With Ishmael Qawiy and Jan Komrska, Pharmacists for the Research Division, Vital Strategies
The STREAM clinical trial is evaluating the efficacy, safety, and cost-effectiveness of an all-oral, bedaquiline-containing regimen for multidrug-resistant tuberculosis (TB). As trial Sponsor, it is paramount for Vital Strategies to ensure STREAM trial sites have an uninterrupted supply of a wide variety of clinical, laboratory and other products needed for the trial. Because the trial is being conducted at 13 sites globally, each with very different operating and regulatory environments, it has been essential for Vital Strategies to effectively manage multiple supply chains.
What are clinical trial supply chains and clinical trial supply chain management?
Clinical trial supply chains ensure that supplies needed to conduct a clinical trial are ordered, manufactured, transported, and paid for so that trial implementation is not disrupted. The process of designing, planning, executing, and monitoring supply chain activities in a timely and cost-effective manner is referred to as clinical trial supply chain management. The importance of uninterrupted supply and quality assurance of products for a clinical trial makes it essential to implement robust supply chain management.
Tell us a bit about supply chain management for STREAM.
In STREAM, we designed and manage multiple supply chains covering approximately 300 stock-keeping units (SKUs). Trial supplies include products ranging from medication, to test kits and laboratory equipment and testing material, to medical consumables, including gloves, gowns, masks and syringes, in addition to other tools needed by doctors and nurses to provide care. In all, the trial has shipped more than 25 tons of goods since late 2015.
The most important STREAM supply chain covered the 13 study medicines. These medicines were manufactured in seven countries in Europe and Asia and transported to a central depot in Singapore for repacking before being shipped to the trial’s regional depots and study sites. The essential nature and relatively short shelf-life of medicines drove decision-making regarding the strategy for this supply chain. Quality-assured suppliers were pre-qualified, and we pre-positioned sufficient quantities of trial medicines in regional depots to help address uncertainties in recruitment, manufacturer lead-times and regulatory approval timelines. Alternative local sources of clinical supplies closer to trial sites were identified and used, but only in exceptional circumstances (i.e., to ensure uninterrupted supply). We also operated separate supply chains for close to 250 different laboratory items sourced from suppliers in 10 countries.
Given the complexity of the trial’s supply chains, in addition to careful up-front planning, we incorporated regular monitoring of delivery lead times and stock levels as an essential component of our supply chain management strategy. Analyses of these data provided important performance benchmarks and enabled us to respond more quickly to delays and potential disruptions.
What are some of the challenges of clinical supply chain management?
The biggest challenge for a clinical supply chain is prevention of trial drug stockouts, which can result in treatment interruptions for participants. On the one hand, you need to accurately predict required quantities of medicines, while minimizing cost and waste. On the other, you need to do that without knowing exactly how many and when participants will be recruited to the trial and without knowing the weight of participants (which significantly affects quantities of medicines needed). Expiration dates – which, in STREAM, were often quite short – also need to be considered. This required us to develop a robust supply chain management strategy for STREAM, and to continuously monitor risks of disruption. The strategy we implemented for the trial relied on pre–positioning medicines at the regional depots of our partner – World Courier – for onward shipping to sites, regular monitoring of stock levels, and continuously reforecasting the trial’s needs based on the latest recruitment data to mitigate the risk of supply chain disruptions.
How does supply chain management affect clinical trial participants?
The most direct impact of supply chain management on trial participants relates to ensuring a continuous supply of quality-assured trial medicines.
STREAM trial participants take different combinations of up to 13 medicines during a 9-month treatment period, and our most important job is to ensure the trial never experiences a stockout of any drug for any patient. If we did, participants could develop drug resistance and be less likely to have a favorable outcome, study data could be incomplete or difficult to interpret, and participants – who must make frequent visits to health facilities to collect their medicines – could experience discomfort or be inconvenienced.
In addition to avoiding stockouts, we need to ensure that the trial medicines that reach the participant meet appropriate quality standards. Vital Strategies’ pharmacists followed rigorous processes to select quality-assured suppliers, with appropriate oversight of manufacturing processes. Because storage conditions during shipment and storage at depots could also impact the quality of medicines dispensed to participants, Vital Strategies’ pharmacists worked with supply chain partners to implement temperature-controlled environments throughout the supply chain – from the suppliers’ premises through to site pharmacies. Once dispensed to participants, packaging and labeling trial medicines in a language understood by participants was the final step taken to ensure the quality of drugs ultimately taken by participants.
How can a global crisis, like COVID-19, affect a clinical supply chain?
Supply chains for multi-country clinical trials like STREAM are very vulnerable to global crises, such as the COVID-19 pandemic. These vulnerabilities arise from pandemic responses, such as restrictions on movement of goods, interruptions to international and domestic cargo and passenger air traffic, restrictions on local movement of people resulting in loss of access to depots and delays in obtaining needed regulatory approvals, halts in production of key supplies, and restrictions on exports, among others. STREAM medical supplies are transported from suppliers by air and, therefore, disruptions to air traffic during the pandemic have affected supply chain functioning. Since the start of the pandemic, shipment times to Mongolia have increased five–fold from 12 to 60 days and shipment times to Uganda tripled from 5 to 15 days. Despite these disruptions, the built-in risk mitigation systems in STREAM supply chains have enabled the trial to avoid major stockouts and any treatment interruptions for STREAM participants.
What can be done to strengthen clinical supply chains to plan for unexpected events?
The COVID-19 pandemic has exposed the downside of the “lean” supply chains, a method meant to minimize waste and reduce costs and production time, that are the norm in today’s economy. While lean supply chains help ensure efficiency by reducing excess inventories, they are also vulnerable to disruption during any sudden change in supply or demand, and disruptions to transport systems. For clinical trials, pre-positioning significant volumes of supplies in closer proximity to trial sites can be helpful to cushion against disruptions – although, for trial medicines, relatively short shelf-lives are often a limiting factor. Identifying alternative sources of clinical supplies closer to trial sites is an alternative worth exploring, although quality of goods needs to be assured. This alternative would also require more upfront work and increase the complexity of a trial’s supply chains. A second way to address supply chain vulnerabilities is to implement rigorous monitoring of trial drug consumption, recruitment forecasts and participant treatment progress (i.e., number still in treatment) to assess whether adequate supplies are available at (and close to) trial sites based on the latest available information.
To read more about the STREAM trial, please visit www.treattb.org