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EDC : Getting it Right - EDC Rescue Studies  INFORMATION TECHNOLOGY : How Health Intelligence Leads to Smarter Research  CRO/SPONSOR : The Proactive Advantage in Risk Management  Also in this issue : All Eyes on R&D as U.S. Talks Health Care, Fragmented System Stifling EU Research, IT Convergence: Are We There Yet?, Why Virtual Meetings Make Sense

Applied Clinical Trials Digital Edition - August 2009

Planning and Analyzing Patient Recruitment

New module broadens planning and forecasting at site level

 has added a new module in its Enrollment Metrix Application called SiteView. SiteView offers users the ability to examine enrollment KPIs derived from site level data. The new module allows users to anticipate the expected number of patients to be recruited from any given site as well as the time it takes any given site to complete recruitment.    

SiteView joins with the TrialView module, which both access KMR Group's industry data, which includes disease, phase, and geography obtained from over 100,000 sites from recently completed trials in the biopharmaceutical arena. 

New reporting solution addresses timeline/supply in global trials

 announced its new reporting solution as part of its ClinPhone Randomization and Trial Supply Management (RTSM) technologies, which offer validated randomization methods, automated inventory control, dispensing and titration management, and emergency code break capabilities. 

The reporting solution features a Universal Report Suite to monitor clinical trial management performance, RTSM Dashboard with trending and forecasting functions, and a Self-Service Module with customizable search criteria for in-depth data analysis. 

Enhancements Address Diaries and Interactivity

Design tool offers added function and flexibility for clinical trials

 announces TrialMax 4.0, which extends its ePRO software suite function. The TrialMax eDiary design tool allows real-time development between study teams and trial sponsors. In addition, TrialMax 4.0 includes

automated email notification and messaging, enhanced user account and password management, configurable data exports in a variety of output formats, report content export to Microsoft Excel, enhanced report printing, and configurable patient status icons. 

TrialMax 4.0 has also been updated with new user interface graphics and the ability to embed links in study reports. 

eShowcase

The latest eclinical software in the clinical trials industry.

eClinical Software: August 2009

In a lot of ways, clinical research seemed a whole lot easier in the old days. Data was collected on paper CRFs and keyed into a Clinical Data Management System (CDMS) for cleaning and analysis. Sure it was primitive, awkward, and slow but it was also familiar, generally accepted, and predictable. At most, you might have to load an external lab file, and most of the data you needed would be in one place where you could run your queries, review your listings, and fire off a complete set of SAS datasets to the statisticians for final analysis.    

Of course, memories tend to gloss over some of the grimmer aspects of past realities. Paper also causes lots of other problems such as quality, data reusability, and lack of timeliness. Yet, it seems like those double data entry clerks were pretty fast, efficient, and cost effective at the time. 

I also recall giving a talk at RAPS back in those days, describing my experiences as a global road warrior. In those days my 007-like attaché included a profusion of communication and work devices. I had a laptop and attachments, with a series of international electrical and modem telephone connectors. I used a Palm Pilot to manage my calendar and contacts, and a clunky cell phone and a sleek pager to keep in constant voice contact. I carried a walkman to help distract my brain from the pain of distance running using my digital chronograph to keep track of my training times. Add in spare batteries and power supplies and I was ready for the road. Obviously, this preceded my inevitable back surgery, which resulted from hauling all that gear around the globe. 

Today, my kids pretty much manage to do everything they need with just a mobile phone (and a laptop for more complex and visual computing purposes). They don't even bother with a wristwatch anymore. Not only do their smart phones have most of the computing applications they need, it also has their data: contacts, URLs, photos, music—basically all they care about on a day-to-day basis. Being able to use one multipurpose device that covers your essential daily activities and information needs—that's what we mean by convergence. 

Now convergence of clinical applications didn't seem so essential in the old days, because everyone had their own distinct tasks and the tools they themselves needed for their particular job. Sure there were those who tried to create a Swiss army knife out of a portable computing device, but these were found to be deficient in too many respects and excelled at nothing. Meanwhile, clinical study data rolled along the assembly line without much cross-utilization by different functions. Back then a CDMS served as an adequate data repository for clinical trials, when the primary purpose was to enter and process data for a regulatory submission. Once a study was locked, we'd just package up the individual SAS datasets and send them over to Statistics for reporting. 

Oh, maybe the clinical people used some sort of Clinical Trials Management System too, which, more often than not, came down to a collection of spreadsheets and documents. And then there were those safety folks obsessing over the Serious Adverse Event reports—they inevitably used their own system as well. But that was okay—each group minded their own business most of the time. 

Like most other computer systems of that era, none of these applications talked together very well. Once in awhile, someone would buy an integrated suite of products with high-gloss marketing literature claiming to bring everything together in a seamless package, but it turned out these didn't talk to each other much better either. This didn't surprise anyone—and as a result didn't quite sweep the market either—which was tolerable as long as there was a good enough tool for each specific job. 

But after years of psycho-dependency on my smart phone, I tend to travel a little lighter these days. And I've developed a keen appreciation for a smaller set of multipurpose tools that can access most of the information I need via the Internet. 

I suspect a lot of others feel similarly and wonder why clinical applications haven't kept pace with the rest of technology. Because times have changed, different types of data are coming in faster in much greater volume in many different ways, and the old study CDMS's aren't necessarily up to the task anymore (especially as the world finally edges over the tipping point to EDC). 

We are discovering many more important uses for data that traverse functional silos, with the frustration of knowing it's not always easy to fit data together so we can pursue those uses. Some believe the answer is data standards. But, while these have improved the situation in many ways, they don't always work so well in practice as they appear in demos when applied to more complex, real business scenarios. 

And it usually seems the current standards are hobbled with functionality gaps or are being supplanted by the next great standard before they ever get where we need them to be right now. Semantic interoperability is the next nirvana, but today we often still can't reliably exchange even the simplest types of data without manual intervention, much less ensure meaning is conveyed unambiguously. 

