Marilyn’s Curse

Editorial Note: This an unexpected eighth part to the Lasagna Trilogy that started with Not So Bad Pharma and runs through to Witty A: Report to the President.

Ondine

Ondine was a nymph whose lover swore that his every waking breath was a testimony to his love of her. Finding him unfaithful, she cursed him – should he fall asleep he would stop breathing.

Marilyn died of an overdose of barbiturate sleeping pills (Tragedy). A bystander, Lou Lasagna, noted she had been denied access to a sleeping pill that was safe in overdose, the first pill of any sort that had been proven to work and be safe in an RCT before it was marketed. She was denied by doctors who put more weight on uncontrolled clinical observations than RCT data. As she died, she uttered a curse. Life went on. At first Lou noticed nothing but over the years his horror grew (Empire 1, Empire 2).

Fishers

In the Spring of 1926, Ronald Aylmer Fisher, a lifelong smoker and denier of the idea that smoking might cause lung cancer, undertook some studies on the effects of fertilizers on seed growth in some fields outside Cambridge. Many factors could confound the results of a fertilizer study from differences in soil drainage, to the angle of the incident sunlight, exposure to wind and a myriad of soil elements that could only be guessed at. Fisher hit on a way to control both known and unknown confounders – he randomized the fertilizer to alternate seed and soil patches. And so the randomized controlled trial (RCT) was borne.

Fisher tied significance testing to RCTs. If we got the same result every time, we had designed a good experiment. There was a Quod Erat Demonstrandum quality to this – shave a bit off one side of a coin and you can expect heads to come up nineteen times out of twenty. He was looking for something close to a Euclidean Theorem – if you understand something the results will almost always be the same. But this insight on what Fisher meant by statistical significance, like most things about RCTs, has been inverted or perverted.

In 1947, Bradford Hill applied Fisher’s randomization to testing whether claims made for the efficacy of streptomycin for tuberculosis held up. He didn’t discover that streptomycin worked – others had done that in laboratories and clinics. But against a background of desperation and false claims, he showed that this time the claims could not be dismissed.

The RCT tide came in quickly after that and by the mid-1960s Hill noted that drug company salesmen ironically were encouraging doctors to use our products based on RCT evidence. While believing RCTs had a place in medicine, Hill noted that if RCTs ever became the only way to evaluate drugs that the pendulum would not just have swung too far it would have come off its hook.

Pharmers

RCTs have since been fetishized – made into a Golden Calf. Few can see any problems with bringing the rating scales and other measuring tools linked to them into clinical care – to make it more scientific. But just as with Midas, the touch of Gold brings death not benefit.

The pendulum has not just come off its hook, Pharma has picked it up and is battering people and governments over the head with it. We have recently had the close to degrading spectacle of the UK government in a parliamentary committee touting for Pharma “clinical trial business” and being told by GSK and Roche that UK clinical practices are just not Pharma friendly enough.

In this battering of people and governments, Pharma’s most useful allies are the proponents of Evidence Based Medicine, who insist clinical trials are if not the only way forward then by far the most useful way. RCTs, they indicate, would be just perfect if trial design was taken out of Pharma’s hands, if we had a registry of all trials done, and if we were let have a Witty-style peek at the data from time to time. It’s this fetishing of trials by independent academics that gives Pharma its grip over US and European governments.

Mediculture or medicine?

For 80 years we have unthinkingly celebrated Fisher’s apparent managing of confounders. Many trumpet the ability of RCTs to demonstrate cause and effect. Few accept that these trials are simply association studies with a particular method for controlling confounders. Few guess that there are more disturbing problems.

Let’s return to whatever image an agricultural field outside Cambridge conjures up in your mind. Using her FishCam, Crusoe watched Fisher weed his patches of Rye, exclude all stones, meticulously ensure each of the A patches was the same size as the B patches and got the same amount of seed. After days of preparation, he allocated the fertilizer randomly and headed home to his pipe. (For more on Crusoe see The Girl who was not Heard). She saw him check the patches weekly and then on the night of June 1, just as the first plants were sprouting, she saw a Sprite arrive and sprinkle Pixie Dust on Fisher’s handiwork.

Some weeks later when there was clearly much more Rye growing on the A than on the B patches, and the Rye on B was moldy, she saw Fisher race out to invest in Company A shares.

Using her Sprite tracking App, Crusoe locates where the imp dwells and while he is out one night creating mischief, she sneaks into his tree-house, finds the bag containing the Pixie Dust, steals some and brings it home to analyse. And for good measure she borrows a pretty pink envelope lying beside it.

