A study that once fueled enthusiasm for hydroxychloroquine (HCQ) as a COVID-19 treatment has been retracted more than four years after publication. The retraction, issued by the International Journal of Antimicrobial Agents, cites concerns over ethical approval and research conduct.
The paper, co-authored by Didier Raoult, formerly at Marseille’s Hospital-University Institute Mediterranean Infection (IHU), had garnered over 3,600 citations, making it the most-cited COVID-19 paper to be retracted and the second-most-cited retraction overall. Raoult, already under scrutiny for ethics violations, has since retired.
Concerns Raised
Critics, including Elisabeth Bik, a scientific-integrity consultant, had long questioned the study's data quality and ethics-approval process. The retraction notice indicates that the journal could not confirm whether ethical approval was obtained before participants joined the study or whether they could all have entered it in time for data to be analyzed and included in the submitted manuscript.
Ole Søgaard, an infectious-disease physician at Aarhus University Hospital in Denmark, emphasized the study's negative impact, stating that it "partially side-tracked and slowed down the development of anti-COVID-19 drugs at a time when the need for effective treatments was critical." He added, "The study was clearly hastily conducted and did not adhere to common scientific and ethical standards."
Authors' Discord
Adding to the controversy, three of the study's co-authors requested their names be removed, citing concerns about the methods used. However, five other co-authors disagreed with the retraction, disputing its grounds. Philippe Brouqui, an infectious-disease researcher at the IHU, defended the study, asserting that there were "no ethical or regulatory issues" and "no deviation from scientific integrity."
The Rise and Fall of Hydroxychloroquine
Early in the pandemic, preliminary studies suggested HCQ might be a viable COVID-19 treatment. Raoult and his IHU colleagues reported that HCQ, sometimes combined with azithromycin, reduced viral load in 20 participants. This preprint quickly gained traction, amplified by mentions from then-US President Donald Trump. The International Journal of Antimicrobial Agents accepted the manuscript within one day of submission, though a note was later added stating that co-author Jean-Marc Rolain, who was editor-in-chief, had no involvement in the peer review process.
However, flaws were soon identified, including a lack of clarity regarding ethics approval timelines and potential confounding differences between control and treatment groups. Six individuals treated with HCQ dropped out of the study, with one death and three transfers to intensive care.
In April 2020, the International Society of Antimicrobial Chemotherapy (ISAC) stated that the paper did not meet its standards. Critical reviews followed, including one by Frits Rosendaal, an epidemiologist at Leiden University Medical Center, who cited "major methodological shortcomings." Despite these concerns, the ISAC initially chose not to retract the paper, citing the importance of open scientific debate during the pandemic.
Reopened Investigation
In June, Elsevier reopened the investigation following renewed calls for retraction and the requests from three authors to remove their names. Consultant microbiologist Jim Gray guided the investigation, which ultimately led to the retraction based on ethical concerns and the inability to establish equipoise between treatment groups.
