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International Clinical Trials

On Demand

Today’s clinical trials are more sophisticated than ever before. From large multinational studies to adaptive trial design and evolving technologies, the growing complexity of clinical trials has added a layer of difficulty to ensuring that the necessary supplies of patient kits are in the right place at the right time. Adaptive trial design, which enables mid-study modifications based upon accumulated data in particular, is growing in popularity. This study design holds the promise of smaller sample sizes, more efficient treatment process development, and an even greater likelihood of achieving the primary endpoint, but also creates challenges in clinical supply if the supply chain lacks flexibility.

For studies of all designs – adaptive ones in particular – it can be quite challenging logistically to ensure that each clinical site has the right quantity and type of clinical supplies needed to meet patient demand in a timely fashion, while balancing the risk of running out altogether or having excess inventory that eventually expires or otherwise goes to waste. Successfully achieving the right balance can be very important when study drugs are limited in supply, have a short use-by period or are very expensive.

Current Approaches

The traditional supply-led approach to clinical supply chains lacks flexibility, and is an ill-fit for studies where the supply demand is likely to be fluid. Just-in-time (JIT) models are much better suited to the challenges created by fluid demand and can ensure that clinical sites receive necessary supplies in a timely, but typically cost-inefficient manner. Next-generation approaches to clinical supply, such as demand-led models, can be used to address the added complexity found in today’s studies, and have the potential to achieve the ideal balance between timely supply and cost efficiency.

As study sponsors are under internal pressure to set studies up quickly, drive efficiency, quality and value – while simultaneously reducing risk – it is important for the right drug to be in the right place on time and on budget. In order to determine which approach to clinical supply is best suited for the challenges that are likely to be encountered by that particular clinical study, it is important to first understand the key components, advantages and disadvantages associated with the different supply models. There are three primary types of clinical supply models: supplyled; JIT; and demand-led, described below at the highest level. Variations on these approaches and combination or hybrid models may also be employed.

Supply-Led Model
The traditional or supply-led model, which has been used for several decades now, is a static, linear, stock-based approach. Discrete primary and secondary packaging runs for each protocol are performed in advance of the study start. Long lead times are necessary for packaging runs, and this process needs to start several weeks ahead of the projected study start date, with multi-country studies requiring booklet labels to introduce at least a degree of flexibility to the patient recruitment process. Booklet labels are costly to produce and need a long lead time, and the regulatory approval requirements for booklet labels are considerable.

Clinical estimates and forecasts are used to determine how long these packaging runs need to be, and how much inventory will be required. Each clinical site will receive a bulk shipment of individually numbered patient kits at the start of the study, and resupply shipments as required based on the clinical algorithm. Reforecasting may also be needed during the study to guide follow-up packaging runs and make site-volume adjustments. Because this model uses centralised inventory, a sizeable planned overage of 200% or more is built in even though much of it may eventually go to waste.

The supply-led approach is highly sensitive to variability in patient recruitment rates, and uses complex processes that lack flexibility and make inefficient use of resources. However, there are instances when the traditional supply-led model is the preferred choice. If a study has a large pool of available patients, and is expected to have a stable list of clinical sites and countries, then it can be the most cost-effective and efficient model. It is more likely to be suitable for early-phase trials where the protocol is simple, or for regional studies. Similarly, if the drugs – both investigational and any comparator or co-dosed products – are inexpensive or have longer expiry dates, then a supply-led approach may be appropriate.

JIT Model
A variant on the supply-led approach involves JIT labelling. This model is also structured as a static stock-based approach that uses discrete primary and secondary packaging runs by protocol to produce partially finished, base-labelled patient kits at a central location, which are moved to regional and local warehouses where they will await final labelling, release and distribution. The baselabelling contains basic regulatory compliance information such as storage conditions and route of administration.

Orders for finished patient kits are routed to the central inventory for processing via the study’s interactive response technology (IRT) system. The partially finished kits needed to fulfil the order are pulled from inventory, have the final preprinted label – with details such as protocol and the unique patient number applied – and are then inspected, released and shipped to the clinical site. JIT takes the same approach to initial and mid-study forecasting as the supply-led model.

