Managing the Global Clinical-Trial Material Supply Chain

Arise in the number of developmental compounds, greater complexity in clinical trials, and an expansion of clinical-trial sites globally are raising the bar in managing the clinical-trial-material (CTM) supply chain. Pharmaceutical companies and their suppliers must align product supply with demand at multiple sites in several countries with fluctuating patient-enrollment rates and greater complexity in dosing regimes while maintaining product quality and supply continuity. As a result, strategies that use best practices in drug modeling, simulation, packaging, labeling, logistics, and supply-chain management are of increasing importance.

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Greater complexity and global reach

Since 2000, the number of developmental drug compounds has increased as has the complexity of clinical trials. Approximately 2040 compounds were under development in 2001, and this number increased nearly 50% in 2010 to 3050 compounds, according to a recent report by the Pharmaceutical Research and Manufacturers of America (1). Between 2000–2003 and 2004–2007, the median number of procedures per clinical trial increased by 49% while the total work burden per protocol grew by 54% (1, 2). As complexity increases, so do eligibility criteria for volunteers, which lead to lower volunteer recruitment and retention rates. The average number of eligibility criteria for volunteers has increased by 58%, and volunteer enrollment and retention rates have declined by 21% and 30%, respectively (1, 2).

Concurrently, the number of clinical-trial sites outside the United States has increased. Eighty percent of FDA-approved marketing applications for drugs and biologics contained data from foreign clinical trials in fiscal year 2008, according to a 2010 report by the Office of Inspector General of the US Department of Health and Human Services (HHS) (3). More than half of clinical-trial subjects and sites were located outside the US (see Table I).

Table I: Number and percentage of foreign subjects and sites from clinical trials supporting drug and biologic marketing applications approved by FDA in fiscal year 2008.

Western Europe accounted for most foreign clinical-trial subjects and sites (approximately 60%). Central and South America had the highest average number of subjects per site, accounted for 26% of all subjects enrolled at foreign trial sites, and 7% of foreign sites. According to estimates cited by the HHS report, between 40% and 65% of clinical trials investigating FDA-regulated products are conducted outside of the US. A recent analysis of ClinicalTrials.gov, a National Institutes of Health registry and results database of federally and privately supported clinical trials, examined recruitment in industry-sponsored Phase III clinical trials and found that as of November 2007, one-third of the clinical trials of the 20 largest US-based pharmaceutical companies were conducted at foreign sites (3, 4).

Defining the challenges

As the number of clinical-trial sites expands on a global basis, several challenges arise in managing on-time CTM delivery. "The use of technology to track delivery and inventory is critical," says Frank Lis, vice-president and general manager of clinical-supply services with Catalent Pharma Solutions. "Because some studies involve many countries, investigators, and depots, you need tools to help track shipments and inventory."

Others agree. "A key factor is the management of a depot/site network," says Jim Curry, president and CEO of OpStat, a consultancy specializing in supply-chain management, lean manufacturing, and inventory management. "There needs to be accurate and timely management of inventory information from those involved in the clinical supply chain, including from third-party logistics providers." Managing CTM supply requires that information on CTM be created and maintained accurately. "Problems can arise in entering or omitting data in inventory systems or interactive web response systems (IWRS). IWRS collect and provide access to clinical-trial study data. "Such errors may, for example, relate to the number of patients in a trial at a given site, level of patient recruitment, the level of patient dispensing, or other entry errors that affect the dose requirements at a given site, which in turn, affect the CTM supply chain," says Curry.

When expanding the number of sites globally, additional challenges may arise. "Import and export permits are a challenge with some countries," says Lis. "You need to make sure all documentation is completed well in advance and that permission has been received to ship products into these countries." Once documentation and permission are received, the transport and storage of product, particularly temperature-sensitive ones in a cold chain, are crucial. "In some countries, transportation and storage of controlled-temperature products are difficult," says Lis. "Some of the investigators are not near major cities and have little experience with conducting studies and handling product."

