represent either a department (responsible for implementing and running e-clinical trials), or a specific part of the trial, for example the collection of just the research data using an e-CRF. In each case, all seven elements apply and need to be addressed to meet the objectives of the exercise, although to different degrees in each case.	

The model also accommodates and easily assimilates other views of the e-trial processes and outcomes that a clinical trial requires. For example, the requirements demanded by computer systems validation, where other standardized models are available (examples include installation qualification [IQ], operational qualification [OQ], and production qualification [PQ]), immediately become part of one or more of the frameworks, elements.

 (In the case of Stokes's model, IQ and OQ become part of validated processes, and PQ becomes part of production configuration and production processing, respectively). Investment in other approaches is therefore maintained, and, it is hoped, enhanced.	

Unlike process-oriented methods, this method operates fundamentally with work products, not procedures. The links between elements represent a product requirement, not a process flow. For example, Figure 1 shows that before it can proceed, the production configuration element requires products from the design and build element (such as the online data collection system, which must be built before the production configuration element can be configured for a specific investigational site). Although the model does not demand any order to be stated, in practice an order naturally emerges. Thus, the last four elements of the above list represent the central operational or project process, which starts with design and build activities, whose products are used by the production configuration and production processing elements, which in turn provide the products required by the close and archive element. These elements therefore represent the core intent of the system (in this case, running an e-study). The other elements support this core set and, depending on the specific case, may be required to provide products to these four elements before they can begin any activity. The most critical is the validated processes element, which can be linked to all elements (because documented evidence is required to show all e-trial functions are operating as intended).		

TABLE 2  Key objectives and products of model elements	

In contrast, the human resources and qualified staff elements, representing the staffing requirements for the e-trial, do not have to be addressed at any particular time. The model clearly shows, however, that a failure to address them prior to the activating core element tasks will lead to problems with project resourcing, both in terms of availability and qualifications.	

The rest of this article uses these elements as the basis for identifying and discussing the factors for success when implementing and running an e-clinical trial. It discusses the key objectives and success factors from the perspective of a department initiative to set up and run its first e-clinical trial.	

For any e-trial, three general factors will always govern the overall success. These are that it is known how e-izing any component of the trial will benefit the overall outcome.				

it is known how e-izing any component of the trial will benefit the overall outcome.

it is understood who is doing what, and when they need to do it.

all of the tools (systems), training, and study configuration are completed and ready for use before being needed for the first time.

In a recent paper, Nickel presented the wide range of areas where e-izing can benefit the clinical trial.

 The range, which seems never-ending, includes the direct collection of the clinical research data via electronic data collection or e-CRF, Internet-enabled study clinical laboratories services, departmental support systems (such as pharmacy and drug supplies, trial monitoring and reporting, adverse event reporting, investigator portals and support systems, through-to-patient/subject identification and recruitment, and so on). In each case it can be argued that an advantage will be gained through e-ization, either in time or quality, or both. This does not, however, guarantee overall success.	

Two examples illustrate typical issues. First, if an automated-request, just-in-time-delivery drug supply system is triggered by a clinical research associate responding to a laboratory result on site during each visit, it is clear that the study will not gain significantly in time, even though the pharmacy may enjoy better quality. Second, if any e-ized component is mirroring (or duplicating) another system, then it may be necessary to confirm equivalence between the data in the two systems, an overhead that may be out of proportion to the value added. Thus, the key point for the project is to ensure that each e-ized component is really adding value to the clinical project, knowing where this occurs, and that it will not be compromised by a need to interact with other contributors to the project. Finally, it is a good idea to have available clearly defined and measurable methods to monitor success.	

Even with the advantages of the e-clinical trial clearly stated, understood, and measured, a successful outcome will not emerge if the staffing needs are not met when required. Unlike the traditional, paper-based study, where requests for activity and transfer of information can be, and often are, managed through a project manager orchestrating each departmental contribution, the e-clinical trial demands a service-oriented, "please-complete-the-defined-task-now," approach. This changes the project manager's role from one of orchestrating an ongoing activity, to one of preparing the players to respond-and thereafter monitoring that they undertook the tasks. Understanding who is involved with the e-trial from both the core and extended project team members is therefore critical to e-trial success. Having identified each role or required resource, one must also define clearly what that person is contributing and what he or she must be able to contribute. Planning must then ensure that all team members, both core and extended, understand the stages at which they have to be available to the e-trial.	

Table 1 illustrates a range of contributors to the e-clinical trial and their involvement over the course of delivering an e-trial project. Using the standardized framework developed earlier, it shows the involvement of a typical set of clinical trial operational groups in establishing and delivering a study. For each element the group with the primary responsibility for delivery is identified, together with those involved directly or indirectly in the delivery activities. What is immediately clear from the figure is the wide range of skills needed to deliver an e-clinical trial, and the varying levels of involvement of each group over the course of the study. It also illustrates how the primary responsibility for delivery of the e-trial products moves between different groups at different times and shows how the e-trial may have no "study champion." In the figure, no one is identified as having a primary project responsibility for delivering qualified human resources.	

The final general success factor for all e-clinical trials is to ensure that all the tools are available when they are first needed. Unlike traditional approaches, where subject recruitment is started before many key products are available, e-clinical trials must have all tools and systems available before the first subject's first visit (FSFV). Failure to achieve this simply means delay until all e-trial components are in place. It is helpful to separate clearly what is required to be in place to support any e-trial (the infrastructure requirements) from what is required to deliver the specific project. In terms of the framework described in Figure 1, this means that all validated processes (and the systems supporting them) must be in place before any design and build, production configuration, production processing, or close and archive activities occur. It may or may not mean that human resources or qualified staff are available, but as discussed above, failure to address the e-trials staffing requirement early will affect the ultimate outcome of the e-study.	

The general factors for success discussed above are not specific enough to help with the day-to-day tasks needed to implement and operate an e-clinical trial. With their wide-ranging implications over a large part of the organization, these general factors belong predominately to the senior owners of the e-trial project. Presented here are the major objectives of each element, together with a discussion of the factors that are central to the successful outcomes that need to be achieved.				

In the following sections, the example of a small- or medium-sized clinical operation needing to establish and run an e-clinical trial has been selected for discussion. Because of the wide range of operational and organizational methods used in our industry, the discussions may not always apply directly in a particular organization. However, the general principles should always be applicable.	

Table 2 presents the major e-trial objectives for each of the elements of our model. Each objective or product would be satisfied or created using documented standard operating procedures, some of which will be e-trial specific and some that will not be. An early practical exercise that can contribute significantly to the success of an e-trial project is to question of each element, "What products and/or objectives and what supporting procedures required to run an e-trial are currently not available?"	

 This element establishes the basis for running the e-trial. The key objectives are to establish the e-trial internal infrastructure (systems, software, procedures, and so on) to confirm that they are operating as required (computer systems validation, and so on) and regulatory requirements and guidelines are met. This element should also be able to present and define clearly the scope of the e-ization and determine or develop the metrics and other review tools against which the systems will be measured.	

