With the approval to Covaxin even in the absence of efficacy data, the Indian regulator has joined the ranks of China and Russia. What good is a vaccine that is safe but the efficacy is unknown. Transparency in the approval process is vital for gaining the trust of people to avoid vaccine hesitancy and increase uptake of vaccines. However, the conduct of the Indian regulator leaves much to be desired and in no way helps in building trust in vaccines.
The two COVID-19 vaccines — Covishield and Covaxin — tested and manufactured in India by the Pune-based Serum Institute and Bharat Biotech based in Hyderabad, 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 in the approval process is vital for gaining the trust of people so that they don’t hesitate to take the vaccine. If there is already some degree of anxiety and 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 the concerns.
Contrast this in the manner in which the U.S. FDA and the U.K. regulator had approved COVID-19 vaccines. The FDA had a live telecast of the advisory committee examining Pfizer and Moderna vaccine data before granting an emergency use approval. It also made the detailed briefing document of the clinical trial of each vaccine and its assessment publicly available. The U.K. regulator too made the assessment of the two vaccines — Pfizer and AstraZeneca — publicly available.
Timing of second dose not studied
The Phase-2/3 trial of Serum’s Covishield vaccine was carried out on 1,600 participants and was intended to study only the 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 to be tested on 400 individuals. The trial did not study the efficacy of the vaccine.
Approving Serum’s Covishield vaccine 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 the company collects efficacy data from the Indian trial before seeking a 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 beyond four weeks. Accordingly, it has recommended that the second dose be administered 4-12 weeks after the first. Serum 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 Bharat Biotech’s Covaxin vaccine, the phase-3 trial began in mid-November last year. 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. What good is a vaccine that is safe but the efficacy is unknown.
By giving approval to Covaxin without data on its efficacy, the Indian regulator has joined the ranks of China and Russia. In end-June, when the Chinese regulator approved CanSino Biologics’ vaccine that had not undergone a phase-3 trial, it at least limited its use for the military. And even in mid-November, three months after approval, Russia’s claim of 92% efficacy for its Sputnik V vaccine was based on review of just 20 COVID-19 cases.
Also, the assertion that Covaxin that uses inactivated virus will protect against the new variant is not backed by evidence. No efficacy data against any SARS-CoV-2 virus strain, including the new variant, are currently available to conclusively say Covaxin would be effective against mutant strains.
A trial on four high-risk groups
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 folowing remain unknown: how informed the informed consent will be, who would inform the recipients the intricacies of the vaccine “trial”, how well will the “participants” be monitored, who meets the medical expenses of “participants” in the event of serious adverse events, 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 an EUA.
How FDA upheld approval process sanctity
Compare this with the manner the FDA upheld the sanctity of the approval process. Despite pressure from the U.S. President Donald Trump to make vaccines available before election day, the FDA made it abundantly 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”.
While daily fresh cases and deaths have been increasing sharply in the U.S. and hospitals in at least some States are already strained, the new variant that has been spreading rapidly in the U.K. has been causing havoc. In stark contrast, the number of daily fresh cases and deaths has been steadily dropping in India since mid-September. The companies and the regulator should therefore have taken advantage of the situation here to ensure that emergency use approval is backed by data.
Risk of increasing vaccine hesitancy
Not only has India squandered a great opportunity to collect robust data and build trust in COVID-19 vaccines but 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 (MMR) injection that led to death of two infants in the Pacific island nation of Samoa led to a sharp drop in vaccine uptake leading to measles outbreak there.
Back in India, a December 2018 study in 121 Indian districts that have higher rates of unimmunised children found that 24% children did not get vaccinated due to apprehension about adverse effects. If there is any vaccine hesitancy among the four high-risk groups who would get it on priority, the companies and the regulator have themselves to blame.