EDC Management and Reporting Adds Features

New enhancement expands Rave's EDC data-reporting capabilities

 (New York, NY) introduced its latest enhancement to the company's Medidata Rave EDC management and reporting system.The Dynamic Tabulation Engine expands Rave's data-reporting capabilities to increase data availability and ease of use.  

The Dynamic Tabulation Engine employs an interface that allows users to define how clinical data sets and tables are collated, formatted, and extracted. Clinical data can then be immediately viewed, extracted to an external data warehouse or processed by third-party reporting and analysis tools. 

Once defined, tabulation formats can be reused across studies in Rave, to streamline data extraction and ensure consistency across studies. 

Web-based Solution for Trial Site Recruitment

Solution to speed up site and investigator selection

(HMS; King of Prussia, PA) announced its Clinical Investigators, a Web-based software service for pharmaceutical company and CRO clinical trial site recruitment.  

Health Market Science Clinical Investigators 

Clinical Investigators links an intuitive Web-based user interface with a national, comprehensive database of trial experience detail, claims data, and the HMS Provider Master File. The database features over 4.5 million individual providers, and 1 million health care organizations.  

The database includes physician reference data, clinical trial experience, and claims volume rankings, which can help accelerate, identify, and recruit investigators with access to the patients needed for a particular trial. 

Software based on Microsoft office eliminates incompatible apps

TranSenda International (Bellevue, WA) announced Office Smart Clinical Trial Manager, a clinical trial management system (CTMS). The software is an Office Business Application and is built on Microsoft Office SharePoint Server 2007. The product offers clinical trial study software that works with Microsoft Office, which eliminates redundancies of data entry and toggling between applications.    

ClinBUS, a data interchange technology from TranSenda, creates a common data repository for a clinical trial's business process data. Leveraging open standards and CDISC conventions, ClinBUS addresses clinical data syntax and semantics and offers insight into metadata for dashboards, reports, and workflow. 

TranSenda International, (866) 895-1300, 

Articles

eShowcase

The latest eClinical software in the clinical trials industry.

eClinical Software: October 2008

For hundreds of years, the doctor/patient relationship has been asymmetric, with the physician traditionally seen as holding the balance of power and the patient being dependent on the physician. While there are many reasons for this, one of the most important is the asymmetry of knowledge: The physician controlled almost all information and often parsed it out sparingly. Over the past 30 years, beginning with the first direct-to-consumer advertising in 1981, we have witnessed a dramatic shift in the information available to patients. And this shift has contributed to a noticeable increase in patient autonomy and choice in medical care. However, the revolution has just begun, brought to you by the Internet and Health 2.0. 

Health 2.0 is an outgrowth of the Web 2.0 era. Using modern, flexible Web site design methods, Web 2.0 Web sites typically leverage social networking and the collective knowledge of the masses to create value and quality for users of the Web site. Two good examples of Web 2.0 are Facebook and Wikipedia. Health 2.0 Web sites apply these same principles and designs to health care. 

Even in it's infancy, Health 2.0 Web sites have begun to demonstrate the potential to dramatically shift the doctor/patient relationship and perhaps even disintermediate the need for a physician in some cases—in other words, remove the middle man. Eventually, Health 2.0 may bring dramatic change to the economics and practice of medicine itself. Through Health 2.0 Web sites a patient can do amazing things: search for and obtain tailored, high-quality medical information, medical diagnoses, personal medical record keeping, exhaustive SNP analysis of their own genome, and even some do-it-yourself epidemiology.   

The most common use of the Internet for health purposes is the search for health information. Since the Internet first became publicly available, patients have been using the Web to gather information about their health. But the content was often uneven and easily dismissed when brought to physicians and sometimes simply dangerous. Although Google Health and its cousin Microsoft Health Vault offer an improved search of high-quality health Web sites, independent Health 2.0 Web sites such as OrganizedWisdom have begun to deliver high-quality information about patient illnesses and treatments. 

OrganizedWisdom uses physician "guides" to vet search information as high quality and organize it in an easily digestible form for individuals seeking answers to health care questions. Armed with data from these sources, patients sometimes know more about therapies and clinical trials than their physicians, and are now taking on new roles in driving the doctor/patient dialogue. 

Beyond information, some of the latest Health 2.0 Web sites actually allow patients to disintermediate the physician in many cases, much as Amazon eliminates the bookstore middle man and Dell the computer store. Through online Web sites, patients are now able to comparison shop for medical care in some markets (Carol) and buy care packages in the same way they might buy a book from Amazon. Additionally, dozens of Web sites allow consumers to rate their physicians, such as Vitals and rateMDs, and many have links to make appointments (ZocDoc) or search for disciplinary actions and malpractice claims against a physician. These sites allow patients to make more informed choices about their care and share with others their experiences. 

