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SCIENCE POLICY: THE DRUG NESIRITIDE - A MARKETING SCANDAL?

The following points are made by Eric J. Topol (New Engl. J. Med. 2005 353:113):

1) How can a drug that is associated with higher rates of both renal dysfunction and death than placebo -- and that costs 50 times as much as standard therapies and for which there are no meaningful data on relevant clinical end points -- be given to more than 600,000 patients and be promoted throughout the United States for serial outpatient use, an indication not listed on the label?[1-5] The answer to this question can be discerned, at least in part, from a review of the clinical development and marketing of nesiritide: recombinant human brain natriuretic peptide.

2) On May, 17, 2005, the New York Times reported that tens of thousands of patients around the country are receiving nesiritide treatment once or more per week, over a period of several months, for what is described as an outpatient "tune-up". This application of nesiritide -- which costs approximately $500 per dose, as compared with less than $10 for nitroglycerin or nitroprusside -- is the subject of an aggressive marketing campaign by the manufacturer, Scios, which is encouraging physicians to start their own "infusion centers" for whose services they can bill Medicare as if they were providing chemotherapy. But when nesiritide was approved by the Food and Drug Administration (FDA) in 2001, it was designated for the treatment of acute, decompensated congestive heart failure. Moreover, it had apparent safety problems -- and no proven clinical advantage over existing treatments in terms of the key end points of improved survival and prevention of subsequent hospitalizations.

3) In a 2000 report, Colucci and colleagues concluded that "nesiritide would be a valuable addition to the initial treatment of patients admitted to the hospital for decompensated congestive heart failure."[1] But their placebo-controlled, dose-ranging trial was focused on short-term monitoring of the pulmonary-capillary wedge pressure. Follow-up data on these subjects, which were not part of the study design as reported in that article, suggested that nesiritide may have had an adverse effect on 30-day mortality, which was 7.1 percent in the nesiritide group, as compared with 4.8 percent in the placebo group.[2] Over this longer period of follow-up, the incidence of substantial deterioration of renal function was more than three times as high among patients treated with nesiritide as among those given placebo.[3]

4) The author concludes: We practice medicine in an era in which there is one pharmaceutical-company representative for every five physicians and in which companies will stretch the limits in their marketing of drugs. The boundary lines that previously separated industry from the FDA and academia have unfortunately become blurred. The European Agency for the Evaluation of Medicinal Products, the counterpart of the FDA, has still not approved nesiritide and awaits the results of a trial involving 1900 patients before it will even consider doing so.[5] In the author's view, nesiritide has not yet met the minimal criteria for safety and efficacy. Until a trial definitively proves that this drug reduces the risk of death or repeated hospitalization for heart failure, there will be questions about the appropriateness of the drug's use or even commercial availability. The author suggests we need a tune-up of our procedures to eliminate indiscriminate use of drugs, such as nesiritide, when there is not proper evidence of their safety.

References (abridged):

1. Colucci WS, Elkayam U, Horton DP, et al. Intravenous nesiritide, a natriuretic peptide, in the treatment of decompensated congestive heart failure, N Engl J Med 2000;343:246-53.

2. Sackner-Bernstein JD, Kowalski M, Fox M, Aaronson K. Short-term risk of death after treatment with nesiritide for decompensated heart failure. JAMA 2005;293:1900-1905

3. Sackner-Bernstein JD, Skopicki HA, Aaronson KD. Risk of worsening renal function with nesiritide in patients with acutely decompensated heart failure. Circulation 2005;111:1487-1491

4. Publication Committee for VMAC Investigators. Intravenous nesiritide vs nitroglycerin for treatment of decompensated congestive heart failure: a randomized controlled trial. JAMA 2002;287:1531-1540. [Erratum, JAMA 2002;288:577.]

5. Teerlink JR, Massie BM. Nesiritide and worsening of renal function: the emperor's new clothes? Circulation 2005;111:1459-1461

New Engl. J. Med. http://www.nejm.org

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PUBLIC HEALTH: PHYSICIANS AND DRUG COMPANIES

The following points are made by David Blumenthal (New Engl. J. Med. 2004 351:1885):

1) When a great profession and the forces of capitalism interact, drama is likely to result. This has certainly been the case where the profession of medicine and the pharmaceutical industry are concerned. On display in the relationship between doctors and drug companies are the grandeur and weaknesses of the medical profession -- its noble aspirations and its continuing inability to fulfill them. Also on display are the power, social contributions, and occasional venality of a very profitable industry whose products contribute in important ways to the health and longevity of the American people, but an industry that at times employs methods that are deeply troubling and even criminal. Government also plays a part as it tries with limited success to help the profession stay true to its own tenets and to deter the industry's most egregious excesses. The spectacle is profoundly human and, like most such spectacles, seems never to end or to lose its fascination.

