There and back again

It’s hard to put into words how the world has changed over the past few months, but we’ve all felt it. The Covid-19 pandemic has changed how we work, how we shop, how we socialise, even whether or not we can go outside. The virus has closed borders and restricted movement, not to mention the horrendous human cost it continues to inflict.

All of that had an immediate impact on the pharmaceutical industry. As supply chains and clinical sites pivoted to deal with the immediate threat, sponsors had to make difficult decisions about whether or not to pause or delay ongoing and upcoming trials. In mid-March, Eli Lilly’s research became the first major casualty, and Bristol-Myers Squibb announced a more limited postponement of new trials and sites shortly after.

Between March and April, Evaluate Vantage identified 170 commercial trials suspended because of Covid-19. A GlobalData survey later revealed that 69.9% of disruptions between April and May 2020 were due to the suspension of enrolment, 17.3% due to slow enrolment and 12.8% due to delayed initiation. And those figures only hint at the supply chain disruptions.

For Kevin Crawford, head of clinical operations at Tenax Therapeutics, the pandemic will affect clinical supply for some time.

“It’s definitely had a huge impact on clinical trials already,” he says. “Anybody who needs to wear a pair of protective gloves can no longer do that while the supply of personal protective equipment is low. It puts enrolment into clinical trials on hold for everybody, because even if you are doing something as routine as a blood sample, without the proper equipment, it isn’t happening.”

Circular economy

Even before the outbreak, however, it was widely recognised that trials were increasingly difficult to successfully complete, largely as a result of mounting regulatory burdens, issues with recruitment and retention, and the growing trend towards multicentre studies across numerous locations.

The management of study supply chains has inevitably had to adapt too. One of the fastest-evolving components currently is drug reconciliation, which Crawford feels is shifting into “a new paradigm”. Knowing where a trial drug is, whether it has been used, when it’s due to expire and, ultimately, where it ends up has long been a critical part of a study. But understanding how your suppliers and investigational partners work is becoming more important.

“What I have found with our latest clinical trials is that we are working in concert with our investigators, instead of just trying to shove a drug accountability record down their throat,” Crawford explains. “If they have a way of doing reconciliation that fits our purpose, we can bend to that method and not just tell them ‘this is the way we’ve always done it’.” It’s all about using the considerable knowledge that’s already there, he believes, meaning collaboration and relationships are key.

On the right track

Tracking the movement and use of a study drug is vital. This begins at the manufacturing stage, going right along the chain to their use by subjects. Even if those trial therapeutics aren’t used, they still need to be monitored. Crawford says that the mantra “what goes out must come back” organises the whole system. In order to live up to it, he recommends picking vendors with the right tracking and tracing capabilities from the very beginning.

“Working with a vendor that has the capability to provide a sponsor with transparency into its system and visibility into how these things are being tracked and traced is good,” says Crawford. He also notes that asking vendors specific questions about their best practices for clinical trial sites and what works best for them, are helpful guides for setting up the most effective collaborations. Trying to make good at the end, when regulatory authorities want to see the paper trail, could be catastrophic otherwise.

Crawford believes the issue of how sponsors are monitoring their vendors has grown in prominence more recently with monitoring plans changing to reflect this. However, he urges caution, suggesting the plan needs to be “sensible”, and not something that will overburden the trial and those involved.

Another crucial piece of advice from Crawford concerns balancing understanding and trust of investigational sites, with ensuring their work is properly overseen. Today, institutions have wellestablished processes and mechanisms in place, but building a strong working relationship is, nonetheless, still critical.

According to Crawford, “One of the things that we found very helpful is, during our initiation visit, when we went out and talked to [people at] our investigational sites for the first time, we would ask that the pharmacist be there so we could talk to them and create that relationship.” This has its obvious benefits, providing pharmacists the opportunity to ask questions directly and head off possible issues. “We didn’t have to go through multiple layers of communication,” he says. “Those people were allowed to meet and talk directly to us.” It’s his belief that these relationships can form the backbone of compliance. “No person is an island. We’re kind of a web of interconnected communication; my team does not necessarily just consist of me.”

