Making medicines safer for all of us

Adverse drug events are now the fourth leading cause of death in hospitals.

It’s a reasonable bet they are an even greater cause of death in non-hospital settings where there is no one to monitor things going wrong and no one to intervene to save a life. In mental health, for instance, drug-induced problems are the leading cause of death — and these deaths happen in community rather than hospital settings.

There is also another drug crisis — we are failing to discover new drugs. [Read more...]

Archive for RxISK Stories

A Call to H*ARMS

Editorial Note:  This is the fourth and final post in the Trick or Treat series that started with Vampire Medicines. These posts need to be read linked to the RxISK MAP posts. These are the theoretical background.  The MAP posts are the practical – what needs to be done posts.

Access to Medicines

In the 1980, we faced one of the greatest medical crises of any century – AIDs.  At its height the epidemic was claiming 50,000 deaths per year in the US.

Facing the AIDS epidemic, some called on Homosexuals to change their lifestyles.  But AIDS was caused by a human immunodeficiency virus (HIV) rather than lifestyle issues.

The answer lay in developing a science base and producing treatments. The treatments that emerged have arguably been the only decently effective treatments that have been developed in the last 40 years with the exception of Glivec.

One the extraordinary things about the response to AIDS was how the homosexual community embraced the stigma and mobilized around finding a cure.

Another extraordinary feature was a celebrated Access to Medicines campaign that took shape around 2000, when it became clear the greatest number of cases were in underdeveloped regions of Africa, and that these patients were being charged First World prices.  Campaigners led by Bill Haddad, Jamie Love and Yussuf Hamid, working to ensure access to these life-saving treatments at affordable prices, drove the price down from from $50 per day to under 50 cents.

It was one of the greatest triumphs of the human spirit and an example of what medicine and the pharmaceutical contribution to medicine could be all about.

There is a less inspiring Access to Medicines campaign under way at present, with European politicians mobilizing to control the cost of the latest drugs to hit Western markets – drugs of much less benefit that the Triple Therapy AIDS cocktails.

Access to Real Medicines (ARMs)

Starting around 1980, a new virus emerged that has led to a new and lethal and global epidemic.  One drug group alone, the opioids, now causes 50,000 deaths per year in the US.

Treatment induced drug wrecks are the leading cause of death and disability on the planet. Studies suggest treatment accounts for up to a third of deaths in hospital settings, where deaths may be caused by chemotherapy or the cardiac effects of drugs but will be put down to cardiovascular causes or cancer.  The drug induced death rate can only be greater in community settings where most deaths occur and where people are less likely to have conditions that can be blamed as the cause.

As for disability rates, roughly 1 billion people are on SSRI and related antidepressants in Western settings – that’s 1 billion people with their sexual functioning disabled.  If only 0.1% of these get PSSD or PGAD, that’s 100,000 people with their sexual functioning possibly eliminated forever.  This is the disability toll from only one drug group and one set of problems.

Faced with a Drug Wreck epidemic, the medical establishment is playing a moral card and calling on doctors and patients to change their lifestyles – diagnose less and treat less.

The answer lies in restoring a science – adverse eventology.  And in creating a climate where adverse events can be recognized and people can be got off treatments if they are maiming and killing them – something that is increasingly impossible to do at the moment.

The Drug Wreck epidemic is caused by a clinical immunodeficiency virus (CIV) whose primary mode of transmission is through major journals like BMJ, NEJM, AJP, through which it takes out the white cells of adverse event knowledge.  See Vampire Medicines and Raiders of the Lost Drug Wreck.

No doctor willingly harms patients.  If she dishes out drugs it’s because she has not been told about the harms, or has had them dissed.  No patient would take chemicals glibly – but this is what is happening increasingly as the information needed to manage the risks linked to the chemicals we take has been steadily degraded.

The reason drugs are being dished out and taken on such a massive scale is because the harms have vanished. RCTs are one reason for this. Drugs have 100 effects.  Most of them vanish in RCTs, leaving us with Vampire Medicines – actors without a shadow.

Another reason is journal funk. Our major journals are scared shitless and will not publish anything hinting at any treatment harms. Because of journals and RCTs, doctors have stopped listening to or looking at their patients – if the adverse events aren’t recognized in places like our journals it is more than a doctor’s life is worth to notice them. We might be sitting in front of our doctors but we are effectively invisible.

The hiding of harms has contributed to a growing medical nastiness, when we raise them. Faced with adverse events, some doctors get very nasty. Sensing this, and having no way to know who will and who won’t get nasty, we become increasingly nervous to mention adverse events.

Just as in 2000 the world needed an Access to Medicines campaign, we now need an Access to Real Medicines campaign. The core message of this campaign would be that a Medicine is a chemical plus information and without full access to all the information we don’t have access to the Medicine. The chemicals have always been and will always be risky.  The information component has been steadily degraded since 1980 making today’s medicines riskier than the treatments we had back then.

This campaign would be about saving lives on a global basis rather than just in parts of the underdeveloped world.  The wealthy of America and Europe are probably at greater risk than anyone.

