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In clinical trials, labels play an essential role in helping patients adhere to their treatment regimen. They contain vital information, about dosage and frequency, for example, that can impact the outcome of a trial. Their design, however, is largely defined by the needs of regulators rather than those of trial participants.

If anything, printed labels seem to have low patient utility. Many are never opened and, on the rare occasions they are, even the most assiduous and meticulous find their small fonts hard to read. And, as the world moves rapidly from paper-based to digital processes, there is an opportunity to replace these ineffective and often cumbersome labels with electronic alternatives – e-labels – that could reduce costs and provide much more information to patients. But so far, no one has seized this opportunity.

“Traditional labels have limitations,” says Steve Jacobs, board chairman of the Global Clinical Supplies Group. “For example, global clinical trials need booklet labels, which might be over 50 pages long. Very few of those booklets are usually even opened by the trial participants, even though they cost millions of dollars to produce.

“Furthermore, the only country that does not need an expiry date on clinical supply labels is the US,” he adds. “Some products that are early in development might not have a great deal of stability data, so in most other countries, someone needs to update the label with a new expiry date as stability information becomes available. One large pharma company did an evaluation of the cost to update the expiry dates on the labels for one of their global phase-III clinical trials. It showed that updating the labels cost more than $5m and five full-time equivalents – about 10,000 hours over the life of the study.”

Jacobs, who is also president of Global BioPharm Solutions, is a true e-label evangelist, having been introduced to the technology by the developer of an innovative system that combines pictographs on the clinical supply container with an embedded microchip. This microchip can then connect to a smartphone or tablet using near-field communication (NFC). When scanned, it triggers a connection to cloud-based data specific to the patient that uses the system. It not only provides dosage instructions and reminders, but also monitors adherence and improves the inventory management process.

Proof of concept

The device that Jacobs saw went to TransCelerate BioPharma to be studied for its e-labelling initiative. The non-profit organisation sponsored a report titled ‘The near-term viability and benefits of e-labels for patients, clinical sites and sponsors’. It examined the current regulatory and technological landscape for e-labels for investigational medicinal products, and set out to show proof-of-concept for a foundational e-label, investigating possible patient-centric enhancements along the way.

The study’s results showed that e-labels deliver real value. Health authorities involved expressed no problems with e-labels per se, though the report highlighted that in some jurisdictions regulatory requirements made it impossible to reduce the content on the paper label.

E-labelling could, according to the report, be used effectively alongside conventional labels, aiding progress towards a more patient-centric approach to clinical trials. The 2018 paper recommended that the industry begin building a platform to enable a fully connected, patientcentric experience, with e-labelling a key element.

So far, little progress has been made towards that goal, but regulatory change could provide an important catalyst – even if it’s more by accident than design.

The way clinical trials are conducted in the EU will undergo a major change when the Clinical Trial Regulation (CTR) comes into force. The aim is to redesign clinical trials but, as far as Jacobs is concerned, some of the changes are based on bad information about labels that could result in rising costs and complicated logistics.

“Currently, studies are conducted with the expiry date on the secondary packaging of the IMP kits, but not on the primary bottles, or vials, inside. So, we send folks out to over-label those kits with a new expiry date,” he says. “Having people do that at the various investigator sites and depots is costly.

“The new CTR, however, requires the expiry date to be on the primary packaging as well,” he continues. “So, you have to open the tamperproof sealed kit and update each bottle or vial, as well as the secondary packaging. That process is considered manufacturing, and so, it would require a Qualified Person [QP] certification each time – and there are not enough of those to travel to all the investigator sites.”

The new regulation was adopted and entered into force in 2014, but the timing of its application still depends on the confirmation of full functionality of the EU’s Clinical Trials Information System.

“When it comes into effect, we won’t be able to do what we’ve done in the past, which was to pre-package large amounts of clinical supplies and have them ready to go out as needed,” warns Jacobs. “We would need smaller packaging runs, and, in the EU, you would need a QP to certify each batch, while in the US you would need Quality Assurance to release each batch, or move to a justin- time or on-demand process with a quality control check. All of that brings cost and complexity to the clinical supply chain.”

