In order to redirect health care resources and protect patients during the COVID-19 pandemic, many drug companies have paused enrollment in some or all of their ongoing clinical trials. But patients still in the studies need to be followed for safety and efficacy, creating challenges for the industry.
"Ongoing trials have potential to benefit millions of people with debilitating chronic diseases long after the coronavirus pandemic has ended," Mary McDermott, of Feinberg School of Medicine at Northwestern University, and Anne Newman, of University of Pittsburgh Graduate School of Public Health, wrote in a viewpoint in JAMA. "Furthermore, discontinuing ongoing trials wastes previously invested resources and squanders the time and effort of participants who may have already completed the trial."
RBC Capital Markets analyst Brian Abrahams noted that the pause will have a major effect on the industry. "In addition to pushing out timelines, clinical trial disruptions also put significant up-front investment for companies at risk and delay potentially meaningful therapeutic agents from reaching patients, and we anticipate further setbacks as all trials for non-life-threatening conditions experience some form of pause," Abrahams wrote in a note to clients on March 26.
On April 2, the FDA issued updated guidance for the industry, investigators and institutional review boards on how to run clinical trials for medical products during the COVID-19 pandemic.
"These challenges may lead to difficulties in meeting protocol-specified procedures, including administering or using the investigational product or adhering to protocol-mandated visits and laboratory/diagnostic testing. FDA recognizes that protocol modifications may be required, and that there may be unavoidable protocol deviations due to COVID-19 illness and/or COVID-19 control measures," the guidance reads.
Despite the challenges, the agency notes that "ensuring safety of the trial participants is paramount … In all cases, it is critical that trial participants are kept informed of changes to the study and monitoring plans that could impact them."
McDermott and Newman concurred about keeping patients informed, noting that "communication from research staff is likely to help protect against dropout or nonadherence by reassuring participants that their trial involvement remains important, even during the pandemic."
While clinical trial sponsors usually have to gain approval by institutional review boards (IRBs) and sometimes the FDA, the agency is waiving that necessity in some cases. "Such changes to the protocol or investigational plan to minimize or eliminate immediate hazards or to protect the life and well-being of research participants (e.g., to limit exposure to COVID-19) may be implemented without IRB approval or before filing an amendment to the IND or IDE, but are required to be reported afterwards," the FDA noted in its nonbinding recommendations.
If scheduled visits can't be conducted, the FDA notes that the reasons for missing data should be well documented to help the sponsor and the FDA. In some cases the trials may require amendments to the data management and/or statistical analysis plans, but the FDA would like to have a discussion about companies' plans. "Prior to locking the database, sponsors should address in the statistical analysis plan how protocol deviations related to COVID-19 will be handled for the prespecified analyses."
In addition to patients not being able to go their clinical trial sites, monitors of clinical trials who ensure the integrity of the studies may not have access to sites. The FDA notes that "sponsors should consider optimizing use of central and remote monitoring programs to maintain oversight of clinical sites."
To help facilitate the remote monitoring, Veeva Systems Inc., which has a suite of cloud-based clinical trial products, added remote monitoring capabilities to its offerings. "We decided to accelerate the development of the source document remote monitoring capabilities,” Jason Methia, vice president of site engagement and ETMF at Veeva, told BioWorld, noting that it added the capabilities in just four or five days.
While clinical trial enrollments are paused, sponsors can take the opportunity to identify potential patients for the study once enrollment restarts. "While baseline in-person visits will not be possible during the pandemic, self-isolation facilitates telephone eligibility screening by staff working from home, who may have few other study activities they can carry out. Potentially eligible participants who are identified should be encouraged to attend study visits later," McDermott and Newman noted.
"To maximize public health benefits, creativity and persistence are required, especially during these unprecedented and uncertain times," McDermott and Newman concluded.
Over the last few years, many companies, including Los Angeles-based Science 37 Inc. and Medable Inc., of Palo Alto, Calif., have sprung up to help sponsors with decentralized clinical trials to reach patients where they're located, albeit with limited success.
"The industry being so risk adverse – everyone kind of wanted to wait for others to test out the model and feel more comfortable once it's established," Ching Tian, senior vice president of strategy and solutions at Medable, told BioWorld.
Now those risk-adverse companies are rapidly adopting decentralized trials to keep patients where they are. "COVID-19 absolutely underscored this need for the industry to really become more aggressive in adopting technologies," Tian said. "With COVID-19, all of a sudden everyone is being caught unprepared."
While decentralized studies offer the opportunity to record many endpoints virtually, patients often still have to go into a clinic for some tests, such as blood tests. To reduce the burden during the pandemic, Medable recently enlisted the services of Medical Research Network Ltd., of Buckinghamshire U.K., a global provider of home health care and site nurses for clinical trials.
"Home nursing has been in existence probably for 10 years at a minimum, but it's really deployed as a niche service in rare disease patient populations just because it's so difficult to run those trials without such support," Tian said. "Our technology completely enables decentralization; however, there are still needs for services, such as a home nurse that can make the decentralization even more comprehensive and further enhance our goal to reduce the burden on patients – make it convenient for patients – and even, to some degree reduce the burden on sites."
In its guidance for clinical trials during the pandemic, the FDA notes that sponsors should consider "phone contact, virtual visit, alternative location for assessment, including local labs or imaging centers" as potential ways to maintain visits during the pandemic.
Veeva's Methia said he sees the pandemic as an opportunity for companies and the FDA to come together and embrace remote monitoring. "It's something that folks have been dabbling in, but we still haven't fully implemented virtual capabilities to run decentralized hybrid trials. I think COVID is forcing the industry to think about ways to run trials more virtually that, honestly, are things that we probably should have done years ago."
Ramping up as well
At the same time as clinical trial enrollment is shutting down, Methia noted that many companies are also ramping up clinical trials for treatments and vaccines for COVID-19.
"You have clinical trial activity that is being ramped up and in many ways is being executed in ways that clinical trials have been trying to push towards for years," Methia said, noting that companies are "coming together and working in a collaborative way that I've really never witnessed with an amount of speed that really I've honestly never really seen before."
Methia noted that different technology vendors that would have been competitive in the past are more willing to work together to get the clinical trials running. "That trickles all the way down to regulators and ethical committees," Methia said. "We're seeing this openness, I think, from regulators to be a little bit more flexible around some of the red tape and bureaucracy that we typically see from the client standpoint in clinical trials. I hope some of that flexibility, some of that openness without compromising patient safety can continue to persist when this thing is all said and done."