Social networks and communities are the bedrock of Health 2.0 and continue on the theme of shared information empowering personal health decisions. The most ambitious of these is Revolution Health, which provides health information, physician searches, health blogs and information, and many different health communities. Other similar communities such as iMedix follow the same concept of a general community for all health and wellness issues. 

Many Health 2.0 communities specialize in a particular disease or small group of diseases, creating a Facebook-like user experience. Targeted communities have sprung up on Web pages devoted to diseases such as diabetes, mood disorders, and alcohol abuse and to wellness topics like exercise. Through these sites, patients are sharing their experiences, motivating commitment to treatment, and providing a support community for each other. 

One of the most dramatic demonstrations of patient empowerment through the Web is PatientsLikeMe, where patients with severe chronic conditions post detailed, longitudinal data on their disease courses, treatments, and side effects. Interestingly, this information is often quite intimate, and patients are posting these details without concern for their privacy. By cleverly structuring, aggregating, and hyperlinking this data, PatientsLikeMe allows patients to understand how their symptoms and treatments compare with others. With thousands of patients reporting, the aggregated information provides users with a rich, understandable, and intimate view of their illness. 

This type of information has never before been available to patients and it might even teach a physician a thing or two—although it may create some headaches for pharmaceutical companies and regulators who have to sort through it, looking for safety issues. 

Physicians sometimes don't have the time needed to completely educate their patients about all the medicines they are taking. In fact, physicans and pharmacists alike may sometimes overlook important interactions. Again, Health 2.0 Web sites such as PharmaSurveyor, iGuard, and doublecheckMD allow patients to enter their medicines, search for interactions and adverse effects, and even be notified when new ones are identified and reported. 

A plethora of personal health records (PHRs) have recently arrived—from the Google and Microsoft entries to Medem, MyMedicalRecords, MedCommons, and many others. These PHRs allow patients to keep a permanent, longitudinal record of their health data, either hand entered or linked from medical records, and provide access to anyone who needs it—from new physicians to emergency room physicians. The transfer of authority over medical records, although slow in coming, is a major step in patient empowerment. 

Patient empowerment through the Internet can go far beyond searches, communities, and record keeping. If a patient doesn't want to bother with actually scheduling a visit to a physician, he or she can log on and have an immediate online visit with one through AmericanWell. A variety of specialists are immediately available for medical consultation and referral if necessary, with notes from the encounter available to the patient and their nonvirtual physician. Obviously online visits aren't going to work for many medical problems, but they can be enormously empowering to patients with simple questions and easy to address medical issues. 

Sometimes self-diagnosis may require a laboratory test or two, something previously restricted to physicians—until Health 2.0. Now, a patient can go onto MyMedLab and order from hundreds of lab tests, go to a local lab for the blood drawing, and receive the results without the intervention of any physician. More importantly for some patients, these tests are performed outside of any medical record or insurance record. 

Going beyond personal care, we come to the role of familial and genetic components of health and illness. Simply understanding one's family history of illness can be very valuable for identifying and mitigating medical risks and even medical diagnoses. MyFamilyHealth allows members of a family to create a shared, detailed family tree that can be annotated with medical histories, providing valuable knowledge for the patient and an important tool for the physician. 

Nowadays, there is much to discover about genetic diseases. Through sites like 23andMe, a patient can order (now for only $399) a genetic SNP analysis of more than 80 different genetic loci for diseases, genetic traits, and health conditions. The amateur geneticist can determine whether they have the genetic traits associated with macular degeneration, type 2 diabetes, various malignancies, and other less ominous traits. In some ways, this is the ultimate in empowerment, but may leave some patients with too much information. 

An interesting application of Health 2.0 and Google maps "mashup" technique is the do-it-yourself epidemiology site, WhoIsSick. With this site, anyone who believes they have an infectious illness such as influenza or a gastrointestinal virus can enter their symptoms and their geographic location on a Google map. They can then search for geographic clusters of patients with similar symptoms occurring within a specified time window, theoretically giving clues to developing outbreaks of nasty viral illnesses. 

Medicine in the United States is one of the few industries in which the consumer of the products and services has little to no say in the setting of prices and delivery of services. The painfully cumbersome economic infrastructure of health care has thus far prevented a serious overhaul in consumer choice to bring it up to the same level as in almost any other industry. However, the transformative nature of Health 2.0 may very well bring choice and the free market to the consumer long before the government can or will. 

				Paul Bleicher			MD, PhD, is the founder and chairman of Phase Forward, 800 Winter Street, Waltham, MA 02451, (888) 703-1122, 

Technology Viewpoint

How the Internet is blurring the lines between patient and physician and redefining old roles.

Health 2.0: Do It Yourself Doctoring

• With 20 years of experience within the IT industry, particularly for life sciences companies, 

 (Whippany, NJ) managing director of Europe, after having served as the company's director of business development. 

