In India, which has the world’s second-largest COVID-19 outbreak, there is a desperate need for effective treatments. But researchers are concerned about how the country’s drug regulator is handling potential therapies. The Drugs Controller General of India (DCGI) has approved several repurposed drugs for ‘restricted emergency use’ for treating the disease, the first time it has used such powers. Yet scientists say it’s unclear on what basis the drugs were approved, and critics argue that the manufacturers’ data on their effectiveness is unconvincing so far.
“Transparency is even more important in the pandemic,” says Anant Bhan, a public-health researcher at Yenepoya University in Mangalore. “It’s a new virus where we don't have definitive treatments available.”
Scientists are also concerned that the emergency authorizations are influencing other countries’ decisions. One of the drugs approved for COVID-19 in India is itolizumab, which is used to treat the autoimmune condition psoriasis. This has now been approved for emergency use in Cuba, partly on the basis of Indian data and approval, according to Cuban media. And Equillium, a biotech company based in La Jolla, California, which has a licence to manufacturer itolizumab, received approval in the United States on 29 October to proceed with a large trial. Equillium’s filing to the US financial regulator notes that it was encouraged by India’s data and approval.
The DCGI has granted emergency authorization for the use of at least three drugs for treating COVID-19. The influenza drug favipiravir was approved for treating mild to moderate cases in June; remdesivir, a broad-spectrum anti-viral drug, was also authorized in June; and itolizumab was approved for treating moderate to severe acute respiratory distress in people with COVID-19 in July.
India is not alone in fast-tracking COVID-19 treatments. The US Food and Drug Administration (FDA) has granted emergency-use authorizations (EUAs) for three putative COVID-19 drugs: infusions of antibody-rich plasma from people who have recovered from the disease; the malaria drug hydroxychloroquine; and remdesivir, which has since been granted full approval for use in adults. Once an EUA is granted, the FDA issues a public notice of the evidence — or lack thereof — for its decision, and hospitals and doctors are required to monitor patients for side effects. Although EUAs only require evidence that they “may be effective”, some researchers criticized the lack of information on the hydroxychloroquine authorization. The FDA later revoked the hydroxychloroquine authorization, after clinical trials showed the drug did not work for COVID-19 and had serious side effects.
But in India, it’s unclear what ‘restricted emergency use’ means, says Sahaj Rathi, a visiting hepatologist at the Mahatma Gandhi Institute of Medical Sciences in Sevagram. The term is not mentioned in any law, regulations or policy documents available to the public.
A safety committee that the DCGI established to fast-track COVID-19 drugs and vaccine approvals recommended the approvals. But membership of the committee is unknown, and the evidence underlying its decisions has not been made public, says Bhan. The most detailed information about the approvals is the committee’s brief meeting minutes.
In the case of favipiravir, the committee has granted emergency use to several manufacturers of the drug, but for different dosages — of 200, 400 and 800 milligrams, according to meeting minutes. “In the interest of getting approvals passed, I think scientific rigour has taken a back seat,” says Rathi, who has written about his concerns in the Indian Journal of Medical Ethics.
India’s health ministry, which oversees the regulator, did not respond to e-mailed questions about emergency authorizations.
Emergency approvals are typically granted on the basis of preliminary evidence that a drug works. But scientists say there is little evidence so far that favipiravir and itolizumab can treat COVID-19 successfully.
A month after favipiravir was authorized for emergency use, its Mumbai-based manufacturer, Glenmark Pharmaceuticals, revealed that the drug had been tested in just 150 patients with mild to moderate illness. But the trial didn’t determine whether people taking the drug were less likely to develop severe forms of the disease, or die from it. Instead, it measured the time it took patients to stop shedding the virus, which Rathi says does not establish that the person recovered faster or was less infectious.
Glenmark says the drug is effective against COVID-19 and its choice of trial endpoint was based on the state of knowledge at that time. The drug has also been approved for emergency use in China and Russia, but regulators in the United States and South Korea have not authorized its use.
In India, at least 15 pharmaceutical companies are selling the drug, and sales have reached 2.8 billion rupees (US$37.6 million) since June, according to AIOCD, a pharmaceutical market research company. Physicians say it is being widely prescribed for mild COVID-19 infections, and that families who are desperate to help ill family members were initially paying around 12,500 rupees (US$168) for a 14-day course.
“It leads to a kind of an emotional blackmail on the family,” because there is no evidence that this drug works, says Shriprakash Kalantri, an internal medicine specialist at the Mahatma Gandhi Institute of Medical Sciences.
Scientists have also questioned the preliminary data on itolizumab, which is developed by Bengaluru-based Biocon. A company press release says that a phase II safety trial on 30 people hospitalized with COVID-19 reduced mortality. But researchers at the All India Institute of Medical Sciences in Bhopal wrote in a commentary in BioDrugs that the trial was poorly designed, and that it was not clear what constituted “standard of care” in the control arm. (BioDrugs is published by Adis, part of Springer Nature, which publishes Nature. Nature’s news team is editorially independent of the publisher).
The trial was also too small to show that the drug works, Kalantri says. Biocon did not respond to a request for comment on scientists’ criticisms of its trial, although it started a post-marketing trial in October.
The current data is not strong enough for either favipiravir nor itolizumab to be on the government’s medical guidelines for treating COVID-19, says Randeep Guleria, director of the All India Institute of Medical Sciences in New Delhi, who helped to prepare the guidelines. “More data needs to be generated,” he says.
It is not clear how long the drugs will continue to be approved for emergency use. In the United States, companies need full approval to sell their products beyond the emergency period. This typically requires them to conduct a robust clinical trial, known as a phase III trial, in thousands of people. Kalantri says the Indian regulator should ask pharmaceutical companies to set up such trials to show that the drugs actually work.
But this would be difficult because companies cannot ethically give patients a placebo when an approved drug exists, says Gagandeep Kang, a vaccinologist at the Christian Medical College in Vellore, who defends the emergency-use approvals. Ideally, the government should establish a clinical-trial network to independently test repurposed drugs for treating COVID-19, similar to the UK Recovery trial, before or after EUAs are granted, she says.
Nature 587, 187-188 (2020)