Covaxin, India's first indigenous vaccine for COVID-19, was recently hit by a row with allegations that external pressure to deliver the jab quickly forced vaccine-maker Bharat Biotech to skin certain processes and expedite clinical trials.

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The vaccine development by Hyderabad-based Bharat Biotech International Ltd (BBIL) and the regulator came under scanner after some media reports highlighting discrepancies in the process.

The vaccine maker allegedly came under political pressure to accelerate the process by making certain modifications to the process and the same was approved by the regulator.

Last month, the Boston-based health news website Stat News reported how the vaccine's clinical trials were dictated by speed. One of the company's directors reportedly admitted that they had to skip certain processes because of political pressure to deliver the indigenous vaccine quickly.

The report cited irregularities reported in the three phases of the clinical trials and highlighted discrepancies in the number of participants in these.

The number of participants enrolled in the first two phases of the trials as mentioned in the papers published in The Lancet Infectious Diseases differed from the numbers specified in the trial protocol document.

It is also alleged that a set of participants were not administered a placebo or dummy vaccine as done in any clinical trial for a new vaccine. In the trials of any vaccine, one set of participants receives active forms of the vaccine, the other is given a placebo. In the case of Covaxin, the participants were given two different formulations of the vaccine.

According to experts, the placebo arm can't be dropped when the vaccine is being evaluated for the first time. Placebo arms help understand a vaccine's effects against a disease relative to how that disease might have progressed without the vaccine. If the placebo arm is replaced with another formulation, the investigators will only know which of the two formulations is better.

Controversy also hit the country's first indigenous COVID vaccine as the Central Drugs Standard Control Organisation (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 was given on the basis of pre-clinical studies which are conducted on experimental models.

Similarly, the company also commenced Phase 3 trials without the results of the Phase 2 trials. Phase 3 trials were also reportedly initiated on the basis of preclinical studies.

The CDSCO approved Covaxin for Emergency Use Authorisation (EUA) in January 2021, two months before the publication of Phase 3 data. The approval in "clinical trial mode" and without interim efficacy data sparked a row.

Bharat Biotech developed Covaxin in collaboration with the Indian Council of Medical Research (ICMR). ICMR's National Institute of Virology (NIV) had isolated the novel coronavirus to make Covaxin. 

The Union Ministry of Health and Family Welfare, however, maintains that EUA was granted to Covaxin while following a scientific approach and prescribed norms.

"CDSCO has followed a scientific approach and prescribed norms in approving COVID-19 vaccines for emergency use authorisation," the ministry had stated in response to the reports. "It may be noted that the Subject Expert Committee (SEC) of the CDSCO had held deliberations on January 1 and 2, 2021, and later recommended Restricted Emergency Approval for Covaxin."

Prior to granting EUA to Covaxin, the SEC looked at the data on the safety and immunogenicity of the vaccine. Further, the SEC had approved the commencement of Phase 3 clinical trial of the proposed dose of Covaxin on the basis of scientific data presented by the vaccine-maker and, while adhering to established practices in this regard, added the ministry.

On alleged "unscientific changes" made in clinical trials of the vaccine, the government said these were made following submission made by Bharat Biotech before the CDSCO, compliance of due process in the CDSCO, and with approval from the Drugs and Controller General of India (DGCI).

Controversies are not new for Covaxin. It took the longest time to receive the approval of the World Health Organisation (WHO). The Technical Advisory Group of the WHO that was assessing the vaccine demanded more data from the vaccine makers before it was satisfied with the vaccine's efficacy and safety. It was only in November 2021 that WHO granted Emergency Use Listing (EUL) approval to Covaxin.

In April, the WHO suspended the supply of Covaxin to UN agencies citing deficiencies in good manufacturing practices. Covaxin was the only COVID-19 vaccine to be suspended by the WHO.

The WHO also said that Bharat Biotech made some changes in the manufacturing processes after receiving an emergency-use license for Covaxin.

In March, Brazilian drug regulator ANVISA listed several issues in the company's good manufacturing practices. However, the agency later approved the vaccine's import into Brazil.