 (Wayne, PA) senior consultant of clinical data strategies. Bringing with him nearly 20 years of experience in the pharmaceutical industry, he previously served as a senior director of clinical information systems at 

 to the company's newly created position of chief information officer, where Owens will serve on the executive committee and provide leadership to IT and development projects. 

 (Santa Clara, CA), allotting him the responsibility of the company's business development, client services, software development, and quality assurance. 

 • Bringing with him 18 years of experience in a range of therapeutic areas, 

 MBA, will serve as vice president of Clinical Operations for Global Neurology, with 

 (Montreal, Quebec Canada) has appointed 

 to chief executive officer, after serving as chief development officer since 2007. 

•Serving as the company's president and chief operating officer since October 2007, the board of directors of 

 (Marlborough, MA) appointed two senior managers within the organization: 

 fills the new position of executive vice president, human resources and administration; and 

, MD, has been appointed to senior vice president of medical affairs.   

 has become the vice president of drug discovery for 

 (Toronto) where he will lead a group of research scientists in focusing on the company's new discovery projects. 

 (Wilmington, NC) as its new chief operating officer, which leaves him responsible for the company's global drug development services operations.     

•After acting as BioDuro's vice president of business development and collaboration management, 

 will become the new vice president of business development at 

 to vice president of synthetic chemistry.   

 has increased its staff with seven new members: 

 will become the senior director of business development; 

 is the new coordinator of lab and logistics. 

 (Clinton, NJ) has added two new executive members to its team, including 

 as senior vice president of commercial operations, and 

 who will serve as senior vice president of human relations. 

•Continuing on its ambitious goal of discovering as many drugs as possible within 18 months, 

 (Durham, NC) has added three new members to its team: 

, MBA, has become vice president of commercial operations; 

 is the new senior director of scientific affairs; and 

Extending their collaboration for an additional year, 

 (Madison, NJ) intend on continuing to identify and develop subjects and further assess clinical possibilities in the treatment of atherosclerosis.

 (Indianapolis, IN) is undergoing, it is also outsourcing its clinical trial monitoring work in the United States and Puerto Rico to 

 (Research Triangle Park, NC), which is expected to effect about 265 of Lilly's employees.

 (Stuttgart-Wangen, Germany) has become the first company in the world to utilize 

 (Indianapolis, IN) xCELLigence System, which was purchased at the Analytica 2008 trade in Munich.

 (Ridgefield, CN) have extended their Alzheimer's disease collaboration for an additional year.

Based on a recent marketing services agreement, 

 (Rockville, MD) with the task of identifying new manufacturing clients.

Upon signing a business development contract with 

 (Bilthoven, The Netherlands) clinical research services will soon be promoted in the North American medical device market.

 (Fort Lauderdale, FL) CRO Preferred Program, 

 (Tuscon, AZ) will use its EDC software in a Phase II oncology study.

With intentions of furthering its capabilities in Asia and enhancing access to new medicines that may benefit patients with inoperable Hepatocellular Carcinoma (HCC), 

 (Wilmington, DE) has entered a partnership with the 

 (Singapore) to develop anticancer compounds.

 (Boston, MA) has entered into an agreement in which it will utilize 

 (Woburn, MA) high-speed chemistry technologies and capabilities in its obesity program.

Upon expanding their three-year partnership, 

 (Redwood City, CA) exclusive manufacturer for the pharmaceutical intermediates and active pharmaceutical ingredients that it offers.

 (Mountain View, CA) WinNonlin AutoPilot has been purchased by a global biotechnology company, making it the seventh company to adopt the software.

Inc. magazine has announced its list of the 5000 fastest growing privately owned companies in the United States, which includes 

 (Boston, MA) has been awarded CIO magazine's 2008 CIO 100 award, which is an annual award program that acknowledges organizations worldwide for exemplifying excellence in information technology.

 (Waltham, MA) Lincoln Safety Group, has been named to the Boston Business Journal Champions in Health Care list.

 (North Yorkshire, UK) has launched a new resource division called Medvance Resourcing, which was designed to provide the industry with clinical professionals that have experience with clinical trials for medical devices.

After working with over 1000 clinical trials across more than 70 languages in the past five years, 

 (Leeds, UK), a translation and interpreting company, established a new division specifically for life sciences.

The Women's Business Development Center-Chicago has certified 

 (Deerfield, IL) as a Women's Business Enterprise, which confirms the business is at least 51% woman-owned, operated, and controlled.

 (Miramar, FL) has established, Acromon Clinical Research Organization, a new company formed to further expand its clinical research management services.

People interested in learning about or joining a lupus clinical trial now have the Center for Clinical Trials Education, created by the 

The U.S. Drug Approval Trends and Yearbook 2008/2009, 

 (Boston, MA) overview of drug approval trends and metrics, shows that U.S. marketing applications for new molecular entities increased 33% in 2007.

The Foundation for Improving Data Quality

 (FIDQ; Southeastern, PA) had its first meeting, in which the discussion focused on future initiatives to achieve stronger success rates of clinical trials dependent on subjective endpoints.