So far, the vendor community's answer to this need is a new generation of integrated product suites. It's possible that this time these really might be the answer—assuming they actually work as advertised and we have the opportunity to start anew with a clean slate. But how well are these working right now with so many existing disconnected or loosely connected tools and legacy data structures? And aren't most of these still straddled with a few gaps or weak links in the chain? 

Despite the increasing focus on such a suite approach, the client community still tends to purchase ala carte. Perhaps this is because they want to hedge their bets, or have mixed experiences with some of the individual components in the suite, or don't want to relinquish the one tool that really works for them now for the unknown. As a result, some sponsors make due with what they have, others plan for the future when the perfect solution will be available, and still more forge ahead to make it work now—using system integrators to glue together the various components and fill in the holes. And maybe some of these will actually get close to the ideal—at least until the versions of the products or standards change. 

One noteworthy case study of a sponsor who needed to do it all themselves is the National Cancer Institute (NCI) whose ambitious cancer Biomedical Informatics Grid (caBIG) initiative has been developing an integrated, open-source architecture (caGrid) that includes a set of tools for conducting clinical trials and exchanging data. 

The caBIG program is heavily committed to using model-driven development along with CDISC and HL7 data standards to provide a comprehensive research infrastructure that ensures that interoperability and integration is built-in from the very start. Although it wasn't designed to support commercial product development, it provides a very interesting benchmark on what some sponsors may be looking for in their next generation systems. Perhaps caBIG offers a glimpse of what industry really needs in their ideal suite. 

In addition to having integrated tools, we also know that sponsors—as well as regulators, researchers, and pretty much everyone—want all the data they need in one place (or at least available from a single access point). EDC systems do this for a single trial, but not so well for a full program or domain of interest. As a result, many sponsors are investing in clinical data warehouses. 

Again, standards are critical because they should make it easier to bring the different types of data together. But it can be a lot of work to make existing data conform to these standards and, as we've said, the standards we have don't necessarily have all the standardization we need for all the data we're using at this point. 

So it's incumbent upon the vendor community to prove that an integrated suite of tools really can operate on the enterprise level and fit smoothly with standards-based data repositories. And vendors must also commit to standards-compatible suite components that can be switched in and out, because it's not realistic to expect sponsors who have invested heavily to implement a particular product—with which they may be fully satisfied—to replace it just to integrate with other related tools. 

We now have some evidence that such a degree of convergence is looking like it's possible. Perhaps we can actually achieve it this time, especially if sponsors and vendors work together more effectively to deliver the solutions that work for most everyone. Perhaps in our lifetime the convergence that our kids have experienced will begin to extend to our professional lives as well. And if so, the age of convergence may finally reach our world too. 

is Senior Vice President and Chief Quality Officer at Lincoln Technologies, Inc., a Phase Forward company based in Waltham, MA. He can be reached at 

Technology Viewpoint

Evolving out of disconnected technology solutions and working toward integrated processes.

Welcome to the Age of Convergence

Sponsors of biomedical research generally support initiatives to make the nation's costly health care system more efficient and effective. Expanding coverage to some 45 million Americans is not only a moral necessity, which President Barack Obama emphasizes, it also would greatly enlarge the pool of customers for drugs and medical products and enhance compliance with prescribed treatments.   

That said, pharmaceutical companies are leery of being hit with cost controls and regulatory changes designed to help pay the trillion-dollar cost of achieving universal coverage. Congressional leaders propose to increase access to health care by expanding Medicaid; requiring all individuals to obtain coverage; mandating that employers play (provide insurance to workers) or pay a penalty; reforming the insurance market to limit exclusions based on pre-existing conditions; and forming an insurance exchange that will offer coverage options to the uninsured, including some kind of government-supported public plan. 

Policy makers are looking to pay the $1 trillion coverage bill with tax increases, Medicare and Medicaid savings, and policy changes designed to reduce health care expenditures. The main concern of medical product manufacturers is that such approaches will curb revenues needed to support future R&D and will promote product cost over quality and effectiveness. 

"Encouraging innovation needs to be the purpose of U.S. health care reform, not its victim," said Eli Lilly Chairman John Lechleiter in a speech in Washington in May. He complained that the word "innovation" never comes up in the health care debate, but that it's imperative to "preserve an environment where innovation is possible." 

The mantra for industry is that appropriate drug utilization and better compliance with prescribed treatment will curb health care spending over the long run. Lechleiter acknowledged that the status quo is not an option, and that improved access and cost management are critical. At the same time, reform needs to maintain choice in coverage and treatment and to address the health care needs of individual patients. 

The tradeoff between protecting innovation and expanding access to needed medicines is central to the debate over establishing a legal pathway for FDA approval of follow-on biologics (FOBs). Innovator firms now support authorization for biosimilars, provided that establishes sufficient market exclusivity for biotech manufacturers to recoup investment in R&D. The Congressional Budget Office (CBO) has calculated that an FOB program with a moderate exclusivity period, say around seven years, would generate about seven to $10 billion over 10 years. The savings would be less with the 12 years of exclusivity adopted in legislation approved last month by the Senate Health, Education, Labor and Pensions (HELP) Committee. Even fairly modest savings estimates, though, are enough to spur negotiations to get an FOB measure into the final reform bill.  

Reformers also eye other proposals for increasing access to generic drugs, such as a ban on payments by brand-name firms to generics companies to delay generic competition. Barring pay-for-delay settlements, according to Federal Trade Commission chairman Jon Leibowitz, would save the federal government $12 billion over 10 years and yield even greater savings to consumers and states. Leibowitz also supports curbs on authorized generics, but evidence that these products may lower drug prices may keep it out of the health reform legislation. 

