Tag: Bharat Biotech

A gentle push over the cliff

From ‘Rotavirus vaccine: tortured data analyses raise false safety alarm’, The Hindu, June 22, 2024:

Slamming the recently published paper by Dr. Jacob Puliyel from the International Institute of Health Management Research, New Delhi, on rotavirus vaccine safety, microbiologist Dr. Gagandeep Kang says: “If you do 20 different analyses, one of them will appear significant. This is truly cherry picking data, cherry picking analysis, changing the data around, adjusting the data, not using the whole data in order to find something [that shows the vaccine is not safe].” Dr. Kang was the principal investigator of the rotavirus vaccine trials and the corresponding author of the 2020 paper in The New England Journal of Medicine, the data of which was used by Dr. Puliyel for his reanalysis.

This is an important rebuttal. I haven’t seen Puliyel’s study but Bharat Biotech’s conduct during and since the COVID-19 pandemic, especially that of its executive chairman Krishna Ella, plus its attitude towards public scrutiny of its Covaxin vaccine has rendered any criticism of the company or its products very believable, even if such criticism is unwarranted, misguided, or just nonsense.

Puliyel’s study itself is a case in point: a quick search on Twitter reveals many strongly worded tweets, speaking to the availability of a mass of people that wants something to be true, and at the first appearance of even feeble evidence will seize on it. Of course The Hindu article found the evidence to not be feeble so much as contrived. Bharat Biotech isn’t “hiding” anything; Puliyel et al. aren’t “whistleblowers”.

The article doesn’t mention the name of the journal that published Puliyel’s paper: International Journal of Risk and Safety in Medicine. It could have because journals that don’t keep against bad science out of the medical literature don’t just pollute the literature. By virtue of being journals, and in this case claiming to be peer-reviewed as well, they allow the claims they publish to be amplified by unsuspecting users on social media platforms.

We saw something similar earlier this year in the political sphere when members of the Indian National Congress party and its allies as well as members of civil society cast doubt on electronic voting machines with little evidence, thus only undermining trust in the electoral process.

To be sure, we’ve cried ourselves hoarse about the importance of every reader being sceptical about what appears in scientific journals (even peer-reviewed) as much as news articles, but because it’s a behavioural and cultural change it’s going to take time. Journals need to do their bit, too, yet they won’t because who needs scruples when you can have profits?

The analytical methods Puliyel and his coauthor Brian Hooker reportedly employed in their new study is reminiscent of the work of Brian Wansink, who resigned from Cornell University five years ago this month after it concluded he’d committed scientific misconduct. In 2018, BuzzFeed published a deep-dive by Stephanie M. Lee on how the Wansink scandal was born. It gave the (well-referenced) impression that the scandal was a combination of a student’s relationship with a mentor renowned in her field of work and the mentor’s pursuit of headlines over science done properly. It’s hard to imagine Puliyel and Hooker were facing any kind of coercion, which leaves the headlines.

This isn’t hard to believe considering it’s the second study to have been published recently that took a shot at Bharat Biotech based on shoddy research. It sucks that it’s become so easy to push people over the cliff, and into the ravenous maw of a conspiracy theory, but it sucks more that some people will push others even when they know better.

The BHU Covaxin study and ICMR bait

Earlier this month, a study by a team at Banaras Hindu University (BHU) in Varanasi concluded that fully 1% of Covaxin recipients may suffer severe adverse events. One percent is a large number because the multiplier (x in 1/100 * x) is very large — several million people. The study first hit the headlines for claiming it had the support of the Indian Council of Medical Research (ICMR) and reporting that both Bharat Biotech and the ICMR are yet to publish long-term safety data for Covaxin. The latter is probably moot now, with the COVID-19 pandemic well behind us, but it’s the principle that matters. Let it go this time and who knows what else we’ll be prepared to let go.

