The Promise and Reality of Decentralized and Hybrid Clinical Trials in Europe Today

To understand the challenges related to hybrid and decentralized clinical trials and ways to overcome them, we spoke with Dr. Hervé Solatges, Product Management, Evidence, and Innovation (DCT & RWE) at Alira Health and medical professional with more than 20 years of experience. Dr. Solatges has led medical device trials across Europe on Transcatheter Aortic Valve Implantation (TAVI), and surgical sutureless valves, and was recently a co-investigator in a sleep apnea treatment study. As Medical Director for BePatient in the early 2010s, he led the development of a web portal for chronic diseases and set up patient education programs and web services for chronic patients, and he returned as a consultant in 2015, working on remote patient monitoring. With a medical specialty in palliative care, Dr. Solatges has worked with patients in France, Guadeloupe, and Reunion Island.

How did the pandemic affect the adoption of DCT and hybrid trials?

Sponsors could not continue with traditional trials and in-person visits. The only way to gather data and keep trials going was to work remotely and adopt technology much faster than they would have otherwise. Since the COVID-19 restrictions have eased, most sponsors have returned to conducting clinical trials the way they’ve always done it, with patients coming to a centralized location to see medical professionals and provide their data. Some roles in the trial process, such as site monitoring, have evolved to leverage technology more than before, but in general, at least for now, it’s been easier for sponsors to return to the traditional approach because that’s what they know. But the promise was certainly seen.

What IS the promise of DCT and hybrid trials for Europe?

The promise is that by using technology to gather patient data remotely – either completely in a decentralized trial or partly in a hybrid approach – it is easier to recruit and retain patients, it’s easier and less time-consuming for patients to provide data, and sponsors can more easily follow up with trial subjects and have access to a database of patients that they can use for future trials.

How would you describe the reality today and what are the major challenges in making trials fully decentralized?

The reality is that sponsors and patients are not quite ready for this major change in how trials are managed. Several hurdles must be overcome first, and it won’t happen overnight. You can’t flip a switch and find that all traditional clinical trials have become fully decentralized.

I can outline three major challenges in fully embracing DCT:

• Potential trial patients are still uncomfortable with technology.
• Sponsors are reluctant to change their processes and are also uncomfortable with technology.
• Industry regulations vary widely across Europe.

Moving some aspects of a traditional trial to technological solutions, in a hybrid approach, makes the most sense and is the first step – and we are witnessing it right now. But I believe that ultimately, both DCT and hybrid clinical trials will become commonplace and will in fact make for more successful outcomes.

Can you talk first about the issue of patient comfort with technology?

Sure. There are two issues, actually – one is how the technology is designed, and one is how the technology is used. In both cases, the age of the patient matters. Typically, patients over 65 are excluded from clinical trials, but we still want them to participate in studies as they represent a large percentage of the population who use prescribed medicines. Therefore, an app for electronic patient-reported outcomes (ePRO) must be designed for all ages. Developers need to keep in mind that some users may be uncomfortable with technology, designing user interfaces that have large icons, labels that are clearly understood, and process flows that are extremely intuitive. If patients are handed the app to use that they don’t understand, they may become confused or even overwhelmed. Without proper training to build a comfort level with the technology, data collection will fail, and the patients will drop out of the study or may be too intimidated to even begin.

These challenges can be overcome by designing easy-to-use tools and training patients of all ages appropriately.

How do these challenges affect patient retention?

The impact is huge. Only if patients are well trained with tools designed for easy use will patient retention become a major benefit of a DCT or hybrid approach. In traditional trials, those patients who don’t drop out during the trial often disappear once the trial ends. It can be devastating to a sponsor who has spent significant money; they can’t get additional data from a patient with whom they can’t follow up.

The potential for patient retention linked to apps and web portals is enormous, because the sponsor has an automated way to remain present in the patient’s life. The patient will get a reminder – an email, a notification on the app – to say that it’s time to connect, and it becomes a regular habit for the patient to connect, share data, and answer questions. The patient receives a benefit from the app because it lets them measure and track their vitals and provides them with high quality information about their condition. So, they’re willing to participate, especially if it’s easy to do.

How does patient recruitment for trials fit into the mix?

Patient anxiety and confusion over technology can also prevent successful eRecruitment and use, but if potential participants were properly trained to use a well-designed app or web portal, and use it consistently over time, eRecruitment could be successful and have lasting benefits. For example, if a sponsor needs patients with multiple sclerosis, they can plug into the solution, contact those with the disease who have indicated an interest in participating in a trial, and invite them to join.

Those who want to join would receive specific questionnaires and provide the needed data, and at the end of the program, the patients would be able to stay in the program and be available for follow-up.

For example, Alira Health successfully ran a campaign of eRecruitment for patients with spondylitis, a chronic condition. The physicians running the program then decided to contact these patients for a follow-up survey on COVID-19, receiving an excellent 35% response rate. eRecruitment holds great promise, if the barriers around technology acceptance can be addressed.

What about how sponsors feel about technology, and about change in general?

Right, it’s not just patients who are uncomfortable with new technology. In the drug development industry, a lot of employees are still used to documenting on paper to be ready for audit purposes and are reluctant to change. They may be willing to accept basic technology that replicates the paper process – using a computer to scan and store documents, for example. But that’s not the dramatic change required to execute a hybrid or DCT trial. Change management, accompanied by training and executed over time, will be necessary to gain sponsor acceptance.

How do industry regulations in Europe present a challenge for hybrid and DCT trials?

Industry regulations across Europe are another challenge that must be overcome for DCT/hybrid trials to become widespread. One example is electronic informed consent (eConsent). eConsent is universally accepted for consultations and for surgery, but for clinical trials, it’s still not permitted everywhere in Europe. Some countries still require a wet signature, most of them require a qualified signature, while some will accept an advanced signature.

The complexity that results when every country has its own regulations is a challenge for anyone running a trial. Hopefully, the day is coming when cohesive regulations across the European Union allow electronic signatures and other necessary adaptations for clinical trials in every EU country. Discussions are underway.

Another challenge is, of course, that Europe has multiple languages, and you really need people on the ground who speak the language and can work with sponsors and regulators locally. For example, there is a new “Early Access” regulation specific to France: Decree n° 2022-164 from 11 February 2022. Alira Health came up with a solution and is one of only a few vendors who will be aligned with this new regulation on 1 September, 2022, something that would not have been possible without local representation.

Meanwhile, what are some ideal hybrid applications that would make a good first step?

As sponsors await more unified regulations for Europe and work to manage the change necessary for technological adaptation, some applications are ideally suited for a hybrid approach now. For example, after running a traditional trial, with face-to-face patients visits with a nurse or physician, generating Real-World Evidence electronically is a perfect fit. One goal of RWE is to prove that in the long-term, the positive effects of the drug or device on patients are maintained over time. This goal is ideally suited to electronic data collection, because while trial participants may be willing to visit a site in person over the course of a year, they are less likely to continue visiting over two, five, or ten years. The dropout rate is significant and impacts the success of data analysis. An ePRO app is excellent for the patient retention necessary to extend data collection over time – electronic reminders and touches keep the relationship going automatically, with perhaps an annual in-person visit as needed.

Another great candidate for a hybrid trial is Early Access. For example, if a sponsor is developing a drug for an orphan disease, there won’t be enough patients to run a proper clinical trial, but they can run a data collection app with a pool of patients to prove that there’s an interest and claim a new indication before conducting a traditional trial.