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 June 2012

Pharmacosis: So long and thanks for all the fish

In 1860 at a meeting of the Massachusetts’ Medical Society Oliver Wendell Holmes made one of the most celebrated comments in medicine. While noting that medicines, particularly opium, could help, he nevertheless made it plain that he thought that on balance medicines risked doing more harm than good. You can’t be much plainer than this:

 “I firmly believe that if the whole materia medica, as now used, could be sunk to the bottom of the sea, it would be better for mankind and all the worse for the fishes”.

Holmes’ note of skepticism marked a point at which medicine began to become scientific. Doctors began to distinguish themselves from quacks who dished out Mercury – also called quacksilver (see Pharmacosis: the day the music died). They began to grow into a role that had been sketched out for them by Philippe Pinel fifty years earlier:

“It is an art of no little importance to administer medicines properly: but it is an art of much greater and more difficult acquisition to know when to suspend or altogether to omit them”.

A Faustian bargain

A century later regulators faced with the emergence of new drugs of which Holmes and Pinel would undoubtedly have approved, and aware of the risks these drugs might pose and the need for skepticism, and distrusting the public to be suitably skeptical, turned to doctors and made these new drugs available on prescription only.

Doctors who for centuries had being trying to push quacks and hucksters out of the medical marketplace were being offered the means to conclusively do so. You would only be able to get the drugs that really worked from your doctor.

But the bargain was Faustian. Few if any doctors seemed to spot that patients would no longer be the consumers of drugs. If by consumers we mean those who are the targets of pharmaceutical company marketing, then doctors were the new consumers. These new consumers moreover would consume by putting drugs into their patients’ mouths and so would consume without side effects. This was a win-win of which Mephistopheles would have been proud.

Doctors – the most naive consumers on Earth

Recent estimates suggest companies spend over $50,000 per annum on marketing to each and every doctor in the United States – possibly considerably over $50,000. Despite this, there is not a single medical course on earth that teaches doctors about pharmaceutical company marketing.

Has this marketing done anything to erode the skepticism of doctors? In 1960 doctors rarely had patients on more than one drug at a time and the drugs that were used were for the most part only used for a limited course. Until the early 1990s, the recommendations for antidepressants were for a three-month course, now patients are told they are like insulin and will have to be consumed for life. Now an increasing number of every doctor’s patients are on 10-15 drugs indefinitely. Doctors in other words are consuming several thousand times more drugs than they once were. Left to their own devices few of a doctor’s patients would ever take 10-15 over the counter drugs at the same time for indefinite periods no matter what the supposed benefits.

When pregnant you might be safer with a Quack

There is no better symbol of what has happened than the use of drugs in pregnancy. Drugs are available on prescription only because we have every reason to think they will be riskier than alcohol, nicotine and other drugs we were prepared to let people manage for themselves in the 1960s. Now, pregnant women are skeptical of and avoid not just alcohol and nicotine but tea, coffee, uncooked meats and soft cheeses. Pregnancy is an area even quacks and hucksters steer clear of. But far from endorsing this skepticism, doctors cajole or frighten women into taking more antidepressants in pregnancy than any other drug, even though these come with greater risks of causing birth defects, miscarriages and learning difficulties in children than are linked to modest alcohol intake, nicotine, cocaine or most over-the-counter treatments.

When salt loses its taste it is useless. When doctors lose their skepticism they are worse than useless, they become dangerous.

If doctors were sunk to the bottom of the sea…

Like Faust, doctors may be approaching their hour of reckoning. The world we are in is a world where medical art is not needed to get patients on medicines – this is now done by algorithm or checklist. This is also a world where prescription privileges have been extended to nurses and pharmacists who are cheaper to employ than doctors.

Doctors have become just one more element in the distribution channel for drugs, part of a juggernaut that is pumping people fuller and fuller of medicines. If  Holmes were to return would he remark:

“I firmly believe that if doctors could be sunk to the bottom of the sea, it would be better for mankind and all the worse for the fishes”.

Can doctors save themselves? In Holmes’ day, except for metals like Mercury and arsenic the drugs of the time were rarely lethal in their own right. They did not kill as many children as were killed by diphtheria, or adults as died from influenza or tuberculosis.

