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 Pharmacosis

The Devil’s Disclaimer

Disclaimer rubber stamp

Editorial Note: The marketing of pharmaceuticals avails of something given to no other area of marketing – the product is made available on prescription-only. In this post Johanna Ryan, from RxISK’s Community Advisory Board, spells out the risks this gives rise to. This is a theme that has come up often and one we will return to.

Direct to consumers?

If you live in the USA, I don’t have to tell you about Direct-to-Consumer Advertising of prescription drugs. You’ve seen the TV spots all the time, introducing some disease that sounds awfully serious but whose symptoms are broad enough that you start wondering if you should “Ask Your Doctor.”

Then you hear about the wonder drug that is helping sufferers Get Their Lives Back. Happy couples stroll hand-in-hand through meadows or romp with their adorable children … while a polite voiceover tells you about vague but ominous side effects, from strokes and cancer to “certain fungal infections.” (And of course, those alarming “erections lasting more than four hours” which have become a staple of TV comedy thanks to DTC ads for Viagra and Cialis.)

Many of us suspect the drug’s advantages are being oversold and its risks artfully downplayed. But we also assume there must be at least one thing restraining all that hype: If patients run to the doctor asking for the drug, and suffer harm as a result, won’t that rosy TV ad be playing for a jury somewhere soon? Surely they can sue the drug company!

Cynthia DiBartolo

Actually, no, they can’t. An earlier column on this blog told the story of Cynthia DiBartolo, who developed head and neck cancer after treating her psoriasis with Humira, a widely advertised biologic drug made by AbbVie Corp. If you don’t live in the USA, you may be amazed by this sample ad for Humira aimed at women with psoriasis.

Ms. DiBartolo faces an uphill fight for justice because of something called the “Learned Intermediary Doctrine,” which holds that AbbVie’s only responsibility is to inform the doctor of all the relevant risks – not the patient. No matter how aggressively a drugmaker advertises, they can still leave the doctor holding the bag for their failure to warn the patient. In recent years the Texas Supreme Court upheld this doctrine even in the case of a woman who watched a drug-company video at the clinic where she got her first IV infusion of the drug (Centocor, Inc. v. Hamilton, 55 Tex. Sup. J. 774). And in Illinois, a man whose doctor sent him to a patient-education class taught by a drug-company nurse was not allowed to sue the company for its failure to warn him of the risk of blindness (Hernandez v. Schering Corp., 958 N.E.2d 447).

Given the odds consumers face, perhaps these ads ought to come with their own set of warnings. Here’s my proposal for a “Devil’s Disclaimer” to run with American DTC advertising[1]:

THE DEVIL’S DISCLAIMER FOR DIRECT-TO-CONSUMER ADVERTISEMENTS IN U.S.A.

If you should experience any adverse effects from this medication, please note the following legal disclaimer:

Don’t Come Crying To Us. Legally Speaking, It’s Not Our Problem.

It’s true, we have used this ad to approach you about your personal medical problems while you were innocently leafing through a movie-star magazine or surfing the Net. We seem quite warm and friendly. And we have supplied you with a long list of possible side effects and contraindications, via the small print or the mellifluous voice-over. (Not that you know what a contraindication is, you poor sucker.)

However, we do not and never will have a Relationship with you. So, it’s been nice getting to know you  – but no commitments, baby.

It’s not just us saying that either. The courts of just about every state in the nation are backing us up on this. So don’t go muttering about your father the police chief or your sister the lawyer. They can’t help.

Specifically, if you want to get all technical, we have no FIDUCIARY relationship with you. That’s the kind of relationship where we’d be expected to look out for your welfare, with the same degree of care that a reasonable person would devote to their own affairs. That’s up to your doctor.

All we’re obliged to do is give your doctor all the appropriate warnings, and let him sort it out for you. He’s the one that’s supposed to care, according to the courts. (Yeah, that guy – the one you just picked off the insurance company list. You can’t remember his name, and he can’t remember yours. But we’ve been snuggling up to him since he was in med school.) He’s in charge of digesting all that information, and thinking hard about how it applies to little ol’ you. And he’s the one we think you should sue if things go wrong. Let us know how that goes for you, okay?  LOL.

And what if we don’t tell him everything? What if we’re manipulating what he sees in his doctor journals and his continuing-ed seminars, just like we do with that celebrity magazine you were skimming? Oh, don’t worry. The FDA will make sure we do the right thing. (We know, because nowadays we pay the bulk of their salaries. Betcha didn’t know that.) And if the FDA doesn’t catch us, then we’ll definitely pay some kind of fine in nine or ten years. That’ll keep us in line for sure! ROFL.

So don’t come around whining that we promised you this, we promised you that. To quote that old country song, Here’s A Quarter, Call Someone Who Cares.

Or as we like to say: Ask Your Doctor.

LMAO,

<<Insert name of drug company>>


[1] Here is the actual disclaimer posted on one of AbbVie’s websites:

“The content on this site has been created solely for U.S. residents. It is intended for informational purposes only and should not be used to replace a discussion with a health care professional. All decisions regarding patient care must be handled by a health care professional, and be made based on the unique needs of each patient.”

Prescription-only Homicide and Violence

These are the speaking notes for two talks given in Chicago on Monday February 18th and Tuesday February 19th. The S2, S3 in the text refers to slides which are available on the RxISK.org Video Gallery. Video will be posted when available.

The first slides features RxISK.org where we have created a Violence Zone and want you to get anyone who may have been made violent or had their behavior disturbed by drugs to report – we will give you a megaphone to help ensure that what has gone wrong for you doesn’t blight someone else’s life also.

What stops us recognizing how drugs cause violence

This talk is about the things that impede recognition that drugs can cause adverse effects – and in particular stand in the way of recognizing they can cause violence.

You see here (S2) a child taking medicines from the medicine cupboard. In 1960 this would have been a barbiturate sleeping pill and it would have killed your child. Now you can replace this with Distaval – the new and safe sleeping pill.

Distaval is thalidomide which caused a major tragedy around 1960. In 1962 we put mechanisms in place to ensure that you would be safe from this happening again. The main safeguard was randomised controlled trials – RCTs. Companies now had to prove their drug worked before it would be allowed on the market. This is the major thing politicians and doctors think is keeping you safe – maybe you do too.

The person responsible for RCTs was Lou Lasagna whom you see here. He was one of the first people to do clinical trials, the first to put the placebo effect on the map, he wrote the modern version of the Hippocratic oath which doctors take when they qualify. Which of course, as you know, has the famous phrase ‘First do no harm’ (S4).

Dancing with pythons

There was recognition then that dealing with industry was like dancing with a python. They Dance with Pythons in Malaysia – S5. The trick is to make sure the python cannot anchor its tail onto anything because if it does it can squeeze you to death. This woman made a mistake and was later squeezed to death.

Lasagna made the same mistake and we are being squeezed to death by the clinical trials that he put in place that industry now run. We are squeezed by the fact that they withhold the data that comes from the risk you take in these trials.

RCTs do more harm than this. Here you see S6 a doctor and a pilot. Both report on adverse events. When a pilot reports a near miss or a problem she is believed – things change on the basis of her report. When a doctor reports on a near miss or a problem this is regarded as an anecdote and is discarded. Nobody pays heed to what the doctor says because clinical trials have persuaded everyone that you cannot believe the evidence of patients or doctors eyes.

Regulators never say a drug causes a problem

But there is an even more profound problem (S7). Any of you who are waiting for Health Canada, FDA or academics to agree that a drug has caused a problem will be waiting forever. The response from companies and regulators to thalidomide was that how do we know that it’s not preventing spontaneous miscarriages so that these children who wouldn’t have been born if their mother hadn’t been on the drug are now being born. They did not concede the obvious – that the drug was causing the problem.

Thalidomide is still on the market and still causing birth defects – this is not a baby from the 1960s this is a baby from Brazil in the 1990s where over a thousand babies have been born with birth defects.

The handling of the problems around thalidomide is in fact the norm. Let me introduce you to Matt Miller (S8). Matt was a 13 year old boy who had just changed schools and was feeling nervous. His parents prompted by the teacher brought him to a doctor who put him on Zoloft. Seven days later he hung himself in the bathroom between his parent’s bedroom and his bedroom. Trust me when I tell you the Zoloft caused this suicide.

The response from regulators and companies was that this could have been auto-erotic asphyxiation (S9). They went so far as to scour the carpet in the bathroom to collect potential evidence for seminal stains. Companies and regulators will NEVER say that a drug has caused a problem.

Shoot yourself in the foot – Report an adverse event to a regulator

They also make it difficult to report a problem. Look at the case in your handouts (S10-15). This is an American woman living in Michigan. She contacts GSK because she was on Paxil, became pregnant and found after six months that her baby had truncus arteriosus. She had a termination. This woman comes from an intensely Christian community where terminations are not acceptable (see American Woman).

She is hoping to get pregnant again but wants to know whether Paxil is safe. If not she wants to stop it.

GSK may have sent her the datasheet and told her to go and talk to her doctor. ‘We encourage patients to take questions to their doctor because your physician knows your condition and is best suited to answer your questions’. The datasheet says nothing about birth defects on Paxil and the doctor will have been told nothing. In fact all doctors are subject to an intense propaganda campaign saying that the only risk of birth defects stems from untreated depression.

Whether she has got the email from the company or not the woman responds asking is there any evidence that women on Paxil can have healthy babies. She ends up by pleading ‘where can I get this kind of information?’

It’s extraordinary that she got her email through to anybody. GSK have many phone numbers that don’t lead anywhere. The real phone numbers that would get through to them are hard to find. The phone numbers you see on DTC adverts or adverts in medical journals don’t reach GSK. The phone numbers that come with the drug often don’t reach anything to do with the drugs any more.

But since 2001, company adverts now advocate that you get in touch with FDA’s MedWatch system and talk to your doctor if you have a problem. What better way of doing things can there be than this. It almost looks like turkeys voting for Xmas.

Except that companies have a legal duty to follow up adverse events, to check and see what happened in order to work out did their drug cause the problem. Health Canada does not have this obligation, and so diverting reports to the regulators saves money, reduces legal liability and relegates any reports of adverse events to anecdotes. The same happens when companies refer you to your doctor but IT WON’T HAPPEN if you take your report to RxISK.org.

One rule for investors, another rule for mothers

So our Woman got through to GSK and they have a duty to follow up. What happened? S16 – two weeks later you see a letter saying: ‘In order to follow things up we have to contact your doctor, can you please give us his details’. But the letter went to a postbox and was never collected. Somehow the company has managed not to follow up.

Despite this, as you see here S17, companies have to categorise problems like this as unrelated, unlikely, possible, probable or almost certain.

In this lady’s case her report was categorised as almost certainly caused by Paxil.

Here is Dr Jane Niemann (S18) of GSK being asked under oath should this woman have been told that GSK had decided Paxil had caused the problem and she says no. She’s asked, ‘As a doctor, do you think this woman should have been told?’ And she says ‘No’.  She’s then asked, ‘As a mother, do you think this woman should have been told? And she says, ‘Yes, I do’.

Two years ago (S19) the Supreme Court in the Matrixx case decided that if you’re an investor in GSK you have a right to be told the adverse effects profile of a company’s drug. You have no rights if you’re a patient or a doctor but you do as an investor.

Shower and bidet

So how do we clean this mess? We can take a top down or bottom up approach, a shower or a bidet approach (S20).

RxISK.org is a bidet approach (S21). It’s all of us collecting what we observe is happening to us on drugs because the top down approach hasn’t worked. If we’re going to clear this mess it’s going to require all of us to report and build a database that companies and regulators and the media cannot ignore.

Unlike regulators we aim at getting quality reports of events and taking you through a causality assessment like the ones companies do – but we will also put local knowledge in local hands.

