Outsourcing Clinical Trial Materials

Supplying clinical trial materials (CTMs) is an important activity for contract research organizations (CROs), contract manufacturing organizations (CMOs), and other contract service providers. Several major CROs and CMOs are enhancing their CTM capabilities in an increasingly competitive market.

Patricia Van Arnum

Crunching the numbers

A review of recent data shows that the number of drug candidates entering preclinical and clinical development has increased during the past several years, but the rate of attrition of drug candidates has increased. The data are based on a representative sample of public and private companies with developmental pipelines in multiple countries and in multiple indications from an analysis by Life Science Analytics, a biomedical database company whose product is MedTRACK. The number of drug candidates entering preclinical development increased nearly 19% in 2007 compared with 2006, but increased only 10% in 2008 compared with 2007 to reach 2224 in 2008. The number of drugs entering Phase I development increased 22% in 2007 compared with 2006, but increased only 12% in 2008 compared with 2007 to reach 1668 in 2008.

This trend of slowing growth continues in the later stages of development. The number of drug candidates entering Phase II development increased 18% in 2007 compared with 2006, but increased approximately 14% in 2008 compared with 2007 to reach 2754 in 2008. And in 2007, the number of drug candidates entering Phase III development increased 16% compared with 2006, but increased only 9.6% in 2008 compared with 2007 to reach 1050 in 2008.

As a separate measure of clinical drug development, Figure 1 identifies the number of original new investigational drug applications received by the US Food and Drug Administration's Center for Drug Evaluation and Research between 2004 and 2008.

Figure 1

Shifting market dynamics

The level of drug candidates, however, is not a full representation of the dynamics shaping the CTM market. "As the paradigm of drug development is under increasing pressure to improve time to market and to make better decisions earlier in the process, it has become a much larger puzzle to extract the variability out of the process and align expectations for more efficient and reliable on-time delivery of clinical trials materials," says John Bucksath, senior vice-president and general manager of the pharmaceutical division of Analytical Bio-Chemistry Laboratories (Columbia, MO). "The cost of making and releasing CTMs as compared to missing a clinical timeline start cannot only be calculated in hard costs, but [through] the realization of the incurred costs that are associated with missing contracted clinical start dates."

The pressure to advance clinical development and the reliance on external partners is particularly important as small and emerging pharmaceutical companies face increased financial pressures and Big Pharma restructures. "Small and emerging pharmaceutical companies typically do not have in-house resources to perform many drug-development activities or to coordinate those activities with other service providers such as clinical sites or formulators," says Bucksath. "But with recent restructuring activity, this is becoming a greater concern for large pharma as well. Regardless of size, many sponsors have lost some of their senior talent; consequently, their expectations for contract research organizations are very high."

CROs and CMOs expand

During 2008 and 2009, several CROs and CMOs expanded or announced plans to enhance their CTM capabilities. Almac (Craigavon, Northern Ireland) is constructing a new approximately $100 million North American headquarters in Lower Salford, Pennsylvania, which is scheduled to be completed in 2010. When finished, a 166,600-ft² facility will house clinical supply warehousing and storage, packaging, shipping and receiving, and label-control areas. A second 75,000-ft² facility will house administration, communication, and a network-operations center. To accommodate growth until the new headquarters is completed, Almac added 6000 ft² of space at its Yardley, Pennsylvania, facility. It also increased capacity for specialist storage of controlled and refrigerated clinical supplies with the opening of an additional storage facility in Craigavon, Northern Ireland.

In 2008, Azopharma (Hollywood, FL) expanded its manufacturing capabilities at its Hollywood and Miramar, Florida, sites with the addition of 17 new manufacturing suites to increase its capabilities to develop and manufacture CTMs. The addition of the 17 suites brings the company's total to 29. The company also added new laboratory facilities and office space in Welwyn Garden City, United Kingdom, which provides analytical, QP release testing, preformulation, and formulation-development services to the European market. Also, in 2008, Azopharma's clinical pharmacology research facility, AvivoClin Clinical Services, expanded its clinical research management services to include clinical study development, protocol design, clinical monitoring, and data management. The company also added microdosing and central laboratory services to complement its human clinical pharmacology services.

In December 2008, Patheon (Research Triangle Park, NC) opened its new US headquarters and analytical laboratory facilities in the vicinity of Research Triangle Park, North Carolina, and a new pharmaceutical development laboratory to support its pharmaceutical development operations in Cincinnati, Ohio. In October 2008, Patheon opened a new pharmaceutical development services suite for manufacturing products for Phase I–II clinical trials at its facility in Whitby, Ontario, Canada. The expansion supports Patheon's Quick to Clinic program, which was launched in 2008, and is designed for rapid CTM distribution for first-time-in human (Phase I) studies. Patheon also opened a 13,500-ft² early-phase development facility for solid, semisolid, and oral liquid dosage forms in Milton Park, United Kingdom.

Patheon is using partnerships to advance its CTM capabilities. In November 2008, it signed a master-service agreement with the CRO Omnicare Clinical Research (King of Prussia, PA) for CTM distribution in Europe and the Asia–Pacific region. Omnicare is providing Patheon's customers with various clinical supply services that include monitoring, distribution, and return accountability. Also, in support of its Quick to Clinic program, Patheon formed a global alliance in 2008 with Solvias (Basel, Switzerland) for early-development services, including characterization of active pharmaceutical ingredients, salt selection and cocrystallization, polymorphism screening, solubility determination, excipient compatibility, and formulation.

