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Why do we even know this?

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Prior to 19 March 2020, the antimalarial drug hydroxychloroquine was quietly doing pretty much what it had been doing for the previous 75 years.  Its antimalarial properties had been known for much longer.  Originally derived from the bark of the Cinchona Tree and sometimes referred to as “the Jesuit powder,” quinine – from which hydroxychloroquine is derived – was used by Europeans as a treatment for malaria since at least the seventeenth century.  In the 1940s, quinine’s use was greatly expanded to treat allied troops fighting in jungle conditions in the Pacific and Burma campaigns.  And then after World War Two, the chemical process of hydroxylation was used to develop the same hydroxychloroquine compound that is listed as one of the World Health Organisation’s “essential medicines” today.

Carry out a Google search for the drug with a custom date range which ends prior to 1 January 2020, and you discover an entirely uncontroversial medicine which has benefitted millions of people worldwide, and which has proved to have a surprisingly wide range of applications.  Crucially, while the drug has long been known to cause a change in heart rhythm in some patients, no heart-related deaths had been reported prior to 2020.

Hydroxychloroquine did however, have one highly controversial side effect.  In 2002 a novel, and deadly, coronavirus – SARS-CoV – began to spread.  Fortunately, human-to-human transmission of the virus was limited.  As a result only 774 people died worldwide.  Nevertheless, in the search for a potential treatment, Vincent et al carried out in-vitro (i.e. in a Petri dish) experiments to test the effect of hydroxychloroquine on SARS-CoV:

“Severe acute respiratory syndrome (SARS) is caused by a newly discovered coronavirus (SARS-CoV). No effective prophylactic or post-exposure therapy is currently available…

“We report, however, that chloroquine has strong antiviral effects on SARS-CoV infection of primate cells. These inhibitory effects are observed when the cells are treated with the drug either before or after exposure to the virus, suggesting both prophylactic and therapeutic advantage…

“Chloroquine is effective in preventing the spread of SARS CoV in cell culture. Favorable inhibition of virus spread was observed when the cells were either treated with chloroquine prior to or after SARS CoV infection.”

Beyond the virology research community, the paper had no impact at all.  After all, SARS had disappeared by the end of 2003, so the research seemed only to point to a treatment we might have used if only we had known about it earlier.  With SARS-CoV no longer circulating in humans there was no way of conducting even a small scale trial of hydroxychloroquine.  And so the whole thing was consigned to the medical databases; where it might have remained unseen if only SARS-CoV-2 had not put in an appearance in Wuhan province in the autumn of 2019.

Picking up on the 2005 Vincent paper, Wang et al reported similar findings in March 2020.  In in vitro research, both hydroxychloroquine and a new proprietary drug – Remdesivir – appeared to inhibit the spread of SARS-CoV-2.

It is, perhaps, the results of this research that US President Donald Trump overheard during one of the briefings with his public health officials.  Unfortunately, with the usual exaggeration, speculation and fabrication that Trump all too often employs, in a March 19 White House briefing he managed to give the impression that hydroxychloroquine was some kind of miracle cure which would halt the pandemic in its tracks.

From this moment on, hydroxychloroquine became central to both the national populist politics of Trump-supporters and the identity politics of the woke-right.  It was no longer possible for anyone to say, “let’s wait and see what the data says.”  If you were anti-Trump you had also to be anti-hydroxychloroquine.  If you were pro-Trump, you also had to be pro-hydroxychloroquine.  And if you were pro-data and reason then you found yourself on the receiving end of a shit storm from both sides.

At this point one of the most contentious issues in modern medicine entered the argument.  The “gold standard” for medical research is multiple, large-scale, controlled, double-blinded, randomised trials (RCTs):

  • Large-scale, because big numbers produce more accurate results.
  • Controlled, by having one group of patients take the drug and another group take a placebo.
  • Double-blinded, so that neither doctor nor patient knows who is taking the drug that is being tested.
  • Randomised, to ensure that the results are not rigged – for example by assigning less healthy patients to the placebo group.
  • Multiple, because the more times the research is successfully repeated, the more likely it is to be correct.

