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eCLINICAL : Global Advantages with CTMS  From EDC to ETMS  The Upfront Cost Hurdle of EDC  eDiaries: Earlier is Better  SUBJECT RECRUITMENT : Recruitment Grows on the Internet  Also in this issue : FDA Wants Better Science, Flawed EU Directive, BRIDG for Better Models, NICE Gets Bad Rap

Applied Clinical Trials Digital Edition - April 2010

The FDA has accepted for review Eisai's NDA for once daily 23 mg Aricept for the treatment of moderate-to-severe Alzheimer's. The higher dose formulation is in an extended release delivery system. The NDA is based on a study comparing the 23 mg Aricept extended release tablet to the currently marketed once daily 10 mg Aricept immediate release tablet. More than 1400 subjects with moderate-to-severe Alzheimer's disease were enrolled in this global study. Eisai and Pfizer copromote Aricept in the United States, Japan, and key European markets. The 

 identifier for this trial is NCT00478205.

Early last month, Pfizer and Medivation announced that the investigational drug dimebon (latrepirdine) for Alzheimer's disease did not meet co-primary or secondary efficacy endpoints compared to placebo. The co-primary endpoints were measures of cognition and global function. The Phase III CONNECTION study comprised 598 subjects with mild-to-moderate Alzheimer's at 63 sites in North America, Europe, and South America, of which more than 40% were enrolled in the United States. A separate tolerability study had positive results. The companies will be reviewing the data to determine next steps. The 

 identifiers are NCT00675623 and NCT00838110 respectively.

Bayer HealthCare Pharmaceuticals late last year, enrolled the first patient in an international Phase III clinical trial to evaluate the efficacy and safety of florbetaben (BAY 94-9172) PET imaging in the detection of beta-Amyloid plaques in the brain, a pathological hallmark of Alzheimer's disease. The Phase III trial is an open-label, multicenter, nonrandomized single dose study enrolling 400 subjects with and without dementia. The 

Semagacestat, Lilly's gamma secretase inhibitor, is currently being studied in two large multinational pivotal Phase III trials—IDENTITY and IDENTITY-2—to assess its effect on the progression of Alzheimer's disease. Enrollment in the IDENTITY trial was completed in the third quarter of 2009 and includes over 1500 subjects in 20 countries. Enrollment in IDENTITY-2 is targeted at 1100 subjects and is expected to be completed in the first half of 2010. The study is planned to be completed in March 2012. The 

 identifiers are NCT01035138 and NCT00762411 respectively.

Also in development for Lilly is its A-beta antibody solanezumab, a monoclonal antibody that may slow the progression of Alzheimer's disease. Enrollment began in May 2009 in two multinational Phase III registration studies—EXPEDITION and EXPEDITION 2. Each study will enroll 1000 subjects for an 18-month treatment duration. The 

 identifiers are NCT00905372 and NCT00904683 respectively.

AFFiRiS AG's Alzheimer's vaccine candidate AFFITOPE AD02 is planned to enter Phase II clinical trials early in 2010. The company based its decision on the first interim analysis of the secondary endpoints at the six-month time point. Based on this analysis, the AD02 patients from the completed Phase I study will be offered an AD02 booster vaccination. The 

This month, EnVivo Pharmaceuticals plans to begin enrollment of 300 subjects for its adaptive designed Phase II randomized, double-blind, placebo-controlled study of EVP-6124. This alpha-7 nicotinic acetylcholine receptor showed improvement in cognition, as well as good tolerability and safety. INC Research is listed as a study collaborator, which has a 

On the heals of Pfizer's acquisition of Wyeth, which included Wyeth's Alzheimer's drug in Phase I/II development with Elan Pharmaceuticals, Eisai and Pfizer restructured their copromotion agreement of Aricept. In that agreement, Pfizer will continue to exclusively sell with Eisai Aricept in all countries it currently sells until July 2022. At that point, it will give Aricept rights to Eisai in Japan only. 

Anavex Life Sciences Corp. selected Forenap Pharma as its CRO for Phase I clinical trials of ANAVEX 2-73, the company's lead Alzheimer's drug candidate. Forenap will perform study set-up, protocol review, site monitoring, and project management for the trials. All work will be performed under individual work orders that fall under a master services agreement executed by Forenap and Anavex, including pre-clinical, pharmaceutical, and clinical development of ANAVEX 2-73.

Challenges in the development of drugs for Alzheimer's disease are evident in the latest clinical trial results released by Medivation and Pfizer on their investigational drug dimebon, which failed to prove efficacy in the Phase III trial. The co-primary endpoints were improvements to cognition and memory, as well as global function for subjects with mild-to-moderate Alzheimer's. 

While Medivation and Pfizer are evaluating the data to determine their next steps, the Alzheimer's community was disappointed with the results. Said Alzheimer's Association Chief Medical and Scientific Officer William Thies, PhD, in a statement, "People with Alzheimer's, their families, and caregivers desperately need more and better treatment options for this devastating, fatal brain disease."  

 Meds in Development: Alzheimers Disease 

Recent reports from the association show that African-Americans are two times more likely than Whites to have Alzheimer's and other dementias, and Hispanics are one and one-half more times more likely. While there is no definitive genetic reason for this difference among ethnic populations, researchers believe that risk factors for Alzheimer's are more prevalent in these populations. Those risk factors are socioeconomic, including lower levels of education and income, as well as a higher prevalence of high blood pressure and diabetes. 

Other data available on the disease from the association includes:  

5.3 million Americans are diagnosed with Alzheimer's.

In 2006, it was the seventh leading cause of death.

Total payments for health and long-term care services for Alzheimer's patients will total $172 billion in 2010.

While dimebon has taken a major setback in its pursuit to approval, other drugs on the market are still viable and making headway. As noted on the previous page, Aricept 23 mg was accepted into review to be approved as an extended release tablet for moderate-to-severe Alzheimer's. Namenda, Forest Laboratories' approved therapy for the treatment of moderate-to-severe Alzheimer's, represented 34.2% of the total prescriptions as of March 2009. It is anticipated to go off-patent in April 2015. 

