Serum Institute of India (SII) said on Thursday (September 10) that it would pause the ongoing clinical trials in India of the Covid-19 vaccine candidate developed by the University of Oxford.
The move follows a show-cause notice issued by the drug regulator to the Pune firm over a single adverse reaction that was detected at one of the global trial sites.
SII is sponsoring mid- and late-stage human clinical trials for the vaccine candidate in India. The firm, the world’s largest vaccine manufacturer, has been contracted by the Swedish-British pharma giant AstraZeneca and the University of Oxford to manufacture the vaccine for low- and middle-income countries.
What is this vaccine?
One of the most closely watched candidates globally, this vaccine works on a mechanism that uses a weakened common cold chimpanzee virus to carry instructions to make part of the SARS-CoV-2 virus like a Trojan horse.
Once injected, the virus will infect a cell and tell it to make the spiky outer layer of the virus, known as the ‘spike protein’ – the part of the virus that allows it to infect humans in the first place.
The body’s immune system is expected to recognise this spike protein as a threat, and develop antibodies to fight it so that it will be ready to defend against the real virus.
At what stage was the testing in India before the pause?
AstraZeneca had started global trials in the United Kingdom at the end of May. Trials have since been underway in countries like Brazil and South Africa as well – and the India trials started on August 26.
The candidate, called AZD1222 globally, has been named ‘Covishield’ in India. The vaccine is in phase 2 human trials in the country, and is to be tested on 1,600 volunteers to check how effectively it helps the body develop an immune response.
Around 100 of these 1,600 participants had been enrolled and vaccinated as of September 2. The testing sites had then stopped vaccinating more participants, because they had to observe this smaller group for seven days and submit follow-up information from these participants to a Data Safety and Monitoring Board (DSMB).
This board would check to see if the vaccine was safe enough for the trials to continue – and only after this clearance had been obtained would the sites be able to vaccinate more participants.
So why has SII paused the trials in India?
The development stems from a decision by AstraZeneca to temporarily halt the global trials of the vaccine candidate after a volunteer developed a “potentially unexplained illness”.
This volunteer was reportedly enrolled in the UK arm of the trials, and had reportedly developed a serious spinal inflammatory syndrome called transverse myelitis.
The pause, which means that the trial sites would not vaccinate any more participants for the time being, was to allow an independent committee to review the safety data from the trials, and to ensure that this “single” incident was not caused by the vaccine.
Now, when AstraZeneca announced the pause (early on September 9 India time), SII initially said this would not impact the India trials, which would continue, as no adverse reactions had been found in participants vaccinated so far in the country.
However, the firm failed to officially inform the Drug Controller General of India (DCGI), who heads the country’s top drug regulatory body (CDSCO), about the global pause on trials.
So, later on Wednesday (September 9), the DCGI sent a notice to SII taking this up – and asked the company to explain why the permission given to it to carry out testing in India should not be suspended until patient safety was established.
SII then decided to halt the testing in India until there was clarity on the adverse reaction detected in the global trials.
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But if the adverse reaction was detected in only one participant, and in an arm of the trials unconnected with India, why did SII have to halt the trial?
This makes it crucial to ensure that any unanticipated adverse reactions are thoroughly scrutinised.
SII’s failure to inform CDSCO of the global issue is significant because it is on the basis of the previous global trial data that the company had received permission to skip the first phase of human testing that checks the safety of the vaccine.
The regulator also noted that SII had not submitted a “causality analysis” – an assessment of the relation between a treatment and the occurrence of an adverse event – of the reaction observed in the UK volunteer.
Given the fact that the same vaccine is being tested globally and in India, it is important to ensure that there is no possibility of a similar incident occuring in participants here – especially since the number of volunteers in India is much less than the 5,000-10,000 who have been vaccinated in other countries.
Also, CDSCO had granted SII permission to conduct the trials in India on the condition that clinical data generated from trials conducted by Oxford-AstraZeneca globally would also be considered when approvals were being granted.
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OK, but could this mean that the vaccine is not safe? Will the testing ever resume?
This is only a temporary pause to make sure that the adverse reaction has not been caused by the vaccine.
It is too early to jump to any kind of conclusion about the safety of the vaccine – the issue has been flagged in only one participant out of over 10,000 volunteers, and it is entirely possible that the reaction is unrelated to the vaccine.
In fact, the whole point of large late stage trials is to give the vaccine candidate to people without first carrying out an in-depth analysis of their underlying health conditions, so that the trial closely mimics the inoculation of entire populations.
In India, the DSMB is expected to review safety data from the 100 participants in the trial in the country, and is likely to also look at data from the adverse reaction that was detected at the global site.
If it finds the vaccine safe, and if the independent committee looking at the data submitted by AstraZeneca concludes the same, trials should resume everywhere.
After the phase 2 trials are complete, the vaccine candidate will move to phase 3 trials – the last stage of testing – before the regulator decides whether it is safe and effective enough to be approved for the Indian population.
Have trials been stopped like this earlier?
Indeed, there have been past instances of vaccine trials paused for similar reviews, including in India.
For instance, the enrollment of volunteers to test an indigenously developed rotavirus vaccine had been halted for a few weeks after a similar incident occurred in one of the sites.
However, vaccination resumed after the DSMB completed its investigations and gave the green light for trials to continue, according to Christian Medical College Vellore professor and former
Translational Health Science and Technology Institute executive director Dr Gagandeep Kang, who played a key role in developing this vaccine.
Researchers say that adverse events are likely to occur in large studies like these and that pausing the testing is “part and parcel” of any vaccine trial.
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