As of 19 March 2020, the only published evidence that hydroxychloroquine was effective against Covid-19 came from the two in vitro experiments.  Both fell a long way short of the gold standard for medical evidence.  This however, is not the same as “no evidence” – which became almost a rallying cry in the establishment media every time hydroxychloroquine was mentioned.

It may surprise readers to find that far more authorised medical interventions fail to meet the gold standard than those which do.  Surgery simply cannot be subjected to RCTs.  How could a trial possibly be double blinded?  If the surgeon doesn’t know what procedure he or she is to carry out, the patient would have to be a complete imbecile to proceed with the operation.  RCTs only really work with drugs.  But even here more of the drugs in use have not been subject to clinical trials than those that have.  For example, Fanaroff et al recently asked:

“What proportion of recommendations in current American College of Cardiology/American Heart Association (ACC/AHA) and European Society of Cardiology (ESC) guidelines are supported by evidence from multiple randomized controlled trials (RCTs)?…”

The answer was that out of 6,329 recommendations just 8.5% of US and 14.3% of European interventions were supported by multiple RCTs.  The same is true across medicine and for good reason.  RCTs are devilishly expensive.  In a 2019 article for Clinical Leader, Amit Rathore reports that:

“According to the study published in JAMA Internal Medicine in 2018, the costs of trials ranged from $2.1 million for a trial that enrolled four patients to test uridine triacetate for a rare hereditary metabolic disorder to $346.8 million for a noninferiority trial that assessed the impact of a new combination cardiovascular drug for chronic heart failure on hospitalization and cardiovascular mortality. The clinical trials cost a median of $41,117 per patient and $3,562 per patient visit.”

That’s a lot of money that someone has to come up with.  And there are only three potential sources:

  • Charitable foundations
  • Governments
  • Pharmaceutical corporations.

Of these, pharmaceutical corporations have by far the deepest pockets.  Indeed, in practice, trials sponsored by charities or government agencies often only progress when they can secure matched funding from one or more of the pharmaceutical companies.  This causes immediate problems in medical specialties where there is seldom a proprietary product for pharmaceutical companies to exploit at the end of the research.  And so treatments which are routinely used in healthcare settings are tested to a far less rigorous standard.

Most commonly in the absence of funds from the pharmaceutical corporations, researchers will employ a “new treatment v treatment as usual” model.  This has its flaws – it isn’t random, it cannot be blinded, and it may mistake correlation for causation.  Nevertheless, such results are regularly used as a basis for approving treatments; particularly where there are no safety issues.  We already know what happened with treatment as usual, and so if a tested intervention has better results (such as fewer deaths or faster recovery) it is worth pursuing.  This is especially the case with medicines which are already in use and which are known to be safe – for example, the now widespread use of aspirin as a blood thinning drug.

If, prior to 19 March 2020, you were a journalist looking to speak to a world-renowned expert in communicable diseases about Covid-19, one man stands out head and shoulders above the crowd.  With more than 3,000 published, peer-reviewed papers, Professor Didier Raoult from IHU – Mediterranean Infection would have been first on any credible list.  For his sin though, Raoult made the unacceptable political error of publishing his own preliminary findings on hydroxychloroquine as an early intervention against Covid-19 on 20 March 2020.  The English-language media went ballistic, portraying Raoult as some kind of crank conspiracy theorist – a process of ad hominim, and often racist, attack which would later be deployed against any clinician or researcher who suggested that hydroxychloroquine might have some role to play in the treatment of Covid-19.

Less obviously, around the same time an obscure, and previously dormant, Big Data research company was activated:

“The internet footprint of this company dates back to the registration of its website in March 23, 2007. However, this site would only be really active since March 2020… The website of the company gives the impression of only existing or of having activity since March 2020 and nothing between 2013 and 2020. A dormant activity… Twitter activity begins in 2013 and is almost zero until March 12, 2020.”

On 22 May 2020, the BBC triumphantly exclaimed that, “Trump drug hydroxychloroquine raises death risk in Covid patients.”  The story was repeated across the establishment media and shared with some glee by the woke-right on social media – as if the failure of a potential treatment for a pandemic virus that was killing millions worldwide was anything to celebrate.  According to the BBC:

“The Lancet study involved 96,000 coronavirus patients, nearly 15,000 of whom were given hydroxychloroquine – or a related form chloroquine – either alone or with an antibiotic.

