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GLOBAL TRIALS : South Africa?s Positioning Fosters Healthy Trial Landscape  Croatia?s Dynamic Qualities  CROs Must Manage Italy?s Regulatory Makeover  EDC?s Evolution in Japan  Also in this issue : Postmarketing Pushes Back Approvals, EU Regulators Increase Involvement, Site Shake-Out Benefits Those That Remain, Is in Silico Modeling the Economic Solution?

Applied Clinical Trials Digital Edition - November 2009

• Formerly holding a quality management position at 

 (South Wales, UK) where he will manage a 22-person quality management team. 

• With 17 years of clinical research experience, 

 will work in the medical and clinical development division of 

 (Oldenburg, Germany) where he will perform clinical studies and prepare clinical reports for the pharmaceutical service provider. 

 (South Wales, UK) as the head of analytical services, in which he will manage 45 analytical chemists. 

• Filling the role of associate director of business development for Japan at 

 will work with the company's Japanese partner, Site Support Institute (SSI), to facilitate sales activities and improve domestic support of Japanese sponsors and sites. 

, PhD, has become the senior director of clinical statistics for 

 (Wayne, PA), where he will oversee all statistical activities and staff. 

 (Cincinnati, OH) as its new managing director of Europe and 

 will become the director of clinical operations. Both men will be located in the company's Germany office. 

• With more than nine years experience in the central laboratory industry, 

 will become the new head of business development in Europe for 

 (Durham, NC) increased productivity goals, the company has hired 

• The new clinical pharmacology unit of 

 (Dublin, Ireland), located in Omaha Nebraska, will become 

, MD, PhD, new place of work as he has been appointed the company's vice president and medical director. 

 (Dijon, France) as the Vice President of Drug Discovery, 

, PhD, will be responsible for  establishing and directing integrated drug discovery activities. 

 (Seoul, South Korea) has chosen to implement 

 (Redwood Shores, CA) Health Sciences applications, which includes the use of Oracle Remote Data Capture 4.5.3 and Oracle Clinical.

• To support the research and development for 

 (Corvallis, OR) exon skipping candidate drugs for treating Duchenne Muscular Dystrophy,

 (London, England) has collaborated with the company.

• A $145 million, five-year contract with

 (Whitehouse Station, NJ) to purchasing genomic analysis services from the company.

• The signing of a license agreement between 

 (Fort Lauderdale, FL) and a West coast clinical research organization will allow the CRO to use the company's TrialMaster solution in a technology transfer model.

• Being selected as the preferred provider for a top 10 pharmaceutical company, 

 (Washington, DC) has been awarded with several cardiac safety service contracts.

• Ranking 20th among America's fastest-growing small public companies, 

 (Waltham, MA) has moved up from 38 on last year's Fortune's Small Business 100 list.

• At the SAS Professionals Convention held this past July, 

 (Cary, NC) acknowledged a group of six from 

 (Middlesex, UK)—a niche CRO providing innovative clinical outsourced solutions—for their success in BASE SAS certification. Each person was awarded a certificate as well as £5000 worth of SAS training.

• Experiencing growth across the UK, Central and Eastern Europe, India, and South Africa, has led 

 (Manchester, England) to double its head office capacity.

 (Philadelphia, PA) to lead its global PR campaign.

 (Seattle, WA) has recently launched a newly redesigned version of its Web site.

 (Reston, VA) has recently launched CE-Dedicated FastTrack, a CE marking program intended to conduct reviews at an accelerated pace.

• With the anticipation of future growth at its Craigavon headquarters, 

(Craigavon, Northern Ireland) has the potential to create over 500 jobs during the next five years and has also acquired a 5.4 acre site.

• After changing its name from Cardinal Health to 

 (San Diego, CA), the company has taken part in a string of marketing activities, including being added to the New York Stock Exchange and ringing the bell on Wall Street.

Care Fusion's truck parked outside the NYSE. 

• The Web-based ePRO and late phase solutions company 

(Whitehouse Station, NJ) Seattle-based Gene Expression Laboratory. 

• After opening new offices in Belgium, Hungary, and Brazil, a new office in Edinburgh, Scotland, marks 

 (London, UK) fourth new office opening since the New Year.

Community

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

Business and People Update November 2009

What does it mean to be European but not yet in the Union while conducting clinical research projects? Central and Eastern European (CEE) countries are well known to commercial sponsors of clinical trials, but which countries are included in this umbrella term can vary. Many business maps of Europe would include the following countries within the CEE region: Albania, Bosnia, Bulgaria, Croatia, the Czech Republic, Estonia, Hungary, Latvia, Lithuania, Poland, Romania, Serbia, and Slovakia—those countries formerly behind the Iron Curtain. However, many of these countries are now either new members of the EU or preparing for entry within the foreseeable future. 

