It seems that the country's roughly 87,000 drug reps, those appealing salespeople who pop in on doctors in their offices and in hospital conference rooms to promote new drugs, aren't selling enough. So the pharmaceutical industry, ever inventive, is recruiting and funding a potent new marketing force: our nation's doctors.
This new marketing force is being mobilized under the guise of educational or quality improvement ventures. But whatever they are called, these ventures are still marketing gimmicks, often designed to promote so-called off-label use of drugs -- uses for the treatment of specific conditions other than those approved of by the Food and Drug Administration (FDA). The pharmaceutical industry and its reps are prohibited by law from advertising off-label uses of drugs. Doctors, however, can legally prescribe the medications as they see fit and discuss those treatments with their fellow physicians. While sometimes off-label uses of drugs are appropriate, low in risk and beneficial, other times doctors behave in ways that blur the lines between medicine and marketing.
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Consider the National Anemia Action Council (NAAC), a group of 25 academic physicians from across the country. The council recently produced a glossy brochure for the general public called "Anemia: A Hidden Epidemic," which reports that anemia is under-recognized, under-treated and often associated with chronic diseases.
Amgen, the maker of a drug commonly used to treat anemia, supports all the projects of the NAAC through an "unrestricted educational grant," and more than a third of the council's members are paid consultants or speakers for Amgen. So perhaps it should come as little surprise that several chapters of the council's brochure also mention "preliminary data" suggesting that Amgen's drug "has also shown to be of benefit" in treating disorders for which it has not yet been approved by the FDA.
There are worthy applications of Amgen's drug. Anemia, especially when severe, causes great disability, including weakness, breathlessness and loss ofendurance. Some anemias are caused by a deficiency of a hormone called erythropoietin, which is synthesized by the kidney. As a result, patients with kidney failure benefit greatly from the Amgen drug, Epogen, also known as epoetin alpha or Epo, a synthetic version of the hormone. For patients with kidney failure, Medicare foots the bill. The FDA has also approved Epo for AIDS patients and cancer patients who have undergone chemotherapy.
But the agency has not specifically approved Amgen's drug for other kinds of anemia. And that's where the NAAC doctors come in. Several chapters in "Anemia: A Hidden Epidemic" suggest that a deficit of erythropoietin might characterize many of these other conditions and that "Epoetin has also shown to be of benefit" in treating them. But the basis for these conclusions is flimsy. For example, the chapter on heart disease describes "preliminary data in a pilot study" involving 22 patients. Such a tiny sample is insufficient to conclude anything about the effectiveness of the drug. Yet any patients who have one of these conditions and feel tired might read the brochure and ask their doctors if epoetin can help them, as one Amgen pamphlet says, "Get the Most Out of Life." And though the use is off-label, it is legal under FDA rules for a doctor to prescribe it. And many doctors, encouraged by anecdotal evidence, their own medical experience or groups like the NAAC, may do so in the spirit of experimenting with solutions to stubborn complaints.
NAAC also sends out e-mails called AnemiaAlert to physicians. In two e-mails sent in the past year, all the entries avoid specifically recommending Amgen's epoetin for unapproved applications, yet the bias is palpable. Articles trumpet the frequency of anemia in various conditions, the risks of being anemic, the risks of blood transfusions and the benefits of erythropoietin in certain settings. It takes little imagination for any reader to draw the obvious conclusion: treat with epoetin.
There are many other groups in which similar relationships exist between doctors and drug companies; the net effect is drug promotion. The organizations have names that lend them an air of academic respectability or of promoting government standards. They include the Council for Leadership on Thrombosis, the National Lipid Education Council, the Council on Hormone Education and the National Initiative on Sepsis Education. They sponsor Web sites, provide free patient education or continuing education for physicians, collect patient data and publish free books for doctors.
While pharmaceutical companies fund the organizations, the groups would not be effective without the participation of doctors. Prominent academics head these organizations. They hire academic physicians to collect and edit medical content, which is distributed with the avowed purpose of educating doctors and improving patient care. The material looks like other academic medical content, but it has not undergone a process known as "peer review," an examination by independent experts who have no financial connections to the drug company sponsors. Although much of the material is probably worthwhile, some is subtly biased in favor of the sponsors' products and some of it is grossly biased.
Supplements to medical journals are another way that pharmaceutical companies can make such material look objective. Here is one example.
In recent years, the FDA approved a new wakefulness drug, Provigil, but only for use in narcolepsy, an uncommon condition in which sufferers have an overwhelming feeling of sleepiness, and for sleep disorders caused by work on night shifts. A 2003 supplement of the Primary Care Companion to the Journal of Clinical Psychiatry contained several articles about medical conditions characterized by fatigue, such as depression. It also described a phenomenon dubbed "executive dysfunction," supposedly marked by fatigue, apathy, bad mood and an inability to communicate clearly. Even those who diagnose executive dysfunction say that it has "no standard medical definition and is better regarded as a concept." Though each article in the Primary Care Companion supplement contains a disclaimer that Provigil is not approved by the FDA for these symptoms, virtually the entire issue is a thinly disguised pitch to try Provigil when treating them.
Cephalon, the manufacturer of Provigil, paid for the publication of the Primary Care Companion supplement. The lead authors of all eight papers in the supplement have received honoraria, consulting fees, speaking fees or (in one case) research funds from Cephalon. (The authors disclosed this in the publication, as the Accreditation Council for Continuing Medical Education requires for material it approves for medical education.) The company also paid for a teleconference at which the material in the supplement was presented. Plenty of people seem to feel excessively sleepy. In 2003, more than $250 million of the $290 million in sales of Provigil was for off-label uses such as fatigue, depression and attention deficit disorder. Some students use it while studying for exams and some truck drivers use it to ward off sleep on long-distance hauls. Yet the danger of these uses and the long-term side effects of Provigil (which acts in a way similar to amphetamines) are unknown. The Primary Care Companion supplement is essentially a marketing tool, made possible by physicians who wrote for it and by the journal that let its name be used.
There are plenty of reasons for concern about the role of doctors in marketing and prescribing off-label drugs. Approval by the FDA requires years of painstaking clinical trials to discover the appropriate dose, adverse reactions and efficacy of drugs. Off-label drugs have never been tested using these rigorous standards, and thus neither their benefits nor risks are known with certainty. Recall what happened a few years ago after the discovery of multiple cases of severe lung and heart damage from off-label use of diet pills Redux and fen-phen. The drugs, which had been approved separately for short-term appetite suppression, had been prescribed by doctors in tandem for long-term dieting, a combination not approved by the FDA.
Despite the restrictions on advertising, the market for off-label drugs is huge. For many drugs, 90 percent of sales come from uses that are off-label. Marketing, some of it prohibited by law, is one explanation. Some drug companies have been caught violating the law against promoting off-label uses of drugs. In May, Pfizer and a subsidiary agreed to $430 million to settle a variety of state and federal allegations involving the promotion and marketing of Neurontin.