E-clinical trials have the potential to extend both the range and complexity of the specific items that need to be addressed here. The range is extended by the requirement to assure compliance with general regulations (ICH Guideline for Good Clinical Practice [E6] and 21 CFR 312.62), while at the same time conforming to computer systems requirements (Guidance for Industry: Computer Systems Used in Clinical Trials) and electronic records regulations (21 CFR 11, Electronic Records and Signatures). In some jurisdictions it may also be necessary to adhere to data transfer or data privacy rules. The important key success point here is to know which regulations are relevant, to confirm that your e-trial systems conform, and to know how they are to be defended.	

It is critical during this stage to understand the general and study-specific training requirements that an e-trial brings. Leaving the identification and planning for training (not, however, the specific scheduling; this should be managed elsewhere) to later stages only compromises the availability of the all-important human resources later on.	

Finally, ensure your initiatives incorporate and define fallback positions for all activities. All e-trials rely on technologies that will fail sometime, somewhere. Ensure that where the e-application is supporting regulatory or subject safety issues (adverse events, for example), backup procedures are in place to respond nontechnically to the e-system failure, and nontechnical recovery procedures are in place to reestablish the e-system fully.	

 The primary purpose of the activities in this element is to identify and commit the human resources needed to run an e-clinical trial. Although most organizations manage this along departmental lines, this element does not necessarily represent a human resources (HR) department. HR can and should be involved, however. The primary internal goal here is to train staff in the basic e-trial skills and, if possible, to identify investigator sites sympathetic to e-trial methods and to confirm and/or train the staff in the general site e-trial requirements.	

A key to future success is ensuring that all participants, both within the core and extended e-trial project team, understand their roles and responsibilities, what will trigger their being on e-trial duty, and how and to whom to communicate that tasks are completed. Omitting these points leads to resources not being available, additional unplanned work for the project team, and potential development of processing backlogs. The immediacy of the information flow in e-trials can make it very hard to recover from this position, if it is allowed to develop.	

 The qualified staff element is designed to take the "ready for an e-trial" human resources and convert them into "ready for this e-trial." The key goals here are to first identify and then train staff in the specific skills (e-trial or otherwise) required by the study. This type of training is often mixed with basic skills training. You should take care to ensure that both are addressed satisfactorily.	

Attention to three areas will help considerably in minimizing subsequent issues. First, train all staff to recognize the difference between clinical and technical issues and omissions. Clinical issues can be presented as technical problems, and technical issues as clinical problems. Ensure that the project team can identify each and organize the correct response. Second, train investigator sites as close as possible to their site's FSFV. And third, ensure that sites understand the extended range of responsibilities that working with an e-trial brings, especially from the technical viewpoint (the protection of user names and passwords, for example).	

 E-trials rely on well-designed, well-built, and well-configured systems and software. In this element, all the study-specific tools and procedures must emerge, with the key goals being	

the analysis of requirements and e-trial specification development such as e-CRF, supplies logistics, and so on.

Articles

Feature Article

The interest in exploiting the Internet and its associated technologies to revolutionize the conduct of clinical trials continues to be discussed at length in journals and at conferences.1-4 Although increasing numbers of clinical trials are being commissioned and performed as e-studies, the general take-up is still low when compared with traditional methods. Estimates suggest that approximately 5-10% of all clinical trial data are collected and managed currently as e-trials.5

Planning and Running the e-Clinical Trial

Six years ago, our department of a large academic research center was having difficulty enrolling enough subjects in osteoporosis studies. We wanted to expand into a variety of trials and increase the number of participants. Despite our experience and expertise, our enrollments were down. We wondered if the pool of eligible participants was shrinking, if our competition was doing a better job than we were, or if we needed to modify our project management style.		

12 Tips for Community Presentations and Health Fairs	

Eight million women in the United States have osteoporosis,

 so we were confident that our target population existed. Other local investigators were conducting osteoporosis trials, and although we knew very little about how they were doing their studies, they did not appear to be immune to the same challenges we were experiencing. So, after a critical look at how our projects were managed during recruitment, we decided to modify our project management style.	

First, instead of one clinical research coordinator (CRC) handling all the tasks of a clinical trial from beginning to end, we adopted a team approach, beginning with how we conducted the telephone and study visit screenings. Over time, we evolved a recruitment team consisting of a CRC project manager, a dedicated recruiter, a CRC specialist in database management, the technical staff, and research assistants.	

With our staff reorganized in this way, we turned our attention to the problem of effective communication with our target audience. Were potential subjects aware we existed? What was their opinion of our research, and of research in general? How could we make them aware of study participation opportunities? What could be done to make the telephone ring? This article presents some of the lessons we learned in our efforts to improve our recruitment results.	

To effectively recruit subjects, you must understand your organization and identify its resources. This includes the mission, institutional regulations, available study personnel, collaborators, physical facilities, and budget.				

An effective recruitment plan will be based on the organization's identity and will project an image consistently reflecting this to the population. Make use of the image and relationship your organization has already built with the community by always using your logo, for example. When developing a recruitment plan for a particular study, consider how it will affect future recruitments, just as past recruitments are foundations for the current recruitment.	

In addition to understanding your own organization's identity, you'll need a thorough understanding of the intended study population. The questions will be similar for each recruitment. The answers, however, will vary, because every recruitment has a specific study population. What are the priorities of potential subjects? Where do they get information? How do they feel about research?		

Figure 1. Evolution of a newspaper advertisement. Top: The logo is absent. Also, the name of "Butch" is unnecessary, distracting, and confusing. It conjures up the image of a plaid-shirted truck driver, not necessarily someone the intended audience would feel comfortable calling to discuss "female issues." Middle: This is better, but what are "menasureeents?" Insist on reviewing the final proof of material produced by the newspaper's staff. Bottom: Now we're on the right track, with the logo and Web site included.				

In addition to the prospective study population, you need to understand the makeup of the whole community. What are their norms and mores? What do they already know about you? Community members such as physicians, nurse practitioners, physician assistants, and past participants are also potential participants and potential referral sources. 	

Understanding your community members' perspectives is as simple as asking and then listening. Advertising vendors and businesses spend a tremendous amount of effort and financial resources on surveys and focus groups in an attempt to understand consumers. For researchers, however, it is more realistic to communicate with current participants and network within the community to understand the intended study population. Speak to neighbors or to persons you meet at community or church activities or at local shopping centers. Any place people gather provides you with an opportunity to communicate and learn.	

Don't assume that your community understands your work. Although clinical research professionals are very familiar with the normal conduct of research studies, the public may have a misconception about, or mistrust of, the motives and goals of researchers. Remember that the relationship between the clinical research team and the participant is built on trust. Every member of the team, from the receptionist to the investigator, is responsible for maintaining the highest ethical standards and complying fully with regulatory standards. Additionally, everyone is, in effect, a goodwill ambassador.	

