A Growing Madness

THE PERFECT MARKET?

David Healy MD                 

We are at a most unusual juncture.  The US Congress is the most polarised ever.  The most divisive issue of all is healthcare, where costs are rising toward 20% of GDP and threatening to sink the economy.  Far from producing better outcomes, there is a widespread perception that health is getting worse rather than better.  

The only thing both sides agree on paradoxically is a healthcare issue, speedier access to new drugs and devices.  There is a Bill before Congress to speed up access and get FDA to consider not just the efficacy and safety of drugs but also the fact that drug manufacturing leads to US jobs (Scott 2012).  Better and more efficacious drugs not unreasonably seem like a solution to the healthcare crisis.  

In the UK, everything from The New Internationalist through to brochures for PharMA suggest thatthat 15-20% of us are mentally ill and in need of access to treatment (Godrej 2012).  All fifty shades of the political left and right agree we are awash in a sea of unmet need.  

The Therapeutic Paradox

But the more we meet these unmet needs, the worse health gets.  Life expectancy in countries that consume the greatest amount of recently developed medicines is falling relative to other countries.  This suggests that the market in healthcare is not working.  

The usual social democratic response to market failure is to call for more regulation.  In this case, regulation has arguably created the problem.  The conservative response is to call for a freeing of the market but in this case those most likely to object to a freeing of the market are private enterprises.

The Origins of a Unique Market

In the face of a widespread and dangerous exploitation of patients at the start of the 20th century with mark ups on drugs of 500%, the creation of an advertising industry that sold beauty rather than health, product labelling that was grossly fraudulent, and a lack of effective treatments, there was a push to regulate the pharmaceutical industry.    

The first regulations were adopted in the United States in 1906 and followed in other countries.   It is now clear that a consequence of regulation is to foster a growth in size as companies create apparatus to manage their regulatory requirements and this is built into the cost of drugs. This much is a simple story about a predictable consequence of regulation, not unique to the market in drugs.  Since then we have had the development of a unique market that was not predicted and had not been discussed in detail elsewhere.   

The initial thrust behind the regulation of drugs was patient safety. The first call was for accurate labelling of products.  During the 20th century there was a 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 randomised controlled trial (RCT) bolstered the argument that demonstrating efficacy was important and a requirement for controlled trials was built into the 1962 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.

The 1962 crisis with the sleeping pill thalidomide produced other changes also.  These included a decision about the patent status of pharmaceuticals, and a requirement to make new medications available on prescription only. 

These distinct regulatory elements have shaped the pharmaceutical market, the practice of medicine and global consciousness to this day.  They have produced the perfect raw material – clinical trial data, the perfect product – patented and branded drugs, and the perfect consumer- doctors.  

Alcohol as an Antidepressant

The regulatory hoops through which a company has to jump to get on the market are now such that it would be easy to get alcohol, nicotine or opiates on the market as antidepressants.  

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 factor that prevents companies bringing alcohol on the market as an antidepressant is consumer familiarity.  This 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

Current UK regulations only require two positive studies to get a drug on the market.  This allows us multiple opportunities to get a positive result for alcohol.  For some antidepressants only one third of trials have been positive. 

In an antidepressant trial, 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 so that simply taking the drug 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 would produce substantial benefits on scales like the Hamilton rating scale for depression or scales for anxiety.  

We can compare alcohol to placebo in a set of mild problems rather than against a treatment known to work or in a set of severe disorders.  We can improve the profile of alcohol by screening out anyone showing a good response to placebo or a bad reaction to alcohol during the first week of the study.

Only some of the studies we undertake have to show a benefit for alcohol over placebo.  If there are a lot of studies, perhaps even a preponderance of studies, in which alcohol fails to beat placebo, regulators will conceal the fact that they have seen studies where alcohol has failed to beat placebo. As a result patients and doctors will be unaware of negative studies. 

In the case of alcohol and nicotine, placebo effects might well account for 80-90% of any rating scale benefit found.  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.  Non-existent patients conveniently 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 this comes to light, 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 of aripiprazole as a mood stabiliser, it proved no better than placebo in 30 North American study centres, but turned out to be dramatically better than placebo in 2 Mexican centres.  When all the centres were added together, the overall results for aripiprazole 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. 

With this kind of license, it is almost impossible not to achieve a positive result for alcohol.

