Earlier this month, the Department of Justice announced that the pharmaceutical giant GlaxoSmithKline had agreed to settle criminal and civil complaints related to its illegal marketing of the popular antidepressants Paxil and Wellbutrin from the late 1990s through the mid-2000s. In addition to a number of other offenses, the settlement also covered allegations that the company had failed to report safety data to the Food and Drug Administration (FDA) for its diabetes drug Avandia. In order to settle the case, the company agreed to plead guilty to promoting Paxil and Wellbutrin for uses that had not been approved by the FDA. The company also agreed to pay $3 billion in criminal and civil fines, which might seem like a huge amount of money until you realize that Paxil, Wellbutrin, and Avandia earned the company at least $28 billion during the period covered by the settlement. As one industry analyst commented, “a $3 billion settlement for half a dozen drugs over 10 years can be rationalized as the cost of doing business.”
For those of us interested in the machinations of Big Pharma, neither GlaxoSmithKline’s behavior nor the terms of the agreement are particularly surprising. Over the past decade these types of settlements have become increasingly common. In 2007, for example, Purdue Pharma settled for the relatively modest sum of $634 million for illegally promoting OxyContin as less addictive than other painkillers. In 2009, Eli Lilly settled for $1.4 billion for illegally marketing Zyprexa for the treatment of dementia, among other problems, despite being approved only for the use of schizophrenia and bipolar disorder. In the same year, Pfizer settled for $2.3 billion for illegally promoted its painkiller Bextra, and in 2011 Merck agreed to pay $950 million to settle complaints that it had illegally marketed Vioxx. In May of this year, Abbott Laboratories settled for $1.6 billion for illegally marketing an anti-seizure drug. Any day now, the Justice Department is expected to announce that Johnson & Johnson has settled claims that it illegally promoted Risperdal, a drug currently approved for the treatment of schizophrenia. The expected settlement is about $2.2 billion. Earlier in the year, a judge in Arkansas had ordered the company to pay $1.2 billion in fines for hiding the dangers of the drug in its promotional efforts. I could go on, but I think you get the point.
There is a tremendous amount to be said about all this, most of which isn’t good, but for the moment I want to focus on the effort to promote drugs for so-called “off-label” use. Under the 1938 Food, Drug, and Cosmetic Act (and subsequent amendments and laws), it is illegal for pharmaceutical companies to promote drugs for uses that are not approved by the FDA, or for the treatment of patients that are outside of the approved age range, or to promote the use of drugs at higher doses than for which they are approved. However, it is perfectly legal for physicians to prescribe drugs for any condition, to any patient population, and in any amount that they see fit. The result is that there is a tremendous incentive for companies to promote their products illegally: doing so expands the use of the product into the treatment of new conditions, and even if companies are forced to discontinue their efforts at a later date, the influence of the marketing campaign continues to shape prescription practice for years to come. Paxil, for example, was promoted by GlaxoSmithKline from the late 1990s through the mid-2000s for unapproved use in children. Despite widespread concern that the drug increases the risk of suicide in children, and the fact that the drug is still not approved for pediatric use, Paxil remains one of the most widely used antidepressants for the treatment of pediatric depression.
Pharmaceutical companies use a variety of disturbing strategies to promote their products, including the use of “thought leaders” in the medical community to educate their peers about the usefulness of a company’s products. More troublesomely, ghostwriting appears to be widespread in the medical literature. David Healy, Carl Elliott, and others have drawn attention to the practice of drug companies writing scientific articles and then publishing the articles under the name of reputable physicians, often concealing their own role in the process. A significant amount of evidence exists for this practice, including case studies based on internal industry documents, investigative journalism, the testimony of former ghostwriters, and the revelations of practitioners who have been approached by industry to participate in the practice. Not surprisingly, the practice has attracted a substantial amount of critique. “Ghost writing initiated by industry is a big concern,” notes Robert Fletcher, professor emeritus at Harvard Medical School and chair of the editorial policy board of the World Association of Medical Editors. “When it is undetected, it distorts the scientific record, substituting marketing and persuasion for the balanced exchange of views and the search for sound answers that characterize the contents of medical journals at their best.” The concern here is clear: ghostwriting is widely assumed to distort the scientific process toward the goals of corporate profit. It is widely considered unscientific, unethical, and even dangerous to the health of the public.