The JIT approach is a positive step towards improving the flow of supplies to the clinical sites and reducing the amount of inventory that these sites must store and manage. However, changes to the kits are difficult to make, and high drug waste remains a problem. A JIT model may be appropriate if multiple studies are being run in parallel within the same region using the same kit types, where protocols are simple in design, if wide variability in patient recruitment is anticipated, or if the study drugs are expected to be in short supply.

Demand-Led Supply
This can provide a way around the lack of flexibility inherent in both the traditional supply-led and JIT models, because demand-led supply takes a dynamic approach to inventory management through the use of bright stock and delayed secondary packaging processing, which is conducted regionally instead of from a central location. Under this approach, the drug product first undergoes primary packaging at a central location, and is then sent to regional and local secondary packaging facilities situated much closer to the clinical sites involved in the study.

Importantly, the primary packaged bright stock bears a batch-lot barcode, which is scanned into a centralised inventory tracking system. Samples from each lot undergo necessary analysis and quality release immediately following primary packaging. This approach enables the movement of the bright stock to be tracked throughout the supply chain and, importantly, removes the need to later test samples of the finished patient kits and slow down the release process.

The bright stock will be split according to the ratio of forecasted demand for patients across regions, and sent to the appropriate regional Good Manufacturing Practice packaging facility. Bright stock can be pooled across protocols, eliminating the need for multiple packaging runs. Secondary packaging (kit assembly) and final, patient-specific labelling all take place within the regional packaging facilities once an order is received via the study’s IRT system. Barcode scans during secondary packaging verify that all elements have been assembled correctly in each package and update the centrally tracked inventory.

Similar to the JIT approach, patient kits are distributed to the clinical sites based on actual patient need, rather than bulk shipped in advance based on predicted demand as seen under the supply-led approach. Finished kits receive single-panel, country-specific labelling and are shipped directly to the clinical site from the packaging facility to arrive in a few days. The absence of a booklet label greatly reduces the lead time required for the secondary packaging process, and additional countries can be easily added at any point in the study. Furthermore, the latest possible expiry date can be applied to all patient kit items at the point of assembly into the finished kits. This facilitates the efficient use of stock, and eliminates the need for clinical sites to update expiry dates.

Is Demand-Led Supply the Solution?

A demand-led model may be appropriate when accelerating study start-up time is critical, significant variations in patient recruitment rates are anticipated, or if it would be useful to have the option of adding or removing clinical sites or countries from the study. It is also advantageous if reducing drug waste is essential to the overall feasibility of the study. Another scenario suitable for demand-led supply is for a trial with complex or multi-layered patient kits that are not suitable for a JIT approach.

The potential for both cost and time savings is also significant and can be estimated in advance to help study sponsors determine which supply model is best suited to their needs. The majority of these savings come from a reduction in the amount of both investigational medicine and comparator product required, and enable drug waste to be reduced from upwards of 200% or more to 20%. Clinical storage requirements are also minimised, and the need for expensive and time-consuming multilingual booklet labels is eliminated altogether.

The ability to achieve shorter timelines, improve supply chain flexibility and nimbly respond to mid-study changes are hallmarks of the demand-led approach and make them well suited to adaptive study designs and studies, where pooling of products is possible and recruitment rate changes in studies could be unpredictable. Earlier trial completion is an especially important consideration for studies investigating novel or first-in-class therapies. Hybrid solutions can be particularly useful for studies that include countries with challenging requirements, where the import licence process may make it difficult to bring in unlabelled bright stock. In this case, secondary packs can be assembled in another country alongside the demand-led packs being produced for local use.

Clearly, no single model is a perfect fit for every study, but the increased options provided by demand-led supply make it possible to create customised approaches that match individual trial requirements very closely. By applying the demand-led model wherever possible, significant savings in both time and money can be made, enabling earlier trial completion and accelerating a new drug’s time to market.

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Dr Paul Ingram is Global Director for Strategic Business Development at Catalent. His career has focused on Medical Device and Pharmaceutical Research and Development. Paul obtained his PhD in Pharmaceutical Development from Strathclyde University, Scotland, and has over 15 years of experience in clinical supplies, working both in Phase 1 units and trial supplies service companies including Quintiles (Aptuit), Fisher Clinical and Catalent.
Dr Paul Ingram
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