But more importantly, as The Hindu reported on May 25, the BHU study is too flawed to claim Covaxin is harmful, or claim anything for that matter. Here’s why (excerpt):

Though the researchers acknowledge all the limitations of the study, which is published in the journal Drug Safety, many of the limitations are so critical that they defeat the very purpose of the study. “Ideally, this paper should have been rejected at the peer-review stage. Simply mentioning the limitations, some of them critical to arrive at any useful conclusion, defeats the whole purpose of undertaking the study,” Dr. Vipin M. Vashishtha, director and pediatrician, Mangla Hospital and Research Center, Bijnor, says in an email to The Hindu. Dr. Gautam Menon, Dean (Research) & Professor, Departments of Physics and Biology, Ashoka University shares the same view. Given the limitations of the study one can “certainly say that the study can’t be used to draw the conclusions it does,” Dr. Menon says in an email.

Just because you’ve admitted your study has limitations doesn’t absolve you of the responsibility to interpret your research data with integrity. In fact, the journal needs to speak up here: why did Drug Safety publish the study manuscript? Too often when news of a controversial or bad study is published, the journal that published it stays out of the limelight. While the proximal cause is likely that journalists don’t think to ask journal editors and/or publishers tough questions about their publishing process, there is also a cultural problem here: when shit hits the fan, only the study’s authors are pulled up, but when things are rosy, the journals are out to take credit for the quality of the papers they publish. In either case, we must ask what they actually bring to the table other than capitalising on other scientists’ tendency to judge papers based on the journals they’re published in instead of their contents.

Of course, it’s also possible to argue that unlike, say, journalistic material, research papers aren’t required to be in the public interest at the time of publication. Yet the BHU paper threatens to undermine public confidence in observational studies, and that can’t be in anyone’s interest. Even at the outset, experts and many health journalists knew observational studies don’t carry the same weight as randomised controlled trials as well as that such studies still serve a legitimate purpose, just not the one to which its conclusions were pressed in the BHU study.

After the paper’s contents hit the headlines, the ICMR shot off a latter to the BHU research team saying it hasn’t “provided any financial or technical support” to the study and that the study is “poorly designed”. Curiously, the BHU team’s repartee to the ICMR’s makes repeated reference to Vivek Agnihotri’s film The Vaccine War. In the same point in which two of these references appear (no. 2), the team writes: “While a study with a control group would certainly be of higher quality, this immediately points to the fact that it is researchers from ICMR who have access to the data with the control group, i.e. the original phase-3 trials of Covaxin – as well publicized in ‘The Vaccine War’ movie. ICMR thus owes it to the people of India, that it publishes the long-term follow-up of phase-3 trials.”

I’m not clear why the team saw fit to appeal to statements made in this of all films. As I’ve written earlier, The Vaccine War — which I haven’t watched but which directly references journalistic work by The Wire during and of the pandemic — is most likely a mix of truths and fictionalisation (and not in the clever, good-faith ways in which screenwriters adopt textual biographies for the big screen), with the fiction designed to serve the BJP’s nationalist political narratives. So when the letter says in its point no. 5 that the ICMR should apologise to a female member of the BHU team for allegedly “spreading a falsehood” about her and offers The Vaccine War as a counterexample (“While ‘The Vaccine War’ movie is celebrating women scientists…”), I can’t but retch.

Together with another odd line in the latter — that the “ICMR owes it to the people of India” — the appeals read less like a debate between scientists on the merits and the demerits of the study and more like they’re trying to bait the ICMR into doing better. I’m not denying the ICMR started it, as a child might say, but saying that this shouldn’t have prevented the BHU team from keeping it dignified. For example, the BHU letter reads: “It is to be noted that interim results of the phase-3 trial, also cited by Dr. Priya Abraham in ‘The Vaccine War’ movie, had a mere 56 days of safety follow-up, much shorter than the one-year follow-up in the IMS-BHU study.” Surely the 56-day period finds mention in a more respectable and reliable medium than a film that confuses you about what’s real and what’s not?

In all, the BHU study seems to have been designed to draw attention to gaps in the safety data for Covaxin — but by adopting such a provocative route, all that took centerstage was its spat with the ICMR plus its own flaws.