While treatments for later stage Alzheimer's are important, therapies in development target the neurogenerative aspect of Alzheimer's, which requires identification before patients exhibit even mild cognitive symptoms. As Charles Albright, PhD, Group Director at BMS, pointed out in a session on biomarkers at the 22nd Annual DIA EuroMeeting in March, it is important that Alzheimer's be detected in the predementia stage. When Alzheimer's is detected, brain atrophy has already begun and the prognosis is about nine years to death.  

To achieve predementia diagnosis, advanced biomarkers are needed. The potential biomarkers Albright discussed were neuroimaging (MRI structural: volumetric MRI and Amyloid PET); blood (ApoE4 and others in development); and cerebrospinal fluid (CSF) analytes (Amyloid beta 42). However, each currently have limitations. "MRI is not specific to Alzheimer's yet. Amyloid PET is used to detect plaques, however, the access to ligands is limited and costly," said Albright. "That should resolve in a few years." 

As for the ApoE4 blood biomarker, it is simple and ApoE4 carriers do progress more rapidly from pre- to prodromal Alzheimer's, however, it also is not specific. Albright noted that 30% to 50% of predementia Alzheimer's patients are non-ApoE4 carriers and 10% to 30% of the ApoE4 carriers have normal CSF biomarkers, making them slow progressors. 

Albright outlined BMS' Phase II clinical trial in predementia Alzheimer's subjects for BMS-708163, a y-secretase inhibitor, and how it identified subjects. Cognitive and caregiver scores were used, as well as an MRI, but it also incorporated a CSF profile. The challenge? The current CSF Assays are "research use only" and therefore not GCMP compliant. 

"There is a significant amount of work to get an assay validated," noted Albright. And many groups are working toward this. It is clear that biomarkers are key to the future of Alzheimer's treatment and drug development. 

Phase News

Updates on the RA market, including Phase III study results and drug approvals, and related business news.

Alzheimer's by Phase

Since the mid-1980s, Belgium has been a very active clinical research territory in Europe. Currently, it is far more active than its neighbors or the United States in terms of new clinical trials per million inhabitants per year. 

This is due to the qualification of Belgian investigators and their staff; the concentration of technology at the sites; the high level of education of the population, allowing participants to comprehend the purpose of complicated trials and thus to provide informed consent; and the high standard of living, which enables patients to defend themselves in case of investigator abuse (e.g., the means to access a lawyer and a functioning legal system). 

Through the globalization of research, sponsors and CROs have discovered by trial and error sites with an enrollment productivity three to 10 times greater than in economically advanced countries like Belgium. Twenty years into the globalization process, are we sure it is acceptable to pool data from extremely diverse origins, including from countries where: 					

The investigator is in a dominant position vis-à-vis the patient, such that patients minimize adverse reactions and maximize the effect of the investigational product to "please the doctor?"

A vast proportion of the population lives in poverty, for example, with a GDP per capita below that in the EU Member State with the lowest GDP?

Access to health care conforming to disease-specific guidelines in advanced countries it is not available routinely, or where our level of standard of care is so unaffordable that the financial and logistic intervention of the sponsor is required to ensure that local participants receive it in the context of the trial?

A contrario, it is perfectly adequate to accept clinical data exclusively from poor countries where the primary disease studied in the trial is much more prevalent in the poor countries of the world. 

The mere equivalence between countries of baseline characteristics of participants in a study concerning sex, biometrics, risk factors, and disease markers is not enough to justify the indiscriminate pooling of clinical results from all over the world. The transnational pooling of clinical data should be justified by demonstrating equivalence in relevant health care and socio-economic standards in the countries participating in the trial. 

Equivalence should be demonstrated in the qualifications of health care staff involved in the research, in the capacity of participants to give free and informed consent, in the availability of alternative care if the participant turns down the trial, as well as equivalence in local standards of care. The latter is closely related to GDP per capita. Infant mortality rates and life expectancies for males and females correlate with living standards and the quality of health care in the population, and therefore differ enormously between countries. How different can the health care environments be from where trial data is derived to still justify transnational pooling? 

The probability of a GCP inspection of participating sites is much higher in the EU and North America than in the rest of the world. Trials migrate today to regions of the world where the probability of a GCP inspection, and thus the detection of fraud and misconduct and corresponding sanctions, are close to nil. 

Our standard of care in the future in Europe depends on clinical research with new products today. However, testing these new products in vastly inferior health care and socio-economic environments favoring hyper-fast recruitment solves only the sample size challenge.

A Closing Thought

How different can the health care environments be from where data is derived to justify pooling?

The Deeper Data Debate

Electronic data capture (EDC) is a well-established building block for bringing far-reaching efficiencies to the clinical trials process. It has gained a firm foothold in the clinical trials market, with estimates for new trials starting with EDC in the 50% range.

  EDC's growing presence has come a long way from its early roots of double entry systems on stand-alone desktop computers in the 1990s, emerging as a Web-based user-friendly tool for improving data quality, lowering costs, cutting clinical development timelines, and ultimately accelerating time to market.

Despite EDC's established history and a perception that "everyone is using EDC," many biopharmaceutical and medical devices sponsors continue to conduct paper-based studies. Mostly they cite the upfront cost of transitioning to EDC as a barrier. As part of this perception, they may believe that EDC solutions are generally too big for smaller companies, or they may be unsure about the vendor's ability to deliver high-quality technology, training, and customer service, as promised. There could also be some level of discomfort as to how EDC will be implemented and how processes, standard operating procedures, and jobs will change to accommodate the new technology. 

Yet, research supports that EDC is here to stay. As evidence, a recent report by William Blair & Company

  states that the benefits of EDC are recognized by major industry players such as GlaxoSmithKline, Merck, and Novartis, who are moving toward using EDC in 100% of their clinical trials. The Blair report states that the EDC market is projected to grow 15% annually through 2012. 

At a time when sponsors are challenged with filling pipelines, conducting complex global clinical trials that generate a rising volume of data points,

  and complying with postmarketing requirements for additional safety and efficacy data, they are seeking to streamline as many processes as possible along the product lifecycle continuum. Clinical development is targeted as a key area in need of greater efficiencies and a lower cost structure. Research suggests that while costs associated with drug development are increasing at an annual rate of 11.8%,

  sales are growing at a slower pace, in the range of 4.5% to 5.5% globally, and 2% to 5% in the United States.