Understand and remove barriers to recruitment

When you know your organization, you may come to understand some of the barriers to recruitment experienced by your site. Barriers can include limited appointment times or a shortage of staff members to field telephone inquiries, leading to a critical lag in response time. Your site may be inaccessible, suffer from limited parking, or be in a department that is difficult to find once the participant has entered the building. Certain times of year, such as holidays, can make recruitment more difficult, and severe weather may affect appointments in some areas of the country. Talk to current participants and look at this from their perspective. Understanding what the barriers are is the first step to removing them.				

Short- and long-term goals will be based on the enrollment target and timeline established by the sponsor and investigator. Establish weekly and monthly goals for the number of incoming telephone calls, screen visits, qualifiers, and enrolled participants. Evaluate each category weekly and provide regular reports to the investigator. The sponsor or monitor will want a daily or weekly report on the screen visits and qualifiers.				

Your team will need a few tools to do their work.		

Figure 2. You can create appealing flyers like the ones at top left and middle using a page wizard in a basic desktop publishing program. Vary the look of the materials from study to study so that your audience is not confused. Devices such as the memorable telephone number in a bone-shaped font help catch readers' attention. Reminder postcards like the one at top right are useful. Tailor your materials to the audience's needs, like the flyer at left. Is your flyer appealing and culturally sensitive? Will you need materials in more than one language?				

 Visual affirmation of study progress keeps the entire team informed and focused, and promotes teamwork. Keep available a dry-erase board or wall chart for each study. For one of our osteoporosis studies, we had a progress chart in the shape of a bone that was colored in and dated weekly. Another chart had three columns for each of the "hurdles" the participants had to move through toward final qualification and enrollment. Use your imagination; just make sure that confidentiality is maintained and there is no identifying information about the participants.	

 The sponsor will be providing case report forms (CRFs), but sometimes we've had to develop worksheets such as the telephone contact sheet for source documentation. 	

We record each telephone contact on our telephone worksheet, which has space for noting the demographic information, appointment times, and outcome notes. The study-specific screening questions are listed on the back. We make these pages on colored copy paper so they're easy to find on the desk; the color ties into the study theme.	

Our screen visit folders usually contain a copy of the study consent, our registry form, the sponsor's screen visit worksheets, laboratory and procedure requisitions, and our internal billing sheet. The telephone call sheet for each person who passes the telephone screen is placed inside a preassembled screen folder for use when a study visit is scheduled. Call sheets for people who are not eligible are filed together and entered weekly into the recruitment database.	

Communication among your recruitment team members is facilitated by regular meetings, brainstorming sessions to work out problems, and email to keep everyone abreast of small changes that need to be implemented as soon as possible.				

Early in the process, have each team member read the consent form; it's an excellent way for everyone to have a general understanding of the study. Draft a telephone script and the screening visit procedures and review all steps with your team for everyone's input. Work with the team members who will be helping with calls. Encourage them to stick closely with the script. You are aiming for conversational calls, but it is important to remember your mission. Five to seven minutes is typical for our screening telephone calls.	

 Choose a nickname and theme for the study. We've used colors and simulated political campaigns. For one study, finding persons to fill the "B" stratum was challenging, so the buzzword became "Find the Bs." Pictures of bumblebees began to pop up everywhere. When we used the bone-shaped progress chart colored with blue marker, the buzzword became "Think blue." (This was problematic, because we like to bring in "theme" food, and there are few blue food items.)	

When recruitment is completed, our investigator gathers the project team members and hosts a luncheon. Then the team enjoys the afternoon off. I like to make award certificates or signs for the workspaces of team members as morale boosters.	

The development of a recruitment database may initially seem to require an excessive time investment, but the benefits in the areas of organization, reporting, and control are enormous. Your database will let you track not just the qualifiers, but also the screen failures and those deemed ineligible based on the telephone screening-vital information to have when you're analyzing recruitment problems.				

You can start with the same database for every study and modify it as necessary. The working recruitment database will help you identify where someone is in the recruitment loop, flag those who have requested no future contact, and create suppression lists when doing mass mailings. You do not want to recontact enrolled subjects, annoy people who have already asked not to be contacted, or rescreen people you've already found to be ineligible. The database from one study can be used to recruit subjects for a subsequent one, although many sponsors and institutions require subjects' permission before their demographic information can be entered into a permanent registry to be used for future studies.	

 After the first 50 telephone calls, you will not be able to remember anyone's status in the recruitment loop. A telephone screen sheet can be easily completed at the time of the telephone call and data entered on a weekly basis. Interested individuals receive a follow-up letter and a registry form they can use to give permission to enter their names into the permanent registry. Sponsor- and IRB-approved informational postcards are an inexpensive and easy way to inform selected database members of a new research study.	

At a minimum, be sure you capture information about the referral source, demographics, and the reason for ineligibility. A typical referral source may be a newspaper ad, friend, or health fair. Key demographic information includes first and last name, address, and daytime telephone number. The reason for telephone failure could be, for example, that the participant declined due to study length, had no desire to take medication, or was excluded because of protocol criteria. Again, be sure to specify which exclusion criteria, because this will help in assessing whether or not the target audience is hearing the message. If you are rejecting many women for the same concomitant medication, you might want to modify your informational flyer to say, "Women currently taking hormone replacement therapy will not be eligible."	

Other things to consider capturing include number of contact attempts, special needs, or red flags. If it takes more than five attempts to reach an individual, or if a person leaves messages such as, "Please call me after 9 p.m.," it is unlikely he or she will be available for study visits.  People who comment that they never take pills, or that they are perfect for the study because they have such an unusual medical history, need an explanation of what a research study consists of and its goals. Although these individuals are unlikely to qualify for the study, you still need to clarify and teach, treating them with the same respect and courtesy that would be shown to a qualifying participant. They may spread the word to friends or relatives who will qualify.	

In addition to your recruitment database, a project management database is useful for tracking appointment dates, advertising costs, and serious adverse events (SAEs).	

Once your team, tools, and database are in place, it's time to start publicizing your study.	

Conventional communication methods fall into two categories: public relations and medical marketing. Both communications methods have value for the clinical research coordinator.				

Public relations practice consists of building and maintaining relationships. Every organization practices public relations when interacting with the public. After all, the "public" includes people, other organizations, the media, and the organization's own employees. The public relations practitioner represents his or her organization to the public and conveys the attitudes of the public back to the organization.

 Thus, the CRC is a natural public relations practitioner.	

Marketing is the exchange between a person or organization with a product or service to offer and a person or organization that desires this product or service.

  In the case of a clinical trial, you are offering potential subjects the opportunity to enroll, which they may desire for any of a variety of reasons-to learn more about their own health, to fulfill an altruistic desire to help others, or because they enjoy the experience. 	

Learning some fundamental marketing principles will help you communicate with your audience of potential subjects, even though many marketing methods are not appropriate for research recruiting.	

