Representative photo: NCI/Unsplash.
Bengaluru: In November, two leading Indian COVID-19 vaccine manufacturers, Bharat Biotech and Serum Institute of India (SII), found themselves embroiled in controversy. Media reports alleged that there had been a “serious adverse event” in phase 1 of Bharat Biotech’s clinical trials for Covaxin. Phase 1 tests the safety of a new drug or vaccine in human subjects for the first time.
Then, a 40-year-old man in Chennai, through a legal notice to SII, sought compensation of Rs 5 crore for an illness he alleged appeared after he participated in a clinical trial for Covishield, SII-made version of University of Oxford and AstraZeneca’s COVID-19 vaccine candidate.
Both firms confirmed that serious adverse events (SAEs) had occurred. Both said that all due process had been followed and that the SAEs were found to not be related to their candidates. However, neither firm shared any more details. And both Bharat Biotech and SII applied for emergency use authorisation for their candidates earlier this week.
SII called the volunteer’s allegations ‘malicious and misconceived’ and said it would seek damages in excess of Rs 100 crore. But experts said this response sets a bad precedent. “You respond to a legal notice like this with logic and reasoning, dignity and empathy, so the trial participant is satisfied,” T. Jacob John, a retired virologist who was formerly at the Christian Medical College, Vellore, told The Wire Science. “Instead, the company’s response is saying ‘who are you to question?’. When there’s stonewalling, public trust becomes a casualty.”
Indeed, to understand how much is really at stake here, it’s important to understand what SAEs are and how they’re addressed within a clinical trial in India.
Serious adverse events
No medicine or vaccine is 100% safe, Santanu Tripathi, a clinical trials specialist at the Calcutta School of Tropical Medicine, said. “What we can expect is an acceptable risk-benefit ratio – that is, [the product] will only be allowed for marketing when its benefits outweigh its risks.”
That’s what a clinical trial sets out to test – both the safety of the new drug or vaccine and how well it works. Clinical trials also often run for several months, sometimes for a few years. In this period, it’s difficult to guarantee that a participant will never fall sick, Tripathi said.
For example, a trial participant may get fever, develop skin rashes or slip on a wet floor, fall and fracture her arm. A volunteer might also fall terribly ill with neurological complications – as has happened with the SII volunteer – and have to be admitted to the hospital for several days. Someone may die. The important thing, experts said, is to determine whether these events are related to the trial drug or vaccine.
Any deviation from normalcy, like fever, headache or pain at the injection site, is an adverse event, according to John. “But we’re not very worried if they’re mild.”
The adverse event becomes concerning when it is deemed to be serious. And it usually qualifies as ‘serious’ when one of the following occurs: a patient or participant dies during a trial; the participant gets hospitalised whereas the study did not involve any hospital stay to begin with; the participant’s hospital stay gets prolonged (if the study was being conducted on in-patients); the participant suffers from a chronic or life-threatening disability; or a participant gives birth to a child with congenital defects.
The Chennai volunteer’s neurological symptoms and hospitalisation after injection of the first Covaxin trial dose is considered to be an SAE. The recent hospitalisation of Haryana’s health minister Anil Vij with COVID-19 two weeks after participating in the phase 3 trial of Bharat Biotech’s Covaxin also qualifies as one, Tripathi said. But a “relatedness assessment using objective tools” is necessary to check if the trial medication or procedures had something to do with it, he added.
There’s an SAE. What next?
Every time a participant falls very sick or dies during a trial, steps prescribed in the New Drugs and Clinical Trial Rules of 2019 kick in. First, the principal investigator of the trial needs to report every SAE within 24 hours of learning about its occurrence to three parties: the trial sponsor; the Drugs Controller General of India (DCGI), who heads the Central Drugs Standard Control Organisation (CDSCO); and the ethics committee that approved the trial protocol.
“It is also the prime responsibility of the principal investigator to provide and ensure complete and the right medical care to the subject,” Mira Desai, a professor of pharmacology at the Nootan Medical College and Research Centre, Visnagar, Gujarat, told The Wire Science. The cost of medical treatment is typically borne by the sponsor.
