Pharmageddon. David Healy

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      The copper-fastening of prescription-only arrangements that came out of the Kefauver hearings would alone have put doctors in the sights of pharmaceutical company marketing departments in a way they had never been before. But constraining companies to market their drugs for diseases and to demonstrate their efficacy through what was then a new medical invention, the controlled trial, made it necessary for companies not just to have doctors in their sights but to understand doctors better than doctors understood themselves.

      In the case of some hugely profitable trademarked drugs, such as Marlboro, medicine has played an honorable part in bringing lethal problems to light. But what would have happened had tobacco been available by prescription only? It is clearly helpful for ulcerative colitis. In all probability it could be shown to be just as good an antidepressant as Prozac and the SSRIs—so the market might have been substantial. How quick then would doctors have been to do the independent studies that pinpointed the problems linked to smoking or to insist on the seriousness of the risks while the tobacco industry was systematically creating doubt about those risks?

      Doctors don’t view themselves as consumers, subject not only to the extraordinary pressures that modern marketing can bring to bear on any consumer but also, by virtue of prescription-only arrangements, to these forces in the most concentrated form that exists anywhere on the globe. Typically, they blithely go their way without seeing the need to understand marketing. They bunker down behind a Maginot Line of what they believe are untainted controlled trials and evidence-based medicine, unaware that the tank divisions and air force of their opponents give daily thanks for that Maginot Line.

       THE RISE OF THE BLOCKBUSTER

      The possibilities for a new generation of branded medicines—and extraordinary sales—that opened up on the back of a regime that allowed drugs to be patented and that made these drugs available on a prescription-only basis were first revealed in the course of a battle in the 1980s between pharmaceutical giants Glaxo and SmithKline over the ulcer drugs Tagamet (cimetidine) and Zantac (ranitidine).

      James Black was one of the most successful medicinal chemists ever; he was also one of the first to win a Nobel Prize while working in the pharmaceutical industry. Black had initially worked for Imperial Chemical Industries, where he had developed the concept of a beta-blocker. These drugs, which blocked the beta-adrenergic receptors on which stress hormones like epinephrine exert their effects throughout the body, turned out to be particularly useful for treating hypertension, the most rapidly growing medical market in the 1970s.

      Black then moved to SmithKline, where he turned his attention to the antihistamines, helping to distinguish among two different histamine receptors, H-1 and H-2. This opened the way to develop H-2 blockers that would target histamine receptors in the gut, reducing gastric acid production, then thought to be responsible for ulcers. Tagamet was the result, a drug that embodied a genuinely novel approach to the treatment of duodenal ulcers, then one of biggest problems in internal medicine.⁸ Within a few years of its introduction, surgery for ulcers had become a rarity—had Tagamet been available earlier, it would have saved my mother much misery. This epitomized the best hopes of both science and industry—new and innovative products making it into healthcare and making a big difference to patients.

      In the course of developing Tagamet, Black presented details of his experiments at scientific meetings, stimulating interest among chemists at Glaxo, who also determined to develop an H-2 blocker. Glaxo’s efforts led to Zantac, a drug almost identical to Tagamet. Since Tagamet had been the breakthrough compound and had come on the market in 1979, six years before Zantac, and with the prestige of Black’s endorsement, few doubted that Tagament’s sales would vastly outstrip those of Zantac.

      Glaxo, far from undercutting the price of Tagamet, as might have been expected in a normal market, decided to make Zantac pricier. And it put huge resources into marketing, which focused on minor differences in the side-effect profiles of the two drugs. Much to the surprise of observers, Zantac’s revenues soon outstripped Tagamet’s, and it became the first blockbuster—a drug that makes at least a billion dollars per year.⁹

      Glaxo and SmithKline merged at the turn of the millennium to become the biggest pharmaceutical company in the world. But before they did, Glaxo’s response to an exciting development in the science of ulcers is indicative of important shifts that were taking place in the world of medicine and corporate interest. In Australia, Barry Marshall, then a medical resident in Perth, spotted an unusual bacterium, helicobacter pylori, in tissues removed from ulcers. This led him to a series of experiments where he cultured helicobacter, drank it, produced an ulcer, and later cured his own ulcer with antibiotics.¹⁰

      Marshall made overtures to Glaxo but found they had no interest in a cure for ulcers. The beauty of H-2 blockers was that once they began taking them, many patients remained on them indefinitely. Actually eliminating ulcers, the treatment of which had just become the cash cow of the pharmaceutical industry, was not what Glaxo had in mind. The decade between the contrasting scientific experiments of James Black and Barry Marshall had propelled medicine into a new world, one in which it could not be assumed that science and business were on the same side, as they had appeared to have been over the previous three decades.

      Zantac was a brand like no other. It came with attention to color coding, with free pens and trinkets for doctors, and a lot of support for doctors to attend educational meetings nationally and internationally. It set a template for aggressive drug promotion. Its very success led, in reaction, to movements like No Free Lunch, a group set up by Bob Goodman to persuade doctors to remain independent of pharmaceutical companies by refusing the free pens, lunches, and the like that companies handed out so liberally. Glaxo’s aggressive marketing at the end of the 1980s also made many doctors more receptive to the idea that evidence-based medicine, which emerged in the 1990s, could be used as a way to contain the power of marketing.

      But No Free Lunch and similar efforts to eliminate conflicts of interest fail to ask just what it is that would make a brand appealing to doctors. A brand is something whose value lies in the perception of the beholder—and in this case doctors repeatedly tell us that the evidence about a drug’s benefits and risks trumps the color coding of the capsule or the lunches, no matter how good they might be. And insofar as creating a brand involves building a set of exclusively positive associations and eliminating any negative associations, this is not going to be done by getting the color right.

      The problem is that a brand is meant to be an uncomplicated good. It is a partial truth that seduces by directing our attention away from any messier realities. It doesn’t fart; it doesn’t have body odor. Against a background of clinical complexity it offers a point of reassurance. But it is, by this definition, incompatible with a medicine, which is—or was—understood to be a poison whose delivery involves a judicious balancing of risks and benefits.

      The combination of brands like this and prescription-only privileges leads to a tragedy in the classic sense of that word—as with Hamlet, “whose virtues else be they as pure as grace as infinite as man may undergo, shall in the general censure take corruption from the particular fault.” Here’s how. Brands married to product patents have created the conditions that have made blockbusters possible, and the fortunes of pharmaceutical companies increasingly now depend on the success of these blockbusters and their branding. They have to be hyped to the max and their hazards concealed. These dynamics of brand creation are, through prescription-only status, welded to an profound bias in medicine—doctors tend to attribute any benefits in a patient’s state to what they have done and couple this with a tendency to overlook any harm they might have done. Doctors have to be enthusiastic about treatment—their very enthusiasm can make the difference between success and failure. Being readily able also to spot the harms they do would likely in many cases lead to clinical paralysis.

      The fortunes of pharmaceutical companies hinge on this weld holding fast. The tragedy is that there is little risk of it coming undone: both companies and clinicians are biased to attribute any harms to the disease being treated—it is depression that gives rise to suicidality in patients on antidepressants, not the drugs; it is the poor state of a person’s arteries that leads to coronary artery bypass surgery and is responsible for any confusion after the surgery