It's taken a long time, but the much-discussed European Union regulation on medicinal products for pediatric use has finally come into force. It's almost with a sense of weariness that I report this, since I have the feeling I've wearied readers of this column with repeated accounts of the successive stages of its long gestation. 

However, the culmination of this process is far more important than any minor quibbles about how long it's taken the European legislative machine to get here. The new regime should be good for children and good for drug development. It should also provide plenty of additional work for the clinical trials community. 

The new regulation certainly received an enthusiastic welcome from the European pharmaceutical industry. "More medicines designed especially for children will soon be available across Europe," said the European Federation of Pharmaceutical Industries and Associations (EFPIA). "It will undoubtedly change Europe's research and development environment." 

Throughout the long debates—going back well before 2004—EFPIA has consistently argued for scientific and regulatory measures to encourage the development and authorization of medicines assessed for use in children; for incentives to support pediatric investigations into new and older products; and for the creation of a pediatric R&D infrastructure in Europe. 

According to Brian Ager, EFPIA director general, "the final text overall maintains a balanced approach between obligations and incentive measures. We sincerely hope these measures will contribute to Europe reclaiming a central role in innovative drug development as quickly and efficiently as possible, with a view to meeting the needs of the pediatric patient population." 

The new regulation features prominently in the 2007 agenda of the European Medicines Agency. It is one of the factors that will lead to "a considerably increased volume of activity," according to its just-published work program for the year.

Its work program has also been heavily influenced by the entry into force in January 2007 of the legislation on pediatric medicines. This is an important new mandate for the agency, giving it a significant role in stimulating the availability of safe and effective medicines for children, and is likely to lead to a 30% increase over 2006 in its provision of scientific advice to applicants. 

The agency will have to set up a new pediatric committee in the second quarter of 2007 to deliver opinions and decisions on pediatric investigation plans (and waivers where justified), and will have to provide information on pediatric clinical trials. Although the agency anticipates around 50 requests in 2007 for scientific advice relating to pediatric medicines, it expects overall some 400 requests or applications relating to pediatric activities (such as pediatric investigation plans, waivers, and scientific advice). 

The new committee will assess, agree, and verify compliance with pediatric investigation plans and waivers. An agreed pediatric investigation plan may lead to information on the pediatric use of medicines being included in a centralized or national marketing authorization for new medicines, and in a pediatric-use marketing authorization for off-patent products. 

The agency will also begin the gradual establishment of a European network for pediatric research, and in liaison with the European Commission and the 27 EU member states, it will start delivering guidelines for transparency of the pediatric clinical trials database. Work will also commence in the area of pediatric pharmacovigilance. A number of related guidelines will be implemented, and expert fora for the investigation of new sources and methods for intensive monitoring of the pediatric use of medicines will be established. 

There are plenty of other clinical trials-related activities facing the agency this year. It expects intensified activity on evaluation and supervision of medicines, and scientific advice and protocol assistance for sponsors will remain major areas of activity, particularly to foster new innovative technologies and therapies and to improve the chances of early availability of new medicines. The agency says industry is showing greater interest in seeking early scientific advice, with a significant increase in the number of requests from year to year translating into a high workload. 

In line with its declared policy of supporting innovation, the agency promises to focus in 2007 on providing special support for small- and medium-sized enterprises and contributing to pan-European initiatives for facilitating innovative research. Its efforts will particularly include continued support for the EU orphan medicines policy. 

Emerging therapies and new technologies are posing new challenges too. The agency is already engaged in providing advice in early stage development of advanced therapy medicinal products—gene therapy, somatic cell-therapy, and human tissue-engineered products—as well as other new technologies that will not fall within the scope of the upcoming EU regulation on advanced therapies. 

The agency plans to promote early dialogue with sponsors of potential applications for advanced therapies and emerging products and technologies, and will widen its exchanges to academia and society at large, in a bid to identify expertise, expectations, and bottlenecks relating to new treatment solutions. One of the consequences during the year will be the drafting of a "Strategic plan for new technologies." 

There is a shift underway in general pharmacovigilance, too. Medicines agencies have traditionally relied on spontaneous reporting of adverse reactions, but the agency says it now wants to take this a step forward. It is planning to work with member states' authorities and academic centers on establishing networks of experts to run intensive drug-monitoring programs that will actively study the safety of targeted medicines. 

Faced with a surge in responsibilities, the agency is also starting to insist on improved cost-effectiveness of its own operations, and on the need for further financing. It must be "supported by a corresponding increase in finances, human resources, and allocated national experts," says its executive director, Thomas Lönngren. 

The agency will carry out GCP and pharmacovigilance inspections, and organize training activities on GCP. It will also develop the cooperation between inspection and assessment functions, particularly through joint sessions with GCP inspectors and clinical assessors. It will have to continue its support for the implementation of directives on GCP. 

The detailed work plans for some of the agency's working parties also indicate where they will be impinging on the world of clinical trials. The pharmacogenetics working party—which will meet five times during the year—will be contributing to the scientific advice and protocol assistance on relevant pharmacogenetics and pharmacogenomic aspects, and will hold briefing meetings with applicants in response to specific requests. 