  Moving away from paper-based processes that are labor-intensive, repetitive, and error-prone, and edging toward electronic solutions, such as EDC, is essential for achieving the efficiencies needed to speed development and better align development costs with sales revenues. 

Fortunately, there is evidence that this is already happening. A contract research organization (CRO) survey performed in late 2008 reveals that 45% of respondents (n = 18) currently conduct more than half of their studies using EDC. The survey also revealed that within three years, 85% of respondents predict using EDC in 50% of their trials.

  Another study performed by a provider of clinical trial services showed similar acceptance.

  It was performed in late 2006 and included 190 respondents, mostly biopharmaceutical sponsors. Fully 86% reported using EDC at least once. Additionally, 50% stated that EDC was more attractive as an outsourced service than as a technology-only offering to be managed internally. 

With these data as background, it is apparent that EDC has made substantial inroads. But still, many cling to paper. For companies considering making the transition, they may want to evaluate not only the benefits of EDC but also what it takes for successful implementation. Deciding factors include cost of EDC compared to paper, ability to make necessary internal process changes, buy-in from key managers, and identifying the right EDC provider with the right solution. 

Making the decision to conduct trials with EDC requires a careful analysis of its total costs versus those of paper-based processes. When making a true cost comparison, decision makers need to consider more than the upfront cost of purchasing an EDC system. Focusing only on the upfront cost completely overlooks the significant downstream cost savings realized by being able to reduce the number of queries, have faster query resolution, faster visibility of the data by sponsors and CROs, and fewer monitoring visits. There are also significant savings accrued by completing the last patient/last visit weeks or months sooner than its paper-equivalent, and by locking the database faster. And these benefits tend to be cumulative as efficiencies linked to new technologies generally increase over time as end users gain familiarity with them through repeated use. 

Research by Banik found measurable improvements in clinical trial efficiency when using EDC as compared to paper.

  In an analysis of a five country, 19-site asthma study with 226 subjects, the EDC arm showed a 30% decline in study duration, a 43% decline in the time to database lock, and an 86% drop in the number of queries. These findings support the value of including downstream savings as well as direct costs and upfront expenses when evaluating costs. 

When making a cost comparison, direct costs should include the cost of double data entry per page, monitoring visits, the average cost of query resolution, downstream savings and other factors (see sidebar Cost Considerations: EDC vs. Paper). 

Using these factors, two cost comparisons were performed that document the overall savings that are possible with EDC. First is a study conducted by an industry consultant, using a cost model.

  The study is based on 11 actual Requests for Proposals (RFPs) developed by multiple EDC providers for Phase IIb and III trials. Clients, as well as the providers, are large, medium and small.  

The cost model includes the following assumptions:  

Costs of $1.50 to $1.75/page for double data entry for paper-based systems, and $1.50 to $1.75/page for printing and mailing costs of paper documents 	

Table 1 compares the cost of query resolution throughout the study, Table 2 depicts savings in monitoring costs, and Table 3 shows net savings after factoring in the cost of an EDC system. Based on these assumptions, there are significant savings linked to reductions in the cost of query resolution, monitoring visits, and paper handling. As shown in Table 3, considering the cost of an EDC system, the overall benefit of EDC exceeds $368,000 for a single study. 

The second comparison, a study conducted by Forrester Research, projected similar savings when comparing use of EDC against paper in a Phase II study: $347,600.

The findings were based on a 20-site study, 200 subjects (10 patients/site), and a 12-month study duration plus time for data cleaning. Furthermore, in a Phase III scenario with 200 sites, 2000 subjects (10 patients/site), and a 24-month duration plus time for data cleaning, Forrester identified downstream savings of $6.25 million in favor of EDC (see Table 4). 

The cost models illustrate that EDC brings measurable cost efficiencies to sponsors, CROs, and end users, but with an estimated 50% acceptance rate in the industry, there is room for greater utilization. At this point in the adoption cycle, it is useful to measure views of EDC users, such as their opinion of their EDC solution, how they chose an EDC provider, and the role of cost in their decision making. This information may prove meaningful for companies intending to make the switch. 

To start the process, a recent survey was conducted by StudyManager, maker of a suite of clinical trial management system (CTMS) and EDC solutions of the same name. Results of the survey are meant to generate supportive data to identify desired EDC options, key performance indicators, and purchase factors.  

The survey contained 22 questions and was conducted online over a six-week period, starting in May 2009. It was sent to a targeted audience, including members of the Society for Clinical Data Management (SCDM) and the Association of Clinical Research Professionals (ACRP). It was also placed on multiple social networking sites that have biopharmaceutical, medical device, and clinical trial groups, such as Twitter, Facebook, and LinkedIn. 

There were 62 respondents. Of those, 95% reported having some experience with EDC, and 89% reported having at least six months of experience. Approximately 90% claimed that their organizations have used EDC. 

Questions were divided in various categories. First, it asked respondents about the length of time it should take to become competent in using the system; and for those whose companies have already chosen a system, whether it contains all of the necessary features and integrates well with external sources. Next were a series of questions about the selected EDC provider, looking at areas such as cost, service, and support; ease of implementation training; and user interface. It also asked whether the provider is CDISC Operational Data Model (ODM)-compliant and if the system provides a portal or document management system that can host documents or communicate with external sites. The final four questions were targeted at respondents with at least six months of EDC experience. 

What did the survey show? Perhaps the most important finding is that only 47% of respondents ranked cost of the EDC system as highly important when choosing a vendor. Among factors deemed as highly important, cost ranked the lowest of the four choices offered. As shown in Table 5, the factor to which the most respondents gave a highly important rating was user interface, at 75%. This finding is significant because upfront cost is most often pegged as the key barrier to EDC acceptance. Yet because nearly all of the respondents have experience with EDC, it is possible to speculate that they have begun to recognize and appreciate that initial costs are offset by the downstream benefits of the tool. So, their focus has possibly shifted from cost to factors that impact daily use, such as the importance of a good and easy-to-use interface. 

