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than it is if one were studying actual clinically relevant outcomes. And, there’s a bonus: It’s not uncommon that a drug will lower a surrogate marker promptly but show a serious adverse reaction only if taken for some months. If the company is lucky, it can get in and out with its study in time to “prove” success with the surro- gate marker, but not run the study long enough to pick up any unwelcome signs of bad side effects.
The recent career of rosiglitazone (Avandia) nicely illustrates the success of
“prescribing by the numbers.” Rosiglitazone is one of a class of drugs introduced with much fanfare for type 2 diabetes in the late 1990s, because they promised a new biochemical approach to drug therapy. They were approved for use because they worked well on the surrogate marker, glycohemoglobin, or blood sugar, even though no studies had been sufficiently lengthy to see whether any of these drugs actually reduced the long-term complication rates. Indeed, no evidence was ever accumulated to show that rosiglitazone successfully prevented major diabetic com- plications. Ideally, such a drug would not have been used at all for type 2 diabetes, or else it would have been a third-line drug for use in selected recalcitrant cases. Yet with aggressive marketing, Avandia was quite widely used, despite its high cost.
With time, however, worrisome evidence accumulated that rosiglitazone actually increased the risk of serious heart disease. At first the manufacturer simply hid the evidence and attacked independent investigators who attempted to publish such findings (Nissen and Wolski 2007; Moynihan 2010). In the end, the company had to admit the problem and submit to a major warning label. The drug was released in 1999 and by 2006 had reached a sales peak in the USA of $2.5 billion. Once the negative heart disease information was published in 2007, US sales plummeted, but even then Avandia racked up $1.2 billion in worldwide sales in 2009 (Noble 2013).
Since the drug would have faced stiff competition from cheaper generic versions after it went off patent in 2012, the company got to enjoy almost a full lifetime of generous profits from a largely useless and actually dangerous drug. Whatever the effect on unfortunate patients, as a business plan, Avandia succeeded splendidly.
In short, success was declared for the drug in the absence of any data whatsoever that patients received any benefit. At the same time, as was later demonstrated, all the patients given Avandia suffered a higher risk of later developing heart disease.
To explain the phenomenon of which this Avandia study is a single example, sociologist Donald Light and I proposed an inverse benefit law (Brody and Light 2011). According to this “law,” intended as a heuristic rather than as a quantitative predictor, the public health consequences of the use of a drug worsen proportion- ately to how aggressively a drug is marketed.
The inverse benefit law is illustrated in the figure:
The example of blood sugar level works particularly well to illustrate the law.
A physiological variable such as blood glucose is distributed normally through the population, generating the familiar bell-shaped curve. Let’s say that the line in the figure marked X is the cutoff level for the diagnosis of diabetes. If a drug is sup- posed to treat diabetes, the area shaded in black represents the population of patients who are candidates to receive the drug. The likelihood that the drug will cause adverse reactions is distributed (we assume evenly) throughout the entire popula- tion. That is, if a drug like Avandia causes more risk of developing heart disease, it does so across the entire population, regardless of one’s blood sugar level.
If a drug is a good drug for treating diabetes—we have seen that Avandia isn’t—
two good things happen when it is prescribed for the group of people in the black- shaded area. First, there’s a decent chance they will be helped, since they actually have the disease for which the drug is recommended. Second, relatively few people are at risk for developing adverse reactions, since such a small part of the total popu- lation are exposed to the drug. The ratio between harm and benefit, therefore, is likely to be favorable.
The black-shaded area may be a good sign for the public health advocate, but it is bad news for the industry marketer. So long as such a small percentage of the population is a candidate for the drug, profits will be severely limited. The market- er’s goal is to pull off a “left shift,” that is, to move the threshold for prescribing the drug from X to Y in the figure. Claiming that Avandia is good for treating
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“prediabetes” as well as diabetes is an example of such a shift, if we assume that the line Y corresponds with the lower blood sugar level at which the condition “predia- betes” is diagnosed.
The “left shift” from X to Y is a huge success for marketing due to the shape of the bell curve. The actual difference in blood sugar value between X and Y may be slight, yet the population considered candidates for drug treatment (now both the gray- and black-shaded areas) has much more than doubled. By contrast, the left shift has been a public health disaster. The patients in the gray area are much less likely to derive actual benefit from drug therapy compared to the black area. Since they begin with a lesser chance of developing serious complications, the drug has a corresponding lesser chance of preventing those complications. Yet a much greater number of people have now been exposed to the risks of adverse reactions. The harm-benefit ratio has shifted considerably to the negative side.
In summary, drugs generally prove to be a public health benefit when science is able to identify a specific population that benefits from the drug, and prescriptions of the drug are then targeted at that specific population. Drug marketing almost inevitably seeks to extend the use of the drug beyond that population, which in turn almost always constitutes a threat to the public health. Marketing, one might say, turns good drugs into bad drugs. Marketing fails to serve patient-centered care and even falls short in promoting the less desirable disease-centered care. Instead, mar- keting creates an unfortunate parody of good medicine—drug-centered care.
Conclusion
When drug-centered “care” takes the blatant form of what amounts to bribery or corruption, as when physicians are given financial incentives to overprescribe, it may be extremely difficult to find effective ways to rein in the corrupt practices and to restore some semblance of professional integrity to the arrangement (Gøtzsche 2013). But from a conceptual viewpoint, there is, at least, little mystery about what is happening, what is wrong with it, and whose interests are served.
By contrast, when drug-centered “care” takes the more insidious form of altering the way we think about illness, it may be much harder to detect, let alone correct, the problem. At first blush, the altered way of thinking is almost always presented to us as a true scientific advance or alternatively as mere common sense. (“Everybody knows” that diabetes is basically a disease of too high blood sugar, and “everybody knows” that depression is caused by a deficiency of serotonin.)
The danger of drug-centered “care” extends even beyond the realm of disease and extends to how we think about life generally. The term “disease mongering”
was coined to label the tendency of industry marketing not to be content merely by redrawing the lines at which a disease is diagnosed, as shown in the figure. An even more effective way of extending a drug’s potential market is to relabel as disease something that previously was not viewed as a disease at all, but merely as a common problem of living or as one variant of normal behavior (Moynihan and Cassels 2006).
Patient-Centered Care or Drug-Centered Care: The Influence of Pharmaceutical…
As men age, for example, they commonly find themselves having less energy and perhaps less interest in sex, but now they are informed that these may be serious symptoms of a testosterone deficiency (handily redesignated “low T”) that requires drug management (Braun 2013). The women married to these men may find them less desirable as sexual partners, but recently there was a serious effort to label a condition of their own as “female sexual dysfunction,” also requiring pharmaceuti- cal intervention (Tiefer 2006). We used to imagine that grief after the loss of a spouse or parent might go on for a long time without triggering the prescription for a medication; a recent psychiatric guideline tells us to mark our calendar for day 13 after the death, and if grief has not resolved by then, one has to start inquiring as to whether a pathological reaction exists that might benefit from a drug (Friedman 2012).
There are sound ethical and policy reasons to replace doctor-centered care and disease-centered care with patient-centered care. But drug-centered “care” is a ret- rograde step which threatens the integrity of both medical science and medical prac- tice, along with posing a serious danger to the public’s health. How severe that threat to the public health has become is illustrated by calculations that indicate that taking prescription drugs as prescribed (not errors or overdoses) is now either the third or fourth leading cause of death in the USA (Light 2012; Gøtzsche 2013). How both the medical profession and the public have come to regard it as normal, indeed desirable, that so many people are taking so many prescription drugs requires thoughtful reexamination.
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