It will also be finalizing new guidance on pharmacogenetics. One paper will deal with pharmacogenetic samples, testing, and data handling. Another will cover pharmacogenetics and pharmacokinetics studies. A reflection paper will be completed on the use of genomics in clinical trials to explore treatment and genomic traits, and another will consider the agency's experience with authorization applications relating to pharmacogenomics in oncology. 

The recently established biosimilar medicines working party will be developing new guidance, too, covering nonclinical and clinical issues on biosimilar medicinal products containing biotechnology-derived proteins, recombinant α-Interferons, or low molecular weight heparins. It will be working too on training on assessment of the quality, nonclinical, and clinical aspects of biosimilars. 

The gene therapy working party will be contributing to the scientific advice and protocol assistance too, as well as to marketing authorization and postauthorization procedures on gene therapy and gene transfer medicinal products. It is also involved in:  					

reviewing its guidance on quality, preclinical, and clinical aspects of gene transfer medicines

preparing guidance on the scientific criteria for qualification as a gene therapy medicine, and on genetically modified cells as gene therapy medicines

preparing a guideline on nonclinical studies prior to clinical use of gene therapy medicines and on monitoring of subjects treated with them.

The burgeoning biomarkers market is also driving intensive work within the agency. A recent study by Kalorama Information

  predicts the worldwide market for biomarkers in clinical trials will jump from $427 million in 2006 to more than $1 billion in 2010. 

Their increasing usage in drug development and clinical trials is expected to have an enormous impact on the success and effectiveness of future therapies, says Kalorama. 

The European medicines agency is currently finalizing a series of definitions to avoid the risk of confusion in this rapidly emerging new field. "The lack of consistently applied definitions to commonly used terminology raises the potential for conflicting use of terms in regulatory documentation and guidances or inconsistent interpretation by regulatory authorities, ethics committees, and sponsor companies," it says. 

A guideline now in preparation provides definitions for genomic biomarkers, pharmacogenomics, pharmacogenetics, genomic data, and sample coding categories "to facilitate the integration of the discipline of pharmacogenomics and pharmaco-genetics into global drug development and approval processes." 

According to the agency, the definition of what constitutes a genomic biomarker is key to understanding the definitions of pharmacogenomics and pharmacogenetics. So it sets out clearly that a genomic biomarker is "a measurable DNA or RNA characteristic that is an indicator of normal biologic processes, pathogenic processes, and/or response to therapeutic or other intervention." It is not limited to human samples, and could, for example, reflect the expression, function or regulation of a gene. It can consist of one or more DNA or RNA characteristics. And if you want to see the full text, and the other definitions, you can find them at: http://

www.emea.europa.eu/pdfs/human/ich/43798606en.pdf

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

eurlex.europa.eu/LexUriServ/site/en/oj/2006/l_378/l_37820061227en00010019.pdf

www.kaloramainformation.com/Biomarkers-Briefing-1059917

Articles

View from Brussels

Regulation will benefit both children & drug development, says EMEA, which has a lot on its plate this year.

Europe's Pediatric Rules in Force—At Last

The escalating cost of drug development is prompting sponsors and researchers to take a serious look at long-discussed but sparsely implemented research methods that promise to reduce the research failure rate and produce more meaningful study results. 

A December (2006) report from the Government Accountability Office (GAO) describes the declining productivity of the pharmaceutical research enterprise: Despite big increases in R&D investment, few new therapies are coming to market. 

Industry increased R&D spending from $16 billion in 1993 to $40 billion in 2004, and estimates put the number at $60 billion last year. But FDA approved only 22 new molecular entities in 2006. The total has been flat in the last few years, but is "way off the historic highs of the mid-1990s," reports Steven Galson, director of the Center for Drug Evaluation and Research (CDER). 

This drug development downturn is taking a serious toll on major pharmaceutical companies. Firms are closing plants, cutting work forces, and looking for new ways to conduct R&D. At the same time, FDA and industry are under intense pressure to demonstrate that those drugs on the market are safe and effective. 

To this end, and in response to a scathing assessment from the Institute of Medicine (IOM) last year, FDA officials unveiled a plan in January to improve how it detects and assesses drug safety problems. 

The FDA report on "The Future of Drug Safety" outlines proposals for developing safety "report cards" on important new drugs and for posting an online drug safety newsletter. FDA is clarifying conflict-of-interest policies for advisory committees and establishing a new advisory committee on communication to gain more outside expertise on conveying risk information. 

The agency will formally assess Risk Management Plans (RiskMAPS) to see if they really address serious safety problems. Another strategy is to seek broader access to health system databanks able to detect safety signals more quickly. Galson also promised to address the tension between pre- and postapproval staffs by engineering a "true culture change" at CDER that involves giving more authority to safety analysts. 

An underlying theme of FDA's drug safety program is that new developments in biomedical science and in information technology offer more efficient ways to address drug safety early in development and to quickly detect safety problems after a drug goes to market. 

Janet Woodcock, FDA deputy commissioner and chief medical officer, heads up a range of efforts to improve risk assessment by sponsors and FDA, many launched under the Critical Path Initiative and described more fully in a January report on progress made in implementing Critical Path opportunities during 2006. 