 (Gaithersburg, MD) Beijing facility, helping to solidify its purpose as a U.S.-based CRO that conducts GLP studies for drug development services globally.

In response to growing demands for the integration of Electronic Data Capture (EDC) with Interactive Response Technology (IRT), 

 (Waltham, MA) has completed the acqusition of 

 (Radnor, PA) for the cost of $40 million.

In attempts to strengthen its drug discovery group, 

 (Toronto, ON) acquired certain assets and exclusive rights to three drug discovery projects from 

News

Industry news focusing on the people and organizations who work in the clinical trials profession.

Business and People Update October 2008

With more and more clinical trials taking place outside the T-(trial) zone—the United States, UK, and Western Europe—comes a unique challenge most companies in the life sciences industry, especially emerging ones, might say is "best left to the professionals." It's easy to understand why when you consider what that challenge can entail.     

Jim Walters, managing director, Life Sciences group of Aon Corporation. 

Imagine being told that one of the trials in your multicountry Phase III oncology study requires liability insurance before it can get under way. Not only that, the policy must be acquired locally and written up in the local language. With every day lost translating into lost dollars for sponsors and possibly missed opportunities for patients, wanting to leave insurance to the professionals can make sense. 

"There's many nuances and requirements that need to be addressed, especially when a company is doing a multicountry trial," explained Jim Walters, managing director of 

 Life Sciences group, a clinical trials insurance consultant based in Chicago. "Weaving your way through this malaise of regulations can be overwhelming." 

And confusing. Although Walters says most sponsors today wouldn't start a trial without first purchasing clinical trials insurance to cover subjects and any liabilities that could arise—think back to the TGN 1412 Phase I tragedy—it isn't always a prerequisite. Some countries require it in the sponsor's regulatory filing package, some don't. Of the countries that do, some will accept insurance certification from a U.S. policy, but many will not according to Walters, who described the insurance scene as a moving target. 

To help its clients—mostly the CROs and smaller companies—successfully weave through the insurance malaise, AON created its Clinical Trials Risk Map. Walters and his colleague Eddie Albers, director of the Life Sciences group, borrowed the idea for the map from another one the company publishes on world-wide political risks. And for the past five years, Aon's vast 120-country global network has cataloged and continually updated the insurance requirements for over 80 countries, publishing it for the first time this year. 

 "The map itself focuses on the government regulations," explained Albers, "we focused on what countries require it [insurance] from a government standpoint." 

So who else would require it if the government didn't? Usually a hospital, ethics committee or investigator involved with the trial will ask for insurance certification. And in addition to trials liability insurance, there's product liability insurance for postmarket drugs, which became harder and more expensive to come by for the big guys after a series of product recalls and problems. Finally, there are the CROs, whose exposures are more "professional": They need to cover employees in the case of a mistake, such as during subject randomization. 

Nowadays, CROs working overseas also sometimes serve as legal representatives on behalf of their sponsor, says Walters. "Many times they're heavily involved in insurance related issues in helping their clients try to get the trials started," he said, "so many of the CROs will ask us to help out clients arrange these kinds of coverage." This has especially been the case for insurance that must be procured locally in one of the emerging trial markets. 

In addition to the Risk Map, Aon is making it easier for customers to handle their insurance needs with RiskConsole. Launched this past August, the Web-based module eliminates many frustrations companies faced pre Web 2.0, including snail mail, time zone challenges, and a heavy reliance on email. RiskConsole brings online efficiency to the insurance process, which fits in with Aon's plan. 

 "The last thing we want is for insurance requirements to hold up the trial," said Walters, "our goal is to inform our clients when they need it, where they need it, how much they need, and how to make that procurement as efficient as possible.—

Insight into obtaining insurance for a clinical trial and if or when it should be left to the professionals.

Trial Insurance Just Got Easier

Sometime this autumn the European Union will announce details of the €600 million ($900 million) funding it is going to put into health care research in 2009, under the grandly titled program, "Optimizing the Delivery of Health Care to European Citizens." Much of the money will be available for assisting clinical trials—on condition that the candidates for funding match the very precise specifications that the EU sets out. 

Based on the almost-final text of the program, it is possible to give interested readers the chance to get ahead of the field in preparing their applications, because many of the areas designated for support involve clinical trials. The inclusion of clinical research is expected in many of the broad themes the EU has chosen for the program. One of these themes, translating research for human health, aims at increasing knowledge of biological processes and mechanisms involved in normal health and in specific disease situations so as to transpose it into clinical applications including disease control and treatment, and to ensure that clinical data (including epidemiological) guide further research.  

The EU's broad-ranging overall objectives include, it says, improving the health of European citizens, boosting the competitiveness and innovative capacity of European health-related industries and businesses, and addressing global health issues, including emerging epidemics. The emphasis of the program is on the translation of basic discoveries into clinical applications and the development and validation of new therapies, and "clinical research will continue to be a main focus." 

