Special Report
Surgisphere Sows Confusion About Another Unproven COVID-19 Drug
Special Report
Surgisphere Sows Confusion About Another Unproven COVID-19 Drug

Surgisphere Sows Confusion About Another Unproven COVID-19 Drug

The company behind a now-discredited study on hydroxychloroquine also posted a report that has been cited by Latin American governments recommending ivermectin as a possible coronavirus treatment. Clinicians there say the effects have been extremely damaging.

Catherine Offord
Catherine Offord
Jun 16, 2020

ABOVE: Iquitos, in the Peruvian Amazon, where some people desperate to protect themselves against COVID-19 have had injections of veterinary formulations of ivermectin, an antiparasitic drug that is not known to be effective against the novel coronavirus
© ISTOCK.COM
, DC_COLOMBIA

Update (June 22): The Pan American Health Organization, a regional office of the World Health Organization, has issued a statement warning against the use of ivermectin to treat COVID-19. The statement notes that the antiparasitic drug is being investigated in clinical trials, but currently, “ivermectin is incorrectly being used for the treatment of COVID-19, without any scientific evidence of its efficacy and safety for the treatment of this disease.”

Medical experts in Latin America are reacting with alarm as health officials promote ivermectin, an antiparasitic drug commonly used in tropical medicine, as a coronavirus treatment despite a lack of evidence that it’s effective.

Just a handful of in vitro and observational studies—including a now-withdrawn preprint from scandal-hit US company Surgisphere Corporation—have examined whether ivermectin could be beneficial against infections by SARS-CoV-2, the virus that causes COVID-19. Yet in the last few weeks, government officials in Peru and several other Latin American countries have publicly endorsed the drug as a treatment for COVID-19, fueling a public rush on supplies and a surge in dangerous practices such as self-administration and the use of veterinary formulations.

“Here in Peru, I was completely shocked when I heard that the ministry of health was releasing this guidance putting ivermectin as a medication,” says Patricia García, a global health researcher at Cayetano Heredia University in Lima and the country’s former health minister. People ran to pharmacies to look for the drug, she says, and when supplies ran out, they turned to the black market and veterinary versions. “It has been a nightmare.”

One of the most influential studies on ivermectin’s effect in COVID-19 patients was a large observational study that used a database owned by Surgisphere, a now-discredited Illinois-based company founded by vascular surgeon Sapan Desai. That study, published on the preprint server SSRN in early April and updated a couple weeks later, reported a strong positive association between ivermectin treatment and COVID-19 patient survival, and has been cited in white papers and reports by Latin American health researchers and governments as evidence of the drug’s efficacy.

With ivermectin firmly entrenched in political and public minds as a weapon against the pandemic, the question of evidence is now of secondary importance for some members of the medical and scientific communities. 

But the preprint disappeared at the end of May after scientists began pointing out problems with Surgisphere’s dataset—which by that point had been used in high-profile studies published in the New England Journal of Medicine (NEJM) and The Lancet. Both journals issued retractions earlier this month after Desai’s coauthors said they were unable to verify the validity of Surgisphere’s COVID-19 patient data. Investigations by The Scientist and The Guardian also revealed discrepancies in Surgisphere’s claims going back years, and the company’s website has now been taken offline. Desai did not respond to multiple requests for comment from The Scientist.

See “Lancet, NEJM retract Surgisphere’s Studies of COVID-19 Patients

Mandeep Mehra, the medical director of the Brigham and Women’s Hospital Heart and Vascular Center and a coauthor on all three Surgisphere papers, tells The Scientist in a statement that he “requested the ivermectin preprint to be removed from SSRN as he felt further analysis was needed to consider additional confounding factors.”

But researchers who spoke to The Scientist say that it may be too late to walk back the regional and national policy changes that the preprint helped instigate. On May 8, Peru included ivermectin as a COVID-19 treatment in official clinical guidelines. On May 12, Bolivia approved the drug’s use for COVID-19 patients who consent and later started handing out hundreds of thousands of doses to residents. By early June, at least one municipality in Brazil had endorsed the use of ivermectin as a preventive medicine for COVID-19. Many ivermectin proponents continue to cite Surgisphere’s preprint even now that it’s been taken down.

In García’s opinion, “several countries are using ivermectin because of that article,” she says. “It’s very difficult to erase what has been done.”

