Pharmageddon. David Healy

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СКАЧАТЬ the patent life of that series ebbed away, Lilly had to decide whether to abandon the hunt. This was a company in serious financial trouble, facing potential takeover. On April 29, 1982, they opted to move forward with a compound from the original series that by definition was not novel—olanzapine, later branded as Zyprexa. To make Zyprexa commercially viable, they needed a new patent, which meant demonstrating some benefit not found with other antipsychotics. In 1991, the only novelty presented in the company's new patent application, which was approved, was a study in dogs in which Zyprexa produced less elevation of blood cholesterol levels than another never- marketed drug.

      Zyprexa has since turned out to be one of the drugs most likely in all of medicine to increase cholesterol levels in man. Lilly has settled over $2 billion worth of claims that Zyprexa has raised cholesterol and caused diabetes and other metabolic problems. There was arguably a better case to be made for patenting it to raise cholesterol than to treat psychosis.³³ Lilly's patent was declared invalid in Canada, though not in the United States or Europe. Despite this, Zyprexa has been one of the biggest selling drugs of all time, grossing $4–5 billion per annum from the late 1990s through 2010. There was no basis to think this drug was any more effective than dozens of others and a lot of reasons to think it was more problematic for patients, but the marketing power that came with its patented status enabled Lilly to hype its benefits and conceal its hazards and steer doctors to write enough Zyprexa prescriptions to save the company.

      In our brave new world, companies can make blockbuster profits out of a Depakote or Zyprexa. If these two compounds were exceptions, the price might be worth paying for a set of drugs that were otherwise innovative and were leading to treatments for serious conditions that previously went untreated. Many might sigh but most would reconcile themselves to the situation—this is the way the world works. But that world does not seem to be working anymore. Where there were a handful of new tranquilizers, antipsychotics, antidepressants, and stimulants introduced annually year after year from the 1950s onward, the flow of novel psychotropic drugs dried up in the mid-1980s.

      The decline of the antidepressants illustrates this all too well. The antidepressant drugs produced from 1958 to 1982 were used primarily for severe mood disorders and as such had a much smaller volume of sales than the benzodiazepine group of drugs, of which the best known, Valium and Librium, quite literally became household names—these were mother's little helpers. Valium and the other benzodiazepines were marketed as tranquilizers for anxiety from 1960 onward. In the 1980s, claims that they caused dependence led to a backlash against the benzodiazepines, leaving the market open for a new group of drugs which, however, could not be called tranquilizers as this term was now too closely linked to dependence and withdrawal. The strategy seemed clear to the major drug companies—to persuade doctors that behind every case of anxiety lay a case of depression. And to persuade them that a new group of drugs, the SSRIs (selective serotonin reuptake inhibitors), were both antidepressant and a therapeutic advance, when in fact the companies had almost consigned the SSRIs to the dustbin in the early 1980s as they were not as effective as either the tranquilizers or older antidepressants. They were also not especially novel, most of them being simple derivatives of preexisting antihistamines, many of which work as well as the SSRIs for nervous problems. Nevertheless this molecular group appeared to offer a modest but patentable amount of novelty and therapeutic benefit. The profits that came with the patent status, amounting to $15 billion per year for the group as a whole, provided the means to transform psychiatry's views of common nervous disorders—until the patent on these drugs expired soon after 2000 and clinicians had to be reeducated that the very same patients were now suffering from bipolar disorder and in reality needed a mood stabilizer.

      If the SSRIs had been a bridge to a more effective group of compounds this again might have seemed acceptable, but since 2000 almost the only novelty has come from three isomers of earlier SSRIs. Many drugs come in mirror image, or left and right hand (isomer) forms. Typically only one of the hands is active. Until the 1990s it was inconvenient to attempt to separate these isomers. But then in the mid-1990s Sepracor isolated esfluoxetine and dexfluoxetine (Zalutria) from Prozac (fluoxetine). Lundbeck isolated escitalopram (Lexapro) from Celexa (citalopram), and Wyeth isolated desvenlafaxine (Pristiq) from Efexor (venlafaxine). The astonishing thing is that companies have been permitted to take patents out on these compounds, which are as alike to the parent compounds as two drops of water.³⁴

      The paucity of genuinely new drugs coming on the market in recent years is not some odd quirk of psychotropic drug development. The best-selling drug for minimizing acid secretion in the gut in the 1980s and 1990s was the proton pump inhibitor Prilosec (omeprazole). Before the patent on omeprazole expired in 2002, its parent company, Astra Zeneca, simply introduced Nexium (es-omeprazole), an isomer of Prilosec, and clinicians shifted from a cheap drop of water to an identical but vastly more expensive drop of water. If a drug does not come in isomeric forms, companies have instead in recent years patented the metabolites of a parent compound and released these as a novel drug with the approval of the US patent office and almost no resistance from medicine.

      When the breakthrough drugs of the 1950s emerged, there were great hopes that not only would they offer remedies for illnesses that we did not have treatments for, but they would also shed light on the nature of the illnesses being treated. In 1896, the advent of diphtheria antitoxin had demonstrated that not all throat infections were diphtheria, thus opening up the idea that bacteriology would be able to carve a mass of respiratory, gut, and other problems into a series of discrete illnesses each of which could be tackled individually. In the 1950s, there were great hopes that the new treatments for disorders like arthritis, depression, hypertension, or schizophrenia might similarly clarify whether these were single diseases or the end result of common pathways into which several different diseases fed.

      The new drugs, to use a celebrated phrase, would help us carve nature at its joints, just as distinctions among bacteria had enabled us to carve infectious diseases at their joints. But we have now arrived at almost the precisely opposite point. Rather than drugs being used to carve nature at its joints, nature instead is being used to differentiate drugs whose differences are essentially trivial.

      With the new possibilities for profit opened up by a lax to nonexistent application of patent laws, the medical arena has ceased to be a domain in which scientists using new molecular tools push back boundaries. Indeed since the passage of the Bayh-Dole Act in 1980, which encouraged scientists, including medical academics, to consider patenting the products of their research, clinicians and scientists have seemed keener on making patent applications themselves and setting up start-up companies than in advancing medical knowledge or healthcare. Pharmaceutical companies meanwhile have no interest in what molecules might reveal about how humans work. Molecules are only interesting insofar as they can be used to capture market niches. Medicine may look the same as it has always done to onlookers; the marketers know it's not.

       BRANDS AND PATENTS

      The emergence of product patents transformed the importance of branding. By the 1980s, when H-2 blockers for ulcers, statins for cholesterol, SSRIs for depression, and other drugs were in the pipeline, branding had become so important to companies that the job was outsourced to specialist Manhattan-based companies like InterBrand and MediBrand. No longer would drugs be called Diuril or Tryptizol. We were about to get Prozac, Viagra, Zestril, and Nexium, names that bore no relation to the underlying chemical or disease but were aimed at differentiating between the new Nikes and Reeboks of the medical world and hinted at the restoration to youthful vigor that nineteenth-century brands had shamelessly promoted.

      Branding now extends far beyond generating and market-testing fancy names for drugs. Brands nest within brands. The new marketers brand drug classes and diseases with far-reaching implications for medicine and society.

      For instance when the makers of the new antidepressants of the 1990s needed to distinguish their drugs from older drug treatments, the term SSRI (selective serotonin reuptake inhibitor) emerged. This is not a medical or scientific term. Serotonin is a neurotransmitter in the brain, but both new and old antidepressants СКАЧАТЬ