Online Medical consultation and treatment, cell phone,
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Andrea Coravos
Andrea Coravos, CEO, HumanFirst

For Andy Coravos the tipping point was the Biogen Conference in Boston, February 2020. While only about 100 people attended the meeting, it became one of the most notorious super spreader events of the COVID-19 pandemic, ultimately leading to an estimated hundreds of thousands of cases around the world (Science, Dec. 2020).

“From that point on it was all hands on deck,” says Coravos, CEO of HumanFirst, a San Francisco-based firm that helps pharma companies and hospitals evaluate, select, and use sensors for clinical trials or home care. “Suddenly, it wasn’t safe for people, even the sickest patients, to go to a clinic or hospital site.” Thousands of trials ground to a halt.

One of the keys to restarting those trials was incorporating digital measures. There were lots of tools available already, but the question was often “Is this tool properly validated – and for this condition? Is it cyber secure?” Coravos says. That’s exactly what her team does. So they jumped into action.

The issues were not just which devices worked best for the job, but what exactly should be measured. “Think about sleep,” Coravos says. “What exactly is sleep? Should you measure how long you stayed asleep? How often you sweated? How you felt in the morning? Could you lift your grandkids up the next day?” In many ways, this was a whole different world from the traditional trial process of giving patients drugs and then checking their vitals and labwork.

Coravos was not alone is mobilizing her team for a full-throttle shift to decentralized clinical trials (DCTs). For anyone in the clinical trial field, no matter how peripherally, the onset of the COVID-19 pandemic was dramatic.

Rosamund Round
Rosamund Round, Parexel

Rosamund Round of contract research firm Parexel called the company’s president as soon as she heard about the pandemic’s surge in China. Vice President of the company’s Patient Innovation Center, Round advised that Parexel start pressing customers to switch to DCTs. “The majority of clients were onboard immediately,” she says. “We had some who said ‘We’re not worried, this will blow over in a couple of weeks,’ but they came along too soon enough.”

She adds that, “I cannot think of a time that innovation has moved so quickly. These last two years have been wild.”

While it was a trial by fire, the crisis was tempered by the fact that so many people had already been working on encouraging the adoption of DCTs. The tools, framework, and mindset for the shift was there, it was just a matter of putting it in action and bringing regulators along. What experts on the frontlines have learned from this experience is straightforward: It’s crucial to validate the tools, some of DCTs tools and methods are now here to stay, and flexibility is mandatory, because not all patients want to do DCTs.

“The embrace of decentralized clinical trials during the COVID-19 pandemic worked tremendously well,” says John Cassidy, Global Head, eClinical Product & Commercial at Labcorp Drug Development.

Dos and Don’ts

At first, the pandemic uncovered the low-hanging fruit – things that were being done inefficiently, just because they were always done that way.

Craig H. Lipset
Craig H. Lipset, DTRA

“There is no reason a patient needs to come into a clinic for gait analysis,” says Craig Lipset, co-chair of the Decentralized Trials Research Alliance (DTRA). “Especially if that’s going to be a hardship for them. Why not use a remote device? They will literally do more walking to get from the parking lot than they do in the clinic.”

This puts digital health technologies (DHTs) in a pivotal position. “People have access to more DHTs now, from fitness trackers to apps and they have become more accustomed to tracking health metrics and continuous monitoring,” says Yashoda Sharma, program director of the Digital Medicine Society (DiMe). But some patients prefer to visit a clinical site. Either they don’t want the intrusion of a home visit, or they may just like the experience of visiting with staff.

Yashoda Sharma
Yashoda Sharma
Digital Medicine Society

“We had one rheumatoid arthritis trial where we were planning for DCT,” says Round “But the patients said they actually preferred clinic visits.” Meanwhile, parents of kids with rare diseases or other conditions, and people with low level chronic diseases far preferred DCTs. The lesson, Round says, is “Don’t make assumptions. Ask patients. Ask them a lot of things, and ask them often.”

Teonna Woolford, CEO of Sickle Cell Reproductive Health, says she found the daily e-diary she had to keep more time-consuming than a visit to a clinic would have been, during the trial she was participating in as the pandemic unfolded. “Maybe it’s because I’m a CEO, so I’m very busy,” she says. “But it seemed like a trip to a clinic once in a while would have been less bother.” Woolford adds that time off work, gas, parking, etc. “adds up” and she understands that for some patients a DCT is probably the only way they can participate in a trial.

Teonna Woolford
Teonna Woolford, CEO
Sickle Cell Reproductive Health Education Directive

Another critical factor was the regulatory environment. While that has typically been a tough landscape to navigate, the pandemic prompted some agencies to fall in step. The FDA quickly issued a guidance, (FDA’s Guidance for Clinical Trial Conduct During the COVID-19 Pandemic).

But just as importantly, the FDA aligned with the European Medicines Agency (EMA) to make it easier to meet both agencies requirements. “For many years the FDA had their rules and the EMA had theirs. But during the pandemic they created a framework so we could meet both agency’s requirements without jeopardizing quality or safety,” says Rasmus Hogreffe, VP of DCT Innovation at Medable.

Kathy Vandebelt
Kathy Vandebelt, Global Head
Oracle Health Sciences

Oracle stepped up to help accelerate the evaluation of the COVID-19 vaccines, some of the most rapidly tested and evaluated products in history. The data giant was well positioned to help with this effort. “We are the best at this,” says Katherine Vandebelt, Global Head of Clinical Innovation for Oracle Health Sciences. “Data collection, data architecture, analytics. That put us in position to lead in remote monitoring, consent, and more.”

