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FDA Leader at ASH: Decentralized Clinical Trials Aren’t “All or Nothing”

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Nicole Gormley, MD, acting director of the Division of Hematology Products at FDA, explained that the agency wants to maintain momentum gained during the pandemic that moved clinical trials beyond the walls of academic centers.

After years of talk and early steps, the pandemic forced clinical trials to move beyond the walls of academic centers—and FDA wants to maintain that momentum, “to bring the research enterprise to the patient,” said Nicole Gormley, MD, acting director of the Division of Hematology Products at FDA.

Gormley opened a Friday symposium on decentralized clinical trials held ahead of the formal start of the 64th American Society of Hematology (ASH) Annual Meeting and Exposition in New Orleans, Louisiana. The hope, said Gormley and speakers from across academia and industry, is that making the process easier on patients will attract more of them—and more from minority groups who have been underrepresented.

“It’s hoped that these efforts will translate into greater diversity of the trial participants, as the hurdles to trial participation are minimized,” Gormley said.

There’s some belief that decentralized trials may be less expensive to run, because patient recruitment will be less time consuming. But some speakers in the session warned that setting up a decentralized trial requires its own infrastructure—the focus should be on getting the right patient population.

What’s emerging, Gormley said, is a “hybrid approach,” where some parts of the trial occur remotely, and other elements take place at a central location. Technology can allow remote collection of online consent and patient-reported outcomes, and some trials may also use local laboratories or clinic visits.

“It’s important to keep in mind that decentralized clinical trials don't have to be an all or nothing endeavor,” Gormley said. “What's much more common is a hybrid approach, where some aspects are done at the central location and other aspects are conducted remotely.”

Although interest in decentralized clinical trials soared during the pandemic, it’s not a new idea. Gormley highlighted examples dating to 2003, and noted FDA issued guidance in March 2020 due to the public emergency based on existing practices. It was updated in August 2021.

“The overarching message of this guidance was that it's important to ensure the safety of trial participants, and sponsors were encouraged to consider alternative methods for safety assessments such as phone contact or virtual visits,” she said. “Although this guidance was developed in response to the COVID pandemic, many, if not all of the decentralized trial components were already in existence.”

There are some considerations, however. Gormley said it’s essential to ensure that data collected are fit for use, that additional steps are taken to ensure patient privacy, and that care is taken by trial leaders to ensure they have full access to patient records if some parts of the study are conducted remotely.

Also, Gormley said trial leaders and sponsors must recognize that not every patient has the same access to technology, so proper technological supports must be in place.

Academic perspective. Following Gormley’s talk, Kami J. Maddocks, MD, of Ohio State University Hospital, and Michael R. DeBaun, MD, MPH, of Vanderbilt University School of Medicine, led a session on the benefits of decentralized trials in hematology. Grzegorz S. Nowakowski, MD, the enterprise deputy director for clinical research at Mayo Clinic and chair of the ASH subcommittee on clinical trials, said it’s important to understand why academia supports this approach.

Nowakowski said these trials could be less expensive and could lead to faster drug development—but he said the real benefit is getting more patients to participate in trials. “For me, it really comes down to the basic principle that the best therapy for the patients is typically participation in a clinical trial,” he said. “To be able to offer our patients best care everywhere—from academic sites to small hematology practices—we really have to move with this idea of decentralization and be able to deliver this locally.”

At present, only 5% to 7% of patients enroll in trials. “So, if you flip it around, over 90% of patients are not receiving the best therapy.”

The current model, he said, puts up too many barriers—from travel to regulatory requirements. He offered the example of mailing samples from “routine clinical labs” that could be processed locally. Many steps currently in place were set up to avoid as much risk as possible, and that’s laudable.

“We want to be perfect or as close to professional as we can,” Nowakowski said. “But we cannot allow this risk aversion to stop us and basically slow down our clinical infrastructure to the point where patients literally can’t get to the trials.”

After Mayo Clinic researched how far patients were driving to trials, it set up a partnership with the Leukemia and Lymphoma Society to extend trials into the community, with the hope of reaching rural patients using the hybrid model that Gormley discussed. Mayo Clinic plans to collect data on patient satisfaction with this system, Nowakowski said.

Industry perspective. Lilli Petruzzelli, MD, PhD, senior vice president of Early Clinical Development, Genentech, said the pharmaceutical industry shares academia’s interest in boosting patient participation in trials.