Treatments now are far more lethal than they were in Holmes’ day and treatment induced injury has become one of the leading causes of death and disability. There has been one confirmed human drug disaster, the SMON epidemic in Japan, which resulted from the accumulation in fish of a modern drug, clioquinol. There are growing concerns about accumulations of other drugs in the fish we eat and water we drink.

The times call for Medical Partisans

Holmes’ and Pinel’s point remains that the greater art “lies in knowing when to stop or altogether to omit medications”. In many areas of consumption, personalized goods or services are branded as artisanal. Given that doctors should be offering professional discernment as a service and should be advocates for their patients and for possible non-consumption, may be doctors need to become p-artisans.

Can markets understand No?

If they are to maintain prescription only privileges and a role for themselves in healthcare, doctors are going to have to come up with something extraordinary. They may even need to become a revolutionary class, partisans, who create a space that markets do not readily understand – a space where No is the operative word.

Or else it may be time to recognize the Faustian bargain medicine was offered in 1962 for what it was, and prior to being consigned to sleep with the fishes, depart stage left with a parting shot such as “So long and thanks for all the fish”.

Pharmacosis: the day the music died

Syphilis appeared in Italy in 1498 just after Columbus had returned from the New World. This later led to suggestions that it had been brought back from the New World, in exchange for the many European illnesses that decimated the populations of North American Indians.

Exposed to a virgin population new infections can be particularly virulent and during the subsequent century in Europe syphilis led to severe physical complications and often death.

 a distinctive and horrifying madness

Thereafter its virulence eased, until around 1800 a new and terrible manifestation appeared – general paralysis of the insane (GPI). This was also called tertiary syphilis or dementia paralytica, a distinctive and horrifying madness. Patients cycled through profound depression to extreme elation, psychosis and later dementia before dying.

Stepping back from the illness, doctors could distinguish it from dementia praecox (schizophrenia) by its course – patients cycled through the various stages before dying quite quickly. They were also much more likely to be male. Schizophrenia lasted for decades and was equally male and female. But at any one point in time patients with dementia paralytica and dementia praecox could look identical.

The first recognizable descriptions of both schizophrenia and GPI can be found in an 1809 book on insanity. It took a century to conclusively link GPI to syphilis. The development of the Wasserman reaction which tested for the spirochete, treponema pallidum, that we now know causes syphilis made it clear that this distinctive madness was invariably Wasserman positive. Before that a range of distinctive neurological features made doctors relatively confident in the diagnosis; these included changes to the pupils of the eye and others.

a lifetime with Mercury

GPI was a late manifestation of the illness. Syphilis begins with a sore on the penis. For the first most virulent century these sores often extended all over the body – a mark of Cain. But later as the virulence declined they might only appear on the genitals and internal organs. One of the early discoveries was that a mercury salve could help. Administered topically as a paste, the sores sometimes healed. This led to a linkage between mercury and syphilis and the famous phrase of “a night with Venus and a lifetime with Mercury”.

Mercury helped but it didn’t cure. Physicians began to work on methods to get mercury into the body. These included getting the patient to sweat while exposed to mercury vapors, or drinking mercury in the form of Calomel – mercurous chloride. Finally in the 1780s Jacob van Swieten developed a mercuric chloride potion, Van Swieten’s liquor.

Van Swieten was working in Vienna and his brief was the health of the army, whose most serious affliction was syphilis. Soon after his liquor came on the market, the first cases of GPI appear. Could Mercury have caused or contributed to the creation of this mental illness?

No Mercury no GPI

Here’s the case against mercury. Many years later in 1925 shortly before he died Emil Kraepelin who coined the term dementia praecox for schizophrenia took a trip to North America to raise funds for an institute in Munich. One of his interests on this trip was to look at mental illnesses among North American Indians. He was struck by the lack of GPI – even though syphilis had supposedly come from North America.

It also turned out that GPI was rare among American Negroes. A later study in American Negroes infamous for its non-treatment of syphilis, the Tuskegee study, reveals that GPI was much less frequent among American Negroes than among Whites at the time.

