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In the first week of December, three companies filed applications to the Drugs Controller General of India (DCGI) seeking emergency use authorisations (EUAs) of their respective COVID-19 vaccine candidates. They were Pfizer, Serum Institute of India (SII) and Bharat Biotech.
The New Drugs and Clinical Trials Rules 2019 define an ‘accelerated approval process’ and provide for “waiver of local clinical trials, if a drug is approved and marketed in certain countries”. These rules were “designed to speed up clinical trials and approval of new drugs in India” (source).
Thus far, only the Pfizer/BioNTech vaccine candidate has received EUA in six countries, including the UK and the US this month. According to early results from the candidate’s phase 3 clinical trials, the vaccine demonstrated 95% efficacy. The efficacy was reportedly consistent across age, race, gender and ethnicity (5% of the 44,000 trial participants were of Asian origin). There were no serious side effects either, although the vaccine group had reported four cases of Bell’s palsy.
We don’t know of the vaccine’s efficacy among children and pregnant or lactating mothers. Pfizer also hasn’t expressed any intention to conduct trials in India for now. Instead, in its application, it has submitted trial data from other countries under a non-disclosure agreement.
On December 14, Business Standard quoted unnamed government officials saying the government may be discouraged by Pfizer’s price point. (The company’s CEO Albert Bourla has said calls for companies to not profit from COVID-19 “fanatic and radical”.) This could also be a tacit admission that the government isn’t insisting on phase 3 trials.
Pfizer faces a demand far in excess of capacity, with reports that it isn’t in a position to supply any additional quantities to the US before June 2021. But while Pfizer has signed agreements to supply rich countries with millions of doses, it currently doesn’t have a deal with India. There is no plan to manufacture the vaccine in India either, probably to avoid new technology transfer.
Instead, India’s bet for a widely available, affordable and logistically feasible vaccine are mostly on Covishield, which is SII’s version of the vaccine candidate developed jointly by AstraZeneca and the University of Oxford. It is stable between 2º and 8º C, and is expected to be priced Rs 225-300 per dose for supply via the Indian government. Given SII is the world’s largest vaccine producer, supply should not be a concern.
An interim analysis, obtained by pooling results from two trials in the UK and Brazil, revealed a discrepancy. In the UK, AstraZeneca was alerted after the trial had commenced that some participants had accidentally received a smaller dose than planned, but who reported a higher efficacy than those who had received the planned fuller dose.
This difference drew criticism from experts. There are also some safety concerns due to two serious neurological events, one reported July and one in September. In addition, 90% of the participants in the interim analysis were found to be 18-55 years old, making the results blind to the vaccine’s effect in older people and children.
SII is relying on AstraZeneca’s international clinical trial results for its Covishield version to be approved in India. It has started so-called phase 2/3 trials with 1,600 participants to compare Covishield’s immunogenicity with that of AstraZeneca’s version, plus assess Covishield’s safety.
However, the phase 2/3 trials aren’t phase 3 trials because they don’t intend to test for efficacy, plus the cohort size is too small relative to the typical size of such trials. It isn’t clear why SII has chosen this path considering the company has the required resources.
Nevertheless, it seems likely that Indian regulators could follow the UK in granted approval.
Bharat Biotech began recruiting participants for the phase 3 clinical trials of its Covaxin vaccine candidate barely a month ago; the targeted cohort size is 28,500. The company will conduct this trial with the help of the Indian Council of Medical Research (ICMR). The vaccine candidate is expected to become available for us by February, even if the trial’s results aren’t due before March. For now, the company has speculated that Covaxin will be at least 60% efficacious.
There aren’t many details about Covaxin in the public domain – except that it’s an inactivated virus vaccine that Bharat Biotech researchers developed with a local strain of the novel coronavirus.
The trials’ conduct itself doesn’t inspire confidence. The results of its phase 1 and 2 trials aren’t in the public domain. The company cut the size of its phase 2 trials from 750 to 380 participants in an unexplained move. The dose regimen for phase 3 trials mentions an interval of 28 days between two doses, which is double the interval in phases 1 and 2. An email to the company went unanswered.
India, as the world’s pharmacy, supplies over 62% of the world’s vaccines and it’s understandable that it doesn’t wish to fall behind in the time of COVID-19. This is why political pressure to have a vaccine asap isn’t surprising – and the relationship between applications from SII and Bharat Biotech and Prime Minister Narendra Modi’s high-profile profile visit to the companies’ plants in November is quite straightforward.
