On March 24, the Subject Expert Committee (SEC) permitted Bharat Biotech to unblind all “participants of age group of more than 45 years and offer to administer the vaccine free of cost as and when they become eligible for the vaccine in the national programme”. The Committee recommended that the company unblind the participants as “vaccines [including Covaxin] are [already] available under the immunisation programme, and therefore all the eligible age groups under the immunisation programme should be permitted for unblinding for vaccination”.
Apparently, Bharat Biotech intends to carry out a phase 3 trial in a cohort in Brazil. The company is now required to submit the “detailed revised clinical trial protocol for inclusion of a cohort from Brazil along with the revised statistical calculation for assessing the efficacy of the vaccine”.
On March 3, based on 43 cases — 36 cases in the placebo group and seven cases in the vaccine arm — Bharat Biotech announced the first interim vaccine efficacy of 80.6% for Covaxin . The second the final time points for further analyses were 87 cases and 130 cases, respectively.
But with the Committee now allowing everyone above 45 years age to be unblinded, the trial can continue only in those below that age bar. “A significant number of participants will no longer be available to study the vaccine efficacy once unblinding of participants above 45 years is carried out,” says Dr. Anant Bhan, global health and bioethics researcher based in Bhopal. “With the current surge in cases, more younger people are getting infected.” In all likelihood, the phase 3 trial may achieve its final endpoint of 130 cases but the trial will not include the most vulnerable population of participants above 45 years.
“More cases might have been recorded in March. Reliability would increase if further analysis too showed efficacy of over 80%. It is not the ideal, but what else is the alternative now?” says Dr. Jacob John, formerly with CMC Vellore.
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Could the SEC have asked the company to request participants above 45 years to continue in the study for the successful completion of the trial and unblind only those who want to withdraw from the trial? According to Dr. Bhan, this could have been done as long as participants are provided adequate information about eligibility to get the vaccine and are allowed to exercise an informed choice. “We are not aware on what basis the decision was taken. More context would have been useful,” he says. “But the decision to unblind those above 45 years will affect the study.”
However, virologist Dr. Shahid Jameel, Director of the Trivedi School of Biosciences at Ashoka University, says the Indian regulator has taken the right decision by allowing Bharat Biotech to unblind everyone above 45 years. “It’s the correct and ethical thing to do,” he says.
“We have some efficacy data of the vaccine. Whether it increases or not when further analyses are done will not make any difference on the ground. It’s only of academic interest,” Dr. Jameel says. “There is so much focus on the efficacy of vaccines. What is ignored is that every COVID-19 vaccine approved for emergency use has 100% efficacy against severe disease and death. And that’s the only efficacy that matters.”
In the U.S., even when three highly efficacious vaccines are available, the AstraZeneca phase 3 trial is continuing without unblinding even after the first interim analysis showed 76% efficacy based on 190 cases. “Every regulator looks at it differently,” says Dr. Jameel.
Dr. Jameel goes further to say that India should not insist on bridging studies especially in the case of Johnson and Johnson, Novavax, and Sputnik V vaccines, where there is an Indian company manufacturing the vaccines. “Restricted use authorisation was granted to Covishield even before the bridging studies were completed. Today, there is a surge in cases across many States. More groups will be eligible for a vaccine if vaccine supply is not limited. Israel has demonstrated how large scale vaccination can control the pandemic. We must rethink our policies,” says Dr. Jameel.
