The problem of clinical trials generating mountains of paperwork is legendary. Stories of semi-tractor-trailer trucks pulling up to FDA-certified warehouses to unload literally tons of paper forms containing clinical trial data are no exaggeration. Consequently, the FDA has published white papers explaining and endorsing a concept called eSourcing: capturing clinical data electronically at the "source"—patient diaries and case report forms (CRFs). Indeed, the FDA is not only endorsing eSourcing methodology, but it is taking this "all-electronic" approach to data capture a step further by encouraging completely paperless submissions of clinical trial results.			

Nevertheless, eSourcing remains the exception to how most drug companies conduct clinical trials today. eSourcing has been tried, but too often patient and/or doctor discomfort or displeasure with the computer interface has ultimately undermined the results. There are other risks as well with eSourcing that must be successfully eliminated or mitigated, including: 					

Total compliance with 21 CFR Part 11 regulations governing the security and reliability of electronic data;

The security and durability of the computers investigator sites use;

The need to seamlessly synchronize trial-site data with a central data management system;

The need for high availability of the data at all times in both directions, from the site to the center data-management (DM) server and back from the DM server to the site.

Despite these risks, Janssen Pharmacuetica, a division of Johnson & Johnson, has implemented eSourcing since 2002 to improve cost efficiencies and time to market. Over the years, the company has slowly grown the number and scope of the paperless trials it has sponsored. These efforts culminated in 2004 with a program to use a complete, end-to-end eSourcing system for two separate clinical trials involving approximately 230 sites that have enrolled 900 patients to date. Both trials, for two new drugs, are 100 percent paperless. 

Doctors are able to travel from room-to-room entering data directly into dedicated laptops; the patient data is then uploaded over a secure Internet connection to a central server managed by Medidata Solutions, a provider of clinical trials data capture and management software, as well as hosting services. All data from the two trials is managed by Rave, Medidata's core platform technology. The data is synchronized and organized for review by Janssen as well as by third-party trial monitors through a secure Web portal. Monitors are able to send edit checks and protocol changes to the trial sites via the portal. 

Several security issues are also typically a concern to eSourcing users, but the centralized architecture system minimizes the risk of data loss from a broken laptop. At the end of each visit, a standard operating procedure (SOP) followed by site investigators is to synchronize with the central server, which copies all original source data downloaded from the laptop. 

The server itself is protected by high-availability architecture, including redundant processing and frequent backup of its data. In the event a laptop needs replacing, the most current data can quickly and easily be uploaded remotely from the server. 

Another SOP is that sites lock up laptops every night, just as they would drugs or a CRF binder. As a result, Janssen has reported only a one percent hardware-loss rate from either a broken or stolen laptop—and a zero percent data-loss rate across both trials.  

A less obvious regulatory element is the 21 CFR Part 11 compliance of the software, which helps ensure data integrity via time stamps and audit trails for all information gathered. The time-stamped data offers a side benefit, too: discouraging log-keeping procrastination—the so-called "parking lot effect" of people filling out information in the parking lot prior to an office visit. 

Because many of the sites that signed on were technology-naîµ¥—for some it was their first clinical trial—a simple user-friendly interface is crucial to successful eSourcing. Doctors and nurses using the software must be able to complete a CRF, for example, with a minimal investment of time in formal training. Plus, automated functions such as data-validation checks needed to be unobtrusive and not slow data entry. 

Key to this process is the translation of paper-based trial processes and information formats to electronic processes and formats. For example, when initiating a clinical study, electronic CRFs (eCRFs) can be created as flexibly as if they were created on paper. When viewed on-screen, the eCRF appears as it would on paper. 

To complement ease-of-use, training is critical to guide users to ask the right questions and properly design the Web-based pages for collecting the necessary patient information. The protocol-design process overall is similar to a paper-based trial, but with the key advantage of speed afforded by the electronic medium. 

Because user satisfaction with the technology would determine long-term success, Janssen surveyed its physicians to evaluate their experience. A strong majority of the doctors indicated they would rather not return to paper-based trials.  

The cost per page of data gathered during trials has decreased for Janssen, but greater ROI has emerged around data quality and data accessibility. 

The eSource model has dramatically changed the way Janssen's trial monitors work. Rather than travel to numerous sites nationally or globally conducting protocol-compliance checks, monitors now examine the data being collected and fully manage trial processes from their home or office via a secure Web portal. They can, for example, query sites and generate data-correction forms with near-real-time speed. Monitors still usually visit investigator sites to initiate or end a trial, but their travel costs have been reduced significantly. 

Also, fewer queries and data corrections need to be issued from monitors because automated edit-checking functions in the investigator's software intercept data-entry errors before they are logged. On-the-fly cleaning of data, which is immediately indexed and fully searchable, is estimated to permit Janssen to close its database two to four weeks earlier than previously possible with paper-based trials. 

A faster database lock will enable Janssen to submit a new drug application (NDA) for FDA approval faster, or publish a Phase IV trial follow-up study sooner. This time saved is money saved—potentially millions of dollars in opportunity costs. 

Janssen initially considered building its own eSource software, but recognized that conducting clinical trials was not its core competency. Marrying the technology and the clinical experience would be difficult. 

Moreover, such in-house development would require large investments in support infrastructure and services. The industry adage is that efficient and effective EDC is 30 percent technology and 70 percent process. It was more economical and practical to engage Medidata to host the system in its own data center and provide help-desk support to users and continue to invest in future functionality. 

Janssen collaborated on the development of Medidata Rave Remote and provided requirements that ensured the software met all of Janssen's parameters and were fully field-tested. The two companies have agreed to make the software available to other pharmaceutical firms that wish to leverage the advantages of eSourcing.  

 is manager of clinical trials and relationship management with Janssen Pharmaceutica, 1125 Trenton-Harbourton Road, Titusville, NJ 08560, (609) 730-2000, fax (609) 730-2323, 

 is chief technology officer with Medidata Solutions, Inc., 79 Fifth Ave., 8th floor, New York, NY 10003, (212) 918-1800, fax (212) 918-1818, 

Articles

Notes from the Field

Janssen Pharmaceutica and Medidata Solutions join forces to institute eSourcing.

Paperless Progress

With drug development and approval in its current state, now more than ever, it is time to address the small changes that create big impact in communication during meetings and training.  Productivity within drug development requires succinct and swift communication between sponsors, contract research organizations (CROs), and sites. In a recent survey of 38,000 people, ineffective meetings, poor communication between colleagues, and unclear objectives were listed as the most common productivity pitfalls at work. Sixty-nine percent of people surveyed stated that meetings were an unproductive use of time.

