Pharmageddon

by David Healy

  The emergence of mood stabilizers coincided with increasing estimates of the prevalence of what, in another successful piece of rebranding, was now almost always called bipolar disorder. Up to the launch of Depakote in 1995, almost everyone had heard of manic-depressive illness but soon this term all but disappeared, replaced by bipolar disorder. By 2005 over five hundred articles per year in the medical literature referred to bipolar disorder in their titles, with almost none mentioning manic-depressive illness.

  This rebranding reengineered the disorder from the ground up. Manic-depressive illness had been a rare and serious condition affecting ten people per million, who invariably had to be admitted to hospital. Bipolar disorder, in contrast, supposedly affects up to 50,000 people per million, and efforts are now underway to persuade primary care clinicians that a wide range of the minor nervous problems they see are indicative of underlying bipolar disorder rather than anxiety or depression, and that these patients should be treated with newer and more costly mood stabilizers, such as Zyprexa or Seroquel, rather than older and cheaper antidepressants or tranquilizers.36

  Bipolar disorder became intensely fashionable with extraordinary rapidity, promoted by assiduous disease awareness campaigns through direct-to-consumer advertising on television in the United States, and patient educational material in Europe, encouraging patients to complete self-assessments and ask their doctor whether bipolar disorder might be the cause of their problems. It became fashionable to the point where clothes and accessories could be bought online celebrating the wearer's bipolarity.37 Within a decade, one of the most serious of mental illnesses had gone from being a devastating disease to being a lifestyle option.

  Everybody, it seems, stood to gain—physicians, companies, and patients. Bipolar disorder could be portrayed as a genetic disorder—not a parent's fault. While no one likes to have a biological disease, this one was portrayed in pharmaceutical company sponsored booklets38 and ads as a disease linked to creativity that supposedly had affected major artistic figures of the nineteenth and twentieth centuries from Vincent Van Gogh and Robert Schumann to Robert Lowell and Sylvia Plath. Public authorities meanwhile could support screening programs such as Teenscreen, introduced in many American schools beginning in 2005, to detect the condition and trigger treatment as early as possible in order to avoid any number of social and individual ills such as suicide, divorce, career failure, crime, and substance misuse that might stem from a failure to detect and treat.39

  For the specialists new journals appeared—Bipolar Disorder, The Journal of Bipolar Disorders, Clinical Approaches in Bipolar Disorders, and others. made possible by unrestricted educational grants from pharmaceutical companies. From 1995 onward a slew of societies and global conferences appeared as well—The International Society for Bipolar Disorders, The International Review of Bipolar Disorders, The International Society for Affective Disorders, The Organization for Bipolar

  Affective Disorders, The European Bipolar Forum, The Australasian Society for Bipolar Disorders, and many others.

  In just the same way impotence vanished and was replaced by erectile dysfunction, frigidity by female sexual desire disorder, boisterousness in children by ADHD. The skill lies in understanding the market and positioning a drug accordingly. In 1980, for instance, the newly created panic disorder was viewed as a severe form of anxiety; the marketing goal for Upjohn was to get Xanax on the market for panic disorder in the expectation that creating the perception that Xanax was good for severe anxiety would lead to leakage into prescriptions for other forms of anxiety also.40 As we shall see in later chapters, marketing like this can conjure diseases like osteopenia, restless leg syndrome, and fibromyalgia out of thin air. This is now called disease mongering. But even more alarming, an “opportunity cost” of marketing like this is that medical diseases with a pedigree going back two millennia, such as catatonia, can vanish if no company stands to make money out of helping medical or nursing staff to recognize its presence and as a result patients may die, when the means to treat them may be lying inches away.41