You see here FDA reports for Paxil which you can get on RxISK (S22). This drug has liver problems – in Japan. Our belief is that it is the Japanese who are going to be able to answer the question as to what’s going on.

In the same way we will put data in your hands so that if a problem is happening here and not in Detroit we figure that someone in either here or in Detroit is going to answer the question what’s going on here. Is it some interaction with other pill, or the local cuisine, or air pollution that is leading to the problem? We believe YOU have the expertise to solve most problems. You do not want to think that academics have this expertise. Regulators certainly don’t – they are just bureaucrats.

Thalidomide and Lasagna – The ultimate symbol

Back in 1962 Lasagna put a shower approach in place – RCTs (S23). Controlled trials will keep you safe. But, as of 1962, only one drug had been through a controlled trial before it came to the market. That trial had shown that this drug worked well and was safe. The drug was thalidomide (S24).

In addition to the above, other factors impair our ability to link drugs with effects including violence.

From Stockholm to Albuquerque

In 1973 the CreditBanken in Stockholm was raided and the staff kept hostage for five days (S25). When finally freed the media were astonished to find the liberated hostages talking warmly about their captors. This led to recognition that if you are isolated with a threat to your life, held hostage by kind captors, you identify with your captors and develop Stockholm Syndrome.

When we’re ill and put on a prescription only pill we’re isolated, with a threat to our life and our doctors who are the only way out are increasingly trained to be nice to us. This blocks our ability to say things that we think may cause them to be unhappy – such as this pill is causing me to feel suicidal or violent.

Prescription only arrangements do something else. The Crystal Meth at the heart of “Breaking Bad” causes terrible sex addiction and violence (S26). But it began life as Methidrine a pill for nerves. It was replaced with the more potent Dexedrine which in turn was banned before later being brought back, as you all know, as a treatment for ADHD. On prescription-only this monster comes with almost no problems it seems, while available on the street it causes terrible problems.

Even worse than Crystal Meth are dopamine agonist drugs like Ropinirole – which cause much more profound sexual addiction and dangerous behaviors such as gambling and promiscuity. But because they’re available on prescription the hazards of these drugs took 25 years to come to light.

The politics of access to treatment

There’s a further problem. Everyone today wants access to treatment. I approached ACLU about the fact that there are people in prison who are likely there because their drugs caused them to become violent but didn’t even get an acknowledgment from ACLU that I had written (S27).

In the same way the Boston Women’s Collaborative don’t want to hear that antidepressants could cause birth defects or mental handicap in children. They only want pregnant women to have access to antidepressants and are part of a movement that has pushed the use of antidepressants in pregnancy up to record levels.

When it comes to violence, a range of political forces are using school shootings as an opportunity to press for gun control (S27). Those pushing this case are not likely to want to hear about a role that drugs may have played in causing school shootings.

Some of the cases I’m going to talk about involve husbands murdering wives. We do have to take into account that even before Prozac the commonest detected murder was a husband murdering his wife. The commonest murder may be a wife murdering her husband (S28).

Finally, as you will see here, when the first warnings about antidepressants causing suicide and violence came out in 2004 the American Psychiatric Association took a stand saying that APA believes antidepressants save lives (S29). To this day they still find it difficult to accept the evidence that these drugs cause more lives to be lost than they save – nowhere more so than here in Chicago.

Do drugs cause violence?

The antidepressants now come with black box warnings of suicide and in some jurisdictions such as Canada they come with warnings of violence also. Exactly the same mechanisms that lead to suicides lead to violence. In one case you have violence directed inward and in the other directed outwards. These mechanisms are akathisia, emotional blunting and psychosis.

Yvonne Woodley whom you see here (S30) went on an SSRI for minor stress and when she got worse the dose was put up and when she got even worse the dose was put up again. This was very clear akathisia. She then committed suicide.

The UK medical director for Lundbeck, who make the drug she was on, was asked by the coroner two questions: “Do you believe that Citalopram can cause someone who would not otherwise do so to take their own life?” (S31). He answers ‘Yes’.

When companies are asked this question ordinarily they refer the media to academics or doctors who are not legally obliged to say “yes” in answer to the first question. Or they will answer the question: “Did your drug cause Yvonne Woodley, to commit suicide?” This is a question can always be answered “No”. But if asked the direct question “Can your drug cause someone to commit suicide?” companies legally have to answer “yes”.

How do drugs cause violence?

The mechanisms that lead a drug to cause suicide are the same that produce violence. The first of these is akathisia. Here (S32) you have great descriptions of the agitation antidepressants can cause. These came from the use of a drug called Reserpine given to normal people as an antihypertensive. There is no mental illness here to cloud the picture.

The next mechanism is emotional disinhibition or blunting. This has been recognized by takers for a long time as you see here in this Peanuts cartoon, and yet another cartoon here from 2005 (S33-36).

I don’t have a slide for the voice of God – to represent the fact that drugs can cause you to hear a voice or become delusional and lead to violence this way. This is strictly speaking delirium rather than psychosis.

SSRIs in the dock

The modern story about drugs and violence begins here in 1989 when Joseph Wesbecker in a mass shooting killed eight of his co-workers before killing himself. He had been on Prozac for a month and the drug had unquestionably altered his behaviour. The company appeared to get a verdict saying that Prozac was not guilty when in fact it turned out the case had been settled (S37).

Schell

Things changed with this case involving Don Schell (S38). Don Schell was a 60 year old man who over 14 years had several brief episodes of anxiety that lasted at the most for a few weeks. In 1990 shortly after it came out he was treated with Prozac but had a very poor response and may have begun to hear voices while on it.

Eight years later an entirely different doctor gave him Paxil having diagnosed poor sleep and anxiety. 48 hours afterwards Schell who you see here put 3 bullets through the head of his wife, 3 bullets through the head of his daughter and 3 through the head of his grand-daughter who were visiting before killing himself. His son-in-law Tim Tobin took a case against GSK and won a jury verdict (S39).

Hawkins

In the same week that verdict came in, the case of David Hawkins was heard. David Hawkins was a 74 year old man with a 20 year history of minor episodes of nervousness, no violence. In one of these he was treated with Zoloft and had a bad response to it. His doctor recorded “Do not give this man SSRIs” (S40).

A number of years later feeling unwell he was seen by a locum doctor who didn’t know the history and didn’t read the notes and put him on Zoloft. He didn’t know that he was being put back on a pill that he had reacted poorly to before. He felt worse after one pill and thinking that more would help took four and the next morning strangled his wife to death. The judge and prosecution agreed with Tania Evers for the defense that but for the drug it was unlikely this would have happened (S41).

Bentley

Here you see Merrillee Bentley, a 32 year old mother of two (S42). She had been anxious for years. She was finally put by her doctor on Paxil and the dose was put up. She did even worse on that and so was switched to Efexor. She got worse and the dose was pushed up and up to 350 mg per day. The notes record that on Paxil and later Efexor she became visibly more agitated.

She took her children for a drive in the car, stopped, plugged a hosepipe into the exhaust and turned on the engine. She gave up when the children talked about being itchy. She drove further and tried again. She didn’t know that her car had a catalytic converter. She turned herself into the police who charged her with attempted murder.

Her drugs were stopped, she returned to normal. The judge concluded that but for the influence of the drug she would not have done this.

Ablixa?

MC’s case involves a 23 year old man with a history of cocaine misuse (S43). He was prescribed Paxil to try and stop him taking cocaine. He stopped cocaine but began drinking more heavily. We now know SSRIs can cause alcoholism (see Out of my Mind: Driven to Drink). This led to a break up between himself and his partner. He lived with his parents but every so often came to stay at her house.

This evening they both drank, they had a quarrel. She insisted he sleep downstairs, she went to bed. He took his pills. Next he arrives covered in blood with the baby at the police station. The police went to his house and found his partner stabbed brutally to death. He has no recollection of what has happened.

The mystery centers on the changes at the heart of Side Effects. It turns out that at this time Paxil was the drug most commonly linked to sleep walking and the next most commonly linked was Zopiclone the hypnotic he was on (S44). These drugs are also linked to nightmares, Paxil is the most commonly reported drug linked to nightmares. They are also commonly linked to sleep terrors. As you can see the SSRIs very heavily represented as are statins which are also a group of drugs linked to violence.

Despite a history of sleep-walking that only started with his meds, MC was convicted of homicide.

Bennett

Here’s Jake Bennett a 66 year old taking Librium and Doxepin – remarried to a younger woman. It was an argumentative marriage but not violent (S45). She was unhappy with the fact that he was just too sleepy. She had been trying to empty out his Doxepin pills, and this led to them both going to the doctor, who recommended a switch to Prozac.

Over the following few weeks Jake became paranoid that his wife was again interfering with his pills. She mentioned this to many of her friends – and that she was getting a little more alarmed about being in the house with him. Two months later he stabbed her brutally to death 200 times. He was found not guilty by reason of insanity. The insanity cleared once the Prozac was stopped but he remains in prison hospital for the rest of his life because, even though the Prozac was stopped, nobody was prepared to take the risk that it really was just the Prozac.

Demeniuk

Leslie Demeniuk here was the 30 year old mother of twin boys (S46). She self-diagnosed with panic attacks. At her local clinic she was given Zoloft by the nurse. Over the next month she became suicidal and began to drink – SSRIs can cause you to drink to excess. She was switched to Paxil and 48 hours later she killed both of her twin boys with bullets to their heads. She overdosed herself heavily but did not succeed in killing herself. When she came to the police were there.

Older Men in Britain

Not featured here is an 80 year old man I saw who had a minor stroke. He didn’t rehabilitate as quickly as his doctors wanted. They regarded the fact that his bed wasn’t coming vacant as an indication that he was depressed. They put him on an SSRI. When he didn’t respond instantly they called me to see him.

I found a man who didn’t seem to be depressed. I stopped the SSRI and came back after a few days to see him. He told me “I’m fine and very relieved now… You see that man across there? I don’t know who he is, but while I was on those pills I had a terrible urge to get up in the middle of the night and go over and kill him. Those feelings have gone completely now that I’ve stopped that drug.”

The next man (S47) was fifty years married, no history of violence or nerves. He became anxious. His doctor put him on Citalopram. He kept a diary during the ten days he was on this that shows him clearly becoming more agitated and restless and beginning to voice thoughts that if he continued to get worse he was going to end up in the madhouse. He began to talk about killing himself to friends. Ten days on the drug he battered his wife to death. He called the police and was jailed.

I wrote a report stating he was not guilty. His legal firm advised him to cut a deal with the prosecution – he would only get 3 years. When released his daughter took him into her home but the community from which he came shunned him. They saw a convicted criminal and no-one would have any dealings with him.

Pittman

Here you see Christopher Pittman and his grandfather (S49). Chris preferred living with his grandparents than with his father and after an argument with his father in Florida he ran away to his grandparents in South Carolina. He was picked up by the police and taken to a facility for young people where he was reviewed, said to have no mental illness, but was still put on Paxil.

His grandparents came to visit him and he was discharged to them (S50). He was switched to Zoloft because their doctor had no Paxil samples. He went to a school he had gone to before. But where before he had got on extremely well, now he had fights and arguments in school and on the school bus. When they went to church he was restless and couldn’t keep still and was told by his grandparents if this kept up he would have to go home to his father in Florida. Later that night he claims he heard a voice telling him to shoot his grandparents. He took his grandfather’s gun and shot both of them while they were lying in bed and then burned the house down.

Chris was 12 when all this happened. He was tried as an adult. The newspaper coverage focussed on the question of Evil or Chemically Compelled (S51). The jury found that the Zoloft that affected Chris. But that he was guilty of murder.