Policy makers hope to reduce Medicare outlays by some $300 billion over 10 years through changes in reimbursement to doctors, hospitals, and other providers. Such moves also threaten to erode market-based competition in the Medicare Part D drug benefit. 

For example, House Energy & Commerce Committee chairman Henry Waxman (D-CA) wants to impose rebates on drugs prescribed to low-income seniors shifted from Medicaid drug benefits to Medicare Part D five years ago. "We're simply going to ask the pharmaceutical companies to pay us back the money," Waxman said at a June news conference to unveil the House health reform plan. Manufacturers fear that rebates on drugs for so-called dual eligibles will be very complicated to administer and thus will open the door to rebates on all drugs covered by Part D plans. 

In an interesting maneuver, Waxman included a new rebate involving duals in the House reform bill as a way to help cover the cost of closing the notorious Part D coverage gap over 15 years. That provision also requires manufacturers to offer 50% discounts on medicines prescribed to Medicare patients that fall into the doughnut hole, as proposed earlier by industry as a voluntary initiative. 

Pharma companies appear more willing to pay higher rebates on Medicaid drugs than to undermine Part D pricing. The House bill also proposes to save $20 billion over 10 years by boosting the basic Medicaid drug rebate from 15% to 22%, extending rebates for new formulations of existing drugs, hiking rebates on generic drugs, and requiring manufacturers to pay rebates to states for drugs provided to Medicare managed care plans. 

The greatest threat to competitive drug pricing, though, has emerged in proposals to establish a public plan option that has authority to pay Medicare rates to hospitals and providers. But it opens the door to a larger government role in pharma pricing. Insurers, payers, and providers strongly oppose a government-run coverage plan for fear it will eliminate private insurance altogether. 

Similarly, proposals to authorize government negotiation of drug prices for therapies covered by the public plan has raised alarms among pharma companies. That's not as threatening as full repeal of the non-interference clause, which prevents federal negotiation of drug prices for Medicare Part D. 

Congressional leaders will continue to fine-tune the public plan option to encourage employers to retain worker health benefits, but current proposals appear likely to undermine the existing system over the long run. Even without a government health plan, Congress is likely to establish some kind of federal health board with authority to make certain decisions on payments and benefits. This board is likely to have authority over medical product coverage, pricing, and cost-effectiveness standards. 

A federal health board also could play a role in overseeing more comparative effectiveness research (CER), which is intended to better inform treatment decisions and ensure appropriate use of medical products. Heated debate over the structure of a CER governing body and its authority exists between some of Congress proposing to position a CER agency within the Department of Health and Human Services, while others prefer an independent public–private entity. 

The really hot-button issue on Capitol Hill is how payers and insurers will use the resulting CER information. Democrats prefer to keep language on the use of CER fairly vague, while Republicans want explicit restrictions against using CER data to determine treatment and reimbursement for fear that would lead to health care rationing and government interference in medical decisions. The IOM report lists a number of CER priorities that seek evidence comparing the effectiveness and costs of prescription drugs to other treatments, proposals that reinforce those who consider cost-effectiveness a valid CER research subject. 

Reform legislation also includes "sunshine" provisions requiring pharmaceutical companies to disclose virtually all payments to physicians and health care providers, including fees to clinical investigators. Industry has supported federal sunshine legislation, provided it establishes national standards and reporting requirements that preempt a growing number of state disclosure policies. The House reform bill, however, permits states to continue disclosure requirements that differ from the federal program. 

Pharma companies also may be hit with new fees and taxes to support expanded coverage. Sponsors may have deflected earlier proposals to curb the corporate tax deduction allowed for drug advertising and for R&D expenditures. But there's talk of new drug re-importing programs and other price-cutting strategies. 

President Obama wants to sign health reform legislation this year and has signaled he'll accept a measure with a $1 trillion, 10-year price tag that covers at least 75% of the uninsured. Many of the details in reform legislation will be hammered out on Capitol Hill this fall by a committee formed to reconcile differences between House and Senate bills. There will be considerable horse-trading and maneuvering over health exchanges, public vs. private plans, tax reforms, and price controls, with everyone keeping a sharp eye on costs and coverage. 

View from Washington

Pressure to reduce health care spending puts R&D, costs, and coverage on the negotiating table.

Health Reform Shapes Drug Development

Last month, Health Industry Insights released its eClinical Buyer's Guide, Part 1, Electronic Data Capture, focusing on the EDC vendor landscape. As Alan S. Louie, PhD, and author of the report told 

, EDC is becoming a mature technology. Couple this with CDISC standards within vendor's products, which provides easier interoperability, and the EDC market actually is "less competitive." 

What does this mean for EDC vendors and the biopharma companies that buy their software products?

For vendors, Louie predicts further consolidation of them by other EDC vendors and by CROs. The report highlights the M&A activity that occurred in this space in 2008, including Parexel's purchase of ClinPhone, BioImaging's acquisition of Phoenix Data Systems (now known as BioClinica), and Medidata's purchase of Fast Track. 

More recently, in June and July of this year respectively, were OmniComm System's purchase of ERT's EDC product suite, and Covance's selling of its IVRS/IWRS services to Phase Forward. 

Steve Johnson, COO of OmniComm Systems, agreed with Louie's consolidation prediction. He called OmniComm's purchase of ERT's EDC suite a move to grow its business to compete with the tier one players, those making over $100 million in revenues, which are Phase Forward and Medidata. 

Johnson explains that the acquisition allowed it to assume a competitor, as well as expand its offerings to customers as a plug and play suite. OmniComm is currently in talks with two other acquisition targets that will round out its line, and is open to similar opportunities. 

OmniComm's current profile models what Louie sees for the near future for EDC vendors: future consolidations that focus on acquisitions of products that complete a company's offerings to a full eClinical suite. Or further consolidations of EDC/eClinical companies that allow market penetration in specific areas, for example, academic medical centers, smaller pharma, medical device sponsors or in a particular country. 