The importance of cost cannot be underestimated, however, because when the "somewhat important" rating is factored in, 97% of respondents pegged cost of the EDC system as an important consideration. Since respondents represented stakeholders of all sizes, this finding suggests that users in general are cost-sensitive. Extrapolating this finding, it is possible to speculate that the focus on cost provides a window into the thinking of smaller users who may believe EDC is out of reach of their more limited budgets. With today's flexible systems and modular structure, however, hesitant first-time users and smaller users can be eased into an EDC system priced to suit their needs. This applies to sponsors and to the growing number of CROs that are assuming responsibility for EDC as technology outsourcing increases.

When asked how long it should take end users to become competent in using the system, 72% responded that it should take zero to two months. This highlights the plug-and-play mindset that prevails, and signals to providers that end-users expect EDC systems to be intuitive and easy-to-use, requiring minimal training. This expectation may overshadow the fact that successful EDC implementation is tied to process change that must be supported across the organization.

More than half, 52%, report that their systems integrate only somewhat well with external data sources. This is a key indicator that users need to explore if they plan to automate functions beyond EDC, to include integration with clinical trial management systems, clinical data management systems, and other point solutions in keeping with the evolution toward eClinical trials.

For users in the six-months or more category, nearly 60% claim that based upon their selection criteria and understanding of the software, their purchase assumptions were only somewhat correct. This finding suggests that potential users may want to spend more time defining their needs and possibly contacting references to better understand the right selection criteria.

Various factors at play are driving the transition from paper-based clinical trials to greater use of electronic data capture. First, there is the need for greater downstream efficiencies and lower costs in the clinical development process. There is increasing complexity, more globalization, and longer duration of clinical trials in response to requirements for more safety and efficacy data. Regulatory agencies around the world are starting to mandate use of electronic formats for submissions to bring efficiencies to the pre- and postmarketing review process, as mandated by legislation, such as the Food and Drug Administration Amendments Act (FDAAA) of 2007.

  And there is the growing adoption of standards from organizations such as Health Level Seven (HL7) and CDISC. 

With all of these elements aligned, EDC is establishing itself as an essential tool for making change possible. Yet, for those sponsors who are still working with paper but want to join the transition, they often balk at the upfront cost of the tool. It is at this critical juncture that EDC providers can work with sponsors to identify the very real downstream savings that can offset the upfront expense. Cost models show significant savings for later phase studies, and these benefits are not just limited to the biggest players. Today's systems can be implemented in modular fashion, are priced to be affordable for users of all sizes, and training is provided. In addition, well-designed solutions can be integrated with functions such as CTMS and electronic patient reported outcomes (ePRO).  

Joining the transition to EDC requires significant process change and company-wide commitment. Sponsors are aware of the needed change as evidenced in the survey. Some 95% of respondents expect EDC implementation to impact internal resource requirements either highly or somewhat. An experienced outsourced provider with a strong customer service focus can ease the transition.  

Going forward, EDC is destined to play a larger role. It has been implemented mostly in studies in Phase IIb and later and its presence will expand, but it is also being considered for earlier studies and for the growing volume of studies linked to postmarketing commitments. With this move, it will be possible to generate electronic clinical trial data earlier on, starting from the beginning, yielding improved efficiencies, as well as time and cost savings, extending across the continuum. 

is President of Medical deScriptions, Cincinnati, OH, email: 

, MD, is Vice President of Medical Affairs at StudyManager, Seattle, WA. 

is an independent consultant located in Seattle, WA.

*To whom all correspondence should be addressed.

 "Electronic Data Capture is on the Way Up," Health Industry Insights. Clinical Development Strategy and Technology Marketplace. Next Generation Pharmaceutical, October 2007, 

http://www.ngpharma.com/article/Electronic-data-capture-is-on-the-way-up

Phase Forward, William Blair & Company, March 18, 2009.  

 P. McGee, "Managing the Clinical Data Flood," 

http://www.dddmag.com/managing-the-clinical-data-flood.aspx

PAREXEL's Bio/Pharmaceutical R&D Statistical Sourcebook 2009/2010

 (PAREXEL International Corporation, Waltham, MA, 2009) p 145. 

 "PRLog. NAPRx Forecasts 4.5-5.5 Percent Growth for Pharmaceutical Market in 2009, Exceeding $820 Billion," 

http://www.prlog.org/10164237-naprx-forecasts-45-55-percent-growth-for-pharmaceutical-market-in-2009-exceeding-820-billion.html

Feature Article

Although costs can force some sponsors to think twice, data show downstream savings add up.

The Upfront Cost Hurdle of EDC

The Food and Drug Administration wants more respect, and less second-guessing of its regulatory actions. Its strategy is to build up in-house scientific expertise and to improve methods for evaluating medical products so that its decision to approve a drug for market or to require postmarketing safety studies don't draw criticism on the political front or from experts with differing opinions. 

Strengthening FDA's science base has been a leading theme for Commissioner Margaret Hamburg since taking the agency's helm a year ago. She has gained modest recognition of its importance from the Obama administration, which earmarked some money for a small science program in the 2011 budget plan, and from the National Institutes of Health (NIH), which is funding research on ways to improve the science of evaluating new drug safety and efficacy. Up until now, the field of regulatory science has not received the resources, or the intellectual power, that it really needs and deserves, Hamburg stated in announcing the FDA-NIH collaboration in February. "We have allowed the arm of regulatory science to become weak and under-developed," she commented. If not fixed, "instead of pulling us into an exalted future, we will row in circles."  

Hamburg warned that if this imbalance persists, "we will not realize all the potential of the revolution in biomedical science." She and others are dismayed that the nation's huge investment in biomedical research, epitomized by decoding the human genome, has not translated into important new treatments for patients. In order for that to happen, Hamburg stated at a February meeting of the Personalized Medicine Coalition (PMC) that biomedical discoveries "must be married to a robust investment in regulatory science." By that she means developing new tools and standards to assess medical product safety, effectiveness, potency, quality, and performance. Priority projects could involve setting standards for novel cell-based therapies, developing reagents to test flu vaccine potency, or implementing strategies for screening compounds for serious adverse events. 

An important component of this initiative is to improve the design of clinical trials to better assess product safety and efficacy and to make the research process more efficient and less costly. Hamburg notes that validating surrogate endpoints can reduce the time and cost of clinical trials and that FDA needs to provide more guidance on study design; clinical trials for rare disease treatments, for example, should involve fewer patients and permit more flexible endpoints.  