For clinical trials, the EU contribution will be limited mainly to Phases I and II, with further studies covered only exceptionally—such as in adapting off-patent medicines to the specific needs of pediatric populations, where consideration may be given to studies including up to Phase IV clinical trials. And, says the introduction to the program, all projects conducting clinical research must take account in their research protocols, methodologies, and analysis of results of possible differences between women, men, children, and the elderly. 

Large-scale funding will be made available for many projects. One concerns optimization of current therapeutic approaches to schizophrenia. "The project should focus on the pathophysiology and treatment of schizophrenia, and has to include a preclinical (e.g., neurophysiology, pharmacology, functional imaging) and clinical component (clinical trials). A strong translational approach with a view of developing new or optimizing existing therapeutic tools is essential," says the EU. 

Another, in translational vaccine research for poverty-related diseases—notably HIV/AIDS, malaria, and TB—will support early human testing of promising vaccine candidates. "The vaccine candidates must already have been selected through vigorous preclinical testing and must have demonstrated efficacy in recognized animal models. Projects will support Phases I and IIa clinical trial activities with a view to preparing the most successful candidates for later development." 

Explicitly, activities related to the preparation of human clinical trials, including GMP production, formal preclinical toxicology, and protocol writing may be included in the projects. A related project will focus on the clinical development of promising anti-HIV microbicides, including studies on new and improved tools for in vitro research and for testing toxicity and efficacy in preclinical as well as in human studies.  

"Academic, investigator-driven multicenter Phase III clinical studies to provide new evidence—not yet addressed by ongoing and/or previous trials—for new strategic decisions in the management of heart failure," will be rewarded with support too. To qualify, projects must address validation of new therapies or strategies, or address identification of the most effective ones among those already available but not well exploited. The study population should address gender balance and may include subjects with different degrees of functional impairment. 

Another grant is available in the same therapeutic area for elucidating the genetic and environmental components that contribute to cardiac arrhythmias, the relative importance of each of these factors, and interactions between them. "Achieving this aim should be ensured by a multidisciplinary approach bringing together basic research studies with clinical investigation, and the involvement of industry." 

Research into potentially new and reemerging epidemics is to be backed as well. The focus will be on confronting emerging pathogens with pandemic potential, including zoonoses (such as SARS and highly pathogenic influenza). Funding is available for the full value chain of health research: from innovative basic research to early stage clinical trials of new prevention, diagnostic, and therapeutic measures and all the way through to the implementation research supporting effective public health responses. 

Identification and development of vaccine candidates for neglected bacterial infections is another area scheduled for support. Projects should give priority to pathogens causing trachoma, leprosy, and/or Buruli ulcer. Essential preclinical testing in vitro and in vivo should be an intrinsic part of the project, and bringing existing lead candidates to Phase I clinical trials is also covered by the funding. 

Another broad theme, translating the results of clinical research outcome into clinical practice, will aim to identify the best clinical practice in order to understand decision making in clinical settings in primary and specialized care and to foster applications of evidence-based medicine and subject empowerment. The focus will be on the scientific benchmarking of strategies; investigating outcomes of different interventions; some aspects of pharmacovigilance evidence; specificities of the subject (such as genetic susceptibility, age, gender, and adherence); and cost benefits. Overall, this should advance the application of evidence-based medicine in Europe, says the introduction to the work program. "The improved use of clinical research findings in clinical diagnosis and treatment as well as subject self-management of disease should be demonstrated and the cooperation between researchers in Europe and other geographic regions enhanced to promote integration and excellence of European research in the area." 

Within the theme of innovative therapeutic approaches and interventions, the focus for 2009 funding is regenerative medicine—enhanced by the recent adoption of the EU regulation on advanced therapy medicines. Three major collaborative project topics are envisaged, all aimed at translating promising therapeutic approaches from the preclinical to the clinical stage. Projects will be expected to include in-patient trials at some stage of their duration, paving the way toward therapeutic products. Proposals containing appropriate preliminary data will be able to proceed to in-patient trials earlier in the project. The essential feature of each project will be the identification of a potential therapy to move into the clinic, and surrounding this with necessary ancillary research. 

In cell therapy for tissue and organs, proposals are invited on transplantation of cells for reconstruction and regeneration of diseased or injured tissue in systems that have potential for appropriate in-patient trials during the course of the project. Proposals with sufficient preliminary data to proceed to in-patient trials at an early stage of the project are preferred. Proposals involving in-patient trials at a later stage of the project will also be considered, provided they include a road map to the clinic containing predetermined milestones. To complement in-patient trials, supporting research—such as improving understanding of mechanisms, immunogenicity, methodology to demonstrate whether the treatments are having a direct effect, or testing refinements to the system—should be carried out.  

