Explained: Is the Data From Covaxin Trial’s Bhopal Site Tainted?

Q&A on how Covaxin's Bhopal trial was to be conducted and why the data from the site isn't kosher.

In January 2021, several media outlets carried reports of worrying ethical breaches at People’s Hospital – the Bhopal site of Bharat Biotech’s phase 3 trial for Covaxin. The claimed breaches ranged from luring participants (by not clearly telling them they were part of a clinical trial, and not a vaccination drive) to not treating the participants when they fell sick during the course of the trial.

Now, a copy of the protocol of the Covaxin phase 3 trial, which The Quint has reviewed, shows that People’s Hospital also violated this protocol, tainting the integrity of data from the site. Several experts The Quint spoke to said such protocol violations, together with already documented violations of the New Drug and Clinical Trial Rules 2019 (NDCT 2019), render the data from the site untrustworthy. This, in turn, will impact Bharat Biotech’s calculations of the efficacy and safety of Covaxin from all of the 26 trial sites at the end of the study.

Both Bharat Biotech and the Indian Council of Medical Research (ICMR), the two sponsors of the trial, have brushed off the allegations. In responses The Quint, both said that People’s Hospital had followed NDCT 2019 to the letter. In a response to this reporter, Director General, ICMR, Balram Bhargava, said:

"All due procedures laid down by DCGI (Drug Controller General of India) for obtaining informed consent, audio-visual recording, reporting AEFIs (adverse events following immunisation) etc have been followed stringently. There has been no violation in conduct of the trial as per the new clinical trial rules of DCGI."

This reporter also reached out to Bharat Biotech for a response. In a detailed mail, they denied any violation and said they strictly followed the NDCT 2019 rules on informed consent, recording of SAE and in investigating the death of the participant.

Neither of them explained some of the most egregious breaches reported in the media, such as the People’s Hospital not giving copies of informed consent forms to every participant – a requirement under the NDCT 2019.

Bharat Biotech’s and ICMR’s responses are troubling because, by claiming there were no violations at all, they are implying that they plan to use data from People’s Hospital as-is in the calculation of the vaccine’s efficacy and safety.

The Q&A below explains how the Bhopal trial was supposed to conducted, how it was actually conducted, and why the data from the site isn’t kosher.

What data was Bharat Biotech collecting from the phase 3 trial?

Bharat Biotech’s phase 3 trial for Covaxin has two key goals – to characterise the efficacy and safety of the vaccine. Broadly, the team conducting the trial will calculate the efficacy by comparing the number of participants who develop Covid disease in the vaccine arm to the number in the placebo arm. Alongside, they will assess the vaccine’s safety by comparing the rates of adverse events in both arms, and evaluating whether the vaccine caused some of events (read about how investigators determine causality here).

According to the protocol accessed by The Quint, Bharat Biotech plans to assess Covaxin’s safety on seven counts. These include the rates of solicited adverse events, unsolicited adverse events, serious adverse events, and the occurrence of so-called Vaccine Associated Enhanced Respiratory Disease (VAERD).

Solicited adverse events mean that the trial team is “soliciting”, or asking each trial participant about expected side-effects within seven days of each injection. According to the protocol, the team was supposed to solicit twelve such events. The first four were pain, swelling, hardness (induration) and redness (erythema) at the injection site. In addition, the team was also supposed to look for fever, chills, headache, vomiting, nausea, muscle pain (myalgia) and joint pain (arthralgia).

“Serious adverse events” are when a participant dies or is hospitalised following a shot. And VAERD is when a vaccinated person develops a more severe version of COVID instead of being protected from it. A respiratory syncytial virus vaccine for babies, developed in the sixties, was seen to trigger this phenomenon. Because VAERD is a risk with Covaxin too, the phase 3 trial will be on the lookout for it.

The trial team at People’s Hospital was supposed to track this range of adverse events in several ways. For solicited adverse events, they were to telephone every participant for seven days after the first and second injections. In addition, each participant was given a daily diary to fill.

This data was to be collected in great detail, by grading each of the twelve solicited adverse events on a scale of 1 to 4. For instance, if a participant reported a fever of 39-40 degrees celsius, the team would record this as a grade 3 event. Or if a participant reported a red spot on the injection site that was between 50 mm and 100 mm wide, that would be a grade 2 event. The trial team was supposed to record such data for every one of the 1700 participants at People’s Hospital.