Meetings and training, however, are staple components during the drug development process. The challenge for sponsors and CROs is to identify components that create greater productivity within the ever diminishing development time lines. A productive meeting must have a clear message and be participant-centric and results oriented. Productive communication usually leads to a change. Research shows that concentrating on how a person needs to hear a message actually changes how much he retains.

 In order to do this, one must understand how people hear and then how they remember.  This article will address how to create this type of message by covering the following: 					

Communication and learning concepts to influence retention of material   

Effective meeting strategies to save time and money.

It is not only what you say that matters; it is also how you say it. There are three basic areas of focus that will increase the effectiveness of every message you deliver: organization, learning principles, and retention. Whether addressing your site personnel, the project manager at the CRO, or study staff, these three concepts will impact the outcomes of your communication and interaction. 

Step by step or big picture? Organization consists of more than a well-structured agenda. Table 1 outlines a typical investigator meeting. This agenda is well-organized, but it is only part of what is needed to ensure a successful meeting. Your audience will invest more in your meeting and retain more information if you organize an agenda for two different types of learners: global and linear. The global learner must understand the desired result and why it is important before investing mental energy. The linear learner does not focus on the big picture.  They need to know step by step what will be covered during the meeting before fully "buying" into its purpose.    

Table 1. Typical agenda for investigator meeting			

Failing to incorporate both types of organizing principles when setting meeting expectations and objectives may cost you 50% of your audience in the first five minutes. Get both groups motivated for the duration of your meeting by stating the big picture goal and then defining the steps needed to get there. This simple change will create more participant interaction and positively impact meeting productivity. 

When was the last time you conducted an Investigator Meeting or Study Coordinator training where you did not want your audience to remember the content? The heavy reliance on lecture for important events reaches the fewest number of people and provides the lowest retention statistics.

 While it may be the standard delivery process during Investigator Meetings, lecturing to sites is not the most effective way to achieve high retention and return on a $250 million meeting. Changing delivery makes all the difference. There are three different learning styles to which people respond. Delivering a message specific to these styles is key to your audience's retention.   									

Auditory learners range from 10% to 30% of our population and learn best with their ears.

 They will often talk out loud while trying to solve issues. An auditory learner can maintain focus during study-update conference calls because they are learning in their preferred style. However, up to 90% of your audience, the other two types of learners, can not retain information during those calls. This statistic should make you re-evaluate the effectiveness of your audio-only conference calls.

Visual learners learn best when their eyes are engaged.  They need to see charts, graphs, words, photos, and movies for information to reach long-term memory. Visualizing is effective with this learner as well. A study-update Web conference call stimulates this learner.  

Kinesthetic learners need to use their entire body "kinesthetically" to most effectively retain new information. This person may say, "Just let me do it" or "Can I try?" while in training. Role playing, skits, quizzes, activity sheets, and group projects are best. Using the interactive Web conferencing features like polling, chat, and application sharing engage the active kinesthetic learner.  

Most groups contain each of the learning styles, so address all of them.  For example, when presenting study data to management vary your tone and pace to stimulate the auditory learner.  Provide colorful subject recruitment charts for the visual learner, and ask interactive questions throughout your meeting to engage the kinesthetic learner. 

When you work with one subject during informed consent, listen for cues to identify which type of learner they are. When someone says, "I'm just not seeing this," adjust your delivery method to require visual focus. Literally draw a picture for this person to more effectively communicate. When you cannot identify the style, speak to all three. Table 2 outlines simple ways to incorporate these styles into your daily routine.  

Table 2. Simple and effective methods to engage all three learning styles during your next meeting or training event			

Incorporating the audience's organizing principles and learning styles into meetings increases effectiveness. However, retention dramatically diminishes, no matter the delivery method, when presentations last 60 minutes or longer without providing a break. 

Accelerated Learning for the 21st Century

, Rose and Malcolm state, "If you want to keep your recall high, make sure you have plenty of beginnings and endings to your learning sessions...keep taking breaks. Most people find it difficult to really concentrate for longer than twenty minutes."

Pay attention to how long you make your audience wait before you provide them mental breathing room. If you schedule a 60-minute staff meeting, prepare three 20-minute sessions with three different speakers rather than one 60-minute session. Apply this simple time constraint the next time you bring people together and get more return from your interaction. 

Bernice Kuca, director, clinical operations at Oscient Pharmaceuticals in Waltham, Massachusetts, cranked up the effectiveness and interaction for the study sites by putting 20-minute limits on each agenda item during an Investigator Meeting. "Mandating a 20-minute time limit for each speaker required them to be more creative and focus on the most important information. We tried to avoid repetition of information, which meant the attendees had to pay attention. This was my most successful meeting ever. The audience was continually engaged and the biggest measure of success...no one left early!"  

When you keep people attentive, they interact and learn more. However, learning more is worthless if you cannot remember the information while on task after training. Creating meaningful exercises that require application of the new concepts prompts people to retrieve information from their memory banks.

 This active retrieval process improves learning and maintains the concept in long-term memory.   

In a recent post-Investigator meeting Web conference, the project manager reviewed inclusion/exclusion criteria for the sites. After doing so, he described three sample subjects.  Three polling questions were posed to each site asking if the subjects were eligible for enrollment based on the criteria.  This immediate and meaningful activity required the sites to apply their new knowledge, thus better securing it in long-term memory. 

These participant-focused Accelerated Learning Techniques speed up the learning process. When site personnel learn faster, more information is covered in a shorter period of time.  Considering costs to get a new medicine to market range from $800 million to $1.7 billion and take over 13 years, both time and money spent are vital considerations.

New delivery methods are not the only way to save time and money. Taking these teaching techniques online with a new delivery tool decreases the investment even further. In the past six years, Eli Lilly has conducted over 150 virtual trainings with thousands of sites. Lilly shows a correlation between their distance learning programs and reduced queries per case report form (CRF) visit, fewer issues with good clinical practice (GCP), and quicker study startups.

Scheible and Pozsgai state that program savings are noticed even more as studies progress and staff retrainings are required due to new site additions and turnover.

 Rather than sending a monitor to each site for retraining, save time and money by conducting an online training event from the CRO's office. Face-to-face meetings are not required. For forward-thinking companies, online tools have saved months and millions.   

