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Where’s the data? Now is no time to sit on Covid-19 trial results


When Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, described the results of a remdesivir study a couple of weeks ago, he was cautious in characterizing how the experimental Gilead Sciences drug helped combat Covid-19.

Patients given the intravenous medicine recovered faster than those on a placebo by 31%, or four days, Fauci said, conceding the result was not a “knockout.” Nonetheless, he insisted in his trademark keep-it-simple-demeanor, that the data showed “remdesivir has a clear-cut, significant, positive effect…. This has proven that a drug can block this virus.”

By and large, this was good news, but there was a caveat — the data were based only on a preliminary analysis. Rather than release all the data, the National Institutes of Health, which sponsored the study, issued a press release saying a forthcoming report would have “more comprehensive data.”

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The rationale is easy to understand. In a pandemic, who doesn’t want insight into a useful therapy as soon as possible? So on this basis, the data were sufficient to allow the Food and Drug Administration to quickly authorize emergency use in hospitals.

Even so, this is not the best approach to science or medicine.

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Rather than release information in dribs and drabs, study sponsors — whether a government, company, or university — should release all the results lickety-split, especially when it comes to medicines for fighting a pandemic. Data should not be held back.

“If we can’t see the study protocol and a concise research report, you shouldn’t be talking about it in the news,” said Joseph Ross, a professor medicine and public health at Yale University, who studies clinical trial practices. “Instead, we now have a situation where partial data is disclosed and physicians have to use that to make a decision in the moment.”

Indeed. In the absence of full results, we lack further insight into safety or how the drug may work on subsets of patients. And for now, the extent to which remdesivir can prevent deaths – a key metric – is unsettled. Fewer patients died while on the drug than placebo, but the findings were not statistically significant and need further analysis. Fauci, however, insisted “the conclusion will not change.”

Maybe not, but until the data are released, doctors are left with a mix of facts and assumptions.

“When we look below the hood, we may find other issues,” said Lewis Nelson, who chairs the Department of Emergency Medicine at Rutgers New Jersey Medical School and University Hospital in Newark. “We’ll eventually get the info, but why shouldn’t we get it now? Whether it’s two weeks or two months, we’re making decisions based on what they’ve given us. But we run the risk of making a decision based on the wrong info.”

David Hill, a pulmonologist affiliated with two hospitals in Waterbury, Conn., agreed. “While decreasing [the] length of stay [in a hospital] is positive, decreasing illness and severity of illness is more important,” he told us. “At this point, I view it as a possibly beneficial therapy in critically ill patients. I would be hesitant to embrace it wholeheartedly until the full trial results were available to review. Without those results, I am more skeptical.”

Of course, no one is suggesting that remdesivir should not be given to Covid-19 patients, despite the incomplete picture. In general, though, the sooner trial data are available for review and scrutiny, the faster physicians and researchers can gain a clearer picture into the best use of a medicine and also understand when it should not be used.

For his part, H. Clifford Lane, the clinical director at the NIH division that sponsored the study, told us that “the full results have been submitted for peer review by a journal. We anticipate a quick review.”

Unfortunately, there is no mandate for reporting results immediately. In fact, a federal law called the Food and Drug Administration Amendments Act requires institutions sponsoring clinical trials to post results to a U.S. government website called ClinicalTrials.gov one year after a study is completed. Sometimes, this can be extended to three years.

But who has time to wait for study results during a pandemic?

Meanwhile, an increasingly popular avenue for disclosure has become the pre-print server, an online forum where researchers can post studies that have not yet been reviewed or published. Last June, one popular site called MedRxiv posted fewer than 100 of these working papers; last month it posted more than 1,500.

However, as the site noted, these papers “should not be relied on to guide clinical practice.” Why? A paper that is not vetted may report selective outcomes, underreport side effects or reach inappropriate conclusions. In short, there is a lack of quality control, according to Deborah Zarin, a former director of ClinicalTrials.gov, who is now program director at the Multi-Regional Clinical Trials Center that is run by Brigham and Women’s Hospital and Harvard University.

By contrast, ClinicalTrials.gov entries are guaranteed to address minimum information needed to interpret studies and the emphasis is on summary data, with minimal opportunities for narrative spin, Zarin explained. Moreover, the data undergo rigorous quality control so that entries are meaningful and internally consistent. And the data must be consistent with the pre-specified study protocol.

“The research community could demonstrate its commitment to serving the public interest by submitting the results of Covid-19 trials to ClinicalTrials.gov as soon as they are available,” she said. “The medical community should not have to sit around in the dark, while critical policy and clinical decisions are being made based on conclusions, but no data, that are promulgated by researchers or sponsors.”

Not everyone is so accommodating. There is, however, a provision in federal law to make that happen. Specifically, the NIH director can require trial results to be posted in 30 days after it has been determined that doing so would be in the interest of public health.

“It doesn’t require immediate posting, but it’s certainly one avenue the federal government can use to disseminate [results of] a particular clinical study,” said David Clissold, an attorney at the Hyman, Phelps & McNamara law firm, which specializes in FDA and regulatory matters.

In this instance, however, the NIH sponsored the remdesivir study. So maybe a different kind of push is needed. Ross has a suggestion — and it makes sense. Before the FDA issues an emergency authorization for a Covid-19 treatment, the trial results should be fully and publicly disclosed. “The FDA has the best lever that could be pulled,” he said. “Otherwise, it’s a ‘trust us’ decision.”

At the end of the day, the data — all of the data — should speak for themselves. Science can be messy enough without incomplete pictures being disseminated during a public health crisis.





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