Hydroxychloroquine (HCQ) has been in the news for more than 3 months. I have been keeping a close eye on what’s happening for the whole time. Now I feel compelled to write down my thoughts on it and now that there is reasonable direction as to where this is headed, I feel confident speaking about it. The HCQ saga proves why politicizing science and research is a very bad idea. In a state of panic, even doctors and scientists can become polarised. Bias creeps in even if unintentional.
When the first study which set off this focus on Hydroxychloroquine- A study headed by a maverick French researcher, Didier Raoult, I was excited as well. My first thought was if HCQ with Azithromycin (AZY) worked so well, why were Italy and Spain struggling to control the case numbers as well as deaths. The US cases and deaths hadn’t unravelled yet. Later reading the full text of that article kind of dampened my enthusiasm further. Any study which claims 100% efficacy should be looked in quite suspiciously. Fortunately, a whole lot of scientists called out the poor study design as well as fraudulent data that study was allegedly based on. The full details of the exposé is available here- Chloroquine genius Didier Raoult to save the world from COVID-19
The gist of this very long counter-article was that data was manipulated in that sensational paper, it wasn’t a Randomised Controlled Trial (RCT), the primary author has had a long history of faking data in his papers and has been banned from publishing in certain journals. But the damage was done.
But when US President Donald Trump started promoting it in his twitter feed and press briefings, shit hit the fan literally! The fake news became political and took a life of it’s own. The idea that we have found some miracle drug against COVID-19 started taking root. Whether it would work would be determined by whether love or hate Donald Trump and not science. Pharmacies all over the world were running out of this humble, cheap and very old anti-malarial drug. Of course in the US and elsewhere, it took off with some physicians using it off-label to treat very severe patients with COVID-19. Many researchers and institutes started trials with HCQ with or without AZY to test the assertion. The damage done by Didier Raoult had far reaching effects.
In India, Indian Council of Medical Research (ICMR) published guidelines on 23rd March, 2020 recommending HCQ as a prophylaxis for healthcare workers based on a few in-vitro studies. This is the same as recommending drinking cow urine to cancer patients because cancer cells in a Petri dish are killed when cow urine is added. However, the medical fraternity in India was unfazed by this absolute lack of evidence in these guidelines and started recommending it to everyone. In no time it became viral across all doctor whatsapp groups and even some family groups with doctors. All healthcare workers and even many lay citizens started raiding pharmacies for HCQ. Everyone were consuming HCQ like it was candy. The risk of serious cardiac side effects was downplayed and what is worse is that not even an ECG was recommended before starting the dubious prophylactic treatment protocol. ICMR has since extended the use of HCQ to care-givers of COVID-19 patients in home quarantine-this being a mandatory condition.
My issue with ICMR is not that they are issuing guidelines for taking HCQ but being a scientific body they should have the ethical responsibility to provide evidence and rationale for their recommendations. If there is not sufficient evidence, they should to be upfront with the level of evidence they are basing it on. Also while recommending mass intake of a drug with serious side effects-even if a very small chance of it occurring- they should warn that it shouldn’t be taken without proper medical supervision. Instead, ICMR has not provided raw data and they keep asserting that HCQ works- against the grain of all studies done elsewhere around the world. As if Indians have HCQ receptor genes which are missing in the rest of the world. Finally on May 31st the ICMR released a observational case-control study in their own in house journal (IJMR) demonstrating benefit of HCQ prophylaxis for COVID-19-again without any raw data provided. Media had a field day with it. The purpose of such a paper was served. Given the fact that the authors of the study have a conflict of interest where some of them are in the editorial board of the same journal, the peer review process is suspect. Case control studies in any case without a placebo group is not enough evidence to conclude on the benefit. Anyone in academia would know that for a fact and I’m very sure the eminent scientists in ICMR also know this. However, this poor evidence was allowed to be used to increase the scope of HCQ prophylaxis on more groups of people in the frontlines. When doctors prescribe medicines to patients there is always a cost benefit analysis done by the doctor. When there is no evidence of a drug showing benefit in prophylaxis of a disease, the side effects even if very small is not acceptable. Cost to benefit ratio is too high.
In the last few days, we’ve had randomised controlled trial of HCQ as a post-prophylaxis use was published in New England Journal of Medicine (NEJM) which was even double blinded. An RCT is the most robust form of evidence available in science. It didn’t show any benefit of HCQ as a prophylaxis for covid-19! There are limitations to this study and it has been pointed out in the editorial of the same journal issue. One should also never make conclusions from only 1 study and I’m sure there will be more such studies which will build evidence for or against. Meta-analysis of several such studies put together will finally answer the question of whether HCQ will be useful or not in the treatment or prevention of covid-19. There is literally no other way to know till then.