That isn’t all. Yet another crucial goal of the trial was to capture every single case of COVID-19 among participants throughout the one-year trial period. This data is central to both efficacy calculations and VAERD analysis. Again, this required People’s Hospital to follow-up participants rigorously, even aggressively. Through multiple channels, including SMS and phone, they were supposed to contact participants atleast once every two weeks, to ask if they developed any COVID-19 symptoms. In addition, participants should have been able to contact a 24/7 helpline number.

Like with most vaccine trials, maintaining constant communication with all participants is emphasised in Bharat Biotech protocol. It is also clear from the protocol that every participant who fell sick during the trial, whether due to COVID or not, would be treated at the hospital.

Did People’s Hospital follow this protocol scrupulously?

No, it didn’t. If the participants are to believed, the collection of data was extremely chaotic. Not only did the trial team fail to contact several participants at the pre-defined times, they also sometimes drove away participants who reported sick to the hospital. Both actions are the opposite of what the protocol demands.

Consider the claims of seventy-year old Man Singh Parihar, a construction worker, who joined the trial and received his first shot on 21 Dec. Parihar says that within two days, he became bedridden with fever, breathlessness and a headache.

If the People’s Hospital team was playing by the rulebook, they would have called Parihar on the first seven days to collect solicited adverse events, and learnt that he was ill. His illness may have been classified as Grade 3 or 4, given that he was incapacitated, and requiring him to come to the hospital. Also, since his symptoms looked a lot like Covid, he would have been given an RT-PCR test. If he was diagnosed with COVID-19, the data would be used for efficacy analysis and for VAERD assessment. If he wasn’t, it would still go into the data sets for solicited adverse events.

But what actually happened was completely different: Parihar says nobody from the hospital called him in this time. Nor did he fill his diary, because he couldn’t read or write.

Around the third day, his family took Parihar to a local medical practitioner, who gave him some drugs. But when he continued feeling ill until 7 January, 2021, Rachna Dhingra, a health activist who works with the victims of the 1984 Bhopal industrial-gas leak and their descendants (Parihar is one of them), told the family to call the principal investigator’s number, listed in the diary.

Eventually, Parihar made his way to the hospital, a whole 16 days after he developed symptoms. This means the hospital lacks crucial data for over 2.5 weeks in his case.

Immediate recording of solicited adverse events is important, because people tend to forget the details beyond 24-hours, says Jacob John, an epidemiologist at the Christian Medical College, Vellore, and a part of the team that conducted the phase 3 trials for Rotavac, Bharat Biotech’s rotavirus vaccine. “Usually, trial protocols are set up for a 24-hour recall of events,” he says.

Several ongoing COVID vaccine trials have similar reporting systems for solicited adverse events. For example, the Phase 2/3 trial protocol for a Pfizer vaccine asks participants to note these events in an electronic diary during the 7-day period following the shot. Trial teams are also required to review the diaries, preferably on a daily basis, and to call participants if they aren’t filling them.

If People’s Hospital lost data from only one participant, surely that isn’t a big deal?

If it was only Man Singh Parihar who slipped through the trial’s surveillance net, and the study team collected data scrupulously from the 1700+ other participants, the data would still largely be reliable.

But too many participants have described experiences similar to Parihar’s, pointing to a badly-done trial and large chunks of missing data. While some, like Parihar, didn’t get any of the seven phone calls (either after the first or second shot), others whom The Quint spoke to said they received only one or two.

Dhingra says she has identified 223 participants who experienced some protocol violation or the other, including not being tracked for solicited adverse events.

Another example that points to the chaos at People’ Hospital is the experience of Jitendra Narvariya. This 36-year old daily wage-labourer received his first injection on 10 December. Four days later, he was coughing, feeling weak, and running a fever. Unlike Parihar, he did go to the hospital on the 14th of December. Here, he says, doctors told him to get a set of investigations done, for which he was asked to pay Rs 450. “Where was I to get the money? I am the only breadwinner in my family, and I was sick,” he told The Quint. Narvariya earns Rs 400 a day.

Not knowing how he could afford the treatment, he went home. Eventually, on 5 January, 2021, nearly twenty days later (by when, Narvariya says, he still didn’t get a single phone call), Dhingra convinced him to go back to the hospital. By then, reports of ethical breaches in the Bhopal trial had been widely covered in the media. People’s Hospital then diagnosed him with a liver abscess, and hospitalised him for ten days.

In Narwariya’s case too, the hospital has not only lost data, but also violated protocol by not offering him treatment when needed.

So, the hospital didn’t track solicited adverse events carefully. What about serious adverse events?

