For other versions of this document, see http://wikileaks.org/wiki/CRS-RL34334 ------------------------------------------------------------------------------ ¢ ¢ ¢ ¢ ¢ ¢ Prepared for Members and Committees of Congress ¢ ¢ ¢ Considerable attention has been focused on the ability of the Food and Drug Administration (FDA) to accomplish its mission with the funds provided by congressional appropriations and user fees. FDA regulates a wide range of products valued at more than $1 trillion in the U.S. economy. The agency plays a key public health role. FDA is responsible for the safety of most foods (human and animal) and cosmetics, and it regulates both the safety and the effectiveness of human drugs, biologics (e.g., vaccines), medical devices, and animal drugs. In congressional hearing testimony and at other public venues, former FDA Commissioners, interest group representatives, and former high-ranking individuals in the agency or in the Department of Health and Human Services have argued that FDA is underfunded and at risk of being unable to fulfill all the statutory responsibilities assigned by Congress. Reports by the Institute of Medicine, the Government Accountability Office, and the FDA Science Board have made similar observations. The main voices in support of FDA budget levels, past and present, have been representatives of the various presidential administrations. Calls for cutting the FDA budget or maintaining it at the current level come from organizations, such as CATO and the Hoover Institute, that propose limitations on the agency's authority and, therefore, its need for funding. Some agency critics have expressed concerns about inefficiencies within FDA and its ability to manage its resources. In order to inform the ongoing discussion about FDA, this report presents FDA's appropriations history and traces the evolution of the agency's statutory responsibility. It first provides a 28-year budget history for the agency along with personnel levels as shown by the number of full-time equivalent employees (FTEs). This report found that direct congressional inflation-adjusted appropriations (budget authority) to FDA doubled, and that the contribution of other funds, mostly user fees, increased more than 12-fold, resulting in an overall budget in FY2007 almost 2½ times that in FY1980. Between FY1980 and FY2006, the latest year with final FTE data, the agency's FTE level increased 19% overall, from a less than 1% increase in budget authority- funded FTEs and an almost fourfold increase in FTEs funded by other sources (mostly user fees). The report also provides a more detailed examination of the budget and personnel levels for each of FDA's major activity areas: Foods, Human Drugs, Biologics, Animal Drugs and Feeds, and Devices and Radiological Health. Findings include the relationship of user fees to budget authority, declining funding of research, and summaries of the major laws enacted since FY1980. ¢ ¢ Introduction ..................................................................................................................................... 1 Agency Scope and Congressional Jurisdiction................................................................................ 2 FDA Budget and Personnel ............................................................................................................. 4 Overall FDA Budget ................................................................................................................. 4 Comparison of FDA Budget with Other Agency Budgets ........................................................ 7 FDA Activity-Area Budgets .................................................................................................... 12 Impact of New Statutory Authorities on FDA Budget ............................................................ 14 FDA Regulatory Research....................................................................................................... 15 FDA Science Board Report..................................................................................................... 17 Major Activity Areas: Budget and FTEs ....................................................................................... 19 Foods....................................................................................................................................... 19 Human Drugs .......................................................................................................................... 23 Biologics ................................................................................................................................. 27 Animal Drugs and Feeds......................................................................................................... 30 Devices and Radiological Health ............................................................................................ 34 Other Activities and Responsibilities ...................................................................................... 37 Toxicological Research..................................................................................................... 37 Headquarters and Office of the Commissioner................................................................. 38 Field Activities: The Office of Regulatory Affairs............................................................ 38 Concluding Comments .................................................................................................................. 38 Figure 1. FDA: Budget and FTEs.................................................................................................... 6 Figure 2. Budget Authority for FDA, CDC, and NIH ..................................................................... 8 Figure 3. FDA Budgets for FY1980 and FY2006, by Major Activity Area and Type of Funding ...................................................................................................................................... 14 Figure 4. FDA Research in Five Activity Areas (Constant FY2000 $) ......................................... 16 Figure 5. Foods: Budget and FTEs(Constant FY2000 $).............................................................. 23 Figure 6. Human Drugs: Budget and FTEs (Constant FY2000 $) ................................................ 24 Figure 7. Biologics: Budget and FTEs (Constant FY2000 $) ....................................................... 29 Figure 8. Animal Drugs and Feeds: Budget and FTEs(Constant FY2000 $) ................................ 32 Figure 9. Devices and Radiological Health: Budget and FTEs (Constant FY2000 $) .................. 36 Table 1. Summary of Increase in Total Budget and FTEs, FY1980 and FY2006 (Constant FY2000 $) .................................................................................................................................. 13 Table 2. Foods Statutory Authorities in 1980 and 2007 ................................................................ 21 Table 3. Human Drugs Statutory Authorities in 1980 and 2007.................................................... 26 ¢ ¢ Table 4. Biologics Statutory Authorities in 1980 and 2007........................................................... 30 Table 5. Animal Drugs and Feeds Statutory Authorities in 1980 and 2007.................................. 33 Table 6. Devices and Radiological Health Statutory Authorities in 1980 and 2007...................... 37 Table A-1. Actions Taken to Address FDA Budget Data Limitations ........................................... 44 Table A-2. FDA Appropriations, Overall and by Major Program, Budget Authority and Other Funding, FY1980 through FY2008, Unadjusted for Inflation ......................................... 46 Table A-3. Full-time Equivalents, Overall and by Major Program, Budget Authority- Funded and Other-Funded, FY1980 through FY2008 ............................................................... 48 Table A-4. Selected Public Laws Since 1848 Significantly Affecting FDA Activities ................. 50 ¡ Appendix. Methodology................................................................................................................ 42 Author Contact Information .......................................................................................................... 