Even in the most well-developed drug or vaccines, where the odds of an adverse event may be slim, the redressal process for issues raised by volunteers is tricky
The Serum Institute of India hit the headlines for the wrong reasons earlier this week — a lawsuit of Rs 100 crore that it filed against a volunteer who flagged a serious medical condition.
The legal faceoff has brought to light the numerous ethical issues involved in vaccine trials on human participants, and best practices in dealing with them.
Commenting on the lawsuit, several experts told Firstpost that engaging with the volunteer and adopting a transparent approach could have been a better response to the controversy.
The row erupted after a volunteer in the Oxford University ‘Covishield’ COVID-19 vaccine trial flagged a serious medical condition called ‘acute neurological encephalopathy’ ten days after he was given the first dose on 1 October.
The volunteer reported having had ‘memory loss, ability to reason and concentrate and personality change’, all of which are considered serious neurological and psychological symptoms. He went on to sue SII (which is conducting the trial along with the ICMR) for a compensation of Rs 5 crore. In response, SII filed a Rs 100 crore lawsuit against him for defamation.
SII said that the volunteer’s illness had nothing to do with the vaccine trial – a statement that was validated by the Institutional Ethics Committee (IEC) of the Covishield trials in India. The IEC, backed by the Data and Safety Monitoring Board (DSMB) and DCGI (Drugs Controllor General of India), confirmed that the symptoms were indeed from an unknown cause other than the Covishield shot.
‘Engage with volunteers’, say experts
Speaking to Firspost, public health researcher and bioethicist Anant Bhan said, “It’s an unusual response, because the reasons for volunteers to participate are altruistic. If there is a concern that a volunteer has, it’s good to engage with them and understand what those concerns are, and to make efforts to try and address them. It’s in the interest of the sponsor, and is also a signal to other participants already in the trial, and potential participants.”
“(It) could spook a few people, as and when a vaccine becomes available. When you do get into these situations, it’s better to be open and transparent,” Bhan, who is a professor at the Department of Community Medicine, Yenepoya University, Mangaluru, said.
So far, from the Covishield India trials, most updates and statements were made by SII, the only party with any conflict of interest in the outcome of the Phase 3 trials. As the trial sponsor, SII has a financial stake in ensuring that Covishield clears the ongoing Phase 3 trials. If this clearance is received, the SII can begin manufacturing doses of the vaccine in the months to come, at a tentative price tag of Rs 500-600 per dose.
“It’s quite possible that everything they’re saying is true. But that doesn’t change the fact that there’s a conflict of interest,” said Bhan. “The regulator is being paid taxpayer money to be able to provide adequate oversight in these circumstances. The expectation is for the regulator to come forward and speak on the issue.”
Firstpost reached out to Serum Institute for its comments on the issue, but has not got a response so far. This article will be updated if there is a response from the institute.
The controversy around Covishield, which SII responded to legally, could have a negative impact on the very altruism that vaccine makers are relying on to test and clear the vaccine for widespread use. SII’s adversarial response comes in the middle of the third phase of human trials in India, at the end of which the company hopes to have 100 million doses of the approved vaccine – to be taken in two separate doses – by January 2021.
The row attracted criticism from several quarters, with some media reports questioning SII’s decision to file a lawsuit. An article in Quint questioned whether this showed a lack of transparency, while an article in India Today quoted experts as saying the lawsuit was an ‘attempt to intimidate’ the volunteer.
For participants in vaccine trials, a major concern would be who would take care of them and their family if they fall ill? Medical bills constitute another concern.
Procedures to deal with adverse events
In order to monitor adverse events, there are many checks and balances put in place for proper monitoring, recording and reporting. Each side effect or adverse event from a human trial is first recorded by investigators and the supervising team, which includes the Principal Investigator and the research team at the trial site. The Institutional Ethics Committee (IEC) is sent a report within 24 hours, and an ‘initial assessment’ is undertaken by the investigator under the IEC’s guidance. This report is sent to the Data Safety & Monitoring Board (DCMB) with other relevant information, which establishes or refutes a causal link, i.e, determine if the investigational product (in this case, the vaccine candidate) caused the adverse event. Finally, a consolidated report is sent to the DCGI within 7 days of the adverse event taking place.