The Dust contains a mixture of MM Rye and MM mold. She opens the envelope and finds a message: If you chant these words on scattering the supercharged Rye will all land on the A patches and the mold on B:

‘Norma-Jeanne thou art, Marilyn thou wilt be, and Queen of Camelot hereafter’.

Crusoe concludes that this can never happen in agriculture and there is no need to warn Fisher he’s at risk of losing his money. But she sees that this can and must happen in medicine, and that it won’t be spotted because medicine is a much more desperate business than agriculture. Human beings and diseases are not an inert field that you sprinkle fertilizer on. In medicine you give poisons that have effects on both a person and a disease that no randomization can control for.

She concludes that RCTs will be of limited use for testing medical treatments but she recognizes that the idea of a simple solution has irresistible appeal to desperate people and the invention of this idea makes investment in pharmaceutical companies worthwhile – because it hands companies the perfect way to market Snake Oil.

Standing back and surveying the clinical domain over seven decades she sees the value of RCTs as a marketing tool for pharmaceutical companies steadily grow until it far outweighs the value of trials to doctors testing treatments in clinical conditions. As this happens she notices one group of clinicians – those with least contact with the pharmaceutical industry – develop a delusional belief in the invincibility of RCTs.

These believers try to update GSK Chesterton’s (and Gandhi’s) message that it is not Christianity that has failed, it is Christians, substituting RCTs for Christianity. She sees the annual Christmas solemnities of a people celebrating their control of confounders, and giving thanks to EBM, completely oblivious to the confounding produced by the Clinical Sprite that cannot be overcome.

The clinical sprite

Imipramine, the first antidepressant, was discovered in 1957, the year Fisher left England for Adelaide. It was launched in 1958 – not an RCT in sight. A year later in 1959, three years before Fisher died of cancer, and a few miles away from his patches of ground, a meeting of psychiatrists was convened in Cambridge to discuss its effects.

At this meeting, some doctors, mainly Danes, noted on the basis of the Christmas Tree lightbulb test that wonderful though it was for many of their patients imipramine could trigger suicidal and homicidal ideation in some (See Time to Abandon Evidence Based Medicine at 38 minutes et seq).

When Christmas Trees had old style light bulbs, after a year laid up there was an annual drama as the lights failed to work. Unscrewing them sequentially would finally lead to one which when unscrewed lit them up. Screwing that bulb back in turned them off again. Jettisoning this bulb fixed the problem, even more conclusively than Fishers nineteen heads out of twenty.

So imipramine causes suicide. But it is also a far more potent antidepressant than Prozac, or any subsequent antidepressant. It got people with melancholia well where later drugs don’t. Melancholic patients are 80 times more likely to commit suicide than mildly depressed patients – according to studies drug companies cite.

Accordingly comparing imipramine and placebo in an RCT would likely show less suicides and suicidal acts on imipramine than placebo. The relative risk might be 0.5. Imipramine protects against suicide.

Had an RCT been done showing no risk on imipramine, we cannot know for sure what effect it might have had on the doctors in Cambridge, celebrating imipramine’s benefits but acutely aware of its hazards.

But some hints come from an RCT four years earlier, in 1955, which found reserpine worked well for depression and caused no suicidality. The immediately preceding articles in the Lancet were Christmas Tree light bulb reports of it causing suicide from Geelong and Dunedin. Where? The field didn’t need an RCT to know that reserpine could be useful. In the face of an RCT from the most distinguished Institute in the world showing no problems, doctors still had no difficulty believing reserpine could cause suicide on the basis of light bulb reports from goodness only knew where. If asked what they made of these new-fangled RCTs, most clinicians would almost certainly have said “interesting but hardly clinically relevant”.

It took a political impasse about drug regulation in 1962 and the need to find something simple enough for bureaucrats to work with to produce the primacy that RCTs have now. Something signed into law by Marilyn’s lover, nine weeks after her death and ten weeks after Fisher’s, that put the lights out on the Christmas tree.

The sprite’s RCT

The findings of our imipramine thought experiment are represented in figure 1. These are the findings even though the drug causes suicide.

Figure 2 shows the findings for suicides and suicidal acts in SSRI trials.

In these trials we get a relative risk that the drugs will cause suicide and suicidal acts of 2.0. This happens because SSRIs are much weaker than imipramine and so were tested in people who were mildly depressed at little or no risk of suicide. When the findings got to be statistically significant, the regulators seemingly felt obliged to agree that the SSRIs caused suicide and came out with a warning to that effect.

The regulators were wrong. The data in this SSRI population show the drugs produce an excess of suicides over lives saved. They say nothing about causality except in so far as there could not be an excess of suicides if the drugs didn’t cause suicide. In the case of the SSRIs and suicide, the evidence comes from Teicher’s 1990 Christmas Tree light bulb paper on Prozac and suicide – and earlier cases.