Collaborations involving FDA, industry, and academia, for example, are developing new tests for drug organ toxicity and for identifying cardiovascular risks of drugs. The Predictive Safety Consortium is sharing data to cross-validate preclinical safety biomarkers. Another consortium based at the National Institutes of Health aims to assess biomarkers for critical diseases, beginning with lung cancer and lymphoma. A new Serious Adverse Event Consortia plans to identify and validate genetic variants that may help predict the risk of drug-induced reactions, starting with liver disease and serious skin rashes. 

Projects to streamline clinical trial design also are moving forward. FDA is collaborating with industry to develop standard formats for case report forms to establish a fully electronic system for submitting all clinical study data to FDA. Another project seeks to reduce the high failure rate of late-phase trials by encouraging sponsors to use clinical trial simulations to help improve dose selection. 

FDA expects many of these collaborations will yield new guidances on topics such as identifying liver toxicity during drug development and utilizing enriched clinical trial designs to gain more safety information. The goal is to "build safety into products" by better understanding the genetic basis of adverse events, explained Woodcock. These approaches can screen out toxic compounds early on and identify patients most likely to have adverse events—or to respond well—to a test medicine. The aim, she said, is to "make products safer from the get-go." 

A researcher's ability to design better clinical trials and make go/no-go development decisions could benefit from a better understanding of prior knowledge in drug and disease areas. This can be enhanced by sharing clinical trial data held by pharma companies, according to many industry R&D leaders. 

The importance of access to information on disease states and biological responses beyond what any one sponsor may have, as well as obstacles to such collaboration, was debated at a January meeting, "Sharing Knowledge to Improve Clinical Drug Development and Regulatory Decisions," co-sponsored by FDA and Drug Information Association (DIA). 

John Orloff, vice president of development at Novartis, voiced support for sharing information at a pre-competitive level to establish models of disease progression and qualification. He urged regulatory authorities to further such efforts by supporting alternative statistical approaches; establishing common principles for reliance on modeling assumptions; accepting industry-generated drug and disease models; and facilitating a greater sharing of disease models, epidemiology, and safety data. 

The poster child for such cooperation is the 1990s effort to validate HIV viral load as a surrogate for testing new AIDS treatments. 

Prior to 1997, FDA required studies with clinical endpoints to approve HIV drugs, pointed out Jeff Murray, deputy director of CDER's Division of Antiviral Products. Prodded by very vocal patient advocates, FDA joined with industry and academia in 1996 to form a Surrogate Marker Working Group to assess correlations between viral load and clinical outcomes through meta-analysis of data from multiple trials. Collaboration was particularly important because AIDS treatment involves multiple drug combination therapies. 

Agreement on the results led to FDA guidance and greatly expedited HIV drug development through smaller and shorter trials. 

The challenge is to transfer the HIV model to treatments for less lethal and more established diseases. A key issue is how strongly FDA officials support model-based clinical trial design and the collaborative efforts needed to establish drug and disease "libraries" of research data—the key to further expanding trial models and simulation. 

For these methods to gain broader acceptance, Donald Stanski, global head of modeling and simulation at Novartis, said it was important for FDA to champion Model Based Drug Development (MBDD) and to persuade agency reviewers to have confidence in this approach. 

FDA is using modeling to assist in NDA and labeling decisions, according to Bob Powell of CDER's Office of Clinical Pharmacology. The combination of modeling prior knowledge (on disease, placebo, dropouts, and drug effect) and clinical trial simulation, he noted, is beginning to be used to justify Phase IIb and Phase III study designs. However, Murray of CDER acknowledged that there is limited acceptance of trial modeling and Bayesian analysis among reviewers making final regulatory decisions. And CDER Deputy Director Douglas Throckmorton noted that FDA sees modeling approaches most often playing a "salvage role" for development programs in trouble. 

And just how eager industry is to share proprietary data remains to be seen. An informal survey of pharma companies indicates general support for sharing summary-level data on placebo responses and active controls, which FDA already makes public when a new drug is approved. But many companies remain reluctant to release patient-level data from clinical trials. 

Most research executives want to see the value of modeling efforts—that such approaches can lead to faster, better, more efficient programs—along with evidence that no one company can build enough models on its own to answer important questions related to drug development. And that kind of evidence is beginning to emerge. 

Richard LaLonde, global head of clinical pharmacology at Pfizer, reported that its Enhanced Clinical Trial Design Initiative saved the company $75 million last year and predicted even more benefits in 2007. Although Pfizer is closing facilities and making big cuts in its workforce, LaLonde said it's looking to recruit more statisticians and pharmaco-epidemiologists for this program. 

Stanski and others want to spur pre-competitive data sharing through a non-profit consortium that will address data needs and modeling approaches. The idea is to start with a specific disease state; perhaps one that raises an important safety issue involving a pediatric treatment or a serious infectious disease would spur interest and support. 

View from Washington

Drug safety concerns, unproductive methods, and high costs encourage innovative study designs and collaborative efforts.

Pressure Mounts to Streamline Trials

Just as this issue was going to press, news broke out of Washington, DC, that a federal health advisory panel was urging the FDA to approve a bird flu vaccine undergoing clinical trials even though research shows it is effective in about only half of all adults. Panel member Dr. Robert Couch of Baylor College of Medicine in Houston says: "Anything is better than nothing." The panel voted to recommend that the FDA approve the shot and indicated they believe the vaccine maker, sanofi-aventis, could play an important role in protecting against a possible pandemic despite the vaccine's limited effectiveness. The vaccine, which is being 

Stockpiled for use by government and emergency workers, protected 45% of adults who received the highest dose. That's well short of the FDA's desired protective rate of 70%. (Regular flu shots protect 75% to 90% of vaccinated adults under age 65.) 