Battle Plan

  1. Insist on access to data. No company claim to be based on science should be acceptable without access to data.
  2. Doctors should refuse to prescribed medicines where there is no access to the data.
  3. Patients should refuse to take medicines when their doctors don’t have access to the trial data.
  4. Restore a Poison sign to all new medicines, and all medicines without data access.
  5. BMJ and other journals to tell their lawyers: We are publishing harms data, among which will be case reports and articles from shady customers like Jureidini and Healy – your job is to work out how to make that happen, otherwise, although we might be a successful business, we are doing harm and may need to wind up the operation.
  6. Work out how to shrink the drugs regulator back to food regulator size and make doctors aware of their regulatory role.
  7. Before thinking about independent trials, create an independent Harms/Safety body.
  8. In the absence of data (Cisparency) to enable us to judge whether possible conflicts of interest have been realized, concerns about conflicts of interest (Transparency) create a counter-productive moral panic. Conflicting views are an important element of what drives science forward and should be resolved by data.  Claims about conflict of interest should only feature exceptionally.
  9. Prepare for the day when robots that can learn take over prescribing.

 

Raiders of the Lost Drug Wreck

Editorial Note:  This post follows from Vampire Medicines and Cisparency and Transparency and links to Relationship Based Medicine on Rxisk.  The painting is of Joshua crossing the Jordan with the Arc of the Covenant – an image that catches the essential features of climactic scene of Raiders of the Lost Arc with Joshua in the Indiana Jones position.

In every generation, there is a slayer.  In this generation, s/he will probably be female.  She need not be a doctor.  She might work for a pharmaceutical company.  She could be a patient or a family member. She will likely be a woman, if only on a probabilistic basis, as more women are injured by medicines and more women are involved in the lives of people who have been injured and now more women are in medicine than men.  And as the BMJ has recently shown even in medical specialities, such as surgery, where until very recently it was common to hear it said women were just not suited, in fact they now do a better job than men. She might be the editor of a medical journal.

In-Diana, besides, looks much more like a girl’s name than a boy’s.

The Slightest Slope

Just as water flows down the slightest slope, so drugs flow at the slightest hint of benefit – in both cases the flow is inevitable unless there are bumps in the way. It’s a bit like taking an apple off a tree. Difficult not to.

Difficult not to, short of seeing the tail of a worm sticking out of the apple and wriggling.

This is where the harms come in.  There is no such thing as a Free Apple. Its only in paradise there are worm free apples. Down here at the very least they have pesticides on them.

Since the Fall, we have lived in a world of Good and Evil – where sometimes what seems like the greatest good turns out to be more harmful than helpful. We need to be alert and make judgement calls that balance harms. In medicine, we were making progress at balancing harms to the point where we could make a reasonable stab at using poisons to do good provided everyone knew what they were doing.

But since 1990 that balance has been lost and the divide between good and evil is getting more marked.  This might sound like a good thing but its not. We are increasingly ending up with fistfuls of medicines branded as All Good Zero Harms – Vampire Medicines. The systems most people now work in or seek medical help from with would shrink in horror from the idea of bringing good out of the use of a poison. We have infantilized. The infantilization is worse by systems that are becoming increasingly brutal to those trying to work within them and those seeking care from them.

Suffer the Children

One of the best symbols is what we are doing to children. There have been roughly 30 controlled trials of antidepressants in children labelled as being depressed – all negative. The Prozac trials the most negative of the lot.

Yet prescriptions for antidepressants are soaring among teenagers, especially girls, so that they may now be the most commonly prescribed drugs in this age group.

This is because of hints of efficacy and a sustained campaign to turn the evidence that there are harms – every trial done shows an excess of suicidal events on active treatment over placebo – into a “controversy”.  The average doctor has been led to believe this is just an arcane dispute among academics.  Nothing of consequence in the real world.

In the real world children’s mental health services are close to collapse because, despite money being poured in, children are waiting so long to be seen that given antidepressants by family docs – to help tide them over – they are attempting suicide while waiting. They then get seen by services who have no sense the suicide attempts might be drug induced and they get treated for something they don’t have.  Meanwhile, the money going into children’s services goes into screening, and auditors and managers rather than clinicians in an effort to ensure adherence to guidelines. The only reason things could be going wrong is non-adherence to the guidelines – guidelines that say give Prozac.

Get that Crucifix out of Here

Another place to see the problem is with vaccines.  BMJ have just bravely run a piece by Peter Doshi on the funding of vaccine propaganda groups. Few people other than Peter could have pulled off something like this.  Others would be too scared. Still the impression left is that everything would be fine if there were transparency about the sources of funding and conflicts of interest.

The real problem is that in vaccine-land its not possible to mention harms. There can be no discussion of the fact that HPV vaccine causes problems, flu vaccines are for the birds, the Swine Flu vaccine caused narcolepsy, hundreds are suing Merck as a result of the Shingles vaccine, and earlier iterations of the MMR were withdrawn because the authorities accepted they were causing problems.

Not only is there a denial that there could be any problems but vaccine proponents have become thuggish and fascist, with alt-health diatribes turning up in the most unexpected of places – the Guardian. It’s enough to make anyone who believes in vaccination despair. The analysis of the growing vaccine resistance in healthcare professionals pays no heed to this.  It scolds us for not telling the public that the safety of vaccines is monitored thoroughly – when this is self-evidently not true.