To be sure, these modules or capabilities that vendors offer to round out their offerings are the larger movement that is eClinical. And that is the future that buyers need to be aware of. As Louie explained, EDC is not sold as a separate offering. "EDC vendors automatically bundle in a CTMS (clinical trial management system) or have a repository built in," said Louie. The hope being that a bundled or comprehensive software product will continue to be used by the client (sponsor) rather than seeking out different products to plug into the system. Other eClinical capabilities can include CDMS (clinical data management systems), drug safety/pharmacovigilance, clinical trial design, ePRO, thesaurus management, IVRS/IWRS, FDA submissions, and CRO management. 

It is the Web that brought EDC to maturity and is bringing the rest of the companies into eClinical. As Johnson explained, "It is the improved security and the performance of the Internet in the past couple years that explains why EDC has taken off." 

The major benefits of Web-based solutions according to Louie are: "You don't have to manage the software on the site." And because of the large, multicenter trials, "the Web-based solutions also serve the distributed trials or global trial data needs." 

As part of its recognition that EDC is no longer the end goal, but eClinical is, Health Industry Insights will present additional reports in its eClinical Buyer's Guide series in the coming months. Louie anticipates that drug safety will be next. 

Market Analysis: The Health Industry Insights eClinical Buyer's Guide, Part 1, Electronic Data Capture is available for purchase from IDC/Health Industry Insights at 

News

The growing adoption rate of EDC will enable companies to reap the benefits of the entire eClinical suite.

From EDC Emerges eClinical

A new clinical trial conducted by the World Health Organization and industry is being launched in three African countries. Moxidectin is being investigated for its potential to kill or sterilize the adult worms of Onchocerca volvulus, which cause onchocerciasis, or river blindness, a leading cause of blindness in Africa.  

 A child leading an adult blinded by onchocerciasis is located outside the WHO's headquarters in Geneva, Switzerland (Provided by WHO/Pierre Virot).			

The blackfly that transmits the disease breeds in fast flowing rivers. Over 100 million people are at risk of infection with onchocerciasis in Africa and a few small areas in the Americas and Yemen. 

The development of moxidectin for onchocerciasis is being conducted by the WHO's Special Programme for Research and Training in Tropical Diseases and Wyeth. They are seeking to develop a formulation for human use, and if the outcome is a positive scientific opinion from the European Medicines Evaluation Agency, Wyeth will request approval by national regulatory authorities in the countries where onchocerciasis is endemic. 

"The moxidectin data have been promising so far, and as the program moves into larger Phase III studies, we are hopeful that moxidectin will constitute a significant advance against this devastating disease," said Dr. Henrietta Ukwu, MD, vice president Wyeth. 

About 1500 people will be enrolled at four sites in Ghana, Liberia, and the Democratic Republic of Congo (DRC). Preparation has been ongoing since 2007, and included building a clinical research center in Lofa County, Liberia, and in Nord-Kivu, DRC. The trial will take 2.5 years. 

Currently, onchocerciasis is controlled by ivermectin, which has been donated for more than 20 years by Merck and reaches more than 60 million people in Africa annually. Ivermectin kills the O. volvulus larvae but not the adult worms, so annual treatments for up to 14 years are required to ensure disease control. If moxidectin kills both the larvae and adult worms, it may be able to interrupt the disease transmission cycle within around six annual rounds of treatment. 

The investigator meeting was organized by Wyeth, and principal investigators, other physicians, ophthalmologists, study coordinators, and clinical monitors. Remote training in database use was given by the company, which is providing satellite-based Internet access to staff. 

"It is very much welcomed that more and more pharmaceutical companies are not only donating medicinal products to Africa but also are supporting those countries to develop their own research, especially in tropical diseases," said Dr. Jenny Mueller, PhD, clinical trials support manager at MRC Laboratories, Banjul, The Gambia. "Clinical trials conducted in the countries where the products will be used have the advantage that the efficacy and safety profile is tested in the ethnic groups that will use them and under the conditions and in the environment they will be handled in later." 

Mueller also finds it encouraging that national regulatory authorities are increasing their involvement in clinical research. Training and education in clinical research by experienced partners helps build capacity and infrastructure, and leads to more collaboration with African investigators and institutions, she noted. 

The main challenges are the lack of functioning health systems, including precise diagnoses, as well as arranging site visits by participants in remote villages. The trial organizers must also focus on appropriate informed consent procedures and safety oversight, including the awareness and reporting of signs and symptoms by participants, said Mueller.—

Global News

Vital players come together in an attempt to find a cure for a devastating illness predominantly effecting African countries.

WHO Boosts Research in Africa

Nearly a decade after the European Union introduced its new clinical trials rules, the system is still stifling rather than stimulating research and innovation, claim many of its critics. But the EU authorities remain hesitant about changing the rules, and until now the clinical research community has remained split over what changes to demand. A workshop in Brussels in July marked the first step in overcoming those divisions, with a concerted attempt to begin drawing up a roadmap for clinical research in Europe.   

The initiative focused on defining the ideal clinical trial authorization (CTA) procedure. Over recent months in Europe, there has been a growing consciousness of the need for a single CTA process that would provide clear definitions of the respective roles of the competent authority (such as in assessment of the investigational product at the EU level) and the ethics committees (such as protection of participants at the national level). The search is now on for greater efficiency that will not increase the risk for trial participants. 

Hartmut Krafft, chair of the clinical trials facilitation group operated by the heads of the European Medicines Agencies (whose day job is head of the Clinical Trials Unit at the Paul-Ehrlich Institute in Germany), admitted that divergent decisions emerged from competent authorities and ethics committees in Europe. Between May 2004 and June 2008, there were 155 cases where the regulatory authorities approved an application but the ethics committees' opinions were unfavorable, and 89 where the ethics committee gave a favorable opinion but the regulatory authority turned the application down. 