On Agnihotri’s Covaxin film, defamation, and false bravery

Vivek Agnihotri’s next film, The Vaccine War, is set to be released on September 28. It is purportedly about the making of Covaxin, the COVID-19 vaccine made by Bharat Biotech, and claims to be based on real events. Based on watching the film’s trailer and snippets shared on Twitter, I can confidently state that while the basis of the film’s narrative may or may not be true, the narrative itself is not. The film’s principal antagonist appears to be a character named Rohini Singh Dhulia, played by Raima Sen, who is the science editor of a news organisation called The Daily Wire. Agnihotri has said that this character is based on his ‘research’ on the journalism of The Wire during, and about, the pandemic, presumably at the time of and immediately following the DCGI’s approval for Covaxin. Agnihotri and his followers on Twitter have also gone after science journalist Priyanka Pulla, who wrote many articles in this period for The Wire. At the time, I was the science editor of The Wire. Dhulia appears to have lovely lines in the film like “India can’t do this” and “the government will fail”, the latter uttered with visible glee.

It has been terribly disappointing to see senior ICMR scientists promoting the film as well as the film (according to the trailer, at least) confidently retaining the name of Balram Bhargava for the character as well; for the uninitiated, Bhargava was the ICMR director-general during the pandemic. (One of his aides also has make-up strongly resembling Raman Gangakhedkar.) In Pulla’s words, “the political capture of this institution is complete”. The film has also been endorsed by Sudha Murthy and received a tone-deaf assessment by film critic Baradwaj Rangan, among other similar displays of support. One thing that caught my eye is that the film also retains the ICMR logo, logotype, and tagline as is (see screenshot below from the trailer).

Source: YouTube

The logo appears on the right of the screen as well as at the top-left, together with the name of NIV, the government facility that provided the viral material for and helped developed Covaxin. This is notable: AltBalaji, the producer of the TV show M.O.M. – The Women Behind Mission Mangal, was prevented from showing ISRO’s rockets as is because the show’s narrative was a fictionalised version of real events. A statement from AltBalaji to The Wire Science at the time, in 2019, when I asked why the show’s posters showed the Russian Soyuz rocket and the NASA Space Shuttle instead of the PSLV and the GSLV, said it was “legally bound not to use actual names or images of the people, objects or agencies involved”. I don’t know if the 2019 film Mission Mangal was bound by similar terms: its trailer shows a rocket very much resembling the GSLV Mk III (now called LVM-3) sporting the letters “S R O”, instead of “I S R O” ; the corresponding Hindi letters “स” and “रो”; and a different logo below the letters “G S L V” instead of the first “I” (screenshot below). GSLV is still the official designation of the launch vehicle, and a step further from what the TV show was allowed. And while the film also claims to be based on real events, its narrative is also fictionalised (read my review and fact-check).

Source: YouTube

Yet ICMR’s representation in The Vaccine War pulls no punches: its director-general at the time is represented by name and all its trademark assets are on display. It would seem the audience is to believe that they’re receiving a documentarian’s view of real events at ICMR. The film has destroyed the differences between being based on a true story and building on that to fictionalise for dramatic purposes. Perhaps more importantly: while AltBalaji was “legally bound” to not use official ISRO imagery, including those of the rockets, because it presented a fiction, The Vaccine War has been freed of the same legal obligation even though it seems to be operating on the same terms. This to me is my chief symptom of ICMR’s political capture.

Of course, that Agnihotri is making a film based on a ‘story’ that might include a matter that is sub judice is also problematic. As you may know, Bharat Biotech filed a defamation case against the Foundation for Independent Journalism in early 2022; this foundation publishes The Wire and The Wire Science. I’m a defendant in the case, as are fellow journalists and science communicators Priyanka Pulla, Neeta Sanghi, Jammi Nagaraj Rao, and Banjot Kaur, among others. But while The Wire is fighting the case, it will be hard to say before watching The Vaccine War as to whether the film actually treads on forbidden ground. I’m also not familiar with the freedoms that filmmakers do and don’t have in Indian law (and the extent to which the law maps to common sense and intuition). That said, while we’re on the topic of the film, the vaccine, defamation, and the law, I’d like to highlight something important.