People’s Hospital’s investigation into the death of Deepak Marawi, a 45-year old participant, has raised troubling questions on this front too. Because serious adverse events lead to deaths or hospitalisation, investigators are obliged to probe any possible link with the vaccine. Even if a vaccine causes a slightly higher rate of such events, compared to a placebo, its risk-benefit ratio can change dramatically.

Yet, People’s Hospital’s conclusion that Marawi was poisoned, and that his death was unlikely to be due to the vaccine, has several flaws.

First, it ignores Marawi’s family’s account of his symptoms before his death. The family says Marawi’s health deteriorated incrementally between December 12, when he got his first shot in the trial, and Dec 21, when he died. During this time, he experienced dizziness and weakness initially, followed by vomiting from December 17th onwards. Marawi’s son, Aakash, also says that the hospital did not call his father between the 12th and the 21st (although the protocol requires seven calls in this period); nor did the investigators interview the family after the death to seek their version.

In contrast to what Marawi’s family says, the dean of People’s Medical College, A K Dixit, has claimed that the hospital called Marawi on all seven days, and that the latter had appeared to be fine.

The report of a post mortem analysis conducted at Bhopal’s Gandhi Medical College only notes a sudden onset of anxiety, vomiting, and palpitations as Marawi’s last symptoms, without specifying when they began.

These discrepancies between the family’s claims and the hospital’s are crucial to any analysis of what led to the demise, says Ajay Balachandran, a forensic pathologist at the Amrita Institute of Medical Sciences in Kochi. Yet, the hospital hasn’t explained why it is not considering the family’s account. Nor has it shared any evidence of the calls it made to Marawi, although the family has asked for it (Clinical trial sites typically maintain records of all attempts to contact participants).

Second, neither the post-mortem analysis, nor an analysis of viscera (internal organs) conducted after Marawi’s death have identified the poison that triggered his symptoms. The results of the viscera analysis, conducted by the Regional Forensic Science Laboratory in Bhopal, and released on February 4th, only found ethyl alcohol and omeprazole, a drug used to treat acidity, in Marawi’s stomach.

“Alcohol is a toxic substance, and people can die if they consume it in large quantities,” Balachandran says. “But here, the symptoms are not consistent with alcohol poisoning.”

Balachandran also cautions that that the viscera report says nothing about the quantity of alcohol found. This is crucial because small quantities of alcohol can be formed in the body, even after death, due to natural processes. There are other flaws with Bharat Biotech’s and People’s Hospital’s claims too. If the hospital knew for sure that Marawi had received a placebo, they could have let the vaccine off the hook. But the hospital has said that the trial investigators and ethics committee continue to be blinded; in other words, they didn’t know whether Marawi got the vaccine or the placebo when they concluded that the vaccine wasn’t linked his demise. All these discrepancies and unanswered questions suggest that People’s Hospital did a hurried and superficial job of investigating Marawi’s death.

When we reached out to Bharat Biotech for a response on SAE investigation, they said,

"This SAE has been thoroughly investigated and has been found not related to vaccine or placebo. All data and reports on this SAE has been submitted to the Site Ethics Committee, CDSCO and DSMB."

Why did People’s Hospital find it so hard to follow the protocol?

It is hard to say. One possibility is that the investigators weren’t trained in Good Clinical Practice (GCP), a set of standard practices aimed at ensuring data integrity and the protection of trial participants. NDCT 2019 requires all trial investigators to be trained and certified in GCP.

Several of People’s Hospitals alleged actions point to a poor awareness of GCP. For instance, the vice chancellor of People’s University, Rajesh Kapur, has admitted in an interview that the hospital gave a copy of informed consent forms to participants only when they asked for it. Sharing copies of the consent form is a requirement under both GCP and NDCT 2019.

The hospital also violated laws by recruiting vulnerable participants without the legally required checks and balances. According to NDCT-2019, when informed consent is sought from participants who are impoverished, or belong to ethnic minorities, the process must be recorded on video. The law also requires that an impartial witness be present when illiterate participants are consented. Yet, People’s Medical College dean, Dixit has said in a press conference that the hospital wasn’t doing either.

These provisions exist in NDCT-2019 to ensure that participants such as Parihar, Narwariya and Marawi aren’t exploited. Apart from not being able to write, Parihar belonged to the Other Backward Class category of the Madhya Pradesh government, while Marawi belonged to a Scheduled Tribe. In such cases, NDCT 2019, and the accompanying National Ethical Guidelines for Biomedical and Health Research Involving Human Participants recognise that the consent process may require investigators to make an extra effort. Video-recording helps document this effort.

But not only did People’s Hospital skip the video-record, the informed consent process seems to have been rushed in several cases. Parihar and others have said they had no idea they were in a clinical trial, which is why it never struck them that they ought to report their symptoms to People’s Hospital, and were entitled to medical care.