  Once the addition of a branded drug to a doctor's arsenal was a minor addition to medical culture, but now the insertion of a Viagra or a Vioxx into the medical marketplace will often replace existing medical culture in an area of treatment, as the examples of mood stabilizers and bipolar disorders illustrate. Disorders that were once defined by patients' needs for medical services and doctors' perceptions of their pathology are now increasingly defined by the goals of marketers. Furthermore this now happens on a global basis. Whereas once the brand names of drugs differed from country to country and huge differences existed between Japanese and American medicine, say, and between French and German medicine, from the mid-1990s drugs like Zyprexa, Lipitor, and Viagra have been launched globally with essentially the same marketing in every country. Partly as a result of these onslaughts, differences in medical cultures are flattening down to a common pharmaceutical denominator. Where almost no one had bipolar disorder, osteoporosis, or female sexual dysfunction two decades ago, these new conditions are now global epidemics.

  Claims like these are cheap. If it were so simple to capture the institution of medicine just by coming up with fancy names for drugs, drug classes, and diseases, the proprietary medicines industry of the nineteenth century would never have died out. But driven by a real desire to care for the most vulnerable in society and a commitment to science, medicine eliminated these imitations of medical remedies for a century, with the exception of some holdovers from the former era such as Listerine and Clearasil. Good medicines clearly pushed out bad ones, in large part because they were based on good science. And good science continues—we now have astonishing developments in genetics and in medical imaging, so the argument presented here needs to pull back the curtains on the tricks of the pharmaceutical trade and show not only how modern marketing has closed in on the holy grail of fooling all of the people all of the time, but also why there has been so little resistance among doctors.

  A great deal of the marketers' sleight-of-hand has involved a manipulation of the appearances of science. There is the early twentieth-century science that produced the sulfa drugs and other antibiotics such as penicillin that let the dying rise from their deathbeds. Science like this cuts across marketing. The results were so dramatic that the drugs in effect sold themselves. But the best-selling drugs today aren't like this. They come wrapped in numbers that appear to come from science but that have been fashioned by marketers to indicate abnormalities of lipids, blood pressure, blood sugar, mood, bone density, and respiratory flow, as well as penile stiffness and clitoral sensitivity that their company's drugs just happen to treat.

  But science on its own, however artfully presented, would not have produced the comprehensive shift toward lifestyle drugs we have seen in recent decades or permitted pharmaceutical companies to penetrate the inner sanctums of medicine and transform it from a profession deeply hostile to marketing into a marketer's dream. There has been more involved. We have dealt with one structural element—the change in patent laws. We will now move on to two others—the emergence of prescription-only status for new drugs and the turn to controlled trials in the evaluation of drugs.

  CLIMATE CHANGE

  In retrospect the twenty-five years stretching from 1937 when the sulfa drugs were first introduced to 1962 when the US Food and Drugs Act was revised to tighten up regulations governing pharmaceuticals seems like a golden age. There were more novel agents introduced during this period than at any time before or since—the first antibiotics, antihypertensives, antipsychotics, and antidepressants, and the first oral antidiabetic drug. The period had not started well, however. Soon after sulfanilamide was introduced in 1937, a pharmacist in Oklahoma, unaware of the risk of ethylene glycol, sold sulfanilamide made up in this solvent, leading to over a hundred deaths.42 In response, in 1938, American politicians stepped in to regulate commerce in medicines, through the Food, Drugs and Cosmetics Act. In 1962, American politicians s
tepped in again to regulate the industry with consequences that will follow us through to the end of the book.

  Up to the late 1950s, prior to the passage of the 1962 amendments, in a history all but forgotten, the American Medical Association (AMA) had laboratories where they conducted their own testing of new drugs. They vetted any advertisements run in their journal, the Journal of the American Medical Association (JAMA), for accuracy and only permitted those that earned their Seal of Approval. They regularly ran assessments of new treatments that were not beholden to the pharmaceutical industry. They were known for their support of generic formulations of drugs in preference to branded drugs. But in the 1950s these curbs on promotion stopped. The Seal of Approval scheme was watered down as the AMA sought further advertising revenue from pharmaceutical and other companies to fight Democratic plans to introduce a bill for Medicaid in Congress. With the new advertising, their revenues doubled.