You can learn public relations and marketing skills just as you learned phlebotomy and computer skills. You can take public relations and marketing courses at the local university. Reading textbooks or networking with professors is a more immediate but short-term solution. Your local bookstore sells many advertising books. You can also learn about public relations and marketing from your daily life. As consumers, we are constantly bombarded with advertising messages. Start critically evaluating what captures your attention, what you like, and what you do not like. Then start thinking in terms of what will capture the attention of your target audience. An ongoing, proactive search for new advertising information is a fact of life for the recruiter.

 Once you've learned something about public relations and marketing, you can apply those principles to clinical trial recruiting.	

 Consider the options available to you at no cost. Perhaps your institution has a public relations department. See if the staff will help by providing study recruitment advice, preparing a press release to inform the media, or finding networking avenues in the community.	

Tap into newsletters or electronic computer communications used in your institution. Inform the editors that regulatory guidelines prohibit editing the written material you submit to them.	

Sponsor- and IRB-approved flyers describing the study can be placed in your institution's clinics and in high-traffic areas such as waiting rooms and kiosks near the cafeteria. Be sure to check first with the appropriate administrators for these areas. In the community, permission may be granted for you to place your flyers on bulletin boards, at local physicians' and dentists' offices, or at small businesses.	

 You can use health education to structure community presentations and health fairs. Spread the word that you are available by contacting the employee health departments of local businesses and community organizations such as women's auxiliaries and church groups. These organizations are usually looking for speakers, which provides you with an opportunity for health promotion and explanations of how your investigator's research is finding answers for medical problems. The accompanying box, "12 Tips for Community Presentations and Health Fairs," explains how to get the most out of these events.	

 Medical marketing options include, but are not limited to, print advertising, radio and television spots, and direct mail marketing. If you decide, based on your understanding of the target audience for the study and the local media options, that you are ready to pay for some advertising, here are some general definitions and tips.	

 You can buy space in large cities' daily newspapers as well as small towns' weekly newspapers. First, make sure your audience reads the paper. Several times a year, city newspapers conduct surveys to understand their readership. They will provide you with extensive information about their readers' ages, income ranges, and the sections of the paper they read. Because we want to connect with mature women, I place our ads in our city paper's "Living" section, which typically has social news, features about food and entertainment, and puzzles and crosswords, or in the "Midlands" section, where the obituaries are listed.	

Each day's advertising costs are different. The mature population in our area of the country reads the paper almost every day, so we can easily run the ad on the least expensive days and not worry that we are missing our target audience. If I were recruiting young adults, I would advertise in the Sunday paper, which according to the newspaper's research, more young adults tend to read.	

Develop copy for the ad, sketch the desired layout, or produce the ad using a desktop publishing program. Obtain approvals from the sponsor and IRB. Then contact the newspaper's advertising representative. The ad rep has the experience and talent to produce an attractive ad, usually at no extra cost. Remember that he or she does not understand the regulatory and GCP guidelines we are working under, so consider that person's advice, but maintain control. Figure 1 shows the development of a newspaper ad.	

 Radio is an excellent medium for connecting with many potential participants. I contact the advertising sales person and ask about the demographics of the station's listeners. The station has ratings reports that document who is listening and when. Taking this information into consideration is important, but you must remember to talk to your audience. During a recruitment several years ago, I set up six radio spots on the number one talk radio station in our city at a cost of $100 per spot. We received no directly measurable response from our $600 investment. During a subsequent recruitment, I decided to try radio again, this time purchasing "remnant space," the off-peak time from 6 p.m. to 6 a.m., at a cost of $10 per spot. I had spoken with mature women, our intended audience, and found that although they did listen during the day, many of them listened to the radio at night until they fell asleep. Also, since we need less sleep as we mature, many women woke very early in the morning and chose to stay in bed, again listening to the radio. This time our $600 bought us 60 spots run over three weeks. After the first week, we began to get calls on our dedicated telephone line at 4:15 a.m.!	

 Television is certainly an advertising option; however, its expense in most cases is prohibitive for our budgets. Television stations charge for production as well as for the 15-, 30-, and 60-second spots. Consider producing a spot and sending it to the station as a public service announcement (PSA), which would be run at no charge to you, most likely late at night.	

ACT 101

Six years ago, our department of a large academic research center was having difficulty enrolling enough subjects in osteoporosis studies. We wanted to expand into a variety of trials and increase the number of participants. Despite our experience and expertise, our enrollments were down. We wondered if the pool of eligible participants was shrinking, if our competition was doing a better job than we were, or if we needed to modify our project management style.

Recruiting Strategies for Clinical Trials

Right up to the end of last year, leading figures in the European clinical trials community were voicing serious criticisms of the way that the European Unions 2001 directive is being implemented at the national level. The anxieties they were experiencing during 2002 about European clinical trials rules clearly will not be dispelled for quite some time in 2003, either.


A lack of harmony in European clinical trial regulations is hurting patients, warned no lesser figure than Professor Franoise Meunier, director-general of the European Organisation for Research and Treatment of Cancer (EORTC), as this issue of Applied Clinical Trials went to press. EU countries must harmonize their rules, she insisted when she spoke at a symposium on molecular targets and cancer therapeutics in Frankfurt, Germany, at the end of November.

 Meunier claims that international clinical trials within Europe are being hamstrung by red tape and disparate legal regulations in different countries. The lack of harmonization is jeopardizing progress in establishing state-of-the-art treatment strategies, denying patients the benefits of advances, and hampering Europes ability to compete with countries outside Europe, she insisted. The situationwhich the EU clinical trials rules were intended to resolveleads to pitfalls without improving patients safety or the quality of science and cancer care, she said.

Claiming to represent concerns felt by European oncologists and research scientists, Meunier went on to spell out that although the EUs 2001 directive was a step toward promoting the conduct of clinical trials and facilitating clinical research, it risked failing to establish the appropriate legal and regulatory framework to avoid duplication of research and cut the time needed to establish state-of-the-art treatments.

 Professor Meunier said that the directive leaves too many key topics open to interpretation by national authorities. These included ethical approval and protocol amendment procedures, regulations for reporting serious adverse events, informed consent documentation, requirements for drug labeling, costs of nonsponsored trials, translational research issues such as exchange of tumor materials and tissue research, and insurance requirements by ethics committees.

As a consequence, she said, We see too many drifts in documents drawn up by nonmedically qualified people who tend to adapt sometimes conflicting directives and national requirements. Subjects should be offered the chance to join a clinical trial with comprehensive yet pragmatic and understandable information, and countries need to have clear rules and regulations in common if research is not to be seriously hampered by bureaucracy and misinformation, said Meunier.

Despite the original goal of the directive to facilitate clinical research in Europe, the regulatory hurdles and approval process may persist. It remains to be seen whether the directive will actually decrease the high level of complexity faced by investigators and promoters of research, she said.


The European Forum for Good Clinical Practice (EFGCP) has also continued to marshal its arguments. In a new position paper on the EUs draft GCP implementing texts, it warns that certain requirements the EU and its member states are imposing are excessive and may actually reduce the number of clinical trials placed in the European Union.

