FDA’s hydroxychloroquine test

Editor’s Commentary: FDA’s decision about the hydroxychloroquine EUA is a test of its independence and credibility

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COVID-19 is testing FDA’s leadership. The agency’s performance will affect both the health of COVID-19 patients as well as public trust in the agency.

One of many challenges facing FDA is whether to keep in place or rescind an Emergency Use Authorization (EUA) for chloroquine and hydroxychloroquine -- and how to explain its decision.

An honest explanation is essential because the public needs to know that FDA is prioritizing its interests, that it is making decisions based on science, and that it has resisted the political pressure that appears from the outside to be influencing its decisions.

Throughout the U.S. response to COVID-19, the White House has hoped for the best and relentlessly refused to plan for the worst.

The implication is that contingency planning will be perceived or punished as defeatism. That runs counter to science-based public health policy. The chloroquine and hydroxychloroquine EUA raises concerns that this fear has seeped over into FDA’s decision-making.

In April, FDA Commissioner Stephen Hahn told BioCentury that if data demonstrate that hydroxychloroquine or chloroquine are not safe or effective for COVID-19, the agency would terminate the EUA. “We would absolutely use those data and we would rescind the EUA,” said Hahn.

Hahn also denied that President Donald Trump has demanded that FDA take specific regulatory decisions.

Data that have emerged since the EUA was announced in March suggest that Hahn’s commitment to independence will be put to the test. So far, all signs point to a lack of efficacy that should lead FDA to scrap the EUA.

Failure to observe benefit

An NIH-funded observational trial of 1,446 patients at New York Presbyterian Hospital reported last week in The New England Journal of Medicine showed that hydroxychloroquine provided no benefit to hospitalized COVID-19 patients. While the authors acknowledge the study’s limitations, they stated that “clinical guidance at our medical center has been updated to remove the suggestion that patients with Covid-19 be treated with hydroxychloroquine.”

A separate study of 1,438 hospitalized patients treated with hydroxychloroquine plus azithromycin, published May 11 in the Journal of the American Medical Association (JAMA), likewise found no difference in in-hospital mortality with either drug individually, or in combination.

Both studies were observational, which is a less reliable format than randomized controlled trials. However, they were sufficiently large to detect an effect of the scale that could justify widespread use of the drugs outside of clinical trials.

The studies fit into the paradigm envisioned in the 21st Century Cures Act, which called on FDA to develop standards for using real-world data to support decisions about the safety and efficacy of new indications for approved drugs. The observational data is stronger than the “anecdotal clinical data in case series” cited by FDA in its EUA decision.

FDA may be waiting for results from the 510-patient randomized, controlled NIH-funded ORCHID study of hydroxychloroquine. The last patients in the trial received the drug in April. Study completion is scheduled for July, but some results could be announced sooner.

If ORCHID doesn’t show a substantial benefit, it will be difficult for FDA to argue that the EUA is in the public’s interest.

There’s much more data coming -- BioCentury’s COVID-19 trial tracker lists more than 50 trials testing chloroquine or hydroxychloroquine due to read out by the end of July -- but FDA has to make a decision on the EUA sooner rather than later.

A promise to follow the science

According to ousted BARDA Director Rick Bright, FDA’s EUA of chloroquine and hydroxychloroquine to treat hospitalized COVID-19 patients was a compromise between White House demands for no-strings-attached expanded access and recommendations from public health professionals against giving the agency’s seal of approval to an untested use of approved drugs (see “Bright Shines Harsh Light”).

Bright says he was terminated as director of BARDA in part because he resisted pressure to seek expanded access authorization for the malaria drugs. Instead, according to Bright, he agreed to a compromise EUA at the urging of Janet Woodcock, director of FDA’s Center for Drug Evaluation and Research.

FDA had the legal authority to issue the EUA, and the agency may have protected the public from greater harm that could have occurred if expanded access had been authorized.

The point, however, isn’t whether FDA could issue the EUA, it is whether it should have. The agency’s goal isn’t to take an action that isn’t as bad as an alternative promoted by the White House, it is to do what is best. Arguing, as FDA has, that physician supervision is sufficient to ensure safety is not consistent with its position on other drugs and it isn’t what Americans expect.

It is often a lot easier to do something than to undo it.

This is especially true if the act of undoing must be accompanied by an explanation that implies or states that the action was a mistake.

It is harder if that mistake was advocated by the president of the United States.

In response to questions from BioCentury about the criteria FDA will use to determine if the EUA should be rescinded, the agency told BioCentury that it “continues to evaluate EUAs issued related to the current public health emergency, including the EUA regarding chloroquine and hydroxychloroquine, to determine whether they continue to meet the statutory criteria for issuance.”

In a statement, FDA said it “may revise or revoke an EUA under certain circumstances, including information related to linked or suspected adverse events, newly emerging data that may contribute to revision of the FDA’s initial conclusion that a product may be effective against the particular threat or a material change in the risk/benefit assessment based on evolving understanding of the disease or condition.”

America depends on FDA to make the right decisions, even if they are hard, unpopular or politically inconvenient.

As data accumulate demonstrating that malaria drugs don’t cure COVID-19, FDA will have an opportunity to show that it will be guided by science and the public interest.

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