57 ¢ ¢ There is growing debate about whether the Food and Drug Administration (FDA) has the ability to accomplish its mission with the resources provided by congressional appropriations and industry user fees. FDA plays a central role in protecting the public health in the United States by regulating most of the food supply and vitally important medical products, including drugs, devices, and biologics that affect American lives on a daily basis. A 2006 report on drug safety by the Institute of Medicine (IOM) made the following observation in a chapter devoted to FDA resources: The Food and Drug Administration lacks the resources needed to accomplish its large and complex mission today, let alone to position itself for an increasingly challenging future.... There is little dispute that FDA in general is ... severely underfunded.1 Several individuals who previously held high-ranking positions in FDA or the Department of Health and Human Services (HHS) have organized advocacy groups to lobby for increased funding for the entire agency.2 These groups present data to support their position that FDA has fallen behind in overall funding in the last 25 years. They warn that the agency is at risk of being unable to adequately fulfill the many statutory responsibilities that Congress has assigned it. While the call for more resources has been heard from many quarters, including some in Congress, some agency critics are concerned about inefficiencies within FDA and that it needs to do a better job managing what resources it does have.3 In general, former FDA Commissioners and interest groups argue that FDA is underfunded for its mission. Calls for cutting the FDA budget or maintaining it at the current level come from organizations, like CATO and the Hoover Institute, that propose limitations on FDA's authority and, therefore, the need for funding. The main voices in support of FDA budget levels, past and present, have been representatives of the various presidential administrations. Over the last 25 years, incumbent FDA Commissioners, when asked during congressional hearings about the adequacy of the FDA budget, have testified that the budget is sufficient to accomplish the job before the agency. However, in non-congressional venues, those same Commissioners have expressed concerns about the constraints on FDA resources and that the agency's core budget has not increased in concert with its rising responsibilities. They have expressed concern about whether the agency can continue to be considered the world's premier consumer protection agency when it is forced to focus its priorities based on the current level of resources that it receives.4 1 Institute of Medicine (IOM), The Future of Drug Safety: Promoting and Protecting the Health of the Public, Alina Baciu, Kathleen Stratton, Sheila P. Burke, Editors, Committee on the Assessment of the US Drug Safety System, Board on Population Health and Public Health Practice (Washington, DC: National Academies Press, 2006), p. 193. 2 The Coalition for a Stronger FDA, at http://www.fdacoalition.org/the-coalition-for-a-stronger-fda, and the FDA Alliance, at http://www.StrengthenFDA.org. In December 2007 the boards of these two groups announced their intention to merge; details of the merger have not been finalized ("Coalitions Lobbying for More FDA Money Are Merging," FDA Week, vol. 13, December 14, 2007). 3 IOM, The Future of Drug Safety, 2006, p. 81; and Representative Rosa DeLauro, "Statement on FDA Science Board Report," December 3, 2007, at http://delauro.house.gov/release.cfm?id=697. 4 Andrew C. von Eschenbach, "State of the FDA," Food and Drug Law Journal, vol. 62, 2007, pp. 423-427; and Jane E. Henney, "Remarks of the Commissioner of Food and Drugs," Food and Drug Law Journal, vol. 54, 1999. ¢ ¢ This report examines FDA's appropriations history and traces the evolution of the agency's statutory responsibilities. The information is presented to help inform the ongoing discussion about FDA. CRS takes no position on whether the agency has the necessary resources to meet its statutory responsibilities. The report first provides an overview of FDA's budget and personnel levels from FY1980 through FY2007.5 That is followed by a more detailed examination of the budget and personnel level over the same period in each of the agency's major activity areas. For each activity area, the report also summarizes the major pieces of legislation that have been enacted since FY1980. Unless noted otherwise, all budget data have been adjusted for inflation to permit comparison across the 28- year period under investigation. The information presented in this report is intended to facilitate an examination of the impact that administrations' budget requests and congressional decision making have had on the ability of FDA to accomplish its public health mission. ¢ FDA regulates a wide range of products valued at more than $1 trillion in the U.S. economy. About 25% of American consumer dollars are spent on these FDA-regulated products.6 As one of the agencies within HHS that comprise the Public Health Service,7 FDA is responsible for the safety of most foods (human and animal) and cosmetics. FDA also regulates both the safety and the effectiveness of human drugs, biologics (e.g., vaccines), medical devices, and animal drugs. The Federal Food, Drug, and Cosmetic Act (FFDCA), as amended, is the principal source of FDA's authority.8 The agency also derives some of its authority from certain provisions in other laws, most notably the Public Health Service (PHS) Act. Under the PHS Act, FDA licenses biological products9 and performs other activities, such as setting standards for mammography quality.10 An extensive list of the public laws that significantly affect FDA activities is in Table A- 4 in the Appendix. In addition to statutory responsibilities that directly involve product regulation, the FDA must also comply with statutory requirements affecting all or most federal executive agencies, regarding such matters as information management, strategic planning, performance measurement, financial management, property management, and human resources management.11 Additional requirements apply only to those agencies, including FDA, that have regulatory 5 Congress had not acted on FDA appropriations for FY2008 at the time this report was being prepared. Except for Figure 4, the figures in this report do not include FY2008 budget or FTE levels. 6 Food and Drug Administration (FDA), "Frequently Asked Questions (FAQs)," at http://www.fda.gov/opacom/faqs/ faqs.html. 7 CRS Report RL34098, Public Health Service (PHS) Agencies: Background and Funding, by Pamela W. Smith, coordinator. 8 P.L. 75-717, 1938, currently 21 U.S.C. § 301 et seq. 9 PHS Act § 351, 42 U.S.C. § 262. 10 PHS Act § 354, 42 U.S.C. § 263b. 11 For a listing of these laws, see CRS Report RL30795, General Management Laws: A Compendium, by Clinton T. Brass. Examples of general management laws with which FDA must comply include the Government Performance and Results Act of 1993 and the Data Quality Act. ¢ ¢ responsibilities.12 FDA's role in implementing provisions of some general federal management laws is substantial. For example, the agency supports more than 50 advisory committees, most of which are mandated in statute and are subject to requirements of the Federal Advisory Committee Act.13 Also, the agency reports that in FY2006 it processed more than 20,000 information requests pursuant to requirements of the Freedom of Information Act.14 The congressional authorizing committees that oversee FDA activities are those with jurisdiction over public health issues: the Senate Committee on Health, Education, Labor, and Pensions, and the House Committee on Energy and Commerce. Because Medicare pays for FDA-regulated products, the agency also falls under the jurisdiction of the Senate Committee on Finance and the House Committee on Ways and Means. Other committees that exercise oversight roles regarding FDA include the House Committee on Oversight and Government Reform, and the Senate Committees on Aging, Homeland Security and Governmental Affairs, and the Judiciary. The House and Senate Appropriations subcommittees on agriculture have jurisdiction over FDA's appropriations. This arrangement reflects, in part, the agency's origin within the Department of Agriculture as the Bureau of Chemistry in 1862. Since 1940, FDA has administratively been part of federal health agencies, specifically HHS and its predecessors.15 Advocates for increasing FDA funding point to this jurisdictional separation of FDA appropriations decisions from the rest of PHS and HHS as a contributing factor to what they see as underfunding. In 2002, former Acting FDA Commissioner Michael Friedman recommended moving the FDA budget process from the purview of the agriculture appropriations subcommittees to the Labor, Health and Human Services, Education and Related Agencies subcommittees.16 Five years later, former FDA Commissioner Frank Young raised the same concern and made the same recommendation in congressional testimony.17 Former FDA Commissioner Jane Henney made a similar observation in February 2007: [T]here are other things Congress can do that directly impact this agency's resources ... if they really wanted to look long and hard, FDA would no longer be under the purview of the Agriculture Appropriations Committees. Those people that serve on those committees do it with honor, but they do it primarily because of their interest in agricultural issues. By the time the allocations come out and the interest of the agriculture areas are satisfied, there are very limited resources that the agency [FDA] can ever hope to receive out of that process. If somebody wanted to do something bold ... it would be looking at appropriations in an area that is more compatible ... with the interests of the members of that committee particularly the ones that oversee health issues.18 12 Examples of regulatory management laws with which FDA must comply include the Administrative Procedure Act and the Regulatory Flexibility Act of 1980. 