The EFGCP is not entirely negative in its approach. It says that:


overall, the set of implementing texts proposed represents a considerable contribution to GCP in the European Union, and through the EU, to countries influenced by EU legislation, which will be able to borrow regulatory texts of high quality. It could turn the EU into a more homogenous regulatory zone for conducting high-quality clinical trials. It fills the regulatory deficit which the EU has had for many years compared to the USA, and thus adds credibility to the outstanding clinical work produced in general in the EU. And it offers the European volunteer and patient participating in clinical trials one of the best protections in the world.

 But the EFGCP complaints are very specific. The documentation required in the EU for starting a clinical trial will be the most voluminous in the world, it says, adding that this is in part because redundant information is required.

Sponsors will have to generate new regulatory documents, the EFGCP points out: the investigational medicinal product dossier (IMPD), a form for each ethics committee, and a form for each member state. But most information to be submitted in the application forms for approval from ethics committees and authorities is redundant, and already available in the protocol and the investigators brochure. The protocol contains a synopsis, and yet summaries of the protocol are required. And a full IMPD will contain much more information than an investigators brochure, so the shorter timelines that the new EU rules envisage for ethics review will be undone by the longer preparatory work for sponsors upstream.

Regrettably, says the EFGCP, information which is already in the hands of the member states will need to be provided by the sponsorincluding the summary of product characteristics of a reference product, all information about reference products, and the decision authorities have granted.

Not only are sponsors going to be required to provide redundant information, they will also have to provide irrelevant information, says the EFGCP. The information required about the number of subjects to be enrolled at each site and the sex ratio is notoriously difficult and so imprecise that the data is already obsolete and irrelevant when the first subject enters the study.

 The EFGCP also lists a string of other equally specific criticisms of the draft texts. The system proposed does not sufficiently protect the sponsors intellectual property, because the possibility of violating confidentiality is very high, with duly appointed experts from member states having access to the proposed European clinical trial database. It introduces risks of delays and inconsistent pan-European study conduct by requiring new authorizations for amendments to studies. More information sharing is imposed on the sponsor, with continuous updating of project management information and greater circulation of safety information. And new, near-impossible responsibilities are imposed on the sponsor, with an obligation to make a declaration that the clinical trial will be performed in accordance with GCP.

 This column has already mentioned some of the European concerns emerging in this area (see Applied Clinical Trials, October 2002). It offered some highlights from an EFGCP conference in September on the subject. Since then, the EFGCP has formalized its conference conclusions, which include some tough talking. In its conference report, it says:


The imposition of administrative and bureaucratic hurdles that impede the realisation of these core values will undermine European health research and healthcare. It is critical that all of the implementing texts are streamlined, systematically related to one another, procedurally and terminologically related to one another, and firmly in agreement with todays international standards for ethics and GCP.

That September conference allowed the EFGCP to articulate a finely tuned expression of optimistic expectation over how the EU texts should be framed. The report ran: 


 Expediency and clarity can be achieved in the practical framework created by the implementing texts if internationally developed and recognised standards, to which the EU institutions contributed, are referenced and not altered in their interpretation without demonstrable reason. In particular, the Declaration of Helsinki and the International Conference on Harmonization guidance texts provide fundamental references and commitments for the vast majority of EU sponsors and researchers involved in the development of medicines. Altering or undermining these commitments without clearly stated reasons will result in conflict, confusion, and inconsistency in applying ethical and scientific principles to European health research, threatening the integrity of protections for human subjects. The EFGCP and the participants in the Forum Discussion considered that no contradiction need exist between these commitments, the Directive, and the achievement of this expediency and clarity in the final implementing texts.

 No changes were made to the EU texts to satisfy the EFGCPs elegantly phrased aspirations. So now that organization has written to the senior EU officials most closely involved in the legislationErkki Liikanen (European Commissioner for Enterprise and Information Society), Philippe Busquin (European Commissioner for Science, Research and Development), and David Byrne (European Commissioner for Health and Consumer Protection).

EFGCP has not minced words this time, making clear that it has serious concerns regarding the potential addition of cumulative hurdles to research that provide neither clear add-on ethical or scientific value, nor demonstrated benefit to the patient or the public. The opposite sometimes appeared to be the case, says the EFGCP. And in straightforward language hardly habitual in the normally placid world of clinical trials in Europe, that group hammers its points home without ambiguity. It says the draft implementing texts: 


will have a dramatic and prohibitive effect on the prospect for European research needed to address todays, as well as future, health challenges for the European citizen. Should the texts be adopted in a form similar to what is being proposed, serious and unnecessary impediments will arise.

 At risk are the development of orphan medicines, cooperative research within the EU and beyond, and the international competitiveness of the entire European pharmaceutical industry. The EFGCP suggests that the stakes are high enough to put into question the future of all health research in Europe.

The original EU intention was to create a research environment in Europe in the interest of improved public healththis will be seriously curtailed if the Commissions responsibilities for producing guidance documents do not achieve an adequate European framework, says the EFGCPwhich claims to represent the point of view of leading stakeholders in European health research from the public and private sectors, members of competent authorities, ethics committee representatives, hospitals, patients, researchers, and others.


The deadline for EU member states to bring in their national rules is May 2003, and the new system is due to start functioning fully in May 2004. The debate is likely, therefore, to be echoing across Brussels for many months yet.


1. Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001 on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use. 

 L121, 3444. (1 May 2001, also available at pharmacos.eudra.org/F2/eudralex/vol-1/new_v1/dir2001-20_en.pdf).

SIDEBAR: Background to the clinical trials conflict


The European Union is proposing a number of implementing texts, providing detailed guidance on specific areas of GCP under the 2001 Directive. The implementing texts are intended to guide EU member states in creating their own national legislation to put the EU rules into effect.

 The usual EU system leaves detailed implementation of EU rules to national legislative systems; however, if too much flexibility or margin for maneuver is left to the member states, the initial harmonizing objective of an EU rule may be frustrated. That is the principal complaint of the European clinical trials communitya fragmented EU context for clinical trials has been only marginally improved by the 2001 directive, and what little improvement it brought is likely to be vitiated by discordant national implementation.

 The texts cover detailed issues such as a European database of suspected, unexpected serious adverse reactions; application formats and documentation for clinical trial authorizations from the authorities; for ethics committee opinionscollection, verification, and presentation of adverse reaction reports arising from clinical trials; good manufacturing practice for medicines used in clinical trials; import of investigational products; trial master file and archiving; and qualifications of inspectors of clinical trials. The latest published drafts of the implementing texts may be seen at pharmacos.eudra.org/F2/pharmacos/dir200120ec.htm.

 About 50006000 clinical trials are set up in the EU every year by the pharmaceutical industry, and 50006000 more clinical trials are set up by other sponsors (physicians, academia, nongovernmental organizations, and public health authorities). In the industry-sponsored sector, about 500,000 subjects and healthy volunteers are enrolled in the EU each year.

 The cost of these clinical trials is estimated at E5 billion per year, including grants to investigators, salaries, and operating costs of clinical research departments in the pharmaceutical industry and contract research organizations, costs of analytical and clinical laboratories, drug packaging facilities, courier companies, telecommunications, transportation, ethics committees, printers, and so on.