Caution comes with a cost

The new regulation does not explicitly open the door to e-labelling, but in the long term it could drive the industry to investigate e-labels as a way to overcome growing cost and complexity.

“I would love to see e-labels used, but regulators are resistant to the technology,” Jacobs remarks. “It could be electronic ink, or it could use NFC with a microchip, the same way Apple Pay does. To update expiry dates on an e-label, you would just need to wave an electronic device over the kit. You could update expiry dates on the fly.

“You can also make the trial more patient-centric by, for example, integrating dosage instructions in the language of the patient’s choosing, with the calendar present on the patient’s smartphone to improve adherence. That would benefit both the process and the outcomes of clinical trials.”

Given the clear advantages of e-labelling in clinical trials, the burning question is why the technology has not been widely adopted. The answer has several facets. The first is how inherently conservative the pharmaceutical and biotech industry is.

“Our industry is known for being risk-averse, or wanting to be first to be second,” says Jacobs. “Everyone is waiting for someone else to make e-labels work so that they can follow suit.”

The second roadblock is caused, in part, by cost concerns, though it is also tied to the industry’s need for solid data on which to base any major change.

“The reason we’re not lobbying regulators with data to show that e-labels improve adherence is because someone needs to collect that data,” Jacobs explains. “We need the data to prove that e-labelling improves compliance, efficiency and quality assurance, while reducing cost, complexity and time, but pharmaceutical companies are busy developing new drugs. They don’t necessarily want to invest the money and, more importantly, the time to prove the value of e-labels.

“They do, however, want to be more patientcentric, and e-labelling would help them to achieve that. Doing nothing will make clinical trials more costly and more complex after the new regulation comes into effect. Processes that may already be inefficient will require even more time and more work. The new regulations will break the system, and e-labelling could be one viable solution to mitigate their inception.”

The price of progress

If the industry embraces the e-labelling concept, the debate will turn to specific technologies. There are various e-labelling systems out there, all of which need to be tested, tweaked and refined for the clinical trials arena. For now, the industry needs proof of concept.

The Covid-19 pandemic, while catastrophic for many, could prompt action. It has certainly caused the pharmaceuticals industry to think a lot about change.

“The industry was not ready for the pandemic,” says Jacobs. “The traditional clinical supply chain has been greatly affected. No one wants to go to a clinic because of the risk of infection, so couriers have had to step up to maintain supply chains.

The FDA has approved direct-to-patient delivery, as have regulators in many European countries, and e-labelling would greatly help that model.

“The pandemic has added some agility to the supply chain, and we are telling the industry that the direct-to-patient model helps not only with recruitment but also retention. E-labelling could also help to reduce attrition and improve patient enrolment by making adherence easier.”

In an industry that is, perhaps rightly, hesitant about change, e-labelling is a challenging concept. It promises much but lacks the support of hard data. Jacobs, however, believes that a transition to e-labels is inevitable, so urges the industry to act early.

“I love change,” he says. “I’m an advocate because I see the amazing opportunities and outcomes that e-labelling could bring. You need to have that vision first, then you need people who will invest the time and the money it takes to collect the data that will persuade the right people to make a change.”

TransCelerate Biopharma’s modular design approach to e-labels

The TransCelerate e-labels initiative has identified three themes for a modular design approach to e-labels for clinical studies.

Foundation

• Providing regulatory-compliant label content via a user-friendly, electronic equivalent with a simplifi ed paper label. Enhance

• Providing the ability for real-time updates to label content.

• Providing enhanced access to information about the investigational product, preparation, dispensing, storage and use.

• In the future, there will be links to multiple media types, and languages could be added to further enhance accessibility.

Add-on

• Enabling innovation through added functionality to improve patient and site experience, and enhance data integrity with:

• adherence reminders

• features to simplify investigator site processes such as receipt, inventory management and accountability

• sensors (for example, temperature, humidity, compliance) to record real-time data.

Source: TransCelerate