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SITES : CTMS - Site Productivity Gains  Why You Need This 10-Step Public Relations Plan  UK Network for Pediatric Research  Also in this issue : REMS Addresses Opioids, Adverse Events Assessment in Europe, Academia, NIH Above Repute?, Financial Impact on CROs

Applied Clinical Trials Digital Edition - July 2009

Flexibility is Key to CTMS Implementation

Clinical trial research sites are at the ground level of clinical research, and are tasked with a myriad of responsibilities. First and foremost, clinical research sites execute trial protocols while providing the best patient care and experience, ensuring patient safety and gathering and providing accurate clinical data. Typically, sites are conducting multiple concurrent trials, in various stages, from recruitment to trial close. Simultaneous recruitment of patients meeting different study criteria is necessary. Patient visits must be scheduled and take place within time windows.       

Regulatory compliance, IRB requirements, meeting milestones, and data gathering and reporting must occur. And trial finances, including sponsor invoices, provider payments, and patient stipends must be managed. Added to these responsibilities are the operational and financial aspects of running and managing a business. 

Patient recruitment and site performance continue to be challenges, and the geographical scope and complexity of trials continues to increase.

  The economic environment is driving increased sponsor focus on cost and timelines, and is resulting in delays and cancellation of trials.

  This is directly impacting research sites. As a result, tools that facilitate communication, address workflow challenges, improve economic return, and provide the metrics to demonstrate performance are becoming increasingly important. 

A clinical trial management system (CTMS) favorably impacts site efficiency and productivity by centralizing information—including searchable patient databases and trial protocols—providing recruitment and screening tools, automating scheduling, managing finances, and providing the reporting and metrics needed for business oversight and growth. The result is simplified workflow, easier recruitment, optimum use of advertising funds, proactive management of finances, more productive staff, and ready availability of proof points and metrics for sponsors. 

Clinical Research Advantage, a site management organization with multiple sites and many concurrent trials, has provided research services for over 18 years. Eric Levie, chief technology officer, says, "As our business continued to grow, we wanted the ability to manage the scheduling and financial aspects of patient activity, and also use the information for staffing purposes and overall business financial oversight." 

Rochester Clinical Research has conducted more than 450 clinical trials since 1994. A single site research organization, Rochester Clinical Research implemented the current CTMS due to the frustration of a disjointed approach. President and Chief Executive Officer Pat Larrabee explains, "We had a system with a partial database and some financials, but we used paper and Excel spreadsheets for scheduling. It was a multistep process. Our new CTMS has improved recruitment, optimized scheduling workflow, and has provided a better handle on metrics and finances." 

DCOL Center for Clinical Research, a dedicated research center and a department of the multispecialty clinic, Diagnostic Clinic of Longview, PA, has been conducting trials since 2005. DCOL implemented a CTMS for the financials. "We needed a better handle on things, and needed to make sure things weren't falling through the cracks," states Sue Faul, Contracts and Financial Administration. 

Sterling Clinical Research was formed as an independent research center in 1999 and now conducts many concurrent trials at three locations. With the growth, Sterling implemented a CTMS to keep everything situated. "We like the idea of having everything in one place," says Betsy Harris, marketing/database manager. "Our CTMS has streamlined operations and provides the metrics to demonstrate success as a clinical research site." 

Benchmark Research conducts clinical studies at six different sites, and at any one time different sites can be running the same study. Charlie Ciarlo, customer service recruitment manager at Benchmark's recruitment center, explained, "We implemented a CTMS because we needed more on reports and budgeting, and wanted a solution that would manage all aspects of clinical trials." 

So how exactly does a CTMS help clinical research sites face challenges and improve performance? 

Subject recruitment continues to be an area of concern for clinical trials. Industry experts estimate that a large percentage of trials miss timelines due to not achieving the number of needed subjects.

  Failure in recruiting and retaining subjects has the greatest impact on trial costs, delays, and failures. Sites that optimize subject recruitment and retention will be more successful in the long term.

  Maximizing the use of existing patient databases and optimizing advertising return can help. 

At Rochester Clinical Research, before implementing a CTMS, recruitment was not efficient. "We kept track of volunteers and patients in books specific to a type of study. We would photocopy information, and put it in the right book. It was difficult and time-consuming to sort through the population of patients. People in books are not easy to target and reach," says Larrabee. "We knew that we needed a patient database, and that it would be a fantastic resource. We wanted one that was searchable, with the ability to sort by conditions and demographics. With a CTMS, we target and manage our patient/volunteer population. All aspects of recruiting have changed. And, we are better and quicker at identifying patients for studies." 

To achieve these gains, a CTMS must have a patient database that can be sorted and is able to create targeted call lists. For studies that are difficult to fill, focused work with the database and call lists can fill those studies quickly. The site has also created a community within the database, with newsletters, email blasts, and advisory boards. 