In 2008, Bilcare Global Clinical Supplies (Phoenixville, PA) expanded its packaging operations and storage capacities at its facility Pune, Maharashtra, India, to allow for the manufacture, packaging, and distribution of CTMs through its in-house interactive voice response system. Other recent CTM investments include an expansion of its US operational capabilities with additional packaging rooms, new high-speed blistering technology, a large-scale bottling line, and a tripling of its ambient storage capacity. The company's US facility expanded preclinical and early-stage development capabilities to include upgraded granulation and capsule-filling technology and enhanced capacity for formulation and analytical-development services. Similar packaging technology upgrades took place at its UK facility. Bilcare strengthened its CTM distribution in Argentina, Brazil, Columbia, Chile, Mexico, Peru, Russia, and Eastern Europe by forming an agreement with World Courier, a specialty courier company with cold-chain expertise.

Piramal Healthcare (Mumbai) has made several investments to support its clinical-trial service capabilities. In August 2008, Piramal launched clinical trials supply capabilities from its Morpeth, United Kingdom, manufacturing site. The newly equipped facility offers primary packaging of solid-dosage forms, including multidose blistering and walleting. A reconfigurable suite of secondary packaging booths are set up for the labeling and assembly of various dosage forms, and distribution is also available. Expansion is in the future footprint through plans to double primary and secondary packaging capacities. The company also opened a 50,000-ft² solid-dose formulation-development and GMP (good manufacturing practices) CTM center in Ahmedabad, India, in December 2008. Scientists will work in two shift operations at the development center, which enables reduced project execution timelines and allows availability to customers in different time zones.

Catalent Pharma Solutions (Somerset, NJ) added a 1000-L bioreactor train in its Middleton, Wisconsin, facility to meet increased CTM demand. In October 2008, Catalent opened a 11,800-ft² temperature-controlled warehouse in Bolton, England, to meet demand for clinical supply services, especially cold-chain storage and distribution.

Last October, Aptuit (Greenwich, CT) launched a program to accelerate early-stage drug development. Aptuit INDiGO is a customizable program that offers an accelerated track from preclinical candidate selection to regulatory submission to support Phase I clinical trials. In January 2009, Irvine Pharmaceutical Services (Irvine, CA) launched Avrio Biopharmaceuticals to provide formulation development and aseptic fill–finish services for early-phase CTMs. And Analytical Bio-Chemistry Laboratories expanded into a new 90,000-ft² pharmaceutical development facility in Columbia, Missouri, which includes GMP development and analytical laboratories with 43,000 ft³ of stability storage. The company offers GMP radiolabelled materials for human studies and has expertise in impurity profiling and identification.

Global CRO expansions

The globalization of clinical trials is an important consideration for contract research organizations (CROs) that provide clinical management and related support. Since 2002, the number of active investigators regulated by the US Food and Drug Administration based outside the United States has increased 15% annually while the number of US-based investigators has declined by 5.5%. (1). Approximately one-third of the trials (157 of 509) are conducted solely outside the US, and a majority of study sites (13,521 of 24,206) are outside the US, based on a recent analysis of industry-sponsored Phase III clinical trials for the 20 largest US-based drug companies as of November 2007 (1). Another analysis shows significant growth in global trials, with Africa, the Middle East, Eastern Europe, and South America topping the list of regional expansion (2).

To keep pace, the major CROs are expanding into developing nations. In April 2009, PPD (Wilmington, NC) acquired AbCRO, a CRO operating in Central and Eastern Europe. The acquisition gives PPD entry into Romania, Bulgaria, Serbia, and Croatia. In October 2008, PPD acquired InnoPharm (Smolensk, Russia), a CRO providing Phase II–IV clinical trials support, data management, and biostatistics services in Eastern Europe. InnoPharm has offices in Moscow and St. Petersburg, Russia, and Kiev, Ukraine. PPD also opened an office in Istanbul, Turkey, in 2008. To meet demand in Southeast Asia, PPD is expanding its global central laboratory services in Singapore. It also formed a pact in 2008 with Peking Union Lawke Biomedical Development to expand its global central laboratory services in China.

In April 2009, Covance (Princeton, NJ) opened clinical-development offices in Santiago, Chile, and Lima, Peru, and expanded its Buenos Aires, Argentina office. In February 2009, Covance opened clinical development offices in Kiev; Bratislava, Slovakia; and Tel Aviv, Israel. Covance is planning to build a preclinical facility in China. The company had originally planned to build the facility as part of a joint venture with the CRO WuXi AppTec (Shanghai), but announced in September 2008 that it would no longer pursue the project jointly and would instead build its own preclinical facility in China.

In other CRO global expansions, Quintiles Transnational (Research Triangle Park, NC) is expanding with a new regional headquarters in Singapore, which is scheduled to be completed in the third quarter of 2009. It is also adding a Phase I clinical unit in Hyderabad, Andhra Pradesh, India, recently opened an office in Jakarta, Indonesia, and expanded offices in Manila, Taipei, Seoul, Kuala Lumpur, Bangkok, Sydney, and Hong Kong. Parexel (Boston) opened an office in November 2008 in Lima to provide regulatory-consulting and clinical-research capabilities. And in 2008, Charles River Laboratories (Wilmington, MA) opened a 60,000-ft² preclinical facility in Shanghai.

Patricia Van Arnum is a senior editor at Pharmaceutical Technology, 485 Route One South, Bldg F, First Floor, Iselin, NJ 08830 tel. 732.346.3072, pvanarnum@advanstar.com

References

1. S. Glickman et al., "Ethical and Scientific Implications of the Globalization of Clinical Research," N. Eng. J. Med. 360 (8), 816–823 (2009).

2. P. Van Arnum, "Globalizing Drug Development," Pharm. Technol. Sourcing and Management, Mar. 2008, PharmTech.com/ptsm, accessed May 12, 2009.