American Women

Medical academics now discuss company creativity at gaming efficacy in clinical trials – the way scholastics once debated the number of angels that might fit on the head of a pin.  But company creativity at gaming efficacy is like nothing compared to their creativity at gaming safety.  One of their best tricks is to get doctors and patients to report harms directly and independently to regulators.  You might have thought this would help but reporting adverse events to a regulator is like pouring water into sand.

This was brought out in two posts some time ago – American Woman and American Woman2.

An entire science has been lost here – the science of adverse events/ drug wrecks.  Doctors have no training in establishing when it is possible to say that drug X is causing problem Y.  They are told that RCTs tell them what a drug causes.

The irony of this is that with most drug wrecks the causal chain is commonly so clear, so lacking in ambiguity, there is no need for an RCT – PSSD and PGAD offer great examples of this.

We Need to Medicalize

Many well intentioned people think they are contributing to a resolution of this epidemic by getting involved in campaigns against Overdiagnosis and Overmedication (ODOM).  As things stand Overmedication Campaigns are like telling people they are a little Overweight – everyone agrees they need to change but, like Augustine of Hippo, they figure they will try to put it right but maybe not just yet. While everything works – is nutritious – or everything is good – like making a diagnosis – it’s difficult to stop feeding your diagnoses.

ODOM is like AllTrials – wonderful for industry.  It gives the “good guys” the feeling they are doing something while behind the fig leaf industry get to hide ever more transformations of medical culture and practice.  Centrally important to all this is that the proponents of ODOM or AllTrials be like BMJ and Fiona Godlee, its current editor, brave and beyond reproach and better again seen as trying to rein in industry.

But this won’t work. The only way the epidemic of treatment induced death and disability can be tackled is to return pharmacotherapy (not quite the same thing as medicine) to its roots which is that everything is a poison and physicians need to act accordingly.

We are Underdiagnosing the injuries being caused by treatment and Undertreating these injuries.  We need to medicalize the problem. A campaign to recognize harms and manage them would require a lot more cojones from journal editors, scientific advisers and consultants than we are currently likely to get from any of these sources.

Relationship Based Medicine

But medicalization is not just about recognizing harms.  It’s about managing harms in a relationship. We need to get back to a Relationship Based Medicine.  The relationship used to be authoritarian. It needs to become consensual. It needs to harness the abilities of those of us who as patients take risks with medicines to contribute not only to our own wellbeing but to the wellbeing of all.  A bunch of reasons why the slayer is likely to be a ….

Of course, doctors should probably also be told they are on the way out of business unless something like this happens.  If drugs work wonderfully well and are so free of harms, nurses and pharmacists would be much cheaper prescribers.

And looming on the horizon are robots that can learn. Pretty soon putting a robot in charge of prescribing for patients, providing they were granted leave to learn by killing a few hundred patients first, would lead to fewer people being injured and fewer dying than is happening at now.  If it was let learn rather than just follow a program, the first thing the robot would learn is to junk the evidence from RCTs.

Cisparency and Transparency

Editorial Note: This post continues Vampire Medicine and links to Reformation Day on RxISK and forthcoming posts – Here We Stand.

Between 2002 and 2004, giving antidepressants to teenagers and the risks of triggering suicidality became one of the most high profile issues in medicine.  Raising a profile should be the way to put things right but things are getting much worse.  The lack of access to services is leading to adolescents self-harming to such an extent this is now accepted by the British government as the area of greatest failure in Britain’s Healthcare System.

What’s gone wrong?

Blowing up the Fishpond

It was BBC’s Panorama and a Los Angeles law firm, Baum-Hedlund who initially raised concerns. Panorama threw a hand grenade into the mostly East Coast fish pond that was American medicine. This led to a series of FDA hearings in 2004, and a derailing of company plans to get their antidepressants licensed for children.

The central event was a document obtained by Panorama which revealed that Study 329, a trial comparing paroxetine, imipramine and placebo, had been negative but was going to be portrayed as positive.  New York State took a fraud action against GlaxoSmithKline.

The document crystallized recognition that close to every article on every on patent drug in any area of medicine was ghostwritten and there was zero access to clinical trial data.

Faced with this crisis, there were two obvious courses of action.

One was go after the docs who were willing to let their names be put on ghostwritten articles whose data they had never seen and who presented these data at meetings – for a fee.

The other was go after the data. In 2004, the British Guideline maker, NICE, considered the second option but funked it.

New York State thought they had secured a commitment from GSK to make the data available which would set a precedent for other companies.  But GSK ran rings around them, making some company authored study reports available that concealed everything about everybody that had anything to do with any of their trials.

The first was the sexy option.  It offered stories the media could understand – docs on company payrolls prepared to say anything. Everyone could understand Conflict of Interest and agree it was a bad thing. Chasing this fitted a zeitgeist which said all problems could be solved with Transparency.

