By Deborah Borfitz

June 16, 2020 | The necessity of running clinical studies in the midst of a pandemic broke through some of the longstanding fears of sponsors and contract research organizations (CROs) about the adoption of telehealth technology and the decentralized trial model. Forced experimentation with both seems to be building consensus that doing research virtually is not only possible but could improve the participant experience, speed treatments to market and prompt better preparedness planning for future pandemics and emergencies.

Telehealth advocates have for years been touting digital solutions for a lot of what ails the research enterprise, including would-be study populations with uneven access to investigators and trials. Brick-and-mortar sites are largely clustered in major metropolitan areas, making participation inconvenient if not impossible for people in the middle of Nebraska, points out Jeff Kingsley, CEO of the multi-phase, multi-therapeutic integrated research organization IACT Health. But telehealth solves the problem only if sponsors and CROS make a complete pivot to virtual trials.

Very few have done so to date. Their preference—for many years now—is for a hybrid model where some data are collected in person and the rest remotely, says Kingsley. Collection of data from wearables and remote monitoring had become commonplace before COVID-19 hit, but virtual visits were rare and even eConsenting was still struggling for acceptance. “No one wants to be the first to have a [fully] decentralized trial.”

Pivotal studies are the last to be done in a purely virtual fashion, says Kingsley, although big pharma and small, venture-capital-backed biotechs have dabbled in the decentralized model for a few of their low-risk trials. The experimentation has been across therapeutic areas and, surprisingly, includes even phase I trials where home health nurses are dispensing drugs and drawing blood in patients’ living rooms.

If the pandemic doesn’t shake up the status quo it’s hard to imagine what would. “COVID-19 created the Wild West” where everyone—including institutional review boards (IRBs) and the Food and Drug Administration (FDA)—quickly adopted a “whatever it takes” attitude, Kingsley says, including relaxation of HIPAA laws and forgiveness of protocol deviations around the way informed consent happens, where safety labs get collected and how patient visits happen. “We were updating our pandemic response plan weekly in the early days because things were evolving so rapidly.”

Pretty much every trial sponsor and CRO is now using video conferencing technology to keep their trials running, continues Kingsley, and “everyone seems to be using something different.” Many companies are building their own platform, as IQVIA did several years ago atop Clinical Ink’s system for paperless trials.

Kingsley says he’s personally a fan of Microsoft Teams, since patients have only to click a link to connect with him virtually. Video sessions are “super easy” to record and they get saved to the cloud in a HIPAA-compliant manner.

The FDA, for its part, has been actively trying to champion innovation for several years now, adds Kingsley. In 2019, in the final days of his term, former FDA Commissioner Scott Gottlieb publicly scolded drug developers for their continued reluctance to adopt innovation.

Cost Perspective

Research is expensive, and early on many sponsors looked at the decentralized model as a way of cost-cutting, says Kingsley. The reality is that savings in one arena simply gets reallocated somewhere else, making it more of a cost-neutral proposition. Sites will get paid a lot less per patient per visit because they’re not doing the procedure work—e.g., EKGs, phlebotomy, and physical exams—but the savings gets offset by new costs associated with lab shipping costs and hiring nurses to make home visits.

The silver lining for sponsors, continues Kingsley, is that they can run their trials faster and get to FDA approvals sooner. Decentralized trials are “absolutely more profitable despite the fact that your trial budgets don’t go down.”

But if they want “good, serious investigators” on those studies, sponsors can’t slash physicians’ budgets so low as to threaten their existence or they’ll stick to the brick-and-mortar studies, Kingsley says. And everyone knows high-performing investigators are in critically short supply.

In the not-too-distant future, it’s conceivable that sponsors will be able to use the decentralized model for a cardiac trial and have one of the best cardiac surgeons in the world be the principal investigator who covers every state in the country, says Kingsley. Although investigators aren’t currently doing research in states where they don’t hold a medical license, the FDA has been pondering the implications of the coming “potential reality,” Kingsley adds.

A colleague involved in a decentralized trial recently reached out to medical boards across 20 states to learn none of them considered clinical research under their purview. But investigators will need to recognize when they’re a scientist and not a doctor, because the licensing rules still apply to medical care.

“Today, if I see a patient in a migraine trial and find out she is anemic, I can go ahead and diagnose her and order her some iron tablets,” Kingsley cites as an example. “If I now see a patient in Ohio where I don’t have a medical license, I can document the adverse event, but I can’t write her a prescription. I’d need to contact a physician in that state.”

Patient Voice

What remains largely unknown is how trial participants feel about virtual study visits relative to ones at a brick-and-mortar site, says Irfan Khan, CEO of integrated research organization Circuit Clinical. But the company’s digital platform, TrialScout, may be able to help. It was purpose-built to not only assist patients in finding trials but to amplify their voice in the research process.

