The decision by AstraZeneca to temporarily halt global trials of the Covid-19 vaccine candidate developed by the University of Oxford after one participant developed a “potentially unexplained illness” will not impact testing timelines in India, Serum Institute of India (SII) said on Wednesday afternoon.
SII is sponsoring mid- and late-stage human clinical trials for the vaccine candidate in India. The candidate, named Covishield in India, was administered to a first set of volunteers on August 26.
It happens – scrutiny is key
This is a singular incident, but vaccine timelines have been crunched — and it is critical to scrutinise adverse reactions. Trials have been paused for similar reviews earlier; it does not necessarily mean that the candidate’s efficacy or safety is suspect – or that testing will not resume.
Responding to a notice issued by the Drug Controller General of India (DCGI) as to why it had failed to inform the regulator of AstraZeneca’s decision to pause the trials, SII said in a late evening statement that it would follow DCGI’s instructions and “abide by the standard protocols”.
The Swedish-British pharma giant announced early on Wednesday India time that it had “voluntarily paused vaccination” in its ongoing global trials to “allow review of safety data by an independent committee” after the event triggered its standard review process.
The issue had been flagged in a “single” event, the company said.
“This is a routine action which has to happen whenever there is a potentially unexplained illness in one of the trials, while it is investigated, ensuring we maintain the integrity of the trials. In large trials illnesses will happen by chance, but must be independently reviewed to check this carefully,” an AstraZeneca spokesperson said.
While the company did not specify which country had reported the adverse event, the issue is believed to have been flagged in the phase 2/3 clinical trials underway in the United Kingdom.
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A volunteer enrolled in the trial had been found to have an inflammatory syndrome called transverse myelitis – but it was unclear when this was diagnosed, and whether it was directly linked to the administration of the vaccine, The New York Times reported.
Phase 2/3 trials of the candidate, called AZD1222 globally, have been ongoing in the UK since the end of May. On September 3, AstraZeneca announced that centres were recruiting up to 30,000 participants for phase 3 trials in the United States. Late stage trials are also continuing in Brazil and South Africa, and the company has planned early- to mid-stage trials in Japan and Russia.
AstraZeneca did not clarify whether the trials were being halted only in the UK or at all global sites conducting mid- to late-stage tests on humans.
A spokesperson for SII said, “We can’t comment much on the UK trials, but they have been paused for further review and they hope to restart soon. As far as Indian trials are concerned, it is continuing and we have faced no issues at all.”
The Pune-headquartered firm, the world’s largest manufacturer of vaccines, has been contracted by AstraZeneca and the University of Oxford to manufacture the vaccine for low- and middle-income countries.
Later on Wednesday evening, however, DCGI Dr V G Somani issued notice to SII, taking issue with its failure to inform the regulator of AstraZeneca’s decision to pause the trials.
One of the conditions for SII to conduct the trials had been that clinical data generated in India would be considered along with data from trials conducted by Oxford-AstraZeneca, the notice said, according to a source directly aware of the development.
The regulator also noted that SII had not submitted a “causality analysis” of the serious adverse event “in light of safety concerns”, the source said. SII has been asked for an immediate response as to why its permission to carry out the testing should not be suspended until patient safety was established.
In its response, SII said: “We are going by DCGI’s direction and so far were not told to pause the trials. If DCGI has any safety concerns, we will follow their instructions and abide by the standard protocols.”
Recruitment of participants in the India trials has, however, been on hold for the past week, as SII prepares to send the data collected from the first 100 participants who were administered the shot for safety reviews, The Indian Express has learnt.
The adverse event flagged in the global trial is likely to be taken up by the expert group that will review the safety information collected from the Indian volunteers, sources close to the development said. The review group, known as a Data Safety and Monitoring Board (DSMB), is scheduled to meet by the end of this week to study the data and decide whether the vaccine candidate is safe enough to be administered to more participants in India, the sources said.
Not all identified sites in the country have begun the phase 2 trial, which is conducted to test the vaccine’s effectiveness in eliciting the required immune response. Testing sites will be allowed to vaccinate more volunteers only after initial clearance from the DSMB. Around 1,600 participants are expected to be enrolled for the trials in India.
Follow-up information on the first set of participants is learnt to have been collected seven days after they were vaccinated. “The last vaccinations were completed around Tuesday or Wednesday last week, so it is likely the data will be collected and sent to the DSMB this week,” said a source on condition of anonymity. Follow-up information for some of the participants is still being collected, another source said.
“The DSMB will review the Indian data along with this particular event that has occurred, and then decide and let us know what has to be done,” said an investigator at a trial site in India. “The trials (in India) had already been paused, so there is no question of stopping anything (now).”
Another investigator said: “We have been told (by SII) that this is unrelated (to the vaccine)… but we have no data and have not seen anything (to ascertain this) yet.”
Dr Gagandeep Kang, one of India’s most eminent medical scientists, said pausing the trials in the wake of an adverse event was the proper thing to do, and it did not mean that the trial would not resume.
“If a suspected unexpected serious adverse reaction occurs, a deep dive to understand what happened and its relationship to the vaccine is essential. This is what AstraZeneca is doing and it is the right thing. This does not mean that the trial will not resume, Dr Kang told The Indian Express.
The scientist, a professor at CMC Vellore who played a key role in the development of the indigenous rotavirus vaccine, recalled that something like this had happened at one site during the RotaVac trial. “Recruitment was halted for a few weeks and resumed after the Data Safety Monitoring Board completed their investigations,” Dr Kang said.
Researchers closely associated with the phase 2/3 clinical trials of the Serum-manufactured Covishield vaccine candidate said halting the trial was a temporary and common setback. “This is part and parcel of any vaccine clinical trial. Adverse events are likely to occur during the large study and DSMB will carefully look at the data before giving the go-ahead (to continue the trial),” the researchers said. The independent group of experts in the DSMB include a statistician, a clinician, a paediatrician, and an epidemiologist.