CRO Industry Update

Addressing expansion, adapting to trends

By Kristin Brooks

In 2006, much of the activity in the CRO realm centered on geographic expansion in new markets for additional capacity, capabilities and services through M&A, and technology pacts for electronic data capture (EDC). Also, the industry as a whole is experiencing a drug development shift, focusing more and more on quality/safety, speed and reduced drug development costs. Some of the trends behind this shift include adaptive trial designs, industry standards, and new all-encompassing EDC solutions. It all boils down to creating efficiencies in these areas. For a CRO, flexibility comes with the territory, but what are the challenges with expansion and what changes will recent trends mandate?

CRO Expansion Efforts

The CRO industry’s estimated value is upwards of $16 billion and Goldman Sachs estimates that the total market opportunity for Contract Research services will reach $22.9 billion in 2009.

It’s no wonder they’re taking every opportunity to expand. According to some of the top CROs, sponsors are letting loose and outsourcing more across all phases of development, from preclinical to post-marketing safety studies, with Phase I, late-stage Phase II-IV, and safety studies cited the most. Partnerships with sponsors that completely redefine the outsourcing paradigm are critical to enabling this full-service outsourcing model.

John Watson, vice president of marketing and sales at Covance, said, “In summary, $65 billion is spent on R&D worldwide with approximately 25% outsourced to CROs, representing a $16 billion opportunity throughout the entire drug development continuum. It’s through strategic partnering and building relationships with sponsors that the opportunity for growth exists.”

Dr. John Hubbard, global president, ICON Clinical Research, added, “Almost every aspect of the R&D process is now outsourced. Sponsors are also leveraging the global footprint of the major CROs for their large multi-national studies.”

Many CROs are expanding capacity for performance, adding capabilities, and entering emerging global markets in an effort to create one-stop shopping for sponsors. Activity from some of the top CROs in 2006 included:

• Quintiles opened a central lab in Mumbai, India, conducted its 200th EDC trial and signed a multi-million dollar contract with Ness Technologies to establish an Extended Development Center (EDC) at Ness Technologies’ facility in Bangalore, India.
• Covance expanded its presence in China with a new Shanghai Central Lab, completed the acquisition of the Phase I/IIa business of Radiant Research, Inc., and expanded its antibody products and services with the acquisition of Signet Labs.
• Parexel acquired California Clinical Trials Medical Group, Inc. and Behavioral and Medical Research, LLC, providing a broad range of specialty Phase I – IV research services.

Dr. Hubbard added, “We have also recognized the growth of clinical research into new frontiers and have increased investments in overseas expansion. In the past year alone, ICON has opened new offices in Milan, Warsaw, Vilnius, Novosibirsk, and Salt Lake City, bringing our total number of offices to 52 in 30 countries.”

MDS Pharma Services has also taken decisive action over the past year to divest non-core operations in order to concentrate on providing drug discovery and development support solutions. Dave Spaight, president MDS Pharma Services, said, “We have exited niche operations such as soil and water testing, fermentation and small batch drug manufacturing, and are focusing on our core competency. That focus included the opening of our first U.S. central lab facility last year. We recently increased our Phase I capacity in Lincoln, NE, and we’re adding a 300-bed expansion in Phoenix to accommodate anticipated future demand.”