“The study found that the patients were more likely to die in hospital and develop heart rhythm complications than other Covid patients in a comparison group.

“The death rates of the treated groups were: hydroxychloroquine 18%; chloroquine 16.4%; control group 9%. Those treated with hydroxychloroquine or chloroquine in combination with antibiotics had an even higher death rate.”

The obvious question this ought to have raised is why a drug that has been around since the Second World War, and which is widely used in the treatment of autoimmune diseases such as Lupus and Rheumatoid Arthritis, should suddenly start killing Covid-19 patients?  Less obvious to journalists – but apparent to the medical research community were questions about the data itself.  In Africa, for example, there were fewer confirmed cases of Covid-19 than there were deaths in the study.  For Australia there appeared to be more hospitals included in the research than there are in the country.

On 28 May 2020, Melissa Davey at the Guardian broke ranks with the establishment media:

“The study, led by the Brigham and Women’s Hospital Center for Advanced Heart Disease in Boston, examined patients in hospitals around the world, including in Australia. It said researchers gained access to data from five hospitals recording 600 Australian Covid-19 patients and 73 Australian deaths as of 21 April.

“But data from Johns Hopkins University shows only 67 deaths from Covid-19 had been recorded in Australia by 21 April. The number did not rise to 73 until 23 April. The data relied upon by researchers to draw their conclusions in the Lancet is not readily available in Australian clinical databases, leading many to ask where it came from.

“The federal health department confirmed to Guardian Australia that the data collected on notifications of Covid-19 in the National Notifiable Diseases Surveillance System was not the source for informing the trial.”

Far more damaging was an open letter to the editor of the Lancet from a long list of scientists raising serious concerns with the research and requesting urgent answers from the lead author and from the Big Data company which had provided the data.  Those answers were not forthcoming, and the Lancet was forced to retract the paper.  The equally highly-esteemed New England Journal of Medicine withdrew another paper by the same author and based upon the same fraudulent data.  In June, the University of Utah terminated the appointment of one of the paper’s authors.  Also in June the University of Zurich opened a research misconduct investigation into another of the paper’s authors.

Somewhat like a dormant bat virus waiting for the right moment to be activated, Surgisphere appears to have been set up more than a decade ago for the sole purpose of generating fraudulent data.  As Leonid Schneider at For Better Science (no lover of Donald Trump; he refers to him as a “fascistoid leader”) explains:

“This fraud case is being presently discussed in all the international news, literally every media is onto Desai’s shady past and the details of his Surgisphere fraud, some even figured out it might have been wrong to slam preprints as dangerous poison, while it is the peer reviewed papers in the two most highly ranking medical journals in the world which served us the biggest fraud and caused the biggest damage.

“This is why I want to discuss some other aspects proper journalists would never touch. Are the heart surgeons and principal investigators of those two high-impact studies, the Harvard professor Mandeep Mehra of Brigham and Women’s Hospital, and Amit Patel of University of Utah, really the innocent victims of Desai’s fraud here?

 “And would the NEJM paper be retracted if the fraud was not exposed by mass protests against its Lancet counterpart, which claimed a suspiciously high rate of mortality from hydroxychloroquine (HCQ) therapy against the coronavirus infection?”

Schneider’s point is that if Surgisphere had stayed away from the increasingly politicalised hydroxychloroquine debate, other fraudulent papers would have gone unnoticed.  Indeed, following the Surgisphere scandal we can only wonder how many other published research papers which provide the basis for medical interventions worldwide are actually based on fraudulent data.

The fraudulent Lancet paper was not, of course, the only research paper to rule out hydroxychloroquine as a potential treatment for Covid-19.  It did, however, set the narrative which the other negative papers were to follow.

As with any drug that has antiviral properties, if hydroxychloroquine was going to be effective, it had to be given early enough to prevent or slow the virus’ replication.  But the negative research almost invariably looked at the impact of hydroxychloroquine on people who were already hospitalised.  One such was the arguably negligent British “Recovery Trial,” which used shockingly high – 2,400mg – doses of hydroxychloroquine on hospitalised patients.  The overdose limit set by NICE for the average person is 500mg; anything exceeding that would be positively dangerous.

