The globalization of clinical trials and more complex protocols, which include adaptive designs and those for targeted therapies, have driven the need for new practices and strategies to reduce waste and inefficiencies in the clinical supply logistics area.
Managing global clinical trial supply logistics has become more difficult and unpredictable as clinical trials are conducted at larger numbers of investigative sites and countries worldwide.
The need to produce and distribute supplies to different global markets with a range of regulatory requirements and the growing number of high-cost biologics entering the R&D pipeline, which require special handling and temperature-controlled environments, have added operational and logistical challenges to the supply chain function. More complex protocols have also made it harder to forecast dosage and quantity of investigational product needed at sites. At the same time, clinical supply professionals face increasing pressure to shorten study start-up timelines and reduce costs.
In response to these challenges, clinical supply professionals have adopted more sophisticated technology to better predict when and where investigational drugs are needed and have devised strategies to mitigate risk when patient enrollment forecasts are either higher or lower than projected.
Significantly, as pressures on global clinical supply chain logistics have increased, there has been greater recognition of the importance of collaboration between clinical operations teams and those managing the drug supply at sponsor companies. In a major shift from the past, when clinical supply logistics weren’t considered until after the protocol was designed and participating countries chosen, the clinical supply function has become a strategic part of clinical development programs in many leading companies and plays a more active role in study planning, forecasting and developing approaches to minimize clinical supply cost and overage.
“Companies that understand the importance of close collaboration will be much more successful than those who don’t. Those who include their supply groups in early planning discussions will have clinical programs that inherently include those considerations as opposed to doing it as an afterthought,” said Luke Moyer, supply chain solutions manager at Almac Group.
Challenges to the supply chain
A key challenge for global clinical supply logics professionals in the current operating environment is reducing study drug waste and planning for minimum overage across studies. A new Tufts Center for the Study of Drug Development (CSDD) study, which gathered survey data and clinical study performance data from 15 companies, found that only two-thirds of all product shipped to sites was dispensed to patients. While waste varies by study, the authors said the finding was typical in the industry and some organizations report even higher rates of overage. A study conducted by Cenduit, which looked at 200 studies completed during the past two years, found that 62% of the material packaged and released was not used by patients. Producing overages of study drug impacts both cost and efficiency of supply, the study authors noted, and ultimately effects the success of a study.
A major source of drug waste is the inability to reliably predict patient enrollment. In the traditional clinical supply logistics model, clinical materials are sent to investigative sites before the study begins based on anticipated enrollment at each site to avoid supply shortfall. Yet enrollment predictions are typically inaccurate and almost half of sites either fail to enroll a single patient or under-enroll, according to the Tufts CSDD study, resulting in a surplus of patient medicine kits at sites. Studies with large numbers of participating sites or countries can experience higher overage rates due to greater uncertainty about which sites or regions will enroll patients. Competitive enrollment practices, which penalizes under-enrollers and offers financial bonuses to over-enrollers, also contribute to unpredictability about which sites will need study supplies at what time.
“We experience a lot of changes in the protocol and in the study assumptions during the startup phase, but more often even after the trial is ongoing. That makes it very difficult to define a supply strategy and estimate demand,” said Stefan Dürr, senior director of Project Management, Cenduit. “Getting reliable recruitment predictions is very difficult, which makes it difficult to plan and can lead to not enough drug being available if recruitment is higher than planned. That’s why most companies are fairly conservative and decided to produce more drug to have an extra buffer to reduce risk. This can lead to a lot of waste and high costs.”
Dealing with regulatory authorities in some countries and obtaining import licenses can cause waste and delays. Clinical supply executives reported facing the greatest challenges in Argentina, Russia, China, Columbia and India. Clinical materials are often sent in advance to regions or countries where regulations or customs requirements typically delay delivery and distribution timelines, yet if patient enrollment projections fall short in those areas, they are difficult to get back due to regulatory or import restrictions.
“We would use a local depot on a study because it may take a long time to ship to that particular country. We can move material into that country and after importation, that depot can quickly supply sites for ongoing need. But once you ship it to a depot, that material is committed to that region. If you overcommit drug supply, that could lead to waste. If you have central depots, such as a depot in the European Union that can ship to dozens of different countries, then that supply remains flexible,” said Almac Group’s Moyer.
Investigational drugs can also expire at the site or be damaged during distribution processes. Tufts CSDD found that out of 57 studies, there were 19 errors in shipping and handling and nine errors with site mishandling. The study authors noted that any clinical supply logistic error could cause a site to run out of drug supply and impact the study results.
New technologies and supply models adopted
Companies are implementing a variety of strategies that can improve supply chain planning and both identify and limit factors that contribute to waste.
Technologies used in clinical trial supply management have evolved in recent years and have become more sophisticated in their ability to forecast supply and the impact of factors such as enrollment, site productivity and country selection. Advanced forecasting methods and real-world demand simulations are used to better predict when and where clinical supplies will be needed, quickly assess trends and adjust supply operations. Organizations have also begun integrating systems—including enterprise resource planning (ERP) and interactive response technology (IRT)—to develop more accurate baseline assumptions.
