Editorial: Part 3 of this Cochrane sequence follows on from last week’s Data Based Medicine.
While the histories of randomized controlled trials (RCTs) celebrate a first use of randomization in 1947, and there was some use of RCTs, primarily in mental health, in the mid-1950s, RCTs were a minority interest until 1962 and might have remained so, never giving rise to Evidence Based Medicine (EBM), but for an accident.
In 1956, no-one knew much about the limitations of RCTs or the harm they could do, when Louis Lasagna suggested that in addition to checking if drugs were safe, FDA might want – as a contribution to safety – to check and see if drugs worked. He had just come across RCTs, was enthusiastic about them and figured they might be a way to check for effectiveness. He repeated the suggestion at the Kefauver Hearings on the pharmaceutical industry in 1960. No one paid any heed to him.
In the wake of a public relations crisis triggered by “irresponsible” media reports in the US in July 1962, about a drug that had been shown in an RCT to be effective and safe, the US political class felt obliged to be seen to do something. The doing involved adapting the wording of the 1938 FDA Act from an Act to ensure the Safety of Drugs to an Act to ensure the Effectiveness and Safety of drugs.
After some head scratching and political horse-trading it was decided with input from Lasagna that effectiveness would be determined by having two positive placebo-controlled trials. The assumption was that a positive RCT inevitably meant any other RCT would be positive; this shows how little people knew about “RCTs” then.
The system that had failed to detect the problem with thalidomide – RCTs – was put in place and sold as a way to prevent future problems. Nobody involved in putting this system in place knew what they were doing – there was no conspiracy. But once RCTs became the gateway to the market, those affected – industry – were incentivized to understand the new system better than anyone else.
Three sequelae of this development can be noted briefly. One is that it has led to large scale consumer “fraud” – it’s hard to find the right word for this particularly to cover the role of regulators in what happened. Since 1963 a large number, perhaps a majority, of drugs have been licensed on the back of demonstrations of efficacy where the statute calls for Effectiveness. They have been licensed on the basis of a change in a rating scale or bone density or lipid levels brought about by drugs which in some instances kill people early or disable them more than non-treatment would have. This is not Effectiveness.
A second is that as RCTs became the gateway to the marketplace, they began to be produced on an industrial basis – both in terms of quantity and quality. The number of industry “trials” or as they have been sometimes called “assay systems” dwarfs all others. Industry assays are conducted by assembly lines, involving CROs and ghostwriting, a process that Cochrane has helped facilitate with acceptance of industry assays as equivalent to medical RCTs. If an assay/trial ticks the myriad quality control boxes Cochrane has helped put in place, then content and motivation are apparently irrelevant.
The third is that almost instantly – by 1964 – industry salesmen began pushing docs to prescribe according to the evidence. “The latest RCT shows this doc!” This has continued ever since with industry to the forefront of pushing docs to adhere to evidence-based medicine.
The fourth sequelum was linked to safety.
RCTs are the gold standard way to hide the adverse effects of drugs. All RCTs are dangerous as a result. Some can also make a contribution to safety. This they do when they show treatments don’t work. A negative trial may get the “wrong” answer but it puts the onus back on those who want to profit from the misery of people at their most vulnerable to work out a way to identify who specifically might be helped by what is usually a MeToo drug.
Whether industry assays or medical trials, RCTs compromise safety by focusing on a primary outcome – does this drug “work” – rather than on the 99 other things that drugs can do. This act of hypnosis leads industry RCTs to suggest that, for instance, 5% of people on an SSRI have sexual dysfunction when effectively 100% do.
But industry assays are additionally biased in that the primary outcome is something we can make money out of – a change in mood – while something that might be much more common – an effect on sex is ignored. Or the far more common effects of statins on muscles or cognitive function are ignored while the rare effects of preventing a cardiovascular event are focused on. Or the possibly more common effects of HPV vaccines in causing POTS or other auto-immune phenomena are ignored in favour of the likely rarer numbers of women saved from cervical cancer.
Ignoring this ignoring, as claims about RCTs – they give us the most reliable information there is about drugs – do, turbo-charges this business interest.
Throw in some pixie dust – any side effects there might have been cannot by definition be statistically significant (statistical significance only applies to primary outcomes) – and the chances of an RCT making any contribution to safety completely vanish. Just to be safe, we can add some more pixie dust – any case reports of an adverse effect on treatment are just anecdotes, the lowest possible form of evidence.
There has, as a result, effectively been no adverse effect of a drug that has come to light because of an RCT. Doubtless some readers will be able to prove the rule by naming a few exceptions but its hard work to find them.
