FDA’s authorization of malaria drugs for COVID-19 looks like political science

Editor’s Commentary: Why FDA's authorization of hydroxychloroquine and chloroquine for COVID-19 is bad for patients

FDA’s decision to grant Emergency Use Authorization for hydroxychloroquine and chloroquine to treat COVID-19 was unnecessary and unwise.

The EUA was unnecessary because the drugs are approved in the U.S. to treat malaria and for other uses. Physicians who believe the evidence for safety and efficacy outweighs the risks can prescribe either drug for COVID-19 on an off-label basis.

FDA can -- and has -- approved clinical trials of the drugs to treat COVID-19.

The main practical effect is that the EUA provides liability protection to physicians who prescribe and hospitals that administer the drugs. More importantly, it will be interpreted as a statement by FDA that the drugs should be used to treat COVID-19.

FDA’s action creates two sets of problems: the potential for harm to patients who will receive one of the two drugs; and damage to trust in the drug approval process that could harm future patients.

There is, of course, an urgent need to get effective treatments into the hands of physicians as quickly as possible. One lesson from previous viral crises, including SARS and MERS, is that therapies that seem like saviors can turn out to be ineffective or harmful. And the failure to carefully collect data about what works and what doesn’t slows medical progress, hurting patients now and in the future.

The foundation of the review system is that it involves a science-based, independent regulatory assessment of safety and efficacy.

That is being jeopardized by the intrusion of politics, as exemplified in public statements by President Donald Trump about hydroxychloroquine and chloroquine.

Prior to issuance of the EUA he exuberantly expressed confidence that they will be “game changers” that will rapidly make the crisis disappear. He asserted that FDA had already “approved” their use for COVID-19 for over a week before the EUA was issued.

Trump has also publicly boasted that he pushed FDA to speed up its review of an EUA for a respirator mask decontamination process and indicated that he is directly communicating orders to FDA Commissioner Stephen Hahn.

At a White House press conference Monday, Trump said “I call up Steve, and Steve says we’ll get it done.” It is difficult to imagine a sentence that more succinctly indicates that FDA’s science-based processes are being subverted.

Trump’s statements and the subsequent issuance of an EUA based on what FDA itself called “anecdotal clinical data,” along with Hahn’s tweeted praise for “@potus,” leave little room for doubt that politics intruded into regulatory decisions.

Everything FDA does creates precedents. Now it will have to decide how it will respond the next time Trump wants something.

It will also have to respond to companies that have far better evidence of safety and efficacy against COVID-19 than is available for the malaria drugs. Will these products be authorized without proper trials? Where will FDA draw the line?

Authorization by anecdote

The impression that politics rather than science is behind the EUA is reinforced by the paucity of data about use of the drugs to treat COVID-19.

FDA’s approvals of drugs for very rare conditions are often based on tiny datasets and sometimes rely on uncontrolled studies, but they are not precedents for the EUA. Far from a rare condition, COVID-19 is rapidly on its way to becoming a common one.

The public health implications of approving a drug for less than a thousand patients are quite different from those the agency must consider when authorizing drugs for a raging pandemic that could kill hundreds of thousands of Americans this year.

While there are debates about the strength of the data supporting many drug marketing applications, sponsors must present data and an argument for why a proposed medicine’s benefits outweigh its risks.

The totality of FDA’s explanation of how it came to the conclusion that the benefits of the two drugs outweigh their harms was: “Based upon limited in-vitro and anecdotal clinical data in case series, chloroquine phosphate and hydroxychloroquine sulfate are currently recommended for treatment of hospitalized COVID-19 patients in several countries, and a number of national guidelines report incorporating recommendations regarding use of chloroquine phosphate or hydroxychloroquine sulfate in the setting of COVID-19.”

That’s an alarmingly low bar. A lot of compounds that have in vitro activity against viruses are completely ineffective when studied in humans.

Researchers at the Institut National de la Sante et de la Recherche Medicale (INSERM) University have noted that chloroquine has in vitro activity against a number of viruses, ranging from HIV to SARS and Ebola -- but it hasn't been demonstrated to be effective in treating patients infected with any of them.

“Anecdotal clinical data in case series” sounds more like a phrase an FDA reviewer would use to denigrate a drug application than a standard for approving one. As the industry commentator Derek Lowe pointed out in his blog, the case series that got Trump excited about chloroquine and hydroxychloroquine doesn’t generate a great deal of confidence.

Trump was right when he said “maybe it’ll work, maybe it won’t -- we’ll have to see.”

He was wrong to think that’s a good enough reason to authorize drugs.

The enthusiasm for chloroquine has caused other hazards. It prompted FDA to lift an import ban on the drug from an Indian company, Ipca Laboratories Ltd. The agency presented no data to reassure Americans that the “cascade of failures” FDA has identified in inspections of Ipca plants have been corrected.

Even more alarmingly, FDA has authorized compounders to make and distribute hydroxychloroquine. Compounding pharmacies don’t have the same kind of quality requirements as drug manufacturers. There will be no oversight to ensure, for example, that compounded hydroxychloroquine is bioequivalent to -- and therefore has the same toxicity as -- commercially manufactured versions.

It is important for FDA to explain why it believes the benefits from importing chloroquine from Ipca, compounding hydroxychloroquine, and more generally of authorizing the drugs’ widespread use to treat COVID-19, outweigh the risks.

In the absence of an explanation, it looks like lifting the import ban and issuance of the EUA are aimed at appeasing the White House rather than enhancing the health of the American people.

Questions that must be answered

The low threshold used to approve the EUA raises questions that FDA will have to face very soon, among them:

• How will FDA respond when companies request EUAs for compounds that have slightly more convincing data than has been presented for chloroquine or hydroxychloroquine? Will these also get authorized with no controlled clinical trials?

• Will chloroquine or hydroxychloroquine be considered standard of care for trials of other potential COVID-19 therapies, and if so, how will that affect those trials? For example, will the presence of chloroquine confound trials, or will its availability deter patients from enrolling in trials?

• If chloroquine or hydroxychloroquine are shown to be ineffective, will this prompt physicians to stop treating an FDA approval as the “gold standard” indicating a drug is safe and effective for its intended use? If so, what will guide their decisions?

• What role has President Trump’s enthusiasm for the drugs played in the EUA decision? Will endorsement from a president, or perhaps some other VIP, influence future regulatory decisions?

Beyond the policy implications, the EUA raises concerns for patients.

Trump has stated that we know chloroquine and hydroxychloroquine are safe because they have been used for decades.

In fact, we know they are not safe because they have been used for decades.

Their labels include a long list of serious adverse effects, and for some indications there’s a narrow gap between the therapeutic and toxic doses.

More troubling, there’s no data on the adverse effect profile in the setting of COVID-19.

Signed commentaries do not necessarily reflect the views of BioCentury.
Further analysis of the coronavirus crisis can be found at https://www.biocentury.com/coronavirus.

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