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India’s Vaccine Approvals Had One Problem. It Gave Rise To the Other Two.

India’s Vaccine Approvals Had One Problem. It Gave Rise To the Other Two.

Bharat Biotech chairman and MD Krishna Ella (right) and Serum Institute CEO Adar Poonawalla. Photos: Twitter and PTI.

For all the Narendra Modi government’s desire to push an Indian company to the forefront of the national COVID-19 response, it has actually put an Indian company in an awkward, even untenable, position.

On January 3, the Drug Controller General of India (DCGI) announced emergency-use approvals for two vaccine candidates in the country: Bharat Biotech’s Covaxin and Serum Institute’s Covishield. The event was met with backlash almost immediately, as droves of researchers hit Twitter and Facebook to interrogate and argue over the terms of the DCGI’s approval.

Bharat Biotech drew a considerable fraction of this flak – largely since no one could explain the basis on which the government had approved its Covaxin COVID-19 vaccine candidate. So at 5 pm on January 4, Krishna Ella, the company’s chairman and managing director, held a virtual press conference in which he promised to clear the air.

There were little nuggets of important information in Ella’s long opening monologue, but even as he concluded and took questions from the audience, one disturbing detail became clear.

Surprise party

Earlier, the DCGI had approved the two vaccine candidates for different reasons. Serum Institute’s Covishield had been okayed on the back of safety and efficacy data from phase 1, 2 and 3 clinical trials conducted abroad and from a small cohort of participants in the company’s bridging trials underway in India. And just as Pfizer’s vaccine candidate is being distributed in the US and AstraZeneca’s is being distributed in the UK, Covishield (a derivative of AstraZeneca’s candidate, in fact) would be distributed in India.

Covaxin, however, had been assigned a different task. The DCGI announced the government’s intention to roll it out such that everyone who got shots of this vaccine would be treated as participants in an open-label clinical trial – to ascertain Covaxin’s efficacy against the new, more-contagious strain of the novel coronavirus. And Ella suggested, in the course of his virtual presser, that the government had sprung this detail on him without advance deliberation.

When this correspondent asked if the ‘open label’ clinical trial would be registered separately on India’s official clinical trials registry, Ella said this was all new to him and that he would need some time to understand the situation. He had a similar response when other journalists repeatedly asked him what the DCGI’s use of the unheard-of term “clinical trial mode” could have meant.

If Ella and Bharat Biotech really didn’t know early enough that the government would grant Covaxin conditional approval in “clinical trial mode”, there are multiple implications.

The foremost is that the government will now use Covaxin in a way that it was not intended to be used. This is crucial because the clinical trials to which any vaccine is subjected are designed according to specific use-cases. No vaccine can be trialled for one purpose and used for another (with some caveats). If its use-case changes significantly, the vaccine-maker is required to conduct another set of clinical trials that test the immunogenicity (immune response), safety and efficacy.

But as it happens, we don’t know the exact contents of Bharat Biotech’s application to the DCGI and the Central Drugs Standard Control Organisation (CDSCO). During his media address, Ella only said his company had submitted phase 1 and phase 2 trial data, and received “emergency authorisation”, alluding to the now-famous US Food and Drug Administration’s (FDA) policy.

A different use-case

Human clinical trials typically have four phases. Phase 1 tests safety in a small group of volunteers. Phase 2 carries over the combinations and doses qualified as safe in phase 1 to a larger group of volunteers and further looks for side-effects, as well as tests the vaccine’s effectiveness – i.e. whether it provokes an immune response. Phase 3 continues from phase 2 but with a much larger group of volunteers (thousands) and checks the vaccine’s safety and efficacy together. Efficacy here is a measure of the extent to which the vaccine works as intended.

At this point, the vaccine-maker may submit the trial data obtained thus far to a national drug regulator – like the DCGI or the US FDA. If the regulator is satisfied with the data, their office may approve it for distribution and sale in the country. Phase 4 begins now: when the vaccine-maker as well as government scientists keep an eye on whether the vaccine causes any previously unknown side-effects, considering lakhs of people will be taking the vaccine over many years.

Unlike in the US and the UK, the New Drugs and Clinical Trial Rules 2019 don’t allow for “emergency use authorisations”. Instead, the Rules have a provision for ‘accelerated approvals’ (Sched. 2 (ii) A). According to the text: “Accelerated approval process may be allowed to a new drug for a disease or condition, taking into account its severity, rarity, or prevalence and the availability or lack of alternative treatments, provided that there is a prima facie case of the product being of meaningful therapeutic benefit over the existing treatment.”

One of the requirements for such approval is the following:

If the remarkable efficacy is observed with a defined dose in the Phase II clinical trial of investigational new drug for the unmet medical needs of serious and life threatening diseases in the country, it may be considered for grant of marketing approval by the Central Licensing Authority based on Phase II clinical trial data. In such cases, additional post licensure studies may be required to be conducted after approval to generate the data on larger population to further verify and describe the clinical benefits, as per the protocol approved by the Central Licensing Authority.

