Necessity Drives Just-in-Time Approaches to Clinical Trials Supply

SCOTT CORNELL - STOCK.ADOBE.COM

Like many business practices brought to the world by Japan in the 1980s, just in time (JIT) brought agility to many industries. For pharma, however, the term often triggers fear and loathing, given chronic and ongoing shortages of comparator drugs and investigational medicinal products (IMPs).

Since the COVID-19 pandemic began, however, more companies have been embracing JIT for clinical trial supply and distribution operations. Both the unique challenges posed by the pandemic and the European Union’s new Annex VI clinical trial labeling regulations have been driving this change. In the past, labels were only required on secondary packaging; however, the new regulation will require labels on both secondary and primary packaging (i.e., the vials, blisters, and metered dose inhalers containing the therapeutic), explains consultant Steven A. Jacobs, president of Global BioPharm Solutions.

Under the regulations, if new stability test data dictate the need to update a label for primary packaging, patient kits will need to be opened, which would be considered a manufacturing process requiring certification by a qualified person (QP), Jacobs explains. However, pharmaceutical QPs are not at clinical sites, so this impasse could potentially affect product quality and supply.

Meanwhile, pandemic-driven changes in clinical trial design, including greater use of pooled trials and direct-to-patient (DTP) distribution, have piqued interest in JIT. “Companies are shifting to smaller packaging runs and pooling supplies to get supply chains running as efficiently as possible,” Jacobs says.

Where, for some,JIT may conjure images of slashing inventories of urgently needed medications, in clinical trial operations, it signals the move to a less wasteful distribution model. Under the old “push” model, an innovator would announce that it was enrolling patients for trials at, say, 100 sites, and supplies would be sent to all of those sites, Jacobs explains. In the end, however, the Pareto principle would usually rule, and 20% of sites would end up enrolling 80% of the patients. “These days, especially with oncology trials and comparator drugs that cost millions of dollars, we can’t have materials sitting in depots or on sites and not being used. These are all key factors that continue to make JIT extremely advantageous,” he says.

With JIT, distribution is based on a “pull” approach. A master document is created in advance, and all packaging and labeling is standardized so that it can be made on demand before being shipped to the clinical site or patient’s home. The economic motivation for JIT is compelling. According to Frost and Sullivan, one third of global clinical trials were disrupted in 2020, affecting some $3 billion in new product revenue (1). Benefits of a “pull” approach include a 75% reduction in overall clinical trial timeframes and reduction in waste and rework, according to Natalie Balanovsky, JIT Solutions Manager at Almac Clinical Services (2). This is especially important in an environment in which each day of delay in a clinical trial costs $37,000 and between $600,000 and $8 million in lost opportunities (3). Research has shown that 85% of all clinical trials experience some kind of delay, 94% of them for a month or more (4).

On the logistics side, Marken has been applying pull concepts to maximize the flexibility of its clinical trial sourcing, increasing the number of supply options available to clients, according to Nina Vas, vice-president of clinical distribution for cell and gene therapies, who discussed trends in a February 2021 webcast (5). For direct-to-patient distribution, which has become much more important during the COVID-19 pandemic, the company relies on strategically placed regional and global networks of depots throughout the world.

Despite its benefits, JIT cannot work without early collaboration, communication, and planning. For one thing, Jacobs says, it’s crucial that all packaging to be used in any clinical trial be in the same configuration. He recalls one clinical trial that started with2-mL vials but then switched to 2-R vials. Even though the two types of vial are similar and R vials offer some improved capabilities, changing midstream added significant complexity because placebo vials had to be manufactured to match the new vials. “There are so many different configurations for drug delivery that it can be difficult to do JIT without standardizing. We need to get everyone to agree, early on, on what packaging will be used; how we get the new drug to the patient; and how patients will take the treatment once they receive it,” Jacobs says. Once agreement is there, he says, JIT principles can be applied to any operation from filling to labeling and kitting.