The European clinical trials community estimates that the problems introduced by these draft texts could increase the cost of clinical trials by 30%.            

View from Brussels

European organizations express their concerns over the implications of the EU guidances issued in response to the 2001 directive.

More Trouble Over EU Clinical Trials Rules

Recent deaths of human subjects at leading medical research facilities and the consequent major lawsuits leveled against those facilities have brought the current consent process under attack. Human subject advocacy groups, federal institutions, trial attorneys, and medical ethiciststo name a few of the interested groupshave all called for an improved consent process.

 Such a process must fully educate subjects about a clinical trial protocol and the trials purpose, risks, and expected results. The financial backers of the trial and the possible financial beneficiaries must be made known, and potential conflicts of interest must be disclosed. The informed consent of the future will verify that the subject truly understands these concepts, and that all concerns have been resolved prior to consent being given. This is the ideal of informed consent that the clinical trials industry seeks and, for its own protection, must soon adopt.

New technologies, such as multimedia presentations, aim to rectify the deficiencies of the current consent process. These presentations educate the subject through a variety of teaching techniquesnarration, illustrations, photos, text, and animationsthat now seem commonplace in our television-based society. More than a quixotic hope for the future, enhanced informed consent technology has already been implemented in several leading research centers. These multimedia technologies claim to deliver benefits to both the investigative team and the subject, and may soon prove to be a revolutionizing force in the consent process.


Several factors are hampering current efforts to provide research subjects with a comprehensive consent experience. A few of these factors include: 

New technologies allow prospective subjects to absorb information about a trial at each individual?s pace.

Multimedia Delivery Can Enhance the Consent Process

Believe it or not, something very, very hot has been incubating in the software and technology world. This new trend may have a major impact on the way we do business and manage data. Despite the tech wreck of the last two years, software developers have been hard at work, fleshing out a new concept of technology integration known as Web services. We can understand more about Web services by considering the difference between the design and assembly of a car and a computer!


Cars are designed and assembled in a mostly custom fashionevery moving and structural part has been individually designed to fit with every other part. The car may have one major function, driving, but it has many minor ones, such as raising and lowering the windows, playing the radio, and heating the passengers. Sure, some standard parts are required, such as spark plugs and oil filters. But each particular car requires specific-model partsany others may not function properly, or may damage the car. Although mass produced, most pieces on the modern car cannot be interchanged from model to model, and very little can be interchanged between different car manufacturers.

The modern personal computer has a completely different design and assembly. The PC is mostly assembled from a set of standard components. Starting with the motherboard, a PC can be assembled by plugging in a power supply, fan, hard drive, floppy disk, CD-ROM, Ethernet card, memory boards, USB ports, and more. Any of these components can be selected from a wide variety of different manufacturers. Any CD-ROM drive that meets the required specifications will be of a particular length, height, and width to fill the slot on any computer chassis. It will read standard CD-ROMs and will output data using a particular communication protocol. The PC can therefore be assembled from a limitless number of different components. Furthermore, the PC is extensiblemore of some components can be added, and new components can be added when they are developed. For example, a Compact Flash (CF) reader used for reading photo files from digital cameras can be added to PCs that were assembled long before the CF reader was developed. The reader can plug into the USB port and a software driver can be loaded that communicates with the CF reader and accepts the data.

The interfaces in a PC are standards-based, specific, and dont change from version to version. Regardless of the manufacturer, the various components work by plug and play.


How does our analogy relate to software and Web services? In the past, we created software much as we built a car. In fact, we used some of the same words to describe some parts of the product (and I dont mean Windows!). Lets think in terms of clinical trial data management software. We often describe the core database of such software as the database engineit is the software that drives the car. However, an engine alone is pretty useless without the rest of the car. A car also needs a chassis to hold the engine, a frame for safety, a body for comfort, and many, many controls to interact with the engine and with the various other components. 

Similarly, the database engine needs a user interface to interact with it as well as security components, various functional controls and components that interact with the database engine, and a reporting module (not unlike the speedometer and dashboard). Each component works smoothly with the others because they were designed and assembled that way.

The design of traditional software includes proprietary interfaces whenever data are passed from one software program to another. The interface has been carefully hand designed and tested. It is specific not only for particular software, but often for a specific version of each software program. Whenever a new version of either software is installed, it is necessary to completely rewire any connections of the software to other programs. Finally, any connections outside the walls of a particular companyto partners and collaboratorswill require a special kind of hard wiring, with a great deal of built- in security.

Now, contemplate a clinical trial data management system of the future that is designed less like a car, and more like a PC. Each component of the system (say for example, electronic data capture, coding, reporting, and adverse event reporting) is designed to meet an input and output specification for data and metadata. The exact design is not fixed, just the input and output specifications. As long as it meets the specification, each software component can be modified, have functionality added, or even be substituted by another productwith minimal disruption to the overall system.

This is the kernel of the vision of Web services. Web services is a very popular buzz phrase in technology that describes developing an approach to the ways that business software communicate with one another. Web services have many different aspects and can therefore be confusing to the uninitiated. Put simply, Web services utilize Internet standards based on the eXtensible Markup Language  (XML) to connect unrelated software programs or data sources. In the most simplistic sense, Web services provides the plug and play environment for connecting software programs together so that they work seamlessly, without intense data manipulation and programming. In a more advanced implementation, Web services provides a framework in which a computer program can seek out a data source on the Internet, connect to the source, and request and receive the dataall without a single human intervention. How is this possible? I will explain and provide some interesting examples.


The core of Web services is the XML language. XML has become a standard in technology and is the basis for the evolving clinical data standards effort, CDISC (Clinical Data Interchange Standards Committee). XML allows the tagging of information content without regard to presentation of the data. This is exactly the opposite of HTMLthe lingua franca of Web pages. HTML tags the presentation of the data, without regard to content. An example of HTML might be:
<b>This is bold</b> and <i>this is italic.</i>

 A Web browser interprets the information in brackets and displays the Web page in the appropriate form:

XML will tag content in a similar fashion:
<?xml version=1.0?><price>	<europe>		<retail>850</retail>		<wholesale>450</wholesale>		<units>E</units>	</europe>	<unitedstates>		<retail>750</retail>		<wholesale>399</wholesale>		<units>$</units>	</unitedstates></price>

An XML query of this information would return $750 if the requester wanted the U.S. full price and E450 if the requester wanted the discount price in Europe. This data can then be displayed on a Web page, entered into a database, or used in a software calculation. The XML tags categorized the data so that its content could be understood and used.

XML is a very powerful language for exchange of any type of data. If two software programs can each understand the particular dialect of XML being exchanged, they can seamlessly work together. This is the underlying principle of Web services.


The first type of Web services is what I will call business-to-business Web services, which allow programmers to build a connection between two software programs without major modifications to either program. The developers create a middleware program that takes requests for data from the first program and converts them into a form of XML that can be transported over the Internet to a second program. The request is transported in simple text, using HTTPthe same protocol that Web pages use. 

