The urgent need to have at least a few proven COVID-19 therapies approved in the U.S. before the pandemic’s expected resurgence in the fall has become biopharma’s Manhattan Project – a coming together of industry, researchers and government agencies to take on a single global enemy in an effort that could fundamentally change future drug development by introducing more efficient ways of demonstrating safety and efficacy.

The monumental task has highlighted challenges of conducting clinical trials during a pandemic and the need for greater interoperability, not only of electronic health records but of clinical trial data systems with those records. It’s also raised questions about why it takes so long to collect and analyze trial data in this era of machine learning and AI. And it’s pointing to a greater role for real-world data (RWD).

With nearly 747,000 confirmed cases in the U.S. as of Monday, there’s no shortage of potential COVID-19 trial participants. But with 72 potential therapies already in trials and another 211 development programs in the planning stages, according to the FDA, the agency and front-line health care providers have their hands full as they try to manage all the requests. (As of April 16, the FDA had received 950 inquiries and proposals concerning COVID-19-related drug development.)

Given the urgent timeline, the FDA created the Coronavirus Treatment Acceleration Program (CTAP) to evaluate proposals for possible therapies. Under CTAP, the agency said it’s using “every available method to move new treatments to patients as quickly as possible, while at the same time finding out whether they are helpful or harmful.”

Considering the volume, the FDA is having to prioritize the strongest proposals for review based on their scientific merits. As a result, the agency is able to turn around documents and reviews in record time, Robert Walker, chief medical officer and director of the Division of Clinical Development at the Biomedical Advanced Research and Development Authority, said Monday in a Duke-Margolis Center webinar on developing a therapeutic response to COVID-19. In many cases, the FDA has responded within 24 hours, Walker added.

“It’s an unprecedented time for all of us,” Walker said, noting what he described as an “incredible degree of collaboration and coordination” across the government and industry.

Trial challenges

Despite that collaboration, there are still challenges in conducting the gold-standard randomized, controlled clinical trials (RCTs) that demonstrate a drug’s safety and effectiveness in response to a pandemic. For one thing, the trials need to be streamlined and make sense for health care workers who are already overloaded with patient care, said Pamela Tenaerts, executive director at the Clinical Trials Transformation Initiative at Duke University.

While the coronavirus has spread to every state in the country, sponsors are likely to seek trial sites in hot spots, such as New York. With more than 238,000 cases confirmed as of Monday, New York accounts for nearly a third of the U.S. coronavirus infections. Neighboring New Jersey has the second highest cases in the country with about 85,000.

When planning a trial in hot spots, sponsors must keep in mind that administering the trial drug and collecting data is on top of everything else that is going on at that site, Tenaerts said. The concern is not adding to their burden as they struggle to keep patients alive.

To incentivize U.S. doctors to take on the extra work, the Centers for Medicare and Medicaid Services announced Monday that clinicians can now earn credit in the Merit-based Incentive Payment System (MIPS) for participating in COVID-19 trials. Doctors who report the COVID-19 trial activity will automatically earn half of the total credit needed to earn a maximum score in the MIPS improvement activities performance category.

In light of the need for therapies and the number of drugs that could be tested, sponsors should focus on quality trials and consider master protocols that enable multiple drugs to be tested against a control arm in one trial, Tenaerts said. Currently, 25 master protocol trials testing potential COVID-19 therapies are being conducted around the world. One international trial, in pneumonia, preexisted the pandemic, Tenaerts said. When the coronavirus started spreading, a COVID arm was added to the protocol.

The control arms in master protocols are critical, Tenaerts said, as many of them call for standard of care (SOC). Since the SOC at several hospitals treating COVID-19 patients is the off-label use of hydroxychloroquine, those hospitals couldn’t be sites for a trial evaluating the safety and efficacy of the antimalarial in fighting the coronavirus.

Tenaerts warned that small trials will not provide the robust answers that are needed. Many trials have had no problem with enrollment. For instance, a trial testing Gilead Sciences Inc.’s remdesivir recently closed enrollment at 900 – 400 more than originally planned. And a U.K. trial enrolled more than 1,000 patients in less than a month. However, enrollment could become an issue as the epidemic ebbs and flows, Tenaerts said.

The biggest challenge with RCTs for quickly spreading infectious diseases is making them move faster, said Luciana Borio, vice president for technical staff at In-Q-Tel, a venture capital firm. Speeding the process requires broad inclusion criteria, rethinking the endpoints for infectious diseases and accelerating the collection and analysis of trial data, Borio said.

She questioned why it takes months after a trial ends to collect and analyze the data. She also pointed out that trial software doesn’t interface with EHRs, which adds to investigator workload and complicates data collection.

RWD role

While trial data is critical, the FDA is recognizing the role RWD could play in responding to the pandemic. Faced with the urgency to learn as much as it can as soon as possible, the agency is scouring existing data sources. “It certainly takes us out of our comfort zone at FDA,” said Amy Abernethy, the agency’s principal deputy commissioner.

“We need to figure this out right now,” Abernethy said of COVID-related RWD. She noted that patient EHRs are critical to this effort, especially datasets that reflect the experience in hospital intensive care units. “That’s a story that keeps changing,” she added.

The FDA is using RWD about the use of hydroxychloroquine as a platform for figuring out how best to use such data in an emergency, Abernethy said. What the agency hopes to learn from currently available data is what questions need to be answered, which can be answered immediately, and which will require clinical trials. With some providers using hydroxychloroquine as an off-label treatment and others not, researchers can look at that data and develop hypotheses for further testing.

The FDA isn’t the only one looking at RWD in the context of hydroxychloroquine use. Members of the payer community are pooling their claims data for evidence to inform COVID-19 treatment and to identify questions that need to be answered, said Cigna Chief Clinical Officer Steve Miller. As part of that effort, they’re looking at the claims data of people who use hydroxychloroquine to treat lupus or rheumatoid arthritis to see if there’s evidence the drug worked as a prophylactic against COVID-19.

“We need to innovate our way out of this,” Miller said. For him, the silver lining is a heightened level of cooperation among industry, payers, researchers and regulators.

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