Norman Baylor, director of the FDA's vaccine office, echoed the sentiments of Dr. Couch. Baylor said the benefit of at least having a licensed vaccine against a possible pandemic flu strain outweighs the disadvantages of not having a flu vaccine at all. 

In the trial, protective effects were observed in patients who received two 90-microgram doses of sanofi's H5N1 vaccine. The company says studies are already underway to look into the use of immune boosters to help increase the vaccine's effectiveness. 

It's a no-brainer that we would be wise to take advantage of protection, albeit imperfect, when we have no alternative. This interim solution, however, should not in any way detract from current and future efforts to develop a more efficacious vaccine against the deadly bird flu. 

Quickly developing more effective treatments against diseases like the avian flu is the thrust of the articles in our EDC & Information Technology supplement this month. 

The supplement covers innovative techniques such as adaptive trial designs, which approach clinical trials with flexibility. These novel strategies continually analyze and monitor unblinded study data separately from the main trial. If enrollment is not sufficient to reach a desired endpoint, data collection technologies help expand or extend the studies. 

The way patient reported outcomes (PRO) data is gathered is also becoming more efficient. And the EDC supplement covers the latest electronic PRO technologies (ePRO) that are making this possible, their regulations, and the convenience and speed they afford. Today's products are more user friendly than ever—portending more widespread use moving forward. 

Finally, the supplement offers strategies for using business measures to select the best technology for clinical research. It's a unique take on how to find the right technology for a clinical program. 

With continuing advances in information technology and data collection, more effective drugs are likely to result.  

From the Managing Editor

The fate of a new bird flu vaccine that provides limited protection rests in the hands of FDA.

Is Something Better than Nothing?

Japan is the second largest country in the world in consumption of pharmaceuticals, yet its clinical development activities are not very advanced compared to the United States and other developed countries. In addition, the lack of infrastructure for clinical trials is an especially critical problem for the country. 

There are several important factors that contribute to Japan's relative inactivity in clinical trials

  (see Table 1), which will be explored. 

Table 1: Factors Conspiring Against Trial Activity 			

From a physician's perspective, several issues reduce their incentive to conduct clinical trials. The first one is unsatisfactory financial advantages. Usually, all the fees involved with conducting a trial are paid to a medical site under a contract between its president and the pharmaceutical company. Although part of the money is paid to the clinicians who participate in the trial, the amount is generally considered insufficient by physicians. 

Second, since most clinical trials for drug/medical device approvals in Japan are conducted after equivalent clinical trials in the United States and other countries, trial-related articles are generally not accepted by well-known medical journals. 

Third, there are not many clinicians familiar with clinical research methods who have time to spend on trials. This is blamed on the Japanese medical education system, which has long focused on daily practice rather than clinical research. 

Similarly, few incentives plus a lack of awareness are credited with limiting patient participation in clinical trials in Japan. 

It is hypothesized that Japanese people are less likely to participate in trials because few financial advantages are offered under the national health care system. In the system, all Japanese people are equally provided with health care and covered under either national health insurance or social health insurance. Therefore, patients do not need to consider being subjects in clinical trials for the sake of financial benefit. However, there is no evidence for this hypothesis, and it would not be appropriate if subjects were willing to enroll in trials merely for financial benefit. An alternative view is that there may be a lack of understanding among Japanese people of the necessity of clinical trials. 

The infrastructure for clinical trials in Japan is also relatively immature. This problem is due to a lack of human resources, a lack of internal and external support at medical sites, limited means for patient recruitment, and other factors. Because it is difficult for pharmaceutical and medical device companies to obtain satisfactory results, they are reluctant to conduct clinical trials for drug/medical device approval. All of these problems are interrelated and constitute a vicious cycle (Figure 1). 

Figure 1: Japans Tepid Trial Atmosphere: A Vicious Cycle			

Figure 2 shows the decline in clinical trial applications filed with Japan's Pharmaceuticals and Medical Devices Agency between 1990 and 2002.

Figure 2: Trial Applications: Trending Downward

Given Japan's relative inactivity in clinical trials, the Japanese government, the Ministry of Education, Culture, Sports, Science & Technology, and the Ministry of Health, Labour, and Welfare released a statement in April 2003 called "A Three-Year Plan for the National Revitalization of Clinical Trials."

  In it, major problems with clinical trials in Japan and several future plans for solving them are presented. One of the action plans called for promoting a clinical trial network. 

So, in October 2003 the Large-Scale Clinical Trial Network (LCN) Project was launched. An important issue related to the launching of the project was the changing of regulations for conducting clinical trials for drug approval. On 30 July 2003 the Pharmaceuticals Affairs Law was changed so that physicians and dentists could conduct trials for drug approval. 

The LCN Project has two main purposes: creating a new nationwide clinical trials network and encouraging physicians, dentists, and related staff to conduct investigator-initiated trials for drug approval. The Japan Medical Association (JMA) has played a leading role in the LCN Project. 

The JMA was established in 1916 and includes 47 prefectural medical associations. The mission of the JMA is to promote policies that protect the health of all citizens and to preserve the autonomy of physicians at the national level of health care policy planning. The JMA's impact comes from its high membership rate. 

