FDA credibility on the line with White House pressure on hydroxychloroquine

How White House pressure to authorize hydroxychloroquine could undermine confidence in FDA

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Demands from President Donald Trump that FDA issue a second Emergency Use Authorization for the use of hydroxychloroquine to treat COVID-19 test agency chief Stephen Hahn’s commitment to public health again, and pose challenges to FDA’s credibility and reputation for making science-based decisions.

The latest drama in the hydroxychloroquine saga came Tuesday as the president made the extraordinary public call for FDA to issue a second EUA, following the release of an observational study by the Henry Ford Health System that produced data that appear to bolster Trump’s enthusiasm for the drug. Specifically, the study found that hydroxychloroquine alone and in combination with azithromycin was associated with reduction in COVID-19 associated mortality.

Trump has not commented on any of the studies in which hydroxychloroquine failed to demonstrate benefit. Nor has he commented on a range of other studies on other compounds that have produced positive or negative results, with the exclusion of comments about the antiviral remdesivir from Gilead Sciences Inc. (NASDAQ:GILD) (see “Clinical Scorecard for COVID-19”).

FDA withdrew its first EUA for hydroxychloroquine and chloroquine on June 15 after determining the drugs are “unlikely to be effective in treating COVID-19.” It also stated: “The known and potential benefits of CQ and HCQ no longer outweigh the known and potential risks” and cited the potential for serious cardiac side effects (see “Asserting Its Independence, FDA Revokes Chloroquine Authorizations”).

Now FDA Commissioner Stephen Hahn has to live up to his commitment to let science and not politics dictate regulatory decisions.

Confidence in FDA will be critically important in the coming months as the agency considers applications for emergency use and approval of COVID-19 countermeasures. Lack of trust in FDA would amplify anti-vaccine messages along with resistance to public health measures such as wearing face coverings in public. It could also have ramifications for global drug developers who view the agency as the gold standard for regulatory approval.

Observational and controlled studies

The hydroxychloroquine controversy is part of an ongoing series of statements and actions from the White House, and responses from Hahn, that raise questions about whether FDA decisions about public health matters are being influenced by political considerations.

The agency said its first EUA for hydroxychloroquine and chloroquine was based on “anecdotal clinical data.”

The intrusion of politics into that decision was detailed in a whistleblower complaint by Rick Bright, following his removal as director of the Biomedical Advanced Research and Development Authority (BARDA), in which he claimed the EUA had been issued after FDA came under significant pressure from Trump, HHS Secretary Alex Azar and administration supporters to grant broad, unrestricted approval to the drugs (see “FDA’s Authorization of Malaria Drugs for COVID-19 Looks Like Political Science”; “Bright Shines Harsh Light On America’s COVID-19 Preparedness, FDA’s Independence”).

The EUA stood for ten weeks before it was withdrawn by FDA, a move that at the time appeared to put an end to the topic.

The Ford Health System has revived the issue, turning it into a new test for Hahn. According to Peter Navarro, assistant to the president and White House director of trade and manufacturing policy, the Ford Health System has submitted an EUA request for hydroxychloroquine to treat and prevent COVID-19. The EUA request covers three indications, he told reporters Tuesday: for early treatment use in a hospital setting, as an outpatient treatment, and as a prophylactic.

“It’s a false narrative to take comfort in a lower rate of death.”

Tony Fauci, NIH

An FDA spokesperson said the agency cannot comment on pending EUA submissions.

However, the study design may not hold up to scrutiny.

Peter Bach, director of the Center for Health Policy and Outcomes at Memorial Sloan Kettering Cancer Center, told BioCentury the study was “unconvincing” because of “severe” baseline imbalances. Patients who received hydroxychloroquine in the Ford study received concomitant treatment with steroids at double the rate of patients in the control arm, meaning the effects of hydroxychloroquine can’t be properly distinguished from the extra dose of the steroids.

In evaluating the EUA request, FDA is likely to consider the robustness of the Ford study as well as evidence from randomized, controlled trials that led it to withdraw the first EUA.

Results have been reported from at least five randomized controlled trials enrolling 5,697 patients in which hydroxychloroquine or chloroquine failed to meet the primary endpoint.

The WHO halted the hydroxychloroquine arm of a master protocol study after determining there was little probability of demonstrating benefit, and the University of Oxford’s RECOVERY study found that the malaria drug failed to benefit hospitalized COVID-19 patients (see “Failing in Master Protocol Casts Fresh Doubt on Hydroxychloroquine”).

Politicized science

Trump is casting FDA’s withdrawal of the EUA, and his insistence that it issue a second EUA to the Ford Health System, as political issues.

His Tuesday tweet about the Ford study, in which he tagged FDA, a conservative television host and Fox News, stated: “The highly respected Henry Ford Health System just reported, based on a large sampling, that HYDROXYCHLOROQUINE cut the death rate in certain sick patients very significantly. The Dems disparaged it for political reasons (me!). Disgraceful. Act now @FDA @TuckerCarlson @FoxNews.”

In his conversation with reporters, Navarro accused the news media of politicizing and creating hysteria over hydroxychloroquine.

Navarro also criticized FDA’s decisions to add a black box warning to the hydroxychloroquine label and to withdraw the EUA, and asserted that FDA’s actions “had a tremendously negative effect on two things: one is the ability for American people to use this medicine to protect themselves, and two the ability for hospitals, like the Detroit hospital system, to recruit patients for the kind of randomized blind clinical trials that everybody wants to settle once and for all the questions of efficacy and safety.”

However, the Administration has argued contrasting positions on the EUA.

In a televised June 15 White House roundtable discussion with Trump, Azar portrayed the EUA as an impediment to widespread use and suggested that its withdrawal would increase access. The HHS secretary had previously celebrated FDA’s decision to grant the EUA, which restricted use to the in-patient hospital setting.

Azar noted at the June roundtable that hydroxychloroquine is an FDA-approved medicine that can be prescribed for any purpose, including treating COVID-19, and said, “FDA’s removal of the EUA takes away what had been a significant misunderstanding by many that had made people think that somehow it could only be used in a hospital setting.”

Hahn’s signals

Hahn has stated that FDA will act independently, based on science and law.

However, Hahn has also repeatedly signaled his loyalty to the president, and his tenure has been marked by suggestions that he has bowed to political pressure. These include allegations that he failed to pursue an aggressive testing policy when the White House was downplaying the pandemic; signing off on the EUA for chloroquine and hydroxychloroquine based on scant evidence following demands from Trump; and failing to correct false statements from Trump about medical issues (see “Coronavirus Crisis Calls for Competence, Clarity and Courage at the Top”).

Asked during a television interview on July 5 to comment on Trump’s assertion that “99% of COVID-19 cases are totally harmless,” Hahn declined to express a view on the topic. Pressed for a response, he said: “I’m not going to get into who’s right and who is wrong.”

Hahn’s deference to Trump on matters of scientific and medical fact comes at a time when COVID-19 outbreaks are intensifying in regions of the U.S. where there is resistance to public health measures.

In contrast, Anthony Fauci, director of NIH’s National Institute of Allergy and Infectious Diseases (NIAID), has publicly contradicted Trump.

Addressing the question of whether COVID-19 is “harmless” during a live-streamed press conference on July 7, Fauci warned Americans not to engage in “false complacency,” adding: “It’s a false narrative to take comfort in a lower rate of death.”

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