The CEE region has been involved in international clinical research for some years. Indeed, during the last decade, the CEE region has consistently proven to be a good place to do clinical research both in terms of quality and enrollment.

  This success demonstrates that being European but not an EU member is not an obstacle to producing high-quality clinical research and meeting enrollment targets. 

Presently, both existing EU member states and those waiting patiently at its gates are busy adapting to the changes recent EU directives on clinical trials have brought to the arena of clinical research. Croatia, one of the countries approaching these gates, has already negotiated many of the choppy waters involved in implementing EU trial standards into local regulations. Consequently, its rates of enrollment remain good compared with larger European Union countries, and good levels of quality continue. 

As a country, Croatia provides a natural conduit between EU and non-EU countries, with the added advantage that the Croatian language is easily understood by the non-EU countries that surround it. Therefore, it is not surprising that during the last decade many CROs have chosen Croatia as their starting point for opening offices in the southern reaches of the CEE area. Clearly, its population of 5 million is small compared to others in the CEE region. But the combination of language commonality coupled with its joint administrative heritage and infrastructure (born out of its days as Yugoslavia), means that Croatia offers a good starting point for business. 

Both commercial and noncommercial sponsors of clinical trials are bound by the regulations contained within the EU directives 2001/EC/20 and 2005/EC/28. As a result, all interventional trials now need to comply with a single set of regulatory standards. This is a significant change for noncommercial interventional trials and is providing challenges throughout Europe. However, it does provide an increased benefit for centers to conduct commercial trials since they will learn the tact and background needed to meet these demanding standards. 

A sizeable portion of Croatia's population—1.5 million—are concentrated in the vicinity of its Capital city, Zagreb. The centerpiece of the capital's health system is the University Hospital. This network is well supported throughout Croatia by a network of both regional and city hospitals, including three medical schools. Data on enrollment in clinical trials is not publicly available, but our experience has been that 47% of centers are located in Zagreb and these have achieved 74% of subjects enrolled. This suggests that there is potential for more research sites, which could be based around Croatia's three other major conurbations: Split, Rijeka, and Osijek (see Table 1). 

 Table 1. The number of clinical trial sites and number of subjects recruited per the largest university hospitals in the country.			

As mentioned, the conduct of clinical trials provides valuable research experience for medical centers, but it also gives patients with a range of illnesses the opportunity to try new treatments. However, such research must be done within the framework of Good Clinical Practice to ensure that patients' rights and well-being remain at the fore at all times. For a small country, Croatia has a rich heritage in terms of science, including two Nobel prize winners, and more recently the development of azithromycin by Pliva, which was subsequently licensed to Pfizer. It is therefore no stranger to the demands and challenges of research. 

Split, on the Adriatic coast, is Croatia's second largest city. Including the surrounding areas of the Dalmatian county, of which it is the capital, there are approximately 460,000 people. In terms of clinical trials, our experience has been that 13% of Croatian sites come from Split and these have contributed 7% of subjects enrolled. Like Zagreb, Split has its own medical faculty within its University. Some 300 kilometers to the north of Split, but also on the Adriatic coast, lies Rijeka, Croatia's third largest city. It too has a medical faculty within its University and has 300,000 inhabitants. Surprisingly, our experience with clinical trials enrollment has been relatively low in this location. Thus far, Rijeka has provided us with 11% of our Croatian sites but only yielded 4% of recruited subjects. 

Croatia's fourth Medical University is located in the city of Osijek in the Eastern part of the country. Including the surrounding areas, it has a potential patient population of 330,000. Thus far, we have selected several sites in this location but the enrollment levels look low when compared to Zagreb's. However, a different picture emerges when we look at studies where sites are confined to Zagreb plus at least one other big city (see Table 2). 

Table 2. The number of trial sites and subjects recruited for studies where sites were confined to Zagreb plus at least one big city.			

Irrespective of which data we look at in relation to enrollment, what separates Croatia from other countries is that it usually reaches its peak recruitment quickly, using less sites than its neighbors in CEE countries. Moreover, timely enrollment is unquestionably a critical factor in the success of both commercial and noncommercial trials.

Apart from a few small deviations, Croatian legislation has already incorporated EU directives. This initially created a few hiccups since Laws on Drugs and Medicinal Devices and the Guidelines on Clinical Trials and GCP gave firm directions to sponsors but then failed to provide the mechanisms to enable all parties to follow them. However, these initial challenges were largely resolved by September 2004, when first trials were approved by a Central Ethics Committee (CEC). This proved cathartic, since up until then an administrative backlog had developed somewhere between the demands shown in Laws and the operational realities of clinical trials. 

However, there was more than a sense of déjà vu in 2007 when we again faced new regulations. But our early experience had made us better prepared for meeting the operational challenges which resulted from the introduction of legislation that has produced a stricter approach to site selection and still closer scrutiny of study contracts. 