Asked about this, lead author Martin Landray made the claim that since Covid-19 is a new illness, there is no recommended dose.  True enough.  But it is surely reckless to exceed the recommended dose for other illnesses by quite this much.  Then at several points in the interview, Landray says that:

“The doses chosen are in line with the dosages used for other diseases such as amoebic dysentery.”

Hydroxychloroquine is not used as a treatment for amoebic dysentery.  The most favourable reading of this error was given in a tweet by US doctor James Todaro:

“France Soir releases part of the audio interview w/ Dr Martin Landray where he clearly bases HCQ dosing off treatment of amoebic dysentery (mentions it twice).  Landray also mistakenly thinks the lethal dose of HCQ is 10 times 2400mg (24 grams!).

“As unbelievable as it sounds, it appears the RECOVERY trial confused hydroxy*chloroquine* (HCQ) w/ the drug class hydroxy*quinolines*”

It appears that Landray read the wrong entry in the (alphabetical) British National Formulary, and used the dosage for the entry adjacent to hydroxychloroquine.

And so, once again, a study which allows us to “know” that hydroxychloroquine doesn’t work proves to be at best poorly designed and at worse, intended to harm the patients being treated.  No wonder conspiracy theories gain credence.

But why is anybody studying hydroxychloroquine in the first place?  After all, Trump often spews nonsense at press conferences and on his twitter feed; like the time he suggested that injecting bleach or inserting ultraviolet light into someone’s rectum might cure Covid-19… but nobody is carrying out research into those.  Susan Brink at NPR goes even further:

“President Trump may be the most high-profile head of state promoting untested approaches to the coronavirus, but he is not alone on the world stage. Early in March, China’s National Health Commission included some traditional Chinese medicine cures on a list of potential treatments for COVID-19. One of those traditional products is tan ri qing, an injectable medicine containing bear bile. Also in March, a top health minister from Prime Minister Narendra Modi’s Hindu nationalist party told reporters that ‘spending 10 to 15 minutes in the sun can provide vitamin D, boost immunity and kills any kind of virus.’

“Madagascar’s President Andry Rajoelina, according to multiple news reports, has promoted an herbal drink called Covid-Organics, which contains artemesia, a bitter root sometimes used to treat malaria. ‘Tests have been carried out — two people have now been cured by this treatment,’ Rajoelina said at the launch of Covid-Organics at the Malagasy Institute of Applied Research, which developed the tonic, according to the BBC.

“Other world leaders, including Serbia’s President Aleksandar Vucic and Belarus’s Alyaksandr Lukashenka, have made off-the-cuff comments pondering whether drinking vodka and other alcoholic beverages might help. And Mike Sanko, the governor of Nairobi, Kenya, has gone even further in his speculation about alcohol by including bottles of the cognac Hennessy in coronavirus relief packages, saying on Kenya’s Citizen TV, ‘I think from the research it is believed that alcohol plays a very major role in killing the coronavirus.’”

Nobody has taken these other suggested “treatments” seriously enough to begin clinical trials.  But someone, somewhere, had enough of a vested interest in hydroxychloroquine to put up the funding for several trials – including the entirely fraudulent Surgisphere one.  And it is negligent at least that, having paid that money, the research turned out to be so poorly designed.  As France Soir pointed out in June, it is probably just a coincidence that pharmaceutical company Gilead Science – whose Ebola drug, Remdesivir, stands to make a fortune if it proves to be an effective treatment for Covid-19 – has close financial ties to the various people involved with the hydroxychloroquine research.  Not that Big Pharma would do anything so conspiratorial as to directly bribe a researcher into faking research to undermine a competitor.  That is not how Big Pharma operates.  Nevertheless, as Leonid Schneider points out:

“This is the crux bigwigs in medicine have to bear, like the Harvard professor Mehra [the lead author of the fraudulent Lancet paper]. People keep inviting you to put your name on their paper without any contribution, and you just cannot satisfy all, so you only go for top-ranked journals, like NEJM and Lancet, because those would bring you the biggest share of academic fame, political influence and personal financial enrichment. That is the most charitable explanation of what Mehra did…”

In Modern academia there are enormous pressures to publish as many peer-reviewed papers as possible; particularly in the most highly esteemed journals.  Failure to do so can cost you your job.  Next to this, bringing in money – no matter how tainted – from the state or the private sector, is the best way of bolstering one’s position.  To be offered more or less guaranteed publication in the world-leading Lancet and New England Journal of Medicine, and funding for future clinical research is probably more than even the saintliest academic could resist.

