Paper on hydroxychloroquine led by French researcher Didier Raoult is second-most-cited study ever to be withdrawn

Controversial COVID study that promoted unproven treatment retracted after four-year saga

Paper on hydroxychloroquine led by French researcher Didier Raoult is second-most-cited study ever to be withdrawn

A study that stoked enthusiasm for the now-disproven idea that a cheap malaria drug can treat COVID-19 has been retracted — more than four-and-a-half years after it was published¹.

Researchers had critiqued the controversial paper many times, raising concerns about its data quality and an unclear ethics approval process. Its eventual withdrawal, on the grounds of concerns over ethical approval and doubts about the conduct of the research, marks the 28th retraction for co-author Didier Raoult, a French microbiologist, formerly at Marseille’s Hospital-University Institute Mediterranean Infection (IHU), who shot to global prominence in the pandemic. French investigations found that he and the IHU had violated ethics-approval protocols in numerous studies, and Raoult has now retired.

The paper, which has received more than 3,600 citations according to the Web of Science database, is the highest-cited paper on COVID-19 to be retracted, and the second-most-cited retracted paper of any kind.

“This is incredibly good news,” says Elisabeth Bik, an image-forensics specialist and scientific-integrity consultant in San Francisco, California, who is among the critics of the paper and Raoult’s work. Several countries, including the United States, approved the drug at the centre of the research, hydroxychloroquine (HCQ), to treat COVID-19 infections, she notes. But later studies showed it had no benefit. “This paper should never have been published — or it should have been retracted immediately after its publication”, Bik says.

Drug delay

Because it contributed so much to the HCQ hype, “the most important unintended effect of this study was to partially side-track and slow down the development of anti-COVID-19 drugs at a time when the need for effective treatments was critical”, says Ole Søgaard, an infectious-disease physician at Aarhus University Hospital in Denmark, who was not involved with the work or its critiques. “The study was clearly hastily conducted and did not adhere to common scientific and ethical standards.”

In a lengthy retraction notice published at the International Journal of Antimicrobial Agents on 17 December, publisher Elsevier, together with the International Society of Antimicrobial Chemotherapy (ISAC), which co-owns the journal, said it had investigated the study and — among other concerns — wasn’t able to confirm whether ethical approval was obtained before participants joined the study, nor whether they could all have entered it in time for data to be analysed and included in the submitted manuscript.

Three of the study’s co-authors had asked to have their names removed from the paper, saying they had doubts about its methods, the retraction notice said. But another five disagreed with the retraction and disputed its grounds.

One of these researchers, Philippe Brouqui, an infectious-disease researcher at the IHU, sent Nature his response to an earlier version of the proposed retraction, from August, in which he and Raoult told Elsevier that there are “no ethical or regulatory issues” in the article and “no deviation from scientific integrity” and said they were “victims of cyber-harassment”.

Raoult declined to comment to Nature on the retraction and the concerns about his research.

Hydroxychloroquine hype

Early in the pandemic, laboratory studies and some reports from China had suggested that HCQ might help to treat COVID-19. Raoult, then head of the IHU, strongly advocated the idea.

On 16 March 2020, he and his IHU colleagues reported in a preprint that HCQ, in some cases with the antibiotic azithromycin, reduced viral load in 20 participants. The study was immediately hyped on US television stations. Four days later, the study was published in the International Journal of Antimicrobial Agents, at which co-author Jean-Marc Rolain was editor-in-chief; the journal had accepted the submitted manuscript in one day. A note was later added to say Rolain “had no involvement” in the article’s peer review. Then-US-president Donald Trump mentioned the paper on Twitter (now X), saying the drugs could be “game changers”.

But critics quickly found flaws with the work. Bik raised concerns including a lack of clarity over the timeline of ethics approval and potential confounding differences between characteristics of the participants in the control and treatment groups, suggesting that the participants had not been randomly assigned to these groups (although the study did not claim to be a randomized trial). Six individuals treated with HCQ also dropped out of the study — of whom one died and three were transferred to an intensive-care unit.

In April 2020, the ISAC said the paper didn’t meet its standards. And that July, the journal published critical reviews of the work, including one by Frits Rosendaal, an epidemiologist at Leiden University Medical Center in the Netherlands, who said the study suffered from “major methodological shortcomings”². But the ISAC decided not to withdraw the paper, saying “in addition to the importance of sharing observational data at the height of a pandemic, a robust public scientific debate about the paper’s findings in an open and transparent fashion should be made available”.

Study investigation

This June, however, Elsevier re-opened an investigation into the study after a group of scientists, including Bik, again called for its retraction, and because of the three authors who had asked to remove their names owing to methodological concerns, the website Retraction Watch reported.

The retraction notice identifies those authors as oncopharmacologist Stéphane Honoré at Aix-Marseille University and infectious-disease researcher Johan Courjon and virologist Valérie Giordanengo, both at Nice University Hospital. It says that they “assert their opinion that they have concerns regarding the presentation and interpretation of results in this article” and didn’t wish to have their names on it.

The notice adds that Elsevier asked Jim Gray, a consultant microbiologist at Birmingham Children’s Hospital and Birmingham Women’s Hospital, UK, to guide their investigation. As well as concerns over ethical approval, the journal added that it could not establish whether there was ‘equipoise’ — meaning genuine uncertainty about the relative effects of treatments in a trial — between participants who received HCQ and controls.

The retraction notice says it didn’t receive a response from the corresponding author — Raoult — about its concerns by the journal’s deadline.

IHU issues

The investigation and retraction come in the wake of wider concerns about research at the IHU. After the 2020 study, researchers there would go on to publish other papers on HCQ and COVID-19, including a study involving 30,000 people³. But other work soon showed that HCQ was not effective against the disease⁴. And sleuths and journalists began raising questions about research ethics in a slew of studies by IHU researchers, mostly on infectious diseases other than COVID-19. Some critics faced legal threats from Raoult — including Bik, although this year a Marseille prosecutor concluded she had no case to answer.

In 2022, the French National Agency for Medicines and Health Products Safety and inspectors at two government-commissioned auditing agencies issued reports finding ethical breaches with several IHU research projects on tuberculosis and other infectious diseases. The findings were referred to a public prosecutor for investigation, although the status of the case is unclear.

That year, Raoult retired as IHU head. As an indication of the potential scale of concerns with IHU work, one commentary by external scientists, published in August 2023, raised concerns over ethical approvals in 456 trials from the IHU⁵. Journals began to issue retractions or expressions of concern over the hospital’s papers, and critics made a renewed call to retract the initial HCQ paper⁶.

“Why it took more than four-and-a-half years after the study was initially published for the journal to come to this conclusion is not clear. It is also somewhat surprising that most of the papers authors still stand by study’s findings and conclusions despite its obvious inconsistencies, methodological flaws and potential ethical issues as outlined in the retraction note,” says Søgaard.

Overall, the IHU now has 32 retracted papers — 28 of them authored by Raoult — and 230 other studies have expressions of concern.

doi: https://doi.org/10.1038/d41586-024-04014-9

This story originally appeared on: Nature - Author:Richard Van Noorden