Until a recent belated involvement of Peter Gotzsche in the SSRI and suicide issues, and now Jefferson, Gotzsche and colleagues in the questions of HPV vaccine safety, Cochrane has made no contribution to detecting adverse events. Forty-thousand people and 25 years later, I can’t name a single adverse event emanating from Cochrane, and no-one from Cochrane has ever taken a stand on safety issues until now.
Even Doshi and Jefferson’s justly famous analysis of Tamiflu trials centered on the lack of efficacy of this drug rather than its adverse effects.
1/ As the detection of or engagement with an adverse effect runs against industry’s and medicine’s business interests, controversy is inevitable. Gotzsche and Jefferson’s engagement with the adverse effects of HPV vaccines and the resulting debacle brings this home.
This controversy has disrupted a vision Cochrane has sold – that the value neutrality of RCTs meant that the lion of science can lie down with the lamb of industry. This is not an option. Under the current rules of the game, it is still the case as Thorsten Veblen said over a century ago in the Theory of Business Enterprise, that the pharmaceutical business needs to keep its scientists in check.
Under the current rules of the game, however, as high cost prescribers, doctors risk going out of business if drugs are wonderfully effective and free of side effects. Nurses and pharmacists are a much cheaper, and a more readily forceable to be guideline adhering, option for governments, and managers.
2/ Beyond the structural features of RCTs noted above that pose a threat to safety, an even greater risk comes from the selling of efficacy. In a risky world, who wants to balance risks? Better to nuke ‘em.
The debate about guns in the US in the wake of school shootings brings the point home. We want to make schools safe. Guns are effective, why not have an armed guard in each school? A lot of people figure this can’t be right but get stumped by the follow-up question – well if you don’t agree, do you think we should remove armed guards from the White House also?
Philippe Pinel offered the definitive answer to this question two centuries ago when he said (paraphrasing) that it’s great to have effective weapons but it’s even greater art to know when not to deploy these weapons.
It didn’t occur to Pinel to offer a view about a weapon that had efficacy (bullets come out the barrel but cannot be stopped from going anywhere even backwards?) but not effectiveness. Readers are invited to offer an update on Pinel to take this into account.
As a result of Cochrane Based Medicine, we have lost the subtlety and nuance that Pinel put at the heart of clinical medicine. Cochrane have us put an armed guard at every school door. It has institutionalized a split between effectiveness and safety that leaves us with no other way to grapple with the problem of school shootings.
The headlines on BBC today are about falling British Life Expectancy. All sorts of people are piling in blaming austerity and inequality.
Nobody so far has mentioned the fact that 50% of us over the age of 45 are on 3 or more drugs and 50% of us over the age of 65 are on 5 or more drugs – none of which are safe and very few of which offer an effectiveness to balance the risks we take in consuming them.
It’s a modern day repeat of the Charge of the Light Brigade.
theirs is not to make reply,
theirs is not to reason why,
theirs is but to take and die
into the valley of death….
Copyright © Data Based Medicine Americas Ltd.
This poem was written to memorialize a suicidal charge by light cavalry over open terrain by British forces in the Battle of Balaclava (Ukraine) in the Crimean War (1854-56). 247 men of the 637 in the charge were killed or wounded. Britain entered the war, which was fought by Russia against Turkey, Britain and France, because Russia sought to control the Dardanelles. Russian control of the Dardanelles threatened British sea routes.
Many in the west best know of this war today because of Florence Nightingale, who trained and led nurses aiding the wounded during the war in a manner innovative for those times. The War was also noteworthy as an early example of the work of modern war correspondents.
The Charge Of The Light Brigade
by Alfred, Lord Tennyson
The Charge of the ‘Light’ Brigade and the Valley of ‘Death’ and ‘modern war correspondents’
Cannon to right of them,
Cannon to left of them,
Cannon behind them
“Nobody so far has mentioned the fact that 50% over the age of 45 are on 3 or more drugs and 50% of us over the age of 65 are on 5 or more drugs…”
Of course, James Le Fanu has been mentioning this quite a lot but you may not hear it on the BBC News.
“Whether industry assays or medical trials, RCTs compromise safety by focusing on a primary outcome – does this drug “work” – rather than on the 99 other things that drugs can do. This act of hypnosis leads industry RCTs to suggest that, for instance, 5% of people on an SSRI have sexual dysfunction when effectively 100% do.
Throw in some pixie dust – any side effects there might have been cannot by definition be statistically significant (statistical significance only applies to primary outcomes) – and the chances of an RCT making any contribution to safety completely vanish.”