Perhaps the best-known example of industry efforts to promote the off-label use of a drug through ghostwriting was Parke, Davis & Company’s remarkable promotional campaign for Neurontin. The drug was originally approved in 1994 for the “adjunctive treatment” of epilepsy, meaning for use in cases where other drugs had not been effective. This meant that the drug had a relatively limited market potential, and the company soon began to dream of larger markets. As David Franklin, a former employee of the firm later noted, the market for the drug as an anti-epileptic was small, but “the market for the others uses of Neurontin contemplated by Parke-Davis – pain management, psychiatric disorders, anxiety, and depression – was huge.” The firm then undertook an aggressive – and illegal – promotional campaign designed to increase Neurontin’s off-label use. In one conference, a marketing executive named John Ford made the goals of the company clear to members of a sales team:
I want you out there every day selling Neurontin….We all know Neurontin is not growing [as an] adjunctive therapy, beside that is not where the money is. Pain management, now that’s money. Monotherapy, that’s money…We don’t want to share these patients with everyone, we want them on Neurontin only. We want their whole drug budget, not a quarter, not half, the whole thing….we can’t wait for them to ask, we need to get out there and tell them out front. Dinner programs, CME [continuing medical education] programs, consultations, all work great, but don’t forget one-on-one. That’s where we need to be, holding their hand whispering in their ear, Neurontin for pain, Neurontin for monotherapy, Neurontin for everything….I don’t want to see a single patient coming off Neurontin before they’ve been up to aat least 4,800 milligrams a day…I don’t want to hear that safety crap either; have you tried Neurontin? Every one of you should take one just to see there is nothing; it’s a great drug.
Parke-Davis’s promotional strategy was tremendously successful. By 2003, total sales for Neurontin had grown to at least $2.3 billion – 94% of which were for off-label use. The company’s sales agents had clearly gotten the message.
Ghostwriting was an important part of the company’s efforts to promote Neurontin. As part of its so-called “publication strategy,” Parke-Davis paid writers to produce scientific articles for publication in medical journals and then paid academic physicians to be listed as authors of the articles. This allowed the company to promote off-label uses for the drug without appearing to have done so – once published, notes one complaint (pdf) against the company, Parke-Davis presented the articles as “evidence of independent research conducted by persons with no monetary interest in Neurontin.” The company pursued a number of other objectionable strategies designed to create demand for the drug in the medical community. In addition to ghostwriting, for example, there is clear evidence that Parke-Davis funded at least one so-called “seeding-trial” for the drug – a clinical trial primarily designed to raise interest in the drug among physicians rather than produce scientifically useful data. The so-called STEPS trial involved more than 2,700 subjects and, as Carl Eliot has noted, “was notable for how poorly it was conducted.” Still, at least two scientific articles were published in peer-reviewed journals based on the data generated in the study. More disturbingly, eleven patients in the study died, and 73 more experienced “serious adverse events.”
This should make anyone pause. Over the past decade, critics have increasingly decried ghostwriting, seeding-trials, and other such practices as simultaneously unethical, corrosive to the scientific process, and a danger to the health of the public. “The biomedical enterprise depends on good science for its foundation, and good science requires transparency of methods and integrity of purpose,” notes physician G. Caleb Alexander in a recent commentary published in the Archives of Internal Medicine about the STEPS trial. Alexander notes that “industry plays a major role in supporting biomedical science,” that “support for clinical research is essential,” but also that “commercial bias may be introduced in a variety of ways,” such as through “nonpublication of negative findings” and “aggressive marketing.” Alexander is not alone in his arguments. Ghostwriting, seeding trials, and other such practices seem to undermine the practice of good science, and as the volume of critique directed against the industry has grown so to have calls for reform. Not surprisingly, Neurontin figures prominently in these critiques – indeed, it is probably the single most widely cited case of industry malfeasance to have yet come to light.
