The right temperature

Henk Dieteren remembers the days when retrieving a patient’s medication during a clinical trial meant phoning a system to ask for their kit number. Then, it would be located and retrieved from a shelf in a similar fashion to sourcing a book in a library. This was an early iteration of interactive response technology (IRT), which today mostly uses cloud-based software to manage the patient randomisation and drug management aspects of a clinical trial – of which temperature control is a crucial element. With IRT, temperature excursions can be monitored more closely, and necessary actions can be taken faster, or even automatically. For example, an IRT could upload a drug’s temperature data to a system for review so that it can be instantly released or quarantined, depending on the reading.

But just as with cars, says industry expert and clinical supply chain consultant Dieteren, some models are better than others. Many of today’s IRT systems do include elements of temperature management, but there’s still a way to go in making these as effective as possible. For example, adds Dieteren, it is not yet industry standard for temperature control to be automated. “There’s still a lot of pharma companies that have a manual process in place.” For sponsors and trial managers, then, tapping into IRT’s potential could mean more efficient excursion control – and, therefore, a smoother and safer trial.

More efficient trials

Jan Pieter Kappelle is senior supply chain strategist and advisor to the Bio Supply Management Alliance (BSMA), and he stresses the importance of monitoring for risky fluctuations in temperature. “At all stages where the clinical drug is either put in inventory or moving from location to location, there’s an expectation that temperature controls are in place,” he says. IRT can be used to instantly monitor drug temperature at each of these touchpoints, and for quick communication between the necessary staff if there has been an excursion. This can hugely speed up the process of either releasing or quarantining a drug.

Typically, a temperature monitoring device is included within the drug shipment that can vary in complexity. Many have constant measuring capabilities and can produce a PDF file, which is then uploaded into the IRT system, Kappelle explains. “The IRT system becomes the system of record with respect to the temperature monitoring information.” If there has been an excursion, the IRT system can set the necessary actions in motion, says senior analyst for UAT and validation and clinical IRT Tom Schiavon, who is currently advising global biopharmaceutical company Bristol-Myers Squibb. “The [IRT] will automatically quarantine the drug, send an alert to the person responsible to review the data, and then allow it to be released for use or damaged. If damaged, typically IRT will automatically trigger a replacement shipment.”

While this certainly boosts efficiency, Kappelle notes that the industry standard is mostly passive monitoring, which means there is one standalone device measuring temperature that gives a singular output once that job is done. “I see a trend into a more real-time, dynamic kind of temperature monitoring,” he says. “Because the cost of medication is increasing, and so you really cannot afford any kind of loss of product financially.” Monitoring is also traditionally done on shipments rather than on individual units. As the industry moves towards more complex drugs and personalised medicine, robust tracking on individual units is going to be increasingly necessary, says Dieteren. “If you look at oncology treatment, where you need to take blood samples and then go to a manufacturing facility which makes an IMP to treat that same patient, you really need to ensure that you get that IMP back. This is really, really specific, and our IRT system needs to serve that complexity.”

Enabling direct-to-patient trials

Being able to accurately track the temperature of individual units creates new opportunities for direct-to- patient (DTP) trials, too, says Kappelle – although there are still a few kinks in that process to iron out.

Typically, a shipment will be sent to the patient from the hospital via a specialty courier, that will likely have a passive temperature logging device in the box. When the package has been delivered, the courier needs to open it and take out the device, stop it, and bring it back to the office to determine whether there was an excursion. “That’s kind of weird for two reasons,” says Kappelle. “One, I wouldn’t like the courier in front of me to open up my package and take something out. And the second thing is that, for a couple of hours, I don’t know if the product is good to use or not.”

Real-time temperature monitoring here could instead give insight on the product’s condition at any moment, say via an app, which removes the need to not only open the box but to do additional checks back at the office.

Ideally, adds Kappelle, the patient would also have an app that they could use to check the safety of the product and provide any necessary feedback. IRT can also provide the flexibility needed to organise DTP trials in the first place. “You need to have a flexible system in place allowing you to switch per site if you want to have direct-to-patient shipments,” says Dieteren. Being able to monitor and switch between different visits means the supply manager can adjust the strategy in real time and as needed, he explains.

Patient safety

Although automated temperature monitoring is yet to be industry standard, it can allow IRTs to instantly block drug assignment if there is an excursion, reducing the risk to patients. Dieteren spearheaded the development of the very first automated temperature monitoring process after noting the risk to patients that comes with more manual procedures.

In a manual scenario, the IRT would be in place, but staff would need to physically receive the data logger for that shipment, and an alarm could be triggered if there was an excursion. The risk is that the IRT wouldn’t necessarily receive this information and therefore could still assign the medication, and the team could then accidentally dispense it.

“You may be aware as a sponsor of a potential temperature excursion. But if there’s a different team handing over medication to the patient, not being aware of a potential excursion, this is a certain kind of risk,” he says.

Excursion profiles, and the concept of a remaining excursion budget, can also allow for more accurate insight on investigational medicinal product (IMP) safety. This refers to the total amount of time a product can be held outside of ideal temperature conditions before it then needs to be quarantined.

“Today, the expectation is, in all the different stages of manufacturing, storage, and distribution, that there needs to be control of temperature. It’s not only in the shipment,” says Kappelle. Considering the cumulative effect of all these potential excursions is already an industry expectation, but this is often difficult to monitor, he adds. “Sponsor companies are having massive challenges with that because they are working with disconnected systems – they need to go to all these different systems to figure out what happened to this product.” This can be tricky for busy sites, too.

“Everyone is so overloaded with systems it can be a challenge to negotiate with sites or other vendors,” says Schiavon. “Sites often don’t know what drug is showing up on a certain day, which can be a problem if they get a lot of shipments and with different temperature requirements.” IRT integrations can make this easier but there’s still room for improvement in linking different systems from clinical teams, sites, and depots.

Looking ahead

IRT has already been a game changer for clinical supply chains, but as technology develops and trial requirements become more advanced, it holds even more potential. For one, IRT could help to enable temperature control over the lifecycle of a product, and act as a centralised hub for all the important data about that IMP. Unit-specific tracking and measuring capabilities will be key here, says Kappelle. “There’s good examples of that technology already in the industry. But it’s early days, and the technology needs to improve – particularly, the reliability of these individual measuring units on the kit need to improve.” The industry may also look to blockchain technology to help deal with systems overwhelmed with data, says Schiavon. “I think blockchain is a really interesting opportunity to alleviate that burden, there is buzz generating more now about blockchain technology in drug supply management.”

In theory, using blockchain could create an audit trail of a drug’s journey that is recorded into a secure ledger, and sensors could be incorporated so that temperature and humidity are noted at each stage.

For Dieteren, IRT temperature control capabilities will need to be able to support increasingly complex trials where treatments are patient-specific, and drugs are manufactured on-demand. As we move in this direction, it is important to anticipate both the needs of the sponsor and the patient, he adds.

“You need to put the patient in the middle, and first of all, know the disease. Then we can ask: ‘How can we treat the disease better?’ And from there, we can start to talk about what we need to develop that drug.”