Within Europe, Norway offered a striking exception – there were very few cases of GPI. The Norwegians preferred general hygienic measures for managing syphilis and apparently steered clear of Mercury.

Finally GPI was much more common in men than in women, except for one group of women – prostitutes. This seems unsurprising perhaps if syphilis was linked to sex.  But if men were infected, their wives were too and should have gone on to GPI also, but didn’t. The initial signs of infection in a woman are more likely to be internal and were accordingly less likely to come to attention and be treated. Women therefore were less likely to take mercury. Except that is for the prostitutes who in a number of cities like Vienna were forcibly treated with mercury in order to reduce transmission.

Against the link to Mercury is the fact that when malarial fever therapy was introduced in 1917, it cured GPI. The conventional view is that the malarial temperatures killed off the spirochete. High fevers of various sorts like this might explain the benign course of syphilis in American Indians for instance.

the Mad Hatter made it clear to Alice 

But it is difficult to ignore the role of Mercury if only because the Mad Hatter made it clear to Alice that it can cause psychosis in its own right.  Killing the spirochete may have stopped one contribution to psychosis.

This is important for a few reasons. It bears on the story of schizophrenia where a growing case can be made that lead neurotoxicity helped transform some other condition into the  chronic psychosis we call schizophrenia (See Healy et al 2012).

Pharmacosis – a distinctive and horrifying madness.

Unlike lead, which was never used to treat schizophrenia (although there was a surprising amount of lead put into medicines in the 19th century), if Mercury did play a role in GPI, it offers a dramatic example of Pharmacosis – a distinctive and horrifying madness. For much of medicine’s history, doctors were a last resort as their treatments often killed. Hospitals were houses of death rather than cures. But the tally of deaths and injuries in the case of syphilis is particularly poignant.

There is some evidence Mozart contracted syphilis. He knew van Swieten’s son. In the short term mercuric chloride was more likely to cause kidney failure than GPI, which fits the bill for his possible death. Beethoven caught syphilis. Mercuric chloride causes deafness. Schubert caught syphilis and died far earlier than was likely to have happened had he been left untreated. Schumann caught syphilis and is more likely to have had GPI than manic-depressive illness.

In recent years, a bipolar industry has claimed that all great artists have had bipolar disorder – a vanishingly rare and much less common illness in the 1800s than GPI was. It’s much more likely that Van Gogh, Baudelaire, Flaubert and others along with Guy de Maupassant, Friedrich Nietzsche, and Oscar Wilde, had GPI rather than manic-depressive illness.

There is a real case today that many of the antipsychotics or mood stabilizers being given cause the psychoses they are supposed to treat or mood swings they are supposed to stabilize. Misled by a short term benefit, doctors often use these drugs in stupefying doses that eliminate any possibility of recovery – and patients are encouraged to cooperate by being told they are just like Schumann, Van Gogh or others.

Pharmacosis: terminator algorithm

addiction-550762_640

The single commonest question to Rxisk.org has been about dependence on and withdrawal from treatments, such as anticonvulsants, statins, diuretics and others. We often think that it is only drugs of abuse that can cause dependence and withdrawal but in fact an astonishing number, perhaps most medicines, can cause problems (see Medicine Induced Stress Syndromes, Dependence and Withdrawal, Halting Antidepressants).

Rxisk.org is the only website that attempts to establish whether you might have become dependent on or have a withdrawal problem from your treatment. Neither controlled trials nor epidemiological studies conducted when the drug is given to treat an illness reliably give us this kind of information.

Studies in healthy volunteers are much more informative and in the case of some SSRIs had given convincing evidence of problems 25 years or more before companies conceded there was a problem. But the data from these studies is buried.

Even though antidepressant withdrawal was first described in 1961 and even though some companies have since gone as close as they can to openly telling doctors that competitor drugs may come with serious withdrawal problems, most doctors still don’t realize that all antidepressants can cause withdrawal.

Withdrawal effects can come in the shape of rebound syndromes, stress syndromes, legacy and other syndromes. Few doctors ever consider some of these possibilities.

These are the questions we ask you on Rxisk, that are of the type an expert would ask if they were attempting to link your treatment to dependence and withdrawal but they focus on rebound and stress syndromes rather than legacy and other effects.

