A medic fills a syringe with Covaxin before administering it to a health worker at Gujarat Medical Education and Research Society, Ahmedabad, November 26, 2020. Photo: Reuters/Amit Dave.
Bengaluru: In a statement at 11 am on January 3, the Drug Controller General of India (DCGI), Dr V.G. Somani, said the Covaxin COVID-19 vaccine candidate was being approved in “clinical trial mode”. Multiple observers – including noted clinician and vaccine expert Gagandeep Kang – were befuddled about what he could have meant.
At 9:40 pm on the same day, Union health minister Harsh Vardhan said on Twitter that those given Covaxin will effectively be participants in a clinical trial to help determine the vaccine’s safety and efficacy.
While Dr Somani’s statement on January 3 mentioned “clinical trial mode”, another note published by the subject expert committee of the Central Drug Standards Control Organisation (CDSCO) said Covaxin would receive “grant of permission for restricted use in emergency situation in public interest as an abundant precaution, in clinical trial mode, to have more options for vaccinations, especially in case of infection by mutant strains”.
A grant of this description is not recognised in India – specifically, by the New Drugs and Clinical Trials Rules 2019 and the Drugs and Cosmetics Act 1940. Dr Somani also refused to take questions from reporters, so there is considerable confusion. However, Vardhan’s tweets confirm that the CDSCO, the DCGI and the Union health ministry are accelerating Covaxin’s public exposure using the new, more contagious strain of the novel coronavirus as an excuse.
A new trial
“Up front, I do believe that eventually Covaxin would turn out to be safe and more than 70% efficacious,” Shahid Jameel, a noted virologist and currently director of the Trivedi School of Biosciences, Ashoka University, Sonepat, told The Wire Science. “I say this based on the platform, which is widely used, and on Bharat Biotech’s own track-record of successfully making inactivated viral vaccines. My concerns are with the process and the utterances of people in responsible positions.”
In India, clinical trials are regulated by a clutch of legal, scientific, ethical and democratic principles administered by three entities: the CDSCO, the company or institution sponsoring the trial and the specific site at which the trial is conducted. Apart from this, the journals that publish papers arising from trials have their own requirements. These boundaries in turn give rise to specific circumstances and contexts in which clinical trials can happen; if trials cross these boundaries, they become at risk of breaking some or all of the rules that guide their conduct.
To understand what these boundaries look like, consider examples in which trials crossed them. As Dr Jammi Nagaraj Rao has written about Biocon’s botched itolizumab trial: the researchers who conducted the trial changed the trial outcomes after it kicked off, didn’t specify how they calculated the sample size, weren’t clear on differences in effect sizes between groups of participants, used an unclear dosing strategy and hid the outcomes of some patients. A different trial indicated that favipiravir is not an effective antiviral agent against COVID-19 – but the researchers published a press release saying the opposite.
In a third instance, Bhopal-based activist Rachna Dhingra alleged on January 3 that a hospital was administering the Covaxin vaccine candidate among unsuspecting people who hadn’t been told they were really part of a clinical trial. Fourth example: Bharat Biotech reportedly asked the principal investigators at its trial sites to invite people older than 50 to participate saying that, otherwise, they might have to wait longer to get a chance to receive Covaxin. And fifth: At the time the Indian Council of Medical Research (ICMR) approved Bharat Biotech’s phase 3 clinical trials for Covaxin, one analysis found several lapses in the choice and constitution of ethics committees that would oversee fair conduct of the trial.
Even now, ICMR and AIIMS New Delhi director Randeep Guleria rushing to the DCGI’s defence has raised red flags. (Guleria told NDTV that Covaxin would only be used as a “back up”.) As Jameel pointed out, “ICMR is a partner in the development of Covaxin and AIIMS is one of the trial sites. This is deeply troubling.”
Where is phase 3?
An ‘open’ clinical trial to be conducted with a vaccine candidate on the basis of “rolling reviews” is at risk of repeating these transgressions – and others besides.
For example, Bharat Biotech, the company behind Covaxin, has already reported that it has recruited around more than 20,000 volunteers for Covaxin’s phase 3 clinical trials. According to a health ministry press release published on January 3, Bharat Biotech has already administered Covaxin to ~22,500 participants, and has determined the vaccine to be safe based on their response.
However, the company has not shared the efficacy and safety part of this information with the public – not even with independent scientists via manuscripts in scientific journals – while experts have said it ought to. The company has only shared it with the CDSCO, pursuant to Covaxin’s approval.