The first point to make is this is not confounding by indication.

The second is that despite mantras to the contrary, RCTs do not and cannot show cause and effect.

The third is that they do not even give useful data on frequency. We in principle cannot have any idea from RCT figures how often antidepressants trigger suicidality.

But here’s the real deal. This finding is not an inconvenience that stems from some oddity to do with antidepressants or suicide or drug companies. It is intrinsic to RCTs within medicine. It can be expected every time a treatment and an illness produce at least superficially similar outcomes – whether a benefit or a harm.

It happens to cardiac rhythm problems in trials of anti-arrhythmics given for cardiac arrhythmias, and to breathing difficulties in trials of anti-asthmatics given for asthma. It happens with vaccines. It happens to the benefits of treatments just as much as their harms.

It holds as true for completely independent RCTs with hard outcome measures, no surrogate outcomes, complete data access, and intention-to-treat analyses, in long duration or short duration studies, as it does for industry studies.

It means that notions of Numbers Needed to Treat (NNTs) or to Harm (NNH) or even treatment effect sizes are for the most part little more than empty statistical artefacts, except in so far as they apply to dead bodies.

Patients can in fact distinguish between depression induced and drug induced suicidality or between antidepressant induced and spontaneous recovery from depression – if we ask them. Patients can tell you if a drug is ‘working’ even if its not ‘working’ – as when they say this SSRI is producing a useful emotional numbing even though it’s not making much difference overall. It is only if you listen to the patient that you can know whether to add another Therapeutic Principle into the mix or whether you should stop the drug they are on and try another.

Having your ears stopped to what the patient says, with the poison of “this is anecdotal data”, is a way to turn your patients into ghosts who must wander abroad seeking someone to come to their aid.

Cardiologists can also distinguish between drug and illness induced arrhythmias.

But if we believe a patient’s answers or a cardiologist’s clinical experience, RCTs immediately shape shift from gold standard evaluation to gold-plated but often misleading association studies.

So, who does not asking patients suit most?

The only trials that the Clinical Sprite cannot confound are Drug Trials. These trials of a drug done in healthy volunteers reveal unconfounded drugs effects. But there is no register of these trials, and no access to their data even though there are no issues of clinical confidentiality involved.

The clinical pixie

The Clinical Sprite has a sister – the Clinical Pixie.

In the late 1980s, Eli Lilly undertook a trial of Prozac in a group of patients with recurrent brief depressive disorder (RBDD). In this trial placebo was sweepingly statistically superior to Prozac. The study was published four years later shorn of all key data.

In the early 1990s, SmithKline Beecham (GSK 2B) undertook study 106 of Paxil – Prozac’s sister SSRI in the same hospital centre, in the same RBDD patients, possibly with some of the same patients who had been in the Prozac trial. This second study terminated early. The results were never published. The rate of suicidal acts on Paxil (Paroxetine) was three-fold higher than on placebo.

Nevertheless a few years later GSK 2B undertook study 057 in a similar group of patients. Several different sets of results from this trial circulate, none of which support using Paxil in this group of patients.

In April 2006, GlaxoSmithKline (GSK Not 2B) issued a press release with the following figures for suicidal acts in the Paroxetine trials in Major Depressive Disorder.

Suicidal Acts in MDD Trials

	Paroxetine	Placebo	Relative Risk
Suicidal Acts/ MDD Patients	11/ 2943	0/ 1671	Inf (1.3, inf)

The MDD patients show a significant increase in the suicidal act risk on Paroxetine. But even though the results of studies 106 and 057 were so bad, GSK Not 2B gleefully added them in to the mix – and when they did so Hey Presto the risk from Paxil vanished. It can even be made protective against suicidal acts (See Table 2).

Suicidal Acts in MDD & RBDD Trials

	Paroxetine	Placebo	Relative Risk
Suicidal Acts/ MDD Patients	11/ 2943	0/ 1671	Inf (1.3, Inf)
Suicidal Acts/ RBDD Patients	32/ 147	35/ 151	0.9
Suicidal Acts/ MDD & RBDD Patients	43/ 3090	35/ 1822	0.7

We can dump lots more suicidal acts into the RBDD trials and still get the same magical outcome – see Table 3.

Suicidal Acts in MDD & RBDD Trials w Sprite

	Paroxetine	Placebo	Relative Risk
Suicidal Acts/ MDD Patients	11/ 2943	0/ 1671	Inf (1.3, Inf)
Suicidal Acts/ RBDD Patients	48/ 147	35/ 151	1.4
Suicidal Acts/ MDD & RBDD Patients	59/ 3090	35/ 1822	0.99

This paradoxical outcome is not a funny quirk of antidepressants and suicide. It is totally predictable and obvious. I could have advised GSK-2B or Not 2B to do studies 106 and 057 to get this outcome. Knowing what a drug can do, you can often design studies that use a problem the drug causes to hide that very same problem.