There are advantages to the JMA taking on the LCN Project: It has a nationwide network, outstanding initiatives in place in the Japanese medical field, and academic resources. In August 2004, the JMA established a new division, the Center for Clinical Trials of the JMA (JMACCT), to carry out the LCN Project. JMACCT activities started in October 2004. 

The LCN Project: to promptly provide the public with medically necessary or new pharmaceutical products and medical devices; organize multiple medical institutions into a network (i.e., the LCN); and conduct model clinical trials to improve the infrastructure for clinical trials in Japan.

Promoting the LCN Project: In pursuing the above, to maintain the activities of the JMACCT and the LCN in Japan; to support and oversee clinical trials in cooperation with the LCN; and to conduct other necessary related activities.

The entire budget for LCN Project activities is subsidized by the MHLW as part of its Health and Labour Sciences Research Grants (HLSRG). In most HLSRG-funded projects, personnel costs are somewhat limited. Apparently, HLSRG regulations have led some researchers to reduce the size of their projects. However, for LCN Projects, use of HLSRG has been more flexible and the JMACCT has been able to expense costs for human resources based on the JMA's internal rules. This has made it possible for JMA to recruit specialists in the field, and is one of the advantages of the JMACCT. 

Improving the infrastructure for clinical trials at each clinical site is important to encourage clinical trials in Japan. The LCN was created to solve this problem, by helping sites gain clinical trial knowledge and skills, including compliance with GCP standards. The JMACCT provides LCN member institutions with various forms of support, thereby creating an environment conducive to carrying out high-quality clinical trials. 

Registration for the LCN may be done either online through JMACCT's Web site (			

) or by submitting a form to the JMACCT by mail (Figure 3 shows the number of medical sites, both hospitals and clinics, recruited between December 2003 and March 2005). The legal definition of a hospital in Japan is an institution with 20 or more beds, and a clinic is an institution with less than 20 beds. 

Figure 3: One LCN Goal: Infrastructure Improvements			

Because investigator-initiated clinical trials (IICTs) for drug and medical device approval are relatively new (July 2003) and it is difficult for physicians to conduct IICTs without systematic help, the JMACCT has been providing assistance. 

Procedure for candidate trial product selection. 

According to the JMACCT view, candidate products should be those likely to be approved as soon as possible so that they may be used in clinical practice in Japan. In other words, prioritized candidates may be new, old, approved or yet-to-be approved, since the focus is on obtaining approval for pharmaceutical products approved overseas but not in Japan—this also applies to other products that have not been permitted for use for their approved indication and are used in off-label ways. 

To select candidate trial products, as a first step the JMACCT requested that the Japan Association of Medical Science (JAMS) recommend candidates by passing on the request to its 99 medical specialty societies to ensure that the listed products were necessary and appropriate. Since 2004, the procedure for candidate trial product selection has changed. Now, a candidate drug is not selected by external committee members but by an investigator. 

The JMACCT supports IICTs not only financially but also in many other practical ways. The JMACCT consults with investigators on trial protocols, case report forms, informed consent forms, etc. Cooperating with two insurance companies, it also created a new type of insurance for IICTs. Under current GCP requirements, the principal investigator of an IICT is responsible for any damage caused by the trial—just as a manufacturing company is responsible in drug/medical device approval trials. The insurance companies agreed to produce the IICT insurance with the JMACCT's approval because they presumed 

that the trials selected by JMACCT would be scientific and ethical. 

Standard operating procedures (SOPs) for IICTs is a hurdle for physicians because they do not have the time to develop SOPs on their own. Therefore, the JMACCT developed templates for SOPs, which is posted on their Web site. Reporting serious adverse events (SAEs) to the regulatory agency is another concern for physicians since sufficient time and human resources are required to fulfill this obligation. The JMACCT has been developing a simplified system for its IICTs to make SAE reporting easier for busy physicians. 

In February 2005, the JMACCT established a Data Management Division to manage data from clinical trials. 

The JMACCT recognizes that there are several challenges to developing better infrastructure for clinical trials in Japan and has been undertaking several activities to resolve them. 

To understand problems pertaining to clinical trial development and find solutions, the JMACCT held a symposium on the activation of clinical trials in November 2004 that was attended by representatives from all sectors. The JMACCT invited executive officers from the MHLW and the Pharmaceuticals and Medical Devices Agency (regulatory bodies), the President of the Japan Pharmaceutical Manufacturers Association (pharmaceutical industry), the President of the Japanese Society of Clinical Pharmacology and Therapeutics (academia), a well-known actress with a national license in nursing (the public), and the President of the National Hospital Organization and executives of JMA (physicians). 

The lack of awareness among Japanese people about clinical trials is one of the challenges facing clinical trial development. The JMACCT produced two posters to facilitate better understanding and provided them to over 150,000 medical institutions through the JMA network in January 2005. Other efforts include distributing JMACCT newsletters to sites registered with the LCN that contain information about trials. 

Developing infrastructure for clinical trials is one of the top priorities of the Japanese government. And the clinical development industry, academics, medical professionals, and the Japanese people expect positive outcomes from the LCN project. While it is true that solving the various problems involved in developing Japan's infrastructure for clinical trials will not be easy, the project represents an important milestone. 