Rxisk Terminator Algorithm

    1. Are there previous reports of withdrawal effects from this drug in the Rxisk or FDA database, or on Google?
    2. If you reduced the dose of the drug did the problem start before or after reducing?
    3. Was the problem different to your original condition?
    4. If you stopped the drug, did the problem start after stopping?
    5. If you restarted the drug, did the problem clear up?
    6. If you increased the dose of the drug, did the problem improve?
    7. How soon after restarting the drug or increasing the dose did the problem improve?
    8. If you tried a related drug did the problem clear up?
    9. Have you ever had withdrawal effects before on another drug? Was it on the same type of drug?
    10. Have you had other drugs of the same type? Did you have a similar withdrawal effect on them?
    11. Could anything else be causing this event?

 Rxisk Score

Rxisk Score
 9+  points strongly to a linkage – take this timeline to your doctor/pharmacist
 4-8  points to a linkage – take this timeline to your doctor/pharmacist for input
 1-4  not enough information to confirm a linkage – take to your doctor/pharmacist
 0  at present unlikely to be a withdrawal effect

 

Other Beasts in the Jungle:

Drugs for osteoporosis alter the bone architecture of women taking them. These changes to bones may last for years after stopping the drug and put the women at risk of breaking long bones such as her femur. A fracture that happens 6 months after a drug is stopped is not likely to be linked to an earlier treatment.

In just the same way, there are almost certainly a number of other conditions that a treatment may trigger that only show up months or perhaps years later. For this reason on Rxisk we ask you about drugs you may have stopped months previously.

Any drug that has been released since 1990 should be considered a possible candidate for problems that appear months after it has been stopped. This is likely to be even more true for the biologic group of drugs now being used widely for a range of conditions.

Rxisk.org is now live in Beta for feedback.

Pharmacosis: trigger algorithm

The first descriptions of a drug causing suicide came in 1955. A few years later in 1958 and again in 1959 the problem was described with imipramine. Treatment induced suicide became a prominent media issue in 1990 with a paper by Teicher and Cole. But it was not until 2004 that regulators and companies conceded that these drugs can cause a problem. There are now 38 drugs listed as causing suicide, including drugs for asthma, obesity and skin conditions in addition to antidepressants, anticonvulsants and antipsychotics.

The first descriptions of risk-taking behavior on l-dopa were described in 1981. Similar problems were described shortly afterward for dopamine agonists given for Parkinson’s disease. Dopamine agonists are now also given for minor conditions like restless leg syndrome. The problems were serious – judges and clergymen were arrested for gambling, prostitution and other risk seeking behaviors (see DBM Dopamine & Parkinson’s Disease). But it was not until 2008 that regulators finally conceded that these drugs given for Parkinson’s disease could cause these risk-taking behaviors.

When it comes to side effects, doctors are Flat-Earthers

The moral of the story is that it can be decades from the time that a problem is first described to the point your doctor gets to hear about it and even then he may not be likely to believe it. When it comes to side effects, most doctors are Flat-Earthers, partly because it’s not a cause for concern for them in the way that it is for those they put on treatment.

There are a number of steps we take you through at Rxisk.org to establish whether your drug is causing your problem – whether you are suffering from Pharmacosis or not. This will work for problems known to be caused by the drug but also for problems not yet linked to treatment. These are the steps that any expert would take you through before deciding there was a linkage. These are the steps pharmaceutical companies routinely work through, based on which they often decide their drug has caused a problem, while still denying in public that it does so.

These are the kinds of questions that need to be asked even when it is known that a drug does cause suicide, gambling, heart attacks or some other problem. Just because someone has begun to gamble or been violent and is on a drug that can cause violence or gambling does not mean the drug has caused the problem. A judgment is still needed as to whether the drug is likely to have played a part or not. Ideally this will be a team judgment – involving the person affected and as many others as possible.

Some of the steps outlined here can be found in other algorithms of which the most famous is the Naranjo algorithm but we ask more questions and score things differently.

