India is facing a brutal second wave of Covid-19, with daily case counts approaching 100,000. Yet the country, one of the world’s largest vaccine manufacturers, is having trouble vaccinating its citizens, with just 65 million first doses and 10 million second doses administered to its citizens, barely a drop in the ocean for a country with a population of 1.36 billion.
This is likely due, in part, to a shortage of vaccines — a fact borne out by the Indian government’s recent knee-jerk decision to impose an export ban on Covid-19 vaccines being manufactured in India.
The country’s drug regulator, the Drug Controller General of India (DCGI), has so far authorized only two vaccines: Covishield, the Oxford-Astra Zeneca vaccine which is manufactured by the Serum Institute of India (SII), and Covaxin, which was jointly developed by the Indian Council of Medical Research and Bharat Biotech.
Covishield is based on an adenovirus vector, like Johnson & Johnson’s vaccine. Covaxin is based on the older technique of inactivating the Covid-causing coronavirus. It has run into a series of controversies, ranging from lack of transparency around documenting serious adverse events during its clinical trials to dodgy practices at clinical trial sites and to a rushed approval of the vaccine by the DCGI even before the interim results from the Phase 3 clinical study were available.
Bharat Biotech got more bad news about Covaxin when Brazil, a traditional ally of India on the international stage, refused to allow the company to export its vaccine to Brazil after its regulator, ANVISA, cited significant violations of good manufacturing practices at Bharat Biotech’s manufacturing plant in India. The violations cited sound all too familiar to the many 483 forms issued by the U.S. Food and Drug Administration to a number of Indian pharmaceutical companies that make generic drugs for the U.S. market.
While the DCGI gave Bharat Biotech an easy pass on its vaccine, it is making it quite difficult for other vaccine manufacturers, which is limiting the supply in India. This includes both foreign-based companies and Indian companies that have partnered with foreign vaccine developers to sell their vaccines in India, including Pfizer, for its RNA vaccine; Dr. Reddy’s, which has a license to manufacture Russia’s Sputnik vaccine; SII, which has a license to manufacture Novavax’s vaccine; and Biological E, which has a license to manufacture Johnson & Johnson’s single-dose vaccine.
These companies have yet to receive marketing authorization despite completion of Phase 3 trials because of the DCGI’s insistence that each new vaccine that has completed Phase 3 vaccine studies outside the country must undergo so-called bridging trials in India.
The traditional logic for bridging trials, or local clinical trials, is sound. They generate data in an India-specific context because the participants represent the Indian genetic makeup, eat Indian diets, and have other characteristics representative of people in the country. This is useful, because certain medicines may behave differently in Indian populations than in American or European populations.
The requirement for local clinical trials has been a part of Indian regulations since the late 1980s, along with a proviso that allows the DCGI to waive such the requirement under special circumstances.
Yet the DCGI has not rigorously enforced the bridging trials requirement. In fact, this issue came up before a parliamentary committee in 2012, when the DCGI came under fire for not being transparent about the conditions under which the requirement of conducting bridging trials or local clinical trials could be waived. An expert committee assembled to study the issue warned against these waivers except in exceptional circumstances, one of which was for vaccines urgently required to combat epidemics.
I spoke to one of India’s leading clinical virologists, Gagandeep Kang, to learn if bridging trials were required for vaccines. She told me that while there have been instances where the safety and efficacy of vaccines has varied across population groups, such events are relatively rare and unlikely to be captured by the limited enrollment needed for bridging studies, and could be captured during real-world use. In other words, safety and efficacy would not be expected to fluctuate at a level that would cause substantive harm to the Indian population with vaccine candidates that have already undergone Phase 3 studies elsewhere.
Given this background, Indian regulators must answer important questions: Are bridging trials conducted among Indian populations really required in the midst of the worst pandemic the world has faced in the last century? Is the decision on bridging trials in India influenced by lack of confidence in data generated at foreign clinical sites? Is there any scientific basis to expect that the efficacy or safety of these vaccines to be different in the Indian population than they have been elsewhere?
Or is the DCGI just being overly pedantic?
A pandemic is not a time for a pedantic approach to regulation. Regulators must balance the virtual certainty of thousands of deaths from a second wave versus marginal gains in knowledge through bridging trials of the safety and efficacy of vaccines that have already been proven to work in phase 3 trials in other countries.
The only scenario that may perhaps warrant local bridging trials is one in which regulators doubt the integrity of data generated at foreign clinical sites. That does not seem to be the issue here.
What’s needed is for the DCGI to be transparent about the factors influencing its demand for bridging trials from these sponsors.
Unfortunately, there is little public discussion on this issue in India. A few newspapers have carried expert views on the issue with most recommending against bridging trials as a way to rapidly expand the supply of vaccines, not just for the citizens of India but low-income countries, which so far have been dependent on Indian vaccine manufacturers.
Unless India dramatically expands its supply of vaccines for domestic use, it is going to be under severe pressure to adopt a policy of vaccine nationalism that has global consequences. While the Quad Vaccine Partnership led by the Biden administration in the U.S. is correctly prioritizing access to low-cost vaccines given India’s capacity to manufacture for low-income countries, this kind of arbitrary application of regulations by the Indian regulator has the potential to extend this public health emergency far longer than it has to be.
Dinesh Thakur is a public health activist.