The increasing number of sites registering with the LCN, the increasing number of JMACCTs supporting clinical trials for drug approval, and the growing scale of the Data Management Division of the JMACCT are valuable achievements. These types of initial developments are vital for progress toward the government's goal. As it is often said: "The longest journey begins with a single step." 

The authors would like to thank Ms. Elizabeth Lee-Hood, Mr. Yoshiyuki Sei, and Ms. Mai Goto for their assistance in the preparation of this manuscript. 

is a visiting scholar of the division of cardiology, Tokyo Women's Medical University. 

is director of regulatory affairs at the Center for Clinical Trials of the Japan Medical Association (JMACCT), 17 Fl. Bunkyo Green Court Center Office, 2-28-8 Honkomagome, Bunkyo-Ku, Tokyo 113-0021, Japan, 81-3-5319-3781, email: 

is director of the data management division at the JMACCT. 

is chief executive officer of Higashikori Hospital, and 

is chief executive officer of Teraoka Memorial Hospital.

Feature Article

Launched in 2003, the LCN Project calls for more studies and an improved trial infrastructure.

Promoting Clinical Trials in Japan

Outsourcing and trial management tool puts professionals in control of all aspects of a study 

 (Houston, TX) released an outsourcing and business process management and governance solution based on Microsoft business intelligence technology. Designed to help manage the complexity of blended outsourcing, offshoring, and internal shared services, the comprehensive governance tool provides an enterprise-wide view, enabling plug-ins for other business process intelligence and outsourcing management tools. 

The Business Services Dashboard helps organizations derive all the possible value from their business process transformation initiatives. The dashboard solution allows users to view the current status of each business process, along with measurement and management of provider performance. The new product provides drill-down details in six critical business process governance areas: financial management, issue management, contract management, performance management, compliance management, and relationship management. 

eShowcase

Outsourcing and trial management tool puts professionals in control of all aspects of a study

eShowcase: Business Services Dashboard

Digital writing solution speeds up data harvest while ensuring traceability and capture ease 

 (Paris, France) is out with a digital pen and paper technology product, called Clin'Form, designed to streamline handwritten entry of clinical trial data into an electronic CRF through a collaborative, Web-based portal. The product is based on the Forms Automation System architecture using the Anoto Digital Pen & Paper technology.  

Clin'Form enables a complete audit trail with full information traceability for data captured with digital pens. Also, tracking key users, including trial investigators, CRAs, and data managers, is possible, as well as study progress reports in real time on such measures as center openings, patient inclusion rates, and CRF completion follow-up. Once collected, Clin'Form facilitates the push of data to clinical data management systems in CDISC-compatible format, adding to its versatility. 

Digital writing solution speeds up data harvest while ensuring traceability and capture ease

eShowcase: Clin'Form

The advancement of new technologies and their adoption by the clinical community poses a challenge to regulators. The regulatory community is charged with ensuring safety and effectiveness and comes under criticism when problems ensue. Likewise, if patient and physician access to an important new therapy is delayed, regulators are the object of criticism by a highly educated and increasingly sophisticated consumer. 

In an effort to stay ahead of a new generation of technologies that range from genomics, cellular therapies, and combination products—where the divide between drugs, biologics, and devices is progressively growing smaller—the FDA has introduced the Critical Path Initiative (CPI).

The CPI is an FDA modernization effort to identify and prioritize challenging product development issues, as well as to identify novel solutions. The CPI, which began in 2004, has identified "opportunities" for collaboration between the FDA, industry, academia, and patients. These issues are all covered on the FDA's Critical Path Web site (http://

The primary goal of the CPI is to ensure that basic scientific discoveries move rapidly into new and better medical treatments, and that new tools and approaches are implemented to facilitate the evaluation of safety and effectiveness. Thus, the CPI is meant to provide practical means for continuous product development, so that as new scientific information is revealed, sponsors and FDA can consider it continually, allowing for a more rapid adoption of a new product or technology. 

As is often the case with efforts to develop new or improved regulatory means of scientific discovery, the CPI is also defined by what it is not. For example, it is not meant to replace existing regulatory structure, but rather fine tune it and allow for more timely and precise scientific examination. 

With the number of submissions for novel compounds down since the mid-1990s (see Figure 1), it is time to look for novel ways to expedite safe drug, biologic, and device development. Time and cost are key factors considered by FDA when reviewing and approving new products, and the CPI's job is to  consider "least burdensome" requirements. 

Figure 1: Decline in Novel Compound Submissions 			

To accomplish the CPI's goals, FDA is planning to work closely with the pharmaceutical, biotechnology, and medical device industries, as well as with the medical and scientific communities. 

The CPI is a future-looking program. In order for the CPI to be meaningful, product developers must have new tools to progress effectively along a multidimensional critical path that leads from discovery, or design concept, to commercialization. Three main areas in the FDA's critical path include: 					

assessment of safety through multiple development stages

demonstration of clinical utility (i.e., will the product benefit the specific people to whom the therapy is targeted)

demonstration of industrialization (i.e., can the laboratory concept or prototype be produced commercially).

Table 1 provides a summary of the dimensions of the CPI. 