The Government Palace in Lima, Peru
© iSTOCK.COM, FRANKVANDENBERGH

Ivermectin becomes central to Latin America’s pandemic response

Ivermectin was developed by Merck in the 1970s and is widely used in tropical medicine to treat parasitic infections such as scabies and river blindness. It’s also recently been touted for use in malaria control due to its ability to kill mosquitoes that feed on the blood of people taking the drug.

Usually taken orally, ivermectin is included in the World Health Organization’s list of essential medicines and is considered a very safe drug with few side effects when it’s taken properly. Veterinary versions of the drug are often used to clear various animal species of worms and other parasites.

Rumors of ivermectin’s potential as a COVID-19 treatment started circulating in WhatsApp groups around early April, according to clinicians in Peru who spoke to The Scientist. Along with unverified anecdotes of miraculous recoveries among patients taking the drug, García says, members of the public began sharing a paper published in Antiviral Research on April 3 that described how extremely high doses of ivermectin could block the coronavirus’s replication in a petri dish.

The title of the study, “The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro,” created a lot of confusion, García says. “It sounds like the ivermectin was approved by the FDA for the treatment of COVID,” she says. “That had nothing to do with it.”

The paper’s publication prompted a response from the US Food and Drug Administration (FDA), which issued a warning on April 10 that the findings did not equate to evidence of ivermectin’s efficacy in COVID-19 patients, and noted that neither humans nor animals had received the drug in this study.

Later in April, Antiviral Research posted two letters to the editor that lay out concerns about the doses used in the study and a response from the authors, which states—with emphasis—“under no circumstances should self-medication be considered without the guidance of a qualified physician, and especially not using therapeutics designed for veterinary purposes!” By then, however, media outlets in Latin America had already circulated stories of ivermectin’s supposed promise in treating SARS-CoV-2 infection, and several hospitals in Peru began mentioning the drug in local clinical guidelines.

Now that ivermectin is in the national guidelines, it’s very difficult for doctors to say no to patients who want it.

Meanwhile, on April 6, Mehra, Desai, and colleagues posted the preprint based on Surgisphere’s proprietary database of hospitalized COVID-19 patients. It reported a dramatic survival difference between people who were treated with ivermectin after being put on mechanical ventilators, and similarly ill patients who didn’t get the drug. Among 52 patients given ivermectin, the death rate was 7.7 percent, the authors reported. For the more than 1,900 controls, the rate was 18.6 percent.

A couple of weeks later, a second version of the preprint replaced the first. In this case-control analysis, the death rate among 704 patients treated with ivermectin was 1.4 percent, while among 704 controls, it was 8.5 percent.

Carlos Chaccour, a global health researcher at ISGlobal in Spain who studies ivermectin’s use in malaria control and is currently overseeing a clinical study of its potential to reduce COVID-19 transmission, says he had doubts about the study as soon as he read the first version of the preprint in mid-April.

“I’ve been working with ivermectin for twelve years,” Chaccour says. “I opened [up the preprint] one morning and I was like, ‘This doesn’t make any sense . . . this massive effect.’” He and other researchers had already wondered whether ivermectin might provide some benefit against COVID-19, but hadn’t expected the drug to work as well as this study suggested.

Suspicions about Surgisphere’s ivermectin data emerge

By early May, the preprint’s findings were being widely shared among researchers in Chaccour’s circle. So he reached out to Joe Brew, a data scientist helping to analyze clinical results from the ISGlobal trial of ivermectin, and the two of them began looking into the findings in more detail.

The pair soon found claims in the first version of the preprint that were “apparently impossible,” Brew says. In particular, the paper referred to three patients treated with ivermectin in Africa up until March 1, while Brew and Chaccour were only aware of two reported cases on the entire continent by that time. The Scientist verified that a third case in Africa was confirmed on February 27, but the patient didn’t show any serious symptoms, according to reports at the time.

It was implausible that three patients in Africa could have been hospitalized, given ventilation, treated with ivermectin, and included in Surgisphere’s database, all by the beginning of March, Brew says. “Our naive assumption at that time was, well, this is a big database and maybe it’s due to coding issues.”

