Spray and pray – the COVID-19 version

Kiran Mazumdar-Shaw is the head of Biocon, a company headquartered in Bengaluru and which has repurposed a drug called itolizumab – already approved to help manage severe chronic psoriasis in different markets – to manage cytokine release syndrome (CRS) in COVID-19 patients. Setting aside CRS’s relevance in the COVID-19 pathology (considering it is currently in dispute), Mazumdar-Shaw and a specific coterie of Biocon employees have been aggressively marketing itolizumab despite the fact that its phase II clinical trial seems by all accounts to have been a joke. (I recommend this account.)

Funnily enough, The Print published an article by Mazumdar-Shaw on September 1, in which she describes her experience of the infection (she’s one of The Print‘s funders). Two portions of the article are striking. One is the following paragraph about her treatment, which tacitly implicates a host of drugs and devices in her recovery without providing any additional information of their respective usefulness:

Dr Murli Mohan from Narayana Health, Bengaluru and Dr Shashank Joshi from Lilavati hospital, Mumbai, were my key medical supervisors. I was put on a course of Favipiravir, azithromycin and paracetamol. Apart from this, I continued with my daily dose of Vitamin C, Vitamin D, Zinc, baby aspirin and chyavanprash. Not to mention my twice a week 200mg dose of HCQ. Day two and three were uneventful. I was measuring my oxygen saturation levels six times a day, which were all between 96-98 per cent even after a brisk six-minute walk. My temperature was normal but late evening on Day three, I felt fluish and it extended to Day four and five. No measurable temperature but frequent bouts of sweating, which suggested that my body was fighting the virus. I was also tracking my Cytokine levels.

Reading this brought to mind a terrible period in early 2010, when I had malaria and jaundice together with an unusually strong spate of migraines. I can’t remember the exact drugs and diet that got me feeling better. But after reading what Mazumdar-Shaw went through, I’m inclined to attribute my recovery also to the mug of Bournvita I had every night before bed.

The other striking portion is a list of suggestions that subtly make the case to pay more attention to CRS and treat it with the drugs available in the market for it: “Doctors should not just treat clinical symptoms but rather the cause of the symptoms. If SpO2 (oxygen saturation) reduces, just increasing oxygen flow is not the answer. Treating inflammation caused by cytokines is the answer.” Wonder why researchers don’t yet have consensus… But the Drug Controller General of India has approved two drugs to treat CRS due to COVID-19 in India (through a highly criticised approval process) – and Kiran Mazudar-Shaw’s Biocon’s itolizumab is one of them.

The list is also prefaced by the following statement, among others: “… avoid TV and social media as negative news is bad for fighting Covid-19.” I wonder if this refers to criticism against hydroxychloroquine (HCQ), favipiravir, azithromycin and purported Ayurvedic remedies as well.

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.

The matter of a journal’s reputation

Apparently (and surprisingly) The Telegraph didn’t allow Dinesh Thakur to respond to an article by Biocon employee Sundar Ramanan, in which Ramanan deems Thakur’s article about the claims to efficacy of the Biocon drug Itolizumab not being backed by enough data to have received the DCGI’s approval to be inaccurate. Even notwithstanding The Telegraph‘s policy on how rebuttals are handled (I have no idea what it is), Ramanan – as a proxy for his employer – has everything to gain by defending Itolizumab’s approval and Thakur, nothing. This fact alone means Thakur should have been allowed to respond. As it stands, the issue has been reduced to a he-said-she-said event and I doubt that in reality it is. Thakur has since published his response at Newslaundry.

I’m no expert but there are many signs of whataboutery in Ramanan’s article. As Thakur writes, there’s also the matter of the DCGI waiving phase III clinical trials for Itolizumab, which can only be done if phase II trials were great – and this they’re unlikely to have been because of the ludicrous cohort size of 30 people. Kiran Mazumdar-Shaw and Seema Ahuja, the former the MD of and the latter a PR person affiliated with Biocon, have also resorted to ad hominem arguments on Twitter against Itolizumab’s critics, on more than one occasion have construed complaints about the drug approval process as expressions of anti-India sentiments, and have more recently begun to advance company-sponsored ‘expert opinions’ as “peer-reviewed” evidence of Itolizumab’s efficacy.

Even without presuming to know who’s ultimately right here, Mazumdar-Shaw and Ahuja don’t sound like the good guys, especially since their fiercest critics I’ve spotted thus far on Twitter are a bunch of highly qualified public health experts and medical researchers. Accusing them of ‘besmirching India’ inspires anything but confidence in Itolizumab’s phase II trial results.

