The head of the Council of Scientific and Industrial Research (CSIR) — India’s largest chain of industrial laboratories — and two other scientists have castigated an influential study published in the Lancet, which purported to show hydroxychloroquine (HCQ), a prominent antimalarial, as being unhelpful and harmful to coronavirus (COVID-19) patients.
The letter signed by Shekhar Mande, Director-General, CSIR; Anurag Agrawal, physician and Director, Institute of Genomics and Integrative Biology — a CSIR institute — as well as Rajeeva Karandikar, Director, Chennai Mathematical Institute, says the World Health Organization’s decision to suspend trials of the drug was a “knee-jerk” reaction.
WHO suspends clinical trials of hydroxychloroquine over safety concerns
“The observational data is sloppy, and the statistics underlying them is faulty. There is no doubt that it will not stand the test of time. You can’t compare apples with oranges,” Mr. Mande told The Hindu.
The study, “Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis”, was published online on May 22. It studied records from 96,032 patients hospitalised between December 20, 2019, and April 14, 2020, and sought to investigate whether COVID-19 positive patients on HCQ alone, HCQ combined with an antibiotic, choloroquine (CQ, an older version of HCQ), and CQ with an antibiotic, benefited over those who were on other treatments. ‘Benefit’ here was defined as either having improved in-hospital survival or less likely to suffer from irregular heartbeat, a side effect associated with HCQ.
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The study concluded that the drug regimens increased in-hospital death by 33-45% and increased frequency of ventricular arrhythmias by several degrees.
On May 25, the WHO cited this study and said it had “temporarily suspended” clinical trials of hydroxychloriquine as a potential treatment for COVID-19. This trial was part of a so-called solidarity trial being overseen by the WHO where four drug combinations — all of them developed for other diseases but showing promise for COVID-19 treatment — were being tested at four hundred hospitals in 35 countries. France, Italy and Belgium have also halted HCQ trials.
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A WHO pause doesn’t stop a country — even India — from conducting any form of trial, Mr. Mande said the “harm” that had resulted from the Lancet study would create “fear” in the minds of people.
However, in the last few days, there have also been independent criticisms of the study. A letter by 140 scientists, researchers and statisticians to the Lancet demanded that the study be more transparent with patient details and explain the data sourcing as well statistical interpretation. They demanded an “independent” verification of the data either by the WHO or another organisation.
They also said the “excess mortality” of 33% in those on the drug was too high, given what was observed in other HCQ trials. This a point underlined by Mr. Mande and co-authors. They argue that HCQ appeared less effective because the data suggested that those chosen to receive the drug were much sicker than the group not on the treatment. “This is not unexpected here and highlights the well-known problem of statistical comparisons of unbalanced unrandomized groups in observational studies,” notes the letter sent to Richard Horton, Editor of the Lancet, and Soumya Swaminathan, Chief Scientist, WHO.
Why is India pushing ahead with hydroxychloroquine?
Mr. Mande said that while observational studies, which in the medical world are considered less reliable that randomised clinical trials, were “valuable”, their findings ought to be interpreted with care. However, India’s medical administration also relies on observational data — and has not conducted randomised trials — to recommend HCQ as a preventive drug to healthcare workers. None of these data are publicly available. “That’s up to the ICMR on what studies they choose but remember they are experienced clinicians and have recommended this drug with a lot of thought,” Mr. Mande added.
HCQ — a common, inexpensive, off-patent drug — rose to global prominence after U.S. President Donald Trump’s endorsement of it and the U.S.’s approval of it as an emergency use drug. India supplies 70% of the world’s HCQ, with Ipca Laboratories, Zydus Cadila and Wallace Pharmaceuticals being the top companies making the drug in India. – The Hindu