On a more prosaic note than these heady heights of new research, some useful advice has just appeared on the processing of products already in the EU authorization pipeline. The European Medicines Agency has issued a guide clearly setting out the time allowed for applicants to respond to questions and issues raised during the assessment of new marketing authorization applications in the centralized procedure. This has been a vexed question for years because of the intrinsic complexities of the procedure, and many executives responsible for development and registration will welcome a clear statement of the rules. 

As is well-known, the legislation sets out a timetable of 210 days for the evaluation of centralized marketing authorization applications, from submission to opinion. But as is equally well known, confusion sometimes arises over how long applicants may take to respond to questions or issues raised during the assessment. The agency says it is aiming to give applicants enough time to respond, including to requests for additional data or for results from additional studies.  

At the same time, it wants to avoid premature applications—which are then supplemented during the review period with substantial new data that should have been presented with the initial application. The note contains a firm reminder that, in general, no substantial data derived from new studies should be introduced as part of the responses to questions, unless specifically requested by the agency. What may be included quite legitimately is new analysis such as follow-up data from previously submitted studies. 

What the agency is recommending is that before an application is submitted, the applicant should seek a presubmission meeting with agency experts, including a discussion of related ongoing studies—covering safety, when those studies will be available, and whether they are critical to the assessment. This will give the agency a sense of whether the application is premature or if it might benefit from the inclusion of data from ongoing studies prior to the application being submitted—although "it is of course recognized that it is up to the applicant to decide when to file and whether to accept the advice." 

The procedure, as the agency sees it, should be as follows. The agency's committee on human medicines (the CHMP) produces a list of questions at day 120. The agency and its designated experts for the application—the rapporteur and corapporteur—should immediately meet the applicant to clarify the intent behind the questions and explain the concerns. Applicants need to be given sufficient time to respond, and the agency is suggesting a limit of three months, extensible by agreement for up to another three months. The clock then restarts on day 121. At day 180, the CHMP produces a joint assessment report with a list of outstanding issues to be addressed by the applicant.  

There is a need for a more streamlined process from day 180 to the opinion being adopted, believes the agency. So the written response to this list should normally be delivered within one month and should contain only very limited new data derived from new studies. In exceptional circumstances, a one month extension in submission of the written responses may be granted if sufficient scientific justifications is presented. Applicants should also be ready to provide an oral explanation at this stage. 

After that, it should be straight downhill to marketing authorization—but that is perhaps still in the realm of pipe dreams. 

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

View from Brussels

The EU provides extensive funds to the clinical trials industry in an effort to better health care delivery.

Helping Trials to Help European Health Care

When FDAAA was enacted last year, the Clinical Trial Databases section of the Act called for a three-year timeline of requirements toward furthering clinical trials reporting on the Web. September 27 was the deadline for sponsors to provide reporting of basic results on 

"This deadline is causing some angst," Tim Bacon, CEO of Newtown, PA-based PeerView, said prior to the deadline. "With the results requirement, sponsors are required to disclose very granular results data within one year of completion of final collection of data for the primary outcome—a data point that most sponsors were not even tracking prior to FDAAA." 

The results requirements include  demographic and baseline characteristics of the study participants, results values for each of the primary and secondary outcomes for each arm of the study, point of contact for scientific queries, and information on sponsor agreements with investigators that could restrict their ability to discuss or publish trial results. What makes the results requirement most complicated is the format in which the results must be submitted: Rather than uploading study results that have already been compiled into a clinical study report for example, using 

's online Protocol Registration System (PRS), sponsors must first create results tables and then enter the data and statistical analyses.    

Adding the results to the trial listing increases the transparency of the drug development process to the public, which is what the Act intended. Stiff penalties and fines can be levied against sponsors who do not comply with FDAAA and its deadlines. Even if sponsors have results listed on their Web page, or in another like repository such as ClinicalStudy 

. "Of the top pharma and biotech companies (by revenue) we surveyed," said Bacon, "seven out of 10 had links to results on their own page." 

As our Washington columnist Jill Wechsler reported in March of this year, the December 26, 2007, deadline for the clinical trials listings requirement led to a doubling of new trial registrations from 250 to nearly 500 a week. Other studies already registered had to be modified to include the additional required data sets. 

Bacon, whose company provides an interface application that helps with this registration process, says that FDAAA and its requirements are only one part of the disclosure picture. "The biggest red flag on the horizon is what's going on in the rest of the world. There is a growing number of other countries that are evaluating mandatory registries such as this," explains Bacon. "But what data are they going to require? In what language? And how will it be posted?" 