Important progress has been made in addressing these problems, such as recent legislation mandating that reports of all clinical trials be published on a new FDA website, ClinicalTrials.gov, within one year of the completion of the study. Such efforts at reform should be applauded, and extended. Yet there is also an important way in which the criticisms leveled against the industry miss a deeper issue. We do not know how much of the scientific literature about Neurontin was written by ghostwriters working for Parke-Davis, nor do we know how much of it violated norms of scientific practice. However, let us assume, for the moment, that all the research that went into all the ghostwritten articles was conducted in a scientifically rigorous manner; let us also imagine that the authorship of all such articles was revealed. Would the problem of “commercial bias,” as Alexander puts it, really then be eliminated? Would our scientific knowledge about Neurontin be rendered, in some sense, pure?
I’m not so sure. Critics since the 1970s have pointed to the process through which increasing domains of life are understood through the framework of disease and rendered suitable for therapeutic intervention. More recently, historians and other scholars have begun to suggest that the impact of the drug industry on biomedical knowledge cannot be limited to a framework which understands medical science as somehow distinct from, or corrupted by, the operations of the market. Pharmaceutical innovation, according to this line of argument, has shaped the very nature of diagnostic categories and the definition of disease itself. Since the end of World War II, biomedicine has expanded its domain from the treatment of acute conditions to the daily management of chronic disease, from the treatment of visible symptoms to the reduction of risk, from problems of the body to difficulties in psychological and social processes; it has occupied and transformed a vast number of realms previously outside its reach, including the control of reproduction, the medicalization and management of deviant behavior, and the optimization of our future selves. Increasingly, we understand ourselves and the world in which we live through the lens of the biomedical sciences; through the language of genes and brain mechanisms, through the identity of the patient or victim of a disease, through our efforts to understand, extend, or resist the expansion of medicine and its allied sciences. There is a type of inflationary pressure here, one in which the biomedical research enterprise continuously expands the definition of illness. This is not the creation of “myths,” and it is not exactly “disease mongering” – a pejorative term for what I am describing that imputes malevolent motives on the people involved in the effort to heal. Rather, it is the expansion and transformation of disease categories through the linked processes of capital accumulation, scientific progress, and the articulation of health and suffering.
I do not want to downplay the dangers of ghostwriting, seeding trials, and other relatively crude efforts to harness the creation and distribution of biomedical knowledge to commercial ends. These are, in my view, dangerous practices that should be eliminated. Yet the problem of such obviously offensive practices, and the problem of off-label marketing of which they are a part, is only one part of a much larger question. Even if all science practiced by pharmaceutical firms was conducted in a scientifically rigorous manner, and even if all data was publically available, all conflicts of interest revealed, all drug advertising tightly regulated, all free lunches banned – even then, I suspect, diagnostic categories would continue to grow and markets for new drug technologies would continue to expand. The problem of disease inflation is not just one of the corporate drive for profit, though it is that; it is not just a question of medical expertise being corrupted by commercial motives, though it is that. Disease inflation results from the fundamental fact that medical science has become tightly wed to the means of accumulating profit – financial, professional, social – and that both medical science and the accumulation of profit have become deeply wed to the act of healing. The person who discovers a new cure for a previously intractable problem is deeply rewarded, and not just with wealth – and who would want it to be otherwise? We want new diseases to be discovered, new cures invented, new technologies deployed to help the suffering. Right?
Perhaps, but perhaps not. The GlaxoSmithKline settlement points to a clear problem in how the biomedical enterprise is currently organized. Drug companies should obviously not be pushing their products for the treatment of conditions for which they are not approved. Nor should they be secretly generating medical articles and presenting them as if they were produced according to the norms of the scientific community. This much seems obvious. Yet what are we to do about the fact that the more we understand it, the more it seems as if the biomedical enterprise is dedicated not only to healing our ills but, in an odd way, making us understand ourselves as sick in new and increasingly complex ways? The problem of disease inflation forces us to ask more fundamental questions than simply how to protect science from the dangers of corruption. It forces us to ask ourselves what the goals of medicine actually are, and whether or not there is a point at which the effort to heal becomes its opposite.