Sterling had "so many spreadsheets," states Harris. Whenever a patient called, a phone screening form was used to obtain all information, and when staff had time, the information would be entered into a database. "With a CTMS, we've eliminated paper forms, and enter all information into the CTMS in real-time. We've eliminated duplicate patient data entry. With the patient database, as soon as we get the green light to enroll, we're ready to start. This is largely due to the ease of doing searches. In fact, some studies are limiting us due to enrolling patients so quickly." 

At Benchmark, many aspects of recruiting workflow have improved. "Before, we had to fax sites in order to get the data needed to prescreen and recruit," states Ciarlo. "Now all the information is in the system. We have call lists, and manage reminder calls, emails, and notes history, directly from the system, saving a great deal of time." 

Rochester Clinical Research is seeing the benefits of tracking return on advertising. Tracking the return on advertising dollars is critical for optimizing recruitment, spending funds wisely, and maximizing sponsor funding. At Rochester, advertising ROI used to be tracked with manual ticks on a piece of paper. As a result, accuracy of the information relied on recall and how busy people were. 

"Advertising is very expensive, and media is in a huge transition—we need to know how effective our advertising dollars are," explains Larrabee. He adds, "10 years ago an ad in the paper might generate 100 calls. Now it might be three. We need to know how to spend our limited budget dollars." 

A key CTMS feature is the ability to analyze advertising metrics somewhat automatically. "We know where a call is coming from. The database is much more powerful than expected. It's changed how we recruit and where we put our advertising dollars. We know what's working and what's not." Efficient use of recruitment dollars has helped the site get to goals sooner. And, the metrics are available to negotiate with sponsors for additional advertising funds. 

With multiple studies, different protocols, specialized needs, and sometimes multiple locations, study scheduling, staffing, and tracking can become daunting, and performance metrics difficult to obtain. Studies show that about half of sites will underperform. Even sponsors admit that they are not certain which sites will meet objectives and which will fail.

  The ability for sites to self-monitor performance and have the metrics to use in discussions with sponsors leads to improved site and overall trial performance. 

At Clinical Research Advantage, the CTMS provides the ability to build study windows and automatically schedule patients. As soon as any site knows a patient is interested, information can be entered into the database in real-time, so call centers can schedule immediately. Previously this was done with paper calendars and visit windows were calculated manually by the coordinator. Now, calendars are shared across sites and site managers have a view of what is going on. 

Previously, Rochester Clinical Research had one gigantic appointment book, and only one person could schedule at a time. Paper scheduling was very frustrating and took a long time. With a CTMS, protocols and visit windows for every study are available to multiple people. "Electronic scheduling has made life easier for so many people," says Larrabee. Now, as soon as someone qualifies, he or she can be scheduled for their first appointment immediately. If something is changed, there is a record of who has changed it. An overview of visits provides real-time data and highlights when patients need to be scheduled to stay within the visit window. 

At Benchmark, since all locations are in the system, the central office is able to enter the database and have immediate access to information. Appointments can be scheduled without calling a location to get all the patient information. "Before, we had to fax sites in order to get the data needed to prescreen and recruit," states Ciarlo. "Now we can just click a button and see what we need to see. Everything is faster. We can get work done more quickly, and don't need overtime." 

Levie is seeing an added benefit. "Before we had our CTMS it was difficult to know which visits were going on at which sites, and managing labor was difficult. Other than paper logs, it was hard to visualize how much business there was at each site without calling or faxing. This took a great deal of time," explains Levie, "and it was just as time intensive to get an overview of where we were with studies and patient loads. We used to have to call constantly, and even then, it was difficult to get up-to-date information." 

Now, all information is available in real time and accessible from a central location. A study dashboard shows the status of each study and how well each site is doing on a particular study, as well as overall, and the forecasting report makes workload planning easier. "The CTMS needed to provide these features," says Levie, adding, "we can now be proactive and shift labor among sites, only hiring temporary help when necessary—this is helping save costs." 

Larrabee is seeing a similar improvement in workload planning, but in a single site environment. Prior to the CTMS, there was no overall and forward view of the schedule and no way to get data on upcoming appointments. This made it difficult to minimize scheduling conflicts, plan workload, and proactively adjust staffing. Also, without past study information, data for workload projections was not available. Larrabee comments that "now we don't need to rely on a 'gut' feel to assign studies. We're able to project what's needed and make assignments based on the workload data." When patients are scheduled, availability of staff and resources are assured. 

A CTMS has also facilitated data collection and has improved study start-up time. Mervyn Weerasinghe, MD, principal investigator, comments that "it's much easier to get things done in time for study start-up. All documents can be turned around quickly and usually within 48 hours or less." Feasibility analysis is a key step in assessing whether a site can execute the trial with available resources, and if not, what is needed.

  A database of historical and accurate information is key for medical and clinical directors who have responsibility for preparing the analysis. 

Levie is also seeing the advantages of a searchable database. Before "we had to dig through charts." He notes, "We've definitely saved time with a CTMS, especially for studies similar in nature." With a solid database, the regulatory department has become more efficient. It's easier to pull data for IRB reporting, and information is available without having to call the coordinator. Also, since data is maintained electronically, it's quicker to get accurate info. 

