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Beyond the Naïve “No‐See”: Ethical Prescribing and the Drive for Pharmaceutical Transparency

2009; Wiley; Volume: 1; Issue: 1 Linguagem: Inglês

10.1016/j.pmrj.2008.11.003

1934-1563

Michael Oldani,

Health Systems, Economic Evaluations, Quality of Life

There was a time, not so long ago, when the American Medical Association (AMA) played a lead role in studying, policing, and literally approving the use of new pharmaceutical products that entered the US market. In fact, into the 1950s the AMA was an "efficient watchdog," according to Philip Hilts [1] in his recent history of the US Food and Drug Administration, Protecting America's Health. The AMA had its own test laboratory, published lists of fraudulent and useless drugs, and developed a "seal of acceptance" program for new drugs, on which thousands of physicians relied. However, the 1950s was also a time of unprecedented pharmaceutical research and development as well as a time of increased sales and marketing. The pharmaceutical industry began to advertise heavily in medical journals and in the 1950s began to shift this advertising (and revenue) away from the AMA's medical journals, which put the organization in financial jeopardy. A group of "conservative leaders" (ie, probusiness physicians) staged an "internal coup" and won back the advertising revenues of industry, making the AMA a more pharmaceutical-friendly organization and ultimately "less critical" of the industry. (The FDA then became the de facto watchdog of new pharmaceuticals but was not able to exercise real power over the industry until the 1970s—see Hilts [1]. Also see Critsler [2] for an assessment of FDA power over the past decade.) From that time on, Hilts argues that the AMA began to participate more directly and profit from "the commercialization of medicine," rather than "examining it critically" [1]. Fifty years later, bioethicists such as Howard Brody, MD, have described the nature of the relationship between physicians and "Big Pharma" (a collective indicator of the world's 10 largest pharmaceutical companies) as one of complete and utter dependence [3]. In his book Hooked: Ethics, the Medical Profession and the Pharmaceutical Industry, he notes industry expenditures on medical journal advertising in 2003 reached $448 million [3]. This dependency is not mutual but rather represents a highly unbalanced relationship between physicians and the industry. For the average clinician, this information may seem to be of no concern—occurring outside the realm of his or her day-to-day activities. However, at the level of the individual physician, the money spent on product promotion is truly astonishing and dwarfs medical journal advertising expenditures. Data collected in 2000 showed that Big Pharma spent $1.9 billion on promotional activities directed at individual physicians; specifically, drug representative (informally known as drug reps or detail men) activity spending totaled $8290 per physician in the United States per year (the average family practice physician receives 28 detail calls per week) [4]. Brody [3] also examines the literature regarding the impact of the pharmaceutical industry at a very local level of practice, at the clinical level between physicians and drug reps. For instance, studies with physicians and residents consistently show that (1) gift exchanges, both large and small, affect the prescribing process; (2) promotional activities influence physicians' attitudes toward drugs even when physicians cannot recall the promotional activity later; and (3) physicians consistently view themselves as immune from industry influence while seeing colleagues as relatively open to influence [3]. The current state of affairs has caused many clinicians to take a more militant stance—to opt out of their relationship with Big Pharma. Part of this movement is grassroots in nature, beginning, for example, with the "no free lunch" movement (see www.nofreelunch.org). At an organizational level, the AMA has created an "opt out" program, where physicians can have their names removed from third party prescribing that the industry uses to target and gift specific physicians, called "high prescribers." Through these efforts, many clinicians are taking the perceived moral high road, becoming what drug reps have described over the years as a "no-see" physician. However, as I outline later, simply becoming a "no-see" (eg, avoiding social contact with drug reps) is not enough in the current climate of the pharmaceutical industry sales practices. Every physician, whether a "no-see" or not, needs to become a personal watchdog of Big Pharma, striving to understand and police the sales and marketing activities of drug reps, while advocating for more transparency at every level of interaction between the medical profession(s) and the prescription drug industry. Specifically, the "no-see" physician makes a conscious decision not to interact with drug reps. A lot of time (and a tremendous amount of money) is spent by the industry and pharmaceutical salespersons alike trying to gain access to the elusive "no-see." Why? For starters, a "no-see" physician may represent a vast untapped reservoir of "prescribing potential" and/or expertise. For example, a "no-see" physician who is an expert in a particular disease or an area of medicine that could potentially benefit product sales is intensively "targeted" by drug reps and management to perhaps become a "product champion" (i.e., a company-paid continuing medical education [CME] speaker), or, at the very least, attempts are made to "neutralize" the "no-see" physician to protect product