Then comes the causality assessment: figuring out whether the symptoms were caused by the drug/vaccine being tested by the trial or by the trial’s procedures in any way. This check is important because if the SAE is related to the trial, it determines whether the participant is owed compensation, and the amount to be compensated as well.
The principal investigator of the trial is the main point of contact and conducts the initial assessment by considering the patient’s medical history, doctors’s opinions, all treatment received and lab reports.
For example, the Chennai volunteer’s discharge summary suggests he was seen by a neurologist, a rheumatologist and a psychiatrist, in addition to other doctors. The volunteer’s wife also told The Quint that doctors suggested his diagnosis of acute encephalopathy – indicating altered brain function or structure – could be because of a pre-existing autoimmune disorder or vitamin deficiencies.
“But the investigator’s judgement alone isn’t enough,” John cautioned.
So the investigator must then send their assessment report to the DCGI, the chairperson of the ethics committee and the head of the institution where the trial is being conducted within 14 days of the SAE happening, according to the 2019 Rules.
The ball then moves to the ethics committee. By reviewing all information that the investigator has shared, the committee tries to piece together the puzzle by working through a number of questions. For instance, did the SAE occur within a reasonable time period from the administration of the treatment? “If someone dies 10 years later,” as John said, “you cannot blame it on the vaccine.”
Some other questions they consider: Can the adverse reaction be explained on the basis of some alternate causes, such as other medicines the patient might be on or an undiagnosed illness that the investigation throws light on? Can the biological properties of the vaccine, such as the virus in it, or the drug’s inherent properties, theoretically explain the symptoms? Has the vaccine or drug caused a similar event in other participants in the same or other trials? Were the patient’s issues resolved once the test drug was stopped or its dose reduced?
In a few cases, the relationship between the treatment and the SAE might be clear – such as a participant going into anaphylactic shock immediately after receiving the drug. But in most SAEs, a definitive link can be intricate and challenging to detect, Desai said.
The interim results of Oxford-AstraZeneca’s vaccine trials in the UK, South Africa, and Brazil, for example, found 168 serious adverse events in nearly 24,000 participants who were either in the vaccine or the control group. The researchers concluded that three of the SAEs were “possibly related” to the trial while two were “unlikely to be related”.
If the ethics committee becomes reasonably certain that an SAE is related to the trial, the committee then computes the amount of compensation it thinks is to be paid to the participant. For this, committee members use a formula specified in the seventh schedule of the 2019 Rules.
If there’s any doubt about whether the trial could have caused the illness or death, and if a link can’t be ruled out, some ethics committees tend to give the affected participant the benefit of the doubt, several experts told The Wire Science.
“At the end of the day, there is a huge imbalance in power, and the weaker person should benefit and that’s the approach we take in most cases,” a member of one ethics committee said on condition of anonymity.
The ethics committee then sends its assessment as a report that also contains recommendations vis-à-vis compensation, if any, to the DCGI.
Sometimes, a third party may be involved – typically in the form of a data and safety monitoring board (DSMB). The sponsor constitutes this committee with several experts, but it is ultimately expected to remain independent of the sponsor’s influence. Indian regulations don’t mandate a DSMB for every regulatory trial, but companies usually do form one, said Anant Bhan, a public health and bioethics researcher at Mangaluru’s Yenepoya University. The board is appointed especially if a clinical trial is high-profile or is happening in multiple locations in India or around the world, such as the ongoing COVID-19 vaccine trials, he added. “And it is good practice to do so.”
When constituted, the DSMB meets at pre-decided intervals to review safety and efficacy data from the trial. It also reviews SAEs when they happen. And when there’s a particularly concerning SAE, the board can ask for the trial data to be unmasked if the study has been blinded (i.e. if investigators and analysts don’t know if a participant was in the treatment or the control group).
“If the DSMB feels there’s an issue and we need to halt the trial, they’ll ask the sponsor to do so,” Bhan said. “It could also be the other way – where they find that one arm of the trial is strongly benefiting so it’s unethical for the trial to continue. That would also be the DSMB’s recommendation.”
