The need for reliable Covid-19 treatments is spurring calls for the government to invoke a legal clause that would require drug companies and NIH-funded researchers to post their study results within a month instead of a year.
Shortening the time frame for posting data to ClinicalTrials.gov could mark one of the first times the clause has ever been tested since it became part of a 2007 drug law in 2016. Such a move from the National Institutes of Health would better arm health professionals with information on how best to treat patients, a former FDA chief said.
“The pandemic compresses the time frame radically because people are dying in large numbers,” Robert M. Califf, who was commissioner of the Food and Drug Administration during the final year of the Obama administration, said in an interview. “Those designing new trials should have access to everything else that’s been done as quickly as possible.”
Section 801 of the Food and Drug Administration Amendments Act requires most FDA-regulated and NIH-funded clinical trials to post their results within a year of study completion. But a lesser-known clause allows the NIH director to require that those results be posted within a month when it’s necessary to protect the public health.
Requiring the faster timeline could be critical to preventing premature authorizations of drugs, based on incomplete data, that later prove to be ineffective. That’s what happened with hydroxychloroquine, the antimalarial drug touted by President Donald Trump to treat Covid-19 that later was shown have no impact on a patient’s recovery.
But the call for action may spark questions over how a shorter data-posting deadline would impact quality control.
The proposal to accelerate publicizing clinical trial results highlights the “very real benefits of clinicaltrials.gov information sharing,” said Valerie H. Bonham, a health and life sciences attorney at Ropes & Gray LLP who was lead counsel for the NIH in implementing the 2007 law when she was at the agency’s general counsel’s office.
At the same time, the 30-day clock set forth in the law is very short and trying to meet it could create potentially serious quality control concerns, she said.
The NIH didn’t provide a comment.
Meaningful Data Lacking
Few clinical trials of potential Covid-19 treatments are producing meaningful results because researchers either didn’t set up their studies to be randomized to eliminate bias in the results or the sample size of their study was too small.
An FDA analysis found just 6% of treatment trials are producing results that are actionable. And just because data is public doesn’t mean it’s good, but at least researchers know it’s there and won’t waste time replicating it. A study published last summer found just 29% of studies on ClinicalTrials.gov met the threshold for high quality.
The situation for Covid-19 vaccine trials was different. Pfizer Inc. and Moderna Inc.—the two vaccines that are in circulation in the U.S. now—were able to rapidly release interim clinical trial results in part due to the wide prevalence of the disease and because researchers studied about 30,000 people for each double-blinded vaccine trial. Both vaccines showed 95% efficacy.
But many of the trials for Covid treatments are much smaller.
Too many small trials are asking similar questions and not enough trials are providing reliable answers to them, Califf wrote in a tweet in which he tagged NIH Director Francis S. Collins and the FDA’s longtime drug chief Janet Woodcock, among others. Califf is now head of clinical policy and strategy for Verily and Google Health.
Califf, with former ClinicalTrials.gov Director Deborah A. Zarin, publicly urged the FDA, Department of Health and Human Services, and the NIH to use the FDAAA provision to get study results into ClinicalTrials.gov “as rapidly as possible.”
Doing so would “improve the ability of our clinical trials system to reliably and efficiently answer key questions essential to optimize treatment in the midst of this crisis,” they wrote. Zarin, who is the program director of the Advancing the Clinical Trials Enterprise at the Multi-Regional Clinical Trials Center, was director of ClinicalTrials.gov from 2005 to 2018. Califf was commissioner when the FDA rule that implemented the reporting requirements came out.
To address the need for answers, leading medical journals have instituted protocols to publish papers in record time, while research manuscripts that haven’t been peer reviewed are released on what’s known as pre-print servers, said Ann Marie Navar, a cardiologist at University of Texas Southwestern Medical Center.
“This isn’t a perfect solution,” she said, noting there’s more motivation to post positive results than negative ones. “As a result, publications may be delayed, or at worse, never even happen.”
Even if they come out a year later, it’s too late for the pandemic, Navar said.
Bonham acknowledged that “building consensus around the need for rapid reporting” is critical. But she also noted that given the size of many clinical trials, “performing complete quality control and reporting out results into the structured format of ClinicalTrials.gov within weeks could be quite difficult.”
Navar, who has written about making clinical trial data open to external researchers, said that once a study ends, there’s a lot of work to wrap it up—such as notifying all participants and verifying that the researchers have collected all of the events that occurred in those patients.
“So while the proposed solution by Dr. Califf is imperfect, I think it would be a great advance if it could be implemented in a way that was feasible for researchers to comply with without sacrificing the quality of end-of-study procedures and analyses,” she said.
Califf has criticized for years what he described as a culture of small, poorly-designed clinical trials that fail to produce meaningful results. The pandemic has proved no exception.
The FDA ultimately pulled its authorization of hydroxychloroquine after clinical trial data showed the drug was ineffective against Covid-19 and potentially harmful. Past FDA Commissioners cautioned two months before the withdrawal about providing “false hope” to patients looking for a treatment.
Another Covid-19 treatment to watch is convalescent plasma, which uses a component of blood taken from recovered Covid patients, Califf said. The agency issued an emergency use authorization in late August, but four months later it’s still unclear about the effectiveness of the therapy.
“We sort of proceeded without doing the proper trials and we’re having trouble getting them done,” Califf said, noting U.K. researchers have already enrolled more than a few thousand people in convalescent plasma trials.
“If the effect was anything there what people were thinking, the trial would’ve been stopped by now like the hydroxychloroquine trial was,” he said.