Sites feel the impact of virtual training as well with decreased travel, more interaction, and flexible scheduling. Each year it is becoming more financially irresponsible for principle investigators to leave their offices. Complex studies that used to require four days for travel and training are now conducted online in five to eight hours over a weekend. No office time required!   

Learning from a distance creates a more interactive environment for timid site personnel. Sites say they feel less inhibited to ask online questions due to a perceived level of anonymity.   

Sites also appreciate training that accommodates their busy office schedules. Frequently, sites train at their convenience after hours or during weekends with archived training sessions. Recorded learning modules allow anywhere, anytime training.   

Technology has both helped and hindered every business, including clinical research and development. Email, for example, takes less time but can end up costing effectiveness with misinterpretation. Data capture did not fare well in the beginning years. Web conferencing and online communication tools are no exception. Five years ago, conducting online Investigator meetings or clinical research associate (CRA) training was an abstract concept. Getting sites online was a struggle. Today, Internet connections are common. A Site Management Specialist at Quintiles Strategic Research Services in San Francisco, California, recently helped support a late-phase online program. He said, "We have been surprised to discover how many sites now have internet connectivity. A lot has changed from only a few years ago!" Web communication tools provide sites easy and reliable access to important study information 24 hours a day.   

In general, online tools are quite similar. In an April 2003 Web conferencing review, Nilssen and O'Donnell discussed their findings and stated, "First and perhaps most important: we believe there is no single vendor offering that should be the universal choice for every customer."

 In most cases, online meeting products have three basic requirements: 					

Audio connection via conference call or computer speakers. 

Picking the technology that best fits your project needs means first determining the goal and size demands. Then, identify whether a live interaction is necessary. Third, choose the product. Questions to consider are: 									

Highly detailed information requires smaller meetings and sufficient time for questions and interaction. Imbedded video clips address all learning styles and help with extremely detailed information.

 When learning new information is the goal, pick a technology that provides testing. High retention does not always require small meetings, but high retention does require highly interactive meetings to hold people accountable to new information.   

 When standardization is a must, consider using a product that creates archives.  Recording allows those that miss your meeting to receive the exact same information as the participants who joined the live session.  

Feature Article

To run productive, results-oriented meetings, you must understand how people hear and how they remember.

Small Changes, Big Impact!

Very few people can say anything good about spam (other than spammers, that is). I am a passionate spam-hater, who goes to great lengths to avoid any exposure to the frequently offensive emails known as spam (named, of course, for a classic Monty Python comedy routine involving Vikings). With that introduction, let me tell you something good about spam. Understanding spam, and the ways we deal with spam, can help understand how to identify and manage problematic adverse events in large, untidy databases of spontaneously reported data. If that seems a stretch, let me explain. 

Spam is unsolicited commercial email (UCE), sent to thousands or millions of email addresses simultaneously, that typically advertises a commercial service or product or promotes a political viewpoint. It is a huge problem in the world of business, for many reasons. The sheer cost of scanning through and deleting spam messages is enormous, often estimated in the hundreds of thousands of dollars annually for a large company. In addition to productivity issues, spam can create significant security issues, allowing viruses, "malware," and other dangerous programs into a company. Finally, spam can create a hostile work environment for employees, creating a liability for companies. 

UCE is estimated to account for 40% to 80% of all email received in the United States. The reason why it is such a huge problem (compared with regular "junk" mail) is that it is free to send email. A commonsense solution for the problem would be to charge for the numbers of emails sent. Unfortunately, most spam is sent through relays and through the illegal hijacking of innocent computers; charging for these emails wouldn't affect the spammers or their pocketbooks. 

Whether an email is spam or "not spam" is sometimes in the eye of the beholder, which certainly complicates company and/or group antispam strategies. Most everybody would think of advertisements for enlargement of body parts to be spam, while there might be a difference of opinion about whether an advertisement for a low-rate mortgage is spam to reasonable people. Most noxious spam emails cannot be traced to a legitimate Web site or company and will likely increase the number of emails if the recipient attempts to "unsubscribe." 

Shortly after the first spam emails began arriving in the early 90's, programmers began developing "anti-spam" strategies, email filters, and programs. In a constant game of cat and mouse, each new strategy to identify and eliminate spam was met by more sophisticated methodologies of escaping spam detection. The earliest strategies used blacklists, initially personal ones, but later shared blacklists that could collect reports of spam and allow the blocking of emails from particular email addresses or domains. While these strategies do block some spam, spammers typically change their email address and even domain regularly, and/or use domains that can't be blocked because much legitimate mail originates within (e.g., 

).  Later methods involved the creation of a "fingerprint" of the spam that could be stored on a centralized server. These "distributed checksum clearinghouses" can compare all incoming emails to known spam and reject those that match.  Unfortunately, the DCC strategy success is related to ongoing reporting of spam, and static spam content. Neither of these criteria are reliable in the real world situation. 

As spammers became more sophisticated, spam-blocking programs developed scoring systems that could eliminate spam email based upon the words and formatting used in the messages. Unfortunately, the rules were available to the spam generators as well, and spam strategies arose to circumvent these algorithms. For example, screening for the word "Viagra" led spammers to begin using V1agra, V!@gra, and many other variations. If a rule looked for a predominance of certain words or phrases, spammers added "nonsense" phrases or text to dilute the actual content. Algorithms which incorporate many different rules are somewhat arbitrary in their weighting criteria, and are prone to errors in overreporting (false positives) and underreporting (false negatives) spam. 

Spam filtering tools dramatically improved with the application of Bayesian   statistics to the methodology. In fact, Bayesian filtering is behind most of the highly successful spam filtering tools available today. The power of Bayesian filtering is that it identifies and weeds out spam at its very core—the message itself —through a simple method that automatically learns and adapts as the spam message changes. The only way for a spam message to evade a Bayesian filter over time is to make the message content more and more like a normal message, with no unpleasant or sales content at all according to a seminal article on the use of Bayesian filtering for spam ("A Plan for Spam," Paul Graham, http://

All of this may sound like magic, but it isn't.  It is the application of a very powerful application of probability theory that doesn't require advanced mathematics to understand.   

Bayes' theorem was developed by the mysterious Reverend Thomas Bayes, who wrote exactly one paper on the theorem that was published several years after his death in 1761. This work was rediscovered in a more generalized form by LaPlace less than 20 years later and has been used a wide variety of analysis since, only taking on the name "Bayesian" in the 1950's.   

