Draft Guidance Reflects FDA’s Thinking Around Decentralized Trials

The US Food and Drug Administration has released draft guidance on the elements that go into conducting decentralized clinical trials, in which some or all study-related processes are not tied to a trial site but instead take place in participants’ homes or local healthcare facilities.

Though the agency is legally obligated to provide such guidance under the Food and Drug Omnibus Reform Act (FDORA) that was signed into law late last year, its release signals that a decentralized clinical research, which took on greater importance in response to restrictions stemming from the COVID-19 pandemic, will have a major role to play moving forward.

“The FDA has long considered the benefits of decentralized clinical trials. Advancements in digital health technologies and the COVID-19 pandemic—when in-person visits were limited or unavailable for many trial participants—have accelerated the broader adoption of these activities,” FDA Commissioner Robert Califf, MD, said in a press release. “As we seek to improve our evidence generation system, decentralized clinical trials may enhance convenience for trial participants, reduce the burden on caregivers, expand access to more-diverse populations, improve trial efficiencies, and facilitate research on rare diseases and diseases affecting populations with limited mobility.”

As reported previously by TCTMD, the COVID-19 pandemic forced changes on how clinical research was conducted, leading to streamlined institutional review board (IRB) processes, greater use of remote trial monitoring, and other measures that showed that trials could be conducted more rapidly and with less expense and less burden to investigators and participants. Though so-called virtual trials—in which patients can be enrolled remotely, drugs can be shipped directly to participants, and much (if not all) of the follow-up can be conducted via telemedicine—were starting to be conducted before SARS-CoV-2 spread around the world, the pandemic accelerated their adoption.

I think it’s important for the cardiology community to start recognizing that there are new approaches and how this might in the next decade really change the way that we’re conducting these trials. Harlan Krumholz

This new draft guidance from the FDA builds on prior recommendations on the conduct of clinical trials during the COVID-19 pandemic that the agency released in March 2020. The content of this guidance does not represent regulatory requirements, which are the same for decentralized and traditional site-based trials, but instead reflects “the agency’s current thinking on a topic.”

The document will be open for comments and suggestions for the next 90 days. It covers a range of topics:

• Decentralized trial design
• Remote visits and trial-related activities
• Digital health technologies for data acquisition
• Roles and responsibilities of sponsors and investigators
• Informed consent and IRB oversight
• Types of investigational products appropriate for such trials and how they should be packaged and shipped out to participants
• Safety monitoring
• Software used to conduct the trials

The FDA provides nonbinding recommendations, but even so, “it’s an important signal from the agency that decentralized trials are a real thing, they’re coming, and also that they need to be at the same level of rigor as site-based trials,” Harlan Krumholz, MD (Yale School of Medicine, New Haven, CT), told TCTMD. “I’m very happy to see it, and I’m really glad to see this signal from the agency that they recognize the need to be able to accommodate these kinds of designs.”

The document indicates, Krumholz added, “that the FDA is spending time thinking about how to incorporate these trial designs into their regulatory decision-making and anticipating, I believe, that this is going to grow dramatically in the future.”

This type of guidance is “enormously helpful” for clinical trialists, said Krumholz, who is one of the principal investigators for an ongoing phase II trial evaluating the use of nirmatrelvir/ritonavir (Paxlovid; Pfizer) for patients with long COVID. It’s a decentralized study, with remote enrollment and outcome ascertainment, shipment of medications directly to participants, and collection of blood and saliva samples at the patients’ homes. No site visits are required.

Krumholz said that at a recent meeting, his research group reviewed the new FDA guidance to see how well the study processes matched up.

“This kind of guidance enables you to create checklists and just sort of give you confidence that the way that you’re pursuing the trial is in accordance with best practices,” he said. “I’ll say it’s less about trying to comply with regulatory requirements, because this is guidance, and more about helping investigators to know what marks they need to hit in order to be conducting these trials according to the highest standards.”

There is the possibility, Krumholz indicated, that decentralized trials can provide even higher-quality data than can be obtained from trials conducted in the traditional way. That’s “because you’re freed from site-based visits, you’re doing a lot more at home. I think you can get better adherence rates to the protocols, you can make it more convenient for participants, and you can improve your retention rates because you’re serving people at their convenience, not at the convenience of the sites.”

He said he’s eager to see these types of trials proliferate in cardiology, acknowledging that not all studies will be suitable for a decentralized design, such as those conducted in the hospital or other acute settings. “But for outpatient studies, I think these can be more efficient, more convenient, and ultimately more effective in helping us to speed knowledge generation through new designs and strategies,” Krumholz added.

In cardiology, fertile areas for decentralized trial designs include therapies for primary prevention and for management of chronic diseases, Krumholz said. Hybrid designs, which could include some type of acute intervention in the hospital followed by remote follow-up, would work for trials that include patients undergoing PCI, ablation, TAVI, or some other type of procedure.

“It’s going to be incumbent upon us as we introduce these new designs to demonstrate that we’re not missing anything,” Krumholz said. “I believe that there’s the possibility that we’re actually collecting more-detailed information at a volume that’s unprecedented because of the way that we’re using technology, but it’s going to be very important that we evaluate ourselves and that we continue to check and iterate.”

Taking a broader view, Krumholz said, “I think it’s important for the cardiology community to start recognizing that there are new approaches and how this might in the next decade really change the way that we’re conducting these trials.”