The process of trial approval in Croatia is now firmly established as a sequential one. The CEC is the first body that reviews a trial. It is required to give its opinion within 30 to 90 days (depending on the study phase and/or type of investigational product) from submission of all requested documentation. Following the approval by the CEC, the Ministry of Health then reviews the documentation and issues the approval using the same timeline. Experience thus far suggests that 60 days is usually sufficient to obtain approval from both of these bodies, provided the applications satisfy the criteria laid out. 

Croatia, although European, is not yet an EU member. Therefore, investigational medicinal products (IMPs) cannot be delivered directly to study sites. Croatian legislation requires that an import license is obtained for both IMPs and laboratory kits. An import license takes 15 working days from the date of submission to obtain and is usually granted in the form of an annual license. Clearing all the necessary regulatory hurdles provides a timeline for initiation of three to four months after conducting site selection visits. 

Access to well-educated, multilingual staff with established relationships with leading clinicians are key factors when placing either CRO offices or studies.

  The country's capital in Zagreb has already proven to be a successful center for clinical research in the commercial sector. Moreover, based on studies conducted by Altiora, there is evidence to suggest that there is still considerable potential in terms of study centers that can recruit well and to a high standard in three other locations: Split, Rijeka, and Osijek. 

The inevitable by-product of conducting commercial trials is that these University Medical Centers will learn and adopt the modus operandi that is now required for all interventional studies irrespective of sponsors and thus attract more noncommercial, international work. 

Sponsors looking for reliable start-up times and timely enrollment would do well to consider Croatia. This small country offers both the medical expertise and geographic concentration of population to ensure both. Like many of its European cousins already in the EU, Croatia also has considerable medical expertise and a proven track record in the conduct of clinical trials to the exacting standards of GCP. But unlike them, it continues to enroll patients in a timely fashion, thus making it an ever more attractive location for the conduct of clinical trials. 

, MD, is managing director of Altiora, Seferova 8, 10 000 Zagreb, Croatia, email: 

1. J. Demeter, "Selecting Sites and Investigators—An Approach for Central and Eastern Europe," 

2. A.M. McDonald, R.C. Knight, M.K. Campbell et al., What Influences Recruitment to Randomised Controlled Trials? A Review of Trials Funded by two UK Funding Agencies, Trials, 7 (9) 2006, 

http://www.trialsjournal.com/content/7/1/9

3. W. Schaub, Strategies for Placing CRO Offices in Europe, 

Feature Article

As a part of Europe, but not the European Union, trials in Croatia can encounter special challenges

Conducting Trials in Croatia

Sweeping regulatory and government changes are pushing pharma to do more than has been expected from them in the past. No longer is the development of a clinically proven, effective, and safe drug always enough. How do drugs compare to other's being marketed for the same therapy? How has the safety and effectiveness of this drug proven itself when used in real-life?  

This information is gaining more value and why it is becoming fundamental that companies begin to look at activities that were typically done in postmarket in earlier phases of a trial. 

Though postmarketing research is in the FDA's hands to enforce once a submission is received, "doing the right thing at the right time will reduce cost and promote better quality of care," noted Nayan Nanavati, vice president of peri-approval clinical excellence, North America for Parexel, while presenting at CBI's conference on registries and postapproval studies this past September. 

In this case, "the right thing" is more elaborate research and "the right time" is starting before the IND or NDA is submitted. 

Bringing in the idea of postapproval strategies earlier will allow for these activities to be factored into trial budgets. At the same time, gaining information from such investments makes for a more concrete foundation and better assurance for a drug. 

"In my group we are doing several safety-related studies, more than I have seen in the last 10 years," Nanavati offered. "And this shift has taken place in the last two years alone." 

If the resources are there, current trends suggest that safety-risk initiatives should be taken regardless if there is a requirement. 

The risks a drug presents should surface by the end of a Phase II trial. Acknowledging and understanding these risks while the study is still up and running enables safety-related issues to be addressed in real-time. Revisiting a trial and all the risks it presented through the entire drug development process can be taxing on a team's resources. 

"If you think of [REMS] at the end of Phase II you can start implementing tools, instead of conducting postmarketing studies at the end and having those costs," explained Jill Robinson, vice president of global safety surveillance and epidemiology for Wyeth and also a speaker at CBI's conference. 

If your drug presents a serious risk, preparation of a REMS is a wise step to take earlier on because upon submission the FDA will likely require it. 

If a drug is not considerably risky and a REMS does not seem likely to arise in a drug's foreseeable future, comparative effectiveness research is worth deliberation. It offers better insight into a drug's true effectiveness not only to treat a condition, but also how it compares to its competitors on the market. 

Similarly, patient registries also provide a unique and valuable information source for a drug's effectiveness and safety. Drugs can be evaluated for treatment of certain conditions and more specifically in various patient populations. 