13 5 U.S.C. Appendix. For more information, see "FDA Advisory Committees" at http://www.fda.gov/oc/advisory/ default.htm. 14 For more information, see FDA, "Freedom of Information Annual Report--FY2006," at http://www.fda.gov/foi/default.htm, and 5 U.S.C. § 552. 15 For histories of FDA and USDA, see their respective websites, at http://www.fda.gov/opacom/backgrounders/ miles.html and http://www.fsis.usda.gov/About_FSIS/Agency_History/index.asp. 16 Michael A. Friedman, "Strengthening the FDA," Science, vol. 298, December 20, 2002, p. 2332. 17 Frank E. Young, statement before the Committee on Oversight and Government Reform, U.S. House of Representatives, May 1, 2007, p. 5, at http://oversight.house.gov/documents/20070501193917.pdf. 18 Policy Workshop on Strengthening the FDA, Project on Scientific Knowledge and Public Policy, George (continued...) ¢ ¢ The primary indicator of FDA resources is its budget. The agency's FY2007 total budget is approximately $2 billion.19 The total FDA budget, also called the program level, consists of (1) direct appropriations and (2) other funds (i.e., funding from other sources that are acknowledged in the appropriations acts). Direct appropriations are the amount of funds that Congress assigns to the agency from the annual total available for appropriations as set by the budget committees. Other funds include reimbursables, cooperative research and development agreement (CRADA) resources, intra- and inter-agency services (such as the Parklawn Computer Center), mammography fees, color certification fees, export certification fees, prescription drug user fees, medical device user fees, and animal drug user fees. FDA annually prepares budget data for Congress that it presents in the Justification of Estimates for Appropriations Committees (Justification) documents. FDA transmits its draft through HHS to the White House Office of Management and Budget (OMB). The final Justification documents, reflecting any HHS and OMB adjustments, are published with the President's annual budget request to Congress. The final Justifications are the major source of FDA budget figures and tables in this report. Like most federal agencies, FDA has, over time, reorganized its structure, activities, and budget accounting, which makes historical budget analysis a difficult endeavor. For further information on the difficulties in compiling a budget history of the agency, and the steps taken to address those problems for this report, see the Methodology section in the Appendix. Until FY1992, direct appropriations formed over 95% of FDA's total program level, with other funds contributing the small remainder. A shift began in FY1992 when Congress authorized: (1) the assessment and collection of user fees from pharmaceutical manufacturers for the review of human drug and biologics applications, and (2) fees for the inspection of mammography facilities. Congress subsequently authorized the collection of user fees for the review of medical device applications in FY2002 and animal drug applications in FY2004. By FY2007, other funds, primarily user fees, accounted for almost a quarter of FDA's total program level budget. Another indicator of agency resources is personnel, available in the Justification documents as the number of full-time equivalent employees (FTEs). This is, however, an imperfect measure of personnel strength because it is not weighted by type of position, pay grade, or responsibility, each of which would provide a different measure of the agency's human resources. FDA has described how adjusting salaries for standard measures of inflation is inadequate because of the unique elements of its staff expenses, such as higher than average employee salaries, cost of health and retirement benefits, and resources required for recruitment and retention.20 FTE numbers do not include contractors and, therefore, provide only a partial measure of workforce (...continued) Washington University School of Public Health and Health Services, Washington DC, February 21, 2007, transcript at http://www.kaisernetwork.org/health_cast/uploaded_files/022107_gwu_workshop_transcript2.pdf. 19 FDA Operating Plan for FY2007 (March 2007), reflecting final funding levels under P.L. 110-5, Revised Continuing Appropriations Resolution, 2007. 20 FDA, PDUFA IV proposal, and "PDUFA Fact Sheet," January 11, 2007, at http://www.fda.gov/oc/pdufa4/ factsheet011107.html. ¢ ¢ strength. If FDA's use of non-employee workers has changed during the 28-year period covered in this report, the numbers of FTEs may be an inaccurate measure of agency personnel strength. Figure 1 shows the total FDA budget (i.e., program level) for FY1980 through FY2007, all adjusted to FY2000 dollars.21 The FDA program level is composed of direct congressional appropriations, what FDA calls budget authority, and other funds.22 Using constant FY2000 dollars allows comparisons of purchasing power over the 28-year period. The stacked bars of the figure show the two broad sources of budget dollars: direct appropriations and other funds (primarily user fees). The figure also provides FTE data over the same fiscal years: FTEs funded by budget authority and total FTEs funded at program level (budget authority plus other funds, primarily user fees). As can be seen in Figure 1, inflation-adjusted budget authority was relatively flat from FY1980 to FY1988, began to increase from FY1989 until FY1993 when it leveled off, coincident with the introduction of user fees in 1993. Figure 1 also shows a decline in budget authority FTEs from FY1993 to FY2001, although the total FTEs remained relatively constant due to positions funded by user fees. Congressional intent in authorizing user fees was that these fees would supplement--rather than replace--resources provided by Congress to FDA. Level funding from Congress--without adequate allowances for inflation, mandatory salary and health insurance increases, as well as other workload-related unfunded mandates--has resulted in declines in FTEs in areas of the agency that do not receive user fees. A 2002 Government Accountability Office (GAO) report on the impact of user fees resulting from the Prescription Drug User Fee Act (PDUFA) states that: According to FDA officials, the agency reduced staffing levels ... to cover the costs of unfunded pay raises. From fiscal years 1994 through 2001, FDA paid about $250 million to cover mandatory federal pay raises for which it did not receive increases in its appropriations. ... [T]his situation reduced the agency's ability to support activities not funded by PDUFA. FDA reduced the staffing levels for non-PDUFA activities each year, leaving the agency fewer resources to perform its other responsibilities. For example, in its budget justification for fiscal year 2002, FDA reported that inspection of medical device manufacturers has decreased and the agency does not routinely inspect the manufacturers of lower-risk products. Although FDA staffing in fiscal year 2001 was about the same as in fiscal year 1992, about 1,000 more FTEs were allotted to drug and biologic review activities in fiscal year 2001 and about 1,000 fewer FTEs were allotted to other FDA programs that ensure food safety, approve new medical devices such as heart valves and pacemakers, and monitor devices once on the market.23 21 "Total Non-Defense" deflators were used from Table 10.1, Gross Domestic Product and Deflators Used in the Historical Tables: 1940-2012, found in Historical Tables, Budget of the United States, Fiscal Year 2008, pp. 192-193. 22 Direct congressional appropriations and funds from user fees (often called offsetting collections) both provide budget authority to FDA. The agency, however, refers to congressional appropriations as budget authority, but not user fee- related sources of funding (which also provide budget authority but are referred to as user fees by FDA). 23 U.S. General Accounting Office, Food and Drug Administration Effect of User Fees on Drug Approval Times, Withdrawals, and Other Agency Activities, GAO-02-958, September 2002, pp. 17-18. ¢ ¢ sETF dna tegduB :ADF .1 erugiF )$ 0002YF tnatsnoC( 7002YF .stnemucod seettimmoC snoitairporppA rof setamitsE fo noitacifitsuJ ADF ,6002YF-0891YF roF :secruoS ton od erofereht dna noitacifitsuJ 8002YF eht ni desu noituloser gniunitnoc miretni na no desab era atad ETF .L.P fo egassap retfa depoleved nalP gnitarepO eht tcelfer atad tegdub 7002YF .ssergnoC yb noitca lanif tcelfer .7002 ,noituloseR snoitairporppA gniunitnoC desiveR ,5-011 resU + $ ytirohtuA tegduB = $ leveL margorP .sETF eeF resU + sETF ytirohtuA tegduB = sETF latoT :setoN .