In 2022, Bharat Biotech sought and received an ex parte injunction from a Telangana court against the allegedly offending articles published by The Wire and The Wire Science, and had them forcibly taken down. The court also prevented the co-defendants from publishing articles on Covaxin going forward and filed a civil defamation case, seeking Rs 100 crore in damages. As the legal proceedings got underway, I started to speak to lawyers and other journalists about implications of the orders, whether specific actions are disallowed on my part, and the way courts deal with such matters – and discovered something akin to a labyrinth that’s also a minefield. There’s a lot to learn. While the law may be clear about something, how a contention winds its way through the judicial system is both barely organised and uncodified. Rahul Gandhi’s own defamation case threw informative light on the role of judges’ discretion and the possibility of a jail term upon conviction, albeit for the criminal variety of the case.

The thing I resented the most, on the part of sympathetic lawyers, legal scholars, and journalists alike, is the view that it’s the mark of a good journalist to face down a defamation case in their career. Whatever its origins, this belief’s time is up in a period when defamation cases are being filed at the drop of a hat. It’s no longer a specific mark of good journalism. Like The Wire, I and my co-defendants stand by the articles we wrote and published, but it remains good journalism irrespective of whether it has also been accused of defamation.

Second, the process is the punishment, as the adage goes, yet by valorising the presence of a defamation case in a journalist’s record, it seeks to downplay the effects of the process itself. These effects include the inherent uncertainty; the unfamiliar procedures, documentation, and their contents and purposes; the travelling, especially to small towns, and planning ahead (taking time off work, availability of food, access to clean bathrooms, local transport, etc.); the obscure rules of conduct within courtrooms and the varying zeal with which they’re implemented; the variety and thus intractability of options for legal succour; and the stress, expenses, and the anxiety. So please, thanks for your help, but spare me the BS of how I’m officially a good journalist.

The biopolitics of Covaxin

In a new investigation, STAT has reported fresh problems with Covaxin’s approval process in India, including the phase 2 trial dropping its placebo arm in favour of one preordained to make Covaxin look good and Bharat Biotech – the maker – commencing phase 3 trials based on results from animal studies. I’m also filing the report under “yet another instance of a pro-government Indian entity responding to the foreign press but not the local press” (following this). Krishna Mohan, one of the company’s directors, responded to STAT by admitting to a wrongdoing, massaging other similar actions, and pointing a finger at the Indian government.

Is this spine? In response to similar evidence-based allegations of wrongdoing, Bharat Biotech met The Wire Science and The Wire with a defamation suit, a demand of Rs 100 crore and that the two sites not publish articles with “defamatory content” vis-à-vis the company, and obtained an ex parte injunction against 14 articles. This was in addition to the seemingly blanket refusal to respond to our questions for reports we were filing. Other senior Bharat Biotech officials also refused to communicate to anyone else asking probing questions about Covaxin’s clinical trials. No: his quote sounds more like Mohan trying to save Bharat Biotech’s face in front of a western audience (the one our government wants us to believe is inferior) while spinning India’s Bharat’s own take on the vaccine approval process.

Mohan told STAT that they didn’t take any shortcuts – at least not those that weren’t first “vetted” by the Central Drug Standards Control Organisation (CDSCO), a.k.a. the drug regulator. That is to say, the shortcuts were CDSCO-approved, so they weren’t shortcuts. I’m inclined to agree: the rules are after all not based on principles of natural justice but on what the government deems acceptable. /s

Of all the allegations, the one that irks me most is the modification to the phase 2 trial. It compromises our ability to learn anything useful about Covaxin, replacing that knowledge with knowledge of how much better one formulation of Covaxin is from another. The drug regulator should have known this is what the trial would have ended up checking, and if it approved this design anyway, it has engaged in wilful neglect – neglect of science, neglect of integrity, neglect of its mandate to look out for the people. But if we’re to believe Mohan, it’s just “product development” for an unprecedented time, not public health:

“In a classic sense of product development, we would do everything the right way — play by the book and all the rules of the game would be followed. But here was a situation the world didn’t foresee. … Please don’t think there was any issue with the veracity of the data. Yes, it was an unusual approach, but it was dictated by the nature of the pandemic.”

Ah, a classic tactic: Why did you burn down the forest? “It’s the climate crisis, which is unprecedented, and we needed land to erect smog towers.”