But Tripathi and others said the DSMBs’ opinions aren’t regulatorily mandated – although, Tripathi added, regulators have often asked to see their reports. The Subject Expert Committee of the DCGI, which reviews COVID-19 vaccine trials’ data, has sometimes asked for DSMB assessments to be presented, according to minutes of their meetings (one example here).
The final decision-making power lies with the DCGI. The regulator may appoint an independent panel of experts to further review reports and share their recommendations. If compensation is due, the DCGI must then pass an order asking the sponsor to pay the participant.
In the SII volunteer’s case, for example, it appears that all three parties – the ethics committee, the DSMB and the DCGI’s expert committee – reviewed the SAE. But it remains to be seen how the regulator found the man’s neurological complications to be conclusively unrelated to the trial.
The chairperson of the ethics committee at the Sri Ramachandra Institute of Higher Education and Research, where the man volunteered for the trial, didn’t respond to an email request for clarification.
Does the system work?
Ultimately, it all depends on how good the vigilance system is, Tripathi said. “It also depends on how well the investigator explains everything to the participant during the informed consent process, and how well the participants then comply with the advice.”
Let’s consider the case of the SII volunteer.
On December 1, while rejecting the volunteer’s claims, Union health secretary Rajesh Bhushan told journalists that every trial has an informed consent form that “tells the subject that these are the possible adverse events that might happen in case you decide to participate in a clinical trial. And if you understand the implications of the prior informed consent form, please sign this form.”
SII’s informed consent form does list several side-effects, like fever, headache and allergic reactions, that participants can expect after inoculation. It mentions the possibility of unforeseen side effects, and also notes that during the international Oxford-AstraZeneca trials, two participants developed “unexplained neurological symptoms” that were found to be either unlikely to be associated with the vaccine, or there wasn’t enough information to show a causal link.
However, in the legal notice sent to SII, the Chennai volunteer alleged a lack of adequate information about the risks during the consent-obtaining process. “There is nothing in the Participant Information Sheet to educate or warn the participants about any serious side-effects of the said vaccine, like the one suffered by him,” the notice says. “Our client states that he believed the assertion about the ‘safety’ of the vaccine in the Participant Information Sheet and decided to volunteer to take the vaccine.”
Details about how information on adverse events was communicated at the Sri Ramachandra Institute aren’t clear.
However, many experts have said simply signing an informed consent form doesn’t necessarily mean the participant understood all risks or the processes that will be followed. As Tripathi put it, “It requires special skill – how do you explain the risks without frightening the volunteer?”
At the same time, he said the investigator ought to explain the details several times over if required. “It is through the informed consent process that you win the trust and confidence of volunteers, so they don’t feel like blaming the investigator,” he explained. “The investigator can also drop a volunteer from the trial if she thinks the volunteer hasn’t fully understood how the trial is to be conducted.”
Anil Hebbar, a health entrepreneur who participated in SII’s trial in Mumbai along with three friends, told The Wire Science he was asked to call the investigator if he fell sick and that the treatment would be taken care of. “They said if there is compensation to be paid they will do as directed by the government.”
But Hebbar said he wasn’t told how he might report any grievances he experienced. And according to Tripathi, this should also be part of the informed-consent conversation.
Experts agree unanimously that clear, honest communication helps avoid hostile situations throughout the trial. The volunteer’s wife, for example, told NDTV they decided to go public after the trials continued sans any resolution or answers about whether her husband’s symptoms were related to the vaccine.
While trials aren’t always halted when there’s an SAE, Hebbar said he still expected more timely and open communication from the investigators – instead of having to get updates from news reports. “My consent form says that I will be informed of any new information about the vaccine, and it already talks about the two cases in the UK,” he said. “So here also it was their ethical duty to tell us that there was an SAE and that they are looking into it. We would have understood and taken the second dose.”
SII’s ambiguous press statements in particular haven’t gone down well with the trial’s other participants. On November 28, the company told reporters that there had been “zero hospitalisations” for everyone who took the vaccine. Then, in a statement about the Chennai SAE, the firm said, “It is only after we cleared all the required processes that we continued with the trials.”
