Survey says: Companies seek regulatory flexibility as COVID-19 makes clinical disruptions the new norm

COVID-19 is no longer an approaching threat to clinical trials; now the concern for biotechs is how to manage their trials through the crisis. A joint survey from BioCentury and BIO finds on-the-fly protocol amendments are fast becoming a necessity, and companies want assurance regulators will be flexible with the resulting datasets.

Over three quarters of the 99 survey respondents said their ability to start new trials or to continue active trials has been hindered by the coronavirus outbreak (see Figure: “COVID-19: Clinical Trial Disruptions Become the Norm”). The survey was conducted from March 16-19, and only full responses were included in the statistics.

The concern is accelerating; at the start of the month a BioCentury survey found under 20% of companies considered a clinical trial delay very likely. The remainder were split with 37% thinking a delay unlikely, and 44% responding that a delay was possible (see “BioCentury Survey”).

Public announcements of suspended trials have started to roll in. In the current survey from BioCentury and the Biotechnology Innovation Organization (BIO), fifteen companies reported that they had delayed the start of one or more clinical trials, and six said they had suspended enrollment of one or more ongoing studies.

Companies have told BioCentury that cancer trials are the most likely to continue. But for most non-life threatening conditions, especially where patients are immunocompromised, they may be better off staying home than risking exposure at the clinic (see “Under Duress, Biotechs Will Have to Make Hard Decisions”).

However, biotechs have limited options for trials under way. Making procedural changes midstream introduces regulatory risk, which cascades to commercial risk. In some cases, even if companies adopt new practices such as remote monitoring, it’s unlikely they can do so fast enough to reach a milestone.

FDA will see its own slate of work expand. While companies will need assistance from FDA in the form of guidance and flexibility, the agency will be simultaneously trying to expedite a large volume of development of programs for COVID-19.

The respondents represent a mix of pharmas and biotechs of various sizes, most of which do not yet have a product on the market. The vast majority are headquartered in the U.S. and Canada (89%), but their trials span the globe.

Companies want action from regulators

In an open question about top policy concerns, 50 respondents called for flexibility from FDA and other health authorities. Among these, 31 listed specific areas for which they’d like flexibility and/or additional guidance (see Figure: “Companies Seek Guidance and Regulatory Flexibility”).

On the whole, these topics reflect the modifications the companies are making to their trials. For example, seven said they’d like flexibility or guidance on use of telemedicine, and six said the same for remote monitoring.

Companies are also worried about what happens if some patients cannot come in for follow-up visits, leading to missed data points. Seven respondents called for guidance or flexibility on changes to statistical plans due to delayed readouts or missing data.

FDA guidance issued on March 18, during the survey, gives drug developers more room to adapt trials to the pandemic by altering monitoring strategies, endpoints and other aspects of their protocols.

Several companies stated they were aware of the guidance but wanted more detail.

For example, several said they’d like more guidance on when COVID-19-related amendments become major, and on how FDA plans to handle major amendments.

On March 20, EMA issued a similar guidance to FDA’s, and FDA followed up with an additional document encouraging companies and healthcare professionals to expand the use of remote monitoring technology to “help eliminate unnecessary patient contact and ease the burden on hospitals, other health care facilities, and health care.”

Eight respondents would like to see more international harmonization, especially of health authorities.

Dozens of companies called for more government support for clinical trials, in particular increased access to testing for COVID-19 to find infected trial subjects.

Seven said governments should provide funding, loans or grants to get biotechs through the crisis.

At least five want governments to keep supply chains open to facilitate reliable shipping of reagents, drug products and patient samples (see Figure: “Companies Seek Government Intervention to Support Trials”).

Many causes for alarm

Among the ways that COVID-19 that could derail trials, companies were most worried about access to trial sites, their ability to enroll and continuity of participation.

Supply of API was the one of the lowest concerns, which could reflect manufacturing starting back up again in China, where many APIs are made. But even that was still fairly high, averaging a score of three or higher across geographic regions, on a one-to-five scale from no concern to very concerned (see Figure: “Many Reasons to Worry”).

Companies are anticipating a range of negative consequences from impediments to trials. Their average concern levels were high across all five consequences asked about in the survey, from loss of investment dollars to delay of active programs (see Figure: “Anticipating the Fallout”).

Almost all companies are taking active steps to mitigate their risk. In a write-in question, 83 respondents listed actions they are taking to keep active trials running or to get new ones off the ground.

The actions range from increased communication with clinical CROs, to review of enrollment numbers and statistical plans to define leeway for modification, to active implementation and documentation of protocol changes.

Remote monitoring of data is the most common, with 35 companies stating they are either considering or are already implementing remote monitoring systems. Virtual patients visits -- via phone, video or other methods -- came in second, closely followed by direct delivery of the investigational compound to the patient. Home nursing was mentioned by nine companies, particularly if their study drug has to be administered by a medical professional (see Figure: “Most Common Measures to Avoid Trial Disruptions”).