Now the pillars of the EBM establishment, so used to dealing with the scurvy knaves from Pharma, look at this and say it is just bad meta-analytic technique – you shouldn’t mix studies like this. And you shouldn’t. There is a horrific scandal here – FDA, MHRA, and the luminaries of EBM have let GSK Not 2B get away with this without a peep of protest.

But there is a deeper problem. We can see what is going on here. But exactly the same thing can happen by accident in clinical trials done in every illness we don’t fully understand – from pain to Parkinson’s Disease.

RBDD patients can meet criteria for MDD easily. Provided there is more than one of them entered into MDD trials randomization will ensure these Pixie patients will hide some benefit or harm.

Unlike fertilizers, drugs have a hundred or more effects. When we Design an Experiment employing randomization to manage the unknown unknowns for one of these effects, we risk generating an ignorance about ignorance regarding most of what the drug in fact does, and sometimes even for the effect we are focused on. This is true for statins, antibiotics and all drugs – not just antidepressants.

Pharmagnosia

Generating ignorance about ignorance is a serious clinical problem – for which pharmagnosia seems a good term. If a good medicine is a chemical that comes with good information, then RCTs through pharmagnosia are leading to a systematic degradation of our medical arsenal.

All RCTs do harm. Some do good as well. Pharmagnosia is worth risking when there are grounds to think a claimed benefit does not hold water and if wrong vulnerable patients are likely to be harmed. If the drug doesn’t work, we don’t CReate Ignorance in MEdicine (CRIME).

The only way to get the result Fisher would have insisted on for the main effect of a drug rather than a fertilizer, that is the same outcome every time, is to understand the clinical condition you are treating and the agent you are using so that you produce a Quod Erat Demonstrandum – this treatment works every time or no it doesn’t work.

But if we understand the clinical population this well, RCTs come close to being irrelevant to moving decent medicine forward. Their main value lies in dealing with the claims of hucksters and charlatans.

The Clinical Pixie looks like Tinker-belle but she is a not a benign fairy. There are far more MDD patients that RBDD patients in this world. If you spot what she has done in this case, you can see that the results show the drug harms more people than not.

But if you don’t spot what she has done, she will beguile you if you are a public health official or regulator into supporting a treatment in front of the press saying it has a favorable risk benefit ratio by which you mean produces more benefit than harms on a population basis. You will do this although in fact the treatment is cripplingly bad for far more patients than it benefits.

At a rough guess, 90% of these pronouncements by regulators are wrong and 99% or more are lacking in appropriate supportive evidence.

One of the most egregious examples of this came recently in a Cochrane review of Statins that focusing exclusively on their lipid lowering effects, neglecting their effects on muscle, endocrine and cognitive function, concluded that the evidence supports their use (Cochrane Library 2013, Issue 1). Only time will tell which of the current blockbuster drugs will in the longer run take the title for the drug group that has caused the most damage but the statins are worth betting on.

In Elsinore

Within the walls of the Elsinore, the citizens of EBM remain at ease. As far as they can see the only Sprites that might confound clinical trial results are those scurvy knaves who work in the pharmaceutical industry. The citizens still believe that the suicide risks of antidepressants were discovered in clinical trials done in children, not knowing that trials were actively and likely deliberately used to hide an obvious link for fifteen years.

Within the Citadel, Claudius has decreed that anyone who seems to question the primacy of trials should never be engaged in public, can be attacked in ad hominem fashion, or failing all else should be consigned to the Antidepressants & Suicide Chamber, on the door of which there is a notice Here be Sprites.

Lethe, the river of forgetfulness runs through EBM. What need is there for History. Things could not have been better in the past. Fisher’s texts are revered as they lie sealed in a glass cabinet. No-one can find out that he was looking for a Christmas Tree light bulb equivalent. They don’t even know he was dealing with agriculture not medicine.

In the Real World, outside the Castle, the one foot on the ground world, RCTs can be seen to function in medicine primarily as a rhetorical device giving the impression that if a drug has passed through them, a patient will get the same beneficial outcome time after time, even when in fact in 80% of the trials the drug has performed worse than placebo.

Cut to the battlements of Elsinore, where a man stands paralyzed with fear by the approach of what his fevered imagination sees as a ghost. The ghost of a beautiful woman. Frozen with fear, he murmurs:

Illustration: Put-Me-to-Sleep Pills, © 2013 created by Billiam James