Regulatory science is key to advancing personalized medicine by providing the scientific community with a better understanding of the genetics of drug metabolism and which patients may be at risk for adverse consequences from a particular drug, as well as those most likely to benefit. The discovery of genetic markers has led to labeling that will prevent use of certain colon cancer drugs on those patients with the K-RAS mutation who are unlikely to benefit. And biomarker validation projects have produced new rodent assays that can pick up early signs of kidney toxicity. Such efforts can support smaller studies that enroll patients most likely to respond to treatment. 

Hamburg promised to issue long-awaited draft guidance on biomarker qualification this year. Another guidance on the codevelopment of drugs and diagnostics will clarify FDA expectations for clinical trials to show that a test is accurate and can inform clinical decisions. Related to this, FDA is working internally to gain agreement across FDA centers about the kind of evidence needed to rely on a test result to shape a drug trial, or product approval or relabeling. 

Because the FDA has very limited resources to expand its scientific capabilities, Hamburg is looking for assistance from fellow government agencies and from the industry. This past February, she and NIH Director Francis Collins joined Health and Human Services (HHS) Secretary Kathleen Sebelius to announce a collaborative effort to promote  regulatory science so that patients will gain access sooner to safer therapies and treatments. 

The three-year $6.75 million program is tiny by NIH standards, but won praise as an important first step toward developing new methods and approaches for biomedical product development. NIH is providing $2 million and FDA $250,000 each year, which will support two or three grants a year to academic researchers exploring new models and technologies related to evaluating the safety and efficacy of drugs, biologics, and medical devices throughout the product lifecycle. 

To define the research agenda and to generate interest in regulatory science across the academic research community, Collins and Hamburg will co-chair a Joint Leadership Council composed of leading scientists from both agencies. The panel will encourage NIH research directors to consider regulatory issues in building their research programs, and also seek to integrate the latest science into FDA's review process. The panel is holding a public meeting this spring to gain input on research priorities and on how NIH and FDA can work better together.  

Many of these issues were examined more fully at a workshop sponsored by the Institute of Medicine (IOM) Drug Forum in late February. The group has been discussing the need to improve FDA's science base since an IOM 2007 report on drug safety highlighted the   gap in agency expertise. Hamburg noted that FDA's partnership with NIH may provide a model for similar relationships with other government agencies, such as the National Institute of Science & Technology (NIST) and HHS' Biomedical Advanced Research & Development Authority (BARDA). 

Despite Hamburg's vigorous campaign to strengthen science at FDA, the path forward is peppered with obstacles. First is limited resources. The Obama administration's FDA budget plan for 2011 provides $25 million for an Advancing Regulatory Science initiative, an amount that reflects the overall squeeze on FDA funding for next year. Only by collecting $1.5 billion in user fees does FDA's total budget reach the $4 billion total and the 25% increase highlighted by the White House. Just looking at the 6% rise in appropriations, FDA barely breaks even, explained consultant Steven Grossman.   

Moreover, much of that $25 million is targeted to specific projects, such as improving FDA expertise in nanotechnology and stem cell research, and setting standards for biosimilars and medical device technology. FDA Chief Scientist Jesse Goodman would have $3 million to oversee initiatives to spur research and collaboration. But there's a paltry $4.5 million for FDA's Critical Path Initiative, which has been struggling to support biomarker validation collaborations and to modernize clinical research.  

The proposed amount will enable FDA to bring in a handful of scientists to bolster these initiatives, improve internal staff training programs, and provide some support for research projects. There is talk of forming a network of academic Centers of Excellence and an independent research entity to help FDA answer tricky questions about product efficacy or safety, but those require much more money to move off the back burner. HHS Deputy Secretary Bill Corr expressed administration commitment to these efforts, describing the admittedly modest funding of science at FDA as a "foundation for more to come." 

However, some important policy makers are skeptical that FDA needs more resources to do its job. Rep. Rosa DeLauro (D-Conn), chairman of the House Appropriations subcommittee that oversees FDA funding, told the IOM workshop that "FDA has many problems that won't be solved by throwing money at it." DeLauro is unhappy that drug safety issues continue to erupt and that FDA has trouble resolving administrative issues.  

One optimistic note, observed Eli Lilly Vice President Gail Cassell, is that other government agencies such as NIH and BARDA are becoming more aware of FDA's importance in facilitating access to new therapies and to countermeasures to protect against biological threats. Cassell recently chaired another IOM meeting on strategies for developing medical products for public health purposes that examined FDA's critical role in facilitating access to emergency treatments and in evaluating innovative clinical trial designs for products with low commercial viability.  

Hamburg acknowledged that current initiatives don't provide enough money to do all that needs to be done, "but it's a start." At a minimum, the commissioner hopes to systematize how FDA addresses regulatory science within the agency and to expand collaborations with external partners. The larger task of restoring the confidence of policy makers and the American people in FDA requires sustained funding and autonomy to "do our work" without being "buffeted by outside forces."  

Even small funding for regulatory science will draw the attention of academia, noted 

 Editor Jeffrey Drazen. And, he added, it may help get the politicians off of FDA's back. 

 is the Washington editor of Applied Clinical Trials, (301) 656-4634 

View from Washington

FDA Commissioner Hamburg seeks resources to build agency scientific expertise & new research methods.

Regulatory Science to Inform Trial Design

The average lifespan of a U.S. citizen increased by more than 30 years in the 20th century,

  and the life sciences industry played an instrumental role in realizing this achievement. The industry continues to innovate today, working toward breakthroughs that will further advance the treatment of serious and chronic disease, as well as open new commercial avenues for biotech and pharmaceutical companies. 

As life sciences organizations press forward in the development of treatments, they face unprecedented operational challenges, including flat and even declining productivity, rising research and development costs (closing in on $1 billion to bring a new drug or treatment to market),

  more complex preapproval trials and large postapproval studies driven by the shift toward biological agents, and increasing regulatory demands. In this environment, life sciences organizations are increasingly seeking greater operational efficiency and productivity in the expensive and time-consuming clinical development process.

The industry is taking a hard look at clinical trials—the cost of which has increased by 40% over the last decade, according to industry analyst Frost & Sullivan.