Imaging in Clinical Trials by Richard Taranto Imaging CRO services, while still a relatively small piece of the industry pie, offers the same benefits of specialized outsourcing as its research counterparts, and is growing just as quickly. As the FDA maintains its dedication to the Critical Path Initiative and Big Pharma looks to faster drug development, the use of diagnostic imaging in clinical trials will continue to increase. Imaging CROs often outsource themselves. While some rely solely on in-house radiologists and technicians, many will utilize readers from independent radiology groups or a research-based institution or hospital. Access to an adequate supply of trained radiologists is of concern to every imaging CRO, as an easily expandable team facilitates the seamless transition from small to larger studies without additional cost to sponsors. Accordingly, when managing trials of the magnitude required by most pharmaceutical companies, operational expertise and quality control measures designed to prevent variability become critical to successful drug development. Because clinical trial imaging is often conducted at multiple global sites, the CRO’s image acquisition protocol and quality control process must be rigorously enforced throughout the trial before images are submitted to the central location for interpretation. A comprehensive process includes imaging site qualification, equipment variability reviews, and site technical support, and has to cover all phases of the CRO’s trial management, from protocol and imaging charter design through the regulatory submission process. Upon receiving images for analysis, the CRO must organize and archive them almost immediately to prevent data loss or confusion. A state-of-the-art workflow and cutting-edge technology is necessary for this successful collection and subsequent submission management. Use of the PACS (picture archiving and communications system), which electronically stores, transmits and displays imaging data, allows for information management and image viewing at various locations and is the industry standard for image transferal. Application software that communicates between sites, maintains a centralized database, and automatically tracks missing scans should be customized for each study, as a complete audit trail must be provided for later regulatory support. Finally, a secure user portal for handling site queries, receiving and processing images, and providing sponsors with real-time trial status are all crucial to trial management from the central facility. Richard Taranto is president of WorldCare Clinical, LLC. He can be reached at rtaranto@wcclinical.com.

According to PPD’s chief executive officer, Fred Eshelman, “Managing growth is among the greatest challenges facing the CRO industry. In Phase II-IV specifically, the ability to hire and retain experienced clinical research personnel globally is an important aspect of managing growth as is the challenge of growing successfully internationally by establishing and maintaining profitable operations outside the U.S.”

Responding to Globalization Challenges

Managing such vast growth can be a heavy burden for CROs, particularly given the obstacles that emerging markets present. Globalization of clinical trials is playing a key role in CROs’ need to streamline existing operations and take up new ones offshore. There are many challenges associated with globalization, centering on logistics, regulation, and communication. CROs are re-sponding by doing some outsourcing of their own in areas such as EDC solutions, translation services, and supply chain services.

One area that is seeing tremendous growth as a result of the globalized market is translation services for clinical trials. Translating in clinical trials, the complexity of which can be enormous, goes beyond simply language. For example, in India alone, there are 30 different dialects. Also, diversity among cultures adds to the complexity. As a result, translation services are fast becoming a functional outsourcing model.

Mark P. Wade, global practice leader, life sciences division at Lionbridge, a company that provides translation services, commented, “Thomson’s CenterWatch estimates that right now 30% of clinical trials are being conducted in ascending regions. That’s going to go through the roof. We are doing more and more trials in developing regions like India, China and parts of the Pacific Rim and the challenges in these regions are staggering.” These geographies require translators with a specialized education and specialized skill sets. “Once we find people with the right qualifications, we put them through exhaustive tests and it becomes a pyramid effect, as some don’t pass. As you move up the pyramid it’s more difficult to get a resource. That’s one of the challenges that face us today.” In other words, they spend a great deal of time and energy to find qualified translators. Is this something CROs and sponsors have time and resources for? Mr. Wade commented, “In five to 10 years, no one is going to get involved with translation in-house because you have to scale up and down so quickly. I think it’s going to be very much like IT outsourcing today.”

Another challenge with emerging global markets is coordinating day-to-day activities such as logistics. According to Scott Houlton, chief operating officer at Aptuit, “Getting clinical supplies to patients in some Asian countries is quite difficult. Transportation in India is a mess. Getting supplies imported into India and distributed to sites around the country, specifically if it’s a cold chain product, is challenging. Some countries in Latin America and Russia are notorious for their customs process, where getting product into the country can take weeks. These challenges drive CROs and sponsors to companies like Aptuit to facilitate the physical supply of product for their trials globally.”