The most common transport protocol for the XML in HTTP is known as the SOAP (Simple Object Access Protocol). Since SOAP uses HTTP, it can easily pass through firewalls, just like a Web page, with essentially no security risk. A second middleware program associated with program 2 receives the requests from program 1, communicates them to program 2, takes the response from program 2, converts the response to XML and sends it back to program 1 where the middleware will once again convert the information into a form useful for program 

Although it may sound complex, this mechanism has a number of important advantages. First of all, the two communicating programs are completely independent of one another. Since the XML transport language is completely platform independent, similarities in operating systems or architectures are not required. One program can operate on Windows XP and the other program on Linux.

Secondly, the underlying programs can be modified and new versions installed or even replaced wholesale with no consequences as long as the underlying connection to the middleware stays the same. Finally, the original software programs can be located across the world from one another, each protected by a firewall. In fact, the underlying programs 1 and 2 dont even need to be physically located anywhere near the middleware. Thus, the security of any underlying data or software is preserved. All the middleware needs to know is the structure of the data request (GiveMeDiscountPriceUS) and the structure of the response (HereIsDiscountPriceUS).

This type of Web service is being used by many companies to connect internal software and to connect to business partners. An article in the 9 December 2002 Wall Street Journal discusses how JetBlue Airways is using Web services to provide pilots automatic updates to their instruction books from anywhere in the world. Instead of carrying a large notebook where they rip out outdated pages and replace them with new ones, this is done automatically by connecting to the Internet and making a request of a Web service. The updates are automatically downloaded and inserted into the electronic manuals. No more paper manuals. The company is planning on distributing flight information to pilots this way, and linking up to their parts manufacturers and fuel suppliers.

It isnt hard to see how this concept could be deployed in clinical trial systemslinking up data management systems with EDC systems, financial systems, clinical trial management systems, and clinical supply systems. A major advantage to this approach would be the substitution of any of these systems with another without the need to engineer or validate the various interactions of the systems.


Web services goes well beyond business-to-business application. A second type of Web services, which I will call broadcast Web services, is the place where Web services is getting the most attention from the media and computer community. In this model, a database owner or software developer creates a middleware interface to their data and advertises it on public or private lists of Web services, called UDDI (Universal Description, Discovery, and Integration) servers. The UDDI server acts like the phone bookthe white pages, yellow pages, and green pages combined. A company with a new Web service would advertise the type of service available, and the location and methodology for querying the service. In theory, anyone can go to the UDDI, search for a type of service, and build a simple tool to access the data. More importantly, a middleware program should be able to automatically search UDDIs and configure itself to receive the data without human intervention.

Excellent examples of these types of broadcast services already have been developed. Microsoft, SAP, and IBM all have UDDI servers available. There are a number of noncommercial UDDI servers as well (see www.xmethods.com, for example). Some broadcast Web services may charge a fee per transaction, but others are free. On Xmethods UDDI you will find examples of Web services that include airline scheduling, package delivery tracking, weather reporting, currency exchange, and translations.Google has opened up its search engine as a Web service, and several companies have built alternative search engines on this data. The results are amazingtry www.staggernation.com/ gawsh/ or www.touchgraph.com/ TGGoogleBrowser.html/ for a fascinating look at how Google data can be reinterpreted. Although these may seem trivial, they are the earliest examples of a coming revolution in the way that we build software.

Imagine a future concomitant medication Web service. A clinical trial safety software program might automatically seek out coding for a concomitant medication by consulting a UDDI directory for coding programs. The UDDI would specify the location of the coding Web service and the communication interface for requesting the service. Many such coding Web services might exist, distinguished perhaps by cost per transaction, specialty area, nationality, or other criteria. The appropriate UDDI would be chosen automatically, a request made, processed, and returned with the conmed coded without any human intervention.

Web services may sound a lot like the old standards storyone that CDISC is making notable strides in surmounting. Certainly, clinical data standards will play a role in clinical trial-related Web services, but only as the vernacular of XML that is being used. In fact, the concept for Web services has been around for years. What is new is that Web services is rapidly being widely implemented. The Web services story is about much more than data standards. Web services is the structure and process that will allow true interoperability and seamless integration of the entire landscape of clinical trial software.            

Technology Viewpoint

Web services and the concept of technology integration are hot new trends that may have a major impact on the way we do business and manage data.

There Is Something New Under the Sun

Republicans gained control of both the Senate and House in November in part by promising to provide prescription drug coverage for 40 million Medicare beneficiaries. President George W. Bush and GOP Congressional leaders now are under pressure to fulfill the pledge.

They seek a program that is relatively low in cost and administered by private insurers and pharmacy benefit managers (PBMs) instead of the federal government, an approach that pharma manufacturers support.

The process of crafting this very costly program, however, will stimulate efforts to rein in pharmaceutical prices, which could undermine incentives for developing new medical therapies. Sponsors already are filing fewer new drug applications (NDAs) with the Food and Drug Administration (FDA); scientific challenges, regulatory requirements, and uncertainty about future reimbursement policies could undermine future research and development programs.


Last year, Congress approved bioterrorism and user fee legislation that increased resources for FDA and other government public health agencies (see sidebar), but left most health policy legislation on the table. This gives the legislators a full health care agenda to address this year.

 Former vice president Al Gore is leading efforts to make the plight of the uninsured a central policy issue for Democrats. While Gore calls for expansion in federal and state health care programs, the Republicans seek to increase tax credits to help consumers purchase health insurance.

 Physicians have made malpractice and tort reform their top legislative issue, creating an opportunity for pharmaceutical companies to seek limits on damages in lawsuits claiming injury from drugs or vaccines. Last year the House passed a bill setting caps on malpractice damage awards, but it died in the Senate. Now there will be Senate hearings on the issue, but any kind of liability reform faces a very tough fight. In the recent debate over legislation establishing the Department of Homeland Security, Democrats almost killed GOP-backed provisions expanding liability protections for vaccine manufacturers, and the measure still may be modified.

 The biomedical research community believes that Republicans will maintain strong support for basic research, but budget squabbles already have delayed promised funding increases. Research funding is likely to become tangled in efforts by conservatives to push through legislation banning human reproductive cloning that also kills stem cell research. Moderates will work to craft a bill that limits only undesirable cloning but allows somatic cell nuclear transfer research on embryos to continue.

 Congress dropped efforts last year to strengthen protections for participants in biomedical research studies but promised to revisit the issue this year. Hearings are slated to address informed consent procedures and researcher conflicts of interest, but legislation may remain on the back burner unless new scandals erupt.

 Senate Republicans are expected to begin the debate with last years compromise bipartisan bill. A prime sponsor is Senator Charles Grassley (Republican, Iowa), who now will chair the Senate Finance Committee that is responsible for Medicare spending. The bill subsidizes insurers and PBMs that offer pharmacy plans within set parameters. Even the modest GOP plan will be costly, encouraging providers to use formularies, generic drug substitution, and other policies to limit program expenditures.