$ seeF Figure 1 also shows that budget authority and FTEs increased markedly between FY2001 and FY2002, coincident with increased emergency funding following the domestic terrorist attacks. However, during the FY2002 through FY2007 period, while budget authority remained flat and other funds increased, FTEs once again declined. In a related matter, the 2002 GAO report expressed concern about attrition among FDA staff which it found to be noticeably greater than in similar disciplines at the National Institutes of Health (NIH) and the Centers for Disease Control and Prevention (CDC).24 The 2002 GAO report states that: [T]he agency continues to experience high turnover for reviewers because of the high demand for regulatory review personnel in the pharmaceutical industry and the higher salaries that experienced FDA reviewers can obtain in the private sector.... FDA officials 24 Ibid., pp. 21-23. ¢ ¢ reported that to retain experienced staff with certain skills, they have increased the pay for approximately 250 [product] reviewers. Specifically, FDA conducted studies of staff turnover and found that toxicologists, pharmacologists, pharmacokinetists, and mathematical statisticians were leaving FDA to work in private industry and academia for higher salaries. Under [federal personnel] regulations, FDA is authorized to pay retention allowance of up to 10 percent of an employee's basic pay to a group or category of employees in such circumstances.25 The GAO report also found that "FDA reviewers, particularly those in CBER [Center for Biologics Evaluation and Research], did not participate in training and professional development activities ... to ensure that the agency meets PDUFA goals."26 The 2006 IOM report commented on the attrition of FDA personnel by stating that "although one explanation for the turnover is that FDA staff leave for promising opportunities in industry ... it is possible that turnover is indicative of a less-than-ideal organizational culture that requires attention."27 A potential indicator of the difficulty FDA has in keeping experienced staff is the agency's issuance of retention bonuses to some employees. This practice is controversial and is under investigation by the House Committee on Energy and Commerce: The payments ... attracted bipartisan criticism from lawmakers ... [who] say that at the FDA many of the bonuses went to the highest-paid officials rather than the scientists, inspectors and doctors most at risk of jumping to the private sector. To critics, the payments bore little relationship to the agency's performance and reputation or to the likelihood that someone might depart. Agency officials disagree and call the program a success.... In 2002, the FDA lost 12 to 13 percent of its employees, while in 2006, with the bonus program in place, it lost 5 percent.... The bonuses--which are funded in part with fees paid by industry for product reviews--bring no guarantee of retention.28 ¢ Figure 2 compares the funding, over time, for FDA, NIH, and CDC, the primary federal agencies with public health duties. In FY1980, CDC and FDA had similar funding and NIH funding was sevenfold greater than the other two agencies, as shown in Figure 2. Since FY1980, Congress has increased the budget ninefold for CDC, almost fourfold for NIH and about twofold for FDA (in FY2000 adjusted dollars). Other regulatory agencies similar to FDA, in that they are science- based and health-related, such as the Environmental Protection Agency (EPA), the Occupational Safety and Health Administration (OSHA), and the Consumer Products Safety Commission (CPSC), have received flat or declining budgets (adjusted for inflation) over this same time period.29 25 Ibid., pp. 21-22. 26 Ibid., p. 23. 27 IOM, The Future of Drug Safety, 2006, p. 81. 28 John Solomon and Marc Kaufman, "FDA's Retention Bonuses Rise to the Top," The Washington Post, August 2, 2007, p. A1. 29 For EPA, see Figure 1 in CRS Report RL32856, Environmental Protection Agency: Appropriations for FY2006, by Robert Esworthy and David M. Bearden; for OSHA and CPSC, see budget data available on the OMB website at http://www.whitehouse.gov/omb/budget/fy2008/db.html. ¢ ¢ HIN dna ,CDC ,ADF rof ytirohtuA tegduB .2 erugiF )$ 0002YF tnatsnoC( detinU eht fo tegduB ,esabataD tegduB cilbuP ,elif ytirohtuA tegduB ,tegduB dna tnemeganaM fo eciffO :ecruoS /bmo/vog.esuohetihw.www//:ptth ta etisbew BMO eht no elbaliava ataD .8002 raeY lacsiF ,tnemnrevoG setatS .lmth.bd/8002yf/tegdub ot %52 ot %02 lanoitidda na dedivorp evah hcihw ,)seef resu( snoitcelloc gnittesffo ADF edulcni ton seoD :etoN .sraey tnecer ni tegdub ADF eht Concerns raised in the late 1970s about the cumulative effects of federal regulations on business resulted in the substantial changes made by the Reagan Administration in the 1980s in "how federal agencies develop and publish rules, and the degree to which federal regulations were overseen by the Executive Office of the President."30 The relatively flat funding experienced by FDA and other regulatory agencies may in part be due to the Reagan regulatory reform efforts combined with attempts to control federal spending and shrink the overall size of government. Former FDA Commissioners, speaking on various public panels, have addressed FDA funding.31 In prepared testimony for a May 1, 2007 hearing before the House Committee on Oversight and 30 CRS Report RL32356, Federal Regulatory Reform: An Overview, by Curtis W. Copeland. 31 Remarks by former FDA Commissioners Jane Henney, Donald Kennedy, and Frank Young at the Policy Workshop on Strengthening the FDA, the SKAPP Project on Scientific Knowledge and Public Policy, George Washington University School of Public Health and Health Services, Washington DC, February 21, 2007, transcript at http://www.kaisernetwork.org/health_cast/uploaded_files/022107_gwu_workshop_transcript2.pdf; and Remarks by former FDA Commissioners David Kessler and Mark McClellan at "Public Policy Implications of the Food and Drug Administration Revitalization Act (FDARA)," Center for Congressional and Presidential Studies, American University (continued...) ¢ ¢ Government Reform, four former FDA Commissioners, Donald Kennedy, Frank Young, David Kessler, and Jane Henney, all agreed that FDA is underfunded. Dr. Kessler made the following observations on the funding Congress has provided for NIH, CDC, and FDA. While Congress has attempted to provide resources for burgeoning public health needs on other fronts, support for the FDA has faltered in comparison. In 1986, FDA's budget was comparable to 97% of the budget for CDC and 8% of the NIH's budget. By [2006], it had dropped to 28% of CDC's budget and 5% of NIH's. Significantly, while the NIH's budget to fund the research that leads to discoveries that ultimately fill the FDA's drug pipeline has doubled over the last five years, FDA's budget has not grown.32 On this same point, former Acting FDA Commissioner Michael Friedman made the following observations: It is myopic to fund a minimal FDA when we have doubled the NIH budget roughly every 10 years for the past 40 years ... or when the pharmaceutical industry annually invests more than $30 billion in research and development. Because regulatory review is the final common pathway for all translational medicine, this lack of resources is rate-limiting. I cannot predict everything that our citizens demand from FDA, but I am sure they are not currently getting it. The issue is not what the FDA "needs;" it is rather what the American public deserves.33 The 2006 IOM drug safety report notes that over the years various groups have examined the same questions about the FDA and its budget and have made a variety of proposals and recommendations to improve the agency that have not been fully implemented. The IOM report goes on to state that: A primary obstacle ... may be the chronic underfunding of core FDA activities owing to inadequate attention to resource needs by Congress and the Office of Management and Budget.34 Some Members of Congress also have expressed concern over the FDA funding level, and have voiced their frustration at the inability to obtain clarification from the agency on the adequacy of the FDA budget. A source of apparent frustration to those Members, including some who serve on the appropriations subcommittees and have indicated their willingness to increase appropriations to the agency, are the FDA officials who, year after year, neither ask for increased funding in their testimony, nor, in response to Members' questions, acknowledge what some observers perceive to be the agency's needs for additional resources. For example, in written testimony regarding the FY2004 proposed budget, FDA Commissioner Mark McClellan stated: We believe our budget request will allow FDA to fund ongoing operations at the current level and also support more than 1,000 recently hired investigators and analytical staff to fight counterrorism [sic].... The President's 2004 Budget was developed within a framework (...continued) School of Public Affairs and FORA.tv, Washington DC, September 12, 2007. 