BarMittzva Romba: Shadow Dance

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.

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”.

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.

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

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

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

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

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

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

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

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

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

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.