The principle behind Bayesian analysis is the derivation of empirical (often historical) probabilities of the occurrence of some event from existing data. These empirical probabilities are then used to predict the occurrence of future events, or the meaning of undefined current events. I originally learned of Bayesian analysis back in medical school in the 1970s, when a small group of physicians began to think about the interpretation of laboratory tests based on Bayesian principles. Examples of this application of Bayesian analysis can be very clear, and can help us set the stage for understanding the use of Bayesian analysis in spam and later in the analysis of adverse events. 			

Consider the use of mammography in the screening of 40-year-old women for breast cancer. This example is taken from a very in-depth introduction to Bayes' theorem at http://

. All estimates are for discussion purposes only, and are not intended to be accurate. Empirically, about 1% of these women will have breast cancer, and 80% of these women will have a "positive" mammogram at a given screening, indicating the need for a further evaluation. Unfortunately, 9.6% of nonaffected women will also have a positive mammogram. The question that becomes relevant to many people is "What can a physician tell a 40-year-old woman who has a positive mammogram on a random screening?" The real answer surprises a great many physicians and lay people alike. Given these numbers, most physicians guess that 70% of women with a positive mammogram on screening will be later shown to have breast cancer. Only 15% or so guess the correct answer—that 7.8% or one of 13 of the positive results actually indicates a woman with breast cancer. 

To understand how we get this result, let's look at 1000 people screened under these conditions. Ten would have breast cancer (as stated, 1%) and of these eight would be screened as positive, as described above. However, of the 990 women who don't have the disease, 95  would also be screened positive, given the 9.6% rate mentioned. Of 1000 people screened, eight would have both a positive result and breast cancer, and 103 total women would have a positive result. Dividing 8/103 gives the 7.8% as the likelihood that a person with a positive mammogram actually has a malignancy. This is known as the posterior probability. 

The key to determining the posterior probability of a particular test result is to have a good estimate of the "prior probability" of the population that you are going to test. Consider how different the results would be for a patient with a strong family history of breast cancer and a palpable lump on exam. Here, an individual physician might estimate a 60% prior probability of the patient having a malignancy. Working the numbers through, this would create a post-test probability of 480/(38 + 480) or 92.7% likelihood that a positive mammogram represented a malignancy. Furthermore, it is likely that 120/(120+362) or 24.9% of the women who test negative under these circumstances will still harbor a malignancy. Further testing or a biopsy could be warranted under these circumstances. 

The power of Bayes lies in having some empirical understanding of the likelihood of a result in an individual patient BEFORE a test is done. Bayesian reasoning can help the clinician decide the meaning of a lab result, whether to test a given patient, or even whether to screen populations for patients based on the specificity, sensitivity, and population prevalence of the condition being tested. 

Back to spam. The same mathematical principles in the example above can be applied to the screening for spam. By examining spam emails and normal emails, it is possible to learn the frequency of particular words in both of these type emails. Certain words (for example, "click") may be found in a high percentage of emails but in very few normal emails. Similarly, there are other words that are common in normal emails but rare in spam. We are, in effect, calculating the prior probability of an email being spam, based on the occurrence of a single word. Thus, an email containing several of these high prior probability words with might have greater than a 99% posterior probability (or likelihood) of being spam. Sophisticated Bayesian spam filters have various strategies to examine 10 or 15 of the highest scoring words suggesting spam and the 10 or 15 of the highest scoring words suggesting normal emails.  They then can calculate an overall spam score for the email. 

Bayesian spam detection is very powerful, detecting greater than 99.8% of spam with virtually no false positives.  Importantly, if false positives and false negatives are identified and "reported" to the spam engine, the quality of spam detection will continue to improve. In fact, as new spam and normal emails come in they will be examined and added to the calculations. Thus, the Bayesian spam engine will "learn" about new spam emails when they first come out, and will adapt. Even strange spelling and other tricks can't fool the filter—they will be easily discovered and screened out. The hardest spams for a Bayesian filter to identify are those that are nearly identical to a normal email—hardly effective spam! 

Bayesian analysis can be applied in many places where it is possible to develop an estimate of the expected probability of an occurrence. Currently, there is interest (and some experience) in the use of Bayesian statistics for determination of efficacy in clinical trials based in part on historical data. While this approach requires the acceptance and buy in of regulatory reviewers, there is another important application for Bayes in clinical data—the data mining of large databases of adverse events. The statistics and principals of this process are far beyond the scope of this column, but it is worth considering the general concept.   

In looking at very large databases of reported adverse experiences, it is easy to identify all of the AEs reported with any particular drug, and even to rank these by the frequency of their reports. For example, headache might be reported in 10% of the AE reports regarding a particular drug or drug class.  This is not particularly meaningful without an understanding of the expected frequency of headache reports. Using a calculated prior probability for headaches (perhaps based on the frequency of headaches in ALL reported AEs), Bayesian statistics can be applied to calculate an adjusted relative risk for headache associated with a particular drug. When other possible confounding variables are eliminated and a visualization and/or threshold is applied, one can identify adverse events that may require further study and analysis to determine if there is a meaningful clinical association between the drug and the AE. This type of Bayesian analysis can also be applied to determine if two drugs together might be associated with particular AEs. 

When applied to a massive data set with appropriate visualization techniques, the Bayesian techniques allow a nontechnical person to sift through an enormous amount of data and relatively quickly identify important AE signals amidst a tremendous amount of noise.  When thought of in this way, it has clear shared characteristics to the identification of useful emails amongst a sea of spam. The techniques of finding the "signal" amongst the "noise" is very different. Yet, for both of these applications, we owe a debt of gratitude to a very private 18th century mathematician. 

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

Technology Viewpoint

How unwanted emails can deepen our understanding of trial probabilities.

From Spam to Adverse Events

The loss of European competitiveness in the pharmaceutical sector has been widely acknowledged.

 The European Union (EU) has begun to address this issue through efforts such as the implementation of EU Directive 2001/20/EC, intended to align the EU with international standards for conducting clinical research and to encourage innovation. For example, the directive opens the door to allowing advertising in patient recruitment efforts for clinical research studies, a technique long in use in North America.  

As the EU gears up to attract more sponsors and clinical trials, the spotlight will turn to the pharmaceutical markets' ultimate customer—the patients who volunteer for trials and who use the resulting products. In a first-of-its-kind effort, the 2004 International Will & Why Survey was designed and deployed in May 2004 to gauge the perceptions and attitudes of Europeans toward participating in clinical research.