 Republican efforts to gain bipartisan support for a Medicare benefit package are likely to encourage changes in policies governing innovator patents and access to generic drugs. The broad generic reform bill that was approved by the Senate in 2002 is not likely to be reconsidered, but Senator Orrin Hatch (Republican, Utah), who once again chairs the Senate Judiciary Committee, is interested in a moderate proposal that codifies some of the regulatory changes recently proposed by FDA.


Restraints on drug reimbursement and patent limits, however, carry the risk of curbing incentives for pharma companies to make the increasingly large investment in R&D required to develop new therapies. Such policies may aggravate an apparent decline in the number of new drugs and new molecular entities (NMEs) approved by FDA in recent years, with similar trends apparent in the European Union.

Some analysts maintain that the pharmaceutical R&D pipeline remains robust, but acknowledge that fewer new products are coming to market. In the mid-1990s, FDA approved more than 120 new drug applications a year, including a record 53 NMEs in 1996. Last year FDA approved only 66 NDAs and 24 NMEs, and 2002 numbers looked even bleaker last fall. Similarly, manufacturers are seeking priority approval status for only a handful of applications, a sign that fewer new therapies warrant regulatory treatment as breakthrough products.

These developments are prompting industry and policy makers to examine what factors may be slowing development and market approval of new drugs. Pharmaceutical and biotech companies point out that they continue to invest huge sums in R&D, but that the payoff has been curbed by regulatory demands and scientific setbacks. Curbs on reimbursement for me-too drugs put more pressure on companies to explore new therapeutic categories, which is more costly and time-consuming.


A key issue is to what extent FDA regulatory policies aggravate these trends. While agency officials insist that they cant approve applications if companies dont file them, sponsors complain that FDA now demands more preclinical and clinical data in NDAs, particularly for highly innovative products. Consequently, companies now run more preclinical screening tests to detect liver toxicity and potential side effects. They also underwrite larger Phase 3 trials to obtain more safety data. Not only do such procedures boost research costs, but the added information also may lead a manufacturer to halt a development program based on problematic early data. Records show that manufacturers have nearly canceled some development programs that eventually produced major blockbusters.

Sponsors believe that increased testing requirements and an apparent slowdown in FDA application review times may be a sign that the agency has become more cautious about approving new products without extensive safety data. This may stem from stiff criticism over several high-profile drug withdrawals over the past five years, some involving patient fatalities.

Agency officials maintain that numbers indicating longer review times are misleading. With fewer NDAs coming into the agency, a few problematic applications can raise overall review-time statistics. The agency believes that added funding under its third new user fee program will address some regulatory difficulties and improve review operations. FDA also is making important changes in its regulatory policies, as seen in recent proposals to overhaul good manufacturing practices (GMP) standards and to consolidate regulation of certain biotech therapies with conventional drugs in the same therapeutic categories.


Most important, FDA now has a new commissioner to manage these new initiatives after two years without a permanent leader. Mark McClellan has been mapping out his agenda, which emphasizes the need to speed safe medicines to market, to accelerate access to generic drugs, to update drug manufacturing standards, to retain FDA scientists, and to reduce medical errors. McClellan wants to set standards for bar coding drug packages to enhance the safe use of medical products. And he acknowledges the importance of addressing regulatory issues on the international front.

Providing agency systems able to review new drugs, devices, and biological treatments as quickly and as efficiently as possible is at the top of the list and may require a reexamination and an updating of the way FDA does its job, the new commissioner told FDA and government officials at a ceremonial groundbreaking for new FDA facilities in the Maryland suburbs of Washington, D.C., on 15 November. FDA is not here just to check boxes on an inspection list, he said, but to implement the best possible approaches to reduce risks to the public health.

McClellan used this opportunity to emphasize the importance of retaining talented scientists for FDA to fulfill its critical missions. The exodus of top professionals from FDAs workforce could accelerate with the shift of key staffers from the Center for Biologics Evaluation and Research (CBER) to the Center for Drug Evaluation and Research (CDER). Jay Siegel, director of CBERs Office of Therapeutics Research and Review, already has left the agency, and other biologics experts are expected to follow suit.

McClellan aims to halt departures by establishing a work environment that encourages creativity, efficiency, and superior performance. In addition to building a new campus to eventually house most FDA offices, the new commissioner supports added educational opportunities and financial incentives for staffers, including salary increases linked to performance and retention allowances for physicians. He also indicated some support for FDA professionals to be involved in research activities relevant to fulfilling FDAs mission, touching on the controversial issue of how much research activity is appropriate for FDA staffers. Effective regulation of emerging technologies such as cellular and gene therapies requires a close connection to the latest scientific developments, McClellan said. Maintaining FDAs capacity to oversee new biomedical technologies on the horizon will provide an early challenge for the new commissioner.


Kathryn Zoon, director of FDAs Center for Biologics Evaluation and Research for more than 10 years, decided to call it quits following the decision by agency leaders to shift oversight for most biotech therapeutics to the drug center. Zoon will return to the National Institutes of Health where she was involved in interferon research before moving to FDA in 1980; now she will be a top official at the National Cancer Institute, which she describes as a more research-oriented job. Zoon headed CBER during a time of intense change in the biotech industry and in the development of biotech products and manufacturing technology. She is highly regarded by FDA staffers, and her departure reflects considerable dismay among CBER rank and file over pending organizational changes.

FDA announced that Jesse Goodman, CBER deputy director for medicine, will replace Zoon as CBER director.

SIDEBAR: Congress backs device user fees and orphan drugs


Although Congress left most health care issues on hold last year, the legislators did adopt some measures that increase support for FDA regulation of medical devices and for development of orphan drugs. The legislators boosted funding for FDAs orphan drug program and, in a separate bill, formally established an Office of Rare Diseases at the National Institutes of Health.

 Congress also approved a long-debated user fee program for medical devices that authorizes FDA to collect fees from manufacturers filing market applications. Similar to the user fee program for pharmaceuticals and biotech therapies, FDAs Center for Devices and Radiological Health (CDRH) has to meet performance goals for reviewing applications and other activities. Congress is supposed to ante up an extra $15 million each year to support speedier review activities plus increased postmarket surveillance.

An important provision creates an Office of Combination Products in FDAs commissioners office, replacing a smaller group handling this issue. Device makers hope this will focus top agency attention on decisions about whether FDA should regulate a combination product as a drug, biologic, or device and bring about a shift in oversight of certain in vitro diagnostics to CDRH from CBER.            

View from Washington

Congressional efforts to establish a Medicare pharmacy benefit will affect R&D, and a new FDA commissioner promises change.

Applied Clinical Trials-01-01-2003

Planning and Running the e-Clinical Trial

Recruiting Strategies for Clinical Trials

More Trouble Over EU Clinical Trials Rules

Multimedia Delivery Can Enhance the Consent Process

There Is Something New Under the Sun

Pharmaceutical Coverage and Innovation Dominate Policy Agenda

The Time for Resolve

Recruiting Strategies for Clinical Trials