When The Quint asked A K Dixit whether the People’s Hospital investigators had GCP certification, Dixit said the principal Investigator had received training from the company, but didn’t answer a question about the remaining investigators.

How could the hospital have done things differently?

When it recruited so many vulnerable participants, the principal investigator and the ethics committee ought to have intensified their efforts to counsel participants and follow them up.

Dixit has said that upto 25% of the trial participants, or roughly 425 people, couldn’t read or write. Dhingra estimates that the total number of vulnerable participants, as defined in the NDCT 2019, is close to 900. A consequence of this was that participants often did not have their own mobile phone, or shared it with several family members. This made the two means of tracking solicited adverse events – telephone and a written diary, useless in many cases.

Such challenges in tracking vulnerable participants doesn’t mean they should not be recruited, says Urmila Thatte, a clinical pharmacologist, bioethicist and Emeritus professor at the Seth GS Medical College and KEM Hospital, Mumbai. What it means is that extra care is taken to consent the participant, and to set up alternative channels of communication such as home visits.

“If a participant is not picking up the phone, you must find out why it isn’t happening. One possibility is that the participant is too sick to answer. So, you have to use an alternate method – send a messenger home. As a caution, the investigators should have taken more than one phone number,” the investigator in another ongoing vaccine trial in India, who didn’t wish to be named, told The Quint.

What should Bharat Biotech and ICMR be doing now?

A lot more than they have.

Bharat Biotech’s trial in Bhopal was being overseen by multiple bodies, including the ethics committee, clinical trial monitor IQVIA, and an independent data and safety monitoring committee (DSMB). The job of each of these bodies was to respond immediately to allegations, and investigate them thoroughly.

But all these bodies have been silent in the matter.

Sahebrao K Sadawarte, a member of the ethics committee, refused to answer The Quint’s questions, saying only that no violations had occurred. IQVIA India directed all questions from The Quint to Bharat Biotech. Meanwhile, the two sponsors of the trial, ICMR and Bharat Biotech, have denied any legal and ethical breaches.

This denial makes little sense in the face of how obvious some breaches are. It is also odd for ICMR to ignore them, because it is the author of the National Ethical Guidelines for Biomedical and Health Research and Human Participants, which Bharat Biotech and People’s Hospital have violated. For instance, the National Ethical Guidelines contain the requirement that every participant be given a copy of the informed consent form. So, for ICMR to claim that there has been no breach, when People’s Hospital’s vice chancellor has admitted that this hasn’t happened, is strange.

Given the lack of response from all bodies overseeing the trial, the Drug Controller General of India (DCGI), the agency tasked with enforcing NDCT-2019, ought to have stepped in. However, it isn’t clear if DCGI has launched any investigation. Questions to the DCGI, V K Somani, from The Quint went unanswered.

If the ethics body had functioned as it was supposed to, it would have evaluated how widespread the breaches were. Several experts told The Quint that if they are indeed as extensive as claimed, data from the Bhopal site cannot be used in final calculations for either safety of efficacy. Thatte reasoned that any trial becomes invalid without informed consent.

“The participant is central to the trial. If they didn’t even know they were in a trial, that was wrong. Then all the data from the trial becomes invalid, to my mind.”

Urmila Thatte, Clinical pharmacologist, bioethicist and Emeritus professor at the Seth GS Medical College and KEM Hospital, Mumbai

Vasantha Muthuswamy, a bioethicist and a member of ICMR’s national ethics committee – which did not oversee the Bharat Biotech trial - agrees.

“If there are protocol violations, they must stop the trial at the site, and find a different site. The data cannot go into the analysis, because it will give the wrong results.”

Vasantha Muthuswamy, bioethics expert

A far bigger worry than the violations at People’s Hospital, however, is ICMR’s and Bharat Biotech’s blanket denial of them. Not only are these bodies overseeing the 25 other phase 3 trial sites, they are also collecting adverse event data from India’s Covid immunisation program, of which Covaxin is a critical part, points out Anant Bhan, a bioethics researcher at Mangaluru’s Yenepoya University. “To not acknowledge the problems, at all, is worrisome, because what does that tell us about how they handle potential concerns about data quality from other sites? If we are giving Covaxin on a large scale in clinical trial mode, and if this happens in a controlled trial, what about larger rollouts?” asks Bhan.

(Priyanka Pulla is freelance science journalist based in Bangalore. The reporting for this story was funded by The Thakur Family Foundation. The Foundation exercised no editorial control on the contents.)