However, at least two experts – Shahid Jameel speaking to The Wire Science and Gagandeep Kang speaking to CNBC TV18 – have said Bharat Biotech has not presented efficacy data thus far. In fact, the best we know of Covaxin’s efficacy is from a statement Bharat Biotech published last year, saying the company “expects” it to be “around 60%”, but which wasn’t accompanied by any discussion on the provenance of this figure.

In addition, and again unlike the US, the Rules don’t demand or empower the DCGI to revoke its ‘accelerated approval’ if the vaccine’s efficacy isn’t borne out in phase 3 studies.

Also recall that the DCGI approved Covaxin as a contingency response to the more contagious novel coronavirus strain. Ella, however, said during his address that the company doesn’t yet have “confirmatory data” that Covaxin works against the new strain. Kang had speculated as much to Deccan Herald as well, calling the DCGI’s claim “quite a stretch”. But even before Ella spoke up, and shortly after the DCGI’s controversial announcement, Indian Council of Medical Research (ICMR) chief Dr Balram Bhargava had rushed to the DCGI’s defence, and said the council thinks Covaxin is “likely to be effective” against the strain.

Also read: Serum Institute Fracas Exposes Loose Ends of India’s Clinical Trial Machinery

If there are so many unknowns, how did India approve its COVID-19 vaccine candidates?

In the middle of this mess, Serum Institute CEO Adar Poonawalla told NDTV that he believed only three vaccine candidates in the world have proven to be efficacious, and that all other candidates have only proved to be safe, “just like water is safe”.

This got Ella riled up. During his address, Ella launched into a coarse rebuttal, saying he was offended by Poonawalla’s remarks and that Bharat Biotech’s research team didn’t deserve to be dismissed as such. He then segued to comments about Serum Institute’s research output, how Bharat Biotech had published more papers pertaining to its vaccine development process, and that while Covaxin was part of what could be the developing world’s largest vaccine clinical trial during the pandemic, Serum Institute had submitted data from first and second phase trials conducted abroad and the data of only 100 participants of its ongoing bridging trials in India.

(“When a regulatory authority or a sponsor is concerned that differences in ethnic factors could alter the efficacy or safety of a medicine in the population in a new region, the sponsor may need to generate a limited amount of clinical data in the new region in order to extrapolate or ‘bridge’ the clinical data between the two regions”: source.)

Three reasons

As it happens, the DCGI’s January 3 statement – announcing the approval of the two vaccine candidates – is controversial for three disparate reasons, and almost none of which the Indian government appears to have addressed. The first and fundamental reason is that the Indian drug regulator has been awfully opaque through the vaccine approval process. Even before vaccines entered the picture, the credibility of the DCGI, the CDSCO and ICMR had taken a blow after the three bodies vouched for hydroxychloroquine, remdesivir, itolizumab and tocilizumab as effective antiviral agents against a novel coronavirus infection despite there being no legitimate data to back-up their verdict.

The second reason is that irrespective of whether Bharat Biotech is in the clear vis-à-vis its application for accelerated approval for Covaxin, the DCGI, the CDSCO and ICMR have devised a plan – with the health ministry’s blessing – to use the vaccine candidate in a way that it wasn’t designed to be, and based on efficacy data that remains conspicuous by absence.

Third, Serum Institute’s Covishield vaccine candidate is derived from AstraZeneca’s AZD1222 vaccine candidate. And AZD1222 is currently caught in a storm of criticism in the US and the UK, where regulators have granted conditional approval but have also expressed serious doubts about AstraZeneca’s conduct and whether its efficacy reports will need to be retested. Considering Serum Institute’s application to the CDSCO used clinical trial data from abroad and bridging trial data from India, it seems Covishield and AZD1222 are similar, if not the same.

So since India became the third country in the world to approve AZD1222/Covishield, why haven’t the questions that arose in the first two countries arisen in India as well? Or, if they did, how did the DCGI and the CDSCO resolve them?

To rephrase what Jameel told The Wire Science yesterday, a phase 3 trial is important because it’s as close as we can get to simulating the characteristics of a population in the testing stage – before actually distributing the vaccine in the population. It’s worth remembering, as Jameel also said, that vaccines – unlike drugs like remdesivir or hydroxychloroquine – are given to healthy people so that they may evade the disease, instead of to people who have already fallen ill. This in turn raises the threshold of acceptability.

These are two fairly quantitative terms that all those who conduct clinical trials abide by. But as too many incidents of wrongdoing, obfuscation and outright deception have taught us in the last year, a rapid vaccine development process followed by a rapid immunisation drive must also be accompanied by clear communication – in a way that allows people to trust their government, instead of having to take ministers’ words for it.

Source: Our World in Data

Put another way, those in power must be ethical as well as must be seen to be ethical. When Bharatiya Janata Party member Vijay Chauthaiwale says “unusual circumstances demand unusual approaches”, he’s right – but only if the DCGI had reacted like the FDA did: by opening its doors and windows wider, instead of nailing them shut. A charitable assessment of Ella’s media address suggests that Bharat Biotech could have fulfilled the former criterion. However, the DCGI, the CDSCO and ICMR botched the latter, and brought the credibility of Covaxin and Covishield down with theirs.

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