We cannot though, infer from the dubious anti-hydroxychloroquine research that the drug is effective.  That is not how science works.  We still need large-scale RCTs for hydroxychloroquine (with and without zinc and azithromycin) as an early intervention – i.e., prior to hospitalisation – for Covid-19.  But nobody with access to the necessary funds has an interest in carrying out such research.  Moreover, in the litigious age that we live in, everyone who previously engaged in undermining hydroxychloroquine, including the establishment media, now has a big financial interest in preventing such research from ever being conducted.

And so the proponents of hydroxychloroquine are left with a growing volume of silver and bronze standard evidence upon which to base their claims.  This is not – as the establishment media would have you believe – “no evidence.”  It is just not the evidence one would ideally generate if only one could persuade a pharmaceutical corporation to stump up the $41,000 (£31,240) per patient needed for a large RCT.

In fact, some of the population-level data is persuasive.  Countries which routinely use hydroxychloroquine as a treatment for Covid-19 have far fewer deaths than those which don’t:

The case of Switzerland is even more persuasive.  Switzerland had been using hydroxychloroquine as an early intervention for Covid-19.  But following the Lancet paper, the Swiss authorities banned its use on 27 May.  Thirteen days later, the case fatality rate rose.  And on 11 June the Swiss authorities ended the ban.  Thirteen days later, the case fatality rate reverted to its earlier level:

Again, none of this is “proof” that hydroxychloroquine works.  It is, however, evidence which disproves the emphatic media claim that there is “no evidence” that hydroxychloroquine works.  Medicine is all too often inconclusive in this way.  As are anecdotal positive results observed by frontline doctors.  Nevertheless, as Harvey A. Risch, Professor of epidemiology at Yale School of Public Health points out:

“In the future, I believe this misbegotten episode regarding hydroxychloroquine will be studied by sociologists of medicine as a classic example of how extra-scientific factors overrode clear-cut medical evidence…”

Biggest of all among those “extra-scientific factors” is the dead hand of Big Pharma, whose own treatment is a mirror image of the treatment meted out to frontline doctors and small-scale independent researchers.  When (less than gold standard) clinical trials of the proprietary drug Remdesivir found that the drug failed to save a single life, and – if a Chinese trial of the drug is correct – may even have hasten the deaths of a few patients, Trump’s chief medical advisor Anthony Fauci obligingly moved the goalposts.  Saving lives was no longer the criteria for approval.  All that was required was that Remdesivir (but not any other generic drug) simply shorten the time that survivors remain in hospital by a couple of days.  If hydroxychloroquine was permitted the same leniency, it would now be available as an over-the-counter medicine.

If only Donald Trump had kept his mouth shut on 19 March, the excessive and potentially life-threatening political divide around hydroxychloroquine might never have opened up.  On the other hand, if the politics had not become so heated, we would have never witnessed the public outing of supposedly respected medical journals like the Lancet and the New England Journal of Medicine publishing “citebate” (see pages 310-11) papers based upon fraudulent research, generated by a fake Big data company to discredit a cheap generic drug.  Nor would we have witnessed the obvious double standard applied to generic drugs by officials with a financial stake in Big Pharma companies which get a free pass when it comes to RCTs.

Irrespective of whether hydroxychloroquine is proved or disproved to be an early intervention for Covid-19, when the inevitable inquiries into various aspects of the pandemic and its handling get underway, we can only hope that Big Pharma does not get another free pass.  Medical research has been a contentious issue for decades, as pharmaceutical companies have a long track record of hiding negative results and overstating benefits; often at enormous cost to both patients and governments.  What this latest affair has added is the apparently deliberate sabotaging of cheap generic alternatives to the proprietary drugs which they hope to benefit from; together with the inevitably corrupting relationship between academic researchers, medical journals and the pharmaceutical companies which currently stump up the funds for almost all of the RCTs which are conducted.

Maybe it is time to have a serious discussion about how we know what we think we know; and about how we fund medical research in future.

As you made it to the end…

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