Early risk-assessment needed

Risk assessment needs to be conducted as soon as possible in the planning stages, says Jacobs, which is much easier said than done when a company is under pressure to meet the types of clinical targets that have been set during the COVID-19 pandemic. He suggests following the principles outlined in the International Council for Harmonization’s (ICH’s) Q9 guidance on risk-based quality management and assessment (6), and gathering all stakeholder groups together for a brainstorming session to ask: What’s the worst that can happen; how likely is it to happen; and what can we put in place to prevent it from happening, or to mitigate the risk?

For the contract development and manufacturing organization (CDMO), Catalent, risk assessment and mitigation has been crucial to ongoing trial successes, says Stephanie Graham, director of clinical supply management. For ongoing studies, she says, the primary focus has been on whether it is safe for patients to continue to visit sites, especially those who might be at greater risk if they contract COVID-19. She also notes the importance of determining whether the frequency of planned visits is necessary.

Challenges drive innovation

Clearly, it became extremely difficult to conduct clinical trials after the pandemic’s impacts were first felt in the second quarter of 2020. The combination of uncertain patient visit scheduling and transportation disruption forced sponsors and their contract partners to perform a delicate balancing act: preventing supply wastage while ensuring that enough buffer supply was available in case of shipment delays or country lockdowns, says Graham. For trials that were still recruiting patients, enrollment slowed, driving the need for specialized packaging campaigns to extend the shelf-life of IMPs, she says.

Sponsors had to make hard decisions about which studies should continue and which should be delayed or canceled altogether. “For those studies that can progress, we have jointly had to answer how, why, and with what changes. Sometimes it has been necessary to explore alternative strategies, such as using decentralized trial designs to reduce risk and maintain continuity,” Graham says.

Raw material availability also posed problems, resulting in the need to manage shipment delays caused by disruption in raw material production or transportation disruption for normal routes, explains Mathias Dassel, storage and distribution manager for Catalent, based in Germany. “Distribution of pharmaceutical supplies could take longer than expected, and transportation costs may increase for high-risk regions when import/export restrictions are introduced because of the pandemic. In such cases, it has become extremely important to manage supplier and courier relationships effectively,” he says.

At the height of the COVID-19 pandemic in 2020, the number of daily commercial flights—which are used to ship 70% of the medicines used in clinical trials—was reduced to 10–15% of its pre-pandemic levels, says Jacobs. Fulfilling orders required more time, he says, typically two to four weeks, instead of the two-to-four-day pre-COVID norm. Some companies even booked chartered flights at a cost of over $100,000 each time, to ship their medications, Jacobs says. “We’re now at 25–30% of where [commercial] flights were before COVID-19, but gaining global acceptance for DTP was an amazing achievement,” he adds.

Focus on ongoing trials

Sponsors and contract partners first began to see a major increase in delayed patient visits in China, from January through April 2020, says Sylvain Berthelot, global head of IRT (interactive response technology) and electronic data capture (EDC) solutions for Calyx. His company, an e-clinical and regulatory solutions provider, was spun off by Parexel and became an independent firm in January 2021. “In Italy and Spain, for example, we didn’t see the same number of delayed visits in the Spring of 2020, despite lockdowns, because sponsors focused efforts on ensuring that patients were supplied with medications directly,” Berthelot says.

Changes in trial methodology, in the context of the unfolding COVID-19 pandemic, also had a major impact on clinical trial operations. With some clinical testing being done in parallel, Berthelot says, sponsors were using more master protocols, which allow different compounds to be tested on the same group of patients or vice versa. “These protocols enable more program-level supply management, which reduces drug wastage, but make managing medications more complex, both for sponsors and for IRT systems, [used to manage clinical trial patients and supplies]” he says.

Increased acceptance for DTP

In the end, one of the most dramatic changes that occurred in clinical trials supplies and distribution during the pandemic was higher acceptance and demand for DTP shipments. The DTP model eliminates a major problem with clinical trials: getting patients on site consistently, without attrition, says Jacobs.

For years, many in the industry had discussed decentralizing trials, and regulators such as FDA and the European Medicines Agency supported the idea. The model was accepted in the United States, yet the pace of its adoption around the world was slow before the pandemic, says Jacobs. After the COVID-19 pandemic began, however, countries such as Italy and Russia, that were originally very resistant to the DTP concept turned around. Out of 195 countries, the number of those permitting DTP shipments doubled, to over 90 in 2020, he says. “This was amazing to see, and on the clinical operations side, we are all supporting this trend to make sure that we don’t go back to the old ways,” Jacobs adds.