2) The interaction of doctors and pharmaceutical companies is also extremely consequential for patients, doctors, and the larger society. The drug industry manufactures, distributes, and publicizes powerful chemical and biologic agents that have proven benefits and that physicians sometimes fail to use as often as they should, or in sufficient doses.(1) In this sense, industry's efforts to encourage the use of some agents by physicians can be seen as contributing to the public health. At the same time, the marketing by the drug industry of its products to physicians is manifestly aimed also at improving industry profits. In the process, such marketing may contribute to less savory social consequences, including increasing drug costs and the misuse or overuse of medications in ways that may adversely affect patients.(2)

3) Several recent developments have focused renewed attention on the relationship between drug companies and doctors. One is the surge in spending on prescription drugs, which totaled $162.4 billion in 2002 after years of double-digit percentage increases.(3) A second is the publicity surrounding a number of prominent legal cases in which drug manufacturers have been convicted of crimes related to their marketing of drugs to physicians or have made huge payments in the settlement of civil suits for similar noncriminal violations.(4,5) A third is an increasing recognition by both pharmaceutical companies and physicians that, in certain respects, the relationships between drug companies and doctors have become embarrassing to both parties and need to change.

4) Interactions between drug companies and doctors are pervasive. Relationships begin in medical school, continue during residency training, and persist throughout physicians' careers. The pervasiveness of these interactions results in part from a huge investment by the pharmaceutical industry in marketing. In 2002, the industry expended 33 percent of its revenues on "selling and administration." In 2001, one company, Novartis, reported spending 36 percent of its revenues on marketing alone.(2) The marketing expenditures of the drug industry have been estimated variously at $12 billion to $15 billion yearly, or $8000 to $15,000 per physician. In 2001, the industry's sales force of drug detailers, whose job is to meet individually with physicians and promote company products, numbered nearly 90,000 in the United States(2) -- one salesperson for every 4.7 office-based physicians.

5) Moynihan (2003) catalogued 16 different ways in which drug companies relate directly or indirectly with doctors. These range from the seemingly trivial (e.g., the ubiquitous dispensing of gifts such as pens and pads with drug names inscribed) to the much more troubling (e.g., the ghostwriting of articles for academic physicians, the payment of large honoraria and consulting fees to prominent physicians who extol the virtues of company products, and the support of lavish trips and entertainment for physicians who commonly prescribe company products).

6) Surveys of residents indicate that they receive an average of six gifts from pharmaceutical companies annually. In a survey of 106 directors of emergency-department programs in 2002, 41 percent responded that their programs allowed residents to be taught by representatives of drug companies, 35 percent reported that residents received free industry samples at work, and 29 percent said that residents' travel to meetings was sometimes dependent on the availability of company support. According to another report, residents in a psychiatry program in Toronto attended up to 70 lunches that had been sponsored by drug companies and received 75 promotional items over the course of one year.

7) As physicians mature, their relationships with drug companies also change, becoming more likely to involve consulting and honoraria and less likely to involve luncheon seminars. A 2001 survey of a random sample of US physicians by the Henry J. Kaiser Family Foundation found that 92 percent of physicians received free drug samples from companies; 61 percent received meals, tickets to entertainment events, or free travel; 13 percent received "financial or other in-kind benefits"; and 12 percent received financial incentives to participate in clinical trials. A 1997 study by Ferguson et al found that 83 percent of internists with the Department of Medicine at the University of Maryland had met with drug-company representatives in the previous year. Wazana (2000) reported that on average practicing physicians meet with drug-company representatives four times a month.

References (abridged):

1. Quality of health care delivered to adults in the United States. N Engl J Med 2003;349:1866-1868

2. Relman AS, Angell M. America's other drug problem. The New Republic. December 16, 2002:27-41

3. Levit K, Smith C, Cowan C, Sensenig A, Catlin A. Health spending rebound continues in 2002. Health Aff (Millwood) 2004;23:147-159

4. Petersen M. Suit says company promoted drug in exam room. New York Times. May 15, 2002:C1

5. Dembner A. TAP officials on trial today in fraud case. Boston Globe. April 20, 2004:1

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PUBLIC HEALTH: ON THE PHARMACEUTICAL INDUSTRY

The following points are made by F.M. Scherer (New Engl. J. Med. 2004 351:927):

1) For more than four decades, beginning with an investigation chaired by Senator Estes Kefauver in the 1950s, debate has raged over the economics of the pharmaceutical manufacturing industry. Critics point to monopolistic pricing and high profits; defenders emphasize the advances in medical therapy achieved by the industry.

