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Waters Muddied As Bharat Readies COVID-19 Vaccine For '21 Launch

Waters Muddied As Bharat Readies COVID-19 Vaccine For '21 Launch

Source : 'Scrip Intelligence'

Bharat Biotech  has claimed “at least 60%” efficacy for its whole virion, inactivated COVID-19 vaccine candidate Covaxin and is preparing for a launch during the fiscal second quarter ending 30 September 2021. 

Though the company’s claim pales in comparison to the over 90% efficacies announced in Phase III interim results from Pfizer Inc./BioNTech SE, Moderna, Inc. and Russia’s Gamaleya Institute, a Bharat Biotech source told Scrip that its figure is based on early stages of trials and the final number is expected to be higher.   

Meanwhile, as companies race to the goalpost of a vaccine globally, questions are being raised over whether they are being ethical and rigorous enough. Russia and China’s vaccines were released for selective immunization well before robust clinical trial data were obtained.  

In India, Bharat Biotech, which is developing Covaxin in association with government body the Indian Council of Medical Research (ICMR), is meanwhile in the dock over a serious adverse event. A 35-year old patient with no comorbidities developed viral pneumonitis post a dose of Covaxin during Phase I trials in August and was hospitalized.

The company says it informed the Central Drugs Standard Control Organisation (CDSCO) under the regulator Drugs Controller General of India (DCGI) within 24 hours of occurrence and confirmation of the event. While Bharat Biotech paid for medical expenses as per law, clinical trials were not halted.

Civil society is worried this sets the wrong precedent. Work had been temporarily paused during Serum Institute of India Pvt. Ltd.'s trials of the University of Oxford/AstraZeneca PLC vaccine candidate following a serious adverse event in the UK. In that instance, however, Serum Institute had not even formally informed DCGI of the adverse event, prompting the latter to issue a show-cause notice and place trials on hold. ()

"The stark contrast in the way that CDSCO responded to serious adverse events in trials of the two vaccine candidates raises questions about differential treatment. In the case of both vaccines, SEC (Subject Expert Committee) minutes do not record any discussion about adverse events or the adjudication of relatedness to the vaccines," Malini Aisola, co-convenor of All India Drug Action Network (AIDAN), told Scrip.

AIDAN, a network of non-government organizations which works to increase access and improve the rational use of essential medicines, was the first to reveal the serious adverse event with the Bharat Biotech candidate.

In its defense, Bharat Biotech says the event was investigated thoroughly and “determined as not vaccine-related” and all documentation, including a complete causality report, was submitted within stipulated timelines as mandated by the ethics committee and CDSCO-DCCGI.

Be that as it may, consent forms mandated to be filled in by trial participants did not have this information when the company sought consent for Phase II and III trials, Aisola said. Bharat Biotech preferred to not comment on this topic when contacted by Scrip.

When the company proposed amendments on 2 September to the Phase II part of the trial protocol, there was no attempt to include information about adverse events in the consent form.

Multiple amendments regarding the Phase II trial were approved, including a reduction in sample size from 750 to 380 while dropping the placebo arm and changing the dosing regimen from giving doses 14 days apart to 28 days apart. The stated rationale for the amendments was to "expedite the Phase II trial" which doesn’t qualify as scientific justification.

“Though the consent form to the seamless Phase I/II trial is usually the same, it could have been amended before Phase II began. Even the consent form for the Phase III trial that is ongoing does not have any information regarding adverse events observed in previous phases,” Aisola added.

In Serum's case, it was permitted to resume trials with conditions that included disclosure of information regarding adverse events to trial volunteers. The consent form version of 15 September before the trials were resumed included information regarding adverse events and relatedness to the vaccine, she said.

While Bharat Biotech is not required to publicly disclose an adverse event, it seems to have erred by not informing trial participants. A double-blind, placebo-controlled, multi-center study for its vaccine with 25,800 participants began in November and is ongoing. ()

Apart from this, civil society is concerned over the fact that Indian companies usually don’t share clinical trial data on pre-print servers or journals for peer reviews. Though sharing of data is not mandatory and companies can rightfully claim that revealing data early could bias trials, it is considered good practice now.

That’s more so in the case of COVID-19, as several proposed cures like hydroxychloroquine and Gilead Sciences, Inc.’s antiviral remdesivir have been found to be ineffective by the World Health Organization after they saw an initial enthusiastic adoption across the globe, including in India.

A Bharat Biotech spokesperson had earlier told Scrip that the company planned to share Phase I/II data on pre-print servers in November or December. 

Globally, independent experts have assigned credibility to claims by companies developing prophylactics or therapies against SARS-CoV-2 only after reviewing their data. The fact that several products have been granted or are requesting emergency use authorizations only makes such rigorous scrutiny essential to ensure that the science is not questionable. 

In India, there have been several questions over the grant of emergency or restricted use authorization to Biocon, Ltd.’s antibody itolizumab for treating moderate to severe COVID-19 and to Glenmark Pharmaceuticals Limited’s antiviral favipiravir for mild to moderate patients of the disease. ()

Recently, AstraZeneca has faced ire after the company publicized 90% efficacy for its vaccine from a subset that resulted from a dosing error and was not part of the initial Phase III trial protocol. Questions are also being raised over whether the company can average results from two different dosing regimens in announcing efficacy for AZD1222. ()

Meanwhile, Bharat Biotech is setting up a manufacturing unit in the Indian state of Odisha at a cost of INR3bn ($40.6m), to produce COVID-19 vaccines apart from those for malaria and other diseases. The company already has facilities in Hyderabad, Telangana state.

Apart from Covaxin, the company is also developing COVID-19 vaccines in association with three different partners. It first entered a tie-up with the University of Wisconsin, Madison and US-based FluGen Inc. for a nasal vaccine. Though trials were to begin by October, there is no word from the company on the status of this vaccine aspirant. ()

An exclusive deal has also been entered with the Thomas Jefferson University in the US for a vaccine using an existing deactivated rabies vaccine as a vehicle for coronavirus proteins.

The third global collaboration, also in the US, is with Washington University School of Medicine in St. Louis for a novel chimp-adenovirus, single dose intranasal vaccine. ()

Though Bharat Biotech hasn’t stated how many doses of the COVID-19 vaccines it intends to produce, India itself will require a large number. Besides, the company has initiated talks with countries like Brazil to supply its indigenously developed vaccine. 

The Indian government has recently begun the process of identifying nearly 300 million priority recipients of such vaccines, which include healthcare professionals and at-risk individuals, who will likely need 600 million doses given that most of the vaccines involve a two-dose regimen.

With such enormous demand at hand, every vaccine being developed is of value. At the same time, scientific rigor cannot be compromised.

By Vibha Ravi