Coordinators also are more efficient. Previously, they spent a great deal of time gathering data for regulatory purposes, questionnaires, and stipend processing. Now, information is easily available, so coordinators can do what they do best: work with the patients and follow the protocols given. Having a CTMS minimizes the amount of time spent on nonpatient related activities. 

Financial management and reporting are streamlined with a CTMS. Without it, it is difficult for sites to know where study finances and overall finances stand. And the day-to-day operational aspects of managing finances are cumbersome. With postponements and delays of trials and an increase in uncollectible receivables, it has become increasingly important for sites to proactively manage finances and improve the ability to link payments received to studies.

Previously, hundreds of spreadsheets were used at Clinical Research Advantage, and it took a great deal of time to gather the information needed for payments. All financial activity was manual. Now, internal controls are in place, and with a few clicks, the central office can take care of stipend payments. Says Levie, "With the overview of visit windows, we're able to budget better, and with real-time data, we have an accurate snapshot of the profitability of a study. Our CTMS is a great tool to forecast cash flows and revenues, and to track payments to providers. It's much simpler when the data is in a central location, rather than hundreds of spreadsheets, and we've just implemented QuickBooks integration to automate our check processing flow." 

Reporting is more efficient, more accurate, and the information needed for internal business management and external communication is available. Having a CTMS has improved communication among all departments—finance, marketing, recruitment, training, operations—and has combined collectively all of the departments' information through access to one centralized database. Before their existing CTMS, Rochester Clinical Research "didn't really know where finances stood until several weeks after the close of the month, and even then it was time-consuming to compile the information and ensure its accuracy," says Larrabee. "Now, at 11:00, we can tell what kind of day we're having, not weeks or months later." 

In addition, a CTMS enables more targeted goals for employees. "Because of the comprehensive metrics, we have a much better idea of which studies are profitable and which will have a better yield. We can prepare a budget more quickly than before because we have the actual costs. Also, we can look at past months and trends when choosing studies, and we know which studies we can do well—and have the metrics to prove it," Larrabee notes. 

"Before implementing a CTMS, we didn't really know the volume of work. We had a ballpark figure, but no specifics," Faul explains. After implementing a CTMS, DCOL is able to track the number of visits, average intake per visit, and dollars to break even, down to the visit level, and can also set break-even volume goals for staff. Faul adds, "We have a complete study budget tracking tool—everything is in sight—we know what we've done, what we've been paid for, and what we've paid to providers and patients." This was very difficult to do before. 

Now every time a payment comes in, DCOL does a "mini audit." "If there's something we haven't been paid for, we can follow up, and shorten the timeline for sponsor payment. It's also easier to tie checks that come in to a particular study," says Faul. DCOL tracks everything from advertising to one-time negotiated fees, and regularly compares actual to budget. Faul adds, "We also track vendor statements within the CTMS. This is particularly important when procedures aren't done on site. We're proactive about paying people." 

Implementing any new IT system can be daunting and goes beyond the technology change. Processes and workflow need to change to gain the benefits, and old habits must change. Transitioning from a different IT system requires data export into the new system. When transitioning from manual methods and Excel spreadsheets sites can decide to switch to the CTMS only for all new studies moving forward, or enter data from all existing open studies. Either way, it's important to train staff, understand how it integrates with policies and procedures, and modify processes and workflow as needed. Although immediate benefits can be derived, a full transition can take months. 

 At Clinical Research Advantage, Ange-Lisa Ashbeck, certified clinical research coordinator and director of training states, "We went from employees thinking they weren't going to have to go through the pain of transition, to an acceptance that now they don't know what to do without it." 

At Sterling, Harris notes that "the training of our staff was probably the most difficult part of the transition. We separated staff and trained them only on things they would do...this was less overwhelming." 

To facilitate its adoption and use, Rochester Clinical Research also separated initial task responsibilities, assigning training and responsibilities by job function, for example, recruitment, finances, and regulatory. People can be afraid to give up paper, and have a natural fear of how the new technology will work and whether it will do what it promises. 

Feature Article

Real-life examples of how a clinical trial management system impacted work-life for the better at five sites.

Improving Site Efficiency and Productivity

•With more than 20 years of expertise in medical device technology and health care business management between 

, the new business development director, and 

 the new vice president of research and development, 

 (Paris, France), will utilize the strengths of these two additions to prepare for an upcoming commercialization of a  new device.

 (Washington, DC) scientific consulting  team, 

, PhD, will assist sponsors with strategic planning, protocol development, expert reporting, and regulatory submissions.

 (Tampa, FL) business development functions and enhancing relationship management and service levels for customer partnerships. 

•As the former director of the Technology Investment Banking Group at Robert W. Baird and a 17-year veteran in enterprise software and IT markets, 

 (Chicago, IL) as chief operating officer. 

•Replacing Takatoshi Sato as the Chair of 

 (Horsham, PA) Regional Advisory Council of Japan (ACJ) is 

, PhD, a former employee of the Ministry of Health and Welfare Japan, the World Health Organization, and what is currently the Pharmaceuticals and Medical Devices Agency. 