Resolving the challenges

In addressing these challenges, experts offer various approaches to mitigate problems of on-time delivery and to align supply with demand at clinical sites. "Senior management must first have the vision to recognize the importance of the supply chain and to recognize that appropriate tools are needed to effectively manage the supply chain," says Curry. "Even for emerging pharmaceutical companies with few drugs entering Phase II and Phase III trials, the complexity grows fairly quickly in terms of levels of patient enrollment, the number of sites, various dosing schemes for a clinical product, and the related need to meet CTM supply requirements. A formal monthly demand and operations planning process that includes the supply-chain, clinical, manufacturing, quality, and R&D functions is important to synchronize the entire chain," he says.

Simulation and modeling. Effective modeling of study forecasts, along with dynamic inventory projections, to predict and modify CTM supply is key, says Curry. He identifies several best practices for effective CTM supply management:

• Perform modeling of clinical study forecasts before initiation and re-forecasts as clinical studies are started to determine the latest projections for all studies for a given molecule.

• Include study-design arms, site activation, and patient-recruitment levels in study forecasts.

• To determine supply requirements for some drugs, depending on the study design and disease, project patient time in a study, including deactivations (i.e., patients withdrawing from the trial) and extensions because both affect the amount of supply required.

• Construct and analyze study forecasts for all clinical studies back to API manufacturing.

• Implement protocols and practices to determine reasonableness of data and for detecting omission of data from clinical sites, which includes the ability to easily adjust for errors.

• Use capabilities for extensible markup language (XML) to make data available for electronic data-capture systems, IWRS, third-party logistics providers, and manufacturers.

• Have a four-year horizon for finance projections (i.e., assuming that most studies are approximately two years in length) for R&D. Although these projections may represent a major investment for large and small pharmaceutical companies, it is strategically important to have such information in place to predict CTM supply.

Curry offers an example of how such a simulation model works in practice. The simulation model is integrated with spreadsheet input and output capability to manage the flow of materials through all phases of the CTM supply chain. The manufacturing processes for APIs, drug product, packaged product, and patient kits are included in a synchronized flow. Inventory may be monitored at each point in the chain, and replenishment rules are established for each plant or work center involved.

Each contract or internal manufacturing site may be modeled to the level of detailed required. A high level model of the flow includes the capability to drill down to identify time slots when production will be required based on contracted lead times. When the model is run, graphics and metrics are available that may be selected as needed. For example, the timing of batches and lots in the production flow are displayed from drug substance to drug product to packaged products and kits. It also is possible to measure how long kitted product has been in the clinical-trial pipeline because each lot is time-stamped as it goes through each process. "Monitoring expiration dates for CTM supply is crucial as the administration of clinical trials may be delayed or adjusted based on clinical results," says Curry.

The demand for patient kits is based on the patient recruitment rate for the clinical-trial, and the usage is based on the study design for the trial. Usage is calculated based on the size of kits, which dictates how long a kit will last and when re-orders from patients will be required. In addition to the normal duration of the trial for each patient, the patient deactivation/extension rate also is factored into the model.

Cold-chain logistics. Managing the CTM supply chain when cold-chain requirements are involved requires additional knowledge, skill, and technology. Dan Gourley, director of global clinical logistics with Catalent Pharma Solutions, gave insight into the factors to consider by providing a cold-chain supply-management case study at a recent conference (5). The example he offered was a Phase III medicinal product, which was packaged in the US, but shipped to multiple countries and depots. In this particular example, the product was required to be maintained at temperatures from 2–8 °C. Large kit sizes required large shipping volumes, and active and passive shippers were used, depending on the application. An active system refers to a system that maintains temperature through battery-powered refrigeration. A passive system refers to a system that maintains temperature through the use of refrigerated and frozen gel combinations.

In developing the appropriate cold-chain logistics and supply-chain management of the product, Gourley noted several key areas to address:

• Security by protecting the product against damage, loss, or theft while en route or upon arrival

• Maintenance of cold-chain conditions in the air and on the ground

• Planning, adaptability, and contingency plans to ensure supply continuity

• Required documentation, including country-specific documentation

• Regulatory compliance to ensure correct valuation of material to decrease any risk of potential delays with countries' regulatory authority agencies

• Improvements in kit design to enable smaller, lighter, and cost-effective packaging

• Real-time assurance by using technology-enabling tracking of temperature and location.