Pharmacosis Trigger Algorithm

    1. When did you start the drug? When did the problem start?
    2. Did the problem start or get worse after a dose increase?
    3. If you lowered the dose, did the problem clear up?
    4. If you stopped the dose, did the problem clear?
    5. If you used any other treatment as an antidote, did the problem clear up?
    6. If you restarted the drug or increased the dose, did the problem reappear or get worse?
    7. Have you ever had this reaction before on another drug? Was it the same type of drug?
    8. Have you had other drugs of the same type as this? Did you have a similar effect on them?
    9. Have you ever had this happen to you before when not on a drug?
    10. Could anything else be causing this problem?
    11. Have you ever been told you are a poor metabolizer of drugs and need lower doses, or do you have a history of sensitivity to drugs?
    12. Could you have taken too high a dose?
    13. Has a doctor or a pharmacist reviewed your problem? Do they see a link?
    14. If a name has been put to your condition is it rare off drugs?
    15. Are there previous reports of this reaction in the Rxisk or FDA database or on Google?

  Rxisk Score

Rxisk Score:

9 +

points strongly to a link – bring to your doctor/pharmacist

5-8

points to a likely link – bring to your doctor/pharmacist

0-4

needs information or input from your doctor/pharmacist (Qs 13, 14, & 15 in particular)

Rxisk Team

No simple score can tell whether a drug has caused a problem. It needs a team and research and judgment. The person on the drug is critical – no-one knows what is going on quite the way the person on the drug does (see Unbearable lightness of being), and as history shows people on the drugs often get it decades before the experts. But there are many side effects that need judgment calls from doctors or pharmacists or increasingly anyone armed with Google and prepared to research things (see Out of my mind).

Birth defects in general like the phocomelia caused by thalidomide cannot be tested by challenge, dechallenge or rechallenge. Babies had been born limbless and deformed like this before thalidomide but it suddenly became a lot more frequent.

Just like phocomelia on thalidomide, conditions that looked like tardive dyskinesia happened before the antipsychotics, but were a lot more common after the antipsychotics were introduced. In this case though the tardive dyskinesia that appeared on the drug cleared up if the dose of the drug was increased – could this be caused by the drug? Scoring on the Rxisk Trigger algorithm might not point to a link but scoring on the Rxisk Terminator algorithm in the next post might have helped to bring out the link.

Ultimately the more reports shared among the greatest number of people the more likely we all are to find an answer (see Unbearable lightness of being).

Rxisk.org has gone live in Beta for feedback as of today June 18th

 

Pharmacosis

blindfolded woman holding spoonful of pills

There is a new Contagion out there. Kate Winslet beware.

Disease with no name

This new epidemic has rapidly become at least the fourth leading cause of death and disability – it may even be the greatest cause of death because all we have counted so far are deaths in hospital where such deaths can be spotted. Where every other disease comes with a guideline for its management, this has none. Where in the case of every other disease we can appeal to an Evidence Base in order to make recommendations about treatment, in this case the Evidence Base is central to the transmission of the ‘virus’. Where every other disease has a name, this has none.

It used to be called iatrogenic disorder but this is a name that suits pharmaceutical companies. It blames doctors, when the greater part of the problem now stems from the information or lack of information doctors and the rest of us are being fed. Doctors are as much in the dark as the rest of us about what it is that we don’t know. This is why Pharmacosis, which suggests a loss of insight and a lack of access to reality, seems the right name.

Fifty years incubating

The first manifestations of Pharmacosis were the limbless babies born in 1961 to mothers taking the hypnotic thalidomide. The latest manifestations are heart attacks caused by Merck’s Vioxx or GlaxoSmithKline’s Avandia, suicide on Wyeth’s Pristiq or Bristol-Myers’ Abilify, or diabetes from Lipitor or Zyprexa. The vectors that lead to the deaths these drugs cause lie in the 1962 amendments to the Food and Drugs Act put in place after thalidomide. These amendments forced companies to make drugs for diseases and to show drugs worked using randomized controlled trials (RCTs). Ironically the only drug that had been RCT tested and proven safe and effective before marketing in 1962 was thalidomide.

the contagion lies in something vital to life

Just as with water-borne infections, where the contagion lies in something vital to life, Pharmacosis comes from the life-saving drugs we need. Or rather it comes from data-suppression and the scientific publications polished by company ghostwriters to made medicines look safe for consumption, but in fact which transform medicines into something more dangerous than chemicals. Medicines are chemicals that come with information about their safe use. Chemicals everyone knows are potentially poisonous and if used at all need to be used with care. The problem now is we are using an increasing amount of medicines stripped of their appropriate information with an abandon we would never adopt if asked to risk taking chemicals. When using drugs like this, we take the risk of poisoning by chemicals and add to that the risk of poisoning by misinformation. It is this spread by poisonous information that makes pharmacosis literally contagious and a new kind of illness.

