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 September 2012

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).


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.

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

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?


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 it’s 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.

Dancing as fast as we can: The crisis in healthcare

This is the first of 6 Dance posts that cover the role of pharmaceuticals in the current healthcare crisis. It is based on Pharmageddon. In succeeding posts the role of clinical trials, patents, and prescription only status will be covered. The first five posts have been renamed from BarMittzva Romba; this combination of Bar(ack) and Mitt seems to have been too clever for its own good.

People dancing

We are at a most unusual juncture. The US Congress is the most polarized ever, with Democrats and Republicans unable to agree on the day of the week. The most divisive issue of all is healthcare. Healthcare is also the greatest problem with costs rising toward 20% of GDP and threatening to sink the economy. If the money were producing better outcomes, there might be less controversy but there is a widespread perception that health is getting worse rather than better.

The only thing both sides agree on is paradoxically a healthcare issue, speedier access to medical drugs and devices. There is currently a Bill before Congress to speed this up and to get FDA to take into account not just the efficacy and safety of drugs but also the fact that drug manufacturing leads to jobs in the United States. In the face of our mounting healthcare crisis, better and more efficacious drugs not unreasonably seem like a possible path to salvation.

In the UK, meanwhile a recent edition of New Internationalist, a Marxist publication, comes with a diagram that is found in everything from Marxist publications through to brochures for PharMA suggesting that 15-20% of us are mentally ill and in need of efficient access to treatment. The issue of access is a recurring theme across healthcare, not just mental healthcare, for stakeholders from both the Right and extreme Left of the political spectrum. All fifty shades of left and right agree we are awash in a sea of unmet need.

The therapeutic paradox

But it seems the more we meet these unmet needs, the worse rather than better health gets. Life expectancy in the most advanced countries, those that consume the greatest amount of the most recently developed medicines, is falling relative to other countries. There is no reason to think that meeting even more needs with more of the latest medicines will do anything other than aggravate this trend.

This raises the prospect that for some reason the market in healthcare may not be working. If this is the case, there are two questions. One is why not? The second is whether there is any way in which we can assert an unmet need not to have unmet needs met until normal market service is resumed.

The usual liberal-social democratic response to market failures is to call for more regulation. In this case, as will become clear, while the answer might be smarter regulation, it cannot be more regulation. Regulation has caused or greatly shaped the problem. The usual conservative response is to call for a freeing of the market. Conservatives have a preference for solutions delivered by private enterprise rather than government. In this case those most resistant to and most likely to object to a freeing of the market are private enterprises.

Solving this problem is not only economically necessary but is likely to cut a political Gordian knot that will have long-term political consequences.

The origins of a unique market

In the late nineteenth and early twentieth century, in the face of a widespread and dangerous exploitation of patients with mark ups on drugs of the order of 400 and 500 per cent, the creation of an advertising industry that sold beauty rather than health, product labeling that was grossly fraudulent, and a lack of effective treatments, there was a push to regulate the pharmaceutical industry.

Industry protested but the first regulations were put in place in the United States in 1906 and a series of regulations followed in other countries. It is now clear that a predictable consequence of regulation is to foster a growth in company size as the companies that survive put an apparatus in place to manage their regulatory requirements and this is built into the cost of drugs while other companies go to the wall.

This much is a simple story about a predictable and manageable consequence of regulation that is not unique to the market in drugs. Since then we have had the development of a unique market that was not predictable – or at least has not been predicted or discussed in detail elsewhere.

The initial thrust behind the regulation of drugs was patient safety. The first call was for an accurate labeling of the contents of products, aimed at empowering consumers. During the 20th century there was a steady push towards some specification of the efficacy of drugs. This interest in efficacy was originally a safety issue. If a drug didn’t have efficacy it couldn’t be safe.

The emergence of the randomized controlled trial (RCT) bolstered the argument that demonstrating efficacy was important and a requirement for controlled trials was built into the last set of regulations we have had, the1962 Food and Drugs Act. But far from improving comparative safety, this development has led to a comparative efficacy market that has had adverse consequences for safety.

As with all other regulatory developments, in 1962 the changes followed on a drug safety crisis, involving the sleeping pill thalidomide. This crisis fed into more general concerns about the pharmaceutical industry. The upshot was a series of changes. One involved the incorporation of controlled trials to determine efficacy. A second lay in a decision taken about the patent status of pharmaceuticals. The third development lay in making new medications available on prescription only.

Just as earlier regulations led to company complaints but also a predictable increase in company size and the emergence of the pharmaceutical companies we know today, so there has been a predictable set of consequences to the 1962 regulations. But there has also been a confluence of changes that created a unique market that few have noticed and none has taken fully into account.

These distinct regulatory elements have shaped the pharmaceutical market, the practice of medicine and global consciousness to this day. They have also produced the perfect raw material, the perfect product and the perfect consumer. But if the outcome being sought is an increase in personal health and national wealth the market has produced an unimaginably bad outcome.

In this election year in the US, one of the candidates has the chance to rise to the occasion and sort things out. A series of 6 further posts in the next few weeks covering different dances and ending with a Dance with Python will lay out the elements of the problem and how to solve it.