Conflicting signals from drug regulator, COVID-19 national task force

There have been at least three instances where the drug regulator has approved a drug or vaccine but the COVID-19 National Task Force has taken a diametrically opposite stand and not included the drug/vaccine in the national treatment protocol. But the task force was quick to accept the and include the approval given to repurposed drugs even in the absence of data.

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 an 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 the 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 has not been included in the national protocol for treatment of coronavirus.

Aggressive marketing

“We have to remember that this drug has major safety concerns. It can cause teratogenicity, mutagenicity and it can also cause cartilage damage and can also be damaging to muscles also. Contraception will have to be done for three months for male and female if this drug is given because the child born could be problematic 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.

“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 like reduction of post-Covid 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.” 

Zydus vaccine faces the same problem 

This is not the first time that the National COVID-19 task force has refused to include drugs/vaccines that have been granted an EUA by the regulator.

On August 20, 2021 Zydus Cadila’s the 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 for children 15-18 years, Covaxin will be the only option for vaccination of children 15-17 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.

On June 4, 2021, months before Zydus vaccine got the emergency use approval, Dr. V K Paul, NITI Aayog member (Health) speaking to the media mentioned that not only Bharat Biotech is conducting a Covaxin trial on children, Zydus vaccine is already being tested in children. “When Zydus comes for licensure [emergency use approval], maybe we have enough data to take a view on whether that vaccine can be given for children,” Dr. Paul said. He was referring to vaccinating 130-140 million children belonging to the cohort going up to 12 years, for which 250-260 million doses will be needed.

Speaking to CNN News18 on December 27, 2021, 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 (ZyCoV-D) and Covaxin will be available for vaccination and children will have an option to choose between the two vaccines depending on the availability.

For reasons not known, the health ministry has not only declined to use Zydus vaccine in adolescents 15-17 years but has also not recognised the emergency use approval granted to ZyCoV-D by saying Covaxin is the only vaccine that has an EUL (emergency use listing). Incidentally, emergency use listing or EUL is a term used by the WHO and not by Indian authorities or the drug regulator.

The questionable clearance for Itolizumab

In the second case, Itolizumab, a monoclonal antibody originally developed by Biocon and sold under the brand name Alzumab to treat of 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 phase-2 trial study being very small in size — just 30 participants — and inconclusive data. For inexplicable reasons, the regulator waived the phase-3 trial for the drug and wanted Biocon to conduct a post-approval phase-4 studies while granting it an emergency use approval.

But three days after approval, Dr Bhargava gave the first indication that Itolizumab might not be included in the national treatment protocol when he said trials have not yet demonstrated that the drug can reduce mortality.

Dr. Bhargava said Itolizumab and Tocilizumab, a Roche product that is distributed by Cipla in India have “not yet demonstrated mortality reduction by any trial and therefore, trials are wanting, and are happening in different parts of the world to look at whether there is mortality reduction with these two drugs.”

On July 27, 2020, it became clear that itolizumab drug will not be included in the national treatment protocol.

Story repeats with 2-deoxy-d-glucose

The anti-COVID-19  drug developed by Institute of Nuclear Medicine and Allied Sciences (INMAS), a DRDO lab along with Dr Reddy’s Laboratories, Hyderabad was granted an emergency use approval by the drug regulator on May 8, 2021.  As is the norm, the regulator approved the drug even when no published data on its performance is available in the public domain. And on May 17, the drug was jointly launched by Minister of Defence and Minister of Health and Family Welfare Dr. Harsh Vardhan. Speaking at the launch, Dr. Harsh Vardhan said the drug as the “potential to become a game changer” in the fight against the pandemic. Drug to reduce average recovery time by 2.5 days and oxygen demand by 40%.

Despite the health minister calling it a “game changer”, the drug was not even included in the national treatment protocol. “If we find in our scientific investigation that it is valid for Covid-19 treatment, we will include it in our treatment protocol,” Dr Samiran Panda, Head, Epidemiology and Communicable Diseases, ICMR told Outlook three weeks after the approval. 

Decisions taken in the 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. Speaking in a TV channel, a Glenmark representative said that the approval for emergency use was granted on June 19, 2020 by the regulator based on an “early readout” from the study. The study is expected to be completed in the coming weeks and months. Essentially, the approval was granted based on sketchy data.

In the case of Remdesivir, on November 20, 2020, WHO recommended against its use 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.

Published in The Hindu on January 8, 2022