The original intent of TrialScout was to get quick feedback from participants on their experience either at the start of a study or on a visit-by-visit basis, to gauge their satisfaction with the research process and their likelihood of returning, explains Khan. The goal was to lower the trial dropout rate—which has been hovering at around 25% across the board—by focusing efforts on the underperforming sites.

The TrialScout rating system works much like other online review systems. Trial participants can opt to rank their research center on a 1-to-5- star scale and offer commentary on the experience.

Up to now, TrialScout has been used to rate the patient experience with in-person encounters. But as studies drift into the virtual realm, sponsoring companies may want to start assessing perceptions about remote visits.

Virtual trial visits are now being viewed as a necessity, with adoption over the past three months exceeding the uptake over the past two years, Khan says. This would be a good time to learn if they do or don’t deliver an experience as “equivalently pleasant” as on-premise visits.

From a patient convenience standpoint, virtual visits seem to make sense. “The tradeoff is that we all like seeing our care teams,” says Khan. “There is something to be said for the physical space we share during face-to-face visits.”

The big paradigm shift moving forward is that sponsors and patients are both going to want more choice from sites,” he continues, including study visits that can flexibly happen in the office or from home. Sites, site networks, and integrated research organizations providing that “two-sided choice” will do very well in the post-COVID environment, he predicts. Having a well built out Plan B could also help prevent clinical trials from coming to a standstill the next time disaster strikes.

New Appetite for eConsent

Delve Health has been supporting trials with technology for 20 years now and had to quickly stand up TeleVisit functionality within its Clinical StudyPal application when COVID-19 hit the U.S., says CEO Wessam Sonbol. An eConsent module was a planned enhancement already in the works. Both were newly announced additions to the comprehensive mobile and web app, designed to help sponsors make their trials “as virtual as possible.”

Traditionally, Clinical StudyPal was used primarily for collecting patient information remotely via integration with wearables or patient-reported outcome (PRO) measurement tools. One of its most utilized features remains an eDiary for the collection of PROs, in part because it doesn’t require participants to download an app, says Sonbol.

Equally popular is SMS text messaging for sending out reminders to trial participants, which has been associated with 95% compliance in responding to diaries and ePRO questions but can also be used to quickly collect patient information in real time. Text messages don’t get lost or routed to a spam folder as do reminder emails, he notes.

The eConsent enhancement is being embraced at unprecedented speed—which can be directly attributed to COVID-19, says Sonbol. Using Clinical StudyPal, sites can push out informed consent documents to participants who can then use the app to send back a secure message to the investigator regarding anything they don’t understand.

TeleVisits are being used primarily by the existing customer base for Clinical StudyPal’s PRO capabilities in lieu of requiring participants to periodically make site visits in person, Sonbol says. In some cases, patients have been allowed to substitute virtual visits with their primary care physician for the customary, in-person visits with their hospital-based investigator.

The teleconferencing platform has Zoom-level video quality, Sonbol says, but was built in-house to be compliant with the documentation requirements of HIPAA, FDA 21 CFR Part 11 and the EU General Data Protection Regulation.

Keeping patients engaged during a trial—from “point zero” until study close—is a central mission of Delve Health, says Sonbol, and a perennial problem in the industry. Currently, 70% of patients live at least two hours from the nearest clinical trial site and between 25% and 40% of participants drop out of studies for reasons that include simple loss of interest.

Gaming is among the tactics utilized. Study teams can use Clinical StudyPal to send out fun, trivia-type questions to participants to help keep them engaged with sites. Their response (or lack thereof) provides a “different perspective” on how they’re feeling about the trial experience and their likelihood of skipping study visits so corrective action can be taken, he says.

Sonbol says clients using Clinical StudyPal are mostly small and medium-sized biotech and biopharma companies, as well as a few large companies specializing in oncology. Delve Health has been involved in only a couple trials that are 100% virtual, and four that have transitioned to the hybrid model since the pandemic struck the U.S.

More Robust Process

At Boston Medical Center (BMC), clinical trialists are now consenting study participants electronically—most for the first time in their career—to limit COVID-19 transmission risk and use of a reduced supply of personal protective equipment. Since most clinical research unrelated to the coronavirus has until recently been put on hold, the patients targeted for enrollment have predominantly been those with COVID-19, says hematologist Mark Sloan, M.D., also an associate professor of medicine at Boston University School of Medicine.

It has been an “extraordinary challenge” to consent patients who are on high levels of oxygen and may be too sick to even pick up the telephone, Sloan says. Nurses can assist with telephonic communication, but it can involve a lot of shouting to be heard over the buzz of in-room equipment.