"Current regulatory framework, which essentially focuses on efficacy, dictates we prove that a pharmaceutical product is proven to work better than a placebo," Nanavati explained. "The regulatory process must be optimized for there to be a way to integrate observational studies before IND submission." 

Gathering comparative effectiveness data on a drug gives sponsors an advantage, especially with the direction in which the health care reform is heading. If Obama's program follows through the prescribing process may see change because doctors will receive suggestions for what has been found to be the best drug for a particular condition. While this is intended to cut health care costs and avoid the use of ineffective drugs, it may very well cut reimbursements for sponsors. 

				With this comparative effectiveness research being collected it may become more of a factor in pharma company's go/no-go decisions.—

News

Implementing postmarketing strategies early on to avoid on-the-spot and costly requirements upon submission.

Preparing for Postmarket

Over the last several years, the Japanese government, in conjunction with its national pharmaceutical industry, has embarked upon an ambitious program to update the country's clinical development procedures to bring them in line with global best practices.  

The results thus far have been striking, as the latest pharmaceutical standards have been adopted by the national regulatory agency, and electronic data capture use in clinical trials—a key hallmark of modernization—has dramatically increased. Japan, once lagging behind its regional competitors, has reemerged as a force in the Asia-Pacific drug development market.  

When discussing the future of clinical trials in Asia, the prospects of China and India elicit much enthusiasm. The advantages that these two countries offer are well documented, but the Asia-Pacific region overall represents an enormous opportunity for the biopharmaceutical industry. The medical infrastructure throughout the region is excellent and clinicians and site investigators, while limited in some countries, are well educated. Data generated in clinical studies have met high Western standards and have been submitted to numerous regulatory agencies, including the FDA, MHRA, and EMEA. 

And while it is easy to focus on the vast potential of India and China, Japan has been rapidly updating its trial practices to great success. Over the past few years, Japan has outpaced all other Asian countries in increasing the rate of new clinical trials starts, according to a 2008 CenterWatch report

With the world's second largest economy, Japan already enjoys many advantages over its aspiring neighbors, and as the clinical development industry in Asia matures, the country could find itself the leader of the Asia-Pacific clinical trial market. This is certainly not a foregone conclusion, however, as Japan has multiple barriers in how it conducts clinical trials that must still be overcome. 

Globalizing clinical development activities is vital for successful pharmaceutical companies in the 21st century. It increases speed to market by opening up diverse new populations for recruitment—including treatment naïve patients—and lowers the overall cost of conducting trials. And yet, until recently, Japan has been reticent to allow clinical data generated entirely outside the country to be included in regulatory submissions. 

Although ICH standard GCP guidance has been in place in Japan since 1997, the country has been slow to adopt global clinical processes, infrastructure, and methodologies to increase efficiency. This, along with many cultural complexities, has led many pharmaceutical companies to bypass Japan when selecting global trial sites and has also led to a performance gap between Japanese sites and many global sites. 

Japan is the second largest pharmaceutical market in the world with approximately $60 billion in sales annually. And yet, despite its market size, it typically takes 2.5 years longer for a drug to come to market in Japan than in the United States, according to the Japan's Pharmaceutical and Medical Device Agency (PMDA).

  This lag generates a great deal of discussion about loss of sales, but more importantly this prevents Japanese patients from receiving the most up-to-date treatments, and has sparked government action to correct the problem. 

A relatively conservative regulatory environment has led to conventional requirements forcing sites and sponsors to adopt out-dated site monitoring, data management, and reporting policies. In response to a government-sponsored survey that outlined the performance gap, the Japanese regulatory authority, the Ministry of Health, Labour and Welfare (MHLW), has recently begun to accept truly global trials and the supporting technology necessary for their success. 

In 2007, the MHLW initiated the New Five Year Clinical Trial Activation Plan in an effort to standardize drug development practices and speed the time it takes to bring a drug to market.

  This government-subsidized plan resulted in a massive infrastructure investment to revitalize the nation's drug development industry. Site personnel were trained in managing global pharma protocols, and the MHLW enacted improved reporting and submission standards, including allowing trial subject data generated outside the country to be included in submissions. The agency is also researching electronic data capture (EDC) technology and its role in national health care. 

The use of EDC in Japanese clinical sites was spiking before the government embarked upon its clinical development modernization scheme. Japanese affiliate offices in the United States and Europe, where EDC has become the preferred method for capturing and managing trial data, were driving EDC back into the headquarter offices in Japan. Because of the success of EDC in the affiliate offices and in the West in general, Japanese headquarters have been forced to embrace this technology. This bottom-up EDC adoption model is a very different paradigm than the typical top-down European and U.S. precedents. 