EDC Scope

EDC use has grown exponentially in the last few years. Thomson CenterWatch estimates that EDC is now used in approximately 40% of clinical trials worldwide and by the end of 2007 it will reach 50%. EDC services are expanding beyond data capture to web-based solutions that can carry a trial through to regulatory submission. These end-to-end solutions cross traditional functional boundaries and have become quite appealing when cost and time savings are of the essence. Some recent examples of EDC investments include:

• OmniComm Systems signed 10 new EDC deals in 1Q2007, securing four studies from new customers and adding six more from existing clients.
• Phase Forward recently announced that Quintiles Transnational Corp. has signed a multi-year license agreement to extend its use of Phase Forward’s InForm EDC solution for clinical trials. InForm has been used in nearly 90% of all Quintiles EDC trials to date. The agreement also extends Quintiles’ use of Phase Forward’s Clintrial clinical data management system and Clintrace adverse event reporting product. What’s more is, Quintiles has been selected to use the InForm application by more than 65 customers in more than 240 trials, involving 140,000 patients and spanning 10,000 sites.

Graham Bunn, vice president of Global CRO Partnerships, for Medidata, provides a sneak peek at what lies ahead: “I foresee EDC systems morphing to take on more functionality within the clinical trial process. These systems will become more encompassing and integrated with CTMS, pharmacovigilance, randomization, project management and other key clinical trial functionality.” Currently, this information for a trial is in many different systems and so a lot of time is spent ensuring it’s the same in each system. “I’d like to see the day when we collect just one accurate, high quality set of data for each trial in just one database,” Mr. Bunn added.

Recent Offerings Trialstat Launches Partner Program for Mid-Sized CROs TrialStat Corp. has launched CROFirst, a new partner program designed to help mid-sized CROs grow their business using ClinicalAnalytics, the company’s on demand EDC solution. CROFirst helps partner CROs to quickly deploy ClinicalAnalytics 4.0, while also supporting activities for new business opportunities and revenue generation. As part of the program, partners have access to co-marketing, lead generation and professional service support: in particular, knowledge transfer to help ensure a fast and smooth deployment of ClinicalAnalytics (CA) to their projects, as well as reduce the overall IT validation burden. Senior executives of CROFirst partners will also be invited to participate on a CRO Advisory Board, which will help guide the program’s initiatives and provide input into the evolution of CA. CROFirst offers advantages such as: EDC On Demand, which eliminates the need for IT infrastructure and helps CROs to accelerate the implementation and management of clinical studies; Knowledge Transfer: TrialStat provides a thorough analysis of knowledge transfer and regulatory requirements for deploying CA, well in advance of deployment; Co-Marketing and Lead Generation: TrialStat works with partners to channel business referrals through joint marketing activities. Partners can also integrate CA into new business bids, expanding their service portfolio; Data Management Services: provides a full suite of data management services that supplement existing CRO services or that help to create new ones; Training and Certification: flexible training and certification using a variety of media, from face-to-face or through the web. Certified CROs can then sell and configure CA for their customers. * * * PharmaNet Releases PharmaSoft 2007 PharmaNet Development Group, Inc. released PharmaSoft 2007, which provides new data capture, monitoring, cleaning and management enhancements to its clinical trial data management software. PharmaSoft 2007 is based on a new platform architecture that helps improves system performance, supports multiple application environments and is independent of server operating systems. The software enhancements include improved scalability, a new edit-check validation tool, new copy/paste protocol configuration elements that allow for the rapid set-up of new studies, advanced search functionality to facilitate customized data mining and ad hoc queries and improved visibility of the clinical report form audit trail. The PharmaSoft suite of software tools provides a complete solution— capturing, verifying and managing the data—to help streamline entry and management of the large amount of data associated with clinical trials without using multiple tools or application environments. Features include: Clinical Data Management (CDM) and Clinical Trial Management System (CTMS) Integral Electronic Data Capture (EDC) Minimizes the need for training at clinical investigator sites, with easy to implement and an easy-to-follow structure Supports a wide variety of study organizations in addition to the traditional site, subject, visit, page structure Accommodates hybrid study environments 21CFR Part 11 compliance Scalable flexible architecture, tools for extensive coding and reporting, and extraneous data import capabilities Global multi-lingual helpdesk support * * * Medidata Announces Rave 5.6 Medidata Solutions introduced Medidata Rave 5.6, which incorporates broad, industrial-strength data management tools into its electronic data capture (EDC) platform. In addition to enhanced multiple language capabilities, scalability and ease-of-use, Rave 5.6 offers life science research sponsors performance improvements to clinical trial processes and new tools for streamlining enterprise-wide implementations. With Rave 5.6, the company has incorporated broad CDMS functionality into its EDC system allowing global clinical study teams to collaborate within a single system. As a result, sponsors are able to increase efficiency, reduce risk and scale to handle any size or phase study, according to the company. Rave 5.6 offers new features designed to help all members of the study team throughout the clinical research process. The following is a list of enhancements designed to improve efficiencies of the study build and life cycle management: Global Library – Speeds design of multiple studies through the reuse of previous studies or study elements, and allows for the secure and controlled establishment of standards libraries that can be leveraged across enterprise wide e-clinical deployments. Architect Loader – Allows for study designs to be edited, moved and stored offline. Amendment Manager Enhancements – manages mid-study changes with analysis tools to determine differences between study versions, and to efficiently deploy selected changes. CRF Attachments – Allows storage of images, documents or other digital files as part of study records with the same level of security and compliance as other clinical data. Local Lab Enhancements – Allows simple referencing of sponsor-chosen ranges for local laboratory results. Data Clarification Forms – Generates and tracks data clarification forms (DCF) for sponsors using Rave’s double data entry (DDE) capabilities. Report Localization – Extends multilingual capabilities to reports, providing the flexibility to present information in the user’s language of choice. * * * Octagon Offers New EDC Capabilities with Acquisition Octagon Research Solutions, Inc. has acquired Ninaza, an electronic data capture (EDC) company based in San Mateo, CA. Ninaza’s EDC technology is used by pharmaceutical companies and CROs in Phase I-IV clinical trials and will now be integrated into Octagon’s product suite to provide full “collection-to-submission” electronic capabilities. According to the company, the newly branded, ViewPoint FUSE technology solution will allow for process efficiency throughout the clinical data lifecycle by automating the collection of electronic clinical data together with process facilitation and visibility. Jim Walker, chairman and chief executive officer, stated, “We are working hard to provide transparent, cross-functional technologies and processes that facilitate the efficient management of electronic clinical data across the enterprise. In the coming months, Octagon will be unveiling a suite of packages originating from the ViewPoint platform that will enable clinical data management (CDM) and clinical trial management (CTM) capabilities. Providing CTM, CDM, EDC, and eSUB functionality will enable quality, cost and time improvements in the clinical research and development process.”   The web-based EDC technology offers complete data entry and validation as well as export of electronic clinical data according to the CDISC’s ODM (Operational Data Model) structure.

