by David Healy
The contrasting fates of reserpine and Prozac bring this out. In the early 1950s, reserpine, one of the first antihypertensives and first tranquilizers, was linked to suicide induction. Owing to the differing patent regimes at the time, twenty-six different companies produced reserpine and so no one manufacturer could have made it into a proprietary blockbuster. Therefore no company had an incentive to defend it to the death, and as a result while many doctors refused to concede a treatment they gave might have caused a problem, the views of others could be heard. A link between reserpine and agitation was established and reserpine fell into disfavor.
But in 1990, when similar concerns erupted that Prozac could trigger suicides, the situation was quite different. There was and could be only one Prozac, and Lilly had all their eggs in the Prozac basket. They could not readily admit their brand might have a flaw. As Leigh Thompson, Lilly’s chief scientific officer put it in an internal e-mail that later came to light in a court case:
I am concerned about reports I get re UK attitude toward Prozac safety. Leber (FDA) suggested a few minutes ago we use CSM database to compare Prozac aggression and suicidal ideation with other antidepressants in UK. Although he is a fan of Prozac and believes a lot of this is garbage, he is clearly a political creature and will have to respond to pressures. I hope Patrick realizes that Lilly can go down the tubes if we lose Prozac and just one event in the UK can cost us that.11
Several years later company documents for Lilly’s post-Prozac blockbuster Zyprexa made it clear that
The company is betting the farm on Zyprexa. The ability of Eli Lilly to remain independent and emerge as the fastest growing pharma company of the decade depends solely on our ability to achieve world class commercialization of Zyprexa.12
Prozac, Zyprexa, and other such blockbusters are products that come with a life plan that covers their use in all global markets.13 Even before the launch of potential blockbusters, ways of promoting their use in children and the elderly, without undertaking clinical trials to demonstrate efficacy or safety, is envisaged. The necessity of acknowledging a side effect that might restrict this use is not part of the plan. When a company is faced with defending a brand that is essential to its survival, commercial logic dictates that it will take any steps necessary to preempt the emergence of a hazard, including doctoring the evidence. This commercial logic led to a relentless marketing of Zyprexa that ultimately saw it being given to children as young as twelve months of age, its clinician prescribers seemingly unable to see the massive weight gain it produces, the diabetes it triggers, the raised lipids it leads to, and the premature deaths it causes.14
As the story of H-2 blockers and the treatment of ulcers suggests, drug companies have little interest in innovative treatments that would eradicate a condition for which they have on-patent drugs that manage it after some fashion. When ulcers vanished, after the introduction of antibiotics, companies like Astra-Zeneca with a new generation of gastric acid antagonists, such as Prilosec, turned to GERD (gastro esophageal reflux disease) to replace it. This disease, which now seems so widespread and crippling, was infrequently encountered when I was training, and as such it is difficult to believe it doesn’t stem at least in part from our increasingly unbalanced and artificial diets and lifestyles. While there are unquestionably severe cases that need urgent medical treatment, it also seems the case that a large number of digestive discomforts that might be better handled by changing lifestyles have now been medicalized and are managed with medication.
Quite extraordinarily GERD has even spread into infancy, incorporating colic, a disorder that lasts a few months and responds to care in the real sense. The first drug treatment for GERD in infants—Prepulsid (cisapride)—killed significant numbers of children where colic had never been known to kill children before.15 The shock of Prepulsid-induced deaths did not lead to a return to traditional medical care of colic— children instead are now getting Prilosec (omeprazole) and other successors of Zantac.
At the eighteenth annual Pharmaceutical Conference in Paris in June 1990, Christopher Adam, then the head of marketing at Glaxo told the meeting “we are moving into the mega-product age.”16 Right he was. Zantac had just become the first blockbuster. The next year all blockbusters combined only comprised 6 percent of the market, but by 1997, when SSRIs like Prozac were the darlings of the media, this had grown to 18 percent, and by 2001 to 45 percent, under the impact of Lipitor and the statins.17 There is no blockbuster that is a life-saving drug. They are all lifestyle or risk management drugs.
