by Sonia Shah
The FDA’s relaxation of drug advertising rules did much more than relieve Hoescht’s business troubles. In the past, in order to build a market for a new prescription drug, the medical community would first have to be convinced of the necessity of the treatment. The doc-as-gatekeeper served as a skeptical check on drug companies that might try to sell a risky or useless drug. Now drug companies could reach consumers directly with their exhortations to get checked for dangerous new conditions and ask their doctors for brand-name drugs—and not just for medical problems, either, but for social problems, even for cosmetic ones. Soon scores of consumers whom most physicians would deem healthy were exposing themselves to the risks of pharmaceutical products, further diminishing the risk-benefit ratio of new drugs.
One such product is Viagra, launched by Pfizer in 1998. Pfizer was about to abandon sildenafil, a failed angina drug, when they picked up on its effect on men’s erections. The company soon ran trials among men who had been impotent for five years or more. The drug appeared to overcome impotence in 70 to 80 percent of test subjects.69 According to the NIH-funded Massachusetts Male Aging Study, started in 1987, over half of the thousands of forty-to-seventy-year-old men it surveyed had endured an episode or two of failed erections over the previous six months, but only about 10 percent suffered complete erectile dysfunction. Most of these cases were among men who had other health problems—they were older, tended to smoke, were overweight, and had high blood pressure.70 Many such men could be expected to be taking medications such as nitrates and beta-blockers, prescribed to millions for angina and high blood pressure; for them, sildenafil could be downright dangerous. Quitting smoking, changing medication regimens, counseling, exercise, and weight loss, moreover, could safely relieve many of the less severe problems.71
And yet it was true, as Pfizer’s marketing director put it, that “most men who are 45 or 47 don’t have the same erections they had when they were 18.”72 These men, with a little help from Pfizer, could be convinced they had a treatable disease. In a prominent television ad campaign featuring no less respectable a personage than former senator Bob Dole, Pfizer announced that “erectile dysfunction (ED),” an obscure medical term dusted off to serve as a more palatable euphemism for impotence, was a serious medical condition that afflicted no fewer than thirty million American men.73 It was, as one executive explained, “brilliant branding.” “And it’s not just about branding the drug; it’s branding the condition and, by inference, a branding of the patient. . . . We’re creating patient populations just as we’re creating medicines, to make sure that products become blockbusters.”74 The vast majority of ED’s supposed thirty million sufferers—about 80 percent—suffered only mild to moderate dysfunction, some as little as one episode of erection loss over the previous six months.75
Pfizer defended what critics would later call disease mongering by saying that they were raising awareness about a shameful disease. Many men “really do want to go to their doctors but can’t imagine bringing it up,” Pfizer’s marketing director for Viagra, Janice Lipsky, said to the New York Times in 2004.76 And yet, there was little evidence of any reluctance to seek out Viagra prescriptions. In Britain, for example, diagnoses of erectile dysfunction doubled.77 By 1999, five million men had been prescribed Viagra, bringing in $1 billion in sales for Pfizer.78 Treatment rates for erectile dysfunction soared above other conditions. In heart disease, by way of contrast, only one-third of patients who could benefit from aspirin are prescribed it by their physicians.79
The drug was obviously being used by people who had no impairment whatsoever. As Playboy’s Hugh Hefner put it, “It’s more than an impotence drug: It’s a recreational drug. It eliminates the boundaries between expectation and reality.”80 Almost immediately upon its launch, Viagra pills were making the rounds among thrill seekers at dance clubs and sex parties.81 Nervous men used the drug for “date protection,” feminist sex expert Leonore Tiefer scoffed. In Taiwan, a campaigning politician distributed the drug for free. In France, restaurants served “beef piccata in Viagra sauce.”82 If any needy men had somehow escaped a Viagra prescription, Wrigley planned to deliver the drug in an even more appealing form: Viagra-imbued chewing gum.83
The FDA logged over one hundred deaths linked to Viagra within the eight months following the drug’s appearance on the market, suggesting that the drug may have been implicated in between two thousand and ten thousand deaths. (Between 1 percent and 5 percent of adverse effects of drugs are estimated to be reported to the FDA.) “My husband was 65 with several medical problems and taking several other drugs, but he got the same dose as an 18-year-old,” complained the widow of one Viagra casualty.84
Regardless, like Prozac and Mevacor before it, Viagra paved the way for a $23 billion “life-enhancing” drug market—drugs designed not to heal the sick but rather to make the well feel better.85 Prozac had established a $12 billion market for antidepressants. Mevacor founded a $10 billion market for cholesterol-lowering drugs, a market that grew by over 33 percent every year between 1987 and 1992.86