Compared to a decade ago, IRT plays a larger role in various clinical supply processes, including drug ordering, randomization and expiry management. IRT systems have taken on new functionality and been integrated into other clinical systems, such as EDC or ePRO, which has increased inventory visibility and allowed for more efficient transport planning. Many sponsor companies have also standardized IRT requirements and established cross-functional governance teams to align processes within the organization and with vendors.
“Most of our larger clients have established IRT governance teams. We have seen many different approaches on how to implement teams and where they fit into the organization. With customers that have established such IRT teams, we work closely on process alignment, establishing IRT standards and we often are highly integrated with the internal and external systems they use in their studies,” said Cenduit’s Dürr.
Many organizations have adopted practices to integrate their supply chain into overall clinical strategy and promote collaboration between functions early in the clinical development program.
“Clinical supply and clinical operations should be strategically aligned in an efficient way with clear roles and responsibilities, and use integrated technology to manage study supply and data collection. Clinical supply is a unique function and can be sitting in many different places depending on each company’s structures and business. But no matter where they sit, the most important thing is to connect clinical operations and clinical supply,” said Richard Hsia, senior director, Clinical Trial Management, Sunovion Pharmaceuticals. “I advocate for a more proactive approach and applying advanced technology that allows for more information sharing and an emphasis on enhanced communication that is more efficient with better control for study quality.”
More flexible just-in-time labeling and demand-led supply models have emerged that can minimize the impact of changes in clinical supply strategy or forecasting during a clinical trial. Inventory can be stored in regional depots, which limits loss at individual sites, and distributed to sites quickly when needed. These late-stage customization models also allow for sharing of one product or package type across multiple sites, countries and studies.
“The clinical supply chain has traditionally used a ‘push’ model. We try to anticipate where these patients are going to be and we ‘push’ material to facilities or depots or clinical sites around the world, which is very wasteful if the sites or country don’t recruit. For the first time, we are now starting to see more of a ‘pull’ model and we are using technology to drive packaging and distribution of clinical materials based on demand, which is a fast, flexible approach with potential for better management of drug use,” said Christine Milligan, Ph.D., global director of Strategic Development Solutions at Catalent Pharma Solutions.
New supply chain technologies and models are being developed to support direct-to-patient models, which were once viewed as unrealistic due to quality and cost concerns. In one example, AmerisourceBergen has developed a small medical-grade refrigerator, called CubixxCT, which allows temperature-sensitive investigational products to be stored in a patient’s home or office, eliminating the need for frequent deliveries. The unit also provides remote temperature monitoring, inventory management and access control.
“People have known about direct-to-patient trials for a while and want to explore them. But the supply chain element has always been the challenge in making sure the quality is there,” said Sam Herbert, president of World Courier, an arm of AmerisourceBergen that specializes in global logistics for clinical trials. “We have seen a very high level of interest in pushing it forward as people have gotten comfortable with the quality side of things.”
Move toward patient-centered clinical medicine kit designs
Sponsor companies also have begun to ask the patient community for feedback about how clinical medicine kits could be designed in a less wasteful way that would help patients comply with the protocol and complete that study. Many companies include a feedback form for patients to evaluate the patient medicine kit at the end of a clinical trial and a few companies, including Catalent Pharma Solutions, have begun to conduct focus groups at the start of a trial to ask patients whether the study drug packaging would work for them.
Medicine kits that are physically difficult for patients to use or have confusing labels contribute to waste since they could cause patients to become discouraged about participating in the clinical trial and drop out or fail to comply with requirements. Study drug sent to sites for those patients is potentially wasted.
The Center for Information and Study on Clinical Research Participation (CISCRP) conducted an international study, commissioned by the International Society for Pharmaceutical Engineering (ISPE), that surveyed 1,425 patients about their experience with clinical trial materials and suggestions for improvement. More than half of respondents believed the design of the medicine kit helped them take their clinical trial medicine on schedule. Patients also indicated a desire for options to customize the packaging of clinical trial materials, such as the ability to choose whether to have child-resident caps on medicine bottles, and how they receive labeling information or reminders.
“Patients have a voice and an opinion on clinical materials we prepare for them to partake in clinical trials. That might seem obvious, but in the clinical materials world, until very recently, we never asked the end-users opinion,” said Catalent Pharma Solutions’ Milligan, who was team leader of CISCRP/ISPE project. “By not asking clinical sites and patients for their opinions we are not maximizing the potential to make the materials easy for the clinical sites to work with and ultimately make it easy for patients to take the medication.”
Companies are implementing a variety of practices and strategies to improve efficiencies and limit waste within the clinical supply logistics area. Yet a rise in the development of high-cost biologics, along with new clinical trial models including those for adaptive trials and targeted therapies, are driving an even greater need for upfront planning and integrating an organization’s supply chain into overall clinical strategy. In addition, the move toward the development of personalized medicine and direct-to-patient clinical trial models will require more innovative approaches to clinical supply chain models going forward.
Karyn Korieth has been covering the clinical trials industry for CenterWatch since 2003. Her 30-year journalism career includes work in local news, the healthcare industry and national magazines. Karyn holds a Master of Science degree from the Columbia University Graduate School of Journalism. Email firstname.lastname@example.org.
This article was reprinted from Volume 24, Issue 06, of The CenterWatch Monthly, an industry leading publication providing hard-hitting, authoritative business and financial coverage of the clinical research space. Subscribe >>