Who can stand up to the virus and survive?

Even the best doctors who try to avoid commercial contamination end up posing a risk to the rest of us. Companies understand them better than they understand themselves and provide suitably doctored articles, embodied in guidelines, to leave no rational option but to prescribe more of the latest drugs. Marketing diseases puts a moral obligation on doctors to treat. Marketing measuring tools produces figures for which a drug appears the only answer. Those few doctors who try to track down the source of the infection, like Kate Winslett in the movie Contagion, are ostracized and die early. Who can stand up against company sponsored evidence and survive?

There has been some push back. Companies have been forced to post their clinical trials in registers but we cannot get trial datasets supposedly because of patient confidentiality. While access to all the data would leave us better placed to assess whether the latest panaceas have the benefits claimed for them, we would still have a problem because of the 1962 amendments to the Food & Drugs Act which encouraged companies to develop drugs for diseases. Trials done in an illness are the most effective way to hide a drug’s problems. If Zoloft causes anxiety and suicidality, so does depression. If Zocor causes memory loss and muscle pain, so do cardiovascular conditions. The illness hides the problems in clinical trials and in clinical practice it is all too easy to say “it’s the disease not the drug” (See The spin that no data can overcome).

The widespread references to drug trials are in fact to condition trials, where drugs are tried on diseases. Companies also do drug trials – phase one studies done in healthy volunteers. These trials that uniquely reveal the risks of drugs are never registered. No data is made available even though there are no confidentiality issues.

In a never-published study of 12 volunteers in Leeds in 1983, 9 years before the antidepressant Zoloft was marketed, and 21 years before FDA required it to carry suicide warnings, after terminating a study early because all women on Zoloft had become anxious or apprehensive, noting thoughts of aggression and related difficulties, Pfizer concluded that Zoloft had caused these changes – as had other SSRIs in phase one studies (See Mystery in Leeds). The costs of non-publication of this trial are incalculable. We pay doubly, both in the high costs of the latest drugs and an even greater amount to treat the injuries these have caused.

How do we escape when the infection and treatment are one?

Faced with plagues in the past we have taken evasive maneuvers but how do we escape when the source of infection and treatment is the same – prescription-only medications? Unlike pilots whose safety coincides with ours absolutely, our doctor’s does not. On average she reports around 1% of treatment related deaths. Unlike the near misses reported by pilots, which lead to changes in the system, a doctor’s reports are dismissed by regulators as anecdotes. How do we escape when the virus ensures medical journals and academic societies side with companies rather than doctors?

How do we escape when the Supreme Court makes companies producing generic versions of contagious drugs legally immune from actions for injury? Ten years ago in Let Them Eat Prozac I made a prediction that the makers of generic prescription drugs would be immune to lawsuits from people killed or gravely injured by medicines – this came to pass a little over two months ago.

Wake the doctor.. 

There are solutions. A registry for phase 1 trials and mandatory access to their data would help. Another is to encourage patient reporting of adverse events, if doctors won’t. If none of these solutions work, there is a quirk built into the virus that may yet help us – it triggers medical groups to commit professional suicide. On several occasions recently the American Psychiatric and Medical Associations have ridden to the defence of drugs, claiming they work well and are safe. Do we need experts to handle wonderful risk free miracles when there are cheaper prescribers than doctors? If doctors wake up to the risk to themselves of risk-free drugs, who knows in helping themselves they might help the rest of us.

The unbearable lightness of being

This is the last of 3 posts laying out the philosophical basis for Rxisk.org which will be live in the next few weeks. The others are Cri de Coeur & Once is Never.