On May 7—after Desai, Mehra, and colleagues had published their NEJM study on cardiovascular disease and heart drugs using Surgisphere’s COVID-19 database, but before the publication of the Lancet study—Chaccour and Brew reached out to Mehra and colleagues with their concerns. That same day, Mehra acknowledged the researchers’ questions about Surgisphere’s registry and directed those questions to Desai and study coauthor Amit Patel. Desai responded, but did not directly address the points the ISGlobal researchers raised, Brew says.

Chaccour says that Mehra also told them over email that he too had doubts about the preprint’s results, on account of the surprisingly large difference in mortality rates between treated and untreated individuals. For that reason, Mehra told the researchers, the team had decided not to submit the work for publication yet.

This response contrasts with public statements made by Mehra and Patel. A tweet posted by Mehra on April 16 refers to having a paper on ivermectin in more than 700 patients “under review at a journal.” A week later, Patel responded to questions about the preprint on Twitter by saying that “many of these queries are being answered as part of the full peer review process.” Patel writes in an email to The Scientist that the team did submit the paper for peer review in a scientific journal near the beginning of April.

This doesn’t make any sense
. . . this massive effect.

—Carlos Chaccour, ISGlobal

In the statement to The Scientist, Mehra denies that he was aware of any potential discrepancies in the Surgisphere database “until questions were raised after the publication of The Lancet study” in late May. He did not respond to requests for comment about the influence of the ivermectin study on health policy in Latin America or about why the preprint was left online until then.

By May 29, when Chaccour, Brew, and ISGlobal clinical epidemiologist Alberto García-Basteiro published their concerns in an article for ISGlobal’s website, the preprint had been downloaded more than 15,000 times and cited as support for ivermectin’s efficacy by researchers and doctors in Peru, Brazil, and Chile, among other countries. 

Now that scientists and journals have raised doubts about the validity of Surgisphere’s registry, it looks as though many Latin American countries’ policies have been informed by a “mix of real data and fake data,” says Brew. “It’s just muddied the waters so much.”

The consequences of ivermectin’s popularity

In the last few weeks, a handful of influential figures in Latin America have cautioned that the scientific evidence for ivermectin’s efficacy as a COVID-19 treatment or preventive medicine is weak or nonexistent.

The Peruvian public health researcher Elmer Huerta, a well-known health communicator in Latin America, told a Peruvian television network last month that he was surprised by the government’s stance on ivermectin and accused the ministry of health of creating anxiety and misleading people into thinking, “if I don’t have ivermectin, I’m going to die.”

A blister on a patient who had received an injection of ivermection designed for veterinary use
COURTSEY OF JUAN CELIS

But with ivermectin firmly entrenched in political and public minds as a weapon against a pandemic that has already claimed more than 70,000 lives in Latin America, the question of evidence is now of secondary importance for some members of the medical and scientific communities.

Peru’s health minister Víctor Zamora, for example, recently told a radio show in Lima that the country didn’t have time “to wait for scientific evidence.” The interview followed President Martín Vizcarra’s announcement that the government had acquired nearly 500,000 doses of ivermectin and around 350,000 doses of hydroxychloroquine for use in coronavirus patients. Zamara did not respond to multiple requests for comment.

That attitude is partly shared by Eduardo Gotuzzo, the former director of the Alexander von Humboldt Institute of Tropical Medicine and Infectious Diseases in Lima and a collaborator on the World Health Organization’s Solidarity trial, which was testing hydroxychloroquine (among other drugs) and was partially suspended after Surgisphere’s Lancet paper raised concerns about the medicine’s safety. The trial was reinstated following widespread criticism of the paper, although later studies have thrown further doubt on hydroxychloroquine’s benefit in COVID-19 patients. The FDA revoked its emergency use authorization this week.

Gotuzzo, who is also a consultant to several pharmaceutical companies and has received research funds from Merck, acknowledges that there’s no clinical evidence that ivermectin is an effective treatment. But, he tells The Scientist in Spanish, ivermectin is a very safe drug, provided it’s administered properly by a doctor. He argues that there aren’t any better options available to deal with the current emergency in Peru, which has counted nearly 7,000 confirmed deaths from COVID-19 so far.

Faced with patients in a serious condition, “what do you do?” Gotuzzo says. “Give them water?” He adds that he believes ivermectin may turn out to have a positive effect, particularly if administered to patients early in infection.