  As such, the focus on reducing costs and elevating R&D productivity is driving tremendous change in the way life sciences organizations conduct trials and how they capture, store, integrate, analyze, and report critical trial-related data to yield new insights that drive down costs. Multinational pharmaceutical companies have increasingly included China in early development to maximize the use of global studies for local registration and to help reduce clinical trial enrollment bottlenecks and costs. 

Two trends hold significant potential for multinational pharmaceutical development: global trials and streamlined data integration. Clinical trial management systems (CTMS) is a way to support these trends and help organizations reduce costs, increase productivity, and respond more agilely to the ever-changing global clinical landscape. 

The number of global clinical trials is growing rapidly and the industry is seeing a significant shift in trial location from North America/Western Europe to the Asia-Pacific region. Analysts predict that between 2008 and 2010, the percentage of trials conducted in North America/Western Europe will fall from 55% to 38%.

  At the same time, the market expects to see further expansion in China over the next few years as the result of the new $124 billion government health care reform aimed at providing universal health insurance to 90% of the population by 2011 and expanding investment in primary care facilities in rural regions.

  This program is expected to enable access to millions of rural patients, who previously were not able to participate in clinical trials due to lack of basic medical insurance coverage.  

Several other factors are fueling the trend toward globalization. Expansive, treatment-naïve patient populations to support larger, more extensive trials, as well as cost savings top the list. For example, clinical trials conducted in China and India can cost 60% less than trials conducted in North America or parts of Western Europe.

  In some Asian markets, investigator and site fees are approximately one-half of those in the United States. Additionally, expenses incurred from the sponsor for providing trial-related medication, investigations, and hospitalization can be as low as 30 percent of those in America.

The shift toward global trials has many implications for sponsors and contract research organizations (CROs), which need to support all operational aspects of global trials—from multiple languages, logistics, access control, and regional requirements to region-specific business processes. Furthermore, sponsors and CROs must understand and meet local regulatory requirements, which add a new layer of complexity to the trial management process.  

As such, some organizations turn to commercial CTMS—typically implemented as enterprise applications—to manage global trials more efficiently. Enterprise CTMS provide a centralized trial repository that enables standard trial management processes across the enterprise and provides end users, who increasingly are more geographically diverse, with real-time data visibility into study progress. However, organizations must balance the need to empower their employees with access to available information against the need for information security—keeping tight control over data access, allowing only those with proper authorization to access key data. 

Flexibility in adapting to meet the unique requirements and needs of investigators around the globe is also important when pursuing a global trial strategy. To capitalize on the true potential of broader research and lower costs offered by global clinical trials, organizations must manage global trials as an integrated initiative as opposed to merely a series of trials conducted in different locations. That said, a truly globalized approach to trials will require near real-time visibility across all sites to drive and guide decisions and trial direction. To achieve this objective, sponsors could benefit from global unified CTMS systems with built-in function that supports specific regional needs.  

The current mindset, however, is still more or less fixed on the traditional North American/Western European requirements and supporting prevailing business needs. This view must change if we are to transition to a truly global system to ensure individuals and departments have an understanding of their roles in the business process. Regional units need to understand how their work affects others in the process so that effective collaboration can take place. It is also important to assess the impact or implication that local infrastructure and culture might have on conducting clinical trials in developing countries.   

Innovative CTMS solutions that are very site-focused, pragmatic, and offer flexibility to adapt to the local infrastructure may help trial sponsors and CROs overcome several inherent barriers, including the following: 

Upholding standards and ensuring data integrity

. Global clinical trials present challenges in terms of maintaining consistent standards of care across sites in various countries. Study sponsors must take this into account as they design trials and work to achieve protocol compliance, patient safety, and ethical standards. CTMS can help sponsors and CROs to support trial sites in ensuring adherence to various standards, such as International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) E6 Good Clinical Practice Guidelines, by clearly defining patient and care protocols, presenting a structured system to ensure data integrity, and facilitating compliance monitoring. Such systems also support investigative sites' efforts to ensure appropriate follow-up via functions that enable an investigator to create a follow-up schedule at a moment's notice for a trial participant.  

As important, CTMS can help to support the growth of local CROs in emerging markets—providing a turn-key solution that they can leverage to design, implement, and manage trials that meet international standards, and enabling them to gain a foothold in a growing industry. 

Adapting to local health care delivery networks.

 To succeed in an era of global trials, sponsors, CROs, and their systems should be able to adapt to variations in health care delivery and data collection across countries and regions. 

For example, in China, clinical trial sites are located primarily in cities at larger, government-certified health care facilities because access to primary health care facilities is limited in many remote areas. As a result, many trial participants may not live locally, making follow-up a challenge after a patient is released from the hospital. Addressing this challenge requires flexibility and innovation. A large Chinese CRO has, for example, proposed utilizing mobile phones as a component of its site management system. The proposed system would allow investigators to send alerts or messages via Short Message Service (SMS), or push reminders to patients regarding visits. This type of collaborative tool, along with better data visibility, will help investigators better manage their trial subjects, clinical research associates (CRAs), and sites, and increase overall study compliance. 

Some trial sponsors and CROs are exploring the possibility of leveraging personal digital assistants (PDAs) as another means of accessing and entering data into the CTMS. In some regions, investigators do not carry or have access to laptops in a clinical setting, but they do carry PDAs. In this case, the PDA provides a more effective way to collect, view, and manage critical trial information. 

Flexibility is also essential to ensuring prompt and correct payments to trial investigators and sites—the lifeblood of any trial. The payment process, always complex, becomes even more onerous with global trials as structures, payment processes, and currencies can vary across regions. For example, investigators in North America and Western Europe are demanding better visibility into the payment process, while in China, payments to investigators still remains too much of a sensitive topic to be captured in CTMS. Moving forward, CTMS must provide the flexibility required to accommodate regional variations in payment structures to ensure prompt and accurate payments. 

Building and maintaining relationships with sites

. As the centers of influence for clinical trials expand to the Asia-Pacific region and beyond, life sciences organizations and CROs must focus on building strong and personalized relationships with investigators around the globe to foster loyalty, just as they would for trials conducted in North America and Western Europe. CTMS can support strategies to strengthen these relationships, such as providing investigators with fingertip access to critical information with easy-to-use productivity tools, such as PDAs and SMS, which make conducting trials less time- and resource-consuming.  