Martyn Ward, Head of the Clinical Trials Unit at the UK's MHRA, conceded that despite the merits of the clinical trials directive, complications had crept into the implementation. A lack of EU guidance had led to local interpretation (and differential timing) when implementing the directive in national legislation, and this had been particularly aggravated by EU enlargement, which had subsequently brought 12 new member states into the picture, with varying experience, resources, and priorities in terms of clinical research. 

As a result, the information to be provided in CTA applications needed clarifying and harmonizing, timelines needed to be more explicit, and there was scope for aligning CTA assessment outcomes in different member states. But in Ward's view, the existing mechanisms were largely sufficient to make the necessary improvements. The current legislation, he said, is intrinsically sound, and a lot can be done without radical change. 

His judgement was not universally shared. Speaking from the viewpoint of a commercial sponsor, Angelika Joos, Director of Regulatory Policy Europe at Merck Sharp & Dohme, pinpointed the ambiguities in safety reporting requirements and in definitions of investigational products or amendments that arose from divergent national implementation. The consequences of this fragmented and complex regulatory environment, says Joos, include a multiplicity of assessments with divergent outcomes and increased administrative burdens, necessitating additional staff for the application and submission process and safety reporting. Companies are obliged to cope with multiple scientific discussion partners with a different focus, the rediscussion of issues at different levels, constant transfer of product and regulatory histories, complex feedback mechanisms, and specific national amendments to global study protocols. 

A still more assertive view came from Mats Ericson of Amgen, speaking on behalf of the European Federation of Pharmaceutical Industries and Associations. He highlighted the complexity of managing large multicenter multinational trials when they are reviewed and supervised separately by each country (and, he pointed out, 60% of all trials are conducted in more than one member state). 

"The issue of divergent interpretations cannot be fully resolved by modifications to the directive," he insisted. That would not be enough to resolve distinct national requirements on CTAs and on good manufacturing practice, or the conflicting review outcomes and requests for changes, or the differing approaches to amendments. It is, he said, "time for a change." 

EFPIA wants to see an optional, centralized, approval process enforced through a new regulation that would generate EU-wide CTAs, based on assessments by the best expertise across Europe. This would be a more efficient use of European resources, and would even be attractive internationally, he said. 

Jane Apperley of Imperial College in London noted the additional problems identified in noncommercial trials of increased time to approval, increased costs—including for insurance, and difficulties finding sponsors for multinational trials. And among the requests from another spokesperson for the noncommercial community, Anastassia Negrouk, Head of the Regulatory Affairs and Intergroup Unit at EORTC, included a call for greater flexibility on the language to be used. 

All member states should be prepared to accept an application in English, Negrouk said. And greater involvement of patient representatives in ethics committee discussions was urged by Jan Geissler of the European Cancer Patients Coalition. Only in Austria, France, and the Netherlands are patient advocates explicitly mentioned as committee members, said Geissler. 

This was the first in a series of five planned workshops over coming months with the aim of offering Europe's regulatory authorities, at a final conference next April, a unified position on how the EU clinical trials rules should be crafted—a component that the organizers say was missing during the original development of the directive. Watch this space. 

The echos of the European Union's inquiry into competition in the pharmaceutical industry are still rippling across the continent—and even into the United States. The clinical trials community may not be hugely concerned over the intricacies of the balance between anti-trust law and intellectual property law that the final ruling—published on July 8—tries to strike. But everyone involved in the development of medicines in Europe will have read with interest the passage about the EU's determination to promote innovation. 

The European Commission, says the final ruling, "is committed to the development of an EU pharmaceutical framework for the 21st century which promotes innovation, in particular in areas with unmet medical needs." The ruling notes that the Commission "will adopt a report on the use of personalized medicines and '-omics' technologies in pharmaceutical research and development and on the possible need for new Community instruments to support them, by 2010." This report will, the Commission forecasts, provide an opportunity to consider the current data exclusivity system, and its ability to contribute to innovation and improve access to medicines. 

After 18 months studying the sector during its inquiry, the Commission now feels able to say with confidence that "with the emergence of new technologies like pharmacogenomics and patient-specific modeling and disease simulators, personalized medicine is now on the horizon. In the long term, doctors may be able to use genetic information to determine the right medicines at the right dose and time. This field is already affecting companies' business strategies, the design of clinical trials, and the way medicines are prescribed. Although it is too early to say whether '-omics' technologies will indeed revolutionize the sector, the Commission closely monitors the area and will reflect on how it can support its development." 

				The Commission also goes on the record in its ruling as fully supportive of "further international harmonization in the area of marketing authorization, mostly between Europe and the United States, "as this has the potential to considerably reduce the costs of market access and innovation by reducing unnecessary regulatory divergences." 			

According to the European Forum for Good Clinical Practice, the current EU rules require a CTA by a competent authority and a favorable opinion from a lead or central research ethics committee as a prerequisite for the performance of a clinical trial. In multinational clinical trials this authorization process has to be followed in each country where the clinical trial is to be performed. The content of the CTA application dossier is defined by each member state in a different way, and the review processes impose different additional requirements, which result in a longer trial preparation period for multinational trials and increased administrative cost. The answer would be a single CTA, irrespective of the number of participating countries, either by the development of a single CTA application across Europe or the mutual recognition of authorizations by national authorities, with a better definition of the roles of ethics committees and competent authorities in the process. 

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

View from Brussels

Contradicting decisions call for a unified clinical trial authorization process.

Disharmony Stifling Research in Europe

Without the need for a prescription or medical illness and with a usual intake requirement of every day, dietary supplements would appear to be a prime market for clinical research companies. So, why are dietary supplements supported by the safety and efficacy data of a clinical trial so few?  

 Najla Guthrie, president and chief executive officer of KGK Synergize.			

Without a solid regulatory requirement across regions and without an outcry from consumers for more scientific evidence of products, there has been little pressure for companies to delve into this field. But as the market continues to experience growth, the clinical research community may eventually be singing a different tune. 

