Hydroxychloroquine Questions Intensify as Journal Says Its Drug Study 'Did Not Meet Expected Standards'

In Monday's press briefing, President Trump would not allow his medical expert, Dr. Anthony Fauci, to answer a question about the anti-malarial drug hydroxychloroquine, which has gotten a lot of attention recently as a possible treatment for COVID-19.

This particular question, posed by a CNN reporter, turns out to be especially pertinent: "What is the medical evidence?"

Three days before, on April 3, the publisher of the scientific paper that first brought the drug to the attention of public health experts--and President Trump—cast doubt on the reliability of the original research.

"The article does not meet the [publisher's] expected standard," said the International Journal of Anti-Microbial Agents in a statement. The journal, which published "Hydroxychloroquine and azithromycin as a treatment of Covid-19: results of an open-label non-randomized clinical trial" on March 20 after an accelerated peer review, stopped short of retracting the article.

The criticism will almost certainly heighten tensions in the White House. Trump's repeated touting of hydroxychloroquine has put him at odds with Fauci and other experts, who emphasize the importance of conducting randomized controlled trials of the drug—the gold standard in scientific research—before recommending its use for COVID-19.

Although hydroxychloroquine is approved by the Food and Drug Administration as a malaria treatment, it has not yet officially approved the drug for use on COVID-19. Last week, the FDA granted "emergency use authorization" in part to make it easier for the Federal government to begin stockpiling the drug.

The IJAA notice was reported by Retraction Watch, a blog founded by journalists Dr. Ivan Oransky and Adam Marcus. "Of course, the horse has left the proverbial barn on this one," they wrote. "An untold number of patients have been receiving hydroxychloroquine, as well as chloroquine, for Covid-19 infection, thanks in large part to cheerleading for the drugs from President Trump."

In the study, the scientists enlisted 42 COVID-19 patients in the south of France. They put 16 in a control group that got only conventional treatment. Of the remainder, some were treated with hydroxychloroquine only and the rest were treated with hydroxychloroquine in combination with an antibiotic. On day 6, when the scientists tested all patients for the presence of the COVID-19 virus, the results were encouraging. Patients who got neither drug were mostly still infected. But only half of the patients treated with hydroxychloroquine tested positive for the virus, and none of the patients who got both drugs tested positive.

The authors posted the paper on a medical scholarly website on March 16 as a "preprint," which means the work hadn't yet run the gauntlet of review by independent scientists, a standard for publication in scientific journals. On March 17, the authors submitted it to the International Journal of Antimicrobial Agents, which accepted it the next day and published it online on March 20. "That suggests that peer review was done in 24h, an incredibly fast time," wrote Elisabeth Bik, a Dutch microbiologist, in the medical blog Science Integrity Digest.

Shortly after publication, scientists who read the paper began to point out flaws in the research that cast doubt on the study. On March 24, Bik published a long list. There were inconsistencies in the way the authors collected and reported data—they say, for instance, the paper was conducted over 14 days but only provide six days of data. She scrutinized the chronology of the study itself and questioned whether the authors had started their research before obtaining approval from the French National Agency for Drug Safety, which would be an ethical lapse. She also said that the composition of the control group did not closely match the composition of the groups that received the drugs—differences that could possibly skew the results.

Anthony Fauci Donald Trump coronavirus hydroxychloroquine COVID-19
APRIL 01: Dr. Anthony Fauci (L) director of the National Institute of Allergy and Infectious Diseases, listens to U.S. President Donald Trump speak from the press briefing room with members of the White House Coronavirus Task Force April 1, 2020 in Washington, DC. Fauci and the president disagree about the efficacy of the drug hydroxychloroquine in treating COVID-19. Win McNamee/Getty

She also pointed out that one of the paper's authors is also the editor-in-chief of the IJAA. The journal denied a conflict of interest. "Given his role as Editor in Chief of this journal, Jean-Marc Rolain had no involvement in the peer review of the manuscript and has no access to information regarding its peer review. Full responsibility for the manuscript's peer review process was delegated to an Associate Editor."

The publishers, the International Society of Antimicrobial Chemotherapy, apologized for the sloppiness of the peer-review process. Under normal circumstances, peer review is supposed to uncover flaws before publication, which the authors are then asked to address. But with thousands of people dying from COVID-19, medical publishers are under pressure to disseminate results quickly. "Although ISAC recognises it is important to help the scientific community by publishing new data fast, this cannot be at the cost of reducing scientific scrutiny and best practices," wrote the Society's president, Andreas Voss.

The new questions about the study are unlikely to have any immediate effect on COVID-19 treatment. With an expected shortfall of hospital beds and ventilators, many doctors are open to prescribing drugs that might alleviate the worst symptoms, let alone lead to a cure.