 The survey was conducted online between May 17 and May 20, 2004 in six EU countries: the Czech Republic, France, Germany, Poland, Spain, and the United Kingdom. The total number of survey respondents was 2339 (1143 men; 1196 women; see Table 1 for a detailed breakdown). 

 Table 1. Number of respondents by country			

An analysis of all respondents in the aggregate revealed that 68 percent would be willing to participate in a clinical study. However, only 6 to 7 percent of respondents indicated they had participated in a clinical trial (see Figure 1). Of these, 89 percent indicated they would do it again (see Figure 2). 

Figure 1. Willingness to participate in a clinical study.			

Of all the respondents surveyed, 71 percent indicated they were not aware of patient protections such as the Declaration of Helsinki, ethics committees, and the informed consent process. However, after these protection measures were described, 42 percent said they would be more likely to participate in a clinical research study (see Figure 3). 

Figure 2. Satisfaction with clinical study experience.			

Over 1490 individuals who had not yet participated in a clinical research study but who said they would consider it were asked about their reasons for being willing to enroll. Of these respondents, 69 percent indicated "To advance medicine/science." "Earning extra money" was the second most influential factor (58 percent); "To help others with the condition" was third (57 percent); "To obtain better treatment for my condition" was fourth (48 percent); and "To obtain faster access to treatment for my condition" (34 percent) was fifth. (See Table 2 for the complete list of possible answers.)

Table 2. Reasons for participating in a clinical study (multiple answers possible)			

Of the Czech respondents who had never participated in a clinical trial, 24 percent would consider participating in a clinical trial and 76 percent would not. Of the Czech respondents who would participate in a clinical trial, the reasons given were as follows: 25 percent indicated altruism (advancement of medicine/science and to help others with the condition), 10 percent indicated they had no other treatment options, and 9 percent indicated they wanted to earn extra money. Of the Czech respondents who would not participate in a clinical trial, 37 percent responded because of the health risks in clinical trials and 21 percent responded because of the "guinea pig" perception associated with clinical trials.

Figure 3. Understanding the impact of international patient protections.			

Of the French respondents who had never participated in a clinical trial, 71 percent said they would consider participating in a clinical trial and 29 percent would not. Of the French respondents who would participate in a clinical trial, the reasons given were as follows: 38 percent indicated altruism (advancement of medicine/science and to help others with the condition), 14 percent indicated they wanted to earn extra money, and 8 percent indicated it would be to obtain access to the latest medical advancements. Of the French respondents who would not participate in a clinical trial, 51 percent indicated the health risks in clinical trials and 21 percent indicated the "guinea pig" perception associated with clinical trials. 

Of the German respondents who had never participated in a clinical trial, 79 percent said they would consider participating in a clinical trial and 21 percent would not. Of the German respondents who would participate in a clinical trial, the reasons given were as follows: 25 percent indicated altruism (advancement of medicine/science and to help others with the condition), 14 percent indicated they wanted to earn extra money, and 13 percent indicated it would be to obtain better treatment for their condition. Of the German respondents who would not participate in a clinical trial, 40 percent responded because of the health risks in clinical trials and 32 percent responded because of the "guinea pig" perception associated with clinical trials.

Figure 4. Percent of respondents who would consider participating in a clinical trial.			

Of the Polish respondents who had never participated in a clinical trial, 74 percent would consider participating in a clinical trial and 26 percent would not. Of the Polish respondents who would participate in a clinical trial, the reasons given were as follows:  18 percent indicated altruism (advancement of medicine/science and to help others with the condition), 9 percent indicated it would be to obtain better treatment for their condition, and 9 percent indicated they would if they had a life-threatening illness. Of the Polish respondents who would not participate in a clinical trial, 45 percent responded because of the health risks in clinical trials and 28 percent responded because of the "guinea pig" perception associated with clinical trials. 

Of the Spanish respondents who had never participated in a clinical trial, 75 percent would consider participating in a clinical trial and 25 percent would not. Of the Spanish respondents who would participate in a clinical trial, the reasons given were as follows: 21 percent indicated altruism (advancement of medicine/science and to help others with the condition), 10 percent indicated they wanted to earn extra money, and 9 percent indicated they would participate if their doctor recommended participation. Of the Spanish respondents who would not participate in a clinical trial, 53 percent responded because of the health risks in clinical trials and 25 percent responded because of the "guinea pig" perception associated with clinical trials. 

Of the British respondents who had never participated in a clinical trial, 86 percent would consider participating in a clinical trial and 14 percent would not. Of the British respondents who would participate in a clinical trial, the reasons given were as follows: 25 percent indicated altruism (advancement of medicine/science and to help others with the condition), 12 percent indicated they wanted to earn extra money, and 10 percent indicated it would be to obtain better treatment for their condition. Of the British respondents who would not participate in a clinical trial, 49 percent responded because of the health risks in clinical trials and 24 percent responded because of the "guinea pig" perception associated with clinical trials. 

Since participation in clinical trials is low, even with an individual  satisfactory experience, and willingness to participate is high, there may be a substantial gap in communication. Actual participation may be hindered by low awareness and/or misconceptions about clinical studies. As the survey suggests, providing information about patient protections increases public willingness to consider participation. The findings of the survey therefore indicate a connection between the level of public awareness of clinical research efforts—with their built-in safeguards—and patient willingness to enroll in clinical trials. 

For sponsors expanding clinical trials into the global marketplace, it is interesting to note that respondents' interest in and reasons for participating in clinical trials were remarkably similar in all of the countries surveyed, with the exception of the Czech Republic. The benefits of the Czech health care system may help to explain the lower percentage of people willing to consider trial participation. For example, Czech patients are not responsible for co-payments at the point of service and can obtain the full range of drug therapy with no out-of-pocket payments. On average, Czechs visit the doctor 14 times per year (compared with an average of seven annual visits in the EU). Frequent contact with health care providers may make Czechs feel less impelled to consider the option of clinical studies.  

In Europe, like many other places in the world, most information reaches patients through health care providers or through disease awareness campaigns. Most spending on promotional materials remains largely targeted to physicians. The lack of direct-to-patient communications via television, radio, and Internet advertising, which are either not permissible or not routinely utilized in all polled countries (United Kingdom, France, Germany, Spain, Poland, and the Czech Republic), presents barriers to helping people understand both the role of clinical research and the potential benefits of participating. Furthermore, respondents' considerable concerns about "the health risks of clinical research studies" and "[being] treated like a 'guinea pig'" reinforce the need for improved education. Investing energy into public education about the measures in place to protect participants in clinical studies could have a significant influence on both willingness and actual participation. 

