A COVID-19 vaccine named Corbevax looked like a triumph for India’s burgeoning drug industry. Because its U.S. developers hadn’t claimed a patent on it, an Indian manufacturer named Biological E was able to sell the two-dose protein-based vaccine to the government at the extraordinarily low price of 145 rupees ($1.90) per dose. In March, the country began to give the shots to 12- to 14-year-olds, a group for which India did not yet have a licensed COVID-19 vaccine.
But the celebration was quickly drowned out by questions over whether India’s drug regulator, the Central Drugs Standard Control Organization (CDSCO), had properly vetted the vaccine.
In February, CDSCO had authorized the use of Corbevax for adolescents ages 12 to 18. But within weeks, the Indian media outlet The Wire Science revealed that the National Technical Advisory Group on Immunisation (NTAGI), an expert group that advises the health ministry on which vaccines to add to the national immunization program, had questioned whether Biological E had shown the vaccine is effective. In adolescents, who are at a lower risk of severe COVID-19, the benefits of a vaccine should be beyond any doubt, NTAGI member Jayaprakash Muliyil tells Science: “Anytime you vaccinate children, you have to be extremely careful.”
Other CDSCO approvals of COVID-19 vaccines have raised questions as well, both from NTAGI and independent experts. The agency has used “suboptimal” standards on several occasions, says Vineeta Bal, an immunologist at India’s National Institute of Immunology. That has led some scientists to ask whether the agency has the capabilities—and is independent enough—to oversee the quality of medicines for India’s 1.4 billion people. The implications go beyond India, because the country is a major global medicine supplier. The World Health Organization has “prequalified” 54 vaccines produced in India for use elsewhere, and WHO relies on CDSCO to oversee the manufacturers.
CDSCO didn’t respond to questions from Science about the criticism. In May 2020, India’s health ministry appointed a committee to advise it on how to restructure India’s drug regulatory system in line with global best practices, but that committee’s recommendations haven’t been published. It’s unclear whether they will address vaccine regulation.
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CDSCO has a decent reputation: Based on an extensive assessment, WHO concluded in 2017 that it was a “functional” drug regulator, a distinction only 30% of its counterparts around the world enjoy. (It ranks a step below 11 agencies WHO credits with a “high level of performance,” however, including the U.S. Food and Drug Administration and the European Medicines Agency.)
But the pandemic has been challenging for CDSCO, says Gagandeep Kang, a public health microbiologist at Christian Medical College, Vellore. For the first time, Indian manufacturers developed new vaccines rather than me-too versions of shots approved elsewhere, and the agency lacked some types of expertise, Kang says, such as the ability to reanalyze data from key studies. Others suspect CDSCO’s decisions have been skewed by political pressure to quickly approve made-in-India vaccines, which have been a point of pride for the ruling Bharatiya Janata Party. “The government has a keenness of publicity, and that has certainly created pressure,” says T. Sundararaman, an independent public health analyst based in Puducherry.
In January 2021, for example, the agency greenlit Covaxin, an inactivated-virus vaccine produced by Bharat Biotech, without data from large-scale efficacy trials—only phase 2 data about the immune response generated by the vaccine. By the time the company published data showing 78% efficacy against symptomatic COVID-19, 6 months later, millions of Indians had already received the shot.
NTAGI also differed with CDSCO’s assessment when the regulator approved a COVID-19 vaccine named ZyCoV-D for use in both adults and adolescents in August 2021. Produced by Zydus Cadila in Gujarat state, ZyCoV-D is the first DNA vaccine approved by any country for use in humans. CDSCO based its decision on results of a trial in about 28,000 participants over 12 years of age, which found the vaccine 67% efficacious at preventing symptomatic COVID-19.
NTAGI, which does not typically make its advice public, opposed the use in adolescents, Muliyil says; it felt a completely new vaccine platform should only be used in adults at first. Moreover, the phase 3 trial had a single efficacy estimate for all ages, says another NTAGI member who asked not to be identified, even though efficacy can differ by age group. (In Western countries, COVID-19 vaccines for adolescents and children were authorized after separate trials in those age groups.)
In March, CDSCO’s reputation took another hit when a WHO inspection of the Covaxin manufacturing facility in Hyderabad found quality control deficiencies, whose nature WHO has not disclosed. WHO recommended that member countries stop using the vaccine, and Bharat voluntarily halted exports. But the company has downplayed the problems and says it will keep selling Covaxin in India. CDSCO did not respond to questions from Science about the problems or why it failed to spot them. “It concerns me that CDSCO, the custodian of public health as India’s national drug regulator, haven’t issued any statements yet on this issue,” says Jayanthi Vuppala, an independent expert on good manufacturing practice based in Hyderabad.
Last month’s approval of Corbevax—which by now has been given to 30 million adolescents—raised more questions. CDSCO authorized the vaccine for 12- to 18-year-olds based on interim data from a 312-participant study that showed the vaccine triggered a rise in neutralizing antibodies. But NTAGI wasn’t convinced the vaccine was entirely responsible for the rise, Muliyil says. Data from the unvaccinated placebo group could have shed light on whether CO VID-19 infections were also contributing, but as a preprint posted on 26 April shows, the trial did not assess antibodies in the placebo group. Biological E did not respond to a question about the data.
Since then Botswana has also licensed Corbevax. And on 21 April, an expert committee advising CDSCO recommended the shot’s approval for 5- to 12-year-olds in India.
Critics applaud the fact that Corbevax is free from patents, but they worry its approval signals a double standard. “[Would] this vaccine be acceptable for pediatric populations in a high-income country with the data we currently have in the public domain?” asks Boghuma Kabisen Titanji, an infectious disease specialist at Emory University.
Corbevax co-developer Peter Hotez, who leads the Texas Children’s Hospital Center for Vaccine Development, says Indian companies have a strong track record for producing WHO-prequalified vaccines. “I’m not aware they apply lower bars and standards,” Hotez says. “It would be unfair to think so and in fact it reflects colonial attitudes.”
But the controversy has led some Indian pediatricians to not recommend the vaccine. And hasty vaccine approvals, especially for children and adolescents, pose a risk that goes beyond the individual vaccine, Titanji cautions: “It sets a dangerous precedent which could be very damaging for vaccine confidence and uptake down the road.”