There have been challenges to implementing EDC in Japan. Despite English being widely taught in the country's schooling system, few people have the opportunities in the work environment to become proficient in the language. Therefore, it is vital to conduct trials in Japanese to ensure data accuracy and increase overall acceptance of the technology. Global clinical trials using English in Japan impose preselection of sites with high levels of English competence. This quickly limits the scope of a study. 

In particular, later-phase trials requiring large patient populations necessitate the use of smaller sites outside of the major cities where site staff often do not speak English. If a principal investigator or a Clinical Research Associate (CRA) is needed to translate any study documentation or data queries into English, it will place an undue time and cost burden on the trial. Likewise, the other option of quick Japanese-to-English translation guides (i.e., cheat sheets) to input data slows the overall trial pace, creating further overheads on the study. 

To address the language barrier challenges and encourage adoption in Japan, many EDC software vendors have added support for a Japanese user interface to make it easier for Japanese sites to collect clinical trial data electronically. However, many Japanese sponsors have realized it is not enough to be able to just capture data in a specific language. EDC solutions also need to efficiently support the processes for building, cleaning, and submitting data for any regionally based or multilanguage trial. For EDC software, capturing data electronically is relatively straightforward; the challenge is recognizing the variety of language character sets to be able to efficiently code adverse event terms and concomitant medications to common industry standard terms. This is a critical requirement for analysis. 

The Japanese language has three different sets of characters: Kanji, Katakana, and Hiragana (four if you count Romaji). As Table 1 shows, each of these character sets are of different widths and sizes, which complicates incorporation into Unicode—a computing industry standard allowing computers to consistently represent and manipulate text.  

The latest EDC technologies offer comprehensive data management and coding tools to address this complex challenge. The new solutions provide a single environment that allows sponsors to streamline design time and clean, code, and submit clinical trial data all within a single environment for use in regional or multilanguage global trials. All of which should significantly support EDC adoption in Japan. 

The consensus-driven nature of the Japanese business climate seeks approval from all stakeholders before any major new initiative is implemented, which can prolong the EDC adoption process. The robust global support structure in place at EDC providers, however, can overcome some of this hesitation. Always available help desks manned by Japanese nationals rather than nonnative Japanese speakers are a great comfort to local organizations, as they can manage the cultural idiosyncrasies. 

eLearning training modules conducted in Japanese can also quickly raise EDC proficiency levels for large numbers of users, which is particularly useful at investigator sites where the number of users is typically much higher than found in the West. With well-trained site staff and a support network in place, organizations quickly see the advantage of applying EDC technology. 

Traditional EDC models have somewhat faltered in the Japan postmarketing area too. Many of the same factors—full Kanji versions, tight start-up timelines, the complexity of training research-naïve physicians, and the flexibility needed in the observational market—contribute to the slow pace of adoption. There are, however, recent additions to the postmarketing eClinical technology market with multilingual capabilities that could speed EDC use. 

Since 2007, EDC adoption has greatly accelerated. According to a 2008 PRTM survey, before 2006 EDC use in Japan was limited, but as of May 2008 40% of clinical sites were using EDC for some or all of their trials.

  However, it is worth noting that in 2008 almost 60% of all new clinical trials conducted in the United States were utilizing EDC.

Between 2007 and 2008, Phase Forward experienced almost 60% revenue growth from its InForm EDC technology in Japan. Currently there are over 1300 trial site instances in the country using the InForm software—over 200 of which have conducted multiple studies using the solution. 

While Japan has been slower to embrace EDC technology and conduct clinical trials in accordance with best global practices, its efforts to address these issues have been quite impressive. The adoption rate of EDC from 2006 to today alone, demonstrates an unparalleled dedication to revamping the drug development industry in Japan. 

"Our aim is to reduce the drug lag by a total of 2.5 years by 2011 through one and a half-year and one-year reductions, respectively, in development and approval time here," said Junko Sato, PhD, Office of New Drug I, PMDA, at the 2008 DIA Annual Meeting. If Japan is able to continue with this rapid turnaround and harnesses the other advantages inherent in its mature economy, then Japan could very well find itself at the heart of the biopharmaceutical industry. 

 is director of international service development for Phase Forward Europe, Ltd. 

 is senior marketing writer for Phase Forward, email: 

 is international marketing manager for Phase Forward Europe, Ltd.

1. S. Gambrill, Japan: Opening the Door to Global Clinical Trials (CenterWatch, Boston, 2009) p. 36. 

2. Pharmaceutical and Medical Device Agency Japan, Annual Report FY 2007. 

3. Ministry of Health, Labour and Welfare, "New vision for the pharmaceutical industry, aiming at the industry with international competitive power taking the mission of innovation," August 30, 2007. 

4. C.R. Albani and Y. Tabata, "Japan—Thinking Global, Acting Local," 

5. L. Hanover, U.S. Electronic Data Capture 2007-2012 Spending Forecast and Analysis (Health Industry Insights, Framingham, MA, 2008). 