•Bringing with him 25 years of experience in the pharmaceutical commercial sector, 

 (Research Triangle Park, NC), a Quintiles company. 

 to the position of the director of business development, which is a newly created role for  the company. 

 (Cambridge, MA) team as the new executive vice president of commercial operations is 

, who will lead the company's worldwide sales and marketing efforts. 

 (Morrisville, NC) team of clinical development professionals, the company has added three new advisors: 

, PhD, an editorial advisory board member of 

 (Research Triangle Park, NC), where he will utilize his 16 years of experience in tactical and logistical guidance. 

 (West Lebanon, NH) to now offer its clients more options for efficient, cost-effective image collection and transfer is a partnership with 

 (Boston, MA), a HIPAA and 21 CFR Part 11 compliant diagnostic imaging network.

 (Holmdel, NJ) TrackWise software for the management of audits, non-conformance, corrective and preventative actions, and workflow verification.

 (Marlborough, MA) S-Cubed will provide customers with an all encompassing solution for creating and managing eCTD, non-eCTD, and paper submissions to global regulatory agencies.

Transitioning from a paper-based to an EDC system, 

 (New York, NY) Medidata Rave for its SOMO-INSIGHT clinical study of an automated breast imaging ultrasound system for early detection of breast cancer.

 (Raleigh, NC) CTMS solution for the management of its clinical trials and has thus far installed the project management, regulatory/ethics management, CRF tracking, visit reports, and site payment modules.

After the signing of an alliance between 

 (Flemington, NJ), SIRO will now be able to expand its oncology clinical development and patient recruitment services into North America, while Advanced Clinical Trials Solutions will gain access to SIRO's services in India and European countries.

 (Drummoyne, Australia) have signed an agreement to conduct the first randomized clinical trial of a papaya product intended to heal venous and pressure ulcers.

Extending on a contract that was signed in 2007, 

 (Little Falls, NJ) have resigned a multiyear, multi-million dollar agreement that entails Everest implementing Phase Forward's InForm and Central Designer in-house.

With the intent of bringing more clinical studies to India, 

 (Bangalore, India) have entered into a joint venture that requires the companies to collaborate and share both experience and services to serve regional and international pharma companies.

Being selected to provide Johns Hopkins University with data management software and services for a Phase I clinical trial of a new vaccine is C-tasc (Baltimore, MD), which will provide its StudyCTMSTM for under $50,000.

The Academy of Molecular Imaging has chosen American College of Radiology (ACR) Image Metrix (Philadelphia, PA) to provide data and image storage infrastructure for a randomized PET/CT bone imaging clinical trial.

Academy of Clinical Research Professional

 (Denver, CO) members were honored for maintaining their Certified Clinical Research Associate (CCRA) or Certified Clinical Research Coordinator (CCRC) status through the Academy for 10 years.

 (Rockville, MD) received the Vaccine Industry Excellence (ViE) award as the "Best Contract Research Organization," which is intended to highlight the importance of contract research services within the vaccine industry.

 (Kearney, NE) at the 26th Annual Healthcare Advertising Awards competition, including a bronze award for the ACR Image Metrix Web site, a merit award for Xcelience, and also merit awards for a BASi campaign print ad and trade show booth.

Based on an independent survey of pharmaceutical and biotechnology companies that questioned their experience with CROs and general trends affecting the CRO industry, 

 has been named as a favorite Contract Research Organization to work with by the fourth annual "CRO Industry Update," conducted by William Blair & Company in association with CenterWatch.

The 2008 Pfizer Development Operations' "Strategic Supplier Excellence Award," has been given to 

 (Tampa, FL) in recognition of its consistent performance in quality, service delivery and reliability, innovation and business processes, and customer service.

 (Basking Ridge, NJ) has been ranked as one of the top 10 places to work in Spain among companies of 100 to 250 employees by the 

 (San Francisco, CA), which was primarily determined by employee responses to an issued survey.

Adding to its already accredited laboratories in New York and Ireland, 

 (Dublin, Ireland) Singapore and India facilities have recently received accreditation from the College of American Pathologists (CAP) as well.

Beyond a name change to CRF Health, the former 

 (Lansdale, PA) has also made changes to the look of its Web site and established new marketing material.

 (Reston, VA) announced that it has successfully scanned and imaged a prototype clinical PET oncology imaging simulator (phantom) at four imaging centers.

Responding to an increase in demand for flexible, skilled monitoring resources, 

 (Buckinghamshire, UK) has expanded its monitoring services division.

 (Kearney, NE) has been chosen to provide 

 (Exton, PA) with a marketing plan, brand development, Web site, and trade show components.

 (Södertälje, Sweden) intends to offer visitors in-depth information on the company's services, current industry news, and a wider variety of case studies.

 (Wilmington, NC) third central lab to earn accreditation by the College of American Pathologists is the company's Beijing facility.