  In the 1950s there emerged a new set of discontents with the practices of the pharmaceutical industry and the prices these companies were charging for their drugs. The discontents were brought to public focus by the Democratic senator from Tennessee, Estes Kefauver. Kefauver's interest was stimulated when members of his staff found that several versions of the same antibiotic, marketed by different companies, had identical prices, and that the prices being charged were of the order of a 1000 percent of the price of manufacture. As they explored the issues, Kefauver's staff found compelling evidence that companies were secretly engaging in cartel practices to maintain the price of medicines and corrupting doctors with backdoor payments to prescribe on-patent and more expensive drugs. There seemed to be, as Kefauver put it, “an upside down competition where prices continue to go up even when production remains low or declines.”43 As the chair of the Senate antitrust and monopoly subcommittee he had the mandate to investigate what might be behind the apparent price-rigging.

  Another concern of Kefauver's was the advertising for drugs. There was the sheer volume. As Walter Griffith of Parke Davis told Kefauver, “the ethical pharmaceutical industry of this country” had turned out “3,790,908,000 pages of paid journal advertising” and “741,213,700 direct mail impressions.”44 But of greater concern was that the ads were commonly misleading and in many cases downright fallacious. Kefauver's staff unearthed one ad for an antibiotic which displayed two chest X-rays, giving the impression of clinical improvement when the X-rays in fact came from two different patients neither of whom had had the antibiotic featured. As Dale Console, a former medical director at the Squibb pharmaceutical company later put it at Kefauver's Senate hearings, “If an automobile does not have a motor, no amount of advertising can make it appear to have one. On the other hand, with a little luck, proper timing, and a good promotion program, a bag of asafetida with a unique chemical side chain can be made to look like a wonder drug.”45

  Yet other concerns lay in drug company practices of withholding safety data on drugs, their lack of testing of new drugs on animals prior to marketing to humans and, more problematically, the fact that the regulators had no procedures in place to ensure a drug worked. The 1938 Food, Drugs and Cosmetics Act solely required companies to demonstrate safety in a number of patients without even basic toxicology testing in animals. As Kefauver's staff noted, if a drug didn't work for a condition for which it was marketed or worked less well than an already available product, then it was inherently unsafe. These discontents led in 1959 to the establishment of the Kefauver-Harris Senate hearings on pharmaceutical practices.46

  Kefauver's main target was the patent system, which he thought was primarily responsible for the artificially high prices American patients uniquely faced. At the hearings, he elicited some revealing testimony from Frederick Meyers, a University of California professor of pharmacology who admitted that “most of the program [in drug research] has come from European and British researchers.” The purpose of much of the work done by American drug firms was, according to Meyers, “partly to exploit and market” these foreign products but “mostly to modify the original drug just enough to get a patentable derivative.”47 Was this a good idea? Kefauver's staff produced figures to show that out of 77 countries surveyed, 28 allowed product patents and in these countries the prices of drugs ranged from 18 to 255 times higher than in the nonpatent countries, with both American-made and European- made drugs costing far less in Europe than in the United States.

  But as Kefauver found, “These drug fellows pay for a lobby that makes the steel boys look like popcorn vendors…anyone who dares seek the truth will be accused of being a persecutor.”48 Up for reelection in 1960, he found himself branded a “socialist hell-bent on ruining healthcare.” He was reelected comfortably, but when it came to his bill, despite having been the 1956 Democratic vice-presidential candidate, Kefauver had no support from the Kennedy administration, who were at the time trying to get Medicaid through Congress and did not want to antagonize the pharmaceutical industry. He also had no support from the American Medical Association, even for something as basic as a requirement that companies prove their drugs work before they are let on the market. The AMA was gearing up to fight Medicaid and was dependent on the increasing revenue it was receiving from pharmaceutical companies advertising in its journals.