Aside from the contents of the proceedings, Jameel disputed the proceedings themselves. “If approval requires both safety and efficacy data for a representative population, phase 2 safety and immunogenicity do not fulfil those criteria. That is why we do a phase 3. It is the closest you get to a population,” he said. “Where is that data? Vaccines are not drugs. They are given to healthy people. They are prevention, not treatment. Both safety and efficacy required.”
In addition to safety concerns, which haven’t escaped attention, there are two claims about the vaccine candidate in the public domain for which the basis is unknown. First, that the vaccine is expected to be around 60% efficacious. Second, that ICMR thinks Covaxin is likely to be more effective against the new strain of the novel coronavirus.
At least Gagandeep Kang was sceptical, however. “The [subject expert committee] argument is that Covaxin would work as some sort of insurance against the UK variant, but I am completely unaware of any data on Covaxin’s efficacy on any strain of SARS-CoV-2, let alone any special efficacy against the variant strain,” she told Deccan Herald. “It is quite a stretch to say it would work against the UK variant.”
Even Krishna Ella, chairman and managing director of Bharat Biotech, said during a press conference on January 4 evening that his vaccine candidate’s “effectiveness against the virus’s mutant strain is a hypothesis” – that there is no data on this front yet and that the company will produce “confirmatory data” in “one week’s time”.
With Covaxin, a vaccine candidate of unspecified safety and efficacy in the fray, its roll-out must also include plans for dealing with adverse events. According to the 2019 Rules, a person injured in the course of a clinical trial is entitled to free medical attention for as long as required and financial compensation from the trial sponsor. While Bharat Biotech is the sponsor for the ‘closed’ trial involving ~22,500 volunteers, it’s not clear who the sponsor for the ‘open’ trial is. Considering the DCGI, the CDSCO and the health ministry have approved Covaxin’s use in “clinical trial mode”, they are likely to share responsibility as well.
Second, to obtain ‘good’ data from a clinical trial requires ‘good’ trial design. This means, among other things, that the number of people in the two groups – the control arm and the vaccine arm – has to be determined beforehand, based on what outcomes the researchers are looking for, what biases and confounding factors they need to evade, and how statistically significant the results need to be.
As things stand, the DCGI and Vardhan have both confirmed that the health ministry is approving Covaxin for emergency use because of the novel coronavirus’s new, more-contagious strain. But we don’t know if Bharat Biotech’s decision to have 26,000 participants in Covaxin’s phase 3 trials accounts for the approval.
Then there is the considerable time and monetary cost. “For any clinical trial, there are both inclusion and exclusion criteria,” Jameel explained. “Would those be followed for every person who is vaccinated?” He pointed to the exclusion criteria attached to Covaxin’s phase 3 clinical trials: if any volunteer met any of these conditions, they would be excluded from the trial. “For example, would every vaccinee be tested for prior infection using antibody and RT-PCR tests? Would every vaccinee be tested for HIV, HBV and HCV? Would this not add to cost and logistics?”
Alternatively, the company and the health ministry could together decide to treat Covaxin’s ‘open’ trial as a new study. If Covaxin’s approval hinges on the new strain, the ‘open’ trial could be used to determine if the candidate is indeed efficacious against the strain. Ella did say during his press conference that the plan for the ‘open label’ trial is to not have a placebo arm, and instead to “keep vaccinating and monitoring”.
On the flip side, such a study will effectively be a single-arm clinical trial or an observational study. And these are both less useful to determine the safety, efficacy and immunogenicity of vaccines than randomised controlled trials.
Right to choose, without choices
In the final analysis, the health ministry has eroded Indians’ individual right to consent to medical treatment – under Article 21 of the Constitution. The government has previously said vaccinations will be voluntary. Government officials have also said that receiving Covaxin will be a choice and that recipients will have to sign a consent form before they do so. At the same time, the novel coronavirus – new variant or otherwise – and the subpar healthcare infrastructure in many parts of the country together make a vaccine less than optional, especially among frontline and healthcare workers, and among the elderly and people with comorbidities.
Add the fact that Covaxin’s credentials are mired in secrecy, and we have a troubling situation in which at least some people might see no other option but to take the vaccine candidate, irrespective of how doubtful they are that they will be protected.
As Jameel said, “Sidestepping processes and poor/complex communication will fuel rising vaccine hesitancy in India. There is already evidence of that on account of fast-tracked development timescales.”
Note: This article was updated at 5:55 pm on January 4, 2021, to include Krishna Ella’s comments from his press conference.