Continuing on its initiative to expand unit capacity, 

 (Lombard, IL) has expanded its Phase I units with the addition of 22 new hospitalization beds in the company's Stuivenberg, Belgium, hospital, bringing SGS' overall bed capacity to 184.

 (Bourne End, UK) eLearning education program will feature 10 eLearning modules,  all of which now include Flash technology that offers interactive  education courses for clinical research professionals.

 (Washington, DC) has announced advancements to its Holter Bin Methodology for ECG data analysis through its success in reducing potential for false positive outcomes in Thorough QT studies by isolating heart rate-related QT effects.

 (Research Triangle Park, NC) has been awarded four new projects by 

 (Morrisville, PA) that will require the company to provide mostly electronic data capture and data management services.

Community

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

Business and People Update July 2009

In 2007, prior to that year's DIA meeting, Parexel announced its Start-up and Accelerated Recruitment Team (START). Now, two years later, the Team has added to its base of experts, as well as its accomplishments. In an interview with 

, Lars-Olof Eriksson, PhD, MSc, recently announced vice president of START, discussed the three-prong integrated approach of START and its influence on clinical trial decisions.  

Eriksson most recently was senior director in Clinical Research Operations specializing in patient recruitment at Merck. Of the START group, he says, "What we have are really clear strategies that were expressed by leadership at Parexel to take a strategic focus on planning and execution of clinical trials and put the right resources in place and apply a more data-driven approach to help sponsors accelerate study initiation and achieve Last Patient In—LPI—milestones."  

To that end, within START, there are three groups that now report to Eriksson. These are the Feasibility and Clinical Informatics;  Study Start-Up  and the Patient Recruitment Planning groups. Each group applies both internal and external tools and databases to its specific clinical trial function and works closely in parallel and in concert to deliver knowledge to the client, as well as develop milestone timelines. 

With a focus on helping sponsors overcome the financial costs associated with both subject recruitment and site start-up delays, START is applying data in an integrated approach earlier in the phase process. 

For example, the feasibility group can apply data mining techniques to both internal resources on investigators (past performance), and external databases (

, as one example), and previous protocol comparison to clinically and medically determine feasibility. From there, specific determinations can be made on the protocol design. "For example, with one diabetes study, we had the possibility of identifying 30,000 to 50,000 patients. After the availability of patients and the cumulative effect of enrollment were modeled, we had 28,000 patients. Weighing this information against the actual protocol, there were nine patients left," said Eriksson. "Our focus is to create more awareness with the client of this type of feasibility assessment, and to discuss potentially  opening up the protocol more, for instance, while still fitting the study requirements."  

From there, the Team then can model and forecast its study timelines for sponsors that are reliable.  

The Start-Up unit uses a propriety calculator (Scenario Planning and Recruitment Calculator or SPARC) to take all the data and apply it in the calculator's algorithms to activate the sites. "The sites can be categorized as simple, or complex, usually based on the regulatory requirements of each. Complex sites usually are the larger academic institutions," explained Eriksson.  

The Patient Recruitment Planning group uses Parexel patient recruitment specialists to develop the outreach plan.  

During the typical two- to six-month period where sponsors are awaiting regulatory approval, the CRO is actively working on the site and recruitment activities. So, for example, the sites are being qualified, but more than that, the specialists are actively pre-identifying the patients that would be eligible for that study. "We can see if each site that has been chosen has enough to deliver on the study according to plan, or if we need to launch back up sites," explained Eriksson. 

The specialists also explore patient records for insight into reading habits, interests, etc., that would help guide the recruitment plan. "It helps to communicate more effectively to the patient, if she is a 50-year-old post-menopausal woman or a 20 year-old college student," said Eriksson. "How do we appeal and respond to those individuals in outreach."  

For Eriksson, who has a 30-year history of experience in patient recruitment, site implementation, project management, and global drug development, his passion for the Parexel approach is evident. "It is a unique program out there in regard to both sponsors and CROs." 

Eriksson believes this aspect of the industry holds unique challenges. Specifically in regard to EMRs, patient registries, and the like, which have promised integration via the Obama administration. "The information is out there that we can use, but the challenge is to mine that data in a legal and ethical way," emphasizes Eriksson. 

News

Parexel's Start-up and Accelerated Recruitment Team (START) is applying an integrated approach to data that is to be applied in early phases to alleviate recruitment and study start-up challenges.

Integrated START for Studies

The focus on outsourcing of not only small and medium sized entities but also big pharma companies due to cost containment and regulatory pressures has led to several years of double digit growth for contract research organizations (CROs). According to the Contract Research Annual Review 2008, the CRO market grew by an extraordinary 28% last year while the pharmaceutical industry struggled with growth of around 5%. Headcounts in clinical development departments at pharmaceutical companies have been static or even decreasing (in the case of mergers and acquisitions) in the past few years, while CROs expanded their offers toward full service.        