The 2004 International Will & Why Survey results present sponsor companies with compelling arguments for expanding patient education efforts. This can be achieved on many fronts in the EU, including promoting an environment with easier access to direct-to-consumer information, maximizing the new regulatory environment, and leveraging communications to patients for clinical study recruitment. By expanding communication channels and making existing information more robust, sponsors can interest, attract, and educate potential study participants and contribute to building strong public support for the clinical research enterprise as a whole. 

Globally, there are still many legislative barriers to full and open communications to consumers and patients. Only the United States and New Zealand currently allow widespread direct-to-consumer (DTC) information.

 But there is evidence that the trend is shifting. EU countries are discovering that as Internet use spreads, the pressure from consumers for more information increases. This pressure is likely to grow as Internet use spreads in developing nations as well. Internet access removes national barriers to information. Online information generated by companies for U.S. consumers will become instantly available around the world and legislative restrictions to Internet information will become moot. 

In addition, one goal for the recent implementation of EU Directive 2001/20/EC

 is to establish parity with the United States so that Europe can attract more clinical trials and a larger share of the resources, jobs, and opportunities that come with them. By the simple act of mentioning advertising, the directive opens the door to reaching out directly to patients with information about clinical research. While it may be years before all EU member nations bring their national legislation in line with the directive and truly reach parity with the United States, the likelihood is that Europe will see a more open and competitive marketplace where countries seek to attract sponsors of research, using marketing communications as a tool for recruiting patients and enhancing participation.  

Sponsors conducting research in the EU can take advantage of this environment and apply lessons learned in the field of patient recruitment in the United States. There, patient recruitment is a growing industry with many pharmaceutical sponsors now outsourcing their recruitment efforts to marketing experts. These experts have broadened the definition of "advertising" to direct-to-patient communications, including a wide range of tactics for reaching patients—from mass media outreach to site-level communications—many of which can be implemented in EU countries. Comprehensive recruitment kits including media advertisements, an assortment of printed materials (i.e., brochures, physician letters, patient appointment books, event flyers, etc.), Web sites, and email information can be used to alert and educate potential participants to the study opportunity and help them make informed decisions about participation. 

The global marketplace offers sponsor companies widespread opportunities. As sponsors expand their clinical trial efforts globally, they are likely to see the marketplace change with developing nations competing for the resources, jobs, and opportunities that come with research studies. With so many countries in Eastern Europe, Latin America, and Asia now offering similar environments (large populations of treatment-naïve	 patients, low operating costs, and improving infrastructures), those sponsors who leap ahead of their competitors in providing more thorough and widespread patient information are likely to gain and retain a distinct competitive advantage.   

 is founding principal of BBK Healthcare, Inc., 320 Needham St., Newton, MA 02464, (617) 630-5505, fax (617) 630-5090, email: 

1. "The Pharmaceutical Industry in Figures, 2004 Edition," European Federation of Pharmaceutical Industries and Associations, 2004. 

2. "G10 Medicines High Level Group on Innovation and Provision of Medicines Consultation Paper," European Federation of Pharmaceutical Industries and Associations, 2001.  

3. BBK Healthcare, Inc., "The 2004 International Will & Why Survey. Internet poll of >2,300 patients," June 2004. 

4. "Direct-to-Consumer Advertising of Prescription Medicines in New Zealand: A Discussion Paper," Ministry of Health, New Zealand, November, 2000. 

5. "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," 

Official Journal of the European Communities

Survey results point to a correlation between clinical trial awareness and a willingness to enroll.

Europeans Weigh-in on Clinical Study Participation

ASnybody who thought GCP would simply become a reality in the European Union on 1 May 2004—the date when the EU Clinical Trial Directive 2001/20/EC became effective—was sorely mistaken. Implementation and compliance continue to cause difficulties.

In Brussels, panelists and speakers tackled the thorny issues surrounding the EU Directive. 

Because the directive is not a regulation, it requires transposition into national law. National variations seem likely to persist, and national laws often prevail, even when they are in conflict with the EU Directive. The harmonizers' vision has not yet materialized. 

"The directive is good, but it is a work-in-progress and it needs to be monitored," Michael Griffith, chief executive of Fighting Blindness Ireland, told delegates at May's meeting of European Forum for Good Clinical Practice (EFGCP) in Brussels. "The biggest problem is lack of information. We need details on how the directive is being implemented in each country, and we need information on specific difficulties in each country." 

The consultation process was very poor, and the views of academic researchers were not sought, he said. He attributed this largely to the fact that the directive comes from the Directorate-General (DG) for Enterprise, rather than the DG Research or DG Health units. 

Griffith identified three common difficulties: 

. The stipulation that a single opinion in each EU country is needed for multicenter trials undermines the work of local committees, which can only veto actual trials being carried out. The position is not sufficiently transparent for pan-European research programs.

Definition and responsibilities of sponsor

. The directive requires that an individual or institution should become the sponsor, who is responsible for the whole trial. This may create unacceptable legal and financial burdens, and although ad hoc solutions are planned, the position is not yet clear.

. This results from the necessity to enter information on the EudraCT and SUSAR (Suspected Unexpected Serious Adverse Reaction) databases, for instance.

Close scrutiny of the situation across the European Union is required to ensure that any problems are immediately dealt with and no undue delays occur, and the European Commission (EC) must introduce a monitoring system and ensure good communication, he noted. To ensure patient groups, national regulators, academics, and the public are made aware of developments, an annual conference should be organized, either directly by the EC or by the EFGCP and European Platform for Patients' Organisations. 

"Morale and enthusiasm for research are waning," commented Maxine Stead, assistant director of the U.K. Clinical Research Network Coordinating Centre. "There is a need to address the problems and provide solutions quickly to maintain interest in research." 

Industry representatives also appear far from happy about the directive. New member states sometimes have unrealistic expectations, leading to trials going elsewhere and undermining the ICH (International Conference on Harmonization) process, according to Dr. Beat Widler, global head of clinical quality assurance at Hoffmann-La Roche. Moreover, regulatory variations between countries are interfering with proper study conduct. 

"Some states are keeping local requirements and adding EU requirements. This causes delays in starting trials and increases costs. Also, a breach of confidentiality may occur when extensive documentation is submitted to ethics committees," he told EFGCP attendees. 