So while the global regulatory outlook on disclosure is an unknown to sponsors, they are still developing internal processes to deal with the known. "Some will develop internal groups or applications to deal with the data requirements," said Bacon. Others may turn to companies such as PeerView to help struggle through the next stages of FDAAA disclosure requirements. According to Bacon, VCTR (the Veritas Clinical Trial Register) system helps standardize the process, and helps with the data creation and capture needed to feed into 

"PRS is a bit of a perfectionist," comments Bacon. "It only accepts certain characters and rejects others." The PeerView system features error and fact checking so that data can be accurately inputted. The system manages the process by taking a regularly scheduled feed from the sponsor or CRO—or both—CTMS, multiple CTMS can be handled. This information is then fed into the backend of the VCTR to create data sets that can be standardized to 

, and routed to the various internal authorities (IP, legal, SOPs) for approval, and then posts it to the public registries on the sponsors behalf. "This helps because the various clinical teams may be using different language and this can standardize their wording and process," says Bacon. 

The next deadline for Clinical Trial Databases? March 2009, which calls for listing information on serious and frequent adverse events.—

An in depth look at industry's reaction to FDAAA, its requirements, submitting the results, and meeting the deadline.

Data Disclosure Clears FDAAA Deadline

Safety management in clinical trials is a process quite distinct from processes applied in postmarketing. It is regulated by a multitude of specific directives, guidelines, and regulations. These guiding and regulating documents have two important characteristics. First, they generally focus on individual aspects of safety management such as expedited regulatory reporting,

  patient exposure necessary to properly assess safety,

  and the set up of data safety monitoring boards (DSMB) as seen from the perspective of the FDA

  and the European Medicines Agency (EMEA).

  Second, they understandably deal with principles—none of them having an individual trial in their focus. The interpretation and implementation is left to trial sponsors.          

Photography: Getty Images    Illustration: Paul A. Belci 

The Council for International Organization of Medical Sciences (CIOMS) is currently the world's leading think tank in the field of drug safety. Many CIOMS recommendations were subsequently incorporated into ICH guidelines. In addition to adhering to applicable regulations, it is wise to consider the current opinions of drug safety opinion leaders given in CIOMS working group publications. 

 This article will offer an approach on summarizing the current regulations, guidelines, and recommendations and applying them in practice at the level of a trial specific Safety Management Plan (SMP). 

Serious adverse events (SAEs) require the most attention from a regulatory point of view, especially if subject to expedited reporting (considered related to the study medication and not observed before). Several parties are involved in clinical trials: sponsor, CRO, pharmacovigilance services or safety database provider, and potentially an additional party to handle the unblinding and regulatory reporting of unblinded expedited reports. Hence, the handling of the event among the involved parties should be defined. 

For example, it should be defined who is the initial recipient of the report and how the receipt is documented, as the date of receipt determines the deadline for regulatory reporting. All subsequent steps like production of narrative, review, decisions regarding reportability, unblinding, and reporting should be linked with the responsible persons, back-ups, communication lines, documentation processes, and defined timelines for execution. 

Investigators will most often need to be queried for additional information or clarification of an event. The sponsor may disagree with the investigator regarding the assessment of the event, most sensitively on the causality assessment, which often determines if the event needs to be reported on an expedited basis. Although justified to request clarification and thereby potentially imply disagreement with the assessment, this process should not include any attempts to unduly influence the reporting investigator. The incorporation of follow-up reports into event narratives or changes to previously reported information should be clearly presented and standardized, having in mind the purpose of an event narrative submitted for regulatory review.  

Clinical trials offer the opportunity for sponsors to get early information on a reported SAE, frequently while it is still ongoing, and to be able to observe it developing and even suggest additional investigations. If the study involves pharmacokinetic sampling, the evolution of the event with respect to drug concentrations offers invaluable insights. 

Pregnancies frequently occur unintentionally, particularly in trials involving young and moderately ill patients. The systematic and planned collection of information on outcomes from early phases of clinical development enriches the safety database. Even unwanted pregnancies provide valuable safety information on the product. They can be used to suggest the level of risk for future events. If the initial reported information shows no increased risk with the use of the drug in pregnancy, focused trials to support marketing claims for safe use in pregnancy can be considered. 

Collection of data on unintentional pregnancies should be seen as a continuous process, from pre- to postmarketing. Trial sponsors should define the procedures to provide the potential parents with relevant information to allow them to make a free and informed decision. Consider designing a standardized supplementary information and consent sheet for follow-up after birth and consider a standardized approach to ethics committee notification. 

The database used in premarketing should allow the transition into systematic collection of data in the postmarketing phase. This database can be essentially the same for all drugs within a company. Hence, a one time effort will benefit all developmental programs. 

A great regulatory effort has been made to support development of treatment for pediatric and geriatric populations. In addition to ICH guidelines E7 and E11, major initiatives are underway at the EMEA

  for stimulating drug development for the pediatric population. The effort on supporting development of treatment in pregnancy is apparently disproportionate, with the exception of a recent guideline by the EMEA.

  The disproportion with respect to medical significance seems striking to the extent that one may ask if pregnancies should be classified as an orphan population. 