The problem now is that even if multiple serial studies (including RCTs) and their meta-analysis conclusively prove that HCQ is not beneficial for either prophylaxis or treatment – the converts among the doctors/scientists will refuse to believe in it. The reason is that their critical thinking has been poisoned by panic and politics.
I should also mention about the scientific fraud and lack of integrity in research from the other side of the HCQ debate. Respected journals like The Lancet and NEJM published papers sourced from a shady US based data company called Surgisphere. When these allegedly fraudulent studies based on possibly fake data came out, WHO stopped trials on HCQ (which have since resumed). Many countries changed policies regarding HCQ use in COVID-19. Again the scientific rigor in taking decisions which determined public health worldwide was missing from a veritable institution like WHO. WHO’s poor handling of this pandemic has already lowered it’s credibility even before this event. The Guardian did an excellent piece of investigative journalism which tracked the antecedents of Surgisphere. Surgisphere: governments and WHO changed Covid-19 policy based on suspect data from tiny US company
It is indeed a shame that such reputed journals do not have the institutional mechanisms to detect scientific fraud. There are insinuations that there was an agenda to discredit a cheap drug like HCQ so that the value of other potential anti-viral drugs in clinical trials now-will have better value. The proponents of this theory will get more ammunition now.
On 5th June The Lancet retracted the controversial article. The NEJM followed suit and retracted another paper (a COVID-19 based but not an HCQ study) based on data sourced from the same data analytics company-Surgisphere with some of the same authors of the Lancet paper (Dr. Mandeep Mehra and Dr. Sapan Desai). This has done irreparable harm to the trust researchers and public have with these reputed journals. The editorial boards of both journals should reflect on the quality of peer review and there should be accountability from those responsible for this fiasco. Heads should roll. The silver lining of this whole episode is that the scientific fraud was detected early and retraction swift. Actual functional damage has been limited only to reputation. It is heartening to see critical thinking scientists still questioning reputed journals. Always question is a golden rule in science.
On the same day the chief investigators of the Recovery trial put out a statement on 5th June saying that their preliminary data shows enough evidence of “no clinical benefit” and hence ethically they are duty bound to stop recruiting patients for the HCQ wing of the trial.
The same HCQ story is being played out with ivermectin and azythromycin as well. ICMR is again guilty of formulating advisories without scientific evidence backing it or at least being transparent about it. Both ICMR and the Roult group that started this whole mess has provided as evidence only poorly conducted case control studies or/and cherry picking of convenient data to suit their conclusions. Scientists should do better than that.
The HCQ studies suffers from the Burden of proof fallacy. The burden to prove that HCQ doesn’t work has been placed upon the scientific community rather than for the claimants to prove that it indeed works. If I had to make a common place analogy to this problem- How do you prove “God doesn’t exist”?
I can understand the allure of HCQ. It’s cheap and non-patented. It can be mass produced and distributed along existing eco-systems. It has been used for more than 6 decades with a predictable safety and complication profile. The idea that India would have a near monopoly in the production of “a miracle drug” is attractive especially when world leaders were begging our Prime Minister for HCQ supplies. This pandemic was a jolt from our comfort zones. Most of the medical and scientific community hadn’t prepared for the enormity of the problem and when such an easily available drug was marketed as a miracle drug by political leaders and used as a tool to make political brownie points- science took a back seat and critical thinking was thrown out of the window. Panic and politics set the tone for further course rather than science leading the way.
The scientific community should be embarrassed that they lost their nerve in the middle of a pandemic. In the race to publish new papers due diligence like peer review and data congruence was ignored by the editorial boards of both the journals involved in the scandal. ICMR leadership too is doing a disservice to scientific thinking in public health policy. Their obscurantism of the HCQ question by publishing vague non-scientific studies actually keeps the world from knowing if HCQ works or not for sure. One can only imagine the number of good quality studies on HCQ that was possible in India given the amount of data ICMR would have at it’s possession. We would have been at the forefront of answering scientific questions for this disease. Alas, it was not to be!
In these polarising times, it is easy to look at my views as political agenda driven. I would be the first person rooting for HCQ to somehow get back in the race for the cure for COVID-19. But evidence is sacred and there cannot be any compromise in science.
In the end, the onus is on clinicians and scientists to interpret findings of scientific articles and take a critical view of data and it’s conclusions. Despite the human factor in research not everything is over now. Humans are fallible but data is god in research. Science will eventually win- even if sometimes it feels that people with agendas are undermining it. However, I’m not so sure that politics will never again affect science and research.