The hospital was also worried about “consent fatigue” among patients with the novel coronavirus who were in high demand for a wave of newly launching studies, he adds. Plus, language interpreters sometimes have to be integrated into the consent process to accommodate the diverse populations served by BMC.

“Some of the barriers are very logistical,” says Sloan, noting a protocol that requires the sign-off of a patient’s care team once an individual has been identified and deemed eligible for a trial. That can be more difficult for trials where COVID-19 patients have to be treated within certain time parameters, such as 48 hours post-admission.

Sloan faces a slightly different challenge with his study of the chemotherapy medication etoposide among intubated COVID-19 patients in the ICU who are on a ventilator and unable to give informed consent. Families and legally authorized representatives are the ones who need to be educated and give consent on behalf of patients, and “they’re very hungry for information.”

In lieu of in-person visits, Sloan says he chats with the various decision-makers by telephone before emailing them the informed consent documents to review. He then schedules a Zoom meeting to go over the particulars and answer any questions. The meeting might involve a patient’s entire family as well as himself, the study team and ICU clinicians involved in the person’s day-to-day care.

Having everyone together in this “technologically optimized” way has had its advantages, says Sloan. “I have appreciated the opportunity to have everyone who wants to be [in on the consenting process] be there remotely. It doesn’t matter if the brother lives in California and the sister is in Florida; everyone can chime in and be on the same page. It’s great to see families discussing what they see as the benefits and risks of clinical trial participation amongst themselves.”

Consenting discussions often happen on several occasions, Sloan says, because families take their responsibility seriously. In fact, eConsenting in this way seems to be a more robust process than might typically take place—and with good reason.

In his oncology practice, says Sloan, he has a preexisting relationship with patients and their entire care team. “When I’m recommending clinical trials, I already have some authority with them, and they trust me.” But even then, he adds, there is at best a couple people engaged in informed consent. “I think [eConsenting] has made us all recognize that the act of informed consent is more than a signature on a piece of paper.”

The need to veer from the way informed consent traditionally happens is something every research institution is grappling with, says Sloan, and some have opted to use DocuSign technology. “The success of that depends on the general technological literacy of the patient population, and if the [hospital-grade version of the] technology is available.”

Post-Pandemic Realities

The waiver of HIPAA sanctions and penalties is likely to go away rapidly once the pandemic passes, says Kingsley, meaning no more telemedicine visits via FaceTime. But the immersive telehealth experience won’t leave clinical research untouched.

People are going to feel more comfortable using digital technology and also have a “healthy fear” of the virus recirculating until a vaccine is found, he continues. Even as life starts to return to normal in some countries, sponsors will be wanting to build “safety valves” into protocol design.

Yet they remain united by fear rather than a true innovation mindset. “Everyone says they’re on the cutting edge… now have patient teams within their company, but the reality is that very few research trials are actually pushing into that innovative realm,” Kingsley says.

He cites as an example a COVID-19 trial recently offered to IACT Health. “There was absolutely no reason the patient population had to be hospitalized, yet the sponsor was mandating it for control reasons. They simply wanted patients locked in a room, so they’d know a nurse was looking down on them when it was time to take their dose at 8 a.m.” It’s not an attitude that bodes well for the decentralized model.

Kingsley says he has been in conversations with dozens of sponsor representatives touting their company’s resolve to build flexibility into protocol design. But he has yet to see a single protocol that gives patients the option to be seen in person or virtually.

Protocols also tend to not give participants the choice of getting standard lab tests done locally, says Sloan. “Travel for clinical trials is super common and we sort of forget even in good times how arduous it is for patients to come back for a lab check when they live in another state. Just because local labs aren’t on the research documentation doesn’t mean that their blood counts are invalid.”

Overall, “telehealth has been a real learning curve for everyone,” Sloan says. But it does “work very well”—especially for clinical trial participants who tend to be the most sophisticated patients out there. “People at least understand a lot more about clinical trials than they did before COVID.”

Patient communities could be playing an important role in simulation exercises during the study design phase, helping sponsors purposefully plan for research participation to be as pleasant and engaging as possible, says Khan. While it is true that the American public has come to think more highly of clinical trials as a result of the pandemic, there is no guarantee that the sentiment will translate into making individuals easier to enroll or retain in trials. “People are very tired, have a lot on their plate and are struggling financially.”

They also may not have a good internet connection, especially if they reside in a rural area, Khan adds. The good news here is that sponsors are starting to stand up telehealth infrastructure and becoming more thoughtful about socioeconomic barriers to technology adoption that can create or enlarge disparities.