Watchdog With A Bone

Some time back (November 2019), our institute had organized an international workshop on ‘Clinical Research Ethics.’ It was an agenda setting workshop for our institution and had representations from several other institutes such as the Department of Bioethics, National Institute of Health (NIH), USA, Indian Council of Medical Research (ICMR), Niti Ayog and Drug Controller (India), CDSCO. We were informed that ICMR is the watchdog of bio-ethical practices in clinical research in India and had formulated guidelines as good as anywhere else in the world. ICMR had placed mechanisms to guide institutional ethical committees in matters of research if required.  There were also discussions about special situations such as research on vulnerable populations such as children, tribal and the underprivileged.

In a few weeks after the workshop, COVID-19 outbreak started unfolding. It was declared as a pandemic by WHO on 11 March 2020.¹ We were struck with shock and awe, as it was an unprecedented situation for all of us. Our institute played its part by creating a separate 500-bed COVID-19 hospital. We, as everyone else, were groping in the dark as to how we should treat our patients with this disease, as very little information was available. In this scenario, ICMR took a bold decision. On 23 Mar 2020, it recommended that health care workers (HCW) in close contact with COVID-19 patients should take a prophylactic dose of hydroxychloroquine (HCQ) weekly for 7 weeks.²   The advisory document suggested that both preclinical and clinical data had supported this strategy.

I remember, a couple of days later a junior colleague had asked me if he should start taking HCQ. I had hesitated for a while. As a professor, I am supposed to give an evidence-based reply, and I wasn’t aware of a single study where prophylactic use of HCQ was found to be useful. I knew that the rheumatologists frequently used HCQ for the treatment of rheumatoid arthritis and systemic lupus erythematosus due to its immunomodulatory actions. It is a close cousin of chloroquine (the antimalarial drug) and its antiviral properties have been known since 1990s, as it could inhibit viruses like HIV, Dengue, Ebola and SARS-1 in vitro.³ Its clinical safety profile was better than that of chloroquine (for long-term use) that can allow higher doses with fewer concerns about drug-drug interactions.⁴ A Chinese study demonstrated that chloroquine and HCQ inhibit SARS-CoV-2 in vitro and HCQ was found to be more potent than chloroquine. A small clinical trial conducted in Chinese patients, showed that chloroquine had a significant effect, both in terms of clinical outcome and viral clearance, when compared to control groups.⁵ Chinese experts recommended that patients diagnosed as mild, moderate and severe cases of COVID-19 pneumonia and without contraindications to chloroquine, be treated with 500 mg chloroquine twice a day for ten days.⁶ Another French study also showed that HCQ treatment was associated with significantly higher viral load reduction/disappearance in COVID-19 patients and its effect is reinforced by azithromycin.⁷ These trials have been on a small number of patients and do not really prove the efficacy of the drug beyond reasonable doubt.

Was this evidence enough to recommend this drug in a ‘prophylactic role’ in a healthy population of healthcare workers? That too for a disease with very low mortality in healthy young population? I was not sure. Since the ICMR recommendation had the backing of the Government of India, it was difficult to ignore. 

It appears that the apex body that supervises bioethical principles of all medical research done in the country, prescribed an unproven drug to thousands of healthy healthcare workers without even informing them of its real value. More explicitly, ICMR failed to disclose the experimental nature of prophylactic intervention (the results of which were going to be published later). The ‘participants’ were to report any side effects voluntarily and there was no provision to screen them for SARS-CoV-2 before, during or after the drug was taken. In a nutshell, it was a large, poorly designed, unmonitored human trial conducted without an informed consent.⁸,⁹

Meanwhile Lancet published a study that added a new twist.¹⁰ It concluded, “We were unable to confirm a benefit of HCQ or chloroquine, when used alone or with a macrolide, on in-hospital outcomes for COVID-19. Each of these drug regimens was associated with decreased in-hospital survival and an increased frequency of ventricular arrhythmias when used for treatment of COVID-19.” These conclusions suggested that we should be moving with great caution. In fact, WHO rapidly went on to drop an arm using HCQ from its studies on COVID -19 treatment. The media has been having a field day talking about HCQ. Before Lancet-COVID-19 paper ¹¹, US President Donald Trump had warned India that the US may retaliate if it did not export anti-malarial drug HCQ to the USA despite his personal request (07 April 2020).¹² Three days later Donald Trump described Prime Minister Narendra Modi as “terrific” for allowing the export of the anti-malarial drug hydroxychloroquine to the US.¹³