The second was more difficult.  Unless you are involved in clinical care it sounds esoteric and geeky. It also risked blowing up a lot the guys we think of as the good guys like BMJ, Lancet, NEJM and JAMA. And it quickly became clear there would be resistance. Let’s call this Cisparency.

Stunned Amigos

When BBC threw their hand-grenade into the healthcare pond stunned fish floated to the surface. Baum-Hedlund picked the fish up and started dumping them on Congressional and Senatorial desks. Most of the fish were ugly and had thwarted data access stamped all over them. A few others were colorful eye-catching dudes.

The key desk turned out to be Senator Grassley’s, where a formidable woman, Emilia di Santo, ran the operation and an energetic staffer, Paul Thacker, got engaged.

Some colorful flashy fish called Alan, Marty and Charlie, the type to feature in Disney movies – a great title would be Three Amigos – caught senatorial or other eyes, rather than the uglier critters. There was nothing notable about the three flashy guys in terms of contributions to medical or mental health science, but at the time details about the conflicting interests of all three were tumbling into the public domain.  Charlie had become the poster boy for conflict of interest across medicine.

If you’re a Senator what’s not to like about a guy who was willing to let himself be featured on the front of a glossy publication as The Boss of Bosses with a question Is Charlie Nemo the most powerful man in psychiatry. Marty was the first author on Study 329, the trial that had kicked everything off, then on its way to becoming the most famous trial in medicine.

Nemo was a Harvey Weinstein like character, capable it seems of charm with those who played ball with him and of being a thug to others. Close to the entire field of US psychiatrists enabled him.

He was probably a greater embarrassment to GSK and other companies than he was to academic psychiatry. GSK could not have wanted him to behave like a loose cannon in the way he did. He was probably central to losing them the Tobin case, which led to Panorama interest, and a bunch of dead fish, which they are still grappling with.

Enter Stage Left

Because of the Toronto episode Paul Thacker called wanting to know anything if I could tell him about Nemo. I told him – nothing much apart from what is in the public domain.  I tried to persuade him Nemo was not the problem. He was irrelevant.  He could even do some good if he could be turned. He and some others like Stuart Montgomery could show us where some of the bodies were buried.  Chop their heads off and others would replace them.

PT wasn’t listening. Nemo had become too juicy a morsel to give up.  But very little came out of his investigations beyond what was already in the public domain.

Let the Sun Shine In

The collapse in August 2007 on the grounds of pre-emption of a Baum Hedlund lawsuit, centered on the suicide of a 13-yr-old boy while taking Paxil, coincided with the introduction in September of a Physicians Payments Sunshine Act by Senators Charles Grassley (R-IA) and Herb Kohl (D-WI).  This act aimed to “shine a much needed ray of sunlight on a situation that contributes to the exorbitant cost of health care”, according to co-sponsor Senator Charles Schumer (D-NY). It would require manufacturers of pharmaceuticals and medical devices with annual revenues of more than $100 million to disclose gifts or payments to physicians in any form, whether cash, trips, or other.

The most bizarre aspect of this was the idea that letting the Sunshine in would bring down drug costs – See Raiders.

But the Bill fit the perceptions of many ethicists, journalists and others that the root of the healthcare problem lay in payments to opinion leaders. Transparency was crowned king despite a complete lack of evidence of opinions being changed by payments.

This model locates opinion leaders as experts – the cream of the profession.  They are only the cream in the sense of being rich and thick. No pharmaceutical company wants someone who can think. The first qualification for being picked by pharma is to be mediocre, and the second is to remain on message.

The model views other doctors and patients as airheads who will rely on a few puppets made over as smart dudes to tell them what to think.  No one would pay any heed to what some cartoon puppets were saying were it not for the iron fist inside the puppets that has all too obviously silenced BMJ, JAMA, Lancet and NEJM – see Vampire Medicines.

The Benefits of Transparency

Baum Hedlund contacted Emilia di Santo again in 2007. It put the Ugly Fish back on her desk. While Grassley wrote to the Department of Health and FDA raising cisparency issues, the die was already cast.  The transparency fish were already sitting in their bowl, scales glinting in the bright sun light. Rather than chase cisparency, Grassley continued with the low hanging fruit of transparency, scooping up a number of other prominent psychiatric academics on the way none of whom seem to have been harmed by the attention.

Just this year Karen Wagner, one of those named and supposedly shamed became the current President of the American Association of Child and Adolescent Psychiatry, despite multiple depositions conceding her articles are all ghost-written and she wouldn’t know what to do with data even if she saw it.

On July 12, 2008, the New York Times reported:

“But now the profession itself is under attack in Congress, accused of allowing this relationship to become too cozy. After a series of stinging investigations of individual doctors’ arrangements with drug makers, Senator Charles E. Grassley, Republican of Iowa, is demanding that the American Psychiatric Association, the field’s premier professional organization, give an accounting of its financing.”

The following year APA voted Alan Schatzberg in as its President.

After a brief period under a cloud, Nemo moved from Emory to Miami and was welcomed into the bosom of places like London’s Institute of Psychiatry who know a thing or two about supporting people who have been vilified by the enemies of psychiatry. A President of the World Psychiatric Association in waiting?