Strategic outsourcing allows pharma companies to focus on their partner's core strengths and long-term goals. This route allows the sponsor to maximize internal resources and capacities of the vendor. Tactical outsourcing relates to short-term projects that cannot be handled internally due to the lack of internal capacity or resources, allowing for streamlining processes, fast turn around times, and access to additional equipment. 

Forecasts predict that there remains a sufficient growth opportunity for the CRO industry until 2012. The last months have been turbulent for the economy with increased merger and acquisition activities of pharmaceutical companies in order to expand market capitalization and tackle the problem of thinning pipelines. 

Complete R&D portfolios have been subject to thorough reviews. Sanofi-Aventis, for instance, announced the discontinuation of 14 development programs, four of these had reached Phase III, leaving 51 projects in the development pipeline. 

The economic downturn will certainly have an impact on CROs, but how substantial and how long will this last? 

Short-term effects induced by delays in payments, shifting of projects, backlogs, and prioritizations with fewer projects have reached the CRO industry already. Kendle, for example, reported a 78% drop in profit compared to the same period last year. Top executives at Kendle categorize the Q1 results as unique and view them as a near-term, manageable event. 

The recession might result in reduced growth rate, but the mid- and long-term effects of downsizing of R&D in the pharmaceutical industry will create opportunities for contract researchers. 

The current outsourcing market is different compared to other industries, such as steel or car production where two or three companies represent the majority of sales in the market. The CRO market is highly fragmented and the number of CROs worldwide has reached over 1100. 

A consolidation of the customer base through mergers/acquisitions should therefore not pose a problem for the majority of CROs. Large global contract research providers like Quintiles, Covance, PPD, Charles River Labs, and ICON—holding 45% of the total market—will expand their capabilities in emerging markets for cost reduction purposes. 

Unmet medical needs in oncology, CNS, cardiovascular, and infectious diseases will continue to be major drivers of drug development. CROs focusing on full-service offerings in these therapeutic areas will continue to grow profits. 

In conclusion, one could state that unlike in other industries, the current financial crisis will create opportunities for contract research organizations. 

Head of Clinical Development CRS Clinical Research Services Mannheim GmbH 

A Closing Thought

A look at how the current financial crisis has established more opportunity for the contract research organization industry.

The Impact of Financial Crisis

Russia remains an attractive country in which to base clinical trials, and the sector does not appear to be suffering markedly from the global economic downturn, according to a comprehensive market report published in early June by Synergy Research Group (SynRG), a Russian-based CRO.     

The Federal Service on Surveillance in Healthcare and Social Development of the Russian Federation (RosZdravNadzor, RZN) approved 113 new clinical trials during first quarter (Q1) 2009, representing a 13% decrease against the same period in 2008. 

Clinical trials in Russia in Q1 2009 were sponsored by companies from 28 countries. A total of 31 trials were initiated by Russian sponsors, and 20 studies were begun by companies from the United States, followed by Germany (12), Switzerland, Japan (8), and the UK (7). Boehringer Ingelheim and Novartis each sponsored seven new studies in Q1 2009, followed by Pfizer with six, Merck & Co. with four, and Hexal Biotech with three. 

"The lion's share of clinical trials in Russia is still being sponsored by foreign companies," wrote the authors of the report, called the Orange Paper. "Whilst their share increased from 68% to 73%, their number is up from 82 in Q1 2008 to 88 new studies in Q1 2009. The number of trials initiated by Russian sponsors, including bioequivalence studies, rose from 31 to 42, but their share decreased from 32% to 27%." 

Around 70% of new studies were initiated in six therapeutic areas: cardiovascular (17), neurology and oncology (16), infectious diseases (14), respiratory diseases (12), and endocrinology (11). The number of bioequivalence studies unveiled in the first quarter of 2009 was 14, compared with 13 over the same period in 2008. 

"It looks like the economic crisis has not yet affected the clinical trial industry. The reason is twofold: the development cycle of a new drug is much longer than any crisis, and the elasticity of a medicine is low enough to stand the chaotic fluctuations of the world stock market," the authors wrote.  

During Q1 2009, FDA's CDER approved 121 new drugs, of which five were tested in Russia. Over the same period, EMEA reviewed 161 applications to market drugs in the EU, and seven drugs were tested in Russia (see Table). 

According to Alexandra Zaichenko, business development director of the OCT Group in St. Petersburg: "My general advice to sponsors is to avoid the prejudice that the infrastructure in Russia is as it was 20 years ago. Each site...is accredited by the Ministry of Health for GCP...and can't be approved without a certain qualification of the PI and other team members.—

Global News

The current state of the clinical trial market in Russia.

Russia Continues to Lure Sponsors

New rules for pharmacovigilance are on the way in Europe. European Union health ministers took their first look at the proposals* in June, and changes can be expected to be decided before the end of this year. The initiative comes from European industry commissioner Günter Verheugen, who made clear last December when he announced a "pharma package" of proposed new rules that he was determined to tighten up EU monitoring of adverse effects.     

Although ministers took no decisions when they met as the EU health council on June 9, they did have an opportunity to review the progress made by the expert working party of national officials that is examining the draft. An extensive report lists where consensus is emerging—and where it is not. 