Many other members of the medical community, however, are worried by the way ivermectin is being promoted as a COVID-19 medication without sound evidence for its efficacy. Juan Celis, a specialist in infectious diseases based in Iquitos in the Peruvian Amazon, tells The Scientist in Spanish that he’s witnessed firsthand the effects of the craze for the drug, or “ivermectin fever,” that took over his area in April.

Ivermectin designated for human use ran out by the middle of month, he says, so some doctors started administering veterinary versions of the drug to patients desperate for treatment. He says he’s seen people with blisters where they’ve been injected with formulations intended for animal use, and adds that some patients have shown side effects including stomach problems, tremors, and panic attacks after taking too much of the drug. Now that ivermectin is in the national guidelines, though, it’s very difficult for doctors to say no to patients who want it.

Peru’s ministry of health recently issued an announcement to warn people to take ivermectin only under the guidance of a doctor and not to use veterinary versions. But that update doesn’t address other concerns clinicians have.

It has been a nightmare.

—Patricia García, Cayetano Heredia University 

Wuelton Marcelo Monteiro, the director of teaching and research at the Fundação de Medicina Tropical Doutor Heitor Vieira Dourado in Manaus, Brazil, tells The Scientist he’s worried that the hype surrounding ivermectin could lower people’s appreciation of the real risks of COVID-19.

“In addition to the unnecessary cost of using a drug without efficiency, it can generate a false sense of safety in the population,” he writes in an email to The Scientist. “In my opinion, the evidence is still low. We urgently need good [randomized controlled trials] to make the decision.”

Obtaining and explaining new data on ivermectin

With ivermectin being so widely promoted, there’s also a risk that clinical research on the drug in Latin America will become more challenging, says García, who recently started collaborating with Chaccour and local researchers to organize a small trial to see whether ivermectin could reduce COVID-19 transmission.

“Everybody at this point wants to take it,” she says. “It’s very difficult to find somebody who could be randomized on a placebo arm. But we will try. I think that will be the only way to try to help to make better decisions.” The Peruvian ministry of health has agreed to provide support with the insurance for the trial, she adds.

Chaccour emphasizes that there are a number of aspects of ivermectin’s action in COVID-19 patients that researchers don’t yet understand. One open question, he says, is whether ivermectin might interact dangerously with other treatments being trialed in COVID-19 patients, such as Kaletra (lopinavir-ritonavir).

For now, data continue to trickle in. A few days ago, researchers in Florida posted a preprint of a study that found a positive association between the administration of ivermectin and survival in COVID-19 patients, though the authors noted the findings should “be further evaluated with randomized controlled trials.” Clinicaltrials.gov, meanwhile, lists clinical studies of the drug in Argentina, Egypt, and Iraq, among other countries.

García says she worries about how scientists will communicate any new findings on ivermectin—or other drugs being explored as COVID-19 treatments—now that government messages have created confusion and scientific scandals have damaged public trust. “At the very beginning of this epidemic, I think people were in the belief that science was going to guide treatment, was going to guide the knowledge, was going to guide everybody through the right path to cure,” she says.

“Now, with what has happened, I think people have lost faith in science,” she continues. “It’s terrible for science and it has been very, very bad for us in Latin America.”

More from The Scientist’s investigation into Surgisphere 

Surgisphere Fallout Hits African Nonprofit’s COVID-19 Efforts

June 7, 2020

The company had helped develop a tool to aid decision-making in distributing limited medical equipment among coronavirus patients, but two high-profile retractions call into question the validity of Surgisphere’s work in toto.

Lancet, NEJM Retract Surgisphere Studies on COVID-19 Patients

June 4, 2020

All authors other than company founder and CEO Sapan Desai were “unable to complete an independent audit of the data,” The Lancet states.

Concerns Build Over Surgisphere’s COVID-19 Dataset

June 2, 2020

NEJM and The Lancet issue expressions of concern as researchers question where the company got its data on thousands of coronavirus patients.

Disputed Hydroxychloroquine Study Brings Scrutiny to Surgisphere

May 30, 2020

Scientists have raised questions about the dataset published in The Lancet last week that triggered the suspension of clinical trials around the world—and about Surgisphere Corporation, the company behind the study.

WHO Halts Hydroxychloroquine Testing Over Safety Concerns

May 27, 2020

A paper published in The Lancet reported that hospitalized COVID-19 patients taking the drug had a higher risk of death, although some researchers have raised questions about the data.