It took less than a week from the publication of Science 37’s whitepaper on March 12 encouraging virtual clinical trials to the FDA’s decision to endorse the idea, tailored to address the COVID-19 pandemic.
It was a decision years in the making, one so swift that it surprised the whitepaper’s author, who said the FDA up to this point had been unwilling to even use the word “virtual” because its mere mention evoked a feeling that the process was not real.
“It speeds up the trajectory we’re already on,” Science 37’s Jonathan Cotliar told BioWorld. “The basic tacit approval that the regulators are giving us is amazing. Even before the guidance and the whitepaper, we were inundated with sponsors who were desperately trying to help to keep studies on track.”
There are plenty of those. Numbers from a recent and ongoing survey from Continuum Clinical, a clinical trials enrollment company, show sites are feeling pressure from COVID-19-related interruptions to recruitment and retention. The concern among U.S. sites jumped 88%, from 25% to 47%, in a mere four days. In Europe, the survey showed, nearly 80% of sites feared their clinical trial enrollment would be negatively impacted.
Others have moved past the fear of delays and into the genuine article. Phathom Pharmaceuticals Inc., of Florham Park, N.J., temporarily paused new patient randomization in its phase III PHALCON-EE and PHALCON-HP trials because of COVID-19-related concerns. The decision, company officials said, was made out of an “abundance of caution” and not on any COVID-19 infections or safety events. American Society for Gastrointestinal Endoscopy guidance about limiting colonoscopies was part of the rationale, as were governmental travel restrictions.
It was much the same with Provention Bio Inc.’s pause in randomizing patients with newly diagnosed type 1 diabetes in its global phase III study of teplizumab. Logistics, particularly travel by patients, was a large consideration when making the decision.
“We would be asking CRAs and staff to travel as well,” Ashleigh Palmer, Provention’s CEO, told BioWorld. “We just felt it was the prudent thing to do, out of an abundance of caution, a phrase I’ve come to love. It just wasn’t wise to continue.”
The new FDA guidance doesn’t affect Provention’s decision, Palmer said, but it provided some stability in a constantly shifting clinical trials landscape.
“We thought the FDA guidance was great. It was spot on and confirmed our decision in how we think about things,” Andrew Dreschler, Provention’s chief financial officer, told BioWorld. “It was timely and well written.”
The guidance, self-labeled as “the current thinking“ of the FDA, offers more alternatives than just conducting trials virtually. Taking into consideration quarantines, site closures, travel limitations for patients and health care workers and supply chain interruptions for the candidates being investigated, the agency comes right out and said it’s “aware that protocol modifications may be required, and that there may be unavoidable protocol deviations due to COVID-19.” The document also states clearly in its introduction that it doesn’t establish any rights for any person, that it’s binding on neither the FDA nor the public and that alternative approaches are acceptable if they satisfy applicable statute and regulatory requirements.
It also clearly states that it does not establish legally enforceable responsibilities and “should be viewed only as recommendations.”
The nine-page document uses the word “virtual” twice, once when addressing efficacy assessments and once when commenting on safety assessments. The guidance recommends that sponsors consult with the appropriate review division regarding protocol modifications with the appropriate review division.
Regarding efficacy assessments, the FDA notes that “use of virtual assessments, delays in assessments, and alternative collection of research-specific specimens” should be reviewed with the agency. If efficacy endpoints are not collected, the guidance recommends documenting reasons for the failure.
Patient safety is a priority in the document. If trial participants are not able to visit an investigational site, sponsors are urged to evaluate alternative assessment methods, such as virtual visits and using an alternative location, when necessary and feasible. Sponsors are told to determine if in-person visits are necessary to fully assure participants’ safety when, for example, carrying out procedures necessary to assess the safety or safe use of the product. The same holds true for making the decision to continue use or administration of the product.
“The sponsor should consider whether the safety of trial participants can be assured with the implementation of the altered monitoring approach,” the guidance states.
Collecting data at home
Science 37’s Cotliar said that since the company was born little more than five years ago, the idea of virtual models for studies were front and center for the company, yet “people thought we were nuts. Collect data in the home? You can’t do that, were told, and we said, ‘Yes, we can.’ We can get high-quality data with a site-based model.”
Science 37 also recommends leveraging telemedicine-based physician visits, with virtual visits that can include physical exams, facilitated, if necessary, by a mobile research nurse in the participant’s home. It also points to the facility of at-home nursing visits to replace visits to the clinic by patients. Those visits can then collect blood and biospecimens, monitor vital signs, complete protocol-specified procedures and capture data. Shipping supplies to the patient, as the company recommends, eliminates the risk of patients traveling to research sites.
Circumstances shift rapidly, sometime daily as the pandemic spreads. Cotliar said market adoption of the model has, until now, been slow. Even if the changes are intuitive and common sensical, he added, regulatory agencies still need to have buy-in. Now they do.
“The FDA has been progressive over the five years we’ve been in the business, but they’ve never been willing to use the word ‘virtual,’” he said.
Now that the word has been positively invoked by the FDA, Cotliar said the company has been continually on the phone with trial sponsors, with personnel learning together on the fly what works and what doesn’t.
“It’s all hands on deck to field inbound inquiries,” he said. “Everybody’s scrambling to figure it out. It’s less about trial planning and it’s more about keeping ongoing trials going to ensure patient safety.”
Unprecedented level of interaction
Greg Dombal, president and chief operating officer at Halloran, a life sciences consulting company, clearly sees the FDA’s urgency in getting new options in front of researchers. In the past, he said, the agency has been slow to act with guidance but in this case he called it “spot on timely.” He said he is doing the best to protect safety with virtual steps.
“I was talking to a client this morning who’s doing an oncology study, which can turn into a remote visit, with Facetime or video, can reduce the number of times they come to the clinic,” he told BioWorld. “The FDA says to document and adjust. That’s a huge help.”
Dombal referred to patient and personnel safety as the single biggest challenge to companies and that adjustments, such as virtual visits, were something he would never have imagined while designing a trial would become reality six or even three months ago. The pandemic forced the agency’s hand.
“Thank god somebody said it,” he added.
Dombal said while the guidance isn’t the law, the comment period will pass and firm decisions will be made.
“We need input. This guidance document allows us to talk as a sponsor. That’s hugely important,” he said. “Even though the whole public debate before document is final, which might be three or six months, the FDA is putting it into practice today.”
If there’s a positive aspect to the pandemic and the changes it’s forcing, he continued, it is the “unprecedented level of interaction between sites, CROs, clients and the FDA.”
He said he is pleased and inspired to witness “the goodness in people, front-line health care workers who are unbelievable and the people who run clinical trials who are up there with them.”
Some market analysts also have noted the changes the pandemic is creating.
"Trials that are fully recruited and those involving the critically ill seem likely to go on without too much disruption," UBS analyst Laura Sutcliffe said in a note to clients. "The situation is less clear for other trials, and several companies told us it is too early to tell if there will be any impact."
RBC Capital Markets analyst Brian Abrahams on Thursday wrote that COVID-19 will have a meaningful “substantial impact on drug development for biotechs” with effects likely to reverberate the remainder of this year and beyond. He recommended that biotechs soften the blow of highly likely clinical study impacts from the pandemic by speaking transparently about potential risks to limit the future downsides as its effects become clearer with the passage of time.
As part of its ongoing coronavirus coverage, BioWorld is tracking the companies that have disclosed impacts to clinical trials.