Serum Institute’s application even states the company intends to make “the country aatma-nirbhar” – Hindi for ‘self-sufficient’ – vis-à-vis vaccines and to fulfil Modi’s “clarion call of ‘vocal for local’ and ‘making in India’ for the world”.
The drug regulation mechanism in India is infamous for its insufficiency. Helped along by the new rules, which legalise acceleration and waivers, there is a significant risk that the vaccine candidates will receive their EUAs without the requisite safety checks — more so if there is also political interference. And if the process does compromise safety checks for speed, the country will get a vaccine quickly but the world will lose faith in India’s conduct, as might the country’s people.
This is why the subject expert committee of the Drug Controller General of India (DCGI) asking Bharat Biotech and SII for additional safety and efficacy data was a glimmer of hope. However, they need to do much more to ensure no scientific standards are ever compromised.
First, the DCGI needs to balance speed in the approval process with safety and efficacy. Most COVID-19 vaccines in the news these days have been developed under the new ‘pandemic paradigm’. Here, developers take multiple steps in parallel that might otherwise have been undertaken in serial fashion. On the flip side, this method carries greater financial risk.
This is also why pharmaceutical companies and regulators have been at pains to reassure people that they haven’t cut any corners. No major country except China and Russia has waived the need for large phase 3 clinical trials. This is crucial since all frontrunner vaccines were developed using previously uncommercialised technologies like mRNA and chimpanzee adenovirus vectors. This is why Pfizer has plans to continue monitoring its trial participants for two years while AstraZeneca has planned new trials even as it works through the ongoing ones.
So any decision to waive phase 3 trials will send out the wrong signals, implying India doesn’t have the wherewithal to conduct these trials and perhaps that India isn’t interested. The DCGI should have anticipated large-scale vaccine trials and come up with clear guidelines when the pandemic began – with demonstrating safety and efficacy in India being the precondition for approval. And in July, the DCGI should have insisted on a phase 3 trial to determine the efficacy of Covishield in the Indian population.
Fortunately, not all is lost. India’s case load and number of deaths have both been falling since mid-September. There is also widespread acknowledgment of the fact that a vaccine isn’t the last stop.
The least the DCGI can do now is to conditionally approve Pfizer’s and SII’s applications if it is satisfied with the information submitted from the global trials. Those who receive the vaccine should be able to do so free of cost, treated as if they were participants in a trial, and have the vaccines’ safety and efficacy monitored. The manufacturer should bear all costs. And Bharat Biotech should submit the primary data from its phase 3 trials before seeking approval.
More broadly, the DCGI would do well to take a leaf out of the US Food and Drug Administration’s (FDA’s) playbook – often recognised as the gold standard in drug regulation. The FDA followed a robust, transparent and democratic process when it approved the Pfizer vaccine candidate, notably without slowing down.
Second, we need to handle serious adverse events in clinical trials sensitively and impartially. There have been at least two serious adverse events in India, one each with Covishield and Covaxin, both of which the respective trial runners kept under wraps and treated in dismissive fashion. Even if the events were really not connected to the vaccine, they should have been assessed transparently, and certainly not by official diktat.
For example, AstraZeneca paused its global trials in September when it was alerted to a serious adverse event in the UK. A similar incident in the Indian trial didn’t invite the same response. This double standard is both bad science and bad optics. The DCGI should seek information about how SII will handle any future incidents, especially since most agreements between AstraZeneca and various countries will protect the company from future product liability claims.
Finally, Indian experts have been demanding more transparency around clinical trials data. The scientific communities of many countries have even asked for radical transparency given the speed of development of COVID-19 vaccines. But India seems to be headed in the opposite direction since the new rules exclude any obligation to share data.
V.K. Paul, head of India’s national expert group for vaccine administration, thinks trial data is strictly confidential, is to be shared only with the data safety and monitoring board, and that sharing this data publicly would be unscientific. This position is untenable and needs to change immediately.
To rephrase the aphorism, the ultimate hope is for Indian regulators to make sure that not only is the science followed, it must also be seen to be followed.
Neeta Sanghi is a professional associated with the pharmaceutical industry since 1982. She is currently working on a book about the industry.