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 Zoloft Study: 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.
Wishing you and your team every success with Rxisk.
SSRIs’ have produced the ultimate conundrum.
If the patient comes off the ssri and is suicidal then clearly the ssri prevented the suicide.
If the patient comes off the ssri and is not suicidal then clearly the ssri cleared up the difficulties.
If the patient comes off the ssri and is dead, then clearly the patient was destined to do it anyway.
Whichever way you look at it ssris’ have a lot to answer for and my wee tuppenceworth is that SSRI = Suicide Sometimes Randomly Interferes ‘with life as you knew it!’
Good luck.
The FDA is unmoved by report of 50,000 suicides? According to the US NIMH, there are about 33,900 US suicides per year.
Of course, US suicide reporting is as terrible as adverse event reporting, so 33,900 may well be inexact.
Currently, the FDA’s needle is moved by publicity and big, fat lawsuits. Otherwise, patient safety be damned.
One wonders if the religion of the free market is not behind this negligence — buyer beware! If enough bodies pile up, consumers will stop consuming, no regulatory intervention needed. As long as consumers besiege doctors for psychiatric medication, all is assumed to be well in the pharmaceutical market, crooked research notwithstanding.
The world is definitely ready for a new model of gathering post-marketing adverse event data.
It’s well established that SSRIs can cause sexual dysfunction, diminished sexual desire, delayed sexual arousal, and muted or absent orgasm. Some reports indicate that as many as 73% of patients on some of these medications can suffer from one or more of these effects. This has major implications for the stability of relationships, attachment, seeking a partner and other important societal issues. In 2004, the director of the National Institutes of Health was called to testify before Congress and justify the amount of money that was being spent on sex research. The Traditional Values Coalition accused the institutes of paying for ”smarmy projects” and studies of ”bizarre sexual practices with little or no bearing on public health.” The group asked Representative Billy Tauzin, a Louisiana Republican who was chairman of the House Energy and Commerce Committee, to investigate. Dr. Elias Zerhouni, the NIH director at the time, said the battle against disease must include behavioral and social factors, not just biological ones. As for studies of sexual dysfunction, he wrote, ”it has an enormous impact on the stability of families and is a major cause of divorce.”
A major problem with sexual dysfunction as a result of SSRIs is that it’s grossly underreported; there’s reluctance on the part of patients and their doctors to discuss the topic. In a study done by psychiatrists in Spain, 344 patients taking SSRIs who came in for an office visit were asked the general question: “Have you noticed anything since your last visit?” Fourteen percent of these patients reported sexual dysfunction. In the very same office visit, researchers asked specific questions about sexual dysfunction. Almost 60% of these patients reported a sexual problem. This suggests that the rate is 3 times the spontaneous report or greater. All the SSRIs, including the serotonin/norepinephrine reuptake inhibitor (SNRI), have negative effects on sexual functioning.
A drug holiday can be tried, but unfortunately you can often see SSRI withdrawal symptoms after a couple of days of not taking a short-acting SSRI.
The issue of absent ejaculation is important in ways that are not the apparent ones. The contents of seminal fluid has been examined and found to contain dopamine and norepinephrine, associated with romantic love; oxytocin and vasopressin, associated with attachment; testosterone and estrogen, associated with lust; and follicle-stimulating hormone (FSH) and luteinizing hormone (LH), associated with regular cycling. The same researchers also did a separate study and found out that it actually does have regular antidepressant qualities. Those women who were directly exposed to it were less depressed than those who used condoms.
Dopamine and norepinephrine are very important in generalized arousal, so it’s very important specifically in sexual arousal as well. Unfortunately, SSRIs have negative effects on both dopamine and norepinephrine function.
While often placed well down the list of adverse effects of SSRIs (after all, not having sex isn’t going to kill you, is it?) there is actually little doubt that, once considered in its proper context, it can be a devastating impairment.
Antidepressant-induced sexual dysfunction, a very common adverse effect, is a red warning flag that these drugs are hormonal disruptors.
A medication that has such far-reaching effects must be destructive to other body systems as well, which we can see in increased risk of diabetes, stroke, cardiovascular events, osteoporosis, etc.
When a doctor prescribes an antidepressant and fails to advise the patient of potential sexual dysfunction, the doctor is making the decision that the patient’s sex life is not important to the patient’s mental health — a decision no doctor is qualified to make.
What’s more, sometimes sexual dysfunction does not resolve after the antidepressant is discontinued, and the patient will never re-experience healthy sex.
Today I want to add to the discussion from another recently encountered positive contribution of Rxisk.org. Feedback I am receiving from colleagues and clients that I’ve been emailing with links to the *trilogy* for introducing this web site has caused me to realize that while the scientific revelations about ourselves as a species are important to us for our own survival, it is the *spirit* behind this endeavor that is cause for celebration. The one basic human quality that is disappearing as Pharmageddon approaches, or is waning because of it, is the one that makes us truly human. Caring about each other and creating community from the innately human capacity for compassion is the *missing link*—the inspiration for refocusing on why we want to survive in the first place.