It’s pretty much the consensus in the industry that EDC makes it easier to follow GCPs and, with the recent progress of CDISC’s (Clinical Data Interchange Standards Consortium, Inc.) SDTM standard, we should see a dramatic uptake in EDC use. Also, industry experts feel that EDC will play a significant role in adaptive trial designs because of the need for reliable, real-time data.

According to Anne Wiles, senior vice president, Data Systems and Processes, AAIPharma, Inc., “EDC makes it easier for the investigator to comply with GCP requirements to ensure the accuracy, completeness, legibility and timeliness of data reported to the sponsor. It also helps in improving data quality since the data validation process tends to occur much more quickly.”

For CROs involved in adaptive trial designs, EDC will play a significant role. Some feel EDC demand will grow as these designs become more prevalent. Dr. Hubbard at ICON said, “The increasing pressures to bring new medicines to market quicker and at reduced costs is such that it is inevitable that new, more modern and innovative approaches such as adaptive designs will be fully implemented. As well as the obvious need to consult with biostatistical technical experts, the use of more advanced technologies available to CROs are enabling more complex adaptive trials to be undertaken. For example, to minimize the risk of inappropriate modifications being made following an interim analysis there is a need for reliable real-time data, reviewed by biostatistical experts. Consequently, one of the major impacts will be a greater demand for EDC, which ICON is already beginning to see.”

According to Mr. Bunn at Medidata, “EDC and adaptive trials go hand in hand. EDC provides the fastest way to obtain accurate information about clinical trial performance and this data forms the input into the adaptive trial design process. The greater volume and more accurate amount of data available for the adaptive trial review, the better the decisions that can be taken about the future direction for the clinical trial design. EDC helps increase the successful outcome of the adaptive trial design review.”

