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ScienceWeek
SCIENCE POLICY: ON THE US FOOD AND DRUG ADMINISTRATION
The following points are made by Eve E. Slater (New Engl. J. Med. 2005 352:293):
1) The US Food and Drug Administration (FDA) is responsible for the safety and efficacy of most food products and all human and veterinary drugs, biologic products, medical devices, cosmetics, and products emitting radiation that are sold within US borders -- a list that accounts for an estimated 20 percent of consumer spending, valued at approximately $1.5 trillion.[1,2] Although the FDA is often at the center of controversy, the agency has consistently commanded the respect of more than two thirds of American adults.[3]
2) The author examines the performance of the agency, with particular attention given to the FDA's relationship with its major counterpart, the pharmaceutical industry, especially in the decade since the enactment of the Prescription Drug User Fee Act in 1992. The author is a former senior vice president of Merck Research Laboratories (until 2000) and a former assistant secretary for health at the Department of Health and Human Services.
3) The pressure to approve drugs more or less rapidly ebbs and flows, largely as a consequence of external events. The publication of THE JUNGLE, Upton Sinclair's expose of the meatpacking industry, helped to create the FDA in 1906.[4] The crisis over the elixir sulfanilamide in the 1930s and the thalidomide tragedy in the 1960s prompted legislation to expand the FDA's authority. In the 1980s, the AIDS epidemic focused attention on the need for faster approval of drugs, especially for potentially lifesaving therapies. For the most part, current convention has demanded rapid review coupled with scientifically sound judgment by a strong agency. The Prescription Drug User Fee Act was passed primarily to improve the efficiency of the FDA, specifying that sponsors pay user fees to provide resources to allow the FDA to be more efficient in reviewing applications. The act's subsequent extension, the FDA Modernization Act of 1997, facilitated certain evidentiary standards for priority drugs. Amendments to the Prescription Drug User Fee Act that are contained in the Public Health Security and Bioterrorism Preparedness and Response Act of 2002 renewed prior provisions, added several more efficiency measures, and provided modest funding for post-marketing surveillance.[5]
4) The FDA currently employs approximately 10,000 people, an increase of 85 percent in the decade since the Prescription Drug User Fee Act was enacted, and commands a budget of $1.7 billion, of which $300 million (18 percent) is projected to derive from user fees that are charged to companies when they submit applications.[1,2] By comparison, the FDA budget is less than 1/50 that of the Department of Agriculture, which has 10 times the workforce of the FDA. The FDA's budget did not increase in tandem with the recent doubling of the annual budget of the National Institutes of Health to more than $27 billion. However, as a consequence of the terrorist attacks of September 11, 2001, additional money (more than $500 million) has been earmarked primarily for food-safety surveillance.[1,2]
5) Under the Prescription Drug User Fee Act, the FDA has made appreciable progress in the efficiency of its review process, especially for drugs that are granted priority status, and has enhanced the scientific quality of its actions. This improvement is largely attributable to the growth in the number of its employees, as well as to the maturing of regulatory science. In 2003, the FDA's Center for Drug Evaluation and Research approved 21 new molecular entities, defined as drugs that differ from others on the market, with a total median time for approval of 16.6 months (6.7 months for priority drugs and 23.1 months for standard review, as compared with 14.9 months and 27.2 months, respectively, a decade ago).[1]
6) Since 1992, the average time that is required for clinical development and regulatory review has been reduced by 25 percent, from 9.2 to 6.9 years, and since 1997, the average time for clinical development of fast-track drugs (as compared with standard drugs) has been shortened by 2.0 to 2.5 years. On the other hand, response times for requests that remain outside tracking mandated by the Prescription Drug User Fee Act have continued to suffer from inefficiencies that are extraneous to science. In important progress that is largely attributable to the Food and Drug Administration Modernization Act, the agency has adopted a more streamlined approach to clinical development -- for example, through the use of surrogate markers for accelerated approval or approval on the basis of a single multicenter clinical trial. Among the provisions of the 2002 amendments to the Prescription Drug User Fee Act are pilot programs involving continuous marketing applications, in which data are submitted and reviewed in continuous fashion, as was done for the first protease inhibitors to treat AIDS, and retrospective performance reviews.
7) It should be noted that the failure rate for compounds during development has remained fairly constant; however, the overall time from the discovery of a drug to its commercialization has increased from approximately 10 years to 12 years. The reasons are that the time that is required for preclinical development has been increasing in some cases and that although priority drugs are coming to market sooner, the review time for standard agents has changed less dramatically. Presumably, the Prescription Drug User Fee Act has not resulted in a reduction in the cost of the development of drugs, a figure that has been increasing rather briskly, according to industry statistics. Furthermore, the sequential legislative actions have placed certain pressures on the agency. According to the Government Accountability Office, performance goals have created overwork for many reviewers. This observation, coupled with the fact that more than 30 percent of the FDA's workforce is eligible for retirement within five years, is cause for concern.[2]
References (abridged):
1. McClellan MB. The Food and Drug Administration's strategic action plan: protecting and advancing America's health: responding to new challenges and opportunities. August 2003. Accessed December 30, 2004, at http://www.fda.gov/oc/mcclellan/strategic.html
2. FY 2004 Justification of Estimates for Appropriations Committees. Promoting public health through patient, food, and consumer safety. Rockville, Md.: Food and Drug Administration, 2003. Accessed December 30, 2004, at http://www.fda.gov/oc/oms/ofm/budget/2004/bib1.htm
3. Taylor H. CDC, NIH, FAA, FDA get highest ratings of eleven federal government agencies. Harris Poll no. 73. Accessed December 30, 2004, at http://www.harrisinteractive.com/harris_poll/index.asp?PID=422
4. Sinclair U. The jungle. New York: Doubleday, Page, 1906:102. 5. Prescription Drug User Fee Act of 1992, Pub. L. No. 102-571, 21 U.S.C. 379, 106 Stat. 4491 (Oct. 29, 1992)
6. Food and Drug Administration Modernization Act of 1997, Pub. L. No. 105-115, 21 U.S.C. 355a, 111 Stat. 2296 (Nov. 21, 1997)
New Engl. J. Med. http://www.nejm.org
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Related Material:
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 FDA's 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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