Cell phone usage is ubiquitous in China. SMS is widely used by people of all age groups to communicate in transit as it is more cost efficient to send a text message than to place a call. One of the largest domestic CROs in China has been routinely using SMS to send reminder messages to investigators regarding planned site visits, as well as to patients to remind them of scheduled study visits. 

Leading CTMS vendors have adopted a customer relationship management paradigm and methodology, and developed robust features to allow companies to deliver these capabilities. By assisting investigators and providing them with the best possible trial experience, individual companies will set themselves apart from their peers and support investigator retention, regardless of the trial location. 

The goal of boosting R&D productivity while driving down costs can present monumental data integration challenges, regardless of where a trial is conducted. To foster collaboration and accelerate decision-making about proceeding with, adapting, or halting a specific trial, today's sponsors, along with their CRO partners, require instant access to myriad data that range far beyond clinical and lab information to encompass adverse events, enrollment, and even financial data. As important, the individuals requiring this data may be located in the same building or on the other side of the world and may work for various organizations. 

Traditionally, life sciences organizations, like their counterparts in other industries, have built customized, point-to-point integrations to connect data from siloed systems. As IT environments increase in complexity, this approach becomes increasingly complex to sustain as development and maintenance costs escalate dramatically. The active merger and acquisition environment in the life sciences industry further underscores the need for streamlined integration as some of the industry's largest and most complex organizations look to combine operations. 

How do CTMS solutions factor into the integration story? In the era of electronic data capture (EDC) and interactive voice response systems (IVRS), CTMS solutions may not be the primary system of entry for critical patient and enrollment data. Nonetheless, they play an expanded role in ensuring that a trial proceeds on schedule and on budget. 

To get a clear picture of a study, view actual subject enrollment against plan, track actual payments against budget, and forecast workload and resource needs, end users must be able to use CTMS solutions to access accurate data on information such as enrollment, as well as CRF completion. Manually entering data into the CTMS after it has been entered into other systems is highly undesirable, as it is labor-intensive and error-prone, and requires costly conflict resolutions. Thus, integration with systems such as EDC, IVRS, and back office financial systems becomes essential. 

With each integration, however, complexity and costs escalate. Life sciences organizations are looking at streamlined solutions that will simplify integration and enable them to deliver data to the CTMS to drive efficiency and accelerate trial results. 

Vendors with products/applications built on standards-based open architecture offer compelling value in assisting biopharmaceutical companies in their integration efforts. Service-oriented architecture offers a new way to build open applications that can be shared by common processes across multiple applications. Service-oriented architecture essentially breaks down the traditional barriers between systems by providing a common platform on which to build solutions that can be shared as "build once; use many times" interoperable services. 

Many software providers are making significant progress in developing next-generation service-oriented architecture-based applications for the clinical industry. These solutions will provide better support for business processes that span multiple applications and will reduce the need for costly point-to-point integration. As important, they will support an organization's efforts to deliver information and intelligence to the fingertips of trial managers and investigators, often via CTMS systems, ultimately helping to drive new levels of efficiency and precision. 

The life sciences industry has driven advancements that were beyond the imagination of industry experts only a few decades ago. This spirit of innovation continues today, helping the industry to surmount new challenges that range from declining R&D productivity to growing regulatory complexity. 

Life sciences organizations are increasingly looking to IT to help them drive down clinical trial costs while accelerating time to market. For example, collaboration tools that improve the productivity of all clinical trial participants—regardless of their location—will afford significant benefits. In this environment, next-generation CTMS solutions that are built to support business processes instead of focusing on data collection are also coming to the fore, while affording the flexibility required to support unique regional requirements. Looking ahead, widespread adoption of service-oriented architecture and turnkey integration solutions should lead to technology solutions that are easier to use, implement, connect, and maintain—enabling life sciences organization to reap the full benefits of the eClinical vision. 

, MD, PhD, is Director, Product Strategy, Oracle Health Sciences Global Business Unit, Oracle Corporation, 500 Oracle Parkway, Redwood Shores, CA 94065, email: 

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P. Webster, "Clinical Development Costs Skyrocket to New Levels," Frost & Sullivan, Market Insights, December 8, 2004. 

W. McDonnell and H. Mooraj, Clinical Trials Are Moving Out (AMR Research, Boston, MA, 2008). 

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R. Collier, "Rapidly Rising Clinical Trial Costs Worry Researchers," Canadian Medical Association Journal, 180 (3) (2009). 

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The difference a clinical trial management system can make in integrating a global workforce.

Data Integration in the Age of Global Trials

When I was a boy, my mother once had a job working at a model factory. This was a geek kid's ideal, because she'd periodically bring home a puzzle activity treat in a box that would keep me enthralled for days, weeks or even months.

	Over the course of her employment she brought me home an armada of modern and classic weaponry, a bedroom-sized lot full of vintage sports cars, and-on one memorable occasion-the piece de resistance in those modest, simpler days: a surprisingly discreet "Visible Woman." Many a kid in my day were fascinated by models, because we could not be certain we'd ever get a chance to see the real thing (well, at least for some of that classical weaponry anyway).

	These models consisted of kits full of plastic parts, which kids like me would assemble with model glue. You could tell we were focused and innocent in those days, because we used the glue sparingly to build the models rather than for other inconceivable recreational purposes (though it did have quite an attractive smell now that I think of it). After your first few tries, you'd graduate beyond glue alone and invest in a set of enamel paints to add the finishing touches to make the monotone models look more realistic (except for those pesky, unintended glue fingerprints and drips of course).

	These models were made to create a scale replica of something real-and something really cool to show off and play with, if you were a kid. (Yes, this was in ancient times, before the Internet. My son's modeling stage was rapidly subsumed by video games.)

	Later, in college, I started working with other types of scale models, such as the model stage sets I designed for my theatre classes and productions, or the whimsical buildings I imagined when contemplating a dream of becoming an architect. These types of models didn't scale down something that already existed to toy size but were a way to represent an idea in three dimensions. Of course, we had to build these out of cardboard, papier-mâché, and balsa wood in those days. Today, for a modest investment (probably less than I spent on all of my hobby materials), one can allegedly buy a three dimensional printer that can render a plastic model from a concept depicted on a computer screen. Oh, to be a geeky kid now.