Judge Pieper you see is disturbed by the implications (S52). “There is no case in South Carolina that addresses involuntary intoxication by prescription drugs…It seems to turn the whole medical system on its side if you can’t rely on the medication your doctor prescribes. It potentially forces you into a situation of lifetime commitment if that drug induces effects of which you are unaware. There is something disconcerting about that, albeit probably of a legal nature that is troubling me (S53).”  Disconcerted or not, Pieper imposed a 30 year sentence on Chris Pittman.

Drug induced frenzy or delirium – The original insanity defence

There is a technical term for the medico-legal issue at stake – an automatism. This is a disturbance of the mind or brain such that the mind an ordinary person would be unlikely to withstand. One of the best examples of this is sleep-walking. If you walk in your sleep and commit a murder you cannot be found guilty because you didn’t intend to commit murder (S54).

In the same way if under the influence of a drug like LSD you step out of a 24th floor window people will not regard that as suicide because you couldn’t have intended to commit suicide.

Prescription drugs introduce an interesting complication of this – the issue of involuntary intoxication.

These issues were discussed and resolved by Sir Matthew Hale, the Lord Chief Justice of England in 1676. You see him here and you see his book which is used much more in the US than in the UK (S55).

Hale outlined the original insanity defence – “If a person by the unskillfulness of his physician, or by the contrivance of his enemies, eat or drink such a thing as causes a temporary or permanent delirium – this puts him into the same condition, in reference to crimes as any other delirium and equally excuses him” (S56).

Most of the insanities of the time were linked to fevers and other physical illnesses such as poisons or drugs. If you are delirious for whatever reasons, you are not guilty. An easy concept then – and now.

This is the original insanity defence and it works perfectly for states of delirium. The problems with the insanity defence began with this man Daniel McNaughton, who didn’t look delirious when he tried to kill the person that he believed was the prime minister of England (S57). He was operating under the influence of a delusional belief. Courts have struggled ever since with the issue of when to excuse people who are deluded. This is a different issue to excusing people who are delirious.

Data on drug induced violence

Let’s move on to some data. Here are data from the Drug Safety Research Unit in the UK showing that roughly 1 in every 200 people put on an SSRI go on to a violent action (S58).

Close to all the scientific literature about all these drugs is ghost written. You see here (S59) part of a brochure of articles prepared for Pfizer on Zoloft by Current Medical Directions, a medical publications agency based in New York. Here on the right, you see the papers have been completed and on the left the authors of these completed papers remain TBD.

In the brochure there are articles in preparation on Zoloft for children. Pfizer later attempted to get Zoloft to the market for children. Here are the data from two ghostwritten Zoloft studies, which combined make it clear that Zoloft poses a much bigger risk than placebo for aggression and states linked to it (S60).

On this slide (S61) you see, Study 329, one of the most famous studies of all time which has an authorship line to die for and was published in the leading journal in child psychiatry. However, none of the authors is on this authorship line. This article was ghost written.

The published data were at odds with the company’s internal assessment of what the trial showed. Here (S62) you see three years previously they face a problem – the results are so awkward they can’t give the data to the FDA even though they will get half a year’s worth of patent extension if they do – close to a billion dollars. What they will do instead is to take the positive data from the study and publish those – and this becomes study 329 which you have seen in the previous article.

This led New York State to take a fraud action against GSK which the company resolved by claiming it posted all of its studies up on the company website. People get the impression that the company’s posted their data on the website. It hasn’t. But from the data there and submissions to regulators we can glean the following data on Paxil and aggression.

This slide (S63) shows you the hostile events that happened on Paxil and placebo in placebo-controlled trials of Paxil. You will see that overall Paxil compared to placebo leads to a doubling of hostile events. Hostile is code which includes aggression, homicide, homicidal ideation and homicidal acts.

You will note that in PMDD trials the risk is infinitely greater on Paxil than leaving PMDD untreated (S64).

Violence in healthy volunteers

Of even greater interest are the healthy volunteer trials you see here. These were done before the drug was ever on the market and you see that there are very clear indications long before – this was in the 1980’s – that the drug could make people aggressive.

In 1983 Pfizer ran a healthy volunteer trial of Zoloft in Leeds (S65). Six women were randomised to Zoloft and six to placebo. All the women taking Zoloft dropped out after a week with agitation and anxiety of various forms and in one case notes about aggressive impulses. Pfizer concluded in 1983 ‘Our drug has caused this and this is a well-known feature of SSRI drugs’. This is 1983 – 9 years before marketing.

Unaware of this result we ran a healthy volunteer trial in North Wales using Zoloft also and two of our healthy volunteers, one of whom you see here, became aggressive on the drug. This, I’m sure you will agree, is a fairly normal looking woman. Not the kind that you would expect to become seriously aggressive (S66).

We’ve known for fifty years

How long has all of this been known? You see here one of the first meetings in England, on the new serotonin reuptake inhibiting antidepressants in this case imipramine. In 1959 a year after the drug was launched a meeting was held. At this the participants at the meeting discussed the fact that in the early days of treatment patients can become very agitated and are at risk of going on to commit suicide. You see here one of the delegates say they also have dreams of aggressive content (S67-70).

Psychiatrists committing suicide

We’ve seen that when concerns about suicide on antidepressants came up the APA responded by saying they believed that antidepressants saved lives. They should of course have written that psychiatrists saved lives (S71-72).

Let me take you back to the Woodley case (S73). You’ve seen the medical director of Lundbeck say that our drug can cause people to commit suicide. He went on to say that if people do commit suicide it’s the fault of their doctor. He said this with the doctors who had been treating Yvonne Woodley sitting in the inquest. One of these, Dr Milner, was then called to testify and you can see to the surprise of the coroner she says no, she doesn’t believe citalopram can cause anyone to commit suicide even though she has just heard the company say that it can (S74).

What you see in the next slide is a collage of photos – the victims from VA Tech, flowers laid at Sandy Hook and the doctor looking after James Holmes, in Aurora (S75). We could have turned these the other way around and had the photographs of the victims at Sandy Hook or at Aurora or the doctor from either of these scenes.

I want to end with another doctor who caused a stir recently when she was convicted after one of her patients hacked a man to death (S76). Danielle Canarelli was convicted of not recognising the hazard and not intervening early enough. Doctors worldwide were shocked at this. They could see the implications.

In the case of prescription drugs, what defence does a doctor have to fall back on? The risk of violence on these drugs has been known for 50 years. It’s known that even giving these drugs to healthy volunteers can cause them to become violent. The data has been out there in warnings in many countries for 10 years. It may be disputed but there is no doctor who can say that they simply couldn’t have been aware of this issue. If there are, they are simply not professional.

The violence and extreme behaviors zone

So back to RxISK. You see here that on RxISK we have created a Violence and Extreme Behaviors Zone (77-78). This gives you all the FDA data linking various drugs to extreme behaviors – for free.

But we need you to report. Controlled trials can never establish a link between a treatment and a complex behavior like violence. Proportional Reporting Ratios can give valuable information on which are the riskiest drugs. We believe that best way to establish whether a drug can cause aggression is by getting good quality descriptions of what happens and seeing what happens when the drug is stopped and then possibly restarted.

Victim support?

There is one final barrier to the recognition of violence on psychotropic drugs – the families of the injured and bereaved have to in some cases be prepared to let the apparent perpetrator walk free.

On the final slide (S79) you see Shane Clancy, who broke up with his girlfriend – and then decided he wanted to get back with her but she had move on to someone else. Shane was brought by his mother to the doctor who put him on Celexa. I know he took them because he developed side effects that almost no-one knows about. He also tried to commit suicide. So he was brought by his mother back to see the doctor who continued Celexa, and a few days later he killed his girlfriend’s new boyfriend and attempted to kill her and the new boyfriend’s brother before killing himself by stabbing himself frenziedly 23 times.

A rural jury of Irish men and women in their 50s and 60s, shop-owners, small business people and farming people returned an open verdict – this was not suicide and by implication not homicide. The familes of those assaulted by Shane cannot see him as a victim and have appealed the issue to the Irish Parliament and are trying to take it further.

It is almost unimaginable that people can be asked to exonerate the person who has killed those nearest and dearest to them. But equally in a time where we recognize the rights of victims, we need to recognize that if we don’t find a way to bridge this chasm then one set of victims – the families of the person who was on the drug – become the most cruelly isolated of all and are isolated by other victims.

Prozac and SSRIs: Twenty-Fifth Anniversary

25th Anniversary

One prescription for every man, woman and child

Prozac was approved in 1987 in the US, and launched in early 1988, followed by a clutch of other SSRIs. Twenty-five years later, we now have one prescription for an antidepressant for every single person in the West per year.

Twenty-five years before Prozac, 1 in 10,000 of us per year was admitted for severe depressive disorder – melancholia. Today at any one point in time 1 in 10 of us are supposedly depressed and between 1 in 2 and 1 in 5 of us will be depressed over a lifetime. Around 1 in 10 pregnant women are on an antidepressant.

No one knows how many new cases of depression there are per year partly because modern depression is a creation of the marketing of Prozac. Until recently what is now called depression was called anxiety, nerves or a nervous breakdown. SSRIs can help some cases of nerves but they are of no use for depression proper – melancholia. But the money for companies lies in treating nerves not melancholia – and as a result any of us with severe depression is likely to get worse treatment now than we once did.  We’ve gone backwards.

How many hooked?

By 1999 the number of us taking SSRIs chronically equaled the number starting an SSRI each year. By 2003, over 6 million Americans were taking an antidepressant semi-permanently – along with over 6 million Europeans.

The number of prescriptions for antidepressants is increasing by 5-10% each year, while the figure for people starting each year remains the same. This means that there is an increase of 5% to 10% in the number of people hooked to antidepressants each year.

Lives lost

There is no research evidence to suggest that anyone’s life is saved by taking an antidepressant but if there are lives saved the research makes it clear that for every life saved there must be another lost. There are probably something between 1000-1500 extra suicides in the US each year, triggered by an antidepressant – an extra 2000 -2500 in Europe.

The data is similar for violence. There are probably between 1000- 1500 extra episodes of violence in the US each year that would not have happened without antidepressant input and between 2000-2500 extra episodes in Europe.  Some of these will include school or other mass shootings which were unheard of twenty-five years ago.

Aborted families

About 4000 families in the US have children born with major birth defects each year because of antidepressants taken in pregnancy. Up to 20,000 women per year have a miscarriage because of these drugs and a large number have voluntary terminations linked to antidepressants. Miscarriages are among the biggest single predictors of later mental illness and substance misuse in women.  In Europe these figures likely run at an extra 6000+ birth defects, 30,000+ miscarriages, and who knows how many extra voluntary terminations.

Most children born to mothers who have been on these drugs do not have obvious birth defects. But it increasingly looks as though these children may show cognitive delay and other autistic spectrum features.

The dead doctor sketch

Perhaps the greatest casualty of Prozac has been holistic medicine. Imagine you have numbness in an arm or pain in a shoulder. If referred to an orthopedic or neurology department you will have every conceivable scan or test to pinpoint the problem. Chances are the clinic will find abnormalities and attempt to put things right – abnormalities that are not the source of your problem. A good generalist, who knows your circumstances, relationships, difficulties at work and the community from which you come, can spot when aches and numbness stem from strain or tension – they see you rather than bits of you.

Prozac has killed Generalism. It did so by focusing attention on mood in the way neurologists hyper-focus on nerves. Psychiatrists have become the doctors who deal in heroic combinations and doses of pills rather than doctors who, like generalists, step back and take a broader view.

Prozac has also killed therapy – just like Prozac CBT has a hyper-focus on thoughts rather than the big picture. CBT has also become a conduit into antidepressant prescribing as therapists regularly suggest softening up a depression with pills.