There are gaps in clarity and consistency, and gaps in implementation, Widler continued. Requirements may change during the transitional phase. Certain countries have demanded that ongoing trials should comply with the directive, while others have not, and this means the same study is conducted according to different rules. Such problems look set to persist for some years. Also, supporting guidelines and guidance documents are still not universally available, and there is a lack of transparency about how documents get prepared. 

On the plus side, EudraCT works and was almost delivered on time, but overall there is insufficient harmonization, he remarked. Local forms are still being used, as well as EU-agreed ones, necessitating translation of documents. German regulators, for example, request full viral safety testing in early trials, while others do not. The definition of an investigational medicinal product varies widely, and Spanish regulators are applying a very broad definition. Certification of third party comparator products is often impossible, and EU member states do not have a common view on how to apply Mutual Recognition Arrangements, or MRAs. 

"The SUSAR process dumps investigators and ethics committees with loads of unhelpful, relatively unfiltered, and uninterpreted information, resulting in no improvements in transparency or patient safety," said Widler. "Inspection manuals are not publicly available, and inspection findings seem to depend on the subjective opinion of inspectors." 

He listed four unanswered questions for the EU regulators: What is the EU position on risk management? Are the European Medicines Evaluation Agency (EMEA) and EU to be aligned with FDA on this approach? Were key performance indicators defined, and are they being tracked? For Phase I, can umbrella protocols become an option to speed up the process, while still ensuring the protection of subjects? He also called for better alignment of regulatory requirements at the EU level and across member states, no rushing through of future legislation, and greater effort in reaching compromises with the EMEA. 

Gunnar Danielsson, GCP inspector at the Medical Products Agency in Sweden, conceded that there is a shortage of experienced inspectors. In addition, he pointed out that member states have different priorities, and local regulations, cultures, and traditions vary widely. However, the situation will improve when guidance documents are developed for performing, evaluating, and reporting trials. Key harmonization objectives include standardization of inspectors' qualifications, quality assurance of inspection procedures, joint inspections, shared training programs supported by the EMEA, and a shared database of inspections, he said. 

The EC can give guidance and introduce formal procedures, and it engages with member states and stakeholders, but the central role in transposing the directive is played by member states, stressed Erik Helstad, a lawyer in the Pharmaceuticals Unit at the EC's DG ENTR. Infringement procedures may be launched against member states that do not implement or apply the legislation. After assessing a complaint, the EC sends a letter to the member state and asks for clarification. If the member state fails to respond adequately, then a formal letter is sent. Unless the legislation in question is amended, the EC prepares a reasoned opinion, after which the case may be heard by European Court of Justice. 

The biotechnology sector is paying particularly close attention to the directive, largely because its future success hinges on the timely registration of new therapies. Industry leaders appreciate the harmonization of administrative aspects, the helpfulness of Competent Authorities, and the pragmatic approach to data requirements for Phase I trials, explained Henk Schuring, director of regulatory affairs for Europe at Genzyme Europe, Naarden, the Netherlands. However, a project team is needed to review the processes, roles, and responsibilities of the main groups. In the post-directive era, the workload of everybody involved in clinical research is increasing, and that is likely to continue for some time, he noted. 

Regulators are requesting extensive data, almost similar to what is required for a marketing authorization application, said Schuring. They often demand stability data, validation of analytical methods, certificates of analyses for all batches, and use of ICH quality guidelines out of their scope. A separate viral safety dossier may be necessary, in addition to Investigational Medicinal Product Dossier section 3.2.A.2. 

"Authorities, ethics committees, and sponsors are still in transition and in a learning phase. Topics keep coming up as experience is gained for different products, different trials, and different member states," he said. "Industry and regulators need to collaborate closely to maintain and improve the directive and the national legislation, to make it effective and to allow patients speedy access to innovative medicinal products." 

Guidance is necessary on the appropriate data requirements for each stage of clinical research, particularly for biologicals and emerging new therapies such as cell and gene therapy, and biotech companies require a full explanation on when a change constitutes "a substantial amendment," Schuring continued. He supports the establishment of a working group to discuss conducting cross-border clinical trials for orphan medicines and developing guidance on trials in small populations. 

"The directive has had a profound impact on the clinical trials environment in Europe. Here is an example of one stakeholder, collectively 'the competent authorities,' who took a bold initiative to regulate the practice of clinical research in Europe," summed up Dr. Jean-Pierre Tassignon, EFGCP president and executive vice president of PSI Pharma Support International in Zug, Switzerland. "Don't ask what the directive can do for you, ask yourself what you can do for the directive!"  

Clinical researchers strive to meet ongoing challenges posed by the EU Directive.

EFGCP Meeting Report

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eShowcase

EShowcase

No apologies for returning to the subject of pediatric medicines yet again. It's the subject that's largely monopolizing the attention of the European pharmaceutical industry at the moment, and the proposed new European Union rules reached yet another critical point on September 7. 

That was the date the European Parliament completed its first reading of this contentious proposal,

 which will both impose new clinical trial obligations on companies applying for marketing authorizations in Europe and offer them some incentives or rewards for extra studies in pediatric populations. 

After an extensive—and occasionally heated—debate, there was a wide consensus on the need for the new measure when the Parliament actually voted. The motion the Parliament adopted urged improvements in the proposal to accelerate the development of medicines for children, faster authorization procedures and shorter administrative delays, and more transparency and exchange of information about what trials are underway to prevent unnecessary clinical trials.  

The Parliament backed the idea of a research program—bizarrely entitled "MICE" (for "medicines investigation for the children of Europe")—to adapt existing substances no longer covered by patents for use in children, and it wanted tougher terms for the proposed Paediatric Committee. This committee, which will be located within the European Medicines Agency in London, should be set up within six months of the entry into force of the new rules, the Parliament said, and should independently evaluate scientific investigation plans put forward by companies wishing to benefit from the incentives created by the regulation. 

The most controversial aspect of the debate was the nature of the incentives to pharmaceutical companies to invest more in pediatric research—as expected, in the light of the energetic lobbying that had taken place on all sides prior to the Parliament debate. For many members of the Parliament, the proposal for an extra six months of patent protection was too generous: they wanted a shorter period, or a period fixed in light of the size of the company. 