In his masterpiece on love and life The Unbearable Lightness of Being, Milan Kundera faces us with a dilemma about the important things in life “einmal ist keinmal” – “once is never”.

Academics need lovers

But Kundera doesn’t mean the same thing as academics, regulators, and others mean when they dismiss adverse events as anecdotal. Academics need lovers to show them how wrong their interpretations of once is never are.

In the last millennium it seems we understood love and adverse events better. Up to the development of the SSRIs, the standard approach to deciding what might be happening when a drug produced a change was to note if the change emerged after taking the drug, reversed itself if the drug was stopped, and reappeared after re-exposure to the drug.

Making love on an SSRI

Women or men making love on an SSRI were instantly aware of delays in orgasm, often within an hour of the first dose. Things went back to normal on stopping so that people could be advised to take a break from their drug for the weekend. It didn’t take a controlled trial to work out what was going on. It didn’t take a controlled trial for companies to work out they had a treatment for men here, only to decide that pre-Viagra cultural factors made marketing this a risky proposition. In fact controlled trials didn’t show the problem because companies didn’t collect the data, in some cases deliberately.

But today, when something goes wrong on a drug, when someone becomes suicidal on an antidepressant for instance, even if the problem clears when the drug is stopped and reappears when the person restarts, we are told this is anecdotal, and nothing is done with the report.

50,000 deaths don’t bother FDA anymore

FDA say the hundreds of thousands of reports they get annually are essentially anecdotes. If there are no details on how many people are getting the drug, and no details on how many are having the problem, we have no denominator and no incidence rate. In the case of suicidality and antidepressants, as Paul Leber of FDA put it 50,000 reports would not give FDA pause for concern – FDA expect depressed patients to be suicidal.

At best a series of reports might produce a “signal”. These signals might be useful for “hypothesis generation” but they are never definitive. Unless a company chooses to investigate further, nothing happens, and companies often choose not to investigate further.

Controlled trials we are told show that even those on placebo can have a surprising number of adverse events – so how can it be said that a drug has caused the problem unless it is happening significantly more often on the active treatment than on placebo?

good quality garbage is not a rallying call

Some of the real difficulties with adverse event data are laid out in a particularly clear way by Science Based Pharmacy – see Goldmine or dumpster dive?, a closer look at adverse events. Science Based Pharmacy, however, adds one key point, which is that the quality of the data is more important than its quantity.

But if anecdotes and signals are just that, why should the quality of reporting of an anecdote make any difference? If garbage in/garbage out is the basic message, having good quality garbage is not much of a rallying call.

If everything is anecdotal it would become impossible to work out whether we were in love, or if drugs were interfering with our love lives, or any of the other important things in life. As this doesn’t seem to be an issue for most of us, the academics must have something wrong. What might that be?

RCTs don’t cut it when it comes to adverse events

First as outlined in Cri de Coeur and Once is Never, RCTs simply don’t cut it when it comes to many adverse events. Even the best RCTs, without a hint of fraud or manipulation are quite likely to hide rather than reveal the problem. This is an intrinsic property of RCTs done in illnesses (the picture is different in healthy volunteer RCTs – see Mystery in Leeds).

This is why the greatest benefit we get from RCTs lies in testing claims that treatments work rather than in testing for adverse events. Even when testing claims for a treatment benefit, RCTs may get it wrong, but in general by making it up to manufacturers to justify their claims for a benefit, RCTs can help keep us safe.

RCTs were added to the evaluation of drugs in 1962 for just this reason. If a treatment doesn’t work, it isn’t safe at any speed.  So claims for efficacy were to be tested using a blunt instrument that should eliminate the possibility of chance, so blunt it risks missing real efficacy. Concealing a real adverse event was not part of the game plan.

Why lovers get it right

Partly why lovers get it right and academics get it wrong is that the lover can tell the difference the drug makes, whereas clinical trial coding is likely to confound treatment induced and illness induced sexual dysfunctions. This is where Science Based Pharmacy’s reference to the quality of the data becomes so important. But data quality is only important if listening to individual cases makes sense.