Psychiatry leads the way

Many see or saw psychiatry as a medical backwater with grim, overcrowded hospitals, and a dim understanding of the disorders it treats. In fact it was the first branch of medicine to have specialist hospitals and journals, the first to discover the bases for and eliminate several serious disorders, the first to adopt rating scales and controlled trials. And with Freud’s son-in-law, Edward Bernays, it was the first to step into public relations.

Twenty-five years ago, no one could have imagined that the bulk of the treatment literature would be ghostwritten, that negative trials could be portrayed as glowingly positive studies of a drug, that controlled trials could have been transformed into a gold-standard method to hide adverse events, or that dead bodies could have been hidden from medical academics so easily. Twenty-five years ago no one would have believed that a drug less effective for nerves or melancholia than heroin, alcohol or older and cheaper antidepressants could have been brought on the market and that almost as a matter of national policy people would be encouraged to take it for life.

The Boy With The Ponytail Who Kicked The Hornets’ Nest

In The boy with the ponytail who played with fire, we saw Jan Akerblom struggle up the side of a mountain in his attempt to drop the Ring of Power into Mount Doom. Where others, especially doctors, are seduced by the Precious he isn’t.

Why do it – because he saw lives destroyed and wonders if we are at risk of destroying society itself. Are any contracts anyone enters into while on an SSRI valid. Far-fetched?

Who cares in Sweden

My wife has left me

Imagine you are approached by someone who says his wife has been on an SSRI for several years and during this time she has changed personality. Where once she was very sensitive and caring she has become more callous and unfeeling. Where once she would be in floods of tears at a weepy movie, at the funeral of a beloved twin-brother who died in tragic circumstances she didn’t cry at all.

He contacts you because now she has left him. He concedes that maybe the marriage was heading for the rocks anyway but he is still concerned that this is not her. That if she ever stops the medication and starts feeling more like herself again she will regret what she has done – if not to him at least to her children.

What do you do?

There is abundant evidence SSRIs can cause exactly this kind of emotional blunting or disinhibition. The comments by Neil Gorman and Allostrata on The boy with the ponytail give detailed accounts and references. One of the first articles on the topic had a Baltimore society hostess while on fluvoxamine serving her guests wine while naked from the waist up.

Its worth thinking for a moment before reading on – if you were the doctor, what do you do?

It’s almost impossible to know. Little details can change the picture dramatically. Perhaps he is much older than her and now that she has grown up she has found herself and resents his control and the SSRI disinhibits her just enough to make it possible to do what she might in many respects be better off doing – leaving him. Would it really be better to live a safer life or a life of quiet desperation?

If you’re her doctor and he approaches you, what do you do? If you suggest reducing the dose and she insists that no this is the real her and perhaps brings friends along who vouch for the fact she is now doing what they’ve implored her to do for years, what do you do? Perhaps she tells you she will get the drug through the internet if you don’t prescribe.

Who are you to decide these important issues for someone else? You’ve had no training in matters like this. Better surely to play Pontius Pilate, continue prescribing, and let events take whatever course they will.

Who cares – about side effects?

Except as Who Cares in Sweden makes clear you cannot wash your hands of this responsibility.

This is not Side-Effects, the movie. You’re not in the position of Jonathon Banks (Jude Law) treating Emily Hawkins (Rooney Mara), whom you’re having an affair with and whom you’ve put on a new prescription drug, who has then perhaps gone on to kill her husband – we have to wait till February to see what actually does happen.

Unbelievable though it doubtless sounds, it’s worse. You are as much a police or probation officer as the doctor with whom every patient you prescribe for might want to have an affair with. This is whether it be an infant or a 96 year old. Prescription-only was a system introduced to control opiate and cocaine addicts. Anyone who gets their drugs through you is trapped in a set of Stockholm syndrome dynamics neither you nor they asked for.

But whether you asked for it or not you make your living out of it and the buck stops with you. Every inappropriate divorce, birth defect, school shooting, suicide, or case where a woman schoolteacher molests a juvenile male pupil that comes from your practice is your responsibility. Every heart attack on Chantix, cognitive dysfunction or muscle weakening on statins or premature death on the next Avandia or Vioxx is down to you. Every love affair that might happen on a clinical trial you are running is down to you. But you can’t find out what dramatists think the implications are because The Effect is booked out.

If it were your son?

If you have a son who is a fireman and his life depends on others in the fire crew “caring” normally, what do you do if a fireman’s wife comes in to you and says that her husband has been showing no emotions lately? Or her husband is a pilot with the airline that your family are due to fly with in a week’s time?

A cutthroat

If you appeal to the fact that you can’t be blamed for companies withholding data, you end up in a cutthroat. Either you say that whatever the data now reveals you would have used the drug anyway in which case the company walks away with no legal liability.

Or else you say you wouldn’t have used the drug but how can you be blamed if companies withhold data. Sounds good, except we’re not talking breaking news here. The information about SSRI induced disinhibition, violence and suicide has been in the public domain for nearly 25 years. The information about significant hazards on prescription drugs in general is out there for up to 20 years on average before you and your colleagues pay heed to it.

These drugs are available on prescription only because it was once thought you were the kind of person that might be able to quarry information out of companies or would steer people away from drugs if you were worried that we weren’t being told the full truth – it’s called professionalism.

They’ve started prosecuting doctors

Just recently a French psychiatrist Daniele Canarelli, 58, was found guilty after a patient of hers hacked a man to death. The court decided she should have recognized the risks he posed. This was the first case of its kind and it led to extensive media coverage worldwide because of the implications for doctors in general. It followed hard on the heels of a conviction of Italian seismologists for failures to warn sufficiently of earthquake risks.

Somewhere around 90% of the school or other mass shootings that have happened in recent years in America or Europe have involved shooters on psychotropic drugs usually antidepressants. The public sympathy for the victims typically also extends to the doctor who is seen as one more victim. But the so called perpetrator is much more likely to be a victim than the doctor. He may have been turned into a guided missile by his doctor. These are people in treatment whose doctors clearly failed to recognize the risks they posed.

Does anyone care in Sweden?

The Boy With The Ponytail Who Played With Fire

Who cares in Sweden

He is 6’4” at least – 192 cm. He has blonde hair tied back in a ponytail. When he first suggested making a program about SSRIs I was not very helpful – very little of the media coverage by 60 Minutes or anything else has ever seemed to make much of a difference. They may have just increased the sales of antidepressants by keeping the names of the various drugs in the limelight. And he was suggesting more talking heads which the cutting edge of journalism tells me is past tense.

But he was persistent and turned up on my doorstep, putting himself up in a very cheap hotel, because as I found out later he had almost no money. Many of the people I put him in touch with as he and his son Elias wound their way literally around the world making their program were far more generous than I in accommodating them in their own houses.

Who is he?

Who was he? He is Swedish and his wife Mexican – a striking genetic and cultural mix. She makes wrought-iron jewellery. He had been a classical musician but had decided orchestral living was not for him. This had led him to film-making. But finding work was difficult.

He was gifted. Seeing him edit the huge volumes of material he amassed, produce graphics to illustrate points and carve out a distinctive story line all in the apartment in Stockholm in which they lived – you couldn’t but be impressed. This was a far cry from BBC or CBS or CBC or NBC studios. When I went to visit him in Stockholm, the American version of The Girl with the Dragon Tattoo had just come out and it was difficult not to think of Lisbeth Salander.

Swedes would listen he said. He knew his countrymen and women. They still believed what they heard on the news and read in newspapers and they just needed to be told the truth up front. This didn’t seem completely naïve to me, Swedes are a bit like this. I was certain the rest of the world wouldn’t listen but if one country really did take the message on board who knows…

Who cares in Sweden?

The central idea was all his. He and Elias both had friends who were put on an SSRI who had lost their personalities. The drug produced a lack of caring that had spreading consequences for everything. Both had lost friends and families. But no-one said anything. Jan talked to eight doctors about it and they all told him he was wrong, “the medicine did not have these effects”. Finally he talked his friend off the medication and his personality was reborn.

If the doctors instead had answered: “That was interesting, I will keep that in mind.” … then he probably wouldn’t have started the project.

He ended up coming to me because he began by asking Swedish doctors to participate in the film and noticed that almost all said no. It would be too dangerous for their careers to be involved. He was regularly asked by doctors and politicians and others if he belonged to the Scientology Church. This puzzled him as he knew nothing about Scientology. He was also not anti-medication – several family members had been greatly helped by medicines.

Slowly he came to the view that Swedish journalists didn’t talk about the obvious corruption in Sweden because they didn’t care about the issue. For Jan the idea that a great deal of money from the pharmaceutical companies is being used to corrupt society is a non-starter as an explanation.

This is the case even though doctors are being corrupted. As he puts it “there is money that is being distributed as cash in small envelops, hand-to-hand or as repayment for consultant missions. The money can also be found hidden as funds for research or equipment or as invitations for doctors and journalists to international meetings. These offers are mostly sponsored by the pharmaceutical industry – all kinds of “services” seduce the recipients.

“Doctors end up getting trapped. On return home their colleagues never find out what really happened. They show their respect or feel envy for their colleagues who receive higher salaries, reputation and influence. Only a few people in Sweden acknowledge today how bad the situation is. Ignorance is massive”.

“That’s why we had to travel to foreign countries in order to find people willing to speak to us. As individuals we can’t make big changes or tell politicians, journalists or the justice system what to do. But as a production company, we are definitely able to produce films that may be helpful for society. There are many people searching the Internet for information about side effects that doctors have been taught to deny”.

Swedish catatonia

I knew nothing about his views when we met first. I was struck by another idea of his. If the treatment could produce something like this in his friend, there seemed to him to be no end to the implications. Would any of the contracts his friend might have entered into during this period, from business contracts to relationship contracts, to legal contracts, to property deals be valid? Were the contracts anyone entered into while on these medicines – stockbrokers, bankers, lawyers – valid?

The more he explored the more he found firemen who were aware of the effects on them or on those who had set fires by accident or on purpose, judges who were aware of the effects within the legal system, doctors treating children who knew of the effects – all of whom facing the problem turned mute and were paralyzed.

There is a condition called Catatonia that can be induced in animals by facing them with tasks such as having to distinguish between an oval and a circle in order to get a reward. As you gradually start making the oval more circular and the circle more ovoid, the dog or other animal gets distressed and finally freezes.

We can cope with judgement calls about responsibility when people who are normal do things and when people who are on an LSD-trip do something – especially if the person has been slipped the drug without knowing it. When someone in the midst of an LSD trip steps out of a twenty-fifth floor window, we do not regard this as suicide. LSD works on the serotonin system. Start making it harder to distinguish between normal and treated serotonin systems and both people and Society freezes up.

A Norse myth

I felt I was being educated about the drugs by someone who had no background in the issues. It was a story that definitely needed to be made if only because it has the dimensions of a Greek tragedy or myth.

The SSRIs are after all a Swedish invention. Arvid Carlsson who later won a Nobel Prize produced the first SSRI, zimelidine, 3 years before Prozac was made. Carlsson deliberately made an SSRI whereas Lilly only produced one as an accidental by-product of a search for a quite different drug. Zelmid was also brought to the market in 1981, 7 years before Prozac. See Let Them Eat Prozac for a history of what happened next.

Can antidepressants and even Zelmid cause suicide? According to Carlsson in 2000 yes – “we have known this for a long time”.

But it doesn’t stop there, Stockholm is of course the place where Stockholm syndrome was born.

In August 1973, a bank robbery at the Kreditbanken in Stockholm triggered a 5-day siege with bank employees held hostage. The media camped outside. After the siege ended, to the surprise of everyone many of the hostages, as if hypnotized, spoke well of their captors. “Stockholm syndrome” was born. Now recognized as common, the conditions that trigger this change in behavior seem to be isolation, a fear that your life is at risk and kindness on the part of the hostage takers.

