Need to know:
- Clinical trials are not immune from current supply chain issues, which makes just-in-time an intriguing approach, as it allows flexibility on how inventory is managed.
- Yet some sponsors have hesitations, such as the added expense, forecasting risks, and extra administrative work. There are also sponsors who may not actively reflect on their end-of-trial drug waste.
- Clinical Trials Arena spoke to experts who debunk some of these perceived issues, but also offer solutions to valid reservations.
The inventory management approach just-in-time (JIT), when used in clinical trials, allows flexibility in the supply chain in addition to reducing waste, which can cut costs. Yet, despite these advantages, some sponsors are yet to dive in.
“Everyone wants to be the first to be second,” says Calyx scientific eTech enabled services vice president Craig Mooney. “Some companies might not see the value as they don’t have the tools to measure how much waste there is in their clinical trials. Or some companies rationalise the waste due to imprecise forecasting of required clinical supplies.”
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JIT uptake is nascent. There have been pilot studies and proof-of-concept one-off instances of JIT use, but the industry is slow to evolve and has a desire to keep with the status quo that is familiar and comfortable, adds PCI Pharma global vice president of product development and commercialisation Justin Schroeder.
JIT in clinical trials means companies would only need to build a smaller stockpile of drugs at a time, instead of larger batches, as much as six months to multiple years’ worth of supply. JIT also allows last-minute labelling before the supply is sent to its destination. This is opposed to labelling and packaging far in advance, meaning supply is committed to a specific study, site, or country from the get-go.
Clinical trial sponsors’ reservations stem from concerns in navigating regulatory requirements, especially in multi-country trials. There is also the expense of having to steer the company’s clinical trial strategy to adopt a JIT approach. There are hesitations around potential operational issues, and a perception that JIT may only benefit certain study designs. And yet, JIT remains an intriguing option, especially with global supply chain challenges further exaggerated by current events.
Different just-in-time flavours in clinical trials
There are different flavours to JIT. Clinical trial sites that work on a drug development program with multiple trial protocols can put on appropriate labels once supply is used, Mooney says. Alternatively, a local or regional depot can apply the protocol label before it goes to the trial site, or the trial packaging facility adds the label when the drug is assigned to a country, he notes.
JIT is based on immediate demand, says BAP Pharma business development director Luigi Galuffo. As a result, labelling, packaging, and release need to happen quickly, with the drug shipped immediately to the site, he adds. But without JIT, especially for multi-country trials, an upfront purchase means labels may need multiple languages. A translation accuracy review is required, which often results in long lead times, Schroeder notes.
The biggest argument for JIT is reducing costs. In fact, it can reduce overage and drug waste around 50% on average, Galuffo says. With a traditional supply approach, if the trial recruits slower than expected, there is a risk of drug expiry, which leads to wastage, he explains.
If the sponsor has multiple trials of the same medication, a pooled stock can fulfil the needs of multiple studies rather than a fixed stock for each study, adds Calyx interactive response technology (IRT) technical solutions global head Sylvain Berthelot. In case of protocol changes and site additions to an ongoing study, the drug will not need to be relabelled, which makes JIT attractive, says a label management software expert.
There are cases where sponsors rely on sites to source drugs. For example, in open-label trials where the adjunct drug or a combo therapy is available in the market, says Myonex clinical trial packaging and distribution senior director Matt Voicheck. If these marketed drugs are restricted or hard to source, that can impact the trials, he adds. And JIT can potentially help solve this sourcing issue.
A reckoning on waste: a case for just-in-time
But for JIT to take off, there needs to be a reckoning on wastage in clinical trials, Mooney notes. “I often like to ask: ‘Is something a solution looking for a problem?’”
Some pharma companies do not seem to actively reflect on the amount of waste after a trial, Berthelot says. Most, if not all, large- and medium-sized pharma companies measure overage medication at the start of a trial. They could anticipate, as an example, 20% overage compared to expected needs. But it is not unusual for overage to be closer to 50–60% by the end of the trial, and this is not measured by sponsors, Berthelot notes.
While some pharma companies analyse drug waste at the end of a trial, they might not want to pay to fix it for future studies, Mooney adds. “If [waste] can be calculated into cost, and if the investment in JIT can offset that cost, this would be a clear argument for JIT,” he notes.
Despite the challenges, the tide may now be changing, especially for trials with expensive medicines such as biologics or when drug quantities are limited. Drugs with narrow expiry dates also support small batch manufacturing and purchasing, which makes JIT attractive, the label management expert says. Voicheck adds: “Trials can be cancelled or delayed, so the fewer products they have on hand, the better. What’s on the shelf is unmanipulated—the product can be reused or resold to a different trial.”