In managing the CTM supply chain, both country-specific and clinical-site-specific requirements, which include potential depot needs, must be considered. Gourley emphasized that it is important to review the capabilities and capacity of depots receiving cold-chain materials. Issues to consider are country-specific restrictions, the capacity of the depot to store the supplies, and the type of shipment package that the depot can handle. Shipment packages can be active, passive, or phase-change. Phase-change shipments refer to reusable shipping systems.

He also emphasized the importance of reviewing country-specific regulations for import, such as import permits or licenses, special packaging and labeling requirements, and physical pack-out of materials. Custom valuation is another important factor to consider when shipping supplies. Custom-valuation methods typically for clinical supplies include four types: the transaction value; the transaction value of identical or similar merchandise (i.e., based on the transaction value of previously imported merchandise); deductive value (i.e., the selling price in the US less certain post-importation costs); and computed value (i.e., foreign-supplier cost information for materials, processing, profit, and general expenses). To mitigate risk with respect to custom valuations, Gourley stressed the importance of receiving input from the finance, procurement, and legal departments, documenting the method of calculation, having shipping documentation reviewed by a customs broker or consignee before shipping, and ensuring that all import license requirements have been completed.

In terms of shipping and transportation, key issues to consider are the estimated travel time to given countries, a review of the method of shipping (i.e., active, passive, phase-change), the type of transportation (i.e., air, ground, or ocean) that will be used, validation of the shipper, and evaluation of the devices used in temperature monitoring. With respect to shipper validation, shippers may fall into three categories: nonqualified (i.e., the shipper provides no documented testing to maintain temperature), prequalified (i.e., the shipper performs documented testing to a shipping standard, such as water), and validated (i.e., the shipper performs documented testing to a shipping standard with a given product). With respect to monitoring, he noted that as part of the packaging decision, it has to be determined whether temperature monitors should be used with all shipment or with some shipments. "All of these decisions affect cost and the quality of the product," says Gourley. "The higher the cost of the delivery system, in general, the more robust."

Another decision point is kit size, noted Gourley. Freight costs are calculated on either the physical weight of the materials or on the dimensional weight of the materials. Kit size will drive the shipping cost based on whichever of these two factors, physical weight or dimensional weight, is greater. Reduced kit size will reduce the cost of shipment.

In these packaging and shipping decisions, packaging software can be used to reduce the size of the kit and to match the best shipper for the intended application. "Before determining the final packaging configuration, however, you will need to know how most material will be shipped and what type of cold-chain packaging will be used," he says.

With respect to security, Gourley emphasized the need to know the capabilities and practices of the shipper to ensure their performance. Some key issues are whether the courier can screen materials, whether the courier has been audited, whether the courier works with the consignee to clear shipments, and how the materials are handled in the couriers' presence.

Looking forward

In the end, adaptability is key. "With the trend toward more complex clinical trials, the ability to remain flexible and rapidly adjust to changes in client demands has been a critical success factor for on-time delivery and receipt of clinical-trial materials," says Randall H. Guthrie, vice-president of Xcelience. He points to the value of project management, integrated supplier networks, and an understanding of regional differences from a regulatory standpoint to meet CTM requirements.

References

1. PhRMA, "Pharmaceutical Industry Profile 2011" (Washington DC, April 2011).

2. Tufts Center for the Study of Drug Development, "Rising Protocol Complexity, Execution Burden Varies Widely by Phase and TA" Impact Report 12, No. 3, May/June 2010.

3. HHS, "Challenges to FDA's Ability toMonitor and Inspect Foreign Clinical Trials" (Washington DC, June 2010).

4. S.W. Glickman et al., N. Engl. J. Med.360 (8), 816-823 (2009).

5. D. Gourley, presentation at the 9th Annual Cold Chain & Temperature Management Global Forum (Philadelphia, Sept. 2011).