*To whom all correspondence should be addressed. 

While it has yet to be fully integrated, electronic data capture is gaining ground in Japan.

EDC Acceptance in Japan

The economic environment of the last two years proved difficult for the previously almost immune pharma/biotech sector. Even as the world climbs slowly out of recession, aftershocks will be felt in the sector as governments seek to address health care costs that they cannot afford to allow to increase unchecked. Although prescription charges make up a relatively small percentage of the overall bill, around 10%, they have been targeted aggressively, with drugs companies already responding in some countries. 

In the United States, drug companies agreed to contribute $80 billion toward the cost of Medicare drugs over the next 10 years. The current business model for our drug companies is not sustainable, and a change of thinking is needed. One way to reduce costs is to reduce the cost of development. Until recently the options for achieving this were limited. But with the onset of Prediction, Preemption, and Personalization that will change. 

With drugs being targeted to specific populations, one can imagine the importance of in silico modeling increasing and becoming more widely accepted. Programs will then run more quickly, and the FDA and other regulators will approve drugs much earlier, once a response in the target population has been proven. It is then possible that the clinical phase will be accelerated. 

This scenario will be very acceptable to health care providers, as the cost of development will be dramatically reduced, allowing for cheaper drugs. The win for pharma/biotech is one of improved cash flow, with revenues coming on stream far earlier than they do now. If patent protection rulings are static, then the negative effect on those revenues by generics or biosimilars is reduced by virtue of prolonged exclusivity. 

It is fairly easy to see how all stakeholders could be satisfied by this model. The question is: Is it realistic to bring down the time to market of new drugs by allowing for targeted therapies? 

I wonder if a parallel can be drawn with off-label use of drugs. With sophisticated in silico modeling providing credible information with respect to how the drug might act, and intelligently designed trials gathering extended volumes of data, the regulators may be comfortable approving drugs into targeted populations. 

A report by Mark Ratner and Trisha Gura in the July 2008 issue of 

 estimates that "off-label use of cancer drugs runs from 50%-70% of total usage, and perhaps higher." In critical care, there is always additional pressure to get new treatments to patients. When sickness management is addressed in 10 years, if the technology in diagnostics has advanced sufficiently and more is known about how the drug will effect its population, the pressure to get new treatment to the patient will only increase. 

With the economic and demographic challenges ahead, industry may have to rely on the benefit from a new approach. They can focus on accelerating the delivery of targeted therapies to specific populations. The main concern surrounding targeted medicine has been the cost. Can a return on investment be made when the market is limited? Under a model where sales begin at the two or three year point and where preclinical work has been accelerated, it may just be possible.  

A Closing Thought

Changing current business models with the use of new advancements for more sustainability.

To Market Faster In Silico Style

The current economic climate combined with changes in investigative site selection and management practices appears to be driving a shake-out among marginal research centers in the near term. There are signs this is occurring.  

Recently, several large commercial IRBs noted a higher relative number of investigators exiting the enterprise. A survey conducted among 150 sites found that a greater percentage is writing off some sponsor grant obligations as bad debt. In addition, a rising number of investigators have reported that study suspensions and terminations, and slow grant payments from sponsors, have contributed to a more difficult operating and financial environment. 

A shake-out may not be unwelcome. Through consolidation and a weeding-out of poorer performing and less stable sites, the investigative site landscape may be better positioned to offer higher levels of efficiency and effectiveness as the economy recovers. A look at the structure of the site landscape, current economic conditions, and sponsor/CRO strategies sheds some light on this speculative yet plausible scenario. 

Grant spending on FDA and NIH-funded clinical trials topped $9 billion in 2008 with the majority, 85%, coming from industry. But growth in spending has been slowing down. Between 2001 and 2004, sponsor spending on clinical trial grants grew 11% annually. NIH-spending during that time period grew 7.5% each year. This compares with industry funding growth of only 5% annually between 2005 and 2008 and flat growth in NIH-funding during the latter years of the Bush administration. 

Data on 2009 industry grant spending is not yet available though it is expected to be as much as three percentage points lower than that observed in the prior three-year period. 

Of the 27,000 FDA-regulated investigators conducting at least one clinical trial each year, the majority (75%) are in private, community-based settings. Of this latter group, a whopping 90% are single sites, most of them part-time investigators juggling clinical practice simultaneously. Why hasn't the landscape consolidated over the past decade? Why aren't there more site networks offering scale economies and centralized infrastructure? 

Arguably, economics are a primary culprit. Due to high levels of turnover, the landscape receives many new investigators each year as one-third of those active in the prior year drop out. This pool of novice investigators and those with minimal clinical trial experience and infrastructure tend to undercut the more mature and established sites for clinical trial grants. Experienced site networks and high volume investigative sites have invested in infrastructure. They are not able to compete with novice sites on cost. 