On March 23 2010 Grassley and Kohl’s Physician Payment Sunshine Act was enacted as part of the Patient Protection and Affordable Care Act.

Sidelining Cisparency

The resolution of New York States’ fraud action against them in 2004 involved an agreement by GSK to post details of their clinical trials on their website. This led to a set of Clinical Study Reports (CSRs) for paroxetine trials in children being posted.

GSK also posted 3-7 page summary reports of trials in other therapeutic areas, including trials of their blood sugar lowering blockbuster, rosiglitazone (Avandia). Reviewing these summaries Steven Nissen, from the Cleveland Clinic, found an increased rate of mortality on Avandia compared to placebo. Avandia was withdrawn from the European market and restricted in the US. These data laid the basis for the Department of Justice to pursue GSK for both Paxil and Avandia.

In 2009. Peter Doshi from Johns Hopkins and Tom Jefferson from Rome, working with colleagues on a review of Tamiflu, Roche’s antiviral drug for influenza, became headline news, when the data they assembled suggested Tamiflu didn’t work.

Governments around the world had stockpiled billions of dollars’ worth of Tamiflu having been told it saved lives by reducing transmission of the virus, kept people out of hospital and got them back to work faster. Fiona Godlee and BMJ helped make Tamiflu a campaign for transparency.

Then in October 2012, facing criminal charges for promoting its antidepressants for unapproved uses and failing to report safety data about Avandia, GSK accepted a $3 Billion fine, then the largest settlement in a Department of Justice lawsuit.

Far from being on the back foot, just as they had out-maneuvered New York State in 2004, GSK took the initiative. They announced plans to make their clinical trial data available to researchers on a secure website, if an independent panel of experts agreed the research proposal met a scientific need – mature transparency.

A few weeks later, AllTrials was born. The idea might have begun with Fiona Godlee. The family present at the birth included Sense about Science, the Cochrane Collaboration, the Centre for Evidence Based Medicine, Iain Chalmers, along with BMJ and PLoS, with the lot now fronted by Ben Goldacre.

The AllTrials ask was for access to the protocols for all clinical trials. The impression given was that AllTrials was seeking access to clinical trial data. It wasn’t. It was named AllTrials rather than AllData. It supported proposals that might enable some investigators, approved by companies, to access certain efficacy data. Exactly what GSK were proposing.

GSK promptly signed up to AllTrials. Within a few months of a record fine in the US, Andrew Witty, GSK’s CEO, featured on the March 9 2013 cover of the BMJ hailed as the acceptable face of the pharmaceutical industry.

Spearing Nemo?

A few years later the time came to dump fish in a Chicago jury box in the Dolin case. Trying to spear Nemo wasn’t going to get anyone anywhere with a Windy City jury – he mightn’t have been visible in a Green River anyway.

It was the ugly brutes the jury got told about. GSK’s lawyers spent their time desperately trying to block any mention of Study 329 and trying to stop jurors seeing the harms data from paroxetine trials, or hearing about the ways the company had tried to thwart access to data.

GSK’ s lawyers went apoplectic at a mention of the idea that if you owe a bank a million dollars, you have a problem but if you owe a billion, the bank has a problem.  This could be reprized as – if Senator Grassley catches GSK out in a little lie – hidden payments to Nemo – GSK has a problem but if the entire thing is a lie Senator Grassley is fucked.

Transparency, efficacy and Nemo were irrelevant in Chicago. Its the Great White Lies about Harms that count, not a few little tiddlers.

To be continued..

Vampire Medicines

Editorial Note:  This is the first of four Trick or Treat posts.  They make most sense when read in conjunction with the RxISK Prize posts especially the series of 3 posts starting tomorrow.

In 1962 RCTs were added to the regulatory requirement for marketing medicines.  This looked like a definitive stake through the heart of hucksterism. No longer would we have to carry crucifixes and garlic around to ward off blood-suckers hawking ineffective remedies.

In 1962 doctors were viewed as the key element of the regulatory apparatus. A great part of their input centred on descriptions of the harms medicines could cause. In addition to news of the latest advances, medical meetings were filled with symposia and medical journals with articles on the harms of treatment and how to manage them.

Company funded RCTs, which played a minor part in clinical practice, were all done in hospitals and universities and academics had the data.

Around 1980, as new drugs got weaker and weaker, company trials became multi-centered, coordinated by CROs, written up by ghost writers, with academic names attached afterwards.  Everyone seemed as happy to enable this increasingly Hollywood like remake of medicine as they were to enable Harvey Weinstein.  In the process access to trial data was lost.

Richard Smith

The key event that marked a transition to the modern world came in 1990, when Teicher et al published 6 cases of people becoming suicidal on Prozac in the American Journal of Psychiatry.  According to all canons of causality, this paper offered undeniable evidence SSRIs can cause suicide. Hearings were convened to discuss the need for warnings.

But coincident with these hearings, BMJ published a meta-analysis of Prozac trials which Lilly claimed showed Prozac was not linked to suicidal events.  This paper had been rejected elsewhere, The BMJ reviewer was lukewarm. But Richard Smith, BMJ’s editor, perhaps spotting an opportunity to push a new kid in town, Evidence Based Medicine, and its shiny new meta-analytic machine, published.

