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ScienceWeek
PUBLIC HEALTH: ON POSTMARKETING SURVEILLANCE OF MEDICINALS
The following points are made by P.B. Fontanarosa et al (J. Am. Med. Assoc. 2004 292:2647):
1) Physicians and patients expect that when medications are prescribed correctly for labeled indications and are used as directed, these medications generally will have beneficial effects and will not cause significant harm. This confidence in pharmaceutical products reflects trust in the effectiveness and integrity of the drug approval and monitoring process.
2) However, the current approval process for drugs and biological agents in the US has come under intense scrutiny, most notably because of concerns about influence from industry. For instance, since adoption of the 1992 Prescription Drug User Fee Act, which augmented the budget of the Food and Drug Administration (FDA) by charging "user fees" to pharmaceutical firms,[1] the FDA has received approximately $825 million in fees from drug and biologic manufacturers from fiscal years 1993 through 2001.[2-3] During that time, median approval times for standard (ie, "nonpriority") drugs decreased from 27 months in 1993 to 14 months in 2001, but as an inevitable consequence of faster approvals, drug recalls following approval increased from 1.56% for 1993-1996 to 5.35% for 1997-2001.[2] In addition, an investigation of 18 FDA expert advisory panels revealed that more than half of the members of these panels had direct financial interests in the drug or topic they were evaluating and for which they were making recommendations.[4]
3) The drug review process has been described as structurally similar to many decisions made by other regulatory agencies, such that it is characterized by high uncertainty, avoidance of observable error, and low (reputational) reversibility, with drug recalls harming the reputation of the FDA for a faulty approval decision,[5] and often severely affecting the manufacturer. Given that new products are the financial lifeblood of pharmaceutical companies, the stakes are raised higher due to intense lobbying by interested parties such as health professionals and patient advocacy groups, as well as pharmaceutical and technology companies,[5] so it is no wonder that, in 2003, the pharmaceutical industry earmarked $4.9 million to lobby the FDA.
4) While these concerns are noteworthy, they pale in comparison to the shortcomings and failures of the current imperfect system for postmarketing surveillance. This system is intended to detect adverse drug events and reactions once new products are in widespread use, and thereby limit exposure of the public to hazards of new medications. The inadequacies of the postmarketing surveillance system (ie, FDAs MedWatch program with passive collection of spontaneous reports of adverse drug reactions) for ensuring safety are well known and include: reliance on voluntary reporting of adverse events by physicians and other health care professionals; poor quality of submitted reports, often with inadequate documentation and detail; underreporting of adverse outcomes with capture of only a small fraction of adverse events that actually occur; difficulty in calculating rates of adverse events because of incomplete numerator data on events, together with unreliable denominator data on exposure; limited ability for spontaneous reports to establish causal relationships; and difficulty in determining whether the adverse event resulted from the drug or the disease it was intended to treat.
5) Yet the major problem with the current system for ensuring the safety of medications is that drug manufacturers are largely responsible for collecting, evaluating, and reporting data from postmarketing studies of their own products. This approach has many inherent problems. For instance, it appears that fewer than half of the postmarketing studies that manufacturers have made commitments to undertake as a condition of approval have been completed and many have not even been initiated. Moreover, despite the mandatory adverse event reporting system for companies subject to the FDAÆs postmarketing safety reporting regulations, drug manufacturers may be tempted to conceal available data that may signal the possibility of major risks. In some cases, the FDA and drug manufacturers may fail to act on that information and fail to conduct appropriate studies to examine a potential risk rigorously and promptly.
References (abridged):
1. Prescription Drug User Fee Act of 1992, Pub L No. 102-571, 21 USC 379, 106 Stat 4491 (1992)
2. US General Accounting Office. Food and Drug Administration: Effect of User Fees on Drug Approval Times, Withdrawals, and Other Agency Activities. Washington, DC: General Accounting Office; 2002. Publication GAO-02-958
3. Carpenter D, Chernew M, Smith DG, Fendrick AM. Approval times for new drugs: does the source of funding for FDA staff matter? Health Aff (Millwood). 2003 Suppl Web Exclusives:W3-618-W3-624
4. Cauchon D. FDA advisers tied to industry. USA Today. September 25, 2000:A1
5. Carpenter DP. The political economy of FDA drug review: processing, politics, and lessons for policy. Health Aff (Millwood). 2004;23:52-63
J. Am. Med. Assoc. http://www.jama.com
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Related Material:
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
New Engl. J. Med. http://www.nejm.org
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Related Material:
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
New Engl. J. Med. http://www.nejm.org
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