Later in the article, in the face of a similar allegation – changing the phase 2 trial protocol – Mohan defends the regulator and blames discrepancies in trial numbers on a company struggling to coordinate multiple teams working separately from each other while being guided by the rule of “let’s get the data out”. I’d buy what he was saying if he was talking about his company HQ installing new air-conditioners and conducting tests of indoor air quality. But he’s talking about a clinical trial for a vaccine, placing misleading data in the public domain and – crucially – implicating a national drug regulator that he claims was in the know but didn’t act.

To STAT, he’s saying they were distracted by the “safety of individuals”, the “ethics of handling subjects” and “manufacturing”, but to Indian journalists, he as well as the regulator have been mum on questions raised by the WHO and ANVISA on manufacturing practices and by almost everyone else about the People’s Hospital death and data.

A (somehow) bigger problem arises soon after when Mohan says:

“Whatever we did was with the clear intention of doing it right. There was no question of reducing sample sizes. … There were not off the cuff or random thoughts. … It was extensively debated with keeping the final objective in mind of getting a vaccine in time and not cutting any corners.”

Getting a vaccine in time and not cutting any corners? It’s baffling that the last sentence is intended as clarification rather than as a potentially tacit admission of wrongdoing. I’m sure you remember when ICMR chief Balram Bhargava called on hospitals around India to complete Covaxin’s phase 3 trials in less than two months, in time for Prime Minister Narendra Modi to avail the vaccine for public use on Independence Day 2020. One independent scientist asked me what I thought Bhargava might have been smoking at the time; it was hard to say.

But what’s tempting to speculate now is that the government realised, based on the backlash to Bhargava’s announcement, that a) a phase 3 trial in six weeks was a bigger problem than it believed, b) it wouldn’t work to have its vaccine development plan in public, c) it could accelerate Covaxin’s clinical trials by forcing Bharat Biotech to do so, and d) approve Covaxin without phase 3 trials by assimilating the drug regulator – all to achieve a similar outcome. Or at least I speculate in the absence of evidence. And until there is, we remain needles in veins.

Bharat Biotech gets 1/10 for tweet

If I had been Bharat Biotech’s teacher and “Where is your data?” had been an examination question, Bharat Biotech would have received 1 out of 10 marks.

The correct answer to where is your data can take one of two forms: either an update in the form of where the data is in the data-processing pipeline or to actually produce the data. The latter in fact would have deserved a bonus point, if only because the question wasn’t precise enough. The question should really have been a demand – “Submit your data” – instead of allowing the answerer, in its current form, to get away with simply stating where the data currently rests. Bharat Biotech gets 1/10 because it does neither; the 1 is for correct spelling.

In fact, the company’s chest-thumping based on publishing nine papers in 12 months is symptomatic of a larger problem with the student. He fails to understand that only data is data, and that the demand for data is a demand for data per se. It ought not to be confused with a demand for authority. Data accords authority in an object-oriented and democratic sense. With data, everyone else can see for themselves – whether by themselves or through the mouths and minds of independent experts they trust – if the student’s claims hold up. And if they do, they confer the object of the data, the COVID-19 vaccine named Covaxin, with attributes like reliability.

(Why ‘he’? The patriarchal conditions in and with which science has operated around the world, but especially in Europe and the US, in the last century or so have diffused into scientific practice itself, in terms of how the people at large have constituted – as well as have been expected to constitute, by the scientific community – scientific authority, expertise’s immunity to criticism and ownership of knowledge production and dissemination apparatuses, typically through “discrimination, socialisation and the gender division of labour”. Irrespective of the means – although both from the company’s and the government’s sides, very few women have fielded and responded to questions about drug/vaccine approvals – we already see these features in the manner in which ‘conventional’ scientific journals have sought to retain their place in the international knowledge production economy, and their tendency to resort to arguments that they serve an important role in it even as they push for anti-transparent practices, from the scientific papers’ contents to details about why they charge so much money.)

However, the student has confused authority of this kind with authority of a kind we more commonly associate with the conventional scientific publishing paradigm: in which journals are gatekeepers of scientific knowledge – both in terms of what topics they ‘accept’ manuscripts on and what they consider to be ‘good’ results; and in which a paper, once published, is placed behind a steeply priced paywall that keeps both knowledge of the paper’s contents and the terms of its ‘acceptance’ by the journal beyond public scrutiny – even when public money funded the research described therein. As such, his insistence that we be okay with his having published nine papers in 12 months is really his insistence that we vest our faith in scientific journals, and by extension their vaunted decision to ‘approve of’ his work. This confusion on his part is also reflected in what he offers as his explanation for the absence of data in the public domain, but which are really his excuses.