The published data showed an increased risk on Prozac, which Lilly and BMJ ignored, claiming nothing was statistically significant.  Beyond this, Lilly played some of the tricks other companies later played – the small print shows the only placebo event hadn’t happened on placebo, so that technically there was a statistically significant  infinitely greater risk on Prozac.

The follow-up letters told RS he had been naïve and wrong. But no one accused him of conflict of interest. What could be wrong with letting good quality evidence (even though he got that wrong) triumph over anecdote?

The way this played in public was that the stories of suicides on Prozac were tragic but anecdotal.  The scientific evidence demonstrated that patients and doctors just can’t believe the evidence of their own eyes and ears. They have to be told what’s what by experts.

This dangerous and misguided message triumphed with regulators, and later in Courts.

This message killed any interest journals like AJP and BMJ had in taking Case Reports. Besides companies didn’t buy reprints of these, whereas they handed over huge amounts of money for reprints of ghost-written fraudulent RCTs with zero access to data, and even more for the best science money could buy – meta-analyses of these trials. Evidence Based Marketing was here.

Vampire Birth

A medicine is a chemical plus information. The information about the effects of chemicals should come primarily from practice on the ground, as in the early days of antibiotic or psychotropic drug use, or street drug use now, or from use of anti-retroviral combinations for AIDS in the 1990s.

When the benefit (not the harms) of a drug is equivocal, RCTs offer a means of examining efficacy ambiguities by focusing a magnifying lens on the ambiguity. They do this at a cost – ignoring safety.  They are an act of hypnosis that gets investigators to focus on one thing while ignoring everything else going on around them.

If we ignore the ignoring of safety, as we do, we compromise rather than enhance safety. The harms vanish. The drugs that come out of an RCT have no shadow – no harms.  They are vampire medicines. Put another way, all clinical trials (RCTs) cause harm but some can also be helpful. They pose the same problem AI and viruses do – if you create one, can you control the consequences?

Co-incidentally around the time vampires began to flourish, companies had poison symbols removed from medicines and from discourse.  Any mention of the celebrated medical wisdom that all medicines are poisons in an expert report will now be met by company motions to have the word poison struck as prejudicial.

Conflict Free Blood

If there was a conflict of interest involved in linking trials to regulation, it was born from hostility to pharmaceutical companies.

But it’s now clear that even if done by angels, RCTs are the gold standard way to hide adverse events.  Their intense focus on a primary outcome rather than the overall picture means that in even the most independent of studies they necessarily neglect adverse events.  Companies overlay a lot of creative hiding on this neglect but this is an extra source of difficulties not the primary problem.

It was doctors who used to go around with stakes. Regulatory bureaucrats never did. RCTs have made life easier for the bureaucrats.  According to the head of Britain’s MHRA, Ian Hudson, formerly of GSK, if events are not statistically significant – and strictly speaking as no adverse event is ever a primary outcome measure, they can’t be – then they aren’t happening.  BMJ helped consign stakes to the twentieth century.

If there was a conflict of interest involved in the move from RCT to Evidence Based Medicine (EBM), it was born from hostility to companies.

EBM was not unreasonable in the early 1990s but it has created a bandwagon that is now out of control contributing hugely to a conversion of poisons into fertilizers to be sprinkled as extensively as possible, from as young an age as possible.

If there was a conflict of interest involved in using trials to create Guidelines in the 1980s, it was born from hostility to pharmaceutical companies.

But now, if NICE and other Guidelines, based entirely as they are in the case of on-patent medicines, on ghostwritten articles whose data is inaccessible, hadn’t been created, Pharma would have to invent them.

Drug harms that took a year or two to come to light in the 1960s take a decade or two now.  In 2003 I predicted we were on our way to having lethal and common drug harms being contested years after the drug had gone off patent. In April 2017, the Dolin case in Chicago centred on just this issue – ten years after paroxetine had gone off patent.

These problems are not being contested because it is difficult to decide if a drug is causing a harm.  They are being contested because of the power of companies to shut down debate in journals like BMJ.

BMJ’s news item about the Dolin trial missed the key issues, and it wouldn’t have occurred to them they had a role in the development of the situation.

Rosemary’s Baby

If it was just one drug harm that might be fine but drug wrecks may well now be the leading source of death and disability on the planet.

BMJ helps this happen in its educational forums by making it clear for instance that giving antidepressants to minors is just fine – no mention of harms.

BMJ helps this happen in its educational forums by making it clear for instance that giving antidepressants in pregnancy – now the most commonly used drugs in pregnancy – is just fine despite a doubling the rate of birth defects and miscarriages and behavioural abnormalities in the children of those taking them.

Buffy the Vampire?

Richard Smith was succeeded by Fiona Godlee, as free of ties to industry as RS once was.

Starting with RS and then later with FG, I and others had a series of articles on drug harms rejected with an increasingly bizarre set of reasons offered for the rejections, and increasing involvement of BMJ’s legal department.

These rejections have two elements.  One is that across all journals anyone interested in a drug’s harms appears to be deemed ipso facto not just biased but perverted. It’s like wanting to publish something about sex around the time Dracula was written.

