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International Clinical Trials
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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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