sales or perhaps the formulary status of a drug. Neutralization occurs when an expert's opinion about a particular drug is deemed by industry/reps as "indifferent"—they will not block a product's addition to formulary, or its removal from formulary; they will not make negative remarks about a product's efficacy or side effects; and so on. This process can occur with or without the tactics used by drug reps. If necessary, however, drug reps will engage in a variety of tactics to neutralize: gifting, paid trips to attend workshops or symposia to develop a deeper understanding of the disorder or disease that a particular product is used to treat; medical department requests for scientific literature sent to the physician directly from the company; and, perhaps most effective, bringing in outside experts to give grand rounds, CME programs, and/or dinner presentations that work to neutralize any concerns about a specific product [5]. This often takes months or even years of effort by drug reps and corporate management to influence this type of "no-see" physician, who often are practicing in academic settings. Additionally, "no-see" physicians, regardless of expertise, who are "high prescribers" are relentlessly pursued by drug reps on a daily basis in the community setting. Activities targeted at high-prescribing "no-see" physicians include co-marketing (ie, 2 or more drug reps selling the same product); intensive gifting (eg, leaving mundane gifts, such as pens, paper pads, coffee mug, etc., to invitations for dinner programs and CME symposia); and possible enrollment in postmarketing clinical trials through an unrestricted educational or research grant (hereafter referred to as an UERG). A high prescriber might eventually be converted into a supporter of a product, or they may remain simply a physician committed to competitive products. In this latter case, a drug rep may choose to "drop them" from their call cycle for a period of time and move on to other high prescribers, or if a rep fails in converting a large pool of high-prescribing "no-see" physicians throughout their sales territories over an extended period of time, the rep may be dropped by their managers—in short, fired. Many physicians take pride in being a "no-see"—removed from industry interaction (but, unknown to them, not removed from scrutiny)—and see this conscious act as owning the moral, or ethical, high ground. And in many ways it remains a noble pursuit in our pharmaceutically saturated health care environment. However, today, clinicians must work very hard to avoid becoming a naïve "no-see," believing that they are immune to or otherwise unaffected by influences from the pharmaceutical industry. This naïveté stems from the lack of both individual and collective knowledge by physicians and health care workers regarding the well-orchestrated, behind-the-scenes maneuvering of Big Pharma that are used to generate billions of dollars of prescription sales. For example, a "no-see" physician (or resident) may be prescribing formulary-approved drugs or prescribing drugs through an institutional protocol without any prior knowledge regarding how these products became first-line "drugs of choice." If the hospital runs a "clean" formulary/protocol system, there may be little to worry about (such members can have no financial affiliation with industry and/or must disclose such relationships in order to avoid conflicts of interest). Formulary members are usually a multidisciplinary group of health care workers (eg, physicians, pharmacists, nurses, microbiologists, etc.) who meet on a regular basis to discuss and make decisions regarding what pharmaceutical products will be made available (or not) for everyday use in the hospital (or through a particular HMO plan). However, if there is no institutionally mandated oversight regarding conflict(s) of interest (eg, in which there are policies regarding the practices of formulary members speaking for the industry; clinicians participating in new drug research and development; receiving UERGs, etc.), then physicians writing those prescriptions may be at risk for becoming a naïve "no-see," which, in turn can be risky for their patients. In short, without transparency, "no-see" physicians could be writing prescriptions for products not evaluated through evidence-based medicine but through social relationships and drug promotion. "Roger"* was a "hospital rep" for a large pharmaceutical corporation in the mid- to late 1990s, and through a series of interviews relayed a story to this author [6, 7] that illustrates quite nicely how reps work behind the scenes and how physicians and entire institutions are naïve. Roger was charged with introducing to the market "Product T," attaining formulary status and later gaining protocol approval for this broad-spectrum antibiotic. His company had positioned this antibiotic as a premarket "blockbuster," with 11 indications ranging from community-based infections (eg, sinusitis) to hospital-acquired infections (eg, postoperative infection with gram-negative bacteria). Roger targeted all the key players at his teaching center and began a series of "preceptorships" with different departments for his district sales colleagues in order to gain eventual support for Product T or to neutralize the possible dissenting voices. For instance, microbiology, pharmacy, and infectious disease departments were all given UERGs in order to ostensibly educate Roger and his district members on their respective topics. Within each department, Roger developed a strong relationship with at least 1 "decision maker" who could affect institutional decisions regarding Product T. Roger