Earlier, during the Phase 3 trial, the vaccine was hit by controversy. At a Bhopal hospital, which was one of the sites where the trial was conducted, one participant died allegedly after receiving Covaxin in December 2020.

Both the government and the company denied that the death of the 42-year-old volunteer was due to the vaccine. It was not made public, however, whether he had received the vaccine or the placebo. The death was not factored in as a potentially serious adverse event in the paper published in The Lancet.

After some media reports published last month, BBIL had come out with a statement denying that there was any external pressure on it to hasten the development of a vaccine. When contacted, the company made it clear that it has nothing to add to what it had already clarified.

"We condemn the targeted narrative against Covaxin put forth by a select few individuals and groups who have no expertise in vaccines or vaccinology. It is well known that they helped perpetuate misinformation and fake news throughout the pandemic. They are unable to comprehend global product development and licensure processes," the company stated.

"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 added.

Claiming that Covaxin is one of the most highly studied COVID-19 vaccines worldwide, the company said it was evaluated in about 20 preclinical studies, including 3 challenge trials and 9 human clinical studies, more than any other Indian COVID-19 vaccine. These trials have clearly demonstrated the safety and efficacy of Covaxin, Bharat Biotech said.

The vaccine-maker further claimed that with several hundred million doses administered worldwide, Covaxin has demonstrated an excellent safety record with minimal adverse events and no vaccine-associated cases detected for myocarditis or thrombocytopenia.

"The entire product development and clinical studies were executed as per global guidelines and submitted worldwide. Data from Covaxin has resulted in more than 20 publications, documenting every aspect of its development."

It had termed as "incorrect and erroneous" the media reports around the approvals for Covaxin. "These few individuals and organisations were mostly involved in fake news and false information during the pandemic. They fail to understand product development and licensure pathways worldwide," reads the statement.

It pointed out that the Phase 1 study for Covaxin was one of the largest in the world, resulting in both the 3 and 6 mcg doses demonstrating safety and comparable immunogenicity. The decision to proceed to Phase 3 trials was taken based on data from Phase 1 studies and results from successful experimental model challenge trials.

"The Phase 2 studies were designed to determine if the lower dose of 3 mcg would be effective, instead of the 6 mcg dose, which would have doubled our manufacturing capacity. In the interest of public health, it was decided to proceed with the 6 mcg dose for Phase 3 clinical trials," the company clarified.

BBIL, a 25-year-old company, claims to have established an excellent track record of innovation with more than 145 global patents, a wide product portfolio of more than 19 vaccines, four bio-therapeutics, registrations in more than 125 countries, and the World Health Organisation (WHO) Prequalification.

Located in Genome Valley in Hyderabad, India, BBIL has built world-class vaccine & bio-therapeutics, research & product development, Bio-Safety Level 3 manufacturing, and vaccine supply and distribution.

The company has so far developed vaccines for influenza H1N1, rotavirus, Japanese encephalitis (JENVAC), rabies, chikungunya, Zika, Cholera, and the world's first tetanus toxoid conjugated vaccine for typhoid. It claims to have delivered more than 5 billion doses of vaccines worldwide.

BBIL's commitment to global social innovation programmes and the public-private partnership resulted in introduction of path-breaking WHO pre-qualified vaccines such as Biopolio, Rotavac, Rotavac 5D, and Typbar TCV combatting polio, rotavirus, and typhoid infections, respectively.

The company is now developing novel vaccines against malaria and tuberculosis through global partnerships. The acquisition of Chiron Behring Vaccines has positioned BBIL as the world's largest rabies vaccine manufacturer with Chirorab and Indirab.

On November 28, the BBIL announced that the world's first intranasal vaccine for COVID-19, iNCOVACC (BBV154), has received approval from the CDSCO under Restricted Use in Emergency Situation for ages 18 and above, in India, for heterologous booster doses.

iNCOVACC is a recombinant replication-deficient adenovirus vectored vaccine with a pre-fusion stabilised SARS-CoV-2 spike protein. This vaccine candidate was evaluated in Phase 1, 2, and 3 clinical trials with successful results, the company said. Last year, it revealed that it is targeting to make one billion doses of its COVID-19 intranasal vaccine.