In 1990, market analysts perceived two threats to Glaxo’s position as the largest drug company in the world—the possible expiry of its patent on Zantac and the emergence of Prilosec, a new drug for ulcers. In fact the danger came from Barry Marshall’s research. Prilosec did displace Zantac but for the GERD rather than the ulcer market, forcing Glaxo into a series of mergers in order to sustain its position among the leading companies. In 1995, it merged with Burroughs Wellcome, at which time its chief executive, Richard Sykes, made it clear he still regarded the company as a serious research company that would have nothing to do with lifestyle drugs like Prozac. Five years later it merged with SmithKline Beecham, whose fortunes rode on Paxil, the company’s biggest earner since. By this time Sykes was gone. The market was changing the character of drug companies and in turn the shape of medicine.
THE FACE IN THE MIRROR
The idea that brands such as Lipitor, Paxil, and Fosamax might now have penetrated medical practice in a way that brands like Clark Stanley’s Snake Oil or Beecham’s Pills never did and that these modern brands might now play as big a part in medicine as Nike and Reebok do for running shoes and Lexus and BMW do for cars is not an idea that sits comfortably with the medical profession’s idea of itself.
In the world of medicine most doctors come from, drugs are good, though they are unfortunately sold by slick if rather sleazy salespeople to whom doctors might try to be polite but whom they otherwise try to avoid—unless “these people” are picking up the drinks tab. But in the new world of medicine, the person doing the selling is not the sleazy- looking suit standing by the exhibit. That person is there to distract attention from the fact that one by one doctors are having marketed back to them exactly what they say are the things that count for them. The industry needs a person out there whom the doctor can identify as a source of corruption, someone they can resist, the way they might resist an obvious honeypot. In this new world, if a group like No Free Lunch didn’t exist, the pharmaceutical industry would have to invent it.
In other industries, when companies manufacture a product they have to move it from factory to retail outlets where it competes with other products and they have to generate demand among consumers. The ideal arrangement is to have a dedicated showroom, such as automobile makers and Apple do, where purchases become almost inevitable as there are no competing brands in sight and, in the case of cars, nothing praising the virtues of walking, running, cycling, or any other means of transport. In the case of a branded drug, the task is to get on a hospital’s or managed care company’s list of approved drugs as well as into national guidelines and to have key articles placed in all the prominent journals. We shall see in chapters 4 and 5 how companies manage this and manage to eliminate competing influences, so that when the doctor gets to the point of purchase, the purchase is as inevitable as it is in a car showroom, but here let us focus on the doctor before he walks into the showroom.
He will likely think he is not particularly influenced by the ads for drugs he sees. And in this he is undoubtedly correct to a point—at least three-quarters of the ads for a drug are not aimed at him. He may even think that most ads make him less likely to prescribe rather than more likely. He will be unaware that just as marketers distinguish between women and men, or between those of us who want high-tech versus retro running shoes, so they also have learned to distinguish between “high-flyers,” “skeptical experimenters,” “rule bound,” and “silent majority�
� doctors.18 Few doctors have any idea how the marketers have pigeonholed them and as a result will not be able to pick out the ads aimed at them from the ones aimed at others that serve a secondary function of throwing any particular doctor off the scent.
High flyers are the doctors keen to try new things. They don’t want to hear what is in guidelines or what colleagues are doing. They are interested in the latest reports that promote a drug for something new, or in a different cocktail with other drugs, or in a higher dose than previously recommended. These are doctors that companies term “early uptakers” and they are important to getting a new product adopted. Skeptical experimenters are similar but more likely to temper their prescribing practices on the basis of experience.
