Corrected 4 June 2020. See full text. A hydroxychloroquine study is being audited. statement, Surgisphere defended the integ- rity of its research and said it was pursu- ing “an independent academic audit” of its results in The Lancet. The journal and non- Surgisphere authors also said data reviews were underway. The episode has left leaders of halted hy- droxycholoroquine trials weighing whether to restart. “The problem is, we are left with all the damage that has been done,” says White, a co-investigator on a halted trial for COVID-19 prevention. It will now be hard to recruit people to key studies, he says. “The whole world thinks now that these drugs are poisonous.” Desai co-authored the Lancet paper with cardiologist Mandeep Mehra of Harvard University’s Brigham and Women’s Hospi- tal (BWH), cardiologist Frank Ruschitzka of Downloaded from University Hospital Zürich, and cardiac sur- geon Amit Patel, who listed affiliations with COVID 19 the University of Utah and HCA Research Institute in Nashville, Tennessee. (Mehra and Patel referred inquiries to BWH. Ruschitzka The pandemic’s first major did not respond to requests for comments.) http://science.sciencemag.org/ The authors describe an analysis of electronic health record data from patients already research scandal erupts treated for COVID-19 at 671 hospitals on six continents—nearly 15,000 people prescribed Critics question patient data used to challenge malaria drugs chloroquine or hydroxychloroquine, alone or in combination with an antibiotic, and a By Kelly Servick and Martin Enserink White, a malaria researcher at Mahidol Uni- control group of 81,000 other patients. After versity in Bangkok. adjusting for potentially confounding factors, n its face, it was a major finding: Anti- As Science went to press, The Lancet issued the researchers found the risk of dying was malarial drugs touted by the White an Expression of Concern, noting “serious 9.3% for the control group versus 23.8% for House as possible COVID-19 treat- scientific questions” about its paper. Hours those getting hydroxychloroquine alongside on June 5, 2020 ments looked to be not just ineffective, earlier, The New England Journal of Medi- an antibiotic. but downright deadly. A study pub- cine (NEJM) issued an Expression of Concern In a 25 May media briefing, WHO Direc- lished on 22 May in The Lancet used about a second study using Surgisphere data, tor-General Tedros Adhanom Ghebreyesus Ohospital records procured by a little-known published on 1 May. The paper reported that cited the results in announcing a “temporary data analytics company called Surgisphere to taking certain blood pressure drugs including pause” in Solidarity’s hydroxychloroquine conclude that COVID-19 patients taking chlo- angiotensin-converting enzyme (ACE) inhibi- arm. Regulators in France and the United roquine or hydroxychloroquine were more tors didn’t increase the risk of death among Kingdom also instructed investigators, in- likely to show an irregular heart rhythm—a COVID-19 patients, as some researchers had cluding White’s team, to halt enrollment in known side effect thought to be rare—and suggested. The journal asked the authors “to trials. And Sanofi said it would temporarily more likely to die. Within days, large ran- provide evidence that the data are reliable.” stop recruiting patients to two trials of its hy- domized trials of the drugs screeched to A third study using Surgisphere data is droxychloroquine formulation. a halt. Solidarity, the World Health Orga- also under fire. In an April preprint, Surgi- Other researchers immediately took issue nization’s (WHO’s) megatrial of potential sphere founder and CEO Sapan Desai and co- with the analysis. The study does not properly COVID-19 treatments, paused recruitment authors concluded that ivermectin, an anti- control for the likelihood that patients get- into its hydroxychloroquine arm. parasitic drug, dramatically reduced mortal- ting the experimental drugs were sicker than But just as quickly, the results have begun ity in COVID-19 patients. In Latin America, the controls, says Matthew Semler, a critical to unravel—and Surgisphere, which pro- where ivermectin is widely available, that care physician at Vanderbilt University. And vided patient data for two other high-profile study led some officials to authorize use of White notes anomalies in the data. Although COVID-19 papers, has come under withering the drug, creating a surge in demand. 