32 David Kessler, "FDA's Critical Mission and Challenges for the Future," testimony before the U.S. House of Representatives, Committee on Oversight and Government Reform, May 1, 2007, p. 2, at http://oversight.house.gov/ documents/20070501193354.pdf. 33 Friedman, "Strengthening the FDA," 2002, p. 2332. 34 IOM, The Future of Drug Safety, p. 18. ¢ ¢ that set a proposed total for discretionary spending in 2004, and each agency and program request reflects the [George W. Bush] Administration's relative priority for that operation, activity or program.35 In contrast to the above testimony which occurred when he was Commissioner, former FDA Commissioner Mark McClellan made the following statement at a March 2007 hearing of the Senate Committee on Health, Education, Labor, and Pensions: First, the FDA will need significantly greater appropriations to improve post-market safety. The FDA is over-stretched, and a lack of trained staff and technical capabilities to perform the oversight necessary on thousands of prescription drugs is an even more pressing issue than providing the FDA with new regulatory authorities.36 Current FDA Commissioner Andrew von Eschenbach provided the following statement when commenting on the adequacy of the FY2008 budget at a Senate Appropriations Committee hearing: These resources are an essential step in building a 21st century FDA that responds to the new opportunities and new challenges of science and technology. Our budget allows FDA to strengthen the tools we use to ensure the safety of foods, evaluate new products, and better predict--earlier and more accurately--the safety and efficacy of drugs, biologics and medical devices. With these resources, we will work to ensure that Americans enjoy the benefits of personalized medicine, a safe and wholesome food supply, and the promise of a better, healthier future.37 The IOM committee that worked on the 2006 drug safety report also was not able to ascertain the agency's funding requirements: Convention dictates that federal agencies do not publicly articulate resource needs that differ from those offered in the President's budget, so the [IOM] committee was unable to understand fully what ... FDA leadership estimate[s] is needed to meet current objectives, let alone the expanded responsibilities the committee envisions for the future.38 In his May 1, 2007 testimony, former Commissioner Donald Kennedy confirmed this point: I hope you and your staff will be diligent about pursuing FDA resource needs. But you may have to rely on grizzled veterans like me, because budget authorities at HHS and OMB specifically prohibit present officials in the agency from speaking out publicly about the need for more funding.... [I]t is important that Americans know, when they hear FDA 35 Written testimony of Mark McClellan, Commissioner of the Food and Drug Administration, in U.S. Congress, House Committee on Appropriations, Subcommittee on Agriculture, Rural Development, FDA, and Related Agencies, FY2004 FDA Budget Request, hearing, 108th Cong., 1st sess., March 6, 2003, at http://www.fda.gov/ola/2003/ fy2004budget.html. 36 Testimony of Mark McClellan, former FDA Commissioner, in U.S. Congress, Senate Committee on Health, Education, Labor and Pensions, Prescription Drug Safety and User Fees, hearing, 110th Cong., 1st sess., March 14, 2007. 37 Statement of Andrew von Eschenbach, Commissioner of the Food and Drug Administration, in U.S. Congress, Senate Committee on Appropriations, Subcommittee on Agriculture, Rural Development, FDA, and Related Agencies, hearing, 110th Cong., 1st sess., February 27, 2007, at http://www.fda.gov/ola/2007/budget0227.html. 38 Ibid., p. 199. ¢ ¢ officials say they are satisfied with their budget allocations, that they have their fingers crossed underneath the witness table.39 Like all federal agencies, FDA's budget history reflects both Administration requests and congressional decisions on appropriations. In general, previous Administrations have not argued before Congress for increased FDA funding over the years. In some situations, however, Congress has decided to grant additional funds to agencies above an Administration's request. For example, the relevant House and Senate appropriations bill reports demonstrate that Congress has often chosen to increase NIH funding when an Administration has not requested additional appropriations. Congress is supported and encouraged in its efforts to increase the NIH budget by various health and research advocacy groups which promote their individual causes. Some agencies are able to bypass budget adjustments made by HHS and OMB via alternative mechanisms. For example, the National Cancer Institute (NCI) at NIH is mandated by the National Cancer Act of 1971 (P.L. 92-218) "to prepare and submit, directly to the President for review and transmittal to Congress, an annual budget estimate (including an estimate of the number and type of personnel needs for the Institute) for the National Cancer Program, after reasonable opportunity for comment (but without change) by the Secretary, the Director of NIH, and the Institute's advisory council."40 The so-called NCI Bypass Budget received by Congress describes the increase required to maintain NCI's present level of operations and the increases required to expand existing initiatives.41 Similarly, CDC has prepared a "Professional Judgment" budget in response to requests from a congressional appropriations committee.42 A regulatory agency, such as the FDA, may be perceived as an impediment to achieving the goals of advocacy groups concerned with the expeditious approval of new drugs or devices for the treatment of specific diseases. However, when drug or device adverse events occur, there is heightened concern about FDA's approval process. In general, attention to FDA's state of affairs seems to be dependent on reaction to crisis. The public and Congress tend to focus on the agency when its regulatory processes fail to meet their expectations. This phenomenon is perhaps best exemplified by the thalidomide episode in 1962.43 However, even significant legislative solutions, such as the Kefauver-Harris Drug Amendments of 1962 (which required demonstration of effectiveness prior to drug approval), were not accompanied by an increase in funding for FDA. In his history of FDA and its regulation of the pharmaceutical industry, Philip J. Hilts, referring to passage of Kefauver-Harris, reported that: Unfortunately, when Congress took this step forward, getting serious about science and testing to protect the public, it did what it had often done before: it voted to give the agency new duties and responsibilities while failing to provide the money to allow the agency to 39 Donald Kennedy, testimony before the U.S. House of Representatives, Committee on Oversight and Government Reform, May 1, 2007, p. 4, at http://oversight.house.gov/documents/20070502110032.pdf. 40 PHS Act, Section 413(b)(9). 41 U.S. Department of Health and Human Services, National Institutes of Health, National Cancer Institute, The Nation's Investment in Cancer Research: A Plan and Budget Proposal for Fiscal Year 2008, October 2006, NIH Publication Number 06-6090, p. 40, at http://plan2008.cancer.gov/pdf/nci_2008_plan.pdf. 42 Centers for Disease Control and Prevention, Professional Judgment for Fiscal Year 2008, April 20, 2007, at http://www.fundcdc.org/documents/CDCFY2008PJ_000.pdf. 43 Philip J. Hilts, Protecting America's Health: the FDA, Business, and One Hundred Years of Regulation, Alfred A. Knopf, New York, 2003. ¢ ¢ carry them out. The error would cause years of dissension and trouble, and would not be remedied for three decades.44 Presumably, the remedy Hilts is referring to is PDUFA and the implementation of user fees by FDA in 1993. Some critics argue that user fees have not solved FDA's funding problems and have led to additional complications for the agency.45 Critics also suggest that the way the agency has been managed and the resource structure imposed by statute contribute to the agency's perceived problems in accomplishing its mission. ¢ FDA is organized into six centers, which cover the broad activity areas for which the agency has responsibility, and two offices that perform agency-wide functions.46 The traditional activity areas are somewhat parallel to the current centers. FDA's major activity areas are: Foods; Human Drugs; Biologics; Animal Drugs and Feeds; and Medical Devices and Radiological Health. This report focuses on the activity areas rather than the centers, to be consistent with the