Covaxin approval sparks questions and clarifications

The Union government and vaccine maker Bharat Biotech on Thursday refuted a report that alleged rules and protocols were bent during the approval process for Covaxin, but the clarifications served to further add to the questions that were raised with some specific issues remaining unaddressed.

On November 15, Boston-based health news website Stat News cited official documents that purported to detail a series of problems in how Bharat Biotech’s Covid-19 vaccine, funded partly by the government, was approved.

Among these were changes to clinical trial designs without adequate scientific explanation, an unexplained decision to drop what is known as a control group, and multiple occasions when the clinical trials progressed without data from prior stages having come in, especially in the case of the critical large-scale Phase III that began while Phase II results were yet to be determined.

“There have been media reports claiming that Bharat Biotech, manufacturer of the indigenous Covid-19 vaccine – Covaxin, ‘had to skip certain processes ‘and speed’ up clinical trials due to political pressure. The reports further claim that there were several irregularities in the three phases of the clinical trials conducted for the vaccine. These media reports are completely misleading, fallacious and ill-informed,” the health ministry said in a “myths vs facts” statement.

The statement added that the Subject Expert Committee of the drugs regulator DCGI( Drugs Controller General of India) gave permission to proceed to Phase III based on “scientific data presented by Bharat Biotech and established practices in this regard”. It isn’t clear what data was available at the time, though.

In a separate statement, Bharat Biotech accepted the decision to proceed to Phase III trials was taken based on data from Phase I studies “in the interest of public health”. “…The decision to proceed to phase III trials was taken based on data from phase I studies and results from successful animal challenge trials. The phase II studies were designed to determine if the lower dose of 3 mcg would be effective, instead of the 6 mcg dose...in the interest of public health, it was decided to proceed with the 6 mcg dose for phase III clinical trials,” it said.

Typically, human clinical trials are run in various phases to determine three crucial aspects: Is the dose safe? What is the correct dose strength? And, is it effective and, if so, how effective in preventing disease? These are determined through three phases — I to III, with the first focusing on safety, the second on dosing strength and effectiveness (or ability to generate immune response), and the third on efficacy estimates.

The State News report identified problems with all three phases. First, the final report of the Phase I trial carried volunteer numbers different from what the company submitted to regulators. In the report published in a medical journal, the company said 375 people were given first doses and 368 given both, while the protocol states this number to be 402 and 394, respectively. Phase II was also allowed to proceed on animal trial data, which is typically not the practice, the report said.

Second related to Phase II, which, the report said, began when Phase I data was not available. The protocol for the Phase II trial was also tweaked to drop the need for a placebo arm, which meant there would be no reliable way to determine if there was a higher immune response than those without exposure to the virus. Third, the Phase III was approved when Phase II was still underway. These specifics hark back to the row the approval generated at the time. Covaxin was approved in January 2021, two months before efficacy data from Phase III trials became available in March. No other Covid vaccine was approved without such data.

The ministry defended this by saying the decision was based on “submission made by M/s Bharat Biotech and assessment of interim efficacy and safety data by SEC of CDSCO” on the condition that the vaccine be given in a “clinical trial mode”.

A doctor, who asked not to be named, said these controversies hit the confidence in the shot. “...many of my colleagues wanted to take Covishield as they weren’t comfortable with the idea of taking a vaccine that was approved without adequate data,” said the doctor in a Delhi hospital.

To be sure, the trial data, when it subsequently became available showed that the vaccine was not just safe but also effective, but it isn’t clear how DCGI could have known this at the time of its approval. The ministry and the company did not offer detailed rebuttals on the other aspect, with the government statement only insisting that decisions were taken based on scientific data.