Disease isolates us as profoundly as incarceration or anything else might. Our lives are at risk, and our doctors who control the exit to freedom are almost certain to be kind. But not a single doctor is trained to manage Stockholm syndrome, to suspect that apparent insouciance or congenial conversation might conceal deep unhappiness with a proposed course of treatment or worse again alarm at new problems that have emerged on treatment.

Doctors are also increasingly likely to suffer their own Stockholm syndrome. If something goes wrong with a treatment a doctor gives, even though the label may concede that the drug can cause the problem, the makers of the drug and other doctors will deny that it is likely to have done so in any particular case. Speaking up about a problem, once the material of medical advance, is now a recipe for professional suicide.  A doctor attempting to rescue a patient is likely to be accused of being a persecutor who takes patient hostage by withholding effective treatment.

Offers to describe problems at professional meetings are turned down. Journals are ever less likely to accept publications outlining a new problem. Invitations to apply for better jobs, to attend conferences, or simply to go with colleagues to local eateries funded by drug companies are ever less likely to happen for doctors linked to adverse events. Those holding doctors hostage have been very kind indeed – there are ever fewer medical departments or medical conferences not awash with company support, when it comes to paying for meals with colleagues most doctors have forgotten what a credit card looks like, and of course in supplying drugs they supply the objects that make doctors desirable.

What can a Hobbit do?

“We all must take advantage of freedom of speech and freedom of press. This is what the small individual can do in a democracy. Thereafter it’s up to the professional journalist and politician to act. The truth is that Sweden needs help from foreign politicians, scientists and journalists. It is very sad to have to admit that many homicides, school shootings and other horrible killings are linked to medication and that this fact is being suppressed as journalists exclusively talk about weapons”.

“Many people decide to stop their medication when they start getting the “numb feeling” or the “derealisation feeling”. However, in the majority of cases, doctors insist they continue until the side effects “disappear”.

So Jan Akerblom made Who Cares in Sweden. This is playing with fire. He has taken on the Swedish establishment for real. Lisbeth Salander is the myth, Jan Akerblom the reality. See this link.

“Our conclusion is that, the best advice, in order to clarify any problems is to talk to the person’s family, friends and colleagues. The person themselves may not be aware of the side effects, the change of personality, the problems he or she creates. People sometimes say that the “medicines work” precisely because they just don’t care anymore”.

This conclusion about what he had to do and also what needs to be done to clarify individual problems are exactly the conclusions that Rosie Meysenburg came to that led her to create SSRI Stories.

In the next post, we’ll see some of the consequences of Kicking the Hornet’s Nest.

Dance With Python: Healthcare In Peril

danger snakes

This is the last in what was once the BarMittzva Romba series aimed at Bar(ack) & Mitt. These have now been renamed as a series of Dances – Dancing as fast as we can, Dance to the Music of Time, Dancing In The Dark, Dance of the Sugar Plum Fairies, & Shadow Dance. Between them they reprise the plot of Pharmageddon.

In Malaysia, Dancing with Pythons is an art form. Women dance to music with a large python draped over and around them. Just like walking on burning coals, it can be done if you know what you’re doing. In this case the art lies in ensuring you do not let the python’s tail attach itself to anything. If the tail can grip something, the python will squeeze the woman to death.

Close to 20% of US GDP now goes on healthcare, up from estimates of  between 1-4% in the 1950s. In the 1960s, the consumption of healthcare in the US, which was the highest in the world, made the country the healthiest and wealthiest on earth. Now US life expectancy has fallen below that of Cuba. Has the pharmaceutical python gripped on to something and is it squeezing the life out of us – literally?

Money spent that makes a population more economically productive by getting people off sick leave and back to work is an investment. Money spent that gives people illnesses they were not complaining off, puts them on treatments that make them less economically competent, treatments that cause more death and disability than they alleviate, comes close to being a tax on us and our jobs but paid to corporations rather than government.

With many treatments, we are doing the equivalent of ensuring as many people take prescription alcohol as possible, and take it indefinitely, and we are reaping the economic consequences that would likely ensue from such a course of action (Shadow Dance).

Alienation

If the economics don’t force a rethink, there is a cost in alienation besides the economic cost that may. The marketing of drugs is changing the fabric of what it means to be human. There are endless egregious examples, such as the rediagnosis of the “terrible twos” as bipolar disorder.

But a key area, because it shows that it is possible to fight back, has been the struggles over female sexual dysfunction. Where once women fell in love, scientists now try to tease apart the components of female desire so that it can be turned into a commodity. Viagra it appears has the same effects on women as men, but the women are not as motivated by these effects as men. The answer apparently is to coat Viagra with testosterone to mimic estrous when females are more likely to respond to the effects of Viagra. If marketed, any benefits that may accrue to some women are unlikely to outweigh the alienation inflicted on all by a marketing that will reduce love to physiology pure and simple. The movie Orgasm Inc shows how women have been successfully fighting back against this.

Doctors are also alienated. Where medicine was once a vocation, for a growing number it has become an industrialized enterprise that makes them increasingly likely to be sacked if they try to practice good medical care. But it is difficult to envisage doctors rising up to put things right for this reason. They are more likely to act if they realize that they are being replaced by cheaper prescribers – provided they realize in time.

But unlike climate change or mass starvation in Africa, where the complexity of the problems induce paralysis in most of us, these problems are ones that we can solve. There are several key changes any of which would radically transform the picture.

Access to the data

The leading problem is that the market is not free. Unless the data on treatments can be accessed and are as comprehensive as possible, no other part of the market can be free. Given that science by definition is based on accessible data, a great deal of what passes for evidence based medicine at present as promoted by pharmaceutical companies can perhaps be described as fraudulent. However it is described, it is costing us money in return for which we are getting on balance more disability and premature death than benefit.

Our current failure to ensure access to the data puts current Western science on a par with the science of the Lysenko era in the Soviet Union where ideology dictated what the science said. Our healthcare has become as totalitarian as the Soviet state once was and as vacuous as the patent medicine era of the nineteenth century once was (Dance to the Music of Time).

Patents not fit for purpose

The problems that stem from data sequestration are aggravated by product patents. Companies would be well rewarded by product patents even were the patent office stringent in their determinations of utility and originality. Having a lax patent system combined with lack of access to the data is the worst of all systems. It is a system that could not be better designed for the purpose of transforming pharmaceutical companies into the equivalent of tobacco companies (Dancing in the Dark).

Why have things worked out this way?

It is possible that as a matter of strategic national interest the USA decided to try to attract the pharmaceutical industry to its shores, by relaxing the application of patent requirements so that companies could print money in return for drugs that were no more useful than bottled water. Whether by deliberate strategy or not, this is what has happened. The price Americans are paying is very high. Everyone else is at growing risk.

Randomized controlled fetishes

Any of the sticking plasters we apply to attempt to stop what is now a hemorrhage of money only aggravate the problem. The latest wheeze is comparative effectiveness research.  This rests on misguided notions of what randomized controlled trials can do and fails to understand healthcare. It assumes that people have a greater desire to get from Washington to Seattle 15 minutes faster than to get there alive. Applied to an airline it is easy to see that being a slightly quicker but less safe airline is not a formula that will work. But somehow getting to the healthcare equivalent of Seattle a few minutes earlier is supposed to solve all our problems.

Effectiveness was originally a component of safety. One of the key conceptual problems at the heart of our current difficulties is the failure to realize that the market will work if it is a comparative safety rather than a comparative effectiveness market. This is not a precautionary principle argument. It encourages innovation and will reward it out of the wealth created by making people healthier – we will be wealthier if we are healthier.

But it does require a shift in perspective. We will need for example to think about guidelines for people rather than guidelines for diseases. Doctors are increasingly killing people very effectively by faultlessly following an ever increasing number of disease guidelines, the results of which are to exponentially multiply possible interactions between treatments and to set up a series of prescribing cascades. Extirpating diseases is not the goal; keeping people safe is.

Keeping doctors safe

Congress likely thought it was creating a comparative safety market when it made new medicines available on prescription only in 1962. It did create one – for doctors. They have had a guaranteed income as a result. It is more difficult than ever to take malpractice actions against doctors even as evidence accumulates that people are likely to be injured unnecessarily for a decade or more by new treatment induced problems owing to the inability of doctors to pick up these problems. We need to find a way to re-educate doctors, or reward them for keeping people safe, or else we need to consider abolishing prescription-only status for many medicines.

The market Congress envisaged in 1962 is at odds with the realities of health today. Congress viewed citizens as dupes, in need of protection. The advent of the internet has meant that many quite average citizens know more about their treatments than their doctors do.

RxISK.org

We need new collaborative models of care that recognize this and harness the drive and energy of patients to making medicines safer. It is this “Yes we can” idea that has driven the development of RxISK.org.

I first heard about Dancing with Pythons from David Weatherall, then the Professor of Medicine in Oxford. He had been struck by it. But mistakes can happen and he later learnt that the woman he had seen dancing made one in a subsequent performance and died.

Shadow Dance: Is alcohol safer and more effective than SSRIs?

cosmopolitan cocktail

This is the fifth in the Dance series tackling the crisis in healthcare. Previous parts were Dancing as fast as we can, Dance to the Music of TimeDancing In The Dark and Dance of the Sugar Plum Fairies.

We have dug a deep hole. The regulatory hoops through which a company has to jump are now so minimal that it would be easy for us to get alcohol, nicotine, benzodiazepines or opiates on the market as antidepressants. Opiates in fact have a much better track record than SSRIs for treating severe depression – melancholia. Benzodiazepines, which are close to alcohol in pill form, have lots of positive trial results for depression, so there is little question that we can get postive results for alcohol also. Alcohol also has anxiolytic properties that have been of benefit in social situations for centuries.

Alcohol with all its risks is a good example because we are happy to have it available over the counter. Prescription only drugs are available on prescription only precisely because we have every reason to think they will be as risky as or riskier than alcohol.

The prime factors that prevents companies bringing alcohol on the market as an antidepressant are patent status and consumer familiarity. Consumer familiarity provides a source of competing information that companies cannot control. In contrast, SSRIs, statins or bisphosphonates are unknown quantities making it possible to manage the views of doctors and patients more readily.

Getting on the market

The regulatory requirements regarding clinical trials allow us multiple opportunities to get a positive result for alcohol. For some antidepressants only one third of trials have been positive. Regulators will conceal the fact that they have seen studies where alcohol has failed to beat placebo. As a result patients and doctors need not be aware of negative studies.

In the trials we run, we can use as our yardstick of success not lives saved or people returning to work or people objectively performing better or people in their own estimation performing better but rather a change in score on rating scales. These rating scales are sensitive to the side effects of the drug and side effects may produce a benefit on the scale whether or not there is a benefit for the underlying condition. The anxiolytic or sedative effects of alcohol (or the stimulant and anxiolytic effects of nicotine) would produce substantial benefits on scales like the Hamilton rating scale for depression or scales for anxiety.

Rather than comparing alcohol against a known treatment in cases of severe mood disorders, we can compare it against placebo in a set of mild problems. And we can improve its profile by screening out anyone showing a good response to placebo or a bad reaction to alcohol during the first week of the study.

In these trials, placebo effects might well account for 80-90% of any improvements found on rating scales. Nevertheless, the studies will be deemed a successful demonstration that alcohol “works”. Regulators and academics will happily give doctors and the public the impression that 100% of the apparent benefits of alcohol for depression stem from the alcohol and none from placebo factors.