2) The bounds of the industry are indistinct. From statistics compiled by the industry's principal trade association, "Big Pharma" companies reported US prescription-drug sales in 2002 of $145 billion.(1) Included in this figure are drug sales of companies that have successfully marketed new biopharmaceutical products. A higher estimate, $192 billion, comes from Intercontinental Marketing Services, a leading independent collector of industry data. The latter figure includes the sales of smaller companies, generic drug specialists, and some over-the-counter drugs.(2) In 2000, prescription-drug outlays made up 9 to 10 percent of total US health care expenditures.(3,4)

3) The pharmaceutical industry is the most research-intensive of US industries that support their research and development with private funds (as distinguished from defense and space contractors). In 2002, Big Pharma companies devoted 18 percent of their sales revenue to research, development, and testing activities.(5) The much lower percentages often reported in the press are misleading because they use companywide data, including the sales of less research-intensive activities such as pharmacy benefit-management services and the production of high-purity chemicals, cosmetics, prosthetics, over-the-counter drugs, vitamins, and so forth. Excluded from the 18 percent figure was roughly $10 billion of activity by start-up companies in biotechnology doing little else but research and development that had not yet yielded salable products.

4) From the industry's research-and-development efforts has come a stream of new therapeutic products, most offering modest variations on existing therapies but some providing groundbreaking new approaches to the treatment of disease. From 1963 to 1999, the number of new chemical entities (or molecules) approved for marketing in the United States averaged 18.7 per year, with an upturn to 27 (plus 4 new biologic entities) per year during the 1990s and a downturn in number more recently. Using advanced statistical techniques with available (but necessarily limited) data, a recent study found that the use of new drug therapies contributed appreciably to the extension of life spans and the reduction of hospital stays. The study estimates that during the last two decades of the 20th century, drug innovations that were rated "priority" by the Food and Drug Administration (FDA) increased life expectancy in the US by an average of 4.7 months.

5) Pharmaceutical companies customarily apply for patent protection on new chemical entities shortly before clinical tests in humans commence. The basic statutory patent life is 20 years, and by the time commercial marketing is allowed, approximately 12 to 13 years of basic product patent life remain, under regulatory conditions of the late 1990s. Drug patents provide particularly strong protection against competition from other companies because even a slightly different molecular variant must undergo the full panoply of clinical tests required by the FDA. Numerous cross-industry surveys have shown that managers of pharmaceutical research and development assign unusually great importance to patent protection as a means of recouping their investment in research, development, and testing. Striving to prolong the period of patent protection, pharmaceutical companies have obtained patents on minor variants in product formulation and production processes, and some have entered into agreements delaying entry of generic manufacturers challenging their patents. Several of these competition-impeding agreements were abandoned in recent years after antitrust complaints.

6) Only about 21 to 23 percent of the new chemical entities that are subjected to human testing emerge at the end of the process with marketing approval; the rest fail at various stages. A recent survey estimated that the cost of research, development, and evaluation of new chemical entities approved by the FDA, mostly during the 1990s, was $802 million on average, with the costs of preclinical research and failed tests allocated to the "winners." However, this estimate must be regarded with caution. Only about half the estimated price tag entailed actual out-of-pocket costs; the remainder was an estimated 11 percent annual cost of financial capital invested in research and testing. Also, the voluntary sample from which the estimates were drawn numbered only 10 companies, including mainly Big Pharma members that placed a disproportionate emphasis on drugs for chronic diseases, which require extensive testing to identify long-term effects. Higher costs for testing may also have been incurred to differentiate a drug's efficacy from that of rival products. There is reason to believe that drugs used to treat acute symptoms and those directed toward small "orphan" markets are developed at a much lower average cost. On the other hand, some costs are ignored -- notably, those incurred for academic research that often identifies molecules likely to have therapeutic effects.

References (abridged):

1. Pharmaceutical industry profile: 2003. Washington, D.C.: Pharmaceutical Research and Manufacturers of America, 2003:79

2. Kumar P, Zaugg AM. Steady but not stellar. IMS Health Business Watch. May 2003

3. Statistical abstract of the United States. 2002. Washington, D.C.: Bureau of the Census, 2002:Section 3

4. Medicare and Medicaid statistical supplement. Table 4

5. Pharmaceutical industry profile 2003. Washington, D.C.: Pharmaceutical Research and Manufacturers of America, 2003:76

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