Pharmageddon (7 page)

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 stepped 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 pregnant 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.

There can be few better symbols of Pharmageddon than prescription only drugs becoming among the most consumed drugs in pregnancy in the face of strengthening warnings that they cause birth defects. The answers to how this could happen lie in great part in how the pharmaceutical companies have managed to capitalize on the very protections put in place by Senator Kefauver in his 1962 bill and in the reforms that defeated him. Prescription-only status has made doctors the targets of a marketing exercise that is far more sophisticated than placing even billions of pages of advertisements in medical journals and bribing doctors to use drugs. As outlined in chapter 1, the patent status of drugs has given companies an incentive to chase blockbuster profits—doing so regardless of patient welfare. Controlled trials have given the companies a means to persuade doctors that snake oil works so well that withholding it in pregnancy would be unethical, and also a means to make problems consequent on treatment vanish. But all of these hinge on the fact that these drugs are available by prescription only.

WHAT THE DOCTOR ORDERED

When Alfred Worcester or Richard Cabot wrote a prescription for a remedy at the dawn of the twentieth century, they were following a centuries-old tradition of asking an apothecary to take certain ingredients and mix them according to a formula (Rx = Recipe). If there was more than one ingredient in the mix, each should have a particular purpose. If the remedy worked, patients were able to take the prescription back to the pharmacy on numerous occasions asking for refills for themselves without further endorsement from the doctor. Alternatively, having once obtained something by prescription that worked, they could revisit the pharmacist and ask for the same medicines again, for family members. A prescription from a doctor was only one means by which people could access the drugs they believed they needed.

Because in Cabot's day all medicines, including opiates, bromides, barbiturates, chloral hydrate (used for sedation), antiseptics, remedies for the gut, urinary system, and heart and respiratory system were available without recourse to a doctor, the threshold for visiting a doctor was far higher than it is today. Until the middle years of the twentieth century, there was no one being treated for latent diabetes, latent hypertension, or raised lipids. Aside from a few wealthy people engaged in psychoanalysis, no one had contact with the mental health system other than those relatively few who had psychoses and were committed to asylums.

When the US Congress passed the 1906 Food and Drugs Act, it contained no prescription requirement, only a requirement that medicine manufacturers state the contents of the product on the label. The pharmaceutical industry lobbied hard against the act, but once it was in place many enterprising manufacturers found ways of working the new situation to their advantage, for instance, by labeling their product “as approved by the Chemical Bureau.”
²

There were no implications here for traditional medical practice. But another regulatory step taken soon thereafter had profound implications. The nineteenth century saw a growing concern about opiate and cocaine abuse, as well as alcoholism. These problems had been of little concern to medicine. Drug addiction, like alcoholism, was considered a social problem, except where the affected people became patients by virtue of cirrhosis or psychosis. After a variety of social approaches to treating the problems of addiction floundered, in 1914 the US Congress passed the Harrison Narcotics Act, which introduced prescription-only status for opiates and cocaine.
³
The problem of addiction would be managed, or so it was thought, by making these drugs legally available only through a medical practitioner.

After the contaminated sulfanilamide tragedy of 1937, the 1938 Food, Drugs and Cosmetics Act encouraged a move toward making new drugs available by prescription only. The calculation was that the sulfa drugs were better categorized with insulin and the steroid and thyroid hormones, which were typically if not exclusively administered by doctors. After World War II, in 1951, the prescription-only status for new medicines in the United States was copper-fastened in place with the Humphrey-Durham amendments to the 1938 act, despite vigorous, sustained, and widespread opposition to the move. Critics complained that a system put in place for addicts was inappropriate for free citizens. But by the early 1950s, one of the side effects of having medicines that really worked was becoming clear—drugs that could really benefit, could really harm also. In 1952, Leo Meyler's
Side Effects of Drugs
appeared, a first-ever medical compendium of drug-induced injuries.
⁴
This new potential for harm took dramatic shape in 1961 with limbless babies born to mothers who had taken thalidomide during pregnancy as a supposedly safer hypnotic than the older barbiturates.
⁵

When it came to his hearings in 1959, Senator Kefauver was exercised by the prescription-only status of the new drugs, a unique characteristic found in no other market. As he put it, “He who orders does not buy; and he who buys does not order.” As a consequence, when it came to drugs available by prescription only ordinary consumers could not protect themselves against the monopoly element inherent in trademarks or patents. Patients were critically dependent on their doctors to be uninfluenced by trademarks, patents, or marketing ploys. Doctors had a choice whether to give their patients the latest on-patent and branded drug or perhaps an older, more effective and less expensive drug, but patients had little choice other than to do as prescribed by their doctor.
⁶

Thalidomide had been available over the counter in many European countries but exactly the same problems arose in the United States where the premarketing samples were available by prescription only. Indeed the problems may have come to light as quickly as they did because doctors in Germany were not inhibited in recognizing the potential for harm of an over-the-counter drug, as they might have been in the case of a drug essential to their livelihoods. But in the United States in 1962, in the face of the thalidomide disaster, retaining the prescription-only status of drugs seemed to make sense: doctors retained some patina of skepticism about drug claims due to medicine's long-standing opposition to quackery, and doctors appeared to be the people who would be able to quarry information from drug companies about possible adverse side effects of their products.

Before 1962 prescription-only status was still something of a novelty—after 1962 it became the center of the distribution system for new drugs when companies were required not only to make their drugs available only through doctors but also to prove that their drugs worked for some medical condition in order to get FDA approval. This combination of controls must have looked pretty foolproof in 1962, but it has not turned out to be an effective way to constrain the pharmaceutical industry within a medical framework. Quite the reverse. When a pharmaceutical company gets a drug on the market for lowering cholesterol, for osteoporosis, or for erectile dysfunction, this now marks the point at which the company begins to sell the condition, the point at which they can gear up to reengineer the medical marketplace to suit their product, as Abbott did with bipolar disorder to make it Depakote-friendly. It seems extraordinary now that no one in 1962 seems to have realized that if pharmaceutical companies were restricted to marketing drugs for diseases, they might start to market diseases.

Had pharmaceutical companies not been required to demonstrate a drug's efficacy in treating a particular disorder, we might all have ended up with a lot fewer diseases recorded in our medical records. The first antidepressants would have been marketed as tonics or stimulants. To get St. John's wort, an herb with SSRI properties, we just have to feel stressed and buy it over the counter where it is sold as a tonic, but to get Prozac now, we have to be officially diagnosed as depressed. In a similar fashion, the statins might have been marketed on the promise of restoring inner youthfulness, or getting our arteries in shape, rather than for a supposed cholesterol disorder, or the biphosphonates might have been aimed at restoring youthful bones rather than for osteoporosis. As insurance companies reimburse in response to diagnoses, fewer diagnoses would likely have reduced our need for doctors in addition to reducing the number of diseases.

The third medical requirement of the 1962 amendments was that companies demonstrate their products worked in well-controlled clinical trials. This was smuggled into the final bill through the efforts of Louis Lasagna, a professor of pharmacology and a believer in controlled trials, who was attempting at the time to encourage some use of controlled trials, rather than trying to make them mandatory.
⁷
Lasagna himself had undertaken the only controlled trial of thalidomide ever done, through which it sailed—an effective hypnotic free of significant side effects.

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.