The two COVID-19 vaccines — Covishield and Covaxin — tested and manufactured in India by the Pune-based Serum Institute and Hyderabad-based Bharat Biotech, respectively, could have played a vital role in ending the pandemic in the country. However, the regulator’s haste and lack of transparency in approving the vaccines for “restricted” use do not inspire confidence. The regulator did not wait for sufficient safety and efficacy data to be collected and did not share information about the clinical trials before granting approval.
Transparency is vital for gaining people’s trust so that they don’t hesitate to take the vaccine. However, the conduct of the Indian regulator in no way helps in building trust in vaccines. If there is already some degree of apprehension about the safety and efficacy of COVID-19 vaccines, given the rushed manner in which the trials have been conducted, the opaque nature of the approval process has done little to mitigate such concerns.
Contrast this with the manner in which the U.S. Food and Drug Administration (FDA) and the U.K. regulator approved COVID-19 vaccines. The FDA had a live telecast of the advisory committee’s examination of Pfizer’s and Moderna’s vaccine data before granting emergency use authorisation (EUA). It also made the detailed briefing document of the clinical trial of each vaccine and its assessment public. The U.K. regulator also made the assessment of the two vaccines — by Pfizer and AstraZeneca — publicly available.
No efficacy data
The phase-2/3 trial of Covishield was carried out on 1,600 participants and was intended to study only safety and immunogenicity, as the details available on the clinical trial registry indicate. According to the informed consent document made available to trial participants, safety was to be tested on 1,200 participants and immunogenicity on 400 individuals. The trial did not study the efficacy of the vaccine. Approving Covishield based on safety and immunogenicity data from the trial in India and efficacy data from the U.K. might be sufficient for emergency use. But it is imperative that Serum Institute collects efficacy data from the Indian trial before seeking full approval.
Though no published data are available, the U.K. regulator has found some evidence that efficacy improves when the second dose of the AstraZeneca vaccine is delayed. Accordingly, it has recommended that the second dose be administered 4-12 weeks after the first. Serum Institute has wasted an opportunity to test the protection offered by the first dose and determine the efficacy of a delayed second dose and the best time to administer it. It is now for the government to decide, without evidence, the timing of the second dose.
In the case of Covaxin, the phase-3 trial began in mid-November 2020. Since the second dose is administered 28 days after the first, the median follow-up after the second dose would have been just a few days and that too from a very small number of participants. In short, the approval for “restricted” use granted to Covaxin was not based on any efficacy data. What level of protection is offered by the vaccine and whether it protects against severe disease and prevents infection and transmission are all not known.
By giving approval to Covaxin without data on its efficacy, the Indian regulator has joined the ranks of China and Russia. When the Chinese regulator approved CanSino Biologics’s vaccine that had not undergone a phase-3 trial, it at least limited its use for the military. In mid-November, three months after approval, Russia’s claim of 92% efficacy for Sputnik V was based on a review of just 20 COVID-19 cases.
Also, the assertion that Covaxin will protect people against the new variant of the virus is not backed by evidence. No efficacy data against any SARS-CoV-2 virus strain are currently available.
What makes the approval for Covaxin all the more galling is the explicit permission to administer the vaccine in a “clinical trial mode”. This is nothing but a large-scale phase-3 clinical trial carried out on people belonging to the four priority groups consenting to receive the vaccine. The following remain unknown: how informed the informed consent will be, who is going to inform the recipients about the intricacies of the “trial”, how well the “participants” are going to be monitored, and how the efficacy will be determined in the absence of a control arm.
Nine global vaccine manufacturers issued a joint pledge last September that they would not seek premature approval from regulatory authorities. Bharat Biotech’s haste in seeking approval stands in contrast. The Indian regulator had earlier stipulated that at least 50% efficacy is necessary to grant EUA.
Compare this with the manner in which the FDA upheld the sanctity of the approval process. Despite pressure from U.S. President Donald Trump to make vaccines available before election day, the FDA made it clear that it would require phase-3 data with a “median follow-up duration of at least two months after completion of the full vaccination regimen to assess a vaccine’s benefit-risk profile”. The FDA also said EUA would be granted only “based on data from a phase-3 trial that demonstrates the vaccine’s safety and efficacy in a clear and compelling manner”.
A lost opportunity
While daily fresh cases and deaths have been increasing sharply in the U.S., the new variant that has been spreading rapidly in the U.K. has been causing havoc. In India, on the other hand, the number of daily fresh cases and deaths has been steadily dropping since mid-September. The companies and the regulator should therefore have taken advantage of the situation here to ensure that EUA is backed by data.
Not only has India squandered a great opportunity to collect robust data and build trust in COVID-19 vaccines but has also set the stage to potentially reverse decades of hard work in building vaccine confidence. In 2019, a single mistake in preparing the measles, mumps, and rubella injection that led to the deaths of two infants in Samoa led to a sharp drop in vaccine uptake and a measles outbreak there.
In India, a December 2018 study in 121 districts that have higher rates of unimmunised children found that 24% of children did not get vaccinated due to apprehension about adverse effects. If there is vaccine hesitancy among the four high-risk groups which will get vaccinated on priority, the companies and the regulator have themselves to blame.