also partook in "champion building" by inviting targeted (ie, "no-see," influential, and/or high-prescribing) trauma surgeons and infectious disease specialists to participate in all-expense-paid "workshops" and "expert exchanges" on Product T-related topics. Several participants became part of the Product T speaker's bureau, a national network of speakers who were paid $500 to $1500 per talk, that reps could access for local CME programs. When Product T was finally introduced to the market, it was placed on Roger's teaching center's formulary within 2 months. However, Roger had one last institutional hurdle to overcome—Product T was not an option on any of the "clinical pathways" (or protocols) used by the house staff and residents. He therefore persuaded the hospital clinical pharmacist, who he described as a "personal friend," to allow him (the drug rep!) to write a draft of "new" clinical pathways in order to have Product T positioned as "the primary," or one of the "drugs of choice" for treatment. The clinical pharmacist had confided in Roger that she was "too busy" and "stressed out" to take on this task. After much deliberation with his co-marketing colleagues at the same company (they wanted all 11 of Product T's FDA-indications integrated into the new pathways), Roger chose six different pathways for Product T, including postoperative infections and community-acquired pneumonia that requires hospitalization. According to Roger, he was being "ethical" in terms of this opportunity and also quite astute because the hospital clinical pharmacist would have surely rejected multiple pathways dominated by Product T therapy.† There was one last problem—getting the new pathways printed. Roger had a solution (and the resources): his company printed about 1000 new clinical pathway pocketbooks to be widely distributed to physicians. These new pathway books also included indications for the company's other products: Product X, another IV antibiotic; Product A, an antifungal; and Product W, an oral antibiotic. Roger, reflecting on these outcomes, stated, "It was a win-win for all parties." Keep in mind as well that these pathway books were distributed to all of Roger's fellow reps in the geographical region to distribute to physicians, formulary committee members, and pathway developers. In short, the book became an invaluable selling tool. Roger (and his company co-marketers) soon led the nation in Product T sales. Unfortunately, the Product T story does not end well. Around 2 years after its market introduction, some patients began to experience serious side effects, such as liver toxicity, liver failure, and, tragically, death. Roger's company decided to cut its losses and quickly stopped Product T promotion by the sales force. Roger was told via voicemail one afternoon to "end all promotion" and begin to "hype" Product B, his company's new, blockbuster cyclooxygenase-2 inhibitor for arthritis. What can we learn from the case of Roger and other drug rep stories [6, 8-10]? Obviously, greater transparency and disclosure for all parties involved with pharmaceutical industry interactions will lead to less naïveté for all prescribing physicians. It is no longer acceptable for health care providers, whether community based or in an academic setting, to remain uneducated in terms of how the current medical system can fall prey to market forces and unethical sales practices. This is the naïve approach. Roger's case illustrates, perhaps in dramatic fashion, how seemingly dubious and unethical practices can be normalized within a teaching institution. In particular, to move beyond the naïve no-see culture that is quite prevalent today, "script-writers" (eg, physicians, nurse practitioners, and physicians assistants) must engage fully in 2 ethical acts: to search for "clean" (ie, unbiased sources) of prescription drug information and to advocate for transparency and disclosure at all levels of medical-pharmaceutical interaction (Table 1). Transparency and disclosure must exist at the highest level of medical institutions—clean formularies and protocol development, public disclosure of all UERGs, no participation in the "ghost writing" of clinical trials conducted by industry or "contract research organizations" (CROs), etc. CROs are an emergent industry within clinical trial drug testing. These are for-profit clinical trial companies that contract to industry to carry out Phase I, II, and III drug testing and produce the majority of data on new drugs. They employ specialized medical/scientific writers who "write up" the data and then produce an article for publication. However, the article requires legitimization through a non-CRO clinician that will be contacted by representatives of the CRO corporation (or public relations firm). A university or teaching center clinician will be paid a stipend to "sign off" on the article, which may be published in a "good" or prestigious medical journal. This is the process of pharmaceutical industry−sponsored ghost writing. And, transparency and disclosure must exist at the level of everyday clinical practice. Script-writers should inform patients of any conflicts of interest regarding the drugs they may prescribe, such as participating in postmarketing clinical trials, being part of a company's speaker bureau, and accepting cash rebates for using a high volume of a company's product (this is common in the injectable chemotherapeutic agent marketplace.) Product T and, to a much greater extent, Vioxx [11] represent cases where large numbers of prescription writers were caught up in the hype, including patient/consumer demand in the case of Vioxx, and began to confidently