The second is anyone who has ever been in any way linked to a lawsuit as an expert against a company is deemed irredeemably conflicted.

For those of us working on the Restoration of Study 329, the review process became beyond odd. BMJ editors kept raising queries that had been answered and talking about conflict of interest.  To which our response was everyone is biased but the way conflicts are overcome in science is to turn to the data – it’s the data that reveals whether someone’s latent bias is operative or not.

BMJ just didn’t get it. My formulation up till then was that a belief conflict of interest is of supreme importance is incompatible with recognizing the importance of accessing the data.  This is still my view in the case of most of those who champion Sunshine.

But then a predicted legal review came into the 329 frame.

BMJ’s lawyers made it clear that if the journal had anything to do with Healy and Jureidini they would be providing GSK or other companies with grounds to claim bias and to sue. This is even though BMJ and GSK are partners in AllTrials and BMJ had a short while before featured Andrew Witty on its front cover as the acceptable face of pharma, helping GSK put a $3 billion fine behind them. Partnership?

BMJ is a business that can no longer support medical practice, a key part of which is describing harms. If a doctor is not prepared to go to Court to stand up for the harms she’s put her name to, she’s writing fiction – a bit like Bram Stoker saying in real life he doesn’t believe in vampires.

That the BMJ editor handling 329 was married to a man who worked for the law firm who defended GSK against a $3 billion Department of Justice fine didn’t seem to be any kind of conflict of interest.  But then patients who have committed suicide or homicide on these drugs aren’t going to sue BMJ.

When it comes to on-patent drugs, BMJ provide news stories about medicine, medical entertainment. They are less likely than the NY Times or BBC to check the integrity of their primary sources.

BMJ and all our major journals have been turned.

Oh for the Blood of a Teenage Girl!

Water and drugs flow down even the slightest gradient unless there is something in the way.

The BMJ got involved in the Tamiflu saga in 2009 making it the basis of a “transparency” campaign – see Cisparency and Transparency next week – and later AllTrials.

Tamiflu is an efficacy story not a harms story.  As Peter Doshi and Tom Jefferson accessed more and more efficacy data the efficacy of Tamiflu shrank to almost nothing. But it only takes 1% efficacy to sell pills provided there are no bumps in the way, and nothing has happened to dislodge Tamiflu from the top of the guideline heap for use in cases of Flu.

The story of antidepressants and teenage girls is even more remarkable. There are now 30 RCTs of SSRIs and related antidepressants for adolescents and children – 29.5 negative.  Fluoxetine/Prozac is the most negative of the lot – there are 7 trials in which it has failed to beat placebo on the primary outcome measure including the two that led to its licensing by FDA and MHRA and EMA.

Surely not – you thought Prozac worked for children.  Why have you not heard of this?  Same reason you never knew Harvey Weinstein was anything other than a nice guy – with the extra reason that whatever about other enablers, bureaucrats never ever admit they’ve made a mistake, and the academic media aren’t any better.

There is an excess of suicidal events on antidepressants in every one of these 30 trials. In the only notionally non-company trial, the investigators in 7 major publications in leading journals from this trial “managed to conceal” the 34 suicidal events on Fluoxetine versus 3 on placebo – this requires an Editorial Nelson to be not just blind in one eye but very short-sighted in the other.

The BMJ has done more than conceal harms. It “enabled” a transformation of these life-ending harms into a “controversy”, when in 2014 it published close to the shonkiest, most ridiculous article any major journal has ever published on anything – the Lu et al article.

There seems no point in submitting an almost entirely data-driven, opinion-free, article on what the trials in teenagers show to BMJ, even though antidepressants are now the most commonly prescribed drugs to teenage girls.

Even though last week, the British Secretary of State for Health declared adolescent mental health services the biggest single weakness in NHS provision.  The great concern is that teenagers are self-harming while waiting for access to secondary services – now why would that be?

A few weeks before, the grisliest case report ever appeared in one of the few media still concerned about primary sources (Panorama). It covered the killing of twelve people in Aurora by a 24 year old on an SSRI, Black Boxed up to 25.  This case report is totally backed up by the RCT data. BMJ played a stellar role in dissing any possible link to the drug – abetted by a posse of Psychiatric Association Presidents and ex-Presidents.

If on a Winter’s Night a Traveller…

With the creation of Dracula, Bram Stoker, a Dubliner, globalized the Celtic feast of Halloween. Both Dracula and Stoker left their place of origin and came to England.  When last heard of, Stoker was working a few blocks down the road from the BMJ office…

To be continued

 

RxISK Prize

Over on RxISK, we have launched a RxISK Prize.  The hope is to find an answer to the debilitating disorders of Post SSRI Sexual Dysfunction, PSSD, Post-Finasteride Syndrome, PFS, and Post Retinoid Sexual Dysfunction (PRSD).

Please check this out and pass the word on to any pharmacologist, physiologist, endocrinologist, biologist, electrical engineer, doctor, herbalist, and anyone else you can think of and get them to pass the word through their networks.  We need someone to find a cure, to whom we can hand over the Prize.