Rival companies predictably jockeyed to muscle into the new markets. But rather than improve upon the trailblazing blockbuster (or trying to improve upon it, failing, and marching forward anyway), many simply resorted to selling copycats. Between 1998 and 2002 “me-too” drugs—those deemed by regulators to offer no advantage over already available drugs—accounted for three-quarters of the new drugs approved by the FDA.87
Not only would the task of developing, testing, and reviewing the copycat drugs further burden already strained health care and regulatory systems, they would intensify the onslaught of drug marketing to dizzying heights. By 1998, drug companies were spending between two and three times more on marketing and administration than they did on research,88 forking over no less than $1.3 billion on advertising directly to consumers.89 The intense marketing says something about the drugs, former New England Journal of Medicine editor Marcia Angell says. “Truly good drugs don’t have to be promoted very much. . . . Wouldn’t the world beat a path to the door of a company that produced, say, a cure for cancer?” Me-too drugs, on the other hand, “require relentless flogging, because companies need to persuade doctors and the public that there is some reason to prescribe one instead of another.”90
Rather than improving upon Mevacor, for example, drug companies launched a plethora of copycat statins. Four years after launching Mevacor, Merck introduced its cousin, simvastatin (Zocor). That same year Bristol-Myers Squibb released its pravastatin (Pravachol). Pfizer soon offered atorvastatin (Lipitor), followed by Bayer’s cerivastatin (Baycol) and AstraZeneca’s rosuvastatin (Crestor).91
The abundance of statins stood in direct contrast to their slender benefits, especially for the millions of Americans who weren’t at especially high risk for heart disease. According to one analysis, more than four hundred people with mild cholesterol would need to be treated with statin drugs in order to prevent a single coronary heart disease event,92 a success rate that pales in comparison to improved diet and exercise regimes. After all, half of all heart attacks occur in people who have normal cholesterol levels.93
Statin makers were forced to exaggerate, with all the problematic public health effects that would follow: “You may think you’re healthy,” Pfizer ads warned, over tragic scenes of middle-aged men dramatically collapsing midmeal, “but too much cholesterol in your blood can cause a heart attack.”94 With all the competition in the already crowded field AstraZeneca lavished a $1 billion advertising budget on Crestor.95
One way drug companies could distinguish their otherwise indistinguishable me-too drugs was by tinkering with the dose. At lower doses the prescription antihistamines effected more marketable claims—they were less sedating, albeit also, it seemed, less effective. In fact, in the RCTs of Claritin submitted for FDA approval, the drug appeared only marginally better than nothing at all: in one trial Claritin affected a 46 percent improvement compared to 35 percent on placebo. According to an allergist on
the FDA advisory committee that considered the drug, at the dose that Schering wanted to sell it, Claritin “is not very different than placebo clinically.” A larger dose might be more effective but would make patients drowsy, undermining the one marketing claim that set the drug apart from its much cheaper over-the-counter alternatives. Schering wasn’t interested.96 In statin drugs higher doses led to better marketing claims. At higher doses statins could reduce cholesterol levels more rapidly and severely, allowing drugmakers to claim their statins were “more effective” and “easier to prescribe” than alternative statins. The trouble, critics complained, was that the higher and one-size-fits-all doses added diminishingly little more effectiveness while significantly increasing the risk of adverse events, such as rhabdomyolysis (the potentially fatal breakdown of muscle fibers).97 All of the statin drugs cause rhabdomyolysis to some degree, a factoid that generally emerged after the drugs hit pharmacy shelves. The problem was so bad with Bayer’s statin Baycol—based on the number of deaths reported, it appears that over six hundred people may have been killed by the drug98—that it was withdrawn after a few years on the market. The latest competitor, AstraZeneca’s Crestor (launched in 2004), is being sold at an even higher dose than the other statins, and triggered cases of rhabdomyolysis even before the FDA approved it.99
While consumers replaced doctors as the originating sources for new drug prescriptions, physicians’ ability to judge new drugs independently weakened. The pressure on doctors to liberally dole out prescriptions for the new blockbuster drugs is intense. Drug company dollars have penetrated nearly every corner of medicine, from medical school to hospital corridors and continuing medical education courses, where they bombard physicians with positive information about new drugs, free samples, and luxurious perks for the biggest prescribers.