In a proportion of our alcohol studies, investigators may find out later that not all the patients actually existed. For us non-existent patients come with one great benefit – they do not have troublesome side effects. The trend towards non-existent patients is likely increasing as clinical trials of more recent alcohols have been outsourced to Mexico, Eastern Europe, India and elsewhere. But even if some journalist finds not all our patients actually existed, it will make no difference. Once on the market, our license to sell alcohol as an antidepressant will not be revoked.

In one important study we did of alcohol for maintenance treatment of depression (a particularly lucrative market), it proved no better than placebo in 30 North American study centers, but turned out to be dramatically better than placebo in 2 Mexican centers. When all the centers were added together, the overall results for alcohol were marginally superior to placebo. The regulators approved this study. The published account of the study gave no indications that alcohol only “worked” in Mexico.

We can therefore do studies in which more people die on alcohol than placebo, fail to get back to work on alcohol compared to placebo, in which alcohol proves better than placebo in perhaps no more than 33% of cases on our chosen rating scale, and in these 33% of cases proves better in only 3% of centers, and we will still be able to market alcohol as an “antidepressant”.

Making the market

After approval, in order to make our market, we can of course only publish the trials in which there were positive findings. But we can publish these multiple times, giving the impression that there were far more positive trials than in fact there were.  We can aim at having up to 50 publications for each trial. Our ghostwriters can also take a negative study and polish the results to make it look positive. Ghostwriters never mention studies that have failed to show efficacy.

In due course when it comes to shaping the marketing campaign for alcohol, the data generated by these studies is almost free-floating content that can be molded into almost any shape we might wish. For instance, if an opportunity arises in the painkiller market, because another compound like Vioxx has run into trouble, some minimal benefits that may have been registered in the trial, in terms of feeling slightly better in painful situations, can be polished by ghostwriters into a series of articles that trumpet the analgesic qualities of alcohol in order to take advantage of any opportunity that has opened up.

While we are busy getting beer on the market as an antidepressant, several other companies can file for product patents on whiskey, gin, brandy, wine, port, and even on Irish as opposed to Scotch whiskey, or Japanese as opposed to Scottish scotch. The combined marketing of both our and other companies can encourage doctors to put patients on combinations of whiskey, gin, brandy and port, or even combinations of Scotch, and to keep patients on these combinations for extended or indefinite periods of time.

Based on the published trials, guidelines will have to endorse alcohol for use in nervous disorders and perhaps owing to its excellent safety profile have it as a first line therapy. Depending on how clever companies are with the trials they run, or choose to publish, the guideline makers may put whiskey forward as a first line treatment with brandy second line and gin third line. This is probably more likely to happen if whiskey makers have a greater presence than gin-makers in the country in which the guideline is being written.

Staying on the market

When it comes to the side-effects of alcohol, ghostwriters can hide these under terms such as ‘failure of response’ or perhaps list an initial side effect such as ‘nausea’ when in fact the individual had nausea, vomiting, followed by an epileptic convulsion. They can also simply fail to mention problems by saying they have only included those problems that appeared at a 10% rate or more.

When patients have an adverse effect on alcohol, such as a convulsion, we can dismiss this as anecdotal – not evidence based. In contrast, we can write up any dramatic improvement on alcohol during its early period on the market in both the academic and mainstream media, even featuring it on television and radio, under headings like “alcohol saved my life”.

One helpful feature of the trials we have to undertake to bring alcohol to market is that they only have to last for six to eight weeks. This is helpful as very few of the problems that might be expected from alcohol (or nicotine) emerge in a six to eight week period. For any problems that appear later, we can argue that no placebo controlled data support the claimed adverse event, and both we and doctors have to operate only on the basis of the scientific evidence.

If there is an increase in epileptic convulsions on alcohol compared to placebo in the course of our clinical trials but this is not statistically significant, we can rely on journals, regulators and academics to say there is no evidence for any increase in the rate of convulsions.

Should there be any hints of liver problems on alcohol in the course of our trials, which is unlikely because of the short duration of the trials, we can attribute this to the depression or other nervous problem for which the person is being treated. Even though the entire medical literature up till then might not have a scrap of evidence that depression causes liver dysfunction, and there may be a substantial amount of other evidence that alcohol causes liver dysfunction, within an astonishingly brief period of time (weeks) we have the ability to get a significant proportion of the medical profession to agree that it is well known that depression causes liver dysfunction.

If some people have difficulty stopping alcohol, we can depend on a bias doctors have (helped by us) to ensure that any symptoms on stopping alcohol will be put down to the nervous problem that was being treated in the first place rather than to dependence and withdrawal. We can be pretty sure that twenty years after alcohol is first marketed that a majority of doctors will fail to recognize that it causes dependence. They will instead be likely to explain to patients that its just like insulin – their bodies are not producing enough alcohol and they need to continue treatment for life.

In the case of pregnancy, this bias and our marketing, means that we should be able to make alcohol one of the most commonly prescribed drugs in pregnancy within a few years. And indeed compared with other antidepressants, a glass or two of wine per day is positively harmless. Doctors will tell women who avoid coffee, soft cheeses etc. that leaving their nerves untreated will harm their babies.

Finally, we know from past experience with other drugs that in a few years’ time alcohol is likely to be linked to suicide and perhaps violence. We have a number of academics who we can enlist to produce graphs to show that as alcohol consumption has gone up that suicide and violence rates have fallen in countries like Holland or in parts of the United States. One of the advantages of getting studies like this published in a leading journal like Archives of General Psychiatry is that we can depend on the editor to refuse to publish any correspondence that might be critical of the study.

We can organize for cost utility analyses as thick as telephone books to demonstrate that the cost of alcohol is minimal compared to the quality of life gained. Provided the analysts stick to the published data, we can show that if governments pay for access to alcohol for large segments of the population, that there will be a net benefit to society.

Doctors – don’t you love them

A major difference between prescription and over the counter drugs lies in a curious inversion of the stranger-neighbor phenomenon. We are in general wary of strangers and comfortable with neighbors. We neglect the fact that we are most likely to be abused or harmed by someone we know. Neighbors and relatives are familiar and we think we can manage the risks.

In this scenario alcohol is familiar while alcohol and nicotine as antidepressants are strangers. We have a feel for the traditional risks of alcohol and nicotine but far from treating therapeutic alcohol or other new drugs as strangers and regarding them as dangerous and risky, mediated through our local risk-laundering service (doctors), we will treat these prescription only drugs as safer than traditional alcohol or nicotine, even though prescription-only drugs are so precisely because we have every reason to think they will be riskier than drugs like alcohol.

If this seems to push the argument too far, consider that we regard prescribed amphetamines as safe enough to give to children, even toddlers, while the authorities jail others for possession of street amphetamines on the basis of the risks they pose. The same is true for prescribed as opposed to proscribed opiates, and other drugs.

Doctors provide us with other services. Getting treatment from a doctor suspends the natural caution that our consumers might feel about taking our new chemical. Even though prescribed alcohol has now been tested in protocols in which it looks safer than and as effective as SSRIs and doctors know what the risks of traditional alcohol are, they are it seems prepared to act as though prescribed on-patent alcohol comes risk free. This is partly because unlike traditional alcohol doctors never get a hangover from prescribed alcohol and never crash because of it.

In fact making alcohol, nicotine or opiates available through doctors is a way to hide hazards such as liver failure, lung cancer or dependence on average for 10 to 15 years from the time that people in the street have begun to claim that their liver failure or lung cancer stems from our drug.

Not only can the medical profession be depended on to deny a link while patients are reporting a link but even after regulators put black box warnings on alcohol about a risk, even if that risk is a lethal one, most doctors will still deny that this risk happens.

Doctors finally provide us with significant insurance against product liability. In the event that a doctor testifies that he would have given alcohol no matter what the warning on it, we are legally immune to any product liability actions stemming from its use.

What’s not to like about doctors? We need to work out what we think about recent moves to have cheaper prescribers, in the form of nurses and pharmacists. It’s always risky fiddling with a winning formula.

Dance of the Sugar Plum Fairies: How prescription-only keeps doctors healthy and wealthy but not wise

ballet shoes

This is the fourth in the Dance series tackling the crisis in healthcare. Previous parts were Dancing as fast as we can, Dance to the Music of Time and Dancing In The Dark.

In 1962, politicians attempting to put things right in the pharmaceutical sector accidentally created the perfect raw material for drug development, and the basis to transform this raw material into the perfect product. But to complete the perfect market needs one extra element – a perfect consumer. By continuing an innovation put in place in 1951, the prescription-only status for all new drugs, the 1962 regulations did just this.

Prescriptions were for addicts

Initially prescription-only status was a police function introduced in 1914 for drugs of abuse.  It was extended to all new drugs in 1951 because these new and effective drugs were thought likely to come with significant risks and doctors as a body would be skeptical of the benefits of new drugs and cautious using them. It was also thought they would be able to quarry the appropriate information out of drug companies about medicines, or otherwise generate the appropriate information to make the use of these unavoidably risky drugs as safe as possible.

From 1951 to 1962, the idea of making new drugs available on prescription only was hotly contested – was it appropriate to treat the citizens of a free country as though they were addicts? The thrust of regulation up to 1962 had been focused on the accuracy of the labeling of over-the-counter drugs. Regulating prescription only compounds broke new ground in 1962, and it is not clear that anyone knew what the likely consequences might be. Nowhere else in the regulatory arena have regulators attempt to constrain the use of products that are sold to a professional body only.

It is clear that in 1962, Congress had no wish to regulate the practice of medicine, but prescription-only status has made this unavoidable. The intrusion of “government” into clinical practice has extended from the thin end of this wedge. It is now common to find administrators who know nothing about medical practice dictating to doctors what the content of clinical encounters must be.

Regulators claim all they are doing is regulating the wording used by pharmaceutical companies that may be misleading to consumers, just as they have done since 1906. But in this case the consumers are doctors and the regulator is undertaking to all but guarantee wording about the compound, written by pharmaceutical companies. Where in fact there is advertising, doctors see authoritative scientific statements.

Before the 1962 regulations were passed, Senator Kefauver noted that prescription only status created a unique market: “He who buys does not order and he who orders does not buy”. The fact that thalidomide had been available over the counter in Germany where its hazards came to light may have influenced the decision making process and allayed concerns about prescription only arrangements. No-one considered the possibility that the risks of thalidomide had come to light precisely because the drug had been over the counter, and doctors had no incentive to hide the risks of over-the-counter drugs.

The only good disease is a medicated disease

Linked to the prescription-only status of drugs and the development of controlled trials the regulations also encouraged pharmaceutical companies to develop medicines for disease indications. As ever the thrust of regulation was to enhance safety, and one of the apparent ways to do this was to restrict the use of medicines to conditions that in themselves posed a greater risk than the risk stemming from the chemicals used to treat them so that there would be a favorable risk benefit ratio.

What was not anticipated was that if pharmaceutical companies were restricted to selling medicines for diseases only, one option for them was to begin to convert what had been a series of vicissitudes of everyday life and normal variation in terms of beauty and functionality into a set of diseases. We could all be made diseased and indeed there was no reason why we couldn’t all be given several different diseases. And so we have all become depressed, osteoporotic and have hyperlipidemia (hypercholesterolemia) where otherwise we might have had burn-out, aging bones that could be managed by exercise, and a diet-related issue that is only significant against a background of more important cardiac risk factors. We are all about to get a rash of auto-immune disorders we never knew we had, as back-aches become ankylosing spondilitis, and depression becomes an inflammatory disorder.

For companies an unexpected benefit of this restriction was that they had to learn to speak the language of doctors – diseases. They have learnt to do this to an extent that medicine fails to appreciate. A huge range of vicissitudes have been transformed into illnesses, acute illnesses have become chronic and the moral imperative to treat that is brought to conditions like tuberculosis has been co-opted to the sales of almost any pharmaceutical product for indications no matter how trivial. Where patients might be wary of taking chemicals, they are increasingly faced with doctors attempting to persuade them that this chemical will correct some abnormality and that they are almost duty bound to take it.