The regulatory climate varies greatly for dietary supplements and not all agencies require that they be supported by clinical trials. For instance, the United States only requires an IRB approval. Unless, that is, a company wants to make a claim to treat, cure, mitigate or prevent a disease, then the same procedures must be followed as for a chemical drug. 

These products in the EU, however, are subject to a scientific opinion of the Committee on Herbal Medicinal Products based on existing scientific data or on historic use of that product in Europe. The EU also has GMPs in place for these products. 

"In Canada prior to January 2004 we only had to apply to an IRB and then they brought in the natural health products directorate, requiring companies with products on the market to apply for a product number to be able to make claims and substantiate the safety and efficacy of the product," explained Najla Guthrie, president and chief executive officer of Ontario-based KGK Synergize—a contract research services and product development company. 

Also, "if you are conducting a clinical trial on a natural health product, that branch reviews your clinical trial and protocol as well as the safety information, quality, and manufacturing. So it's very similar to the drug side," she added. 

While there is no shortage of development, there is a lack of dietary supplements with proven safety and efficacy that ensures consumers are getting what they are expecting. 

A survey conducted by KGK Synergize showed pharma spends under one percent on R&D for dietary supplements, while they shell out up to 20% in the pharmaceutical sector. 

"Current laws do not usually grant exclusivity or patent protection to the manufacturer for conducting clinical research on a nutrient or vitamin—the molecule is available in the food supply so it is not unique," noted Steve Mister, president and chief executive officer of the Council for Responsible Nutrition (CRN). "As a result, dietary supplement research tends to be less driven by individual manufacturers and more by the scientific community at large, including academics and government institutions," he added. 

Still a very young market, dietary supplement trials are typically performed either when regulatory requirements call for it, or if companies want to set their products apart from the rest by gaining the advantage of being able to make certain claims to consumers about their product's capabilities. 

"The market has changed in our industry over the past 10 years...[it] was bringing products to market without a lot of backing behind it. But now industry is consumer driven and the consumer is asking for evidence to be behind these products," reflected Guthrie. 

With global nutraceutical sales projected to reach $187 billion by 2010, according to Nutraceuticals World, a publication serving the manufacturers of dietary supplements, functional foods, and nutritional beverages, there may be incentive to get a piece of this market share. 

In it's almost 12 year run, KGK Synergize has completed at least 60 dietary supplement trials, and currently has 15 ongoing—of which 80% of this business has been generated from U.S.-based companies. "Over the history of our company we had a cycle for a few years where we doubled in growth and then it's been about a 20% per year growth the past couple of years," Guthrie said. 

Though Guthrie also mentioned the company experienced a slowing down recently, she noted that this was felt more on the pharmaceutical side of the company than the nutraceutical. 

Companies can also expect a lighter load on cost and time in these trials. "Consumers are really interested in these products and are interested to know which ones are efficacious and safe and which ones are not," Guthrie explained. She told 

 that her company has very little, if any problems with subject recruitment and retention. 

The dietary supplement clinical trial market is "changing, it's changing slowly. But it's still nowhere near where it needs to be," Guthrie concluded.—

A look at the growing market of dietary supplements and the potential for development of these products in the clinical trials arena.

A Market Worth Watching

The nicest hotel at which I've ever stayed provided lodging while I attended an investigator meeting several years ago. Back then, air travel was almost pleasant and video calls comically blurry. Today, air travel is a big hassle and the cost of developing new drugs has skyrocketed. On the plus side, communications and collaboration technologies have made unthinkable strides—eliminating, for all practical purposes, the distinction between in-person and remote meetings. So, how is that relevant to clinical research?   

As most of us know all too well, R&D productivity has been heading in the wrong direction. The costs of clinical trials have risen sharply. The number of trials has also continued to grow, which is good, but also poses a challenge. As an observer recently noted, "Life science companies need to find a way to decrease these costs if the industry is to fund all those trials." 

A major challenge in reducing clinical trial costs is our heavy reliance on health care delivery infrastructure. Our health care system is neither known for efficiency nor ideally suited for clinical research. It is also hard to change. To improve clinical trials, the industry needs to compensate for these shortcomings. Two pivotal areas where we can do this are investigator meetings and patient visits. 

Bringing investigators together in person, in a single location, used to be the only practical way to conduct investigator meetings. But that's no longer the case. With modern technology, such as our WebEx platform, investigators can stay at home and participate remotely from their desktops. And, in the not-too-distant future, they'll be able to participate at local hotels and conference centers using technology like our TelePresence. 

Such virtual meetings cost a fraction of in-person sessions and eliminate the wasted time and hassle of travel. That makes it possible to hold meetings more frequently, allowing sponsors and clinical investigators to stay in regular contact during ongoing trials. 

Both the acceptance of, and demand for, virtual patient–physician interactions is increasing. In fact, such remote visits are the only way we will be able to deliver health care to our aging population without financial ruin—a new-age twist on the house call of yesteryear. The same goes for clinical trials. 

Replacing at least some in-person visits with remote visits and collecting patient data remotely offers many potential advantages, including improved patient recruitment and retention. These interactions can take many forms, such as remote visits using Webcam-equipped PCs; data collection by medical devices connected to PCs or cell phones; e-mail; and Web-based self-reporting instruments. The benefits include greater convenience, time, and cost savings from reduced travel, the potential for improved protocol adherence, collection of more data, and a smaller carbon footprint. 

When all is said and done, clinical trials are unnecessarily expensive in terms of both time and money. As a result, badly needed medicines are developed at a higher cost, a slower pace, and sometimes not at all. To remedy this situation, pharma companies need to be much more aggressive in taking advantage of collaboration technologies—to meet the needs of trial participants, investigators and, ultimately, patients.  

Jan Malek Director Internet Business Solutions Group Cisco Systems 

A Closing Thought

Alleviating clinical trial costs in two pivotal areas with the use of collaborative technology.

