Decentralized Trials Guidance May Reflect US FDA’s Lessons Learned During COVID-19

BY SUE SUTTER

Executive Summary

Work on guidance that was originally expected in 2020 continues as the agency and industry learn more about the utility and spectrum of decentralized trials as a result of the novel coronavirus pandemic.

The US Food and Drug Administration’s forthcoming guidance on decentralized clinical trials is likely to reflect some of the lessons learned from use of technology to remotely collect clinical data during the COVID-19 pandemic.

Decentralization as an operational approach in clinical research is “here to stay,” Isaac Rodriguez-Chavez, an FDA officer for clinical research methodology, regulatory compliance and medical policy development, said during a panel decision at the Biotechnology Innovation Organization’s recent virtual annual meeting.

“This is the new way, if you will, of collecting clinical data, adding convenience to participants, maintaining safety” and ensuring data quality and integrity, he said.

Decentralized trials have been “pushed ... to the maximum” during the public health emergency, Patrizia Cavazzoni, acting director of the Center for Drug Evaluation and Research, said during the recent Drug Information Association annual meeting. (Also see “COVID-19 And IP: Companies Are ‘Taking A Chance’ Sharing Clinical Trial Details” - Pink Sheet, 23 Jun, 2020.)

Decentralized Vs. Virtual

The FDA had targeted 2020 for release of a guidance on decentralized trials. (Also see “Decentralized Clinical Trials Among Topics Slated For CDER Guidance In 2020” - Pink Sheet, 2 Feb, 2020.) However, much of the agency’s non-COVID guidance development has been pushed to the side while the agency works to address the public health emergency resulting from the novel coronavirus. (Also see “Back To Normal? US FDA Schedules In-Person Meeting But Pauses NonCOVID Guidance Development” - Pink Sheet, 13 May, 2020.)

The forthcoming guidance is expected to outline factors that companies should consider when weighing a decentralized trial approach. (Also see “US FDA Outlines Wishlist For Decentralized Clinical Trials” - Pink Sheet, 13 Mar, 2020.)

Rodriguez-Chavez said the agency remains engaged in the topic of decentralized trials and is committed to completing the guidance.

He also explained what the FDA means when it talks about “decentralized trials,” drawing a clear distinction from “virtual trials.”

Decentralized trials refer to a decentralization of clinical trials operations in which technology – such as telehealth, computers and digital applications – is used to communicate with study subjects and collect data, Rodriguez-Chavez said. In fully decentralized trials, everything is done remotely. In contrast, virtual trials are in silico or computer modeling trials that occur during the preclinical phase, he said. Virtual trials do not use real people but, rather, model subjects to assess drug efficacy and the safety at the preclinical level.

“I guess the confusion between the two terms is because in both cases there is use of technology, but the application of the technology for each of these two cases is completely different,” Rodriguez-Chavez said.

Hybrid decentralized trials include elements of both traditional and decentralized trials.

Rodriguez-Chavez described decentralized trials as a patient-centric approach.

“At the end of the day, the biggest advantage of decentralized trials really is added convenience to the participants and being less disruptive … in comparison with, for example, the traditional trial,” he said. “Many of the participants on clinical trials … they have to travel an average of one to two hours to the clinical site. … Convenience to participants is a very important element and that is enabled because of the use of technologies.”

During a separate session of the BIO meeting, Laure Halloran, CEO and president of the Halloran Consulting Group, said COVID is forcing sponsors to follow in the footsteps of orphan drug developers, who long ago learned they need to smooth the path to clinical trial participation for rare disease patients.

“What happened in the weeks after COVID started is going to transform how products should be developed in the clinical phase of development,” Halloran said. “What COVID has done is it’s made people who were really resistant to doing anything where technology was a support and a facilitator have to think differently.”

“There are so many opportunities to take those lessons and make the patients’ world way easier by employing telemedicine and getting rid of some of the really strict, ‘the doctor must see the patient for the six-minute walk test’ mandates, and think about making it more patient-centric in a bigger patient population,” she said. “The technology’s there, it does not have to be so hard.”

Doing Things Differently, With The FDA’s Blessing

The FDA, industry and other stakeholders collectively are learning more about the utility and spectrum of decentralized trials as a result of COVID.

Travel restrictions, quarantines and social distancing measures have required sponsors and investigators to come up with new ways of collecting patient data when study participants cannot physically visit a study site. Similarly, they have had to develop plans for delivery of study drugs directly to patients, or to alternate locations, when they cannot visit a clinical site in person.

Through a series of “immediately in effect” guidance updates, the agency has provided a steady stream of advice on how sponsors and investigators can mitigate the impacts of the COVID pandemic on clinical trials. The guidance has addressed a host of issues, including virtual visits with investigators and factors to consider when switching from in-person to remote collection of clinical outcome assessment data. (Also see “Patient-Reported Data In COVIDImpacted Trials: US FDA Cautions Against Missing Data, Potential Bias” - Pink Sheet, 7 Jun, 2020.)

The FDA’s guidance has been built around several key themes, including prioritizing patient safety, minimizing risks to trial integrity, and documenting of reasons for any protocol changes and deviations. (Also see “Clinical Trial Sponsors Should Consider Changing Data Collection Amid COVID-19, US FDA Says” - Pink Sheet, 18 Mar, 2020.)

Clinical trial conduct and oversight seems likely to be one of the key areas where adjustments in the FDA’s regulatory approach necessitated by COVID may outlast the pandemic. (Also see “BIO 2020 Notebook: FDA’s Hahn On COVID-19 Lessons To Be Learned; NIH’s Fauci On Health Care Disparities; Pfizer’s Young On Forgoing Gov’t Vaccine Funds” - Pink Sheet, 11 Jun, 2020.)

Learning About What Works, And What Doesn’t

The COVID pandemic has “been the moment of digital health,” Wade Ackerman, a partner in the Los Angeles office of Covington and Burling, told the BIO meeting.

“Because of a public health crisis we have been as a health care system and as a society sort of pushed to adopt technologies in ways that would have been much more of a step-wise approach” otherwise, he said.

“I think we’re absolutely going to see uptake of some of these things,” Ackerman said. “I think we’re also going to see where it’s not working.”

“We’re also going to learn lessons where maybe it’s not the right place to invest. I think the promise of decentralized trials … the access, the patient-centricity of them, the fact that we can have new and better sources of data, all of that promise is there,” but “just because we’re introducing technology does not always mean things are better.”

For example, limiting data collection to use of a smart phone could exclude study participants who lack access to such technology, Ackerman said, also noting that some people are not going to be comfortable with devices that actively monitor their health.

Rodriguez-Chavez emphasized the need for verification and validation studies to ensure a digital technology reliably can be used within the specific context of use of the disease, the drug being studied and the study population.

Valerie Paradiz, vice president of services and supports at Autism Speaks, said sponsors considering a decentralized trial approach should “ensure that every step along the way you’re getting patient input.” The need for study participants to be proficient in using the study technology is particularly important for retaining participants and gathering the best quality data, she said.

“In my world, the world of autism, you do need to help us know why and how to do it,” Paradiz said. “And often that can’t just be relayed verbally or in writing. It needs to be supported with images and other kinds of forms of education.”