Medical Community & Policy Makers not in unanimity in the treatment of Mild to Moderate COVID-19 Patients

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.

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.

Favipiravir permanently registered in Russia for COVID-19 treatment Earlier, the Russian Federal Service for Surveillance in Healthcare informed that Russia had registered three drugs based on Favipiravir: Avifavir, Areplivir and Coronavir

Emergency use
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.

Unconvincing data
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.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.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.

Modi govt panel rejects proposal to make chewable Favipiravir tablets for Covid patients
Committee didn’t find MacLeods Pharma’s proposal adequate, but is considering US firm Mylan’s proposal to test Favipiravir with three other drugs.

New Delhi: An expert committee of the Narendra Modi government has rejected a proposal by Mumbai-based drugmaker Macleods Pharmaceuticals Ltd to manufacture chewable tablets of the drug Favipiravir for Covid-19 patients.

Favipiravir, an antiviral medication developed in Japan, has been the subject of several trials across the world as a potential treatment for Covid-19, and has been approved for restricted emergency use in India.

At a meeting on 6 November, the Subject Expert Committee (SEC) — which advises the Drug Controller General of India on applications seeking approvals for new drugs, vaccines, and clinical trials — found that the justification submitted by Macleods Pharmaceuticals to manufacture and market chewable Favipiravir tablets was “inadequate”.

This was revealed in the minutes of the meeting uploaded on the Central Drugs Standard Control Organisation’s (CDSCO) website. CDSCO is a health ministry arm that regulates the quality of drugs and vaccines in the country.

Chewable tablets are deemed beneficial for factors such as palatability, stability, precise dosing, portability, and ease of delivery. However, such tablets are generally explored for medicines made for children or as supplements.

Mylan proposes to test Favipiravir in three drug combos
The SEC is, however, considering another proposal by US-based Mylan Pharmaceuticals to test Favipiravir with three different drug combinations.

According to the proposal submitted by Mylan, the antiviral drug will be tested with Bromhexine, Colchicine USP tablet and Nitazoxanide tablet in three different arms of a clinical trial, which will also have a fourth arm known as the ‘standard of care’ treatment.

In a clinical trial, arms signify a group of people who receive the same intervention. Clinical studies may have two or more research arms.

While Bromhexine is used in the treatment of respiratory tract disorders associated with mucus, Colchicine USP tablet is used to cure a form of arthritis where patients suffer from pain and inflammation due to deposition of uric acid in the joints. Nitazoxanide, an antiparasitic medication, is used in the treatment of diarrhoea and worm infections.

The expert panel has asked Mylan to submit more details on the proposal, including the “scientific justification for having four arms with different drugs in the proposed study”, according to the minutes of the meeting.

“In the proposed trial of 4 arms, Favipiravir with 3 different drugs is proposed to be compared with Standard of Care (SOC). Justification for comparing the combination therapy versus SOC instead of comparing the combination therapy with Favipiravir plus SOC should be submitted,” the panel further noted.

Treatments based on SOC are known as symptomatic treatments, where a doctor gives medicines to manage the symptoms shown by patients, along with usual care.