By Deborah Borfitz

March 2, 2021 | A keynote address earlier this morning during opening ceremonies of the 2021 Summit for Clinical Ops Executives (SCOPE) offers glimmers of hope that the notoriously rigid clinical trial process may retain at least a few of the warp-speed changes introduced by the COVID-19 pandemic. The forecast on the new-normal research landscape is courtesy of Ken Getz, MBA, founder of the Center for Information and Study on Clinical Research Participation and director of the Center for the Study of Drug Development (CSDD) at Tufts University School of Medicine, and Leonard Sacks, M.D., associate director in the Office of Medical Policy for the Center for Drug Evaluation and Research of the U.S. Food and Drug Administration (FDA).

One of the most notable, pandemic-inspired operational changes is that “stakeholders throughout the clinical research enterprise have become more accommodating,” according to Getz. Out of necessity, they are readily adapting and adjusting “to help every other stakeholder succeed in a highly uncertain environment.”

From that mindset sprung unprecedented “openness and willingness” to collaborate and pivot to operating models that are more virtual and rely on remote data capture and more frequent interim data analysis to inform decision-making, Getz says. High visibility of the research enterprise also positively impacted the willingness of the public and patient communities to “root” for the research cause.

The most enduring lesson learned during the pandemic is the value of remote trials, which is also the focus of FDA-issued Guidance on Conduct of Clinical Trials of Medical Products During the COVID-19 Public Health Emergency, says Sacks. In addition to protecting patients and staff from infection with the virus, the decentralized approach has significant long-term value in making it easier for individuals to participate in studies by allowing clinical trial activities to take place at or near their home.

Decentralized clinical trials could be particularly appealing to people who live far from study sites or have difficulty traveling due to mobility or cognitive difficulties, continues Sacks. Their adoption would also “open the door to more continuous gathering of trial data directly from patients rather than intermittently as we do with site-based trials.”

FDA guidance addresses the conversion from face-to-face to remote visits using telephone or video chats, local healthcare providers to perform study-related functions such as blood draws and routine medical tests, electronic informed consent, direct-to-patient shipment of investigational products, and remote monitoring from a centralized location. The agency also supports these “building blocks of a decentralized clinical trial … when the safety of patients is threatened,” which Sacks says are likely to be increasingly applied to trials in the future .

For many years now, the FDA has encouraged pre-competitive collaboration between drug developers with the support of the independent Critical Path Institute (C-Path), whose biomarker development work has been most impactful, Sacks says. The agency has qualification programs for biomarkers as well as clinical outcome assessments, such as patient-reported outcomes, facilitating preclinical data sharing across companies.

A qualification program for digital health technologies is now under discussion, adds Sacks, and all these tools may prove to be significantly useful in decentralized clinical trials. The FDA also provides online access to reviews of approved drugs and clinical trial methodologies used to support drug approvals. “The sharing of data is really crucial to capitalize on the cumulative experience we gain from clinical trials,” he says.

Some of the available information is relevant to decentralized trials, including how remote visits were conducted and how an investigational product was distributed, and some of the experiences pre-date COVID-19, says Sacks. For example, a remote study for the overactive bladder drug tolterodine was “an excellent learning experience” for the drug development community because it emphasized the demanding nature of enrollment procedures for decentralized trials.

Greasing the Skids

Much of the industry collaboration that has happened was born out of pre-competitive groups such as TransCelerate, says Getz. To help companies collaborate more effectively, the Tufts CSDD may gather de-identified benchmark data and share the information and insights between parties.

The pandemic has “revealed … places where we could grease the skids to make sure a collaboration has room to maneuver, where we identified the priorities where we could treat some of our standard operating procedures with a little more flexibility,” Getz continues. Information-sharing has become “sort of real time.”

At the very least, the insight that “we can do this” should stick, he notes. Late-stage COVID-19 vaccine trials sped through clinical testing to Emergency Use Authorization at a time reduction of 75% to 80% relative to pre-pandemic norms.

The discouraging news is that that there is “a lot of resistance” to seeing this level of collaboration translate into ongoing, long-term behavior, says Getz. In his view, changes wrought by the pandemic will not stick unless the complexity level of studies is also addressed.

Trials today tend to be highly customized—and even more so when introducing hybrid, remote, and virtual support, he says. Eligibility criteria is growing more complex to accommodate improvements in diversity and inclusion, challenging cycle times and often raising the cost and efficiency of drug development. 

Getz is a longtime advocate of patient-centric trials, but even a decade into the patient engagement movement such practices largely remain stuck in pilot mode, he says. Among the exceptions are the use of more convenience-enhancing approaches, such as the collection of data on wearable or handheld devices, which have been popular during the pandemic. “Unfortunately, we don’t have a good read on whether [such tactics] are impacting our cycle time because they are still relatively new and isolated more to anecdotal cases as opposed to being in widespread use,” says Getz.

However, sufficient data has amassed to recommend the use of advisory boards where patients have input on protocol design, which are associated with fewer substantial amendments and improvements in cycle time, he adds. Recent studies also indicate that transparency and disclosure in communicating trial results and communicating informed consent in plain language tend to have a positive relationship with retention rates in studies and higher levels of satisfaction with the participation experience. 

Drug Repurposing

The practice of repurposing existing drugs to treat emerging and challenging diseases has been of interest to the FDA for at least the last decade and COVID-19 is now its “poster child,” says Sacks. “Repurposing of drugs is our only option in the short term.”

Drug repurposing was initially envisioned primarily for rare and neglected diseases that companies had no commercial incentive to invest in and has been a successful practice for many diseases—e.g., the vasodilator drug sildenafil has been approved for both the treatment of erectile dysfunction and hypertension. “During the Ebola outbreaks in West Africa people scrambled for treatments, but unfortunately the gathering of information was very disorganized and the data on off-label use was not interpretable,” Sacks recalls.

“COVID is different,” he quickly adds. “People have really focused on repurposing.” The corticosteroid dexamethasone, for example, has become standard for the treatment of COVID-19.

Additionally, the FDA is collaborating with the National Institutes of Health and C-Path to “systematically capture the repurposing experience … to identify drugs that are promising and to study them further,” Sacks says. “Repurposing has appeal because the safety of approved drugs is well understood so a lot of the preliminary safety studies are not needed.”

To help establish reliable information on the benefits and risks of drugs for new purposes, the FDA and NIH have created the CURE ID platform that is crowdsourcing novel, real-world experiences with approved drugs, including those being used to treating COVID-19 patients who are unable to be enrolled in a clinical trial. “These in turn will have to be studied in more depth to support regulatory actions,” he notes.