David Healy

 

We are the Ninety Nine Percent

99 percent

Editorial Note: This is a Coda to the four posts about Sense about Science and AllTrials – Follow the Rhetoric, First Admit no Harm, Follow the Lawsuit & Follow the Patient.

The last post ended on this note:

Over 18 months ago, RxISK attempted to open up a debate on the ambiguities and conflicts at its heart. Doing what it does, could it operate as a business in the marketplace or should it be a Foundation or an Occupy your Doctors’ Office movement?

It seems clear that although legally obliged to access any adverse event data they are aware of, pharmaceutical companies seem unlikely to endorse RxISK in the way they have endorsed AllTrials. They seem to be pushing us toward finding something more co-operative – perhaps something that is not out there yet – perhaps something that David Graeber or Thomas Piketty might have views on.

Over the next few weeks on RxISK, we will be featuring a series of just published articles based on RxISK data – one on what is now a Ninety-Nine + case series of SSRI induced Alcoholism. A second on what is an over one hundred and twenty case series of persisting sexual dysfunction following SSRIs, isotretinoin or finasteride. The third will be on a novel ethical dilemma linked to reports of QT-interval changes.

There are several hundred cases embodied in these articles covering most antidepressants and a number of other drugs. Companies who are interested in the safety of their drugs, or companies simply keeping to the letter of the pharmacovigilance law should be contacting us to enquire further whether their drug was involved, as might also the companies gearing up to market S-3 antagonists for alcoholism. How do we deal with this? Who pays for the work involved in establishing which version of paroxetine was involved?

Could RxISK be captured?

Quite possibly. Industry can capture almost anything – they may have captured AllTrials. They are making great efforts to capture, defang or otherwise manage patient adverse event reporting systems. GSK’s ability to hide clinical trial data pales compared to the subtlety of their approach to and lengths to which they appear to go to block or otherwise hide adverse event reporting – See American Woman, American Woman 2.

Some pre-capture RxISK principles

  • Doctors and patients make medicines. Industry make chemicals. A medicine is a combination of a chemical and information about how to use that poison to bring good out of a bad situation. Doctors, nurses, pharmacists and patients make the information that transforms a chemical into a medicine.
  • Doctors and patients are the only bulwark against the degradation of medicines caused by branding and marketing. Regulators and academics or other experts aren’t.
  • Medicine involves following the patient. It’s the inconvenient patient, with the inconvenient problem that points the way forward.
  • The marriage of patient and doctor is often cast as a marriage of scientific and personal expertise with lip-service paid to the equality of both forms of expertise. But in fact faced with an inconvenient fact, a doctor’s expertise almost by definition risks getting in the way – this is the time for doctors to work with patients as genuine equals. This is where doctors find out that a motivated patient, even one with no academic credentials, is far more likely to turn up an answer than a bored researcher. This is where each finds out if the marriage is enduring. As part of a dowry, the patient who finds the answer to a problem will often happily let the doctor take the credit.
  • Embracing adverse events can restore the fun to medicine. It calls on doctors, pharmacists, nurses or others to be generalists rather than partialists. None of our drugs act on one system – there is more serotonin in the gut than the brain and more cholesterol in the brain than in the blood. To work out what is going wrong and put it right you have to draw on everything you have ever learned rather than just stick to the tramtrack of standard practice.
  • This is about making the market work properly. We ultimately are where the value lies.

The RxISK report

The main tool to move things forward is the RxISK report. When some anomalous event happens on the street, its axiomatic that the police get as many eye-witnesses as they can. In clinical practice this means you don’t want to leave reporting to hurried and disengaged doctors and you definitely don’t want to leave it to pharmaceutical companies for whom collecting details on a case is all about collecting excuses to rule out an effect of their drug.

It makes much more sense if a doctor or pharmacist or nurse comes to an agreed account with the person affected who has usually spent time with the problem and is motivated to nail down what is going on.

  1. It’s about good quality rather than degraded quality adverse event reports in the belief that good words come before good numbers.
  2. It’s about us being willing to make a judgement call that this event is likely to be linked to a drug in a way regulators will never do.
  3. It’s about intervening early in adverse events to reduce harms.
  4. It’s about adding local knowledge to the mix – getting people in Swindon and London (or Hamilton and Toronto; or Lyon and Bordeaux, or Verona and Milan, or Chicago and Milwaukee) to account for why something is happening in one place and not another rather than thinking someone with no local knowledge is going to sort it out
  5. It’s about taking on the power imbalance between doctors and patients.
  6. It’s about changing doctors into listeners – this can be done by getting patients to quality mark doctors based on those who agree to engage in the process versus those who don’t. We can force the deaf to hear us. We are the Ninety-Nine Percent.
  7. The RxISK report has led to the idea of a RxISK clinic and report as an even more potent way to equalize the power imbalance.

It’s about medicine as it needs to be if its going to survive. Leaving reporting to doctors alone has not worked – at present only 1% of adverse events are reported. The question is whether doctors have what it takes to save themselves by insisting on the evidence of their own eyes and reporting adverse events. Saving themselves will do more to save their patients than anything else could.