The use of central laboratories or central ECG, imaging, and other centralized evaluation facilities allows trial sponsors to review the results in real time. Sponsors may evaluate individual alert values and ongoing adverse events in individual patients. The questions are: How much should a sponsor be involved if the responsibility for patient safety lies with the treating investigator and how much valuable safety information can be obtained? 

Arguably, the sponsor may be more familiar with the investigational drug than the treating investigator, who may not have meticulously studied the Investigators Drug Brochure, or the reported alert value may be outside of the specialty of the investigator. For example, the sponsor may need to have in-house expertise on ECG interpretation if the investigator also needs to seek cardiology consultation. This could support the investigator and contribute to a good sponsor–investigator relationship, in addition to being in the patients' safety interest. 

In addition, investigating a lab finding event in real time has better chances of linking it to a clinical event, thereby leading to a proper diagnosis. It would enable earlier association of the event to similar reports and earlier reaction to a potential safety signal, rather than at the time the clinical study report is written. Importantly, it may help in ruling out the relationship to the study drug if suspecting laboratory artifacts. 

Following a suspected reaction, it is extremely informative to confirm or rule out the suspected drug/event relationship. Taking the risk by rechallenging one study subject would decrease the risk to all other study subjects. If rechallenge confirms causal relationship, the safety information could be distributed to all involved investigators (or prescribers) and additional measures could be taken to prevent or appropriately treat the reactions. The sponsor may make the early decision to halt development if a safety concern is confirmed. This will prevent unnecessary further expenditure and prevent the drug from causing further harm. On the other hand, the rechallenge may confirm no relationship between the study drug and the event. 

  considers intentional rechallenge justifiable only if it may be in the interest of the particular subject. Looking at it from the ethical perspective, the well-being of an individual subject is one of the pillars of ethics in clinical trials as laid down by the Declaration of Helsinki. It should never be placed above the interest of science or the pharmaceutical industry.

  In most decisions regarding re-challenge, it is believed that the likelihood of the drug causing the event is low and that the event, if it reoccurs, will be mild and reversible. However, there is no guidance on delineation between low and high risk. 

Several points to consider regarding rechallenge decisions include:  

Subjects's documented informed willingness to accept the risks.

Investigator's assessment that the risk is justifiable by the expected benefit and the suspected reaction reversible and treatable.

Availability and risk/benefit ratio of alternative treatments.

Ethics committee notification or other necessary local approval. Ideally, a brief informed consent may be prepared for ethics committee approval. This consent could be an addendum to the initial consent signed and would detail the evolving individual risk in case of reoccurrence.

If actually going ahead with rechallenge, close observation and even hospitalization may be necessary to identify the reoccurring reaction as early as possible. All precautions should be taken to treat the reaction if it were to reoccur in a more severe form following repeated dosing. This is particularly sensitive if allergic mechanisms are suspected, which may be more dramatic following prior sensitization. All of the above points considered, is it worth the effort and risk? 

Data Safety Monitoring Boards (DSMBs) are increasingly used in clinical trials. They give credibility to safety monitoring as an external independent body and thereby may facilitate ethics and regulatory approval. In many cases, this is enough to decide to employ a DSMB. The key role is review of data from blinded trials where the sponsor has to remain blinded to treatment allocation in the interest of validity of trial data. 

  both issued guidelines on DSMBs. What these guidelines do not say or maybe suggest only indirectly is that working with a DSMB requires effort, cost, and that receiving feedback from a DSMB may be slow. However, a DSMB may also be used for purposes other than periodic safety data review. If an effort has been made by the sponsor to set up a Board and format and prepare the data for their review, and if the Board members have taken the time to familiarize themselves with the study drug and trial data, it would be a pity to limit their function to merely periodically stating "no significant safety concerns have been identified and the study may continue according to plan," if all is fine. 

For example, consultation may be sought regarding required safety assessments while developing the study protocol. A DSMB may also look at the safety data at the time of clinical study report writing. DSMB members must be experienced trialists who also support review of efficacy data. Safety and efficacy are inseparable, and the responsibility of a DSMB is to evaluate the balance. However, a line should be drawn with the extent of involvement of a DSMB in order to not compromise their position as external to the company. A DSMB does not replace the function of company expert consultants who may support the company in activities other than evaluation of the safety profile of the drug. A separate expert group must be set up for strategic development, promotional or other decisions. 

Approaches to managing DSMBs greatly vary. Some DSMB charters detail the data to be reviewed, including statistical aspects, whereas others limit themselves to responsibilities and meeting organization. The rights of DSMBs in decision making, the extent of unblinding, and the way they communicate recommendations are equally subject to variation. A standardized approach significantly facilitates DSMB management across studies. It may be applied to issues likely applicable to all DSMB, including data format, unblinding, review of external data (data relevant to study subjects reported outside of the study itself), and other issues. 

From pre- to postmarketing, safety monitoring must be a priority that's handled with knowledgeable care.

Applied Clinical Trials-10-01-2008

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