Françoise Grossetête, the French Christian Democrat who had drafted the report for the Parliament, defended the fixed-period approach—the position that was firmly favored by the European pharmaceutical industry too. A system with too many variables would, she said, "lead us from the logic of health to the logic of the market." Since research is unpredictable, she maintained, "we should not add to that by introducing an unstable regulatory framework"—accusing critics of resorting to "arguments of carpet salesmen." She was backed by her UK Christian Democrat colleague John Bowis. 

But strong opposition came not only from the Greens and extreme left-wing and right-wing groups, but also from some sections within all three of the largest political groups in the Parliament—the Christian Democrats, the Socialists, and the Liberals, who shared the view that shorter extensions would avoid citizens financing the industry through inflated prices. French Socialist Anne Ferreira urged a fixed protection period of just three months, with a possible further three months for companies with a turnover of under €100 million. "This is an important question for our social security systems and for all citizens," she said, "as it is public money which will end up paying for all of this."  

The intensity of the debate was demonstrated by interventions such as German Socialist Dagmar Roth-Behrendt's: she backed the six-month term and criticized lobbyists for Poland and Hungary who wanted to see shorter periods of patent protection in order to benefit their generic pharmaceuticals producers. These disagreements reflecting national special interests were turning the discussion into "a pitiful, cheap debate," she said. "Parents of sick children will not understand it. We must think about the interests of patients, not national interests." 

The European Commissioner responsible for industry affairs, Gunter Verheugen, told Parliament during the debate that the six-month fixed period was essential: "This system would be simple to use, is predictable, will produce less bureaucracy and is compatible with existing patent law. The Commission is not prepared to accept any compromise on this point...I ask Members to think of the interests of children, which are far more important than one lobby or another." 

In the end, the majority of the Parliament voted to support a fixed extension of six months—but with the addition of a revision clause which would require a re-evaluation of how incentives were functioning six years after the new rules enter into force. 

The main European drug industry lobby, the European Federation of Pharmaceutical Industries and Associations, acknowledged the Parliament vote as "an important step towards the quick adoption of crucial EU legislation on medicinal products for children's use" and "a further important step towards better medicines for Europe's children." It viewed the outcome as a broad show of support for a balance between the obligations for pharmaceutical companies to conduct often complex, costly, and lengthy pediatric research and the need to stimulate pediatric research in Europe. Brian Ager, EFPIA director general, hailed the vote as "a key opportunity for Europe's children and for Europe's pharmaceutical science base."  

Ferreira was just as critical after the vote as she was during the debate. "The outcome does not amount to an acceptable balance between the interests of pharmaceutical companies and those of society: it is only a limited response to the need to define a public health policy that takes full account of the needs of children." She dismissed the arguments about the complexity of an incentive system customized according to each company's position: "And giving them six months additional monopoly on their sales, regardless of the turnover or the therapeutic value of the medicines, is not very reasonable," she said, accusing her Parliamentary colleagues of conniving at hypocrisy. 

The next step (in Europe there is invariably another step to be taken!) is for national ministers to give their view on the proposal. "Member states will now have the opportunity to take this regulation forward" over the coming months, said  EFPIA, which urged them to do so "without delay." And, as the European Parliament debate clearly showed, divisions still rack Europe over the best way to promote pediatric medicines. 

To prove that pediatric medicines are not just an obsession of this columnist, nothing more is needed than to shift the focus from Brussels to London, where the European Medicines Agency is now consulting on a draft guideline on pharmacovigilance for medicines used in children.

 The EMEA (and when will it stop using its old acronym, derived from its initial title of European Medicines Evaluation Agency, and switch to the more logical EMA in line with its new designation?) launched a six-month consultation period on its draft guideline in August. This is the first guideline to focus exclusively on the issues of safety of medicines in children, and covers not only reporting of adverse drug reactions (ADRs) in children, but also the possible need for studies designed to follow the long-term safety of medicines in children. It applies to "off-label" and unlicensed as well as approved use of medicines—but it does not address the pediatric use of vaccines, for which a separate guideline is being developed.  

As the EMEA explains, while differences in age and the stage of growth and development during childhood make children prone to ADRs that vary in nature, type, and severity from those seen in adults, "the systems for detecting adverse drug reactions in children may not be as effective as for adults." For a start, children may be unable to communicate ADRs, or may not even be aware that they are experiencing an adverse event. And in addition to under-reporting of reactions, off-label use may increase the occurrence of ADRs. So the guideline aims at strengthening the pharmacovigilance system for all medicines used in children, whether specifically authorized for such use or not. Looking ahead to the proposed new pediatric rules the Parliament has just voted on, the EMEA also points out that its guideline will serve as preparatory work for implementing the pharmacovigilance provisions the new rules will contain.  

Specifically in relation to clinical safety and pharmacovigilance before authorization of a pediatric indication, the draft guideline urges that pharmacovigilance measures should be assessed "at all stages of a product life cycle." It remarks that pediatric pharmacovigilance assessment may be rather limited before authorization as there are often relative deficiencies in pre-authorization clinical trials of medicines for pediatric use. Sample sizes in Phase I and II trials are usually low, and even in Phase III trials sample size calculations are nearly always based on efficacy assumptions. "That means that the sample size limits the ability to observe anything less than common reactions," it warns, with the consequence that serious adverse events "are generally not observed in the paediatric clinical trial programme." Given the limitations, "every opportunity should be taken to maximize the information obtained from the occurrence of an ADR"—such as freezing a blood sample for drug and metabolite measurement if an ADR occurs.  

The pharmacovigilance assessment should highlight areas where data to demonstrate safety are lacking, reflecting duration of use, patient numbers—both overall and in the different age categories—and indications studied. It should highlight potential risks for using the medicines in the pediatric population and suggest both postauthorization safety data collection mechanisms (such as postauthorization safety studies) and risk reduction strategies. 

Special consideration should be given to the need for long-term follow up, for example through treatment registries, including possible effects on skeletal, neural, behavioral, sexual, and immune maturation and development. Mutagenicity and carcinogenicity data are also relevant. And consideration should be given to the use of pharmacogenomic/pharmacogenetic methodology to predict risk and to monitor adverse reactions prospectively.  

Whenever a medicinal product is likely be used in the pediatric population, specific pediatric issues should be addressed in the risk management plan that should form part of the application for marketing authorization. A pediatric plan should be included in the pharmacovigilance plan and, where appropriate, specific pediatric risk minimization activities should be included in a risk minimization plan, says the draft guideline. 

Parliament's first review of the new pediatric rules stirs controversy.

Applied Clinical Trials-10-01-2005