Running clinical trials for other drugs in the age of COVID-19

The COVID-19 pandemic and efforts to contain it have caused an unprecedented slowdown in clinical trial activity. With people stuck at home and healthcare systems focused on COVID-19, the core tasks of getting participants into studies, treating them and monitoring the outcomes has stuttered. Yet, there are already hints of a recovery, with drug developers adopting digital technologies and shifting their focus to countries that have the virus under control to keep key programmes moving forward.

Signs that the coronavirus would have a chilling effect on clinical research emerged as the pathogen spread from Wuhan early in 2020. In February, for example, IQVIA CEO Ari Bousbib told investors Chinese “patients are simply not going” to clinical trial sites. Within weeks, a situation that had been unique to China was replicated around the world.

In quick succession, companies including Bristol-Myers, Eli Lilly and Pfizer changed their strategies in response to the virus, typically by halting enrolment in many ongoing studies and delaying the start of most new clinical trials. The actions and situation that triggered them had a big impact on studies, with Medidata tracking a 65% year-on-year drop in new patients entering clinical trials in March. By mid-May, another analysis showed COVID-19 had stopped almost 1,300 clinical trials.

The fallout

The implications of the slowdown are still coming into focus. Upon unveiling the changes to its trial activities, Lilly said it expected the actions to affect the timing of read-outs from tests of mirikizumab, an anti-IL-23 antibody that the company is studying in gastrointestinal indications. Mirikizumab is unlikely to be the only drug affected.

Addex Therapeutics’ situation illustrates the challenges facing many companies that were preparing to start clinical trials as the pandemic escalated. Going into the year, Addex expected to start a phase 2b/3 clinical trial of dipraglurant in Parkinson’s disease patients imminently and deliver data in the third quarter of 2021.

By March, COVID-19 had forced Addex to delay the start of the trial. At the time of writing, Addex hopes to start the trial in the second half of the year and post data in 2022.

The new timeline, which is subject to the lifting of restrictions in the US, pushes the conclusion of the trial past the end of Addex’s cash runway. That situation is echoed across biotech, as evidenced by a pandemic-driven slowdown in Erytech’s phase 3 pancreatic cancer trial that, according to a Jefferies analyst estimate, is set to delay top-line data until after the company will have run out of money. The financial model of venture-backed biotechs means other companies are in similar positions.

Even studies that are fully enrolled and sponsored by well-financed companies could be negatively impacted by COVID-19, particularly if subjects need to be assessed in person to collect data against primary or key secondary endpoints. In theory, the inability to get patients scanned at a particular point after starting treatment could affect the integrity of trials, for example by preventing sites from taking a 12-week MRI to compare to baseline.

The aforementioned analysis by Medidata tracked a 17% drop in visits per subject globally between October 2019 and March 2020. China, the bellwether for COVID-19, suffered a 30% decline between October and February but partly recovered in March, suggesting the downward trend seen in the US may steepen, but also offering encouragement that recovery is possible.

A reduction in site visits will mean gaps in the data. With longer gaps between in-person contact, some subjects may be lost to follow-up, adding to concerns about the integrity of a trial and validity of its findings.

The response

The continued need to gather certain data in person means some trials will be unavoidably affected by COVID-19. However, the pandemic hit at a time when, for more than a decade, the industry had been exploring ways to cut the need for in-person interactions, giving many sponsors access to tools that could help them work around restrictions imposed by the pandemic.

In explaining why it expects COVID-19 to have little impact on its late-stage timelines, AstraZeneca cited “home-based treatment and monitoring options” as an example of how it is adapting. Sanofi is deploying similar approaches and technologies, even using smart glasses to conduct site inspections remotely.

Regulators are supporting such mitigation measures with guidance and revised enforcement policies designed to stop COVID-19 from disrupting trials. In the UK, the Medicines and Healthcare products Regulatory Agency is allowing sponsors to switch from in-person visits to phone calls without filing a substantial amendment. Other agencies have adopted similar policies.

The technology exists for clinical trials to be fully or mostly virtual. However, while advocating for the use of technology to manage studies during the pandemic, Steven Cutler, CEO of clinical trial service provider Icon, cautioned against trying to make the switch away from physical sites at this time.

“This is not the time to be setting up virtual trials or hybrid trials,” Cutler said. “We need a more stable environment, I think, in order to actually move that forward.”

It is currently unclear when a more stable environment will emerge, but the situation in China offers some insights into how the global story may play out. During the eight weeks in which the crisis in China was at its most intense, IQVIA was unable to access around 80% of its clinical trial sites in the country. The situation began to improve in March, with just 40% of sites inaccessible by the end of that month, and returned to normal outside Hubei in April. Icon described a similar situation.

The fact that many Western countries imposed less rigorous lockdowns than China suggests the recovery may take longer in those nations, a consideration that led service provider PPD to model a slower rebound in the US and Europe. Demand returned faster than PPD expected in China.

Despite the prospect of ongoing restrictions in key markets, sponsors are getting back to work. Pfizer, which stopped enrolment in many new and ongoing trials in March, restarted recruitment and study initiations at operational trial sites in April. Broadly speaking, sponsors expect to hit prepandemic targets for clinical trial read-outs.

The next steps

For sponsors running pivotal trials, the next step after delivering data could be a filing for approval. That brings more uncertainty. In March, the FDA postponed an advisory committee meeting to discuss Intercept Pharmaceuticals’ obeticholic acid and GlaxoSmithKline’s Trelegy Ellipta.

At the time, Intercept expected the FDA to hold the meeting on 9 June, weeks before the deadline for reaching an approval decision. However, the FDA later postponed another meeting scheduled for 9 June as part of the “necessary steps” it is taking to continue its “vital public health mission”.

The FDA last held an advisory committee in February. The FDA has begun holding some meetings virtually but, as of mid-May, it was unclear how widely it would adopt the approach. Across the Atlantic, the European Medicines Agency has said it will hold all meetings virtually until August.

Companies at other stages in the process of coming to market are suffering too, as illustrated by bluebird bio. The company delayed the European launch of its gene therapy Zynteglo in response to the pandemic, and cited the virus as a factor in its rolling FDA submission taking longer than planned.

For such reasons, and many others, the coronavirus is set to delay access to new medicines. Yet, as sponsor responses to the crisis show, there are ways to reduce and prevent delays. Ultimately, the unmet medical needs that led companies to start drug development programmes have not gone away. The challenge is to address those unmet needs at a time of social distancing and reduced travel.