Table 1: The Critical Path Initiative: A Future-Looking Program			

Innovation for medical devices differs from pharmaceuticals.  In contrast with drug development, the time from concept to market for a device can take as little as 18 months. In addition, unlike many pharmaceuticals, which are purely driven by clinical need, devices generally require the skill of the end-user. Therefore, the ultimate effectiveness of device innovations, such as a new spine implant, depends on continuous interaction between the industry and consumers. 

In May 2006 the Center for Devices and Radiological Health (CDRH) announced

  it was launching the Medical Device Innovation Initiative

  to make new medical devices available more quickly for patients. The initiative will attempt to expand current efforts to promote scientific innovation in product development, focus device research on cutting-edge science, modernize the review of innovative devices, and facilitate a least burdensome approach to clinical trials. According to FDA, the initiative should promote early interaction between the agency and the device industry, and should optimize review times and foster innovation. 

The CPI is meant to build on CDRH's strong commitment to basic science as well as the additional resources provided under the Medical Device User Fee and Modernization Act of 2002.

  It is not meant to repackage old ideas in a new wrapping. The success of the program will depend on whether it has the commitment from FDA management and is able to provide useful regulatory solutions for the agency's scientific staff. Of course, a number of uncertainties remain. 

Currently, safety issues may be detected during a clinical trial or after a product is on the market. With advances in technology, however, the current way of assessing safety may not be sufficient for cutting-edge medical devices such as drug-eluting stents and imaging devices used to detect cancer. The FDA's aim is to develop reliable methods that will identify significant safety problems early in the development process, ensure the safety of participants in clinical trials, and protect and facilitate the progress of new technologies. 

FDA wants to expedite applications for sponsors so the research and development necessary for demonstrating safety and effectiveness is done as quickly and efficiently as possible, and the time it takes to review new treatments and diagnostics is reduced. The FDA has recently completed the first round of quality reviews in the areas of biocompatibility, sterilization, and statistical analysis—three areas for potential cost and time savings that are common to many medical device submissions. For example, establishing the safety of new materials for use in implants or in combination drug–device products is paramount to the efficient assessment of new technological characteristics of novel devices. 

FDA's internal review process has identified areas for improvement in training reviewers and the need for up-to-date and clear guidance for industry. In the near future, FDA intends to expand the internal quality review program to additional scientific areas, including software validation. In addition, FDA has developed milestones for the review and evaluation of premarket submissions to ensure consistency, predictability, and accountability in the device review process. 

 The FDA plans to develop guidance documents in key scientific areas that will provide additional regulatory clarity, including modifications for PMA (premarket approval) devices, PMA annual reports, real-time PMA supplements, innovative combination product submissions, in vitro diagnostic device submissions, and revision of the 510(k) Paradigm guidance document.

  These guidance documents should increase the consistency and efficiency of the review process and give clear guidance for product development. 

 Since medical innovation is rapidly expanding, the FDA must review an increasing number of industry requests for guidance on developing new technologies. In an effort to manage these requests, the agency is working to enhance its infrastructure and resources. 

Two initiatives the FDA has taken to manage industry expectations is to employ outside experts through the Medical Device Fellowship Program and increase its staff with additional experts. These experts will help enhance FDA's capabilities to remain knowledgeable about new technological and clinical advances and to meet the expectations for timely and predictable reviews of innovative technologies. 

Another initiative that the FDA has taken is to use its own laboratories to perform research to support new medical device technologies. This initiative by the FDA may reduce industry resources necessary to demonstrate the safety and effectiveness of new technologies. 

 Since effective and on-going communication between FDA, industry, patients, and clinicians is essential for fostering medical device innovation and ensuring transparency, CDRH is looking for opportunities to improve interactions during product development and premarket review and to improve its tools for communicating medical information to consumers and practitioners. 

Based on the input it receives from these communities, CDRH will undertake an assessment to improve the manner in which it communicates critical public health information and recalls. This effort is aimed at making sure that regulatory actions are accompanied by the most complete and appropriate information so that individualized treatment decisions can be made about the medical products. As part of this effort, CDRH is updating its device recall procedures to make sure that regulatory actions are communicated in a way that is consistent with good medical practice. 

 FDA is planning to help sponsors develop medical devices in the areas of unmet clinical needs, including pediatrics. For example, the FDA plans to guide the development of new models to assess the safety and effectiveness of new stent designs, innovative toxicology animal models on injured tissues, new efficacy and safety statistical models for implanted cardiac stents, and biomarkers and diagnostics and their application to pharmacogenomics. 

The FDA is working to leverage information technology (IT) and develop better systems to protect consumers and assure the safe and effective use of new medical devices. With the use of new Web-based registries and postmarketing surveillance tools, it should be easier to learn about new devices postlaunch and provide up-to-date information about how to derive the most benefit from medical products. 

The FDA is also developing new IT systems that allow for better monitoring and tracking of regulatory submissions. It is piloting the use of Web-based software for PMA review, which makes real-time information sharing and communication among review team members possible, and creates a central location for document storage and retrieval. In addition, FDA is encouraging manufacturers to file electronic submissions, and provides information on its Web site about it.

A new free software tool, CeSub eSubmitter (CDRH electronic Submissions), evolved as a result of two very successful pilot programs: eLaser and Turbo 510(k).