Third-party buying

Kefauver recognized the risks inherent in third party buying arrangements. These are well-recognized and form a major part of conservative arguments against government involvement in areas such as healthcare. The market will simply not work efficiently if the person ordering doesn’t also buy and benefit from or suffer the consequences of their purchase. If this is not the case, at the very least those doing the buying should be trained in the hazards of what they are doing.

In 1962, it was clear there were risks in such an arrangement even though the third party was seen as an independent professional who most people thought would be working on behalf of their patient, almost to the extent that a pilot flying a plane works on behalf of those entrusted to her care. Since 1962, professional discretion has been all but outlawed and doctors prescribing choices are dictated to them not by market pressure but by a system that mandates the use of the latest and most expensive on-patent medicines, the medicines on which there is the least data as regards safety.

Doctors may be the only significant group of buyers who are not trained in the pitfalls of buying for a third party. Their background means that they do not even realize that they are not trained in an area of huge consequence for them and their patients.

Recent estimates suggest that companies spend over $50,000 per annum per doctors marketing to doctors.  This figure could likely be greatly increased if the cost of “scientific” articles were also included in the mix. Doctors in other words are subject to a greater concentration of marketing power than any other group of people on earth. But, just as they know nothing about buying for a third party, so also no doctors are trained to recognize the way companies market to them.

Let’s play doctors and nurses

Both doctors and patients fail to realize that doctors are the consumers of medicines and that they consume by putting pills in patients mouths. In so doing they consume without consequences or side effects. Companies fully appreciate this and exploit it. If the patient has a problem, company marketing ensures doctors will have to hand a great deal of evidence suggesting that any problems are part of the patient’s illness rather than a consequence of treatment. Evidence based medicine is deployed to relegate any reports of difficulties from doctors or patients to the status of anecdotes.

Companies also work closely on the psychology of individual doctors, categorizing them in terms of whether they are likely to innovate with medicines, want to adhere to guidelines, or merge with the crowd. The approach to each doctor takes this categorization into account.  Doctors rarely if ever know how they are profiled, and rarely if ever realize that the adverts and gimmicks and presentations they dismiss are aimed at others not them, and are indeed working on them in so far as they give doctors the impression that they disregard company promotional efforts. But whatever the orientation of the doctor there is another set of pitches designed for him or her that he is likely inhaling with the air he breathes.

Finally, doctors appear to be more susceptible to the effects of branding than even teenagers faced with choice of designer outfits. This happens because the development of branding feeds into the most powerful bias in medicine. Brands unlike drugs come free of side effects. The temptation for a doctor is to go with the brand, because no-one wants to give a patient something that might injure them. But this is a form of thinking that reduces doctors to playing at doctors and nurses rather than engaging in medicine.

There is some token resistance to using the brand name of drugs in academic articles, but medical textbooks quickly incorporate brands such as SSRIs, statins, and quite meaningless designations such as atypical antipsychotics. More to the point, where academic meetings in the 1950s and 1960s routinely featured symposia on the hazards of using certain drug groups, it would now be as rare as finding snow in the Sahara to find a symposium at an academic meeting today about the hazards of treatment unless the symposium was sponsored by the makers of a competing product.

Stockholm Syndrome

Quite aside from transforming doctors into the perfect consumer in this sense, in 1962 it was not appreciated how much a mechanism designed to improve safety might in fact do just the opposite by transforming clinical encounters into hostage situations. Making drugs available on prescription only means that patients have nowhere else to go to get a medicine they need or think they need. They effectively become a hostage rather than a patient and risk the development of Stockholm syndrome.

In 1962 Stockholm syndrome had not yet been described. It is now known that people whose lives are at risk and who are isolated (anyone with an illness), when held hostage by kind captors concerned about their welfare (as doctors are increasingly trained to be) are highly likely to identify with their captors and want to keep them happy. In these circumstances, especially when the patient finds their condition worsening, it becomes very difficult to raise the possibility that what the doctor has done in good faith to help might in fact be causing problems.

It seems more and more likely that the safety consequences of turning patients into hostages outweigh the risks inherent in the drugs that doctors prescribe. The evidence that treatment induced adverse events have now become a leading source of death and disability point just this way. Meanwhile there is not a medical course on earth that trains doctors to recognize their capacity to induce Stockholm syndrome.

Untrained, unaware but not unremunerated

Someday soon your doctor is likely to suggest Humira for your backache or Enbrel for your ‘nerves’  – or some succeeding biologic drug. Drugs that have triple the reporting rate of serious side effects of antidepressants and antipsychotics. Your doctor will come up with this idea, unaware as to where it came from. He will likely be pleased with the idea of trying something new and he won’t be aware of any discomfort on treatment. You won’t report anything to disturb his equanimity. He might think it prudent to withhold information about cancer and serious infection rates on these drugs in your interest, unaware that “There is simply no constitutional basis for recognition of a right on the part of physicians to control patient access to information concerning the possible side effects of prescription drugs” (1).

He will think he has a right to withhold this information from you and a God-given right to prescription privileges that bring with them annual remuneration rates of several hundred thousand dollars per year. He is the best possible partner any drug company could have, and ideal consumer rolled into one.

See also Professional SuicideProfessional Suicide: the Clancy CaseModel DoctorsPla(u)to: the car that pharma builtSo Long and Thanks for all the Fish

1. Greene J, Siegel Watkins E (2012). Prescribed. p 111. Cite from a ruling in February 1980, by US District Court in Delaware,  Johns Hopkins U Press, Baltimore.

Dancing In The Dark: How patents make drugs the perfect objects of desire

dancing in the dark

This is the third in the Dance series tackling the crisis in healthcare. Previous parts were Dancing as fast as we can and Dance to the Music of Time.

A further step taken in 1962 made it possible to shape the raw material from clinical trials into the perfect product. This development hinged on the strategy chosen to reward pharmaceutical companies. In 1962, the options were to offer product, or process patents for drugs or some other form of reward such as a prize for the development of a medicine that has real social benefit (see Kremer and Glennerster’s Strong Medicine).

With process patents if another pharmaceutical company can find a different way to make a drug they too can bring that drug on the market. Process patents had been the norm in Europe prior to 1960. They had been the method in place for a century during which the German pharmaceutical industry developed as the most successful on earth. Under process patents, it does not make economic sense for pharmaceutical companies to put all their eggs in one basket. They are more likely therefore to diversify and hold a portfolio of compounds.

Process patents give more drugs, and cheaper drugs, so…

On reviewing the differences between countries with process and product patents in 1962, Senator Kefauver’s staff, charged with looking at the regulation of the pharmaceutical industry, discovered that countries with process patent systems were more innovative than those with product patent systems and that the cost of drugs in countries with process patent systems was considerably less.

Initially in the 1960s holding a product patent meant having a patent that applied to a national territory. The United States was the one leading country who had consistently adopted product patents. As of 1962, despite the data on pharmaceutical innovation and the price of drugs, Congress opted to maintain a product patent system. Other countries also switched from process to product patents.

In 1962, product patents were confined to a national territory and the monopoly they offered was therefore limited. But the development of TRIPS in the 1980s, a development in which Pfizer played a significant part, means that product patents now have a global reach. This has transformed the market for drugs. TRIPS laid the basis for the emergence of blockbuster drugs in the late 1980s – drugs worth a billion dollars a year or more for pharmaceutical companies.

There have been two important unforeseen consequences of the emergence of blockbuster drugs. One was that the ability to make so much money put a premium on drugs that could be marketed to the widest number of people rather than a premium on drugs that were effective for diseases that needed cures. By focussing on such drugs companies could most effectively realize the rewards that a global product patent regime offered. This reward system also put a premium on drugs for chronic conditions, so that there was a premium put on transforming where possible acute illnesses into chronic conditions.

It also means that if companies develop substance P antagonists, nicotine receptor antagonists or other novel drugs, they test these out in the big lifestyle indications first and if the drugs fail there they are jettisoned. A great deal of the development costs of modern drugs stems from trying desperately to demonstrate efficacy in conditions like pain or depression for a drug with minimal effects on pain or depression. It would have cost next to nothing to bring the SSRIs on the market for premature ejaculation, but vastly more to create the appearances of efficacy for depression. A drug that proved useful for melancholia today would be abandoned as unlikely to offer a return on investment. In contrast, process patents encouraged companies to bring a range of diverse drugs on to the market and make their money from a range of genuinely useful drugs.

Una pharma, una voce

The second feature was that in addition to marketing panaceas, as companies fortunes have come to depend on the fortunes of a single drug they have had incentives to conceal any hazards that might be linked to the drug. Since 1962 companies have increasingly found ways to shut down any reference to the hazards their drugs might pose, and the length of time to the discovery of the major hazards of a treatment has got steadily longer.

In contrast if several different companies can produce a drug that comes with a hazard the benefits of innovation will lie with the company that can find a way to manage rather than conceal the hazard.

The 1962 regulations were ostensibly about enhancing safety, as the 1906 and 1938 regulations had been. But in fact the motivational incentives pointed the opposite way. One of the important consequences of this is that safety in practice is more neglected now than it was in the 1950s. It almost appears to be assumed that if a drug is efficacious it cannot pose a safety risk. It is highly likely that if a new thalidomide were to come on the market that it might remain on the market for a decade or more as today the risks of prescription only drugs take over a decade to travel from first description to wider recognition.

Patenting water

There is a second notable aspect to the patent system that developed after 1962. In a free market, the patent system is recognized as a perversion, whereby the citizenry of a country for a limited period give a third party rewards beyond what the market would ordinarily support in return for some originality or utility that will benefit the country.

Before 1962 patent officers were a force to be reckoned with, but over the past 20 years this has changed. Companies have applied for and been granted patents on isomers or metabolites of already patented compounds, as with Lexapro, Pristiq, Nexium, Invega and others. They can for instance get patents by modifying the salt composition of an already existing compound – as with Depakote. They are able to take patents out on compounds that their own scientists describe as being as alike to already marketed compounds as two drops of water. The requirement for originality has de facto been abandoned.

The requirement for utility has also been abandoned. If the second drop of water currently being patented were patented for a novel and needed indication this might be acceptable but second drops of water are typically patented for the same conditions for which the first drop of water is already available – as in all the drugs listed above. Indeed in a number of cases, once a new compound is patented companies seem to be able to find safety issues with their initial compound sufficient to withdraw it from the market.

Our most expensive bottled water Sir, I presume

In the face of such laxity in the application of patent law, what happens next depends on the consumers of the product. If the consumers of these products cannot be easily fooled into buying a much more expensive on patent version of an identical cheaper off-patent product, patent laxity might not matter. But as we shall see the 1962 amendments have also created the perfect consumer, one who can be fooled into buying the most expensive bottled water in the shop.

The 1962 regulations created the perfect product. They have gone as close as possible to enabling companies to take product patents out on water. Reflecting this laxity, pharmaceutical companies, which once had scientific divisions and engaged in research, have outsourced most of these functions, and become close to the kind of pure marketing operations expected from a bottled water or patent medicines company, where the brand is all.

Dance to the Music of Time: How clinical trials help pharma invent data

clinical trial

This is the second in the Dance series tackling the crisis in healthcare. Part one was Dancing as fast as we can.

Every product is built from a raw material. The raw material puts constraints on a product developer. There may be difficulties fashioning the product from the material, or the material may be costly or scarce. There is the delicate matter of how the mark-up from raw ingredient to product is perceived – the market will only bear so much.

In the later decades of the twentieth century, bottling water produced a close to perfect product. A few years earlier no-one had imagined that something as ubiquitous and inexpensive as water could be bottled and sold at such a mark-up in places where tap-water quality was good. In the case of bottled water, except in cases of water shortage, almost all the value of the product comes from its marketing, and lies in the eye of the beholder.