Historical site selection practices are another primary culprit. Many sponsors and CROs have largely viewed study conduct services as a commodities business where the lowest bid providers are often favored. As a result, sponsors and CROs have rewarded novice investigators and inadvertently stifled the growth of managed site networks and high volume dedicated and part-time sites. 

All measures of the drug development economy are bleak. On the commercial side, total global pharmaceutical sales are expected to grow less than 1% in 2009 compared with 11% historical annual growth rates. Companies are facing what has been dubbed a Patent Cliff: Nearly $60 billion in patent protected sales is at risk of generic erosion during the next three years. 

First-in-class drugs entering the market have only about one year of sales exclusivity before the next drug in that new class begins to compete. And only 20% of all approved drugs recoup their total development investment—a proportion expected to decline as more drugs in development are now targeting smaller markets. 

Global drug development spending continues to rise by 11% as the rate of drug approvals is declining. Despite 7.6% annual growth in the number of new molecular entities in the development pipeline, success rates have not improved: Only 16% of all drugs entering Phase I ever make it through approval. And an increasingly restrictive regulatory environment is prompting industry to gather more clinical data pre- and postapproval. 

All of these conditions have compelled sponsors to seek more ambitious and resourceful initiatives to drive faster drug development speed, and control development costs while improving data quality. 

The adage "You Get What You Pay For" couldn't be more reflective of many sponsor–site relationships. Overall performance has often disappointed sponsors and CROs: The vast majority (more than 90%) of trials must delay enrollment for an average of six weeks. And in any given multicenter study, the same pattern is observed: 20% of sites deliver the majority of patients. Half of the sites either under-enroll or fail to enroll a single patient. And perhaps most concerning, 14% of all active INDs now have at least one complaint filed against an investigative site for noncompliance with GCP-ICH. This compares with 6% of all active INDs having at least one complaint in 2003. 

Sponsors and CROs are eager to reverse these conditions. A decade ago, sponsors began placing more trials abroad where they could realize substantial savings while accelerating patient enrollment. Between 1995 and 2005, the number of countries hosting NIH- and industry-funded investigative sites doubled. At this time, nearly half of all FDA-regulated trials are conducted outside the United States. An unintended result of globalization is to divert more resources to areas lacking infrastructure. 

Several years ago, sponsors also began hedging investigative site operating risk. They did so by increasing the number of sites per active clinical trial while reducing the requisite number of evaluable patients per trial. Expecting some sites to fail, many sponsors and CROs also routinely queue-up additional sites to engage as needed. Again, unintentionally sponsors have made clinical trials less economically attractive to more mature and established investigative sites. 

Sponsors and CROs are now experimenting with new relationship models to nurture stronger ties with top performing sites. Sanofi-Aventis, Pfizer, Roche, and Quintiles are among a growing list of companies looking to substantially improve the probability of investigative site success. These relationships require a larger investment of personnel and resources to qualify select sites, and integrate systems and operating practices. Ultimately, sponsors and CROs hope to establish long-term, recurring, semi-exclusive arrangements with top performing sites capable of delivering higher quality clinical data faster and more efficiently. 

Performance focused metrics are also playing a critical role in directing stronger, more integrated relationships. Several sponsors, for example, have embraced rapid Last-Patient-First-Visit (LPFV) targets with internal and CRO staffing incentivized to support investigative sites in order to achieve it. Sponsors and CROs are increasingly seeking fewer metrics that best tie strategic and operating goals. 

Since third quarter 2008, sponsors have been actively suspending and terminating development projects and curtailing spending. Divestitures among small biotechnology and pharmaceutical companies; consolidation and downsizing throughout the industry; and mergers and acquisitions, particularly among major sponsors, have all contributed to an unprecedented level of volatility and uncertainty. 

Although speculative, the current operating conditions, combined with growing ambition among sponsors and CROs to deliver higher and more predictable levels of site performance and efficiency, will likely facilitate a shake-out in the short term. Select sponsors and CROs will opt not to engage as many novice investigators. Less experienced and marginal research centers—those that have established little to modest infrastructure—will encounter both financial difficulties and fewer grant opportunities. At the same time, more mature and established investigative sites possess the experience and capabilities to weather the storm and present a more attractive relationship partnership. 

Several colleagues have asked whether this near term shake-out might be isolated to sites in the United States and Western Europe, thereby driving growth among sites in less developed regions. There are a number of factors suggesting otherwise: A large percentage of sites in emerging regions lack infrastructure making it difficult for sponsors and CROs to support more integrated relationships. The relative cost to conduct clinical trials abroad is rising rapidly at the same time that public distrust and negative perceptions of drug development companies is increasing there. Lastly, several stakeholder groups—particularly academia—have begun questioning the scientific merits and ethics of conducting clinical trials among populations abroad for drugs that will be introduced in the U.S. market. 