“A major issue for us is to increase diversity in our trials for better health equity, and to ensure that we're learning as much as we can about the right drug in the right population, she said. If only 5% to 7% of the patients are taking part in trials, and 75% of trials are industry sponsored, “really, the onus is on us to play a huge role in trying to make this happen.”

“Numbers mean a lot,” she said. “A third [of clinical trials] don’t even list the data on race.”

Petruzzelli said it will take “a commitment of resources” to get trials out where patients are. “It will be harder to move these trials into the community. But the win is that we will improve diversity and access,” she said.

The idea that moving trials outside academic centers will harm data validity is a myth that springs from a few anecdotes, Petruzzelli said. By contrast, there’s opportunity for all involved “if we can improve health equity, if we can get the right drugs to patients, if we can really make this happen.”

In her role in early drug development, the need is clear. Right now, Petruzzelli said, “there’s an incomplete understanding of drug behavior across divers populations early—and that really hampers us in advancing drugs as we want to go to a larger study.” This cycle happens repeatedly, and beyond decentralized trials, she flagged exclusion criteria that unnecessarily keep out too many elderly and minority patients. “One of the biggest challenges we have—and we’ve been stagnant on—is protocol, eligibility, and inclusion criteria….It excludes a lot of patients.”

An abstract on this issue—for which Nowakowski was senior author—was highlighted in an ASH press briefing. The study examined a cohort of patients with diffuse large B-cell lymphoma to show that lab values, some of which have nothing to do with the trials or the mechanisms of the drugs, would have caused 9% to 26% of patients to be excluded from 3 recent trials—including POLARIX—with exclusions falling more heavily on minority populations.1

Clinical trialist perspective. Caterina Minniti, MD, professor of clinical medicine and pediatrics at Albert Einstein College of Medicine, spoke from her experience with a decentralized clinical trial involving patients with sickle cell disease (SCD). Minniti described SCD as the “canary in the coal mine of heath care” because one can judge the rest of the system by how well these patients are treated. “Even though in the United States it is considered a rare disease, because it affects about 100,000 patients, most of these patients are African or African American and 10% are Hispanic. And often, my patients reside in socioeconomically distressed communities.”

When the pandemic hit, even before telehealth could be reimbursed, she said, “We just had to do it.” And a remarkable thing happened: the number of patients who were “no shows” to appointments plummeted, and so did the number of visits to the emergency department. That suggests that getting to the appointment the challenge.

Lack of trust is a widely acknowledged problem in enrolling minority patients, but Minniti said lack of awareness is a problem, too. “There is this a big hurdle that is peculiar to the sickle cell community, which is the majority of adults with sickle cell disease do not even see a hematologist or even a caretaker that is familiar with sickle cell disease,” she said. Thus, the patient’s primary doctor may not know about clinical trials that are available.

“There is no research without care. If we don't have patients engaged in care, we cannot enroll them in a clinical trial, we cannot run a clinical trial,” she said, citing data from the state of Georgia show that only 21% of adults with SCD have seen a provider in the past 3 years with expertise in the disease.

Minniti highlighted a decentralized, web-based clinical trial sponsored by Pfizer to measure pain, comparing disease-modifying therapies and patients without therapies. Patient recruitment materials used QR codes that patients could highlight, go to the site, see the eligibility criteria, and take the first step to register. One they completed these steps; a researcher would call the patients back to confirm eligibility. Online processes are also using Instagram and other tools to recruit patients, she said.

As useful as these tools are, Minniti said, there are pros and cons. “I’ve learned is that it takes a lot of time to run a decentralized clinical trial,” with a key reason being the challenge of gaining access to medical records. Some patients don’t even have a primary care physician, so that must be addressed. This may mean the trial must be designed differently, Minniti said.

“I reiterate that even though it's a decentralized clinical trial, it does not mean it's a simple way of doing a clinical trial,” she said.

Reference

1. Khurana A, Mwangi R, Mastoupil LJ, et al. Evaluating the impact of lab-based eligibility criteria by race/ethnicity in frontline clinical trials for diffuse large B-cell lymphoma (DLBCL): a LEO cohort analysis. Presented at: 64th American Society of Hematology Annual Meeting; New Orleans, LA; December 10-13, 2022; Abstract 850.

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