	Now that I've put away (most of) my childish things, in my real life world of systems and technologies for drug development, we have a need-and increasingly available options-for models of another type. These are the models we design to depict the world we know and guide the development of system applications we need. In a sense, these models fall somewhere between the other two types I experienced in my youth-they try to represent the world we already know as a two dimensional illustration, and they also depict an ideal framework in which to represent the world we want to create.

	These are thought-provoking, complex models generally expressing the input of many business and technology experts. They might not be quite so amusingly easy to build, but they do have better uses for a bigger audience. And they're becoming an indispensable part of the processes we use to define standards and systems.

	You can get a lot of different answers when you ask about models. A Chief Technology Officer may talk about Model Driven Architecture (MDA), which is a method for designing software systems developed by the Object Management Group (OMG). A programmer may advocate Model Driven Development (MDD), an agile programming technique that uses tools to generate code from models.

	Both of these probably fall under the umbrella of Model Driven Engineering (MDE). To fully exploit such models in making the transition from concept to implementation, it's necessary to represent the model in a smart model definition language that can be used to generate specifications or even code, such as the Unified Modeling Language (UML). It's difficult to see where the differences, if any, lie between terms like MDA, MDD, and MDE. Instead, it's probably safer just to think about where models are used in our industry.

	Since clinical research is composed of a series of well-defined processes, often governed by regulatory requirements and standard operating procedures, many of us are familiar with process models such as use cases, flowcharts, and activity and state diagrams. Busy people tend to get buried in the weeds when they do their daily tasks, and business process models help them to step back, see the bigger picture, and identify inefficiencies and improvements.

	Within the world of standards, Health Level 7 (HL7) has based its development process on the Reference Information Model (RIM), which is a master model for depicting how the world of health care works and a fundamental organizing principle behind HL7's goals of achieving interoperability.

	Since the RIM is a very abstract model, it's more suitable for the technical elite rather than the layperson. So we use domain models to represent the world in terms more familiar to the rest of us.

	That brings us to the Biomedical Research Integrated Domain Group Model for protocol-driven research, or BRIDG. The first BRIDG model was initially drafted by a core, cross-functional group of subject matter experts from CDISC, and it later evolved into a collaborative effort involving CDISC, the National Cancer Institute (NCI), HL7, and the FDA. BRIDG is a model that is intended to be understood by subject matter experts and participants in clinical research that describes their world. Eventually, almost everything we need to do in clinical research is likely to be represented at some level in BRIDG.

	It's nice to know that models such as BRIDG exist, and that they may be playing a key part in guiding the development of standards. But what can they do for you?

	Well, using a model like BRIDG can be invaluable when designing an information architecture or defining a standard, or even building an application. And the bigger the project, the more essential a model is. Even within our own companies, we often find that the medical professionals and statistical analysts have trouble getting on the same page with the regulatory and technology people. There are very few individuals who can interrelate comfortably with all these different players. Using models like BRIDG help verify that all parties are speaking the same language, which makes it all the more likely that systems and information will be able to interoperate more efficiently. And an outsider with specialized technical skills but no research experience can rapidly develop a more thorough understanding of our business by walking across the BRIDG.

	BRIDG is not everything-in fact, the latest version of BRIDG was adapted so it could represent its concepts not only in domain-friendly terms but also in a way that is fully compatible with the HL7 RIM. Defining actual working business processes and new system applications or data models will still be necessary after BRIDG-but these efforts can be dramatically reduced while avoiding later disconnects. BRIDG should provide a starting point for developing any new data standard or expressing any new concept relevant to research processes, or for developing or implementing any new clinical application.

	We wouldn't try to navigate a strange city on our own without a good map, and we shouldn't be trying to develop an information infrastructure or application without at least consulting the BRIDG. We gain even more if we download the relevant concepts and data elements from the BRIDG to initialize the entire development process before getting into the unique, company-specific details.

	So in our complex world, which is growing more tightly integrated and interdependent all the time, it's clear that we need to depend a lot more on models. We simply can't afford to depend on dense specification documents that must be interpreted by subjective human beings to keep up with the rapid changes to systems, standards, and information. And we need to be using the same models if we expect to consistently exchange and share the information we need to compete in our increasingly challenging world.

	So, fellow retired hobbyists, it's time to pull out those old modeling tools once again. You need to cross that BRIDG to get to the other side.

Editors Note: Users can access the BRIDG at 

 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 

Clinical Trial Insights

Why models such as BRIDG are essential in developing clinical research processes and applications

Memories and Musings About Models

Patient recruitment is a team sport, no individual controls it completely. For a patient recruitment campaign to be successful, the sponsor, CRO, investigator sites, and the supply groups all have to work together. Each party plays a distinct role in educating people about clinical trials and their importance, in informing patients about what trials are available, and in enrolling the right patients into the trial. With new communication channels like the Internet, this process is evolving.

Recent research from Harris Interactive indicates that of the 184 million U.S. adults now online, 150 million have searched the Web to obtain health care information. A further survey conducted by Harris found that online usage in the United States has risen from seven or eight hours a week in 2002, to 14 hours in 2008, with users now including the large majority of demographic groups.

Health is one of the top subjects for people seeking information using the Internet, which naturally makes it a sensible outlet to disseminate general and specific information about clinical trials. This trend means the Internet has increasing impact on the attitudes of the general public, which can help to create a positive climate for recruitment, as well as provide the opportunity to reach people with conditions that might make them appropriate for a clinical trial.

As people flock to the Internet for health information, the Web grows as a patient recruitment pathway.

Applied Clinical Trials-04-01-2010

Applied Clinical Trials Digital Edition - April 2010

Alzheimer's by Phase

The Deeper Data Debate

The Upfront Cost Hurdle of EDC

Regulatory Science to Inform Trial Design

Data Integration in the Age of Global Trials

Memories and Musings About Models

Internet Recruitment

The Next Step for EDC

Increasing Study Sensitivity in Early Trials

The EU Directive Really Doesn't Work!

Pressure Grows on UK Body

Business and People Update April 2010