By Land, Air or Better Yet...PC

Proactive risk management is absolutely vital for every organization in today's fast moving global marketplace. As the recent worldwide financial crisis clearly demonstrated, companies that fail to properly anticipate and mitigate their risks are endangering their business assets, the jobs of their employees, and even their existence.   

 Photography: Getty Images   Illustration: Paul A. Belci  

For the biopharmaceutical industry, several well-publicized incidents in recent years involving the safety of marketed products have brought the issue of risk to the forefront of public awareness and regulatory scrutiny. While most of the industry's risk management efforts have focused on postmarketing drug safety, the clinical trial process holds a broad array of other potential risks that could jeopardize a company's multi-million-dollar product development investment—risks such as site staffing shortages, patient recruitment issues, logistical problems with drug supplies, or regulatory delays. 

These challenges are compounded by the increasing complexity of global clinical trials, as well as significant marketplace pressure to introduce new safe and effective treatments as quickly as possible. Without a comprehensive plan to identify, analyze, and manage potential risks, these issues could prevent important biopharmaceutical products from reaching the market in a timely fashion. 

A focus on risk management from the beginning of the development process encourages a company to examine the trial plan and identify potential challenges. With that information, trial managers can improve the study design to reduce risk and help the project team be better prepared to deal with issues when they occur. 

By integrating this proactive, qualitative risk assessment approach into every stage of development—and monitoring risk profiles as they change during the product lifecycle—a biopharmaceutical company can increase the probability of dealing successfully with both foreseeable and unforeseeable risks to minimize their impact on clinical development and protect the value of its product portfolio and future of the company. 

The first stage of risk management is to identify the risks. Many companies have set up general risk management plan templates that include common categorized risks and potential mitigation strategies. These templates allow project teams to learn from other teams' previous experience. Their quality depends largely on an efficient feedback process from finished trials. This can be achieved by a mandatory post-mortem assessment of trials. Templates do not replace a thorough risk assessment of individual studies. 

In addition to templates, the risk identification process can be enhanced by a review of information from previous studies and interviews with project managers who have worked on similar studies or in similar indications. It is important to take into account all sources for background data and prior experience. Ideally, the entire project team should brainstorm potential risks and openly identify issues of common concern. Given the combined experience of a typical study team, there should be ample input about potential risks and how they have impacted studies in the past. 

What types of risks are encountered during clinical trials? Although there is wide spectrum of potential issues, typical problems might include:  

Study sites with insufficient staff to perform all the necessary tasks required for the trial

Unsatisfactory compliance with patient diary requirements

Delays in study approvals by either regulatory agencies or ethics committees

Patient recruitment that is too slow or too fast

High volumes of data queries and re-queries      

Staff leaves the project team and needs to be replaced without a loss of project-specific knowledge. 

While these types of commonplace issues vary in significance, they all have the potential to delay or disrupt the start up or timely completion of a trial, which means they pose a degree of risk. The list of such risks for a particular trial forms the basis for the risk management plan. 

Once the risks have been identified, the next step in the risk management process is to qualitatively analyze each risk to determine its relative potential to impact the time or cost of the study (see Table 1). This process usually begins with a subjective, qualitative analysis that assigns an impact level of high, medium or low for each identified issue. 

The second part of the analysis quantitatively evaluates the probability that a particular risk will occur. For example, it is very common in larger studies for some sites to have insufficient staff to perform the required study functions, especially at the beginning of a study, so this risk would rank as a high probability. In most cases, the effect of staff shortages at a site would be significant, so this risk might also be designated as having a high impact potential. Other issues such as ethics committee delays are less common and might have low probabilities, but would have a high impact. 

When the analyses have been completed, the risks that have both high probability and high impact would obviously be the focus of the risk management and mitigation efforts. 

Although the risk analysis helps set priorities, all of the risks should be continuously monitored and reevaluated during the course of a study. Risk management must be an iterative process, because risk profiles inevitably change. The risks encountered at the beginning of trials are different than those in later stages, and new risks will appear as a study moves forward. The key for any successful risk management strategy is constant vigilance and adaptation as the circumstances surrounding a trial change and evolve. 

In addition, the risk analysis data determines the extent and direction of a trial's contingency planning, as well as the potential cost of those contingencies. A high probability, high impact risk would obviously require the most extensive contingency plans. If those contingency plans are likely to be necessary, then the trial's contingency reserve budget—which all studies should have—must be sized to accommodate those costs. 

Once the risks have been identified and analyzed, the next step is to develop appropriate risk response strategies. The common response is risk mitigation: to reduce the chance of a particular risk occurring, or to reduce the impact if it does occur. For the high-risk situations that have been identified during the initial analysis, the best response is to design the trial in such a way that risk mitigation is built into the plan. By anticipating and planning for those major risks as part of the trial process, the project team has a greater chance of reducing or avoiding those risks entirely. 

A well-designed risk mitigation strategy and solid contingency plans greatly increase the chances that the trial team will be prepared to respond quickly and appropriately when problems occur. It is expected that even unexpected issues can be handled successfully if well thought out risk management procedures have been built into the trial process. 

Another approach in the biopharmaceutical industry to dealing with risk is to transfer or share the risk with other parties involved in a trial. The most common way to accomplish this is through contractual arrangements. 

Typically, risk transference means that the party with the most control over a risk should be contractually responsible for managing that risk. For example, if a lab is handling patient samples for a trial, then the contract for those services should include specific language about responsibilities and contingencies for dealing with lab sample problems. If the lab has control over the shipment, analysis, and reporting of the samples, then the lab should be responsible for the risks associated with that process. 