It’s in this context that I want to draw attention to one particular word in Ramanan’s article in The Telegraph that I believe signals the ‘you scratch my back, I scratch yours’ relationship between many scientific journals and the accumulation of knowledge as a means to power – and in my view is a further sign that something’s rotten in the state of Denmark. Ramanan writes (underline added):

Itolizumab was first approved by the Drugs Controller General of India for the treatment of patients with active moderate to severe chronic plaque Psoriasis in 2013 based on “double-blind, randomized, placebo-controlled, Phase III study”. The safety and efficacy of the drug was published in globally reputed, peer-reviewed journals and in proceedings (Journal of the American Academy of Dermatology, and the 6th annual European Antibody Congress, respectively).

What does a journal’s reputation have to do with anything? The reason I keep repeating this point is not because you don’t get it – I’m sure you do; I do it to remind myself, and everyone else who may need to be reminded, of the different contexts in which the same issue repeatedly manifests. Invoking reputation, in this instance, smells of an argument grounded in authority instead of in evidence. Then again, this is a tautological statement considering Biocon issued a press release before the published results – preprint or post-print – were available (they still aren’t), but let’s bear on in an attempt to make sense of reputation itself.

The matter of a journal’s reputation, whether local or global, is grating because the journals for whom this attribute is germane have acquired it by publishing certain kinds of papers over others – papers that tend to describe positive results, sensational results, and by virtue of their reader-pays business model, results that are of greater interest to those likely to want to pay to access them. These details are important because it’s important to ask what ‘reputation’ means, and based on that we can then understand some of the choices of people for whom this ‘reputation’ matters.

Reputation is the outcome of gatekeeping, of deeming some papers as being worthy of publication according to metrics that have less to do with the contents of the paper* and more with the journal’s desirability and profitability. As Björn Brembs wrote in 2010:

It doesn’t matter where something is published – what matters is what is being published. Given the obscene subscription rates some of these journals charge, if anything, they should be held to a higher standard and their ‘reputation’ (i.e., their justification for charging these outrageous subscription fees!) being constantly questioned, rather than this unquestioning dogma that anything published there must be relevant, because it was published there.

However, by breaking into an élite club by publishing a paper in a particular journal, the reputation starts to matter to the scientist as well, and becomes synonymous with the scientist’s own aspirations of quality, rigour and academic power (look out for proclamations like “I have published 25 papers in journal X, which has an impact factor of 43″). This way, over time, the scientific literature becomes increasingly skewed in favour of some kinds of papers over others – especially of the positive, sensational variety – and leads to a vicious cycle.

The pressure in academia to ‘publish or perish’ also forces scientists to shoehorn themselves tighter into the journals’ definition of what a ‘good’ paper is, more so if publishing in some journals has seemingly become associated with increasing one’s likelihood of winning ‘reputed’ awards. As such, reputation is neither accidental nor innocent. From the point of view of the science that fills scientific journals, reputation is an arbitrary gatekeeper designed to disqualify an observer from calling the journal’s contents into question – which I’m sure you’ll understand is essentially antiscientific.

Ramanan’s appeal to the reputation of the journal that published the results of the tests of Itolizumab’s efficacy against cytokine release syndrome (CRS) in psoriasis patients is, in similar vein, an appeal to an entity that has nothing to do either with the study itself or the matter at hand. As Dr Jammi Nagaraj Rao wrote for The Wire Science, there’s no reason for us to believe knowing how Itolizumab works against CRS will help us understand how it will work against CRS in COVID-19 patients considering we’re not entirely sure how CRS plays out in COVID-19 patients – or if Itolizumab’s molecular mechanism of action can be directly translated to a statement of efficacy against a new disease.

In effect, the invitation to defer to a journal’s reputation is akin to an invitation to hide behind a cloak of superiority that would render scrutiny irrelevant. But that Ramanan used this word in this particular context is secondary**; the primary issue is that journals that pride such arbitrarily defined attributes as ‘reputation’ and ‘prestige’ also offer them as a defence against demands for transparency and access. Instead, why not let the contents of the paper speak up for themselves? Biocon should publish the paper pertaining to its controversial phase II trial of Itolizumab in COVID-19 patients and the DCGI should publicise the inner workings of its approval process asap. As they say: show us (the results), don’t tell us (the statement).

Beyond determining if the paper is legitimate, has sound science and is free of mistakes, malpractice or fraud.

** There are also other words Ramanan uses to subtly delegitimise Thakur’s article – calling it an “opinion article” and presuming to “correct” Thakur’s arguments that constitute a “disservice to the public”.