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, prove better than placebo in perhaps no more than 33% of cases on our chosen rating scale, and in these 33% of cases prove better in only 3% of centres, and we will still be able to market alcohol as an “antidepressant”.  

After approval, in order to make our market, we need 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 moulded 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 have it as a first line therapy based on its excellent safety profile.  Depending on how clever companies are with the trials they run, or choose to publish, the guideline makers in all seriousness may put whiskey forward 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.

Endorsement by a guideline makes it almost mandatory for doctors to use alcohol. Furthermore we can likely engineer it, while a guideline recommending alcohol first may only do so for a 3 month period – in line with the evidence, the involvement of our consultants and marketing efforts mean that later iterations will successively extend the recommended treatment period so that an increasing number of patients being treated by doctors who adhere to guidelines are likely to have alcohol for life. 

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”.  

The trials we have to undertake to bring alcohol to market only have to last for six to eight weeks.  This is particularly helpful in terms of adverse events in that few of the problems that might be expected from alcohol (or nicotine) emerge in a six to eight week period.  In the case of any problems that emerge outside this time frame, 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.  

We have yet another defence. 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.

The bias of doctors, helped by us, means that a culture will emerge early on in the use of alcohol that will attribute any of the difficulties people may have stopping alcohol to the nervous problem that was being treated in the first place rather than to dependence and withdrawal.  We can be sure that twenty years after alcohol is first marketed that a majority of doctors will fail to recognise 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.  We can depend on the editors of leading journals to refuse to publish any correspondence that might be critical of studies like this.

We can organise 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 widespread access to alcohol that there will be a net benefit to society.

A key difference between prescription and over the counter drugs lies in an inversion of the stranger-neighbour phenomenon.  We are in general wary of strangers and comfortable with neighbours.  We neglect the fact that we are most likely to be abused or harmed by neighbours or relatives.  Neighbours and relatives are familiar and we think we can manage the risks.    

In this scenario alcohol or nicotine in the form of beverages or smoking are 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.  

For instance, we regard prescribed amphetamines as safe to give to children, even toddlers, while the authorities jail others for possession of street amphetamines on the basis of the risks they pose.  We do the same for prescribed as opposed to proscribed opiates. 

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 it is now clear that making alcohol or nicotine available through doctors is a way to hide hazards such as liver failure or lung cancer 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.  

Freeing the Market

Close to 20% of US GDP now goes on healthcare, up from estimates of between 1 - 5% 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 in the world.  Now US life expectancy has fallen below that of Cuba. 

With many treatments throughout the Western world, 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. 

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

There is a cost in alienation besides the economic costs.  The marketing of drugs is changing the fabric of what it means to be human.  The struggles over female sexual dysfunction exemplify this.  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.

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

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

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.  Science by definition is based on accessible data.  In contrast, a great deal of what passes for evidence based medicine 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 get on balance more disability and premature death than benefit. 

The problems that stem from data sequestration are aggravated by product patents.  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.  

Why have things worked out this way?  It is possible that as a matter of strategic national interest the USA decided to attract the pharmaceutical industry to its shores.  Whether deliberate or not, this is what has happened.  The price Americans are paying is very high.  Others are also at growing risk.

Any of the sticking plasters we apply to attempt to stop the hemorrhage of money only aggravate the problem.  The latest is comparative effectiveness research.  This rests on misguided notions of what randomised 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.  It is easy to see that a slightly more effective but less safe airline will go out of business. Somehow getting to the healthcare equivalent of Seattle quicker 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 realise that the market will work if it is a comparative safety but not 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.  

But it does require a shift in perspective.  We need 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 create a series of prescribing cascades.  Extirpating diseases is not the goal; keeping people safe is.  

The US Congress and UK Governments likely thought they were creating a comparative safety market when they made new medicines available on prescription only.  Instead this gave doctors a guaranteed income.  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 that doctors fail to detect.  We need to find a way to re-educate doctors, or reward them for keeping people safe, or consider re-engineering the prescription-only system. 

The market Congress envisaged in 1962 is at odds with the realities of health today.  Congress viewed citizens essentially as dupes, in need of protection. The advent of the internet has meant that many of us know more about our treatments than our doctors do.  We need new collaborative models of care that recognise this and harness the drive and energy of patients to making medicines safer.