Regulations a perceived hold-up
Another limiting factor perceived by sponsors is regulatory requirements. “If you add a label—how hard could that be? But in fact, it is a GMP (Good Manufacturing Practice) act. It is also a process that needs to be controlled through SOPs (Standard Operating Procedure), and this needs to stand scrutiny especially if labelling occurs at the trial site,” Mooney adds. If the labelling occurs at the depot, it also becomes a logistic process.
As for multi-country trials, JIT may be more complex. There are local authorities that might not approve of JIT and that would mean a trial may need different distribution strategies for different countries, says Myonex clinical trial packaging and distribution vice president Markus Vogt. This adds more complexity on demand, supply logistics, and monitoring, he explains.
Galuffo notes that in Europe, the challenge of working with multiple regulatory bodies may be eased. Submission will be harmonised and routed through the new Clinical Trials Information System (CTIS). One potential issue is that this route requires more study details for submission. For example, more information on the trial sites is required, he says. On the flipside, the advantage is that there is more upfront preparation leading to easier operations later, which removes uncertainty, he adds.
There are ways to meet varied JIT regulatory expectations. The trial’s protocol number can be split, Mooney notes. The first few numbers can be specific to the drug development program, with the succeeding numbers relevant to a specific trial. Regulatory agencies can allow the development program to be pre-printed on the label and the latter added at a depot, country, or even site level, he explains.
Sponsors may have two protocol stickers attached to the same drug product, and the irrelevant sticker can be taken off at the trial site. That then leaves the details of the trial in which the medicine is eventually used, Berthelot says.
Expense misconceptions addressed
JIT is a fairly recent concept in drug development, despite longevity in other sectors. And so, preconceptions and hesitations may cause sponsors to shy away, says Almac just-in-time supply chain solutions manager Lyn McNeill.
Perhaps the most common misconception is that JIT is a more expensive method of assuring supply compared to ones a company is used to. JIT requires sponsors to run smaller operations more frequently, which many assume removes the economies of scale advantage, McNeill explains. However, it’s important to look at the bigger picture, because even though initial overheads of JIT may be higher, the scales soon tip back to JIT’s favour with eventual cost savings in waste reduction, shortened timelines, ability to pool supplies across multiple protocols, and lower investment for accountability and destruction, she notes.
Forecasting is critical for JIT. With only small batches of drugs purchased at a time, there is a need to predict how enrolment might look in a specific window of time, Voicheck says. “The question is how much risk is a sponsor willing to take in terms of buying a small amount of product. And some sponsors are not willing to take that risk.” But JIT allows for a quick reaction. Purchasing can be increased or adjusted according to enrolment speed, he added.
Switch from JIT to traditional model possible
Another is the perception that JIT is only suitable for small studies. But JIT can also benefit larger trials, McNeill notes. For example, JIT can be used at the start of a study where the demand can be unpredictable and location of patient population unclear, she says. Once enrolment has stabilised, operations can switch to a more traditional approach. The tipping point for a switch requires planning and early communication on expectations to ensure process alignment and smooth operations down the line, she adds.
A hybrid model featuring JIT and a traditional approach is also an option. This can be ideal in trials with multiple arms where some treatments are optimal for JIT in terms of price and drug availability, McNeill explains.
JIT may require more administrative effort. As an example, JIT needs a Qualified Person (QP) to review every label as it goes out, and that would be laborious to do one at a time, the label management expert says. One answer may be automation, where the QP can get an image of the label and approve it electronically, or the task can be outsourced to companies that provide QP, he adds.
Zooming out, JIT relies on a tightly controlled network of drug product and substance supply, packaging and labelling, product release, distribution, and storage. All this needs careful orchestration to be successful, Schroeder of PCI Pharma says. And if any link in the chain is compromised, delivery to the patient could potentially be disrupted, he adds. Schroeder notes his company aggressively fosters a culture of proactive communication and risk mitigation strategies, but also leverages available technologies.
Flexibility critical with current events
Current events further underscore the reality that there is a finite amount of available drug product. The Covid-19 pandemic exaggerated raw material shortages and supply chain issues. Ukraine and Russia were clinical trial hotspots until recently but, with recent events, sponsors may re-evaluate their clinical strategy and decide the drugs supplied to those countries would be better repurposed, Schroeder adds. Still, compassionate and ethical reasons are added factors for deciding.
Supply chain challenges argue for innovation. “You need to explore what options you have and not just assume you can’t do it. It is not unprecedented, and you can learn from others’ experience,” Mooney says.
McNeill adds, “The types of clinical trials brought to us are evolving—innovation doesn’t stand still. JIT may be able to provide a solution to future challenges that are yet to appear.”