One project Oracle developed, v-safe, helped monitor reported side effects from COVID-19 vaccines via patients’ smartphone or computer. It is an app that allows a confidential health check-in, as well as surveys and other tools. The company reports that over a hundred million records are in the system.

Online Doctor Consultation
Credit: vorDa / Getty Images

That data has already proved very valuable. As early as June of 2021, a New England Journal of Medicine report documented, that: “Early data from the v-safe surveillance system, the v-safe pregnancy registry, and the VAERS do not indicate any obvious safety signals with respect to pregnancy or neonatal outcomes associated with Covid-19 vaccination in the third trimester of pregnancy.”

Finally, there is the pressing issue of logistics. Simply delivering medications to patients became a challenge during the pandemic. Companies such as Medable, Paraxel, and others are now touting their ability to deliver temperature-controlled drugs within tight time windows to ensure that patients receive their medications safely and in a timely manner.

What’s Next for DCTs

“Training and adoption for sites is an area that deserves additional focus and is necessary to the success of DCTs,” says Labcorp’s Cassidy. He points out that decreasing the burden and training curve of using DCT methodologies can broaden the reach of those trials and progress the industry towards broader flexibility in trial conduct.

Lipset was involved in the first all-remote trial under an investigational new drug (IND) application, which was carried out by Pfizer about a decade ago (Orri et al., Contemp Clin Trials, 2014). This was a randomized, placebo-controlled, Phase IV (REMOTE) trial to evaluate tolterodine extended release (ER) 4 mg for overactive bladder.

“Some things worked and some didn’t. We were open about both,” he says. But there was not much momentum for DCTs even after that trial. Lipset points out that the two “guardrails” of clinical trials are patient safety and data integrity. It’s not surprising, he says, that people in this industry are cautious.

While he admits there was a surge of DCT adoption during the pandemic, he says it is premature to fly the “mission accomplished” banner. “It is conceivable that such a conservative industry will slip back into its comfort zone,” he says.

But he also points to the facts that FDA and other regulators (e.g in Sweden and Denmark) seem DCT friendly now, many sponsors have made “sizeable” commitments to this approach, and there is lots of guidance on how to pursue it (See Sidebar: Playbooks, Guidances, and Endpoints).

Vandebelt sees a new push for more real word data (RWD). All this data from remote monitoring provides an opportunity for data aggregators such as Oracle she says. “What happened over the last two years was unprecedented, and it took a lot of money and energy.” Now there can be a focus on using that data in new ways.

Ramus Hogreffe
Ramus Hogreffe, VP, Medable

In keeping with that, Hogreffe anticipates a push toward “bring your own device.” As devices are standardized, which platform patients have for personal use will become less relevant. Digital sensors will be plug and play. Meanwhile, the number of people with access to internet is steadily increasing, reaching a record 5 billion this year.

Says DiMe’s Sharma, “Many of the challenges facing clinical trials in general, still exist. The two biggest are trust and access.” Sharma points out that many patients have little trust in the healthcare system now. “Without a support system of clinicians and study teams, patients may lose even more confidence in the system and become reluctant to participate.”

Another question is whether DCTs can address the nagging issue of diversity, including ethnic and LGBQT participation. Making trials more convenient for people with cellphones or adding home visits doesn’t naturally tend to increase diversity. Many companies and organizations, including DiMe and Paraxel, are now looking at this since it has become clear that diversity is a major issue in data integrity for clinical trials.

Besides the urgency of safety during the pandemic, there is data supporting DCTS. A recent study from Tufts Center for the Study of Drug Development found that, on average, decentralized trials achieved a net financial benefit ranging from 5 to 14 times for Phase II and III trials through reduced trial timelines and other factors.

Working through issues like e-consent, logistics, and security have helped the pioneers of DCTs not only weather the pandemic, but thrive because of it. Participating in a clinical trial should be as smooth as buying on Amazon,” says Medable’s Hogreffe. “One click and you are in.”

He adds that taking about 12 years to bring a drug to market “Is unambitious. People want to invest their time in something more productive.”

Round had a personal view of the crisis as she had COVID-19 herself and ended up taken by “blue lights,” as she says, to a hospital where she was seriously ill. “That was the last place I wanted to be.”

She notes that while she’s always been passionate about patient care, that experience helped her realize what a huge advantage DCTs are for some people. “Patients really appreciate it. DCT is not going away,” she says.

Playbooks, Guidances, and Endpoints

The FDA was quick to release guidances (see below) on how to conduct trials during COVID-19. Proponents of DCTs responded with comments, playbooks, and other documents that helped guide sponsors and others through this unfamiliar terrain.

Below are some of them:

DiMe’s Library of Digital Endpoints:
A crowdsourced library of digital endpoints focused on industry-sponsored studies of new medical products or new applications of existing medical products.

DiMe’s comment in response to the FDA draft guidance on:
Digital Health Technologies for Remote Data Acquisition in Clinical Investigations

DiMe’s Playbook: Digital Clinical Measures

FDA’s draft guidance on Digital Health Technologies for Remote Data Acquisition in Clinical Investigations
Oracle and Informa’s survey on Clinical Trial Management in a Post-Pandemic World
Paraxel’s Discussions on Diversity Report

Malorye Branca is a freelance science writer based in Acton, MA.

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