New Delhi: Covaxin’s maker, the Hyderabad-based Bharat Biotech, cut corners to make the COVID-19 vaccine while India’s drug regulator, the Central Drug Standards Control Organisation (CDSCO), turned the other way, STAT has reported in a new investigation.
In response to these and other allegations, one of the company’s directors has reportedly said that they had to skip certain processes because of “political pressure” to develop an indigenous vaccine, that their modifications to the trial process were “vetted” by the regulator and that the vaccine’s clinical trials were dictated by “speed”.
This is the first time a senior official of the company has responded to allegations against the company. In April, the WHO suspended the supply of Covaxin to UN agencies citing deficiencies in good manufacturing practices. The WHO had also said that Bharat Biotech made some changes in the manufacturing processes after receiving an emergency-use license for Covaxin. The company didn’t say what the changes were nor did it respond to queries related to its ‘corrective’ action.
However, as The Wire Science subsequently found, the WHO had rejected Bharat Biotech’s corrective action plan and that the vaccines continued to remain suspended on the same grounds. The company didn’t issue any statements about the suspension. Of all COVID-19 vaccines in the world, Covaxin is the only one to have been suspended by the WHO.
Now, according to STAT, there were several irregularities in the three phases of the clinical trials conducted for the vaccine. The outlet’s investigation, led by reporter Ed Silverman, found that the number of participants enrolled in the first and second phases of the trials, accessed from the corresponding papers published in The Lancet Infectious Diseases, differed from the number specified in the trial protocol document.
“In reviewing the documents, there was a clear discrepancy in the number of enrollees,” Silverman wrote. “In reporting the Phase 1/2 data, the protocol stated 402 participants were given the first dose and 394 got the second dose. But results published in Lancet Infectious Diseases in January 2021 stated 375 people were given a first dose and 368 received a second dose.”
In response, Krishna Mohan, who is one of Bharat Biotech’s directors, attributed this to difficulties in coordination between people working remotely. Reshma Ramachandran, head of the Collaboration for Regulatory Rigor, Integrity, and Transparency at the Yale School of Medicine, also said these changes were “worth noting” but not necessarily “disruptive” for Covaxin.
But Ramachandran found another discrepancy to be “problematic”: in the phase 2 clinical trial, the trial administrators dropped the placebo arm.
In a clinical trial for a vaccine, it is administered to two sets of participants: one receives the active form of the vaccine and one receives a dummy, also known as a placebo. After a predetermined period, investigators estimate the vaccine’s safety and efficacy by comparatively analysing the data from the two groups.
According to STAT, however, the administrators dropped the placebo arm. Instead, they separated participants into two groups: one received one formulation of Covaxin and another received another formulation of Covaxin.
It is okay to drop the placebo arm only when a vaccine’s efficacy has already been established, not when it is being evaluated for the first time. Specifically, having a placebo arm allows investigators to understand a vaccine’s effects against a disease relative to how that disease might have progressed without the vaccine. Replacing the placebo arm with just another formulation only allows investigators to assess how well one formulation does relative to the other.
As an illustration: if one formulation is bad and the other is terrible, the bad one will still look good relative to the terrible one – but that wouldn’t mean it’s good overall.
STAT’s efforts also found that the CDSCO subject expert committee gave Bharat Biotech the go-ahead to initiate phase 2 trials even before the results of the phase 1 trial were available. The permission had been granted on the basis of preclinical studies, which are conducted with animals, before the first phase of the human trials.
Phase 1 trials are small and this didn’t pique Ramachandran’s concerns – but what reportedly did was the company commencing phase 3 trials without the results of the phase 2 trials.
In phase 2, investigators assess whether the vaccine is safe and effective enough to initiate a phase 3 trial, which typically has a very large number of participants. Bharat Biotech’s Mohan admitted to STAT that the company had initiated a phase 3 trial on the basis of animal studies alone. Mohan also told STAT that the company had made these decisions after repeated “pushback from regulators”.
Since the report was published, Jacob John, an infectious diseases expert and a faculty member at the Christian Medical College, Vellore, has demanded that The Lancet Infectious Diseases review the corresponding papers – which also counted scientists from the Indian Council of Medical Research (ICMR) among their authors.