The objective as defined by the Commission is to "strengthen and rationalize" the EU pharmacovigilance system to ensure full and equal coverage for "all relevant products" across the EU, "with a view to preventing unnecessary patient exposure to risks." The proposals envisage clearer roles for everyone involved, greater transparency on medicines safety and on the way companies' pharmacovigilance systems function, better quality data-collection, and closer involvement of patients. 

The proposals suggest tougher obligations on companies to provide information on their products. "The marketing authorization holder shall forthwith supply to the national competent authority any new information which might entail the amendment of the particulars or documents" covered by the authorization, and "In particular, he shall forthwith inform the national competent authority of any prohibition or restriction imposed by the competent authorities of any country in which the medicinal product for human use is marketed and of any other new information which might influence the evaluation of the benefits and risks of the medicinal product for human use concerned." 

This information is to include both positive and negative results of trials or other studies in all indications and populations, whether or not included in the marketing authorization, as well as data on the use of the medicinal product not in accordance with the summary of the product characteristics. 

 In addition, the marketing authorization holder "shall ensure that the product information is kept up to date with the current scientific knowledge," and "in order that the risk-benefit balance may be continuously assessed, the national competent authority may at any time ask the holder of the marketing authorization to forward data demonstrating that the risk-benefit balance remains favourable." 

The EU's Working Party on Pharmaceuticals and Medical Devices—the technical experts from the 27 member states—has so far examined the proposals six times, and all countries are still holding back from a general endorsement of the proposals. This does not mean they fundamentally oppose it. 

As is clear from the report—drawn up by the Czech Republic, which has been in the EU's rotating presidency seat for the first six months of this year—there is general agreement among national officials that "these important proposals must be pursued with high priority." But officials from some countries are not convinced that the proposals meet the designated objectives, and many national delegations to the working party have reservations on individual provisions. 

For instance, while there is broad agreement that a new scientific committee responsible for pharmacovigilance should be set up in the EMEA, there are divergent views over who should sit on it. The proposals foresee a committee with 10 members appointed by the EMEA Management Board and five members appointed by the Commission, but nearly all the member states insist on every country having a seat. A compromise is under discussion under which every member state would have the right, but not the obligation, to actively participate in the work of the committee. 

There are differences over the role of the pharmacovigilance committee, too. The debate is partly over whether its recommendations should serve merely as advice for the Committee for Medicinal Products for Human Use (CHMP) and the coordination group (CMD), as the Commission has proposed, or should be binding, or binding except where the CHMP and CMD "have well-founded reasons for not accepting the recommendation." Both the composition and the role of the committee in relation to the other scientific committees of EMEA (including CAT) also need further discussion, according to the report of discussions in the working party. 

There have been lengthy discussions of the proposed definitions, in particular the definition of "adverse reaction." Some national delegations support the proposed new definition of adverse reaction, "Adverse reaction: A response to a medicinal product which is noxious and unintended." While some other delegations would prefer to maintain the current definition, "Adverse reaction: A response to a medicinal product which is noxious and unintended and which occurs at doses normally used in man for the prophylaxis, diagnosis or therapy of disease or for the restoration, correction or modification of physiological function." And others would accept the current definition "potentially with minor changes." 

Some delegations have suggested two separate definitions, one covering adverse reactions within the use in compliance with the summary of the product characteristics (SPC) and the other covering off-label use. 

The potential need for a definition of "medication error" has also been discussed, and first suggestions for a definition have been provided. This discussion has in turn produced further complications, since "misuse" and "medication error" are terms that are not yet defined in EU legislation. So the proposed definitions, as well as the missing definitions, require further reflection. 

The proposal for a list of medicinal products for human use under intensive monitoring has generated dissension over its impact and the practical aspects. There are questions over who in the EMEA should manage it and how, and the concept of including a special statement into the package leaflet (PIL) to indicate the medicine's status has raised eyebrows. 

There are many national officials who fear that such a statement to the public would give rise to unsubstantiated concerns for patients, with possible negative effects on compliance. It would also mean what are seen as unjustified administrative burdens for marketing authorization holders—if their product was removed from the list, they might have to seek a variation of the marketing authorization to accommodate the modification of the PIL. Similar concerns have been expressed over the proposed inclusion of the summary of essential safety information in the SPC and PIL. 

Further examination will also be needed of the proposals on supervision of postauthorization safety studies. These constraints will apply to noninterventional postauthorization safety studies that are initiated, managed or financed by the marketing authorization holder, voluntarily or following a requirement, and which involve the collection of data from patients or health care professionals. "The studies shall not be performed where the act of conducting the study promotes the use of a medicinal product," according to the draft text. 

Before such a study is conducted, the marketing authorization holder will have to submit a draft protocol to the national competent authority if only one member state is involved, and to the Pharmacovigilance Risk Assessment Advisory Committee for studies to be conducted more widely. If the committee has any reservations, it will, within 60 days, issue either a recommendation on the draft protocol or letter of objection (based on detailed grounds, for instance if it considers that the study is a clinical trial falling under the scope of Directive 2001/20/EC, or the study promotes the use of a product). 