Long-term, as the economy improves and the volume of clinical trials activity returns, a more consolidated landscape of experienced and mature investigative sites will be waiting. Indeed, in three to five years we may be looking at a very different landscape structure with a larger proportion of site networks and dedicated investigative sites integrated with sponsors and CROs committed to supporting higher performing and more efficient relationships. ? 

 MBA, is a Senior Research Fellow at the Tufts CSDD and Chairman of CISCRP, both in Boston, MA, email: 

Clinical Trials Insights

Economic factors and sponsor practices will dramatically alter the investigative site landscape.

Is an Investigative Site Shake-Out Imminent?

This month, International Business Wales (IBW), created by the Welsh Assembly Government in 2006, is headed to Los Angeles for the AAPS Conference. It will bring several Welsh companies to exhibit, as it recently did when attending the DIA Annual Meeting for its first time this past summer. 

 Paul Viggers, VP of International Trade Development, U.S., for IBW. 			

IBW seeks to attract global companies to invest in Wales by relocating them to the country and helping already established Welsh companies to expand. 

"From a trade perspective, IBW works with the Welsh companies in order to prepare them for market by way of market research, locating potential partners through its in-market partner networks and making introductions," said Paul Viggers, IBW's vice president of International Trade Development, U.S. 

IBW has offices throughout Europe, North America, Asia, and Australia. This global presence provides companies that IBW works with the opportunity to break into international markets via direct contact, whether through trade missions, exhibitions or individual visits, Viggers told 

One of the companies IBW brought to the 2009 DIA Meeting was Brecon Pharmaceuticals (Hereford, UK), an outsource service provider that began working with IBW in November 2008. 

"IBW has encouraged us to attend more international exhibitions than we would have done without them and is currently helping us to exploit business opportunities in Australia," said Sue Miles, clinical trials and customer services director for Brecon. 

IBW's access to worldwide regional markets has helped the company organize meetings with potential new clients. Over the past 12 months, Brecon has contracted business from 23 new clients; a third of them based in the United States. It is now looking to expand into Japan and U.S. markets. 

"Being a small company, Brecon would not have looked to this market without IBW's support," Miles said. 

Biotec Services International Limited (Bridgend, UK), a clinical trials supply company, has been involved with IBW for three years. The initiative has opened the company to new export markets, and has also provided a way of researching and developing these markets, according to Matthew Lakelin, business development manager of Biotec. 

"IBW has also provided assistance with business development, business trips, exhibiting, and participating at conferences," Lakelin said. 

IBW's involvement with Brecon has been a major catalyst in the company's increasing revenue. "The clinical trials business unit has grown 33% per annum on average over the last three years and is set to do the same again over the next 12 months," Miles said. 

According to Miles, the increased international market presence of the Brecon name is a contributing factor to this significant rise in revenue. IBW enabled Brecon to reach a wider range of global markets. She added that 30% of Brecon's revenues are generated from clients based outside of the UK, anticipating that almost half of this is generated from U.S. clients. 

"We currently have three Australian clients and are just about to sign up a fourth. One of these clients has the potential to become a more than £1m account (over $1.5 million USD) over the next 12 to 18 months," Miles said. 

Biotec has also seen a notable increase in revenue due to its involvement with IBW. The company's sales revenue has almost doubled since receiving assistance from IBW, with most of the additional revenue generated in export markets, according to Lakelin. Biotec reports that approximately 60% of their clients are based in the United States. 

The initiative enhanced the experience of Biotec and Brecon at the 2009 DIA Conference in San Diego. 

IBW made the logistics of attending the conference easy and worked hard to set up networking events in which the Welsh companies were able to meet potential new clients, according to Miles. 

"Brecon has attended the U.S.-DIA meeting for the last few years, but we returned home with more solid leads this year," Miles noted. 

Biotec enjoyed a similar experience, meeting with a large portion of its existing U.S.-based clients at the event as well as meeting with many potential clients, Lakelin said. 

To continue promoting growth, IBW will be bringing a number of Welsh companies to AAPS 2009. Along with Brecon and Biotec, these companies include i2c Pharmaceutical Services, Patent Seekers, Penn Pharma, Simbec Research, and Synectix Pharmaceutical Solutions.—

A rising initiative in Wales led by the International Business of Wales (IBW) promotes company growth in the region.

Growth for Welsh Companies

Due to the cost of developing biopharmaceutical products and problems with adequate subject recruitment for clinical trials in the United States and Western Europe, outsourcing clinical research in newly emerging regions is increasingly common. Although the most dominant emerging regions are primarily countries in Latin America, Central and Eastern Europe, and Asia, some countries in Africa are also becoming prominent locations. 

Economical development and regulatory standards make the country a logical choice for trials.

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