The concept of "risk triggers" is also essential to timely risk response and mitigation. In addition to identifying potential risks and developing contingency plans, a trial team must have a way to predict when a particular risk is increasingly likely to occur. Just as a meteorologist can check a barometer to anticipate changes in the weather, trial managers need effective metrics and milestones for key aspects of a study that are predictors of potential problems. For example, if the data management group is validating fewer case report forms every day, that statistic could indicate a problem with monitors who are not collecting as many pages as needed. 

Whatever the problem, the deviation from the expected metrics would be a trigger for a trial manager to investigate the issue and address it before it becomes a serious risk. For this system of risk triggers to be effective, however, extensive trial metrics must be in place and must be closely monitored. Effective, proactive risk management will not only ensure those trigger levels are in place, but ensure that someone is assigned responsibility to monitor them and that sufficient tools exist to allow such monitoring and layout specific actions to take as well as escalation procedures. 

How does risk management work in clinical trials? Following are some typical risk situations that occur regularly in the course of clinical trials, and some possible scenarios for managing those risks. 

Insufficient staff to complete required work at a site.

 If this is a high probability and high impact risk, then more extensive screening at site qualification visits could be built into the site selection process to reduce the probability of staffing issues. After the study begins, managers should stay in touch with the data staff to monitor on-going workloads. If staffing issues still occur, a potential contingency plan could be to offer the site additional funding to recruit needed personnel, or provide additional contract resources. In addition, it is helpful to collect metrics about the sites for future use, which may help to mitigate problems in the future. 

Unsatisfactory compliance with patient diary requirements.

 Problems with the completion of manual patient diaries are commonplace, and this can impact data collection and data quality. One possible mitigation solution is to design studies that utilize electronic diaries, which improve compliance by prompting patients to enter data at the correct times. These systems can also check data as it is entered to minimize improper or incomplete entries. Staff training at the time of study start-up can also be useful to make the site staff aware of typical diary shortcomings so they can help patients comply with the requirements. If problems with diary data become evident during a trial, the situation could be improved by identifying areas with persistent data issues and bringing those issues to the attention of the CRAs and investigators. 

Approval problems with regulatory agencies or ethics committees.

 One way to avoid this issue could be arranging a sponsor meeting with FDA or MHRA personnel early in the trial planning process to discuss potential protocols and gather regulatory input. If the trial team is aware of regulatory or ethics committee issues with similar trials in the past—such as questions about patient care or the selection of a comparator drug—these concerns should be preempted by addressing them in the trial plan. The most reliable contingency plan would have back-up sites, and even back-up countries, identified during the planning process. This is so critical a component that it may be worthwhile to have prequalified alternate sites available to avoid study delays. It is also helpful to involve the principal investigator (PI) at predeployment meetings to address some issues. This is important because the PI will appear before the IRB and should be prepared. 

Patient recruitment success outstrips the capacity of site data team.

 While patient recruitment shortcomings are more typical—and thus more frequently accounted for in risk mitigation plans—rapid patient recruitment can also present risks by overwhelming the data management staff. To avoid this risk, the recruitment forecasts as developed within the project team can be given to the data management personnel so they can build the required capacity into their resource planning process. The contingency plan for a data overload at a particular site is to identify and train back-up data entry and data management resources in advance who can be quickly assigned to the site to meet peak demands. 

 This is another common problem, especially in global trials where language issues can often contribute to poor data quality if not managed properly. To minimize this potential problem, the clinical team should review the data validation specifications and wording to ensure that they are easy to understand, even for those whom English is not the primary language. Training for data management personnel should include a clear process and explanation of the types and timing of responses that are expected for data queries. If repeated queries become a problem during a study, retraining that focuses on specific response shortcomings would be an appropriate contingency. 

Staff leaves the project team and needs to be replaced without a loss of project-specific knowledge.

 The most important mitigation task for this risk should be that a strategy for the training of new staff during the project lifetime is already developed at project initiation. When project staff changes, transition periods need to be put in place where old and new staff work together on the same tasks. Project Coaching, understood as the assignment of an existing team member as a direct coach, is another effective way of dealing with this risk. 

The final step in the risk management process is to continuously monitor risk throughout the clinical development process. Risks change over time, and new risks may arise during the course of a trial, so constant vigilance is required to maintain a strong focus on risk mitigation during the course of a clinical study. 

To meet the challenge of risk management in clinical programs, senior executives need to invest in the people, processes, and technology required to maintain a strong risk management process. Although this process requires investment, the potential costs of trial delays or more significant costs of regulatory failure because of trial issues could be avoided with the right risk management plan. 

A proactive approach to risk management can greatly reduce the chances of a biopharmaceutical company falling victim to a catastrophic risk that could jeopardize its future. A company with a strong focus on risk management will be able to bring its products to market successfully, enhance its reputation among regulators, physicians, insurers, and the other key constituencies, and most importantly get important new safe and effective treatments to the patients who need them. 

1. S. Hanna-Leena, "Risk Management in Drug Development Projects, Helsinki University of Technology," Laboratory of Industrial Management, Report 2004. 

Risk Management: Tricks of the Trade for Project Managers: A Course in a Book

 (RMC Publications Inc, Minnetonka, MN, 2003). 

3. Treasury Board of Canada Secretariat, Integrated Risk Management Framework, 

http://www.tbs-sct.gc.ca/pol/doc-eng.aspx?id=12254&section=text#cha2

* is senior director, project management, and 

 is project director for Parexel International, 200 West Street, Waltham, MA 02451, email: 

*To whom all correspondence should be addressed. 

Feature Article

Proactive risk management helps pharma protect their product development investments and future.

Reducing Risk Through Mitigation Strategies

An aging population, the end of the "blockbuster drug era," and mounting drug discovery and development costs are pressuring organizations to dramatically improve clinical trial efficiency. Innovation in trial design and management to address the growing pressures requires a new approach to information management—one that is collaborative and allows information to be aggregated, accessible, and reusable.   

Uses for next generation information management, called health intelligence, in research.

Applied Clinical Trials-08-01-2009