Indeed, ICMR – which is India’s topmost medical research body – had a direct stake in the development of Covaxin: the ICMR National Institute of Virology had isolated the novel coronavirus to make Covaxin. ICMR also received 5% royalty on the sales of Covaxin. Neither ICMR nor the institute have ever responded to any allegations against Covaxin.
Even if a senior member of Bharat Biotech has responded to a serious allegation for the first time, this isn’t the first time Covaxin has faced such allegations.
At a Bhopal hospital, which was one of the sites where the phase 3 trial was conducted, one trial participant died allegedly after receiving Covaxin in late 2020. The government conducted an inquiry and subsequently rubbished the allegations. But its findings were never made public – nor did Bharat Biotech scientists factor the individual’s death as a potential serious adverse event in their paper in The Lancet.
In fact, before the paper was published, the company claimed that the death wasn’t related to the vaccine. But neither the company nor the government revealed whether the individual received the vaccine or the placebo, nor how they were able to reach their conclusions.
Another controversy erupted when Covaxin became the vaccine to take the most time to receive the WHO’s approval. There were several exchanges between Bharat Biotech and the body within the WHO that was assessing the vaccine, as the latter demanded more and more data before it was satisfied with the vaccine’s efficacy and safety.
On March 30, 2021, the Brazilian drug regulator ANVISA had listed several issues in the company’s ‘good manufacturing practices’ – echoing concerns the WHO had expressed in April 2022. However, there was no clarity on whether ANVISA’s objections to Covaxin were on the same grounds as those of the WHO: the CDSCO has refused to make the contents of the WHO report against the vaccine publicly available. But ANVISA later approved the vaccine’s import into Brazil.
Indeed, Covaxin’s approval by the India government in January 2021 was controversial. There was no interim efficacy data available at the time, and the government had approved it in what it called “clinical trial mode” – a term that left experts confused because it had never been used by anyone before.
In the months following the approval, more and more data about Covaxin became available – although the paper describing the phase 3 trial and its results was published after a considerable delay. In this time, the scientists involved in the government’s COVID-19 response denied any undue pressure to hasten the trial – but Bharat Biotech’s Mohan has reportedly conceded that to STAT.
Update (4:35 pm, November 17):
Bharat Biotech issued a statement on November 17, 2022, condemning the, “targeted narrative against COVAXIN put forth by a select few individuals and groups who have no expertise in vaccines or vaccinology.”
The statement, however, confirmed some of the findings of STAT. The publication had claimed that after getting permission from CDSCO’s subject expert committee, Bharat Biotech initiated the phase-3 trial without having data from phase 2. The company’s statement said, “The decision to proceed to phase III trials was taken based on data from phase I studies and results from successful animal challenge trials [preclinical studies with animals done before clinical trials].”
In its statement, the company also confirmed that the decision to choose one of the two formulations for a phase 3 trial — a 3 mcg per dose or 6 mcg per dose — was taken in “interest in public health”, and not on the basis of phase 2 trials. STAT had claimed the results of phase 2 hadn’t landed before commencement of phase 3, which would have determined the right dosage for going ahead.
One of the company’s directors, Krishna Mohan, has been quoted in the STAT report saying the company was under “political pressure” to get the vaccine quickly out of the laboratory. The statement issued now doesn’t deny pressure but goes on to add that there was no “external pressure”.
“The pressure was all internal to develop a safe, and effective vaccine for the Covid-19 pandemic, to save lives and livelihoods in India and Globally,” it said.
The company also claimed that the vaccine has more than 20 scientific publications to its credit and said. “These efforts to discredit our work will not deter us.” It flayed “recent media reports around the approvals for Covaxin” as “incorrect and erroneous” and added, “These few individuals and organizations were mostly involved in fake news and false information during the pandemic.”
The company did not address a crucial error raised in the STAT report: the difference in number of trial participants as mentioned in trial protocol and what was finally presented in the scientific paper published in The Lancet Infectious Diseases.
The Government of India’s Press Information Bureau also issued a statement on November 17 refuting “recent media reports” on Covaxin as “misleading” and “ill-informed”. The statement claimed the changes in clinical trials are made in “compliance of due process in CDSCO” and with approval from the Drugs Controller General of India.
It also said Covaxin was given restricted emergency approval in January 2021 “in public interest as an abundant precaution, in clinical trial mode, to have more options for vaccinations, especially in case of infection by mutant strains.”