Michael Davies, Ph.D., Phase Forward’s director, sales and global CRO Partnerships, points out some of the major advances with EDC, “The most significant advances are two-fold. From a technology perspective, EDC solutions are expanding to include more data management capabilities such lab data management; IVR and patient reported data; ease of interoperability using Services Oriented Architecture (SOA) and web services development platforms; scalability through optimized Software as a Service (SaaS) offerings and tech transfer deployment and implementation of best practices. From an adoption perspective, 2006 was a very active year for many CROs, with many partnering and renewing partnerships with EDC vendors. CROs that have adopted new EDC technology or that have refocused their EDC partnerships now face a very short ramp up cycle given the ease of use and ease of deployment of the SaaS offerings and therefore, we anticipate the number of CRO awarded trials to grow substantially throughout 2007.”

Most EDC vendors both support and comply with CDISC standards and, with the FDA’s pending requirement of the SDTM standard, we can expect to see an increase in the uptake of EDC. “Getting a standard we can all build towards is really important. We feel the CDISC framework, for a wide variety of functionality that’s required for the conduct of clinical trials, is very important and will have a streamlining effect on clinical research — which is in everyone’s interest. As an IT company, as standards become adopted, it becomes easier to build a better product around that standard,” commented Jonathan Barker, chief executive officer of TrialStat.

Doug Peddicord, executive director, Association of Clinical Research Organizations (ACRO) commented, “CDISC is having an increasing impact on the EDC services being offered. The project has engaged all stakeholders — the pharmaceutical industry, CROs, academic researchers, the National Institutes of Health, and the FDA — which is precisely what a standard-setting organization must do to be effective. With all of these parties involved, researchers can increase their commitment and investment in EDC, and feel secure in knowing they can apply the same approach to each project.”

CDISC Advancement

With the multi-million dollar price tag for Pharma and billion-dollar price tag for Biopharma in bringing a new drug to market, streamlining the drug development process to become better, faster, and cheaper has captured the interest of not only the drug marketers, but also the FDA, and organizations such as CDISC. The efforts to improve time-to-market for safe and effective treatments at reduced costs, point out the necessity for industry wide standards.

SDTM, soon to be an FDA requirement, is the Study Data Tabulation Model for regulatory submission of case report tabulations (CRT) of clinical data. In addition to improving efficiency for clinical research by facilitating the design and conduct of clinical trials and improving CRO and sponsor communication, establishing and defining standards, such as SDTM, also improves efficiency with evaluating the safety and efficacy of investigational drug products in the review process.

“ICON has used the SDTM model in nearly 80 studies to date. Of these, 65 have been submitted to and accepted by FDA. With the recent changes in regulatory guidance, ICON anticipates a rapid acceleration in the use of SDTM, both for new studies as well as legacy mappings,” said Dr. Hubbard at ICON. “The advantages we have seen in the implementation and use of CDISC models have been economies from the re-use of a common standard, ease of review, pooling and mining of data, minimization of the need of further downstream mapping, and ease of interoperability and use with emerging industry-standard review tools.”

According to Frank Newby, chief operating officer at CDISC, “An increasing percentage of submissions to the FDA use SDTM and as time goes on, that percentage will increase. The FDA has stated that once the proposed regulation is implemented there will be a two-year phase-in period. When that period is over, all submissions will be required to use the SDTM model. Since we expect a decision from the FDA very soon, it’s probably going to be during the next three years.”

Expanding and adapting to market trends, the CRO industry represents more than just cost savings and speed to market; their services are proving to be an asset to drug development. With the emerging global market, increasing complexity of clinical trials, the numerous investigative sites and the regulatory environment, more and more resources are required to bring a drug to market. It’s been said that leveraging a CROs capabilities and expertise is a logical choice for drug developers but it is fast becoming a necessity. Also, with EDC solutions that are more comprehensive and efforts to harmonize the drug development process beginning to bear fruit, the industry holds much promise.

Kristin Brooks is associate editor at Contract Pharma. She can be reached at kbrooks@rodpub.com.