“The causal link is objectively assessed at three levels – by the IEC and the DSMB and the DCGI. If someone isn’t satisfied with the assessments of all three regulators, a medico-legal process is the only way to go. These complexities are also explained in the consent form, where it is also clarified that the IEC, DSMB and DCGI will determine the outcomes of any outliers,” explains Dr Samiran Panda, Director of the Indian Council of Medical Research (ICMR)-National AIDS Research Institute (NARI) — the organisation tasked with conducting the WHO Solidarity Trial in India. “The DCGI ultimately decides whether to attribute a side effect to the investigational product, or refute it. In this particular case, the causal link was not found and established,” Dr Panda added.
Compensation and inpatient care are given to volunteers depending on the seriousness of the adverse event, and whether a causal link was found. If evidence was found that the experimental drug/vaccine caused an adverse reaction, all medical support needed by the volunteer is borne by the trial sponsor. In this case, there is also provision for compensation, the amount of which is laid out by the DCGI in the Clinical Trial Rules 2019. If there is no evidence for causality in the trial, then compensation is ruled out. In any case – regardless of the cause – inpatient care is available to volunteers for minor illnesses as well as admission.
With the added element of risk and vigilance in fast-tracked vaccine trials, the responsibility of ensuring a fair and successful trial falls on multiple organisations that work in tandem. Since the nature of vigilance in these trials is subjective and dynamic, it falls on the regulators to ultimately ensure everything is going to plan.
When a qualified volunteer enlists in a clinical trial, an elaborate consent process is undertaken, in which their expectations from the trial are clarified. The form doesn’t just include medical information, but also the participant’s rights at every stage of the process. It also clarifies that the consent form doesn’t take away any of their legal rights, including the right to contest any decisions taken by the ethics committee or regulators overseeing the trial. That said, the process of appealing against a decision taken by the redressal is fairly limited, and possibly underdeveloped in India.
“Let’s say I have an adverse event, and the investigators, ethics committee, regulators decide there is no causality. If I disagree with that, and I want to take it to an appellate authority, the only way out is a legal mechanism. There is no direct process of appealing to the regulator,” Bhan said.
Even in the most well-developed drug or vaccines, where the odds of an adverse event may be slim, the redressal process for issues raised by volunteers is tricky. There aren’t enough resources in place for volunteers to raise legitimate issues in a formal process under the clinical trial. From the volunteer’s point of view, the effort needed to report an issue is inordinately greater than if it came from the trial sponsor or regulator. Once false reports of adverse events are ruled out (like in the Covishield trial), it should be made equally easy (if not easier) for the volunteer to raise a red flag to the trial investigators.
“The whole communication chain of establishing causality for adverse events leaves out the participant — except that the participant’s data is being used for a lot of the decision-making in the process,” Bhan said. “In that sense, a participant is well within their rights to choose a legal pathway. We haven’t seen a lot of action happening in terms of participants suing companies for harms during clinical trials. But that will likely change as we move towards better literacy levels.”
“More community engagement with the scientists with the help of various communication platforms would go a long way in establishing these rights very firmly,” Panda said.
He added, “If this happens, the sponsor of the trial – be it a business or pharma company – won’t be able to take things for granted.”
Risks involved in fast-tracked trials
A successful COVID-19 vaccine trial would leave an unavoidable degree of uncertainty as to side effects that could arise. With human trials for COVID-19 vaccines (and the work of regulators) being fast tracked, the risk is higher, even if still relatively low.
“We tend to assume that a vaccine is like a tablet of Crocin: you take a shot, you’ll be fine. If anything, it’s the other way around because vaccines are heavily dependant on the immune system. If you take the vaccine now, you’ll only find out if it helps you much later – realistically, in 6 to 12 months,” says Dr Om Srivastava, Director of the Infectious Diseases wing at Jaslok Hospital, Mumbai.
Leaving human intention and intervention aside, understanding if/how the immune system reacts to the vaccine takes as much time as it takes. Any figure attached to it is simply an attempt to estimate. Vaccines are identical structures of the pathogen that are made completely sterile, so it doesn’t cause the infection it was meant to prevent. For a vaccine to be effective, a patient’s immune system needs to reprogram itself. This interplay with the immune system is something that can only be assessed thoroughly in the long-term because of its variation from one individual to the next.
From a scientific point of view, some observations will be missed in fast-tracked trials.
“The Ebola virus vaccine took about five years to develop. The Rotavirus vaccine, 15 years, even though the scientific community knew about it for some 8 years before that,” said Srivastava. “When you’re going to condense the process of vaccine development into a year, you’re going to run a greater risk of something being missed, simply because of the variables at every stage.
However stringent one may have been, and howsoever trivial an adverse event might seem to an onlooker, even the slightest adverse event needs to be evaluated, Srivastava adds.
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