I don’t follow this. How does focusing on a primary outcome mean that RCTs suggest 5% of SSRI users have sexual dysfunction when really 100% do? And in what way does statistical significance only apply to primary outcomes? Thanks.
I guess Tennyson actually admired the Light Brigade for loyally following orders:
But tho’ the soldier knew
Someone had blundered
Not so Pete Seeger, who had some very different advice for Our Troops:
Waist Deep in the Big Muddy (1967)
A WWII captain orders his platoon to ford a river — and keeps ordering them to “Push On” as they sink deeper and deeper. When the sergeant tries to object, the frustrated captain takes the lead, and promptly drowns. The troops turn around, and live. (The song was rumored to have something to do with the Vietnam War. Gosh, I wouldn’t know.)
The final verse:
Well, I’m not going to point any moral
I’ll leave that for yourself
Maybe you’re still walking, you’re still talking
You’d like to keep your health
But every time I read the papers
That old feeling comes on:
We’re — waist deep in the Big Muddy
And the big fool says to push on!
I don’t think there is any doubt that Tennyson was genuinely horrified, and though no social revolutionary – more Whig progressive – his poem did place a question over the military caste. Unfortunately, it didn’t stop the Somme six decades later. The lesson we learn is that no lesson is ever learnt, or if it is the wrong people who learn it.
Statement from Cochrane’s Governing Board – 26th September 2018 | Cochrane
Video of Cochrane’s Annual General Meeting 2018
Let’s talk about – THE ELEPHANT IN THE ROOM – that is is how one of the members insisted on asking the question everyone was most concerned about after the chair tried to start shutting down the meeting – a question amongst a whole lot of very critical questions aimed at the way Peter G and colleagues have been treated by the trustees – including that members are still being kept in the dark about proceedings by a board which promotes transparency in other areas but not it seems in their own dealings. There was also an attempt to shut up Peter .G himself up when he began speaking about the ‘show trial’ rather than just accepting oblique references made about him by the trustees. There was a suggestion that the whole board resign – any bets on that happening? Instead it seems the same group will be drawing up new codes and complaints procedures That will be interesting considering the fiasco they’ve generated already. Video of Annual General Meeting 2018 begin at 1:10:25
[…] The Valley of Death […]
Plataforma NO GRACIAS
Car Salesman meets Doctor ..
September 29, 2018
The Cochrane board votes to expel Peter Gotzsche
The reconstituted board was scheduled to meet as The Lancet went to press, when Gøtzsche’s appeal will presumably be decided. Cochrane says that it will be in a position to make more information available after this meeting.
Some people are beginning to question whether the board can survive. “I think we need a fresh start”, said one insider. “This whole thing has done a lot of damage to Cochrane; the only way to regain trust will be to replace the entire management board.”
Not at the 2018 AGM?
Peter is that you
I’m the no longer existing Cochrane collaborator…
Peter C. Gøtzsche’s comments on:
Statement from the Cochrane Governing Board about alleged bad behaviour of “one individual”
Just watched the video, Susanne, and they expected Peter Gotzsche to just sit there and take all that.
How humiliating, and he was then accused of making ‘serious allegations’…
What a ‘Show Trial’ with ‘pointing of fingers’ …
Prof. Peter Gøtzsche
Russian methods in Cochrane headquarters: tampered with our website behind our backs. Nordic Cochrane Centre withdrew from Cochrane Collaboration yesterday.
#sundpol (link: http://www.deadlymedicines.dk) deadlymedicines.dk
5:06 am · 29 Sep 2018
Cochrane in moral downfall
17 September. David Healy: Cochrane Cock-up.
Front page of the website for the Nordic Cochrane Centre 26 September 2018: (after Cochrane headquaarters had tampered with it behind ouar backs
a clearer view of the cochrane mess,
Peter C Gøtzsche
October 1, 2018 at 2:54 pm
It is strange to see so many false statements in so little space, by co-chair of the Cochrane Governing Board Marguerite Koster. I recommend people to look up http://www.deadlymedicines.dk where the events are described in chronological order.
Contraty to Koster’s statements, the lawyers report exonerated me about the issue of using my centre’s letterhead (12 September B. Counsel’s report, which exonerates Gøtzsche from all charges).
I did not breach confidentiality and violated my responsibilities as a member of the Board after 13 September, as Koster claims. Since I was expelled from the Board on 13 September, I had no obligations towards the Board, and I needed to defend myself against the show trial I had been exposed to.
It is blatantly false when Koster claims that the decision to expel me had nothing to do with my criticism of the Cochrane review of HPV vaccines. It had a lot to do with this (look up 17 September F).