“This makes it seem that the trial was paused until all processes were completed,” Hebbar said. “But the man had a problem on October 11 and I got my second dose on November 8. So how can they say that ‘we are now resuming the trial now that all results are clear’?”
Some experts have said going public with grievances is problematic for clinical trials in India in general. But sometimes the volunteer may feel that’s her only choice, according to John.
“When there’s slowness, lack of upfront information and high-handed, angry responses, it usually means that something is being hidden, which is why they must have gone public,” he speculated. “It was only after the beans were spilled by the lawyer of the volunteer that people are now responding. That is not good.”
But even the legal notice hasn’t provoked a response, the volunteer’s advocate N.G.R. Prasad told The Wire Science on November 30. SII hadn’t responded to their legal notice nor had anyone been in touch with the family about the assessment of his illness, he said.
The volunteer’s wife confirmed this, as The Quint reported. The principal investigator hadn’t handed the family the final results of all the tests and the hospital hadn’t told them what, if not the vaccine, could explain his symptoms, according to her.
Closing the loop
John, who has been part of DSMBs and vaccine trials, said the regulator’s decision, along with convincing evidence – not opinion – should have been provided to the volunteer in writing. “Not sharing this information with the volunteer, or being rude, is both unprofessional and unethical,” in his telling.
However, neither the clinical trials 2019 Rules nor the Indian Council of Medical Research’s ethics guidelines are categorical about closing the loop with the participant. In particular, decisions that conclude that the SAE was unrelated to the trial aren’t typically formally communicated to the participant in writing, several experts noted.
“That is certainly a lacuna,” according to Bhan. The person who has gone through the SAE is a key stakeholder in the clinical trial process, he added, and has a right to know what decision was taken and why.
In fact, experts said the participants’ voice is currently missing from deliberations about how an SAE should be addressed. “Rather than treating participants as sources of data, we should ideally be engaging with them in a respectful manner, getting their perspective and their lived experience of having gone through the SAE,” Bhan said. “Perhaps by doing that, we lessen the chances of circumstances that we saw with this incident, where the person felt excluded from the whole process.”
Even if the decision on an SAE is communicated, the trial participant also has a right to disagree and legally contest it, experts said. But again, mechanisms by which a participant can appeal aren’t spelled out in any rules or guidelines.
It isn’t just participants suffering from SAEs who are often left in the dark: ethics committees that have sent their reports on SAEs to the DCGI have also been met with silence in several cases.
For example, the ethics committee member who requested anonymity told The Wire Science that the committee had reviewed three separate SAEs – two deaths and one hospitalisation – that had occurred in clinical trials they’d been overseeing earlier this year. They sent the reports for all three SAEs to the DCGI in a timely manner, the member said, recommending compensation in two cases. There was no response from the regulator.
“For us, it is very frustrating because the investigators and we are doing our jobs conscientiously. We break our heads at the meetings, collecting all documents, writing a well-drafted letter explaining what we want to be done and reasons for that, but there is no acknowledgement, not even to say that the letters have been received and action will be taken. That is seriously problematic.”
Bhan, who has served on various ethics committees, agreed. “It’s almost a blackhole,” he said. “It would be good practice to acknowledge every report of SAE. But it is likely that the DCGI’s office might not have enough people to do a quick enough job.”
In the end, if there is one thing the SII case highlights, it’s this: the legal obligation under the 2019 Rules may have made people aware of the timelines during an SAE. But without formal communication to all stakeholders, it’s difficult to know how closely those timelines are followed – and that in turn can have serious adverse consequences.
As Bhan said, “There are loose ends that need to be tied.”
This report was supported by a grant from the Thakur Family Foundation. The foundation didn’t exercise any editorial control over the contents of this report.
Shreya Dasgupta (@ShreyaDasgupta) is an independent science writer based in Bengaluru, India. Her work has appeared in Mongabay, Nature, BBC Earth, Smithsonian.com, New Scientist, Ensia, and other publications.