Exposés of doctors accepting elaborate resort vacations and free concert tickets from drug companies grab headlines, but the more run-of-the-mill drug marketing, in which boosterism masquerades as research and education, typically goes unreported. For example, nine out of ten physicians rely on the Physicians’ Desk Reference for information about which drugs to prescribe.100 The PDR, delivered free of charge to all practicing physicians in the country and updated annually, presents itself as a useful, unbiased reference book. In fact, the PDR is funded by drug companies, and the book itself is simply an alphabetical compendium of drug companies’ product labels.101 If research not funded by the industry reveals that a drug is ineffective, dangerous, or redundant, doctors who rely on the PDR would never know it, as such information is excluded from the PDR (unless the FDA orders a label change). Nor are independent drug reference books able to compete against the PDR. The well-regarded AMA Drug Evaluations, for example, sputtered along on less than twenty thousand copies worth of sales every year before admitting defeat and ceasing publication in 1996.102
In many states medical boards themselves encourage doctors to participate in drug company–sponsored seminars and workshops. Thirty-four states require that doctors participate in continuing medical education (CME) programs every year in order to maintain their licenses to practice. More than half of the cost of these programs are now paid by drug companies. Their intent is not to teach doctors about the pros and cons of new drug therapies, or to advocate nondrug solutions to medical problems. They are instead openly regarded as marketing opportunities. “Medical education is a powerful tool that can deliver your message,” one CME company announced to drug companies.103 Industry-sponsored CME programs work, too: one study, comparing outcomes among heart attack patients in states with CME requirements and those without found little difference between the two—save for the fact that patients in CME states were “significantly more likely to receive brands of thrombolytic . . . drugs manufactured by drug companies that often sponsor CME events,” as Heart Disease Weekly reported in 2004.104
If all that wasn’t sufficient, drug companies often resort to simply paying doctors to prescribe their drugs. Thousands of practicing physicians are enticed into switching their patients to new drugs through industry-sponsored postmarketing “trials.” For these putative trials companies find physicians who are most likely to prescribe their new drug, and pay them hundreds or even thousands of dollars for “enrolling” patients in the “study” of the new drug. The idea is to entice doctors and patients into trying a new drug in the hope that they’ll continue the prescription after the trial ends, this time at top dollar. “Make no mistake about it,” announced one industry marketing memo. “The . . . study is the single most important sales initiative. . . . [I]f at least 20,000 of the 25,000 patients involved in the study remain on [the drug], it could mean up to a $10,000,000 boost in sales.”105
As doctors’ prestige and salaries nosedive under managed care, drug companies lavish them with free vacations, dinners, reference books, and drug samples. The billions spent on direct-to-consumer marketing had patients asking for drugs by name. Was it really surprising then, that when Americans visited their doctors, two out or three times they’d come home with a new prescription or a free drug sample?106
As each check and balance on the drug industry—rigorous regulation, fairly informed consumers, skeptical physicians—fell by the wayside, so too did the independence of academic medical researchers, who could easily destroy the marketing goliath that the blockbuster drug industry has become. Just as a 60 Minutes exposé or a scathing Consumer Reports review could destroy the sales of other dubious products, a single study exposing the overblown claims of drug marketers, published in a prestigious medical journal like the New England Journal of Medicine or JAMA, could devastate a new drug.