In contrast to these two types, marketers identify most doctors as either rule bound or silent-majority conservatives. For the rule bound, regulatory approval of a drug means the drug should be used for the stated purpose and for that purpose only, and in accordance with the latest guidelines. The conservative majority want everything kept simple. They pick a drug and stick to it; they’re most interested in aspects such as whether the drug comes in a new formulation that might enhance compliance—a tablet that dissolves instantly in the mouth, for example, so that patients cannot but comply.
Where doctors, the media, and others see a salesperson visiting a physician with free pens and an offer of lunch, with a pitch based perhaps on the results of some recent clinical trial on a drug, the key exchange is of a different order: it is not what is handed over to the doctor but how he or she responds to various probes and what is then fed back to the company. After that, the pitch to a high flyer will be as different as the one to a rule-bound doctor just as a car salesman’s pitch is different to someone keen to buy a sports car compared to someone who wants to buy a family car.19 The ads and the patter directed at high flyers will show a doctor on a mission to tackle the scourge of disease, a mission that sometimes justifies extreme measures, where the ads to the rule bound may feature the latest authoritative guideline. The idea is to get the mood music right in the showroom, to get the brand speak in the right tone of voice.
Doctors won’t have to make their own way to the showroom—they will likely be transported there even if the showroom is in a different country, being wined and dined en route. Once in the showroom, a doctor won’t meet a salesman but instead, colleagues, or a local professor, or some medical eminence. The knowledge needed to construct a blockbuster brand is derived almost entirely from the physicians to whom the product is being sold. The careers of Lipitor, Nexium, Vioxx, Prozac, and Depakote make this clear. Doctors tell the company what they, the doctors, want to hear.
In the course of a drug’s development, panels of medical academics— opinion leaders—are convened to see what the consumer wants. Pharmaceutical companies do nothing so crude as call these focus groups, but this is essentially what they are. The consumers being courted are jobbing doctors, and the process is aimed at guessing how these clinicians can be influenced. At the 1990 Paris pharmaceutical conference, Glaxo’s marketing chief told the audience “concepts sell drugs.”20 The academic focus groups are where a company will find out just what concepts are current. After the demise of Vioxx, doctors needed something new for pain relief but rather than sell them Lyrica, a not very good analgesic, Pfizer married Lyrica to fibromyalgia and sold this combination. Fibromyalgia is a suitably vague condition characterized by nonspecific complaints of pain that had been knocking around medicine for a century.21
The new role of medical academics is to broker this process. Where once these academics were the repositories and creators of medical culture, they are now a resource to be plumbed by companies to establish what prescribers can be induced to want rather than what’s best for the patient. The key thing is to establish what prescribers do want from a drug and ensure they appear to get what they want, whether or not there is much basis in the drug to think it might do what the prescriber wants. If pain has become an issue for doctors, the marketing of a new product will emphasize this quality even if there is nothing to recommend the new product for this purpose compared with older products. Companies trumpet the huge research and development budgets needed to bring a drug to market today. But it costs very little to make these medications. Research is undertaken on the new pill, but most of the studies are designed to secure therapeutic niches rather than to advance medical knowledge. The real “research” budget is devoted to establishing the mindset of clinicians at the time of launch. In 2003, it was estimated that thought-leader development in the United States accounted for a stunning 20 percent of marketing costs and was rising,22 compared with 14 percent put into direct-to-consumer ads.23
Take the bladder stabilizer Yentreve (duloxetine). Lilly had jettisoned duloxetine as a potential antidepressant in the 1990s because it triggered urinary retention among other effects, but then brought it onto the market in Europe as a bladder stabilizer. When Prozac went off patent in 2001 and its designated successor, Zalutria, appeared to produce cardiac problems, Lilly opted to bring duloxetine back to antidepressant life as Cymbalta. Cymbalta was marketed heavily as a pain reliever in addition to helping depression. Why? Because doctors had told market surveys they often have patients in pain of one sort or another and were uncertain how to treat them.
