Home School: Clinical Trials Went Virtual in COVID-19—Are They Here to Stay?
Lockdowns opened doors for RCTs without in-person contact. Time will tell whether they deliver on diversity and outcomes.
In the early months of the COVID-19 pandemic, clinical trial enrollment slowed to a halt, centers shuttered or heavily curtailed day-to-day contact, patients cancelled study visits, and important follow-up visits involving imaging or functional tests went out the window. Given everything else going on in the world, it’s no surprise that expected event rates built into study designs never materialized. Patients who otherwise would have gone to the hospital or a doctor’s office for symptoms like chest pain or shortness of breath simply stayed home.
“This really put an exclamation mark on the need for a different approach for clinical trials that leverage a virtual or completely remote execution,” said James Januzzi Jr, MD (Massachusetts General Hospital and Baim Institute for Clinical Research, Boston).
Enter the virtual clinical trial.
The idea of research protocols that eliminate the need for actual patient contact predates COVID-19—the Apple Heart Study being one of the most ballyhooed examples. But as SARS-CoV-2 ramped up worldwide, the severe constraints place on medical and research groups limiting the ability to have patients come to a study site for screening, enrollment, intervention, and follow-up vastly accelerated their development and implementation.
Multiple studies reported last month during the American Heart Association (AHA) 2021 Scientific Sessions—itself virtual—involved virtual designs, including I-STOP-AFib, the Fitbit Heart Study, CRAVE, and CHIEF-HF, among others, highlighted the feasibility of performing research in this fashion. And, according to trialists interviewed by TCTMD, there’s growing interest in using virtual study designs after the pandemic ends. Proponents point out that even without the risks posed by the virus, such trials could reduce patient inconvenience and transportation hurdles, potentially improving the diversity of study populations by reaching patients missed by traditional methods, while also reducing operational costs and personnel.
“Just as the coronavirus continues to evolve rapidly, we’re sort of seeing a rapid evolution of how clinical trialists are thinking about modern designs,” Januzzi, senior author of the CHIEF-HF study, said. “There was interest already developing for disruptive designs for clinical trials even before the pandemic arrived, but the advent of the pandemic really pressure tested the clinical trial world in multiple ways leading to a greater emphasis on virtual-type designs beyond what was already present before.”
Mary Norine Walsh, MD (Ascension St. Vincent Heart Center, Indianapolis, IN), a past president of the American College of Cardiology (ACC), said this more hands-off approach to research during the pandemic was facilitated by the necessary shift in clinical practice to greater use of telehealth. That was made possible by payers agreeing—after some prodding by advocacy groups that included the ACC and others—to reimburse the same amount for video or phone visits as for in-person visits.
Though the number of in-person visits has risen after the initial shock of the pandemic, the idea of performing research virtually has remained attractive. Certain trials will always need patients to come in for blood draws, imaging, ECG, and other evaluations, Walsh said, but the pandemic has “opened everybody’s eyes to how we can change enrollment strategies, increase diversity of enrollment, and also decrease cost and patient inconvenience.”
Suited or Unsuited to Virtual
Of course, not all clinical trials can be conducted in this way—if they involve hospitalized patients of course, or if they require implantation of a device or will track outcomes using imaging or another procedure.
Mary McDermott, MD (Northwestern University Feinberg School of Medicine, Chicago, IL), deputy editor of JAMA, said trials best suited for virtual designs are those in which eligibility can be assessed well remotely and the intervention can be sent to the participant—pills, for example. Also, trials in which outcomes can be effectively tracked without requiring patients to hoof it to the clinic by using either electronic medical records or video or phone calls—clear-cut outcomes like hospitalization or mortality—might be amenable to a hands-off design.
In particular, studies focused on patient-reported outcomes—increasingly being recognized as valid endpoints by regulators, including the US Food and Drug Administration—are good candidates for virtual conduct, multiple experts said. Questionnaires can either be self-administered or completed through telehealth platforms. Similarly, trials with endpoint data that can be collected at home, like blood pressure measurements, can take advantage of this design.
CHIEF-HF is a good example of a virtual trial with patient-reported endpoints. The trial started the same week COVID-19 shut everything down. Though stopped early, it showed that canagliflozin (Invokana; Janssen) significantly improved quality of life in patients with heart failure.
There was interest already developing for disruptive designs for clinical trials even before the pandemic arrived, but the advent of the pandemic really pressure tested the clinical trial world. James Januzzi Jr
“We were able to show a significant, robust effect of canagliflozin on health status, with improvement in the Kansas City Cardiomyopathy Questionnaire, without a single patient being encountered in the course of the trial,” Januzzi said.
David Cohen, MD (St. Francis Hospital and Heart Center, Roslyn, NY), director of clinical and outcomes research at the Clinical Trials Center of the Cardiovascular Research Foundation (which is also the publisher of TCTMD), said it’s important to realize that not all trials will be able to move into a fully-virtual format. “Trying to fit the old traditional trial mechanisms and endpoints and all those sorts of things into a virtual design really doesn’t take advantage of the virtual component,” he said.
Trials with more-nuanced endpoints, like bleeding of certain severity or cause-specific hospitalization that requires some degree of subjective determination, will require at least some in-person contact, he noted.
Studies that require a thorough physical exam to determine eligibility also will not be able to be completed in an entirely virtual way, Walsh observed. And certain interventions—those focused on behavioral modification, for example—might not work as well when delivered by video versus in a face-to-face setting, McDermott said.