Fortunately for the industry, though, by the mid-1990s the handful of independent medical researchers who investigated the veracity of drug industry marketing claims were “an endangered species facing extinction,” according to the NIH. Enchanted by the dazzling promise of the new genetics revolution—so-called basic research based in laboratories—NIH funding for the messy work of experimenting on humans had dried up, dropping to just one-tenth of the NIH’s extramural budget.107
It was either take drug company money or perish, many academic researchers felt. The drug industry, by 1995, was spending nearly 40 percent more than the government did on medical research.108 “For academic medicine not to avail itself of the resources of the pharmaceutical industry and private sector would be foolish,” said University of North Carolina psychiatry professor Jeffrey Lieberman to the Wall Street Journal. “It would be like major sports saying they won’t take advertising from Nike.”109
And so, academic medical researchers under industry contracts cranked out a steady stream of positive research detailing minor differences between nearly identical drugs. According to one analysis, 95 percent of industry-sponsored studies of cancer drugs rendered favorable results as opposed to just 62 percent of those funded by nonprofits. “Is academic medicine for sale?” wondered the New England Journal of Medicine’s then editor Marcia Angell in a May 2000 editorial.110 “No,” came the response from one cynic. “The current owner is very happy with it.”111
Drug companies retorted that they conducted the exacting randomized controlled trials that the FDA’s regulations required. The model’s integrity is unassailable, no matter who implements it, they argued. Experts in the field, by and large, agreed.112 And yet, there is wiggle room in RCTs. They are ill equipped to find answers to questions they don’t ask. What’s more, they can be subtly manipulated to make new drugs look better than they are. A new drug might be pitted against a lower dose of its competitor drug, or against an inferior form of it. The majority of trials comparing Pfizer’s fluconazole to amphotericin B, for example, administered the amphotericin orally, even though that drug works better intravenously. Or new drugs might be tested in subjects much heartier than those who would end up swallowing the meds later on, lessening side effects. For example, arthritis-drug makers fill over 97 percent of the spots in their trials with subjects under sixty-fi
ve years of age, despite the fact that most of the patients who will be prescribed the drugs are elderly.113
Despite such hijinks, occasionally industry-sponsored academics come up with results that don’t jibe with a company’s marketing message. By and large such studies are squelched and the academics sacked. A few months of data might be dropped, for example, or a study might be redesigned to render a more pleasing result. Academics who don’t go along with the game risk being slapped with lawsuits. “Companies can play hardball,” complained Wake Forest University public health professor Curt Furberg, MD. “Many investigators can’t play hardball back.”114
Bruce Psaty, one the nation’s leading cardiovascular researchers, saw firsthand just how.115 During the 1990s Psaty undertook a study funded by the National Heart, Blood, and Lung Institute, looking into the differences between patients who took various popular calcium channel blocker drugs for their high blood pressure and those who didn’t. At the time around six million Americans were prescribed calcium channel blockers, but few long-term studies had been conducted on their safety.116
This was precisely the kind of research that the drug industry would be loath to take on: a study that pitted rival drugs in a head-to-head comparison. And Psaty’s findings were exactly the kind of results that drug companies would be loath to hear. According to his study, contrary to drugmakers’ marketing messages, the most popular drugs increased the risk of a heart attack by about 60 percent (from 10 in 1,000 to 16 in 1,000).117 With millions of people taking the heavily marketed drugs, the increased risk was a significant public health concern.