Tech to trial

Technology is playing an increasingly vital role in tracking trial therapeutics, with data and analytics set to reshape the reconciliation process in the not-toodistant future. “We’re still in a phase of using pen and paper,” sighs Crawford. “But it will evolve into using greater data analytics to better ensure our reconciliation and drug shipments across the entire clinical study.” Although there are already what Crawford describes as “semi-intelligent” technologies used, data and AI will be critical in future trials.

Crawford also believes the sector is growing increasingly interested in utilising blockchain to remedy some of the issues the trial supply chain faces. “Using blockchain technology to understand where a drug is across the globe has potential,” he notes. “If any of the chain is broken – your clinical supply in material for example – you can be notified immediately.” For its part, the FDA has started to investigate how blockchain technologies and AI might impact clinical studies, an area Crawford feels will continue to expand.

Eventually, Crawford believes the benefits of using these technologies in trials will speak for themselves. “I know that in our studies there’s plenty of drugs I’ve sent to sites that will never get used,” he admits. “That’s just cost. It’s shipping, it’s the cost of manufacturing packaging, labelling and then somebody handling it on the other end.”

Like any industry, drug development rarely stands still, and the management of clinical trials is continually evolving and dynamic. Changes are frequent and so too are the challenges they present. As desperate as the global pandemic is right now, Crawford believes there could be some positives to come from it. He says that while there has been much good done by the healthcare and pharmaceutical communities, recent months have highlighted areas that can be improved – particularly in the area of communication. “I think that this is going to push a lot of us to more telemedicine, and strengthening our online footprints to hedge against something where human contact is not reasonable,” he says.

The reality in the clinical trial environment is that as soon as one concern or burden is mitigated, another is just around the corner.

Likening it to fixing a leaking dam just for another leak to appear, Crawford says there are always going to be challenges, but the fact is “a drug needs to move from A to B and back again”. As the world around us changes, there are some things that remain constant: what goes out must come back in.

Key recommendations for managing drug return and destruction

• Keep transit points to a minimum. If possible, have intellectual property moved from the site directly back to the destruction vendor. The fewer hands that are involved, the less convoluted the process could be.
• Sponsors must be sure to use a vendor that uses a secure on-site reconciliation process to avoid future queries, such as missing or lost packages.
• Assess packaging and site-supply strategies to avoid stock overload at investigator sites.
• Monitor stability data to avoid expired stock at site. Minimise the amount of returns if collecting stability data is to be continued.
• Prepare a trusted ‘cradle to grave’ reconciliation method from the start of a study. This will enable destruction as fast as possible.

Source: Clinical Trials Arena

Global guidance on drug accountability for trials disrupted by Covid-19

MHRA

If Covid-19-related issues affect the ability of the investigator or institution to perform IMP accountability, then a risk assessment needs to be undertaken. If accountability is not critical, then the drug can be destroyed instead of being returned to minimise exposure to the virus. The sponsor should be involved in this decision.

If accountability is important, the sponsor should consider whether there are other ways this can be achieved while mitigating risks to virus exposure. For example, asking the participants to make a count or submit a photograph.

If the reconciliation is critical and needs to be done by the site or sponsor staff, then this would need to be handled appropriately. A risk-based approach should be taken when conducting in an environment specialised for this or put in quarantine, so that any virus contained on packaging would no longer be viable.

If additional resources are required to manage potentially contaminated IMPs, then this should be managed by the sponsor. For example, the sponsor may make arrangements for collection and management of returns under these circumstances.

Source: MHRA

EMA

When trials shift to a direct-to-patient model, procedures for the accountability of the IMP must be in place (among others for compliance monitoring). Accountability of the IMP should be maintained. Clear records of shipment from the trial site or from the distributor should be kept in the investigator site file, itemising the medication being delivered and the quantities involved. Documentation of receipt by the trial participant should be kept. Participants should retain unused IMP and containers, and return them to the investigator when the investigator site is next visited.

Source: EMA

FDA

If scheduled visits at clinical sites will be significantly impacted, certain investigational products, such as those that are typically distributed for self-administration, may be amenable to alternative, secure delivery methods. For other investigational products that are normally administered in a healthcare setting, consulting FDA review divisions on plans for alternative administration (for example, home nursing or alternative sites by trained but non-study personnel) is recommended. In all cases, existing regulatory requirements for maintaining investigational product accountability remain, and should be addressed and documented.

Source: FDA