Our scientific commitment as a company stands firm with data generation, data transparency and peer-reviewed publications.

Sharing your data in a secluded channel with government bodies is not data transparency. That’s what the student needs for regulatory approval. Transparency applies when the data is available for everyone else to independently access, understand and check.

Phase 3 final analysis data will be available soon. Final analysis requires efficacy and 2 months safety follow-up data on all subjects. This is mandated by CDSCO and USFDA. Final analysis will first be submitted to CDSCO, followed by submissions to peer reviewed journals and media dissemination.

What is required by CDSCO does not matter to those allowing Bharat Biotech’s vaccines into the bloodstreams, and in fact every Indian on whom the student has inflicted this pseudo-choice. And at this point to invoke what the USFDA requires can only lead to a joke: studies of the vaccines involved in the formal vaccination drive have already been published in the US; even studies of new vaccines as well as follow-ups of existing formulations are being placed in the public domain through preprint papers that describe the data from soup to nuts. All we got from the student vis-à-vis Covaxin this year was interim phase 3 trial data in early March, announced through a press release, and devoid even of error bars for its most salient claims.

So even for an imprecisely worded question, it has done well to elicit a telling answer from the student: that the data does not exist, and the student believes he is too good for us all.

Thanks to Jahnavi Sen for reading the article before it was published.

India’s missing research papers

If you’re looking for a quantification (although you shouldn’t) of the extent to which science is being conducted by press releases in India at the moment, consider the following list of studies. The papers for none of them have been published – as preprints or ‘post-prints’ – even as the people behind them, including many government officials and corporate honchos, have issued press releases about the respective findings, which some sections of the media have publicised without question and which have quite likely gone on to inform government decisions about suitable control and mitigation strategies. The collective danger of this failure is only amplified by a deafening silence from many quarters, especially from the wider community of doctors and medical researchers – almost as if it’s normal to conduct studies and publish press releases in a hurry and take an inordinate amount of time upload a preprint manuscript or conduct peer review, instead of the other way around. By the way, did you know India has three science academies?

  1. ICMR’s first seroprevalence survey (99% sure it isn’t out yet, but if I’m wrong, please let me know and link me to the paper?)
  2. Mumbai’s TIFR-NITI seroprevalence survey (100% sure. I asked TIFR when they plan to upload the paper, they said: “We are bound by BMC rules with respect to sharing data and hence we cannot give the raw data to anyone at least [until] we publish the paper. We will upload the preprint version soon.”)
  3. Biocon’s phase II Itolizumab trial (100% sure. More about irregularities here.)
  4. Delhi’s first seroprevalence survey (95% sure. Vinod Paul of NITI Aayog discussed the results but no paper has pinged my radar.)
  5. Delhi’s second seroprevalence survey (100% sure. Indian Express reported on August 8 that it has just wrapped up and the results will be available in 10 days. It didn’t mention a paper, however.)
  6. Bharat Biotech’s COVAXIN preclinical trials (90% sure)
  7. Papers of well-designed, well-powered studies establishing that HCQ, remdesivir, favipiravir and tocilizumab are efficacious against COVID-19 🙂

Aside from this, there have been many disease-transmission models whose results have been played up without discussing the specifics as well as numerous claims about transmission dynamics that have been largely inseparable from the steady stream of pseudoscience, obfuscation and carelessness. In one particularly egregious case, the Indian Council of Medical Research announced in a press release in May that Ahmedabad-based Zydus Cadila had manufactured an ELISA test kit for COVID-19 for ICMR’s use that was 100% specific and 98% sensitive. However, the paper describing the kit’s validation, published later, said it was 97.9% specific and 92.37% sensitive. If you know what these numbers mean, you’ll also know what a big difference this is, between the press release and the paper. After an investigation by Priyanka Pulla followed by multiple questions to different government officials, ICMR admitted it had made a booboo in the press release. I think this is a fair representation of how much the methods of science – which bridge first principles with the results – matter in India during the pandemic.