presentation in the historical Justification documents. Center names and their activity area responsibilities have changed over time to reflect shifts in agency organization, but the agency's activity areas have stayed fairly constant over the past 25 years. Although FDA consistently reports its budget recommendations broken out by activity areas, it is not possible, using the publicly available Justifications, to determine whether these categories have always included the same activities. Therefore, as with other federal agencies, it is not always possible to accurately compare categories of budget or staffing over long periods of time. An example of this, as discussed below, is the changing placement of Biologics in the agency's budget. Biologics was encompassed for a time within the Human Drug budget, and FDA's Justifications provide no means of separating the two activities. This report contains the most consistent accounting that was possible from the information provided in the FDA Justifications.47 For further information on the difficulties in compiling a budget history of the agency, and the steps taken to address those problems in this report, see the Methodology section in the Appendix. The Office of the Commissioner and the National Center for Toxicological Research do not have direct regulatory responsibilities and, therefore, are only described briefly in this report. Their funding and personnel are included, however, in the FDA totals. The Office of Regulatory Affairs (ORA) conducts FDA's compliance activities, including inspection and enforcement, across all activity areas. The agency's budget justification documents allocate ORA funding to each activity area as "field activities." 44 Ibid., p. 165. 45 Frank E. Young, testimony before the U.S. House of Representatives, Committee on Oversight and Government Reform, May 1, 2007, p. 4, at http://oversight.house.gov/documents/20070501193917.pdf; and Rena Steinzor and Margaret Clune, "The Hidden Lesson of the Vioxx Fiasco: Reviving a Hollow FDA," Center for Progressive Reform, October 2005, at http://www.progressivereform.org/articles/Vioxx_514.pdf. 46 The Center for Biologics Evaluation and Research (CBER), Center for Devices and Radiological Health (CDRH), Center for Drug Evaluation and Research (CDER), Center for Food Safety and Applied Nutrition (CFSAN), Center for Veterinary Medicine (CVM), National Center for Toxicological Research (NCTR), Office of the Commissioner (OC) and the Office of Regulatory Affairs (ORA). The organization tables of FDA overall and its components are available at http://www.fda.gov/opacom/7org.html. 47 FDA cited constraints on its staff time and indicated that it would only be able to provide data for recent years. ¢ ¢ 6002YF dna 0891YF ,sETF dna tegduB latoT ni esaercnI fo yrammuS .1 elbaT )$ 0002YF tnatsnoC( aerA ytivitcA erusaeM 0891YF 6002YF esaercnI % tegduB 000,769,881$ 000,262,673$ %1.99 dooF sETF 804,2 477,2 %2.51 tegduB 000,292,341$ 000,454,634$ %6.402 sgurD namuH sETF 201,2 749,2 %2.04 tegduB 000,400,44$ 000,265,961$ %3.582 scigoloiB sETF 705 979 %1.39 tegduB 000,886,64$ 000,419,38$ %7.97 sdeeF & sgurD laminA sETF 615 295 %7.41 tegduB 000,724,79$ 000,237,812$ %5.421 htlaeH lacigoloidaR & seciveD sETF 993,1 894,1 %1.7 tegduB 000,172,576$ 000,805,795,1$ %6.631 latoT ADF a sETF 281,8 896,9 %5.81 .stnemucod seettimmoC snoitairporppA rof setamitsE fo noitacifitsuJ ADF :ecruoS elbaT ,xidneppA s'troper siht ni dnuof eb nac srebmun ETF dna stnuoma tegdub detsujdanu deliateD :etoN .3-A elbaT dna ,2-A .elbat eht ni detsil era snoitcnuf ADF lla ton esuaceb slatot ADF ot dda ton od srebmun aera ytivitcA .a After adjusting for inflation, FDA's total budget increased by 136.6% between FY1980 and FY2006 (see Table 1). Over the same period, total FTEs increased by 18.5%. Each activity area within the agency reflects a greater increase in budget than in FTEs during the period. As noted above, tracking FTEs is typically an imperfect measure of changes in an agency's level of effort over time.48 A variety of factors might account for the differing rates of growth of FDA's budget and staffing. A precise accounting of the possible causes of these differences was not available in FDA budget Justifications.49 Further exploration of the reasons for the differing rates of growth in budget and FTEs is, however, beyond the scope of this report. Figure 3 compares the FDA budgets for FY1980 and FY2006, displaying the major activity area budgets relative to each other and to the whole agency. The figure also illustrates the relative proportions of the activity-area budgets that user fees finance. In FY2006, user fees comprised 41% of the Human Drugs budget, 30% of Biologics, 14% of Devices and Radiological Health, 8% of Animal Drugs and Feeds, and 0% of Foods. The proportion of the total FDA budget provided in direct appropriations as budget authority was 96% in FY1980 and 80% in FY2006. 48 See discussion of FTEs beginning on p. 5. 49 The authors requested further information from FDA which, as of the date of this report, has not been provided. ¢ ¢ fo epyT dna aerA ytivitcA rojaM yb ,6002YF dna 0891YF rof stegduB ADF .3 erugiF gnidnuF .stnemucod seettimmoC snoitairporppA rof setamitsE fo noitacifitsuJ ADF :ecruoS ni noillim 368,1$ dna 0891YF ni noillim 043$ saw noitalfni rof tnemtsujda tuohtiw tegdub ADF latoT :setoN .htlaeH lacigoloidaR dna seciveD si "seciveD" dna ,sdeeF dna sgurD laminA si "sgurD laminA" .6002YF ¢ New statutory authorities, assigned to specific FDA activity areas, frequently mandate initiatives without resources for implementation. The implementation of major new initiatives requires adequate time and resources to meet congressional intent. Former FDA Commissioner Frank Young indicated that, while he was Commissioner, there were "mandates for 22 new activities without accompanying appropriations," which he categorized as unfunded mandates.50 He also attested to the difficulty for the agency in the implementation of new statutory language. In the case of implementing the Hatch-Waxman Act for the expeditious evaluation of generic drug products, he stated the following: [T]here were major problems in the development of procedures within FDA, inadequate resources available for crafting the regulations, and difficulties in the implementation of the initial ANDA [Abbreviated New Drug Application] processes. Similarly, there were 50 Frank E. Young, testimony before the U.S. House of Representatives, Committee on Oversight and Government Reform, May 1, 2007, p. 6, at http://oversight.house.gov/documents/20070501193917.pdf. ¢ ¢ substantial budgetary needs for adequate enforcement of procedures, for approval of products developed by industry during the initial implementation of the act. The agency was in uncharted water.51 Likewise, implementation of the FDA Modernization Act of 1997 (FDAMA), required the agency to "develop 42 new regulations, 23 guidances and numerous reports and studies," many within a year.52 At the time, HHS Secretary Shalala commented on the complications and costs of carrying out the effort, which she estimated to be $50 million.53 The $1.58 billion that FDA has collected in prescription drug user fees since FY1993 has helped the agency improve the timeliness of its drug review process. These benefits may mask what some FDA advocates see as PDUFA's distorting effects on within-activity-area budgeting. Congress included in PDUFA an important limitation, often referred to as a trigger, to ensure that the user fees would supplement rather than supplant appropriated funds. To collect and spend the drug user fees, FDA must maintain at least the same level of effort on activities related to human drug review as it had before PDUFA. That limitation would not affect other parts of the FDA budget if other funding were to keep pace with both inflation and the needs of the agency. However, according to FDA documents and the observations of external experts, FDA's financial situation has changed over the 15 years since PDUFA began. FDA has had to use directly appropriated funds to keep the PDUFA-related activities at least constant over time, thereby diverting those funds from other uses. FDA financial reports, required under PDUFA, have claimed that this unanticipated PDUFA effect has resulted in "an erosion of core FDA programs."54 ¢ The research program at FDA provides scientific support for regulatory issues addressed by the agency. Research has been a part of the agency almost from the time of its inception in 1906.55 All five FDA activity areas support research with Foods conducting the largest program in FY2006, followed by Biologics, Devices and Radiological Health, Animal Drugs and Feeds, and Human Drugs, which has a very small research program. Research performed in the five FDA activity areas comprises about 50% of the FY2006 FDA research budget. Other entities within FDA that perform research are the National Center for Toxicological Research (33%), Office of Orphan Products (11%), Program Management (3%), and Buildings and Facilities (3%).56 Figure 51 Ibid. 52 Jill Wechsler, "The `R' in CDER and CBER," Pharmaceutical Technology, April 1998, p. 14. 