66% of the patients were reportedly treated in online scrutiny from researchers and ama- Chicago-based Surgisphere has not pub- North America, the reported doses tended to teur sleuths. They have pointed out many licly released data underlying the studies. be higher than the guidelines set by the U.S. red flags in the Lancet paper, including the On 2 June, Desai told Science through a Food and Drug Administration. And the au- astonishing number of patients and details spokesperson that he was “arranging a non- thors claim to have included 4402 patients in about patient demographics and dosing that disclosure agreement that will provide the Africa, but it seems unlikely that African hos- seemed implausible. “It began to stretch and authors of the NEJM paper with the data ac- pitals would have detailed electronic health PHOTO: AP PHOTO/JOHN LOCHER PHOTO/JOHN AP PHOTO: stretch and stretch credulity,” says Nicholas cess requested by NEJM.” And in a 29 May records for so many patients, White says. The SCIENCE sciencemag.org 5 JUNE 2020 • VOL 368 ISSUE 6495 1041 Published by AAAS Corrected 4 June 2020. See full text. NEWS | IN DEPTH study also reported more deaths in Australian COVID-19 treatment protocol to include COVID-19 hospitals than the country’s official COVID-19 ivermectin (as well as hydroxychloroquine) death statistics, The Guardian reported. On for mild and severe cases of COVID-19; 29 May, The Lancet issued a correction say- demand for the drug in Peru has surged. Shuttered ing a hospital assigned to the study’s “Aus- In Trinidad, Bolivia, the city government tralasia” group should have been assigned aimed to hand out more than 350,000 free to Asia and updating a supplemental table. doses of ivermectin after the country’s Min- natural history “There have been no changes to the findings istry of Health authorized its use against of the paper,” it says. COVID-19. The brief response left some researchers Surgisphere’s sparse online presence— museums fight frustrated. “This was very, very annoying,” the website doesn’t list partner hospitals by says James Watson, a statistician at Mahidol name or identify its scientific advisory board, who on 28 May published an open letter—now for example—has prompted intense skepti- for survival signed by more than 140 researchers—that cism. Physician and entrepreneur James calls for the release of Surgisphere’s hospital- Todaro of the investment fund Blocktown But creative scientists vow level data, an independent validation of the Capital wondered in a blog post why Surgi- recovery and move research results, and publication of the peer-review sphere’s enormous database doesn’t appear comments that led to the Lancet publication. to have been used in peer-reviewed research and public programs online “The Lancet encourages scientific debate and studies until May. Chaccour asks how such a will publish responses to the study, along tiny company—LinkedIn lists only a hand- By Elizabeth Pennisi with a response from the authors,” a journal ful of employees—was able to reach data- Downloaded from spokesperson said in a response. sharing agreements with hundreds of hospi- few months ago, retirement was On 2 June, many of the same researchers tals around the world. the furthest thing from David and others published an open letter to NEJM Desai’s spokesperson says the company Thomas’s mind. “Then the world went and the authors of the ACE inhibitor study, has 11 employees and has been developing its upside down,” recalls the archaeo- citing similar problems in that paper. It notes database since 2008. logist from the American Museum inconsistencies including a discrepancy be- The potential of hydroxychloroquine for of Natural History in New York City. http://science.sciencemag.org/ tween the small number of hospitals in each treating COVID-19 has become a political AIn March, the coronavirus pandemic forced country that are said to have shared patient flashpoint. French microbiologist Didier the museum to close its doors. No more data with Surgisphere and the high propor- Raoult, whose own widely criticized studies school groups thronging the interactive ex- tion of those countries’ confirmed COVID-19 suggested a benefit from the drug, derided hibits, no more corporate dinners or lines cases included in the study. the Lancet study in a video posted on 2 June, of international tourists waiting to pay Oddities also appear in the ivermectin calling the authors “incompetent.” $23 a head to marvel at fossils. The mu- study, says Carlos Chaccour of the Barcelona For scientists running randomized trials seum’s income plummeted 60%. Institute for Global Health. There’s evidence of hydroxychloroquine, an urgent question Leaders first asked for early retirements. that ivermectin, the key weapon in the global has been how to respond to the paper and By early May, they had sliced the staff of campaign against river blindness, also has the ensuing flap. A trial funded by the U.S. 1100 by 20% and furloughed an additional antiviral properties. The 6 April preprint, National Heart, Lung, and Blood Institute 250 staff members. Many full-time employ- on June 5, 2020 co-authored by Patel, Desai, and Mehra, opted to keep running after its data and ees now work 3 days a week, mostly from along with David Grainger of the University safety monitoring board (DSMB) reviewed home. Thomas opted to retire early, along of Utah, used Surgisphere data reportedly safety data from already enrolled partici- with four of the other 38 curators.