  Kefauver's bill (S. 1552) was rewritten by his congressional opponents to make it more company friendly and in this form it seemed to have good prospects of passage. But then reports began to surface from Germany of the effects of a drug called thalidomide. Thalidomide was a sleeping pill sold over the counter in Germany and about to be marketed in the United States by Merrell Pharmaceuticals, when it was linked to a new and disturbing problem—babies of mothers who had taken the drug were born limbless or with useless flippers (phocomelia) where limbs should have been. The makers, Chemie-Grunenthal, fought the linkage to their drug and only removed thalidomide from the German market under pressure. Almost a year after the first reports, Merrell were mailing samples of the compound to American doctors, even though it had still not been licensed in the United States.

  These events transformed the political imperative. Kefauver's bill was resurrected and rushed through both House and Senate, resulting in the 1962 amendments to the Food and Drugs Act. This mandated proper animal testing of drugs for toxicity before launch, and gave the FDA control over advertising. The new bill contained three further provisions whose far-reaching ramifications will be explored in chapters 2 and 3— it maintained prescription-only status for all new drugs, it required that companies demonstrate their drugs worked for a specified condition (where before they only had to prove safety), and it required companies to use controlled studies to demonstrate drug benefits. Kefauver's bill, however, was stripped of its provisions to change patent law, despite support from the Chief Patent Officer. And because the patent law wasn't changed, the 1962 amendments had no effect on Kefauver's primary target—control of the prices of drugs.

  While it failed in its primary objective, the stripped-down bill was passed to wide acclaim. Kefauver, flanked by the junior senator from

  Tennessee, Albert Gore, Sr., had been given the honor of speaking to it on the Senate floor. The disturbing changes in the climate of medicine would be stopped or even reversed, he hoped. Kennedy and Kefauver basked in the glow of success. Frances Kelsey, a staffer at the FDA, whose bureaucratic delay in reviewing and handling the license application for thalidomide undoubtedly restricted the number of American children exposed to the drug in utero, received a President's Award for Distinguished Federal Civilian Service. The reforms to the FDA were copied by other regulatory agencies worldwide. When it came to drugs, the management of pregnancy became the one area of medicine that most closely conformed to Pinel's hopes for all of medicine—that doctors in knowing when not to prescribe would demonstrate the highest medical art. Many still think this to be the case, but today's reality is quite different.

  2

  Medicine and the Marketers

  When she became pregnan
t in 2004, 38-year-old Gina Fromm did a range of things that few women would have done in the early 1960s— she took cold rather than hot showers in case she might harm her baby, stopped eating yogurt and incinerated chicken because of the risk of bacterial infection, from listeria to salmonella. She balked at taking prenatal vitamins, though she had been taking Paxil following a fleeting episode of anxiety. She continued to take it through her pregnancy; she had found stopping difficult and her doctor reassured her it posed no risk to her baby. On February 2, 2005, her son was born with congenital heart defects.1

  In the decades following the passage of Senator Kefauver’s bill, women were far less likely to smoke, drink alcohol or coffee, or take painkillers while pregnant. Nevertheless, Paxil and other SSRI antidepressants, among the direct successors of thalidomide, were on their way to becoming the most commonly prescribed drugs in pregnancy— especially in the United States. In 2006, forty-four years after the 1962 amendments to the Food and Drugs Act, the first legal actions were filed for birth defects induced by SSRI antidepressants, resulting in verdicts against GlaxoSmithKline and huge settlements, but this made little dent on the prescribing of SSRIs in pregnancy, which continued to mount.

  Nothing about the 1962 amendments obviously predicted the replays of drug-induced birth defects we now have. Medications continued to be available on a prescription-only basis. With the 1962 amendments to the Food and Drugs Act, companies were to be restricted to selling medications for real diseases rather than for trivial indications like halitosis or fleeting anxiety states. Furthermore, from 1962 onward, companies had to demonstrate by means of controlled trials that their remedies did in fact work.