In the case of suicidality, both clinicians and patients told FDA from early on that they had seen or experienced depression related suicidality before but that the treatment induced problem was qualitatively different. This should have made a difference to the academics or anyone aware of how precious a human life is. Words come before numbers. Unless the words are right, the numbers never can be. “Numbers without words never to Heaven go”.

Even hairdressers do better with adverse events than FDA

Even hairdressers do better with adverse events than FDA now do. It was women and their hairdressers who picked up the change in hair quality produced by oral contraceptives not the regulators.

But far from attempting to enhance the observations of patients, doctors and others, fifty years of neglect of adverse events means that the reporting of events to FDA is now so appallingly bad that there can be legitimate concerns about how useful FDA’s adverse event database is. This points to a failure on FDA’s part, not a failure of adverse event reporting in principle.

There are compelling reasons to improve the quality of adverse event reporting. Adverse events are still the best way to discover new drugs, and it is perhaps no surprise as the quality of reporting has gone down, drug pipelines have dried up.

Getting the words right

How do we improve the quality of reporting and increase the likelihood that good quality reports will lead to substantial findings and even new drug leads?

One way is to incorporate challenge-dechallenge-rechallenge, and dose-response relationships into the original observations  – in the case of an SSRI the higher the dose the longer the delay to orgasm.

A second step is to follow people over time, which FDA does not do. Companies at present seem to be attempting to divert patient reporting to FDA, knowing that the lack of follow up will make the reported event anecdotal. In contrast, if a patient contacts a company, the company is legally obliged to follow up the report and attempt to make a causal determination (see American Woman, American Woman 2).

A third is to look for biological plausibility. When the biological case is clear, FDA have been prepared not just to warn but to remove drugs like Raptiva from the market after as few as 3 adverse event reports.

A fourth and critical element is to foster teamwork. When doctors, patients, pharmacists, nurses and others can bring their combined skills to the description of an event and to assessing whether it is linked to the drug or not, the likelihood of getting things right is enhanced. Filing events away in FDA filing cabinets isolates doctors from patients and all of us from each other and is exactly the wrong way to go.

What teamwork does is to introduce a range of biases into the picture. People contest linkages – the course of true love never did run smooth. This is a good rather than a bad thing.  The singularity of an event is not where bias arises in science. It is when judgments are singular that the risk of bias is greatest. We are on much sounder grounds if a range of people with different biases come to the same conclusion. The effectiveness of any and all methods in science hinge on having input from a team for exactly this reason.

The final element is to get to grips with the propaganda that is inhibiting adverse event reporting.

How do we get from RCTs to real life?

For those who think RCTs are critical in establishing whether an adverse event is happening, that every other piece of evidence is anecdotal, or at best a signal, there is a key question – how do we get from RCTs to real life?

If RCTs show SSRIs can cause suicidal acts or sexual dysfunction, what does this tell me about whether this SSRI caused this suicidal act or that sexual dysfunction? Unless a judgment of this type can be made, no doctor or patient can ever know whether they have reasonable grounds to stop a treatment on the basis that it is actually causing a problem or not. Lives depend on being able to make these judgement calls.

Curiously, no-one seems to have a problem making judgment calls like these in the absence of RCT data when it comes to the off-label beneficial effects of prescription drugs.

Rxisk.org

It is all too easy to outline the problems with current adverse event reporting. The challenge is to improve it. This is what has prompted the development of Rxisk.org. Rxisk operates on the basis that no one knows a drug related effect like the person who is taking a pill, or those living with them, but it also pushes the person to involve their pharmacist or doctor in the assessment of what happens with challenge, dechallenge and rechallenge and when the dose is changed and it seeks follow up data.

Once is not ever Never

As outlined in Pharmageddon, it is probably no accident that it is mothers, wives and daughters, who know how precious each life is and who have seen the changes in loved ones up close, who pose the greatest challenge to company propaganda – the repetition of “once is never”.

In FDA hands adverse event reporting has become so degraded that it differs from the real thing as much as love differs from a one-off event in a dark alley, when perhaps once approaches never. But while in science we look at the anatomy of an event in a way that love rarely does, in both love and science once is not ever never.

RxISK.org will launch in Beta this week. We would like everyone who can to access it, test it out and feedback to us.