Luckily for Lilly, just as Cymbalta was coming to market, the leading painkiller Vioxx was withdrawn from circulation because research showed it caused heart attacks. Anything that would help pain was catapulted forward in the promotions of all companies, and Cymbalta was certainly no exception.24 As a result, a great number of patients attending pain relief clinics or visiting internists or primary care practitioners and complaining of pain were put on it, even though they showed no signs of depression. What doctors were hearing when they listened to the siren song from Cymbalta were their own needs. Duloxetine had nothing to recommend it for pain beyond what other antidepressants have, but Cymbalta relieved doctors’ worries about pain.25 Such marketing might have been developed for Zalutria and simply switched to Cymbalta in just the way that the marketing for one brand of bottled water could be applied to any another. There is nothing in the water that gives substance to any of these perceptions.
The patient given Cymbalta for pain relief is not to know that it is more likely to lead to agitation, sometimes severe enough to trigger thoughts of suicide—and that the FDA banned its use for urinary incontinence for this very reason. They are not likely to know that Cymbalta is more likely to cause urinary retention than it is to ease pain. But the patient is not the consumer, the doctor is, and his pain is eased by Cymbalta without any side effect to cloud the picture.
Once the distinguishing feature of a marketing campaign has been identified, the appearances of scientific support are manufactured. A clinical consensus for a drug such as Lyrica (Pfizer’s drug ostensibly to treat fibromyalgia) or Cymbalta for pain, for instance, is built by means of scientific symposia, with articles apparently written by opinion leaders but usually ghostwritten, or by educational initiatives featuring well-known academics.
Ultimately branding of this sort feeds off blue-skies research and medical education funded by governments in the United States and Europe. Without this there would be very little understanding of the effect a medication has on lipids or bones or blood pressure and as a result very little language available with which to describe the effects of the drugs for marketing purposes. From the point of view of marketing, the advantage of the medical sciences is not that they might lead to better drugs but rather that they provide concepts and languages for marketers to use.
One of the best examples of this process has been the creation of the notion of chemical imbalance. Neurotransmitters were identified in the brain in the early 1960s. By 1965, this led some to hypothesize that the amounts of one or another of two common neurotransmitters, norepinephrine and serotonin, are lowered in depression and that antidepressants could top them up. By 1970, psychopharmacologists ha
d abandoned these hypotheses because of clear inadequacy.26 But twenty years later, the idea that serotonin was low in depression and restored to normal by treatment was resurrected within the marketing departments of SmithKline Beecham, Lilly, and Pfizer, as part of the sales pitch for Paxil, Prozac, and Zoloft. It was marketing copy par excellence, too tempting to spurn. In fact, mindless patter about restoring chemical balances did a great deal to make the SSRIs among the most profitable income streams for the pharmaceutical industry from 1990 onward. In similar fashion when selling drugs for osteoporosis, cholesterol reduction, asthma, and other conditions, marketers cherry- pick from the language of the appropriate science to dress up their products. As they put it themselves, they leverage the bits of the science base that suit them.
In addition to using information from the basic sciences, one of the clearest strategies companies use is to market diseases in the expectation that sales of the pills promoted for them will follow. This has happened from the 1950s onward, when Merck educated physicians to recognize raised blood pressure (hypertension) and its consequences after their new diuretic agent, Diuril, turned out to have antihypertensive properties. They convened symposia and sponsored studies on the benefits of monitoring hypertension.27 This approach speaks directly to clinicians in clinical language. It also puts an ethical onus on them to eliminate a disease by prescribing a pill—one that comes sanctioned by the experts in the field.
Patients also have to be softened up so they are receptive to the idea of being prescribed a statin, or an antihypertensive, or a biphosphonate for their bones. In the United States direct-to-consumer advertisements school people on the importance of their “figures”—their lipid levels, blood pressure, and bone densities—or alert them to the possibility that what they regard as restless legs may be in fact be an illness,28 or that feelings of urgency as regards micturition, low grade pain, or less than perfect sexual potency may be illnesses that can be treated. Ask your doctor if…