Product Development

What clinical holds and pauses mean for COVID-19 countermeasure timelines

Three high-profile COVID-19 trials are now temporarily halted after potential safety issues were flagged by independent Data and Safety Monitoring Boards, but whether sponsors will need to wait for the green light from regulators to resume will depend on whether the regulators decide to put those trials on official hold.

So far, only one of the programs has been placed on an official hold. 

In September, the leading Phase III adenoviral vaccine AZD1222 from AstraZeneca plc (LSE:AZN; NASDAQ:AZN) and the University of Oxford, was placed on clinical hold after a participant in a U.K. trial experienced a spinal cord problem. While that trial has resumed in the U.K., U.S. studies remain on hold. 

This week, two additional programs were paused following DSMB recommendations. Johnson & Johnson (NYSE:JNJ) announced its adenoviral vaccine trials were paused on Monday after a participant experienced an undisclosed illness. The next day, the Phase III ACTIV-3 study of COVID-specific mAb bamlanivimab from Eli Lilly and Co. (NYSE:LLY) and AbCellera Biologics Inc. was paused when that trial crossed a predetermined statistical safety boundary.

The difference between a clinical hold and a trial pause is that a decision to pause a trial is made by a study’s sponsor, usually at the recommendation of an independent DSMB, while a decision to put a trial on “hold” comes from the regulators.

That’s an important distinction because sponsors have the power to decide when to resume a paused trial, while regulators need to authorize the re-start of a trial on clinical hold. 

The decision to place a trial on official hold can take two paths. Usually, it follows a trial pause after a safety issue is flagged by an independent DSMB. That flag is based on predetermined criteria written into the trial’s protocol, with regulators’ help. 

Specific reporting requirements can vary, but there’s usually an independent requirement to report serious adverse events to regulators. 

“Some things are always in legislation, such as adverse events of a particular magnitude or frequency that would be reported to health authorities,” said David Morse, VP of global regulatory affairs at CRO ICON plc. Based on the reported data, the regulatory body determines whether to place an official hold. 

The other path to a clinical hold is directly through regulators.

“FDA can take direct action if they spot a trend across similar programs. They may see patterns across programs that aren’t apparent at the individual program level and can step in,” Morse added.

In all three COVID-19 trials, the issue was flagged by a DSMB.

Whether a trial is on hold or on pause, the next step is a data analysis by the DSMB to determine whether adverse events were related to the intervention and how to proceed. That can inform a sponsor’s decision on whether to resume a paused trial, or support a separate analysis by regulators on how to proceed with a held trial. 

Timeline uncertainty

AstraZeneca will need to wait for FDA to authorize a trial restart, while decisions on resuming the other two programs will fall to the sponsors and their DSMBs.

Timelines are uncertain in all cases, but the FDA review process, at least under normal circumstances, can add weeks.

For a clinical hold under normal circumstances, FDA usually makes a decision within 30 days of receiving the full data analysis, but that review period will likely be compressed for COVID-19 countermeasures, said Nuala Murphy, president of clinical research services at ICON.

“Everything is being expedited by world health authorities. That’s not to say criteria have changed, but the resources to make decisions have been significantly increased, and the entire industry is benefiting from that fact,” Morse added. 

The decision to place a program on clinical hold is made at the regional health authority level, as is the decision to resume a trial. 

For the J&J vaccine, the company does not have information on whether the patient with an undisclosed illness was in an interventional arm or the control arm. That information could inform how quickly the analysis can be completed and the trial can resume.

However, Murphy told BioCentury the company may remain blinded to the information, as unblinding is a highly regulated process and usually only occurs after completion of a trial or for a long-term suspension.

Lilly said its DSMB will meet on Oct. 26 to reanalyze additional data and make a recommendation.