prescribe drugs that were clearly suspect in terms of serious side effects once all the clinical data were examined by unbiased experts [12]. Certain groups of patients, such as children and young persons, the elderly, and women, remain extremely vulnerable to overly hyped, blockbuster drugs. Take the case of Paxil (paroxetine HCl) and the issue of suicidality with children and adolescents. "Negative" clinical trial outcomes with Paxil (ie, low efficacy compared with placebo and/or serious side effects) collected prior to market introduction were hidden from regulatory agencies in the United States and the United Kingdom, because under current laws industry does not have to disclose negative outcome data. And, additionally, side effect data were manipulated, or "sanitized" (eg, suicidality became "emotional liability" in the clinical trial language and eventual package insert) by marketers, scientists, and/or third-party CROs [13, 14]. Nevertheless, Paxil remains on the market, in generic form, as the debate regarding suicidality and selective serotonin reuptake inhibitor treatment continues [15]. One disturbing phenomenon that Product T, Vioxx, and Paxil share is that drug reps were the last people to know that the drugs they were aggressively promoting posed lethal risks for certain groups (young persons in the case of Paxil) and for patients with particular medical conditions (liver disease with Product T and cardiovascular disease with Vioxx). Drug reps promoted Product T and Vioxx up until the day they were removed from the marketplace [16, 17]. A highly risky scenario can occur in medicine today when script-writers naïvely prescribe blockbuster drugs. These products are confidently promoted by pharmaceutical salespersons (through social networking and sometimes behind-the-scenes maneuvering) and may in fact carry serious side effects, which may not be disclosed by the company or discovered until after market introduction. Viagra (sildenafil citrate) is a case in point. Aggressively promoted and then demanded by male patients, it caused unforeseen cardiac events and death in men when taken along with nitrogen-containing compounds. Fortunately, these scenarios occur rarely within our health care system. Moreover, there seems to be 2 trends that point toward a positive change in how medical professionals will interact with the pharmaceutical industry in the future. The first is a generational shift among medical students and residents that reflects a growing awareness of pharmaceutical sales tactics and a desire to both understand these tactics and remove oneself from the "gift-cycle" [10]—to become an educated, or pharmaceutically savvy, no-see. This trend is reflected in the American Medical Student Association's "Pharma Free" campaign (www.amsa.org) and recent how-to books for pharmaceutical company-physician interaction [3, 18]. There also is a generational drive by clinicians to find unbiased sources of drug information. The second trend is a move toward macro-level transparency regarding the clinical trials of new pharmaceutical products. The future may soon be one where drug manufacturers will be legally required to post all clinical trials (published and unpublished) related to FDA-approved drugs. This has only occurred once, when Eliot Spitzer, then the attorney general of New York State, required GlaxoSmithKline (GSK), to post all data for all products after GSK lost a class action suit (Spitzer showed that GSK had avoided disclosure of the risk of suicidality in young persons taking Paxil). Interestingly, clinicians quickly seized upon the data, made public via a GSK website regarding the clinical trials of Avandia (rosiglitazone maleate), which is used for the treatment of type 2 diabetes. When previously unknown data from clinical trials were compiled through a meta-analysis, Avandia treatment groups were associated with an increase in cardiac events [15, 19]. Avandia prescribing (and sales) sharply dropped as physicians began to reevaluate its use in specific patient populations. A positive future for ethical and educated prescribing must involve more pharmaceutical transparency and disclosure at every level of medical care and science. The government could takes its cue from the environmental movement of the 1970s that required corporations to publish a "toxic release inventory" [20-22], which in turn led to scrutiny of corporate practices and forced companies to become better corporate citizens—to literally clean up their act. We seem to be at a similar moment regarding the practices of multinational pharmaceutical companies [23]. Why can't we expect these companies to produce a "side effects release inventory" (or something similar) regarding all the clinical science of a particular product? Ethical/educated prescribers should not allow the industry to be secretive when patient health (and lives) can be at stake. If the industry is allowed a transparent window into the prescribing habits of virtually every physician in the United States, it seems only fair, for the sake of public health, that a critical lens must be placed on the myriad activities of drug companies. The general public may demand good drugs and the industry will no doubt continue to produce blockbusters, but it remains the providence of health care providers, who are ultimately responsible (and often liable) for prescribing efficacious and safe products for their patients within an unbiased environment. I would like to thank participants at a series of "Ethics Rounds" at Northwestern Hospital and the Rehabilitation Institute of Chicago (June 2008) for their comments and feedback regarding these topics.