Other potential concerns with fully virtual trials are that investigators might not be able to keep track of how well patients understand the consent process before entering the study; are performing interventions after enrollment; or are reporting self-collected data—or at least as well as during an in-person visit. McDermott also raised some questions about whether certain types of data can be collected with sufficient rigor remotely. “Until somebody does a study showing me that a 6-minute walk is just as accurate and valid done at home remotely as it is when they come into the medical center and we do it ourselves, I’m personally not going to believe that it’s the same quality data,” McDermott said.
The bottom line is that there is potential for a lot of variability in how certain types of data are collected, McDermott said, adding that ongoing research is needed to explore the issue. “I don’t think we should take things for granted and just assume that what we’re doing in person that requires administration of a test can be done just as well at home,” she cautioned.
Diversifying Study Populations
A commonly mentioned positive associated with virtual trials is that there is the potential to reach patients who otherwise wouldn’t participate in clinical research, ultimately diversifying study populations. Historically, clinical trials have been notorious for failing to mirror the population at large.
“It goes without saying that clinical trials have long been blemished by the underenrollment of women as well as underserved populations such as Black or African-American patients, so a virtual study potentially gives the promise of a more-balanced enrollment of underrepresented individuals than traditionally in clinical trials,” Januzzi said. He noted that CHIEF-HF had better representation of women (45%) compared with many previous trials and a racial/ethnic mix on par with the composition of the US population, with 14% Black participants.
I don’t think we should take things for granted and just assume that what we’re doing in person that requires administration of a test can be done just as well at home. Mary McDermott
Cohen said the impact of remote trial designs on diversity will depend on how patients are recruited and how wide the net is cast, indicating that he sees the potential for positive movement in this area. “I do think that it really has the opportunity to largely diversify things, but we need to learn more about how to effectively recruit the patients from outside of the medical care system to do this.”
While it’s likely that different types of patients will be reached using hands-off trial designs, there is a risk of excluding other patients who either don’t have the appropriate technology to participate or who are not comfortable with using it, McDermott cautioned. Such barriers, she noted, could disproportionately affect people from lower socioeconomic strata.
Walsh agreed, pointing out that even though the vast majority of people, particularly in the United States, have a phone, one thing learned during the shutdowns early on during the COVID-19 pandemic is that a lot of people, especially in older age groups, only have the phone function active. Moreover, she said, broadband coverage is uneven around the country, further serving to exclude some people from participating in a remotely conducted trial.
So while virtual designs may increase the diversity of trial participants, “I do worry that it’s sort of going to be the upper socioeconomic strata that we’re going to be recruiting rather than the population who has the disease that we’re studying,” Walsh said. That concern appears to have been borne out somewhat in the Apple Heart Study, which tended to enroll younger, healthier, and higher-income individuals. “I just think we have to be sensitive to those diversity issues,” Walsh said.
Januzzi acknowledged the concerns about possibly excluding people less comfortable with technology, which is often attributed to older age groups. But he said that in 2021, it’s reasonable to expect that the “great majority” of people, particularly among those inclined to participate in trials, would have some comfort with technology. The average age in CHIEF-HF was 63, and more than half of patients were over age 65, similar to most CV trials, he noted.
The trialists interviewed by TCTMD agreed that use of designs with at least some virtual elements is likely to persist even after the restrictions necessitated by COVID-19 have lifted.
“I think we’re moving rapidly into a space where many trials will be conducted this way, especially as patient-reported outcomes become more and more common as endpoints in the trial and [are] included in the primary endpoint of a trial,” Walsh said. “I think there’s a lot of sponsor and investigator enthusiasm around this.” That’s dependent, she added, on how payment models for clinical care continue to evolve, because that will also drive the structuring of trials.
I think we’re moving rapidly into a space where many trials will be conducted this way, especially as patient-reported outcomes become more and more common as endpoints. Mary Norine Walsh
For Januzzi, “the big question will be whether the necessary infrastructure can be created for virtual trials to deliver the same kind of meaningful results that a classical, in-person study can deliver.”
Extraction of key clinical data from electronic health records, which were developed primarily for billing purposes and are not very user-friendly for research, needs to be eased, he said. And new methods for collecting data on things like blood counts, kidney function, electrolytes, or natriuretic peptide levels without requiring patients to come to the clinic would be desirable for safety and efficacy monitoring, he said, noting that such efforts are in the works.
How regulators will view the results of fully virtual trials relative to more-traditional RCTs also remains unclear, Januzzi added.
Filling in those gaps will take the fully virtual trial design from what is still “somewhat of a curiosity” to something more mainstream, he said: “With the expectation that virtual care on the clinical level will continue and with expansion of technologies to allow for virtual research to continue to expand, such as home lab testing, home measurements of biometric data, etc, I could clearly envision substantial inroads toward intervention clinical trials that are done completely virtually in the future.”
McDermott agreed that virtual trial designs will continue to be used more and more, cautioning that the results of such trials will have to be considered carefully to determine whether a certain intervention didn’t work because it was ineffective or because it couldn’t be effectively delivered remotely.
Ultimately, the best option might be to use a hybrid of virtual and traditional designs to capture the most-diverse mix of patients, she said. “We might be able to recruit the most people, because you’d have the people wanting to come in who could come in and the people who prefer to do it virtually that wouldn’t otherwise participate would also be able to be engaged.”
- McDermott reports being an active clinical trialist funded by the National Institutes of Health, the American Heart Association, Regeneron, and Helixmith in the past 2 years.
- Januzzi reports research support from Janssen related to being senior author of the CHIEF-HF trial.
- Cohen and Walsh report no relevant conflicts of interest.