Soon after the Lancet-COVID-19 paper ¹⁴ was published, Indian Governmental agencies (CSIR, IGIB, CMI, ICMR) and several others severely criticized this study on HCQ as being misleading. They also urged WHO not to suspend trials with HCQ in COVID -19.¹⁵ An interesting criticism came from a journalist, “The study ignores zinc entirely. It’s not randomized.  It deals with very sick people and timing of hospitalization has not been mentioned.” He rounded it off by saying, “Even Donald Trump knows that HCQ is meant to be used with Zinc, so it is surprising that the medical researchers have not even mentioned it.”¹⁶ A statistician Peter Ellis, who is a chief data scientist at Nous Group, an international management consultancy, alleged that “the data behind that high profile, high consequence Lancet-COVID-19  study (about HCQ being ineffective) was completely fabricated”.¹⁷

The infamous lancet- COVID -19 paper has also brought ‘Surgisphere,’ (a relatively unknown company till Mar 2020) into limelight for orchestrating this study in 167 undisclosed hospitals. SS Desai, (one of the lead authors of the Lancet- COVID -19 study) is a cofounder of Surgisphere. (The company has not disclosed all its directors) The first author of the Lancet-COVID-19 paper ¹⁸, M R Mehra works at a hospital that regularly conducts Gilead initiated clinical trials for Gilead’s drug, Remdesivir for COVID -19.¹⁹

Some media reports have also highlighted the link (read funding) between the authors of Lancet-COVID-19 study and Gilead. The latter obviously benefits if HCQ is debunked as it was promoting Remdesivir (HCQ rival) for COVID -19 in a pandemic. In an open letter to Lancet, several shortcomings of this study have been highlighted by various scientists.²⁰ In face of severe criticism, the authors of the Lancet- COVID -19 paper, have retracted their publication from the journal.²¹ They also retracted another paper in New England Journal of Medicine (NEJM) about increased risk of in-hospital deaths related to the underlying cardiovascular disease in COVID-19.²² The Lancet and NEJM were considered very reputable journals, but this event has placed a big question mark on the peer view process being followed by the journals.

The same mistake may be committed by Indian Journal of Medical Research (IJMR), which is ICMR’s own journal and carried a good reputation so far. ICMR published the result of its own retrospective study (?‘trial’) of prophylactic use of HCQ in IJMR (paper received on 28 May 2020, published online 31 May 2020; Obviously no peer review!!!).²³ In this paper, a graph depicts dose response relationship between HCQ dose and proportion positive for SARS-CoV-2. It shows that 52% HCW had infection when HCQ was not taken. Infection rate climbs to 63% if 2-3 doses of HCQ were taken and falls to <20% if 6 or more doses were taken. The trend line has been drawn going downward with increasing exposure to HCQ. The study results seem to absolve ICMR by saying “Until results of clinical trials for HCQ prophylaxis become available, this study provides actionable information for policymakers to protect HCWs at the forefront of COVID-19 response. The public health message of sustained intake of HCQ prophylaxis as well as appropriate PPE use need to be considered in conjunction with risk homoeostasis operating at individual levels.” What is the veracity of ‘observational data,’ where neither the testing nor the adverse effect monitoring has been standardized and the data has not been made available in public domain? Would IJMR have published a similar paper from a second-tier town of India on the merit of its scientific content?

The question is – ‘Should ICMR feel vindicated by the retraction of Lancet and NEJM papers about COVID-19’? Does that prove that HCQ is effective? To add to the worries of ICMR, three more studies have shown that HCQ does not help.²⁴ This includes the RECOVERY trial from UK,²⁵ Post exposure prophylaxis trial from Barcelona,²⁶ and a meta-analysis of several smaller trials of HCQ.²⁷ This dims the chances that HCQ is going to turn out very effective in treatment or prophylaxis of COVID-19.

Does ICMR- COVID -19 paper prove anything? Has it been published just to support its decision to recommend HCQ? Was the decision to recommend HCQ political and not really based on science? While Lancet-COVID -19 paper²⁸ may be attributed to authors’ personal agenda, what is the reason for the odd behavior of our watchdog? The issue of HCQ efficacy may be considered subjudis, but the ugly influence of business and politics on science is already visible. Industry’s control on the science and professional medical associations due to its financial muscle are well known.²⁹,³⁰ Unbiased scientific opinion seems to be becoming a rarity. Unfortunately, we fail to realize that it is the unbiased science that can lead us out of this pandemic crisis.

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