On December 28 last year, Health Minister Mansukh Mandaviya tweeted saying that in further strengthening the fight against COVID-19, the Indian drug regulator has granted emergency use approval for the antiviral drug molnupiravir. He also mentioned that molnupiravir will be manufactured by 13 generic drug manufacturers in India.
“Considering the emergency and unmet medical need in COVID-19, the SEC on December 27 recommended for grant of permission to manufacture and market molnupiravir for restricted use under emergency situation in the country for treatment of adult patients with COVID-19,” the drug regulator said in a statement.
A week later, on January 5, at a press conference, the Director-General of ICMR Dr. Balram Bhargava said molnupiravir has major safety concerns and therefore was not included in the national protocol for treatment of coronavirus.
“We have to remember that this drug has major safety concerns. It can cause teratogenicity, mutagenicity... cartilage damage and can also be damaging to muscles. Contraception will have to be done for three months for male and female if this drug is given because the child born could [have problems] due to teratogenic influence… We have concerns about the drug and its use during lactation, in children, soft-tissue injuries, reproductive age group,” he said.
Public health problem
“After the EUA, Indian generics are now aggressively launching the drug, and it is likely to be prescribed widely to patients diagnosed with COVID-19 with mild/moderate disease in the private sector. This may be problematic from a public health point of view, because of concerns regarding the inherent capacity of molnupiravir to cause viral mutations and its risk to induce more viral mutants,” says Ms. Leena Menghaney, South Asia Head of Médecins Sans Frontières’s Access Campaign.
“The drug is already available and pharmaceutical companies are aggressively marketing it. In all likelihood, the drug is abused already,” says Dr. Lancelot Pinto, Consultant Respirologist at P.D. Hinduja National Hospital and Medical Research Centre, Mumbai. “I have been prescribing it in very old people and old people with high risk of progressing to severe disease.”
“Drug companies are aggressively marketing the drug with blatant lies and tall, unsubstantiated claims [such as] reduction of post-COVID-19 anxiety, depression and fatigue but without a word on potential risks,” says Dr. Shriprakash Kalantri, Professor of Medicine at Mahatma Gandhi Institute of Medical Sciences, Sevagram, Maharashtra. “Why do the two highest scientific bodies — the drug regulator and ICMR — take such conflicting positions. This sends a confusing signal to the public and physicians.”
Not the first time
This is not the first time that the national COVID-19 task force has refused to include drugs/vaccines granted an EUA by the regulator.
On August 20, 2021 Zydus Cadila’s COVID-19 vaccine ZyCoV-D was granted an emergency use approval by the Indian regulator. The vaccine was approved for use in adults and children 12 years and above. However, in a letter dated December 28 last year, Health Secretary Rajesh Bhushan said Covaxin will be the only option for vaccination of children 15-18 years that was set to begin on January 3. He also said Covaxin is the “only vaccine with EUL [emergency use listing] for the age group 15-18”. The same message was conveyed by the guidelines released by the health ministry.
But speaking to CNN News18 on December 27, Dr. R.S. Sharma, CEO of the National Health Authority and Chairperson of the Empowered Group on Vaccine Administration for COVID-19 (Co-WIN) said both Zydus’s vaccine (ZyCoV-D) and Covaxin will be available for vaccination and children will have an option to choose between the two vaccines depending on availability.
For reasons not known, the health ministry has not only declined to use Zydus vaccine in adolescents but has not even recognised the emergency use approval granted to ZyCoV-D by saying Covaxin is the only vaccine that has an EUL. Incidentally, emergency use listing or EUL is a term used by the WHO and not by Indian authorities or the drug regulator.
In the second case, itolizumab, a monoclonal antibody originally developed by Biocon and sold under the brand name Alzumab to treat psoriasis, was granted an EUA on July 11, 2020 to treat patients with moderate-to-severe COVID-19 disease. The subject expert committee greenlighted the drug the previous day despite the very small size of the study and inconclusive data. But three days after approval, Dr. Bhargava gave the first indication that it might not be included in the national treatment protocol when he said trials have not yet demonstrated that the drug can reduce mortality. On July 27, 2020, it became clear that the drug will not be included in the national treatment protocol.
Absence of data
Strangely, ivermectin, hydroxychloroquine and convalescent plasma therapy were included by ICMR in the recommended treatment guidelines even in the absence of data. Hydroxychloroquine was approved in end-March 2020 primarily for ICMR to carry out studies.
Convalescent plasma was dropped from the guidelines only in mid-May last year. Ivermectin and hydroxychloroquine were dropped from the revised clinical guidance for management of adult COVID-19 patients only on September 24 last year. WHO had on March 31, 2021 said there is inconclusive evidence of benefit in the case of ivermectin. “The current evidence on the use of ivermectin to treat COVID-19 patients is inconclusive. Until more data is available, WHO recommends that the drug only be used within clinical trials,” WHO said.
“Even after a year of COVID-19, the ICMR guidelines in May 2021 advised ivermectin and hydroxychloroquine which were well known to have been useless for COVID-19 treatment,” Mr. Murali Neelakantan, Principal Lawyer at Amicus, Mumbai says in an email. “On the other hand, the drug regulator had approved favipiravir and itolizumab to treat COVID-19 but they don’t find place in the ICMR protocol, even though hundreds of crores of rupees worth of these two drugs were being consumed in India. It says something about the Indian drug regulator that favipiravir and itolizumab are not being prescribed for COVID-19 anywhere else in the world.”
Remdesivir and favipiravir were approved by the Indian regulator and included in the treatment guidelines even when supporting data were not available or were inconclusive.
In fact, on November 20, 2020, WHO recommended against the use of remdesivir in hospitalised patients, regardless of disease severity. It said there is “currently no evidence that remdesivir improves survival and other outcomes in these patients.” Yet, the revised clinical guidelines of September last year have retained remdesivir for use in specific circumstances.