One close friend, a nursing colleague said that while she totally appreciates and even looks forward to hearing my latest lecture on the most recent *underground* discoveries in our field, she was deeply moved by Dr. Healy’s writing via her recent introduction —- (by me, of course). Phoning me to thank me for sharing, she cut the conversation short with this :” Just wanted to let you know this is truly ground breaking stuff. I’m about to pour myself a glass of pinot noir and read it …several more times…” click
That’s a rap!
Dear David, I’ve just found madinamerica.com and am reading your posts at the moment. I wonder if you’ve come across The Good Regulator theorem? There’s a neat article here, orthomolecular.org :
Every Good Doctor Must Represent the Patient:The Malfunction of Evidence-Based Medicine by Daniel L. Scholten
The theorem itself can be found at goodregulatorproject.org and the authors urge us to have a go at the maths – set theory- as it’s only logic. But apart from how nice and honourable it would be to be able to ‘do the math’, the theorem states that a good regulator must fit the system – a good doctor must fit his patient; results of RTC trials are like a key to fit all padlocks made by taking the average of all locks and making an average key to fit . Patients are like locks in that they can all be subtly but significantly different.
If the science is not based on good maths, it will never reach the truth.
I hope you’ve come across the theorem already, or will check it out if not. I’m sure it will give your arguments all the more force.
best wishes
Jane Lord [ researcher for a Carmarthen based Circle of Support for a young woman now in the hands of the system.]
There has been another shooting in Hyvinkää Finland, when a man of 18 stood on a roof and took potshots at passersby, killing at least 2. All the talk in the press is about tightening up gun laws. It is barely mentioned that he was taking SSRIs. For me the penny dropped, and the list on Rxisk of all these untowards events really helped that penny fall hard. If it was an ‘illegal substance’, like miaw miaw or whatever, one death is enough to get the public and governments all agitating to get it banned or legislated against, but with a prescribable medication like SSRIs which has lead to so much death and descruction there’s no proper discussion. Given kirchner’s analysis of FDA data and there seeming ineffectiveness, there needs to be a public outcry to ban these drugs full stop.
Everything that you are saying here, Dr. Healy, is so true in relation to vaccine injuries. For example, look at all these accounts of adverse reactions to the vaccine Gardasil:
http://truthaboutgardasil.org/injuries/
http://truthaboutgardasil.org/injuries-continued/
http://truthaboutgardasil.org/memorial/
http://www.judicialwatch.org/press-room/press-releases/judicial-watch-uncovers-fda-gardasil-records-detailing-26-new-reported-deaths/
Then see how the CDC writes these off as coincidence:
http://www.cdc.gov/vaccinesafety/Vaccines/HPV/gardasil.html
Parents have for years tried to get our government interested in studying their vaccine injured children/teenagers, to no avail. Our govt agencies simply say, “Well, some people who didn’t just get that vaccine have those health problems to.” They crunch a few numbers and say there is no statistical significance. They say that the Vaccine Adverse Events Reporting System (VAERS) is unreliable (which is because the system is inadequate – the vast majority of reports are ignored and not studied or verified). They say that there is “no evidence” but that is because they have not even defined what evidence would prove a vaccine injury, how to identify a vaccine injury.
Let’s pretend, for the sake of argument, that the vaccine program is in an ideal state right now – the best of all possible worlds, for the greater good for most people. Even if we had reason to believe that were the case, shouldn’t we be trying to understand better why and how vaccines cause serious adverse reactions in some people? As another Dr. Healy said – the late Dr. Bernadine Healy, former head of the NIH: “What we’re seeing in the bulk of the population: vaccines are safe. But there may be this susceptible group. The fact that there is concern, that you don’t want to know that susceptible group is a real disappointment to me. If you know that susceptible group, you can save those children. If you turn your back on the notion that there is a susceptible group… what can I say?”
http://www.cbsnews.com/2100-500690_162-4086809.html
The vaccines raise complex issues of their own. Challenge-dechallenge etc is not possible. We have to find ways to study the risks which undoubtedly exist. Allied to the question of risks inherent in the treatments, your formulation of the issues raises the risks inherent in company behavior, and what can be done to manage these. (I am distantly related to Bernardine H).
Thanks so much for your response. Amazing that you are distantly related to Dr. B. Healy.
Although I don’t fully understand what is involved in a formal challenge-dechallenge study, I do know that many parents have reported repeated reactions in their babies/children. Babies are re-challenged with every round of vaccines, and sometimes show a pattern of escalating reactions with some degree of recovery between rounds.
And, challenge/rechallenge/dechallenge/no challenge studies could be done with animals.