Two studies conducted on Hydroxychloroquine, the anti-malarial drug that has been widely campaigned by American President Donald Trump and India's top medical research body - Indian Council of Medical Research (ICMR) has come under the scanner yet again.
After a study published in The Lancet Journal claimed that administering hydroxychloroquine to people infected with COVID-19 infection can increase their risk of death, the World Health Organisation (WHO) suspended a large scale trial on COVID-19 patients. Following in the WHO's footsteps, the governments of France, Italy and Belgium halted the use of hydroxychloroquine for COVID-19 patients. The study had shown negative effects of hydroxychloroquine and chloroquine on COVID-19 infected people.
Now, concerns are mounting about studies in two influential medical journals - The Lancet and The New England Journal of Medicine - on hydroxychloroquine used on people infected with the coronavirus.
The New England Journal of Medicine issued an "expression of concern" on Tuesday on a study it published on 1 May that suggested that the widely used blood pressure medicines were not raising the risk of death for people with COVID-19.
The study relied on a database with health records from hundreds of hospitals around the world. "Substantive concerns" have been raised about the quality of the information, and the journal has asked the authors to provide evidence that it's reliable, the editors wrote.
The same database by the Chicago company Surgisphere Corp was used in an observational study of nearly 100,000 patients published in The Lancet that tied the malaria drugs hydroxychloroquine and chloroquine to a higher risk of death in hospitalized patients with the virus. The Lancet issued a similar expression of concern about its study on Tuesday, saying it was aware "important scientific questions" had been raised. Although it wasn't a rigorous experiment that could give definitive answers, The Lancet study had wide influence because of its size.
Hydroxychloroquine - has anti-inflammatory and antiviral properties - is said to inhibit the coronavirus in laboratory experiments but has not been proven effective in humans, particularly in placebo-controlled, randomized clinical trials considered the gold standard for data.
The drug has been mired in controversy since President Donald Trump repeatedly promoted it, calling it a game-changer. He even took it himself without clear evidence that it's safe or effective for preventing or treating coronavirus infection after two people in the White House were tested positive.
Dr Mandeep Mehra of Brigham and Women's Hospital in Boston, is a professor of Medicine at Harvard Medical School and the lead author of both studies, along with Sapan Desai, Surgisphere's founder. He defended the use of the Surgisphere dataset as an intermediary step until clinical data is available.
"I eagerly await word from the independent audits, the results of which will inform any further action," Mehra said in a statement after The Lancet note.
A hospital statement says the authors launched an independent audit of the data in The New England Journal paper on Monday. A second statement notes that The Lancet posted a correction Friday on a discrepancy found in that study and that an independent review would be done of its data too. The correction did not change the overall results or conclusions.
A statement on Surgisphere's site says it stands behind the integrity of its studies and notes that observational data like what it supplied from electronic health records are not a substitute for rigorous experiments to test a drug.
Surgisphere also said in a statement that the audit "will bring further transparency to our work (and) further highlight the quality of our work."
Nearly 150 doctors have signed an open letter to The Lancet last week calling the article's conclusions into question and asking to make public the peer review comments that preceded publication.
"This is not some sideshow or minor issue," Dr Walid Gellad, a professor at University of Pittsburgh's medical school, who was not a signatory of the letter but has been critical of the study, told Reuters. "We're in an unprecedented pandemic. We've organized these enormous clinical trials to figure out if something works. And this study stopped or paused a couple of those trials, and changed the narrative around a drug that no one knows if it works or not."
The Lancet and the authors need to do more to address the many concerns that scientists have raised, said Dr Eric Topol, a research methods expert and director of the Scripps Research Translational Institute in San Diego to The Associated Press.
"I had accepted The Lancet paper on its face" because the journal and lead author are highly regarded, and because the results are consistent with prior research -- 13 studies have found no benefit from hydroxychloroquine for coronavirus, Topol said.
With the new concerns and correction, the cloud around the database "has now been greatly amplified," Topol said.
With inputs from agencies