  CeSub eSubmitter allows sponsors to electronically: 					

complete and submit 510(k) premarket notification applications to the Office of In Vitro Diagnostic Device Evaluation and Safety (OIVD)

submit information for a variety of radiation safety Product Reports and Annual Reports for radiation emitting products to the Radiological Health Program.

The agency is continuing to evaluate new electronic databases to facilitate the application process. 

In the very near future, innovations in medical technology will fundamentally transform health care and delivery systems, providing new solutions that will challenge existing paradigms and revolutionize the way treatments are administered.  The FDA has clearly indicated a desire to be a partner in the development of these new and emerging technologies. 

As these technologies advance, the critical paths from concept to market present greater challenges for both innovative device manufacturers and the FDA. Since current review methods for assessing the safety and effectiveness of these products may not be sufficient, development and review processes must change. The evolving CPI program is a means for the agency to better use its resources to bring efficiency to the review process for emerging technologies, and close the developing gap between the practice of medicine and the practice of regulation. 

The authors would like to thank Mark Citron, MS, senior vice president, regulatory affairs & quality systems, BioMimetic Therapeutics, and Joyce Hays, MS, CEO, Target Health Inc., for reviewing the manuscript. 

 MBA, PhD, is president of Target Health Inc., 261 Madison Avenue, 24th Floor, New York, NY 10016, email: 

 BS, JD, is manager, regulatory affairs, 

 MS, is senior manager, regulatory affairs, RAC, and 

 PharmD, is senior director, clinical and regulatory affairs, with Target Health Inc.

Interaction is high on FDA's list of ways to improve the development & review process for technologies.

The Critical Path Initiative Meets Medical Devices

Most of us spend our lives working with a personal or shared computer that we use for basic tasks: checking email, writing documents, creating spreadsheets, and accessing the Internet. Unless something goes wrong or we are using an old, tired computer, we typically use less than 25% of its processing power—with occasional bursts to 100%. 

The utility model at work is "one person, one computer." And our ability to work is rarely limited by access to one, although it is still occasionally limited by lack of access to the Internet. Today, computers are an essential part of our work (wherever we are). 

There is, however, another world of computers that differs dramatically from the one we all know best. That is the world of servers. 

These workhorse computers live in heavily air conditioned facilities, stacked one on top of each other on "racks," and provide the underlying infrastructure of corporate networks. They also house the central store of corporate email, documents, and other essential data, along with the applications that deploy the data to users. Nowadays, whenever a new application (from a "collaboration space" to a new EDC application) is offered to a user in a company or hospital, you can be sure that there is a server (or many servers) that are involved in managing the application. 

Fortunately, the world of servers is one that few non-IT professionals need to understand or work with. Nevertheless, there is a quiet revolution taking place, one that has been growing for several years now. The concept of virtualization, or virtual machines, is a very important trend that may eventually spill over into our world of personal computers. It's worth understanding, even if you don't plan on a career in IT. 

For the uninitiated, the server sounds like a very sophisticated and foreboding specialty IT hardware device. Although this may sometimes be true, it is best to think of a server as a high-end version of your personal computer. 

Although any computer, including your laptop, can act as a server, the typical corporate server is a specialized hardware box that can contain several central processors, slots for rapidly plugging and unplugging large hard drives, and other modifications. Servers are found on networks both large and small, where they "serve" data and applications upon request from other computers on the network. 

When someone types a URL into a Web browser, they are actually making a request of a Web server to display a page. In fact, that page may be assembled, behind the scenes, by cascading requests to several other servers. When someone accesses email on a network, they are again making a request of an email server, which provides the email to the client on the PC or workstation, or to a Web server for display in a Web email application. 

Servers are not necessarily expensive hardware devices, but they can be quite inefficient and costly for companies. The additional operating system, software, management, and maintenance fees can add up to a substantial total cost for ownership. 

It is also very common for each server to house a single application. The major reason for this is to avoid the conflict that sometimes happens between two applications, which leads to server crashes and downtime. However, most applications don't use nearly the entire capacity of a single server—some use 5% to 15% or less. 

Since modern businesses often run many different applications, the server room can house dozens of servers, each running at very low capacity. IT staff are very reluctant (as they should be) to upgrade software or apply patches to the production server because they want to avoid taking critical systems down for hours at a time. They prefer to test updates on an identical implementation of the software to confirm it works and not crash the server. This means that every major system has a parallel "practice" system for testing, validation, etc. 

Finally, server hosting is limited by two practical considerations: the cost and availability of hosting space and electricity.  

Fortunately, there is a very practical solution to many of these problems known as virtualization, which uses "virtual machines" (VM). 

In a traditional server (or most computers, for that matter) the hardware includes a central processing unit (CPU) and a variety of devices for inputting, saving, transmitting, and viewing data—along with a very rudimentary system for using the basic operations of these devices. 

In almost every computer, the manufacturer (or occasionally the owner) installs an operating system (OS) that knows how to work with the various hardware devices to do the basics of computing: reading data, writing to a hard disk, displaying on a screen, etc. The user interface to operating systems is, nowadays, a graphical environment that gives visual feedback to these system tasks. 

An example of an OS you know well is Windows (and now, Vista). Most applications are designed to be installed "on top of" the OS, and will make extensive use of OS functionality in performing operations that interact with the hardware of the system. 

Virtualization offers companies a practical solution to bypass server limitations.

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