Another achievement was increased acceptance of JIT and on-demand packaging, and more use of planning, forecasting, and simulation tools, says Jacobs.

For both sponsors and contract partners, flexibility has become key, as have proactive and clear communication and collaboration, Graham comments. Where possible, she says, DTP services can limit the need for patients to visit drug dispensing sites, allowing DTP and site-to-patient distribution strategies. For new trials, building such supply strategies within the protocol, the randomization and trial supply management, and the IRT design allow flexibility to minimize risk in the future, she says.

However, that flexibility should have some limits, Graham says. “Some sponsors are providing patients’ full treatment supply at the first visit. Although this approach can work, it is not optimal for an investigational product with a limited shelf life, or one that requires temperature monitoring. It is up to CDMOs and clinical supplies managers to work collaboratively with customers to determine the optimal solutions that work best for patients, sites, and the sponsor,” she adds

Since the start of the pandemic, Graham has seen more sponsors use adaptive designs in clinical trials. In addition, she remarks, many are exploring ways to provide healthcare remotely through DTP or site-to-patient distribution strategies of the clinical trial material/investigational drugs. For biologic drugs, she also sees greater use of autoinjectors for non-COVID-19 therapies, and IRTs built to handle the additional functionality required. In terms of small-scale manufacturing, Graham says, Catalent has developed manufacturing processes that permit switching to different batch sizes using the same manufacturing lines to meet the challenge to scale production up or down quickly.

Breaking down silos

For a risk-averse and often siloed industry, pharma made great progress in removing the barriers that can separate different stakeholders in clinical trials management and operation. In a typical scenario, Jacobs says, clinical operations used to be in one area, and chemistry, manufacturing, and control in another, with the clinical supply chain department functioning as the bridge to success. During the pandemic, says Berthelot, “vendors and sponsors are functioning more as part of a single team.”

That all this change could take place during a time when people didn’t meet face to face is significant, Jacobs says. “Before the pandemic, one could hear ‘weak signals’ of developing problems, just by overhearing snippets of conversation in the hallway or cafeteria. This gave teams more time to plan remediation. You can’t do that on Zoom,” he notes. There is also more acceptance of the concept of clinical operations as a work in progress, and an understanding that procedures may have to change. “A few years back, sponsors used to wait until they had the perfect protocol before starting a trial. Now they’ll start recruiting for a trial that they know that they will have to change,” Berthelot says.

On the technical side, better integration between IRT and EDC has seen substantial improvement, reducing errors and the need for data reconciliation between the two systems, and enabling more automation, says Berthelot.

In the future, he sees technology playing a more important role. “Real-world data are already becoming incorporated into more clinical trial designs. Use of machine learning will improve patient recruitment and site selection, and, from the supply chain perspective, will help reduce drug wastage and better identify risks that could have an impact on the supply chain,” he says.

References

1. Frost and Sullivan, Post-Pandemic Global Healthcare Market Outlook,2020.
2. Almac, “Practical Application of JIT manufacturing in Clinical Operations,” an Almac webcast, August 19, 2000
3. O. Johnson, “An Evidence-based Approach to Conducting Clinical Trial Feasibility,” Clin. Investment (London) (2015).
4. A. Grignolo, “Managing Continuity in Clinical Trials in the Covid-19 Environment,” parexel.com, May 20, 2020.
5. Marken, “Decentralized Trials: How to Develop a Flexible Supply Chain,” xtalks.com, Feb 2, 2021.
6. EMA,“ICH Guidance on Quality Risk Management,” ema.europa.eu, September 2015.

Article details

Pharmaceutical Technology
Vol. 45, No. 3
March 2021
Pages: 58-62

Citation

When citing this article, please refer to it as A. Shanley, “Necessity Drives Just-in-Time Approaches to Clinical Trials Supply," Pharmaceutical Technology 45 (3) 2021.