During the conduct of the study, the marketing authorization holder will have to continuously monitor the data generated and its implications for the risk–benefit balance of the product, and communicate to the authorities any new information that might influence the risk–benefit balance. 

Final study reports are to be submitted to the national competent authority or the Pharmacovigilance Risk Assessment Advisory Committee within 12 months of the last patient visit unless a written waiver has been given. The marketing authorization holder has to consider whether the results of the study have an impact on the terms of the marketing authorization and is required if necessary to submit an application to vary the marketing authorization. 

Other areas where differences still have to be resolved among national officials include a risk management system covering all products; the setting up and maintenance of national safety Web portals; and direct reporting to the Eudravigilance database by the marketing authorization holder and by patients. 

The next crucial stage in this process will be the first opinion from the European Parliament, but this is not expected until the autumn, since the new parliament elected in June will not start work until July, and then takes an extended summer break. 

* Proposal for a Regulation of the European Parliament and of the Council amending, as regards pharmacovigilance of medicinal products for human use, Regulation (EC) No 726/2004 laying down Community procedures for the authorization and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency and Proposal for a Directive of the European Parliament and of the Council amending, as regards pharmacovigilance, Directive 2001/83/EC on the Community code relating to medicinal products for human use. 

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

View from Brussels

European Union health ministers begin reviewing proposals to better adverse event assessment in Europe.

EU Looks Closer at Pharmacovigilance

If you are not already doing so, it's time to make crisis communications preparation a standard part of your clinical trial plan. Lawsuits involving clinical research trials are on the increase, so much so that a new area of law is developing—research malpractice.      

 Photoography Getty Images   Illustration: Paul A. Belci 

Unlike standard medical malpractice lawsuits, in research malpractice plaintiffs and attorneys target just about anyone associated with a clinical trial: doctors, universities, research institutions, drug companies, clinical trial review boards, and even patent holders of certain medical devices. 

Not only does this open up everyone involved to the possibility of having to make potentially large financial payouts, but more damaging and long-lasting is the negative image and damage to your institution's reputation. With today's 24-hour news cycle and the Internet, any negative news can spread around the world at lightning speed. 

Add to the mix the explosion of citizen reporting and blogging and you have a volatile combination that can cause irreparable damage to all involved in a clinical trial if not properly managed. Individual, corporate and/or institutional reputations can be blemished, if not ruined. 

This article provides a summary overview of the changes that have occurred in the legal and research environment, what caused them, and how researchers and institutions can prepare and manage their strategic communication plans to avert or manage these new potential crises. 

Until recently, few would have thought such crisis communication preparations were necessary. Two events in the 1990s triggered the change. The first was a 1995 report by President Clinton's Advisory Committee on Human Radiation Experiments, which documented abuses in radiation experiments on unwitting citizens during the 1940s. The second, and better known, was a widely publicized lawsuit involving the 1999 death of Jesse Gelsinger, an 18-year-old participant in a gene-therapy trial at the University of Pennsylvania.

Before these incidents, lawsuits involving trials were very rare. Signed forms by participants giving their informed consent were thought to give researchers immunity against potential lawsuits. So what happened? As Alan C. Milstein, the Pennsauken, NJ, attorney who represented the Gelsinger family in its suit against the University of Pennsylvania, explained, the outcome of that case "eviscerated the cloak of immunity" that informed consent signatures had provided for the research community. The lawsuits showed it was possible to find flaws in the informed consent process and sufficient room in the wording to be successful. 

Noting that he himself has successfully filed and settled 20 such cases since then, Milstein said, "Signed consent forms are no longer worth the paper they are written on. Most of the time they fail to really inform subjects in a way so they understand everything about the study and how it will affect them"

  (See Sidebar: Why Informed Consent May Not Protect You). The ensuing litigation triggered a number of similar suits alleging, among other things, inadequate informed consent, breach of informed consent, and conflicts of interest. 

Why Informed Consent May Not Protect You 

Although no precise data are available on the number of injuries that have occurred from clinical trials—partly because no one government body regulates them all—or exactly how many lawsuits have been filed or settled during the past decade, clearly there is a significant trend toward more lawsuits involving clinical trials (see Table 1).

Those accused range from pharmaceutical and biotech companies to hospitals and IRBs as well as individual researchers. Most of the allegations focus on the issue of informed consent, and are based on claims that the research participants did not receive enough information before agreeing to participate.

There are a number of reasons for the spike in lawsuits, not all of them related to the massive number of clinical trials currently underway. To begin with, public distrust of pharmaceutical companies and concerns about possible lax ethics of clinical investigators and research institutions are on the rise. Lawyers say that public risks have increased over the last decade as the drug industry tries to meet Wall Street's demand for steady growth in profit.

Today's drug sponsors need to prepare and practice for worst-case clinical trial scenarios.

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