Patent medicines… the perfect product

In the nineteenth and early twentieth centuries patent medicines, which often contained little more than water were equally perfect products. The mark-up on these proprietary products was even greater than for bottled water now. The creation of a market in patent medicines was perhaps the single greatest contributor to the development of modern marketing, and the greatest influence on the marketing of medicines to this day.

Compared with patent medicines and bottled water, prescription-only drugs are complex products that require two sets of ingredients. First, they require a chemical that forms the basis for a medication. Second, they require information to transform the chemical into a medical product. This information specifies the conditions under which the chemical might best be used, and its likely effects at particular doses and in particular circumstances.

The costs of chemicals today are little more than the costs of bottling water. The information required since 1962 to make a chemical into a drug at least superficially seems not so readily manufactured. But in fact, the current constraints on the informational component needed to produce a medicine are so lax as to make this information close to the perfect raw material.  It took companies a while to realize that they are all but able to invent this information.

Added value that increases rather than reduces the risk from the chemical

The invention of this information adds apparent value that supports mark-ups of an order not seen in any other market. Were the value real rather than apparent, these mark-ups might be justifiable but far from being real what appears to be added value in many cases increases rather than reduces the risk from the chemical.

Problems with the informational component of medicines lie at the heart of the therapeutic paradox and are the reason why the more we access medicines, the more problems we have.

At the center of this information is the requirement introduced in 1962 that drugs would only be licensed if they could be shown to be efficacious. The development of randomized controlled trials (RCTs) made it tantalizingly possible to insert this requirement into the system – a requirement that seemed to force the financial camels of the pharmaceutical industry to get through the eye of a scientific needle if they were going to make money out of sick people.

Controlled trials were introduced in the 1950s after they had demonstrated that they could weed out unwarranted claims for treatment efficacy. This appeared to raise the bar to entry into the market in a way that would keep the purveyors of patent nostrums out of healthcare. Trials have since been portrayed as a method that was going to give medicine the objectivity and certainty linked to sciences like physics and chemistry. Medicine could become evidence-based, and in the process would harness the pharmaceutical industry to its purposes.

If the use of trials had been restricted to keeping drugs that don’t work off the market, this use would have been a major contribution to drug safety. If trials had been rigorously used to weed out ineffective treatments they would have helped produce a dramatically different market to the one that has developed. For better or worse a number of drugs we currently have would not be available.

Through the looking glass

More to the point RCTs would not have become the vehicles used to sell drugs, hide side effects and drive clinical practice they have become. Instead as evidence based medicine has developed we have entered a stranger and stranger world.

First, the primary use of RCTs – to disprove claims of efficacy – has been completely subverted. Even if a preponderance of the RCTs undertaken fail to show a drug is of benefit, if any trials show hints of a positive outcome the treatment is likely to be permitted on the market. The way the system in fact works, the makers of snake-oil would have little problem getting on the market. In the case of some of the best-selling drugs in modern medicine the preponderance of evidence suggests the treatment may be no more helpful then and distinctly more harmful than snake oil.

Bizarrely, the treatments supported by independent reviewers taking an evidence based medicine approach are in many instances treatments that have the greatest amount of negative trials. This happens as guidelines have to be based on published trials and can neither take into account the negative trials that remain unpublished nor access the data that shows many negative trials are published as positive studies.

This has been clear for decades. Finally last year Peter Doshi and colleagues who recently reviewed the evidence on Tamiflu came out straight and said it is not possible to assess the efficacy of a drug without full access to all the studies that have been done. Yet on the basis of the original published data, governments throughout the world spent several billion dollars stocking Tamiflu in 2007-2008.

Second, running studies in which there are huge numbers of participants makes it likely that some irrelevant benefit will be shown for a drug.  Snake oil could almost certainly be demonstrated to be of benefit in large studies. Far from seeing through what is happening doctors can be relied on to be more impressed by a study that contains thousands of patients than by one that needs a handful of patients to demonstrate a benefit. The most prestigious journals are also more likely to take a multicenter study with thousands of patients showing a trivial clinical benefit, than they are to take a small study showing a clear cut clinical effect.

Third, the only data from a trial that can ordinarily be generalized are the estimates of the reliability of a trial’s primary outcome measure. But in practice almost anything that turns up in the course of a trial – that is of use to a company – is taken as having been established simply by virtue of the fact that it happens in the course of an RCT.

Few trials include the right instruments to measure outcomes other than the primary outcome. This is particularly true for adverse events where in addition the data are commonly creatively coded or relocated or otherwise massaged to make problems vanish.

Fourth, trials are primarily run by pharmaceutical companies. From the start these trials are aimed at producing knowledge to serve a purpose rather than aimed at producing knowledge. Any inconvenient knowledge that turns up in the course of the studies is likely to be discounted.

RCTs – a gold standard – for hiding adverse events

RCTs are indeed a gold-standard method as is so often claimed by the adherents of evidence based medicine. However, for the reasons just outlined, they are in practice a gold-standard method for hiding adverse events rather than for demonstrating efficacy. They might have made a significant contribution to safety if their use had been restricted to weeding out ineffective agents, but in practice their use has been to conceal adverse events and as such they have been detrimental to the development of a comparative safety market.

There is however little or no recognition that the mantras of gold standard and statistical significance and evidence based medicine are essentially rhetorical tropes that need dismantling.

Transforming base metals into gold

A new default has been created. Where before drugs were viewed as poisons with the art of medicine lying in an ability to find the right dose in order to balance the risks and benefits of treatment, now supposed proof that they “work” has transformed these chemicals into fertilizers to be administered as widely as possible. Where once the greatest art in medicine had lain in knowing when not to treat, now it seemingly lies in knowing how to get people on as many drugs as possible for as long as possible.

This stems from the use of controlled trials. Extraordinarily a technique that was introduced to contain company claims has become the means by which companies create knowledge within health care and drive the sales of drugs. We have almost arrived at the point within healthcare where if parachutes hadn’t been through an RCT no one would be let use them.

But it is the actual conduct of trials that makes them into the alembus in which pharmaceutical company alchemists can transform base metal into gold.

Hiding “drug” trials

First, an initial set of trials are conducted in healthy volunteers. These trials uniquely reveal the hazards of drugs in a way that clinical trials in patients do not. Perhaps because this is the case, the data from these trials are impossible to access. While the data from clinical trials are also concealed, there are now registers of trials undertaken in clinical conditions. There is no register of healthy volunteer trials and publications from these studies are commonly deeply misleading.

The trials that doctors and others hear about are undertaken on patients. In these, patients volunteer to participate. If the treatment is new, they unwittingly take the risk of ingesting chemicals that will likely prove too toxic to market. They do so without being informed of these risks. As the exercise is billed as scientific, most participants likely believe that the data that results from their participation will be made available to experts and will contribute to a knowledge base that is incrementally driving medicine forward.

In fact while clinical trial registers now offer some evidence that the trial took place, the actual data is sequestered by companies. When it comes to transforming the data into information that will shape clinical practice, companies can select which trials they wish to publish. They can also select the data from these trials that suit their purpose. In some areas of medicine, a third of trials may remain unpublished and of those published up to one third are portrayed as positive when regulators or others who have seen the data deem them to be negative studies of the drug.

Marketing aids designated as scientific articles

The data are written up to produce a “publication” which is the primary marketing tool of companies. Owing to a supreme sleight of hand, these marketing aids are designated as scientific articles, although they fall at the first scientific hurdle by not making the data on which claims are based publicly available.

Once the publication is complete, in order to add value to the marketing copy, ghost writers add the names of distinguished medical academics. Academics provide this service in return for very modest amounts of money. The publication is then sent to a journal. Unlike quality newspapers which check the integrity of the primary sources on which a story is based, journals never do so. Even after the claims in an article have been shown to be fraudulent, journals refuse to retract these publications so that they continue to influence medical practitioners.

These publications are then embodied in guidelines that de facto require doctors to use the latest on-patent and more expensive drugs rather than older, less expensive and more effective drugs. The guidelines process is one that enables companies to co-opt even the most independent and company hostile academics into endorsing their products.

Another confusion may demonstrate how badly efforts to constrain commerce within the clinical trial process have infected therapeutics. In 1962 the idea was to demonstrate a drug worked before it was let on the market. As a result studies are conducted in disease states.  If the trial is not negative, companies are then licensed to advertise the fact that drug Y works for condition X. But the drug in fact may work for many other conditions or purposes, and indeed work better for these other conditions. Imipramine for instance is a far more effective treatment for panic disorder that any of the drugs that have been licensed for this purpose. SSRIs are more effective treatments for premature ejaculation than they are for depression.

If a company promotes its drug for some purpose without undertaking a study in that condition this is called off-label promotion. There is a great deal of concern about off-label promotion. As a result of this concern, a majority of doctors think that they cannot prescribe off-license. And guidelines only endorse the licensed indications of a drug. This effectively hands medicine over entirely to pharmaceutical companies.

Patients come for nothing and doctors for peanuts

Having a resource like this that can be molded into virtually anything that the company wants might be expected to cost money. But in fact it costs very little. The patients who generate the data are paid nothing. They take risks with compounds that have unknown unknown risks, known (hidden) unknown risks, as well as known risks, for free. They have been sold the idea that it is their civic duty to participate. In the 1960s this civic effort did liberate us from scourges that had plagued humanity for millennia. The same effort today is inflicting harms on people that will take decades to eliminate.

Doctors also come cheap. In many jurisdictions, doctors have been told that it is government policy that they “partner” industry and one way in which they can do this is to participate in clinical trial networks to make the testing of new drugs quicker and easier. Policies like this stem from government efforts to keep pharmaceutical business “in country” even though it is difficult to see the economic return on this. The doctors running the trials for companies are paid by the state. Any notional fees they get are a fraction of the true costs of the exercise.

Meanwhile, for economic reasons pharmaceutical companies are relocating most clinical trials to countries such as India, where the oversight and costs are less. The publications that come out of these Indian trials are still likely to have Western academics listed as their authors.

Thalidomide safer than antidepressants

As a symbol of how the field has developed, it is hard to beat the fact that as of 1962 the only drug that had been demonstrated to be effective and safe in a placebo-controlled trial before being brought to the market was thalidomide. Fifty years later antidepressants have become the most commonly used drugs in pregnancy, despite increasing evidence they double the rate of birth defects and miscarriages and likely cause significant cognitive delay in the children born to mothers who have taken them through pregnancy. The increased prescriptions for antidepressants is happening on the basis that these drugs have supposedly been shown to be efficacious and withholding something that is efficacious is increasingly portrayed by public relations and media companies as unsafe and unconscionable.

In terms of policy, the one indisputable fact for both conservatives and liberals is that this market is not free. Companies are able to sequester data so that it is impossible for consumers (either doctors or patients) to know what the risks and benefits of a treatment are. The consequent labeling of most drugs is deeply misleading, has in some cases been charged to be fraudulent, and is in all cases in breach of the norms of science.

These norms include access to the data and a commitment to empiricism. They make science democratic and the ultimate free market. When this market was free, it worked to enrich and liberate us all. Within healthcare however companies have been able to create the appearances of science and deploy these to their benefit but our detriment. As healthcare costs escalate dramatically based on a subversion of the scientific market, while actual health deteriorates, this deployment of the appearances of science poses an increasing threat to the economies of developed countries.

This deployment of the appearances of science enables companies to generate mark-ups not seen since the days of patent medicines. In Anthony Powell’s Dance to the Music of Time, when young the author faces what he thinks are unique and individual situations only to find later in life that even the most distinctive of individuals and unlikeliest of events replay themselves.