53 Ibid. 54 See discussion of "triggers" in "Human Drugs" section of this report, as well as the FDA White Paper Prescription Drug User Fee Act (PDUFA): Adding Resources and Improving Performance in FDA Review of New Drug Applications, at http://www.fda.gov/oc/pdufa/whitepaper11-10/whitepaper11-10.html, and the FY2001 PDUFA Financial Report, at http://www.fda.gov/oc/pdufa/finreport2001/financial-fy2001.htm, and the FY2000 PDUFA Financial Report, at http://www.fda.gov/cder/pdufa/financial-fy2000.htm, and the FY1999 PDUFA Financial Report, at http://www.fda.gov/oc/oms/ofm/accounting/pdufa/1999Report.htm. 55 The Bureau of Chemistry established a Food Research Laboratory shortly after it was created within the Department of Agriculture. See the Science Board Subcommittee on FDA Research, "Recommendations to the Science Board of the Food and Drug Administration," Final Draft Report, March 13, 1997, Appendix D, "An Abbreviated History of at Least Four Decades of Efforts to Upgrade the Quality of Science in the FDA," at http://www.cfsan.fda.gov/~frf/ sxsbrd.html. 56 FDA research budget data from RAND Corporation RaDiUS database, November 7, 2007. RaDiUS, which stands (continued...) ¢ ¢ 4 shows the amount of support for research within the five FDA activity areas from FY1993 through FY2008. )$ 0002YF tnatsnoC( saerA ytivitcA eviF ni hcraeseR ADF .4 erugiF $180,000 $160,000 $140,000 Dollars (in thousands) $120,000 $100,000 $80,000 $60,000 $40,000 $20,000 $0 1993 1995 1997 1999 2001 2003 2005 2007 Fiscal Year Foods Human Drugs Biologics Animal Drugs Devices eht gnisu noitaroproC DNAR eht fo mussoF annoD yb dedivorp saw atad tegdub hcraeser ADF :secruoS rof detcelloc atad ADF .3991YF htiw nageb SUiDaR rof noitcelloc ataD .7002 ,7 rebmevoN no esabatad SUiDaR noitatneserP dna noitalumroF tegduB fo eciffO ADF morf DNAR yb deviecer erew 8002YF hguorht 6002YF .7002 hcraM ni ,tegduB dna tnemeganaM rof yraterceS tnatsissA eht fo eciffO SHH ,gniK drawdE aiv )PFBO( ,relliM treboR htiw noitacinummoc lanosrep rep detsujda erew 8002YF hguorht 6002YF rof sdooF rof stnuomA .7002 ,91 rebmevoN no ,PFBO-ADF The appropriate role of research in fulfilling FDA's mandate to license and approve safe and effective products has been a contentious issue at least since the early 1970s.57 At the request of former Deputy Commissioner for Operations Michael Friedman, a review of FDA research was conducted in 1996 by a subcommittee of the FDA Science Board. The Chairman of the subcommittee, Dr. David Korn, stated that "Congress has not been asked to support research explicitly; [research] has always been buried in the agency's budget."58 Dr. Korn suggested that it would require a major educational effort by industry to convince Congress that research is essential to the function of FDA because "industry is, in a sense, the FDA's customer," and "if the (...continued) for "Research and Development in the United States," tracked all research and development activities and resources of the government from FY1993 through FY2008. The contract for RaDiUS operations and maintenance has ended and the database is no longer available. See https://radius.rand.org/. 57 Charles Marwick, "FDA Funding Problems Imperil Safety of Biological Products in the United States," Journal of the American Medical Association, March 25, 1998, pp. 899-901. 58 Ibid., p. 900. ¢ ¢ thrust came from industry, it would carry weight with the Congress."59 The final report of the subcommittee, dated March 1997, stated that: The decreasing agency [research] budget is of overarching concern. Although there is general appreciation of the fact that in times of constrained resources the agency must take particular care that its mandated regulatory responsibilities are competently discharged, there is a widely held perception among agency scientists that the research programs do not have strong advocacy at the highest levels of agency leadership and are front-line targets for curtailment or elimination as discretionary resources decline. The subcommittee believes strongly that starving the agency's base of intramural scientific expertise must inevitably compromise the quality of review and regulatory activities.60 The role of FDA research and the level of resources required for its support continues to be identified as an issue for the agency. During the May 1, 2007, congressional hearing, the former Commissioners specified the lack of financial support for the research program at FDA as a major concern. Former commissioner Frank Young stated that "research at CBER has been eviscerated through a recent reorganization and is almost non-existent in CDER. To maintain the expertise necessary for expeditious but highly competent decisions on new breakthrough products,... it is essential to have a well trained scientific staff that is given the time to not only maintain scientific expertise but to pursue career development in their chosen field of science."61 On this same point, former commissioner David Kessler stated that: The erosion of funding has struck hard at the Agency's ability to support its proud tradition of groundbreaking research in regulatory science. While in the past, the Agency led the way in developing new scientific paradigms for approving biologics and assessing food contaminants--to the benefit of both industry and consumers--resources for FDA to lend its intellectual firepower to addressing key regulatory questions are increasingly scarce.62 A report that assessed "whether science and technology at the FDA can support current and future regulatory needs" was released in November 2007.63 The report was requested by FDA Commissioner Andrew von Eschenbach in December 2006 and was prepared by the FDA Science Board, a group of independent advisors. It found that FDA "suffers from serious scientific deficiencies and is not positioned to meet current or emerging regulatory responsibilities."64 The report points at two reasons for the deficiency: the demands on FDA have soared, and resources have not increased in proportion to the demands. It states that "due to constrained resources and 59 Ibid., p. 901. 60 The Science Board Subcommittee on FDA Research, "Recommendations to the Science Board of the Food and Drug Administration," Final Draft Report, March 13, 1997, at http://www.cfsan.fda.gov/~frf/sxsbr.html. 61 Frank E. Young, testimony before the U.S. House of Representatives, Committee on Oversight and Government Reform, May 1, 2007, p. 3, at http://oversight.house.gov/documents/20070501193917.pdf. 62 David Kessler, "FDA's Critical Mission and Challenges for the Future," testimony before the U.S. House of Representatives, Committee on Oversight and Government Reform, May 1, 2007, p. 3, at http://oversight.house.gov/ documents/20070501193354.pdf. 63 FDA Science Board, Subcommittee on Science and Technology, FDA Science and Mission at Risk, November 2007, at http://www.fda.gov/ohrms/dockets/ac/07/briefing/2007- 4329b_02_01_FDA%20Report%20on%20Science%20and%20Technology.pdf. 64 Ibid., p. 2. ¢ ¢ lack of adequate staff, FDA is engaged in reactive regulatory priority setting or a fire-fighting regulatory posture instead of pursuing a culture of proactive regulatory science."65 The FDA Science Board was specifically asked to review the status of science and technology at FDA, and not to evaluate the available resources. However, the report states that the status of science and technology was "so intertwined with two decades of inadequate funding that it was impossible to assess technology without also assessing resources."66 The Science Board also looked at reports on FDA issued by previous review committees, each given a similar charge over the past 50 years. It found that the concerns outlined in past reports were the same as those in the present and that FDA has consistently been unable to implement the needed changes. An advisor to the Science Board, Garret A. FitzGerald, blamed a faction of "congressional majorities and presidential administrations that has serially stripped the agency of assets."67 Representative Rosa DeLauro, who in the 110th Congress was appointed chair of the House Appropriations Subcommittee on Agriculture, Rural Development, FDA, and Related Agencies, stated that the November 2007 report confirms facts that she believes have been apparent to Congress and FDA for some time. "[S]cience at the FDA is deteriorating and the agency lacks the planning, management structure, and resources to restore their scientific capabilities."68 She further states that although her subcommittee is working on providing additional funds for the agency, "money alone will not resolve the problems at FDA--these additional funds need to be supported by an adequate management structure and a sound plan on how these funds will be used to ensure that they are not wasted."69 The FDA Science Board report concluded that "FDA can no longer fulfill its mission without substantial and sustained additional appropriations," and that the agency is in danger of "losing its remaining dedicated staff" if the "chronic underfunding of the agency" is "not addressed immediately."70 The report stated that there is "insufficient investment in professional development [for FDA staff], which means that the workforce does not keep up with scientific advances.... Inadequately trained scientists are generally risk-averse, and tend to give no decision, a slow decision or, even worse, the wrong decision on regulatory approval or disapproval."71 The report also concluded that funding increases recommended by other groups, such as IOM and the Coalition for a Stronger FDA, are insufficient to allow all the changes necessary for the agency to fulfill its mission. "Without a substantial increase in resources, the agency is powerless to improve its performance, will fall further behind, and will be unable to meet either the mandates of Congress or the expectations of the American public. This will damage not only the health of the population of the U.S., but also the health of the economy."72 65 Ibid., p. 4. 66 Ibid., p. 6. 67 Gardiner Harris, "Advisers Say FDA's Flaws Put Lives at Risk," The New York Times, December 1, 2007. 68 DeLauro Statement on FDA Science Board Report, December 3, 2007, at http://delauro.house.gov/release.cfm?id=697. 69 Ibid. 70 FDA Science Board, Subcommittee on Science and Technology, FDA Science and Mission at Risk, p. 7. 71 Ibid., pp. 4-5. 72 Ibid., p. 8. ¢ ¢ ¢ The next sections of this report provide, for each FDA major activity area, a brief description of the statutory responsibilities in 1980 and an overview of how the agency's responsibilities have expanded over the years up through 2007. Juxtaposed with the presentation of increasing responsibilities for the activity area is a presentation and analysis of the budget and number of FTEs for the period FY1980 through FY2007.73 The descriptions of FDA's responsibilities and resources provide a background against which to examine FDA funding needs. Other CRS reports examine the particulars of many FDA activities and their funding.74 FDA is responsible for promoting and protecting the public's health in part by ensuring that the food supply is safe, sanitary, wholesome, and accurately labeled. The agency regulates all foods, except for meat and poultry which are regulated by the U.S. Department of Agriculture (USDA).76 It is also responsible for assuring that cosmetic products are safe and properly labeled. The agency regulated $417 billion worth of domestic food, $49 billion worth of imported food, and $60 billion worth of cosmetics in 2001.77 These numbers encompass the economic activity of about 50,000 food establishments (manufacturers, processors, and food warehouses) and 3,500 cosmetic firms.78 Not included in these figures are the roughly 600,000 restaurants and institutional food service establishments and 235,000 supermarkets, grocery stores, and other food outlets that are regulated by state and local authorities, for which FDA provides guidance, model codes, and other technical assistance. Although FDA is responsible for ensuring the safety of the food supply, its role is primarily reactive since most foods and their ingredients are not subject to prior approval or even review before they enter interstate commerce. The agency does have responsibility over some product ingredients that require premarket approval, such as food and color additives. FDA also performs postmarket monitoring of food labels and investigates food safety problems that arise. The agency's surveillance program tests food samples to determine if pesticide residues or heavy metals are present in unacceptable amounts. It also sets standards for label information to assist consumers in determining the ingredient and nutrient content of the foods that they are purchasing. The agency's current activities related to foods are primarily conducted by the Center for Food Safety and Applied Nutrition (CFSAN). The Pure Food and Drug Act of 1906 gave the agency its initial authority to prohibit the interstate commerce of adulterated or misbranded food products, along with the authority to assess criminal penalties for violations and seize offending products. The Federal Food, Drug, and Cosmetic Act 73 Budget size varies across the activity areas within FDA. The budget range shown in each figure reflects a scale appropriate to allow clear illustrations of the within-activity area budget variation across years. 74 See listings of CRS products relating to FDA-regulated foods, human drugs, biologics, devices, animal drugs, and cross-cutting issues at http://apps.crs.gov/cli/cli.aspx?PRDS_CLI_ITEM_ID=2678 and http://apps.crs.gov/cli/ cli.aspx?PRDS_CLI_ITEM_ID=2621. 75 This section was prepared by Donna V. Porter, Specialist in Food Safety and Nutrition. 76 CRS Report RS22600, The Federal Food Safety System: A Primer, by Geoffrey S. Becker and Donna V. Porter. 77 FDA Science Board, Subcommittee on Science and Technology, FDA Science and Mission at Risk, 2007, p. 11. 78 See http://www.cfsan.fda.gov/~lrd/cfsan4.html. ¢ ¢ of 1938 (FFDCA), building on the provisions of the 1906 Act, required the agency to promulgate definitions and standards for foods and informative labeling. It also prohibited false advertising and the addition of substances that would render the food adulterated. Over the years, several amendments to the act added authorities that required FDA to establish (1) tolerances (safe levels) for pesticides on agricultural commodities; (2) premarket approval systems for food and color additives, and packaging substances; (3) rules for labels to facilitate price comparisons; and (4) rules to assure that packages contain the amount of product the label claims. By FY2007, Congress had added a number of new FDA authorities to those that existed before FY1980 (see Table 2). Under the Infant Formula Act of 1980 (P.L. 96-359) FDA established requirements for the manufacturing, labeling, and nutrient standards for these products. The Nutrition Labeling and Education Act of 1990 (NLEA, P.L. 101-535) provided authority for (1) mandating nutrition labels on most food products, and (2) following the agency's review, allowing nutrient content and health claims. In addition, NLEA preempted most state and local requirements for labeling, giving FDA responsibility for regulating all aspects of nutrition labeling information. NLEA resulted in the promulgation of a significant number of new regulations and revisions of old rules for consistency with the new authorities. The Dietary Supplement Health and Education Act of 1994 (DSHEA, P.L. 103-417), provided specific authority for the regulation of supplements and placed the burden of proof on the agency to demonstrate that a supplement already on the market was unsafe and needed to be removed. The Food Quality Protection Act of 1996 (P.L. 104-170) established a single health-based standard for pesticides in all foods and provided special safety provisions for infants and children. After FFDCA provisions were amended by the FQPA of 1996, FDA continued to monitor pesticide residue levels in food in interstate commerce (which it does through its total diet study) and enforce tolerances through its food inspection programs, while EPA remains the lead agency on setting tolerances and related issues. The Food and Drug Administration Modernization Act of 1997 (P.L. 105-115) eliminated premarket approval of food-contact substances (i.e., packaging materials), replacing it with a notification process, along with expanding procedures for FDA authorization of health and nutrient content claims under the NLEA statutory standard. The Public Health Security and Bioterrorism Preparedness and Response Act of 2002 (P.L. 107- 188) required all domestic and foreign facilities that manufacture, process, pack, or hold food for U.S. consumption to register with FDA and maintain records for agency inspection. The act also required prior notice to FDA of products being imported into the United States and provided the agency with administrative detention authority and penalties. The Food Allergen Labeling and Consumer Protection Act of 2004 (P.L. 108-282) required that a specific statement appear on a food label when any of the most common allergens are present in a food. In 2006, the Dietary Supplement and Nonprescription Drug Consumer Protection Act (P.L. 109-462) was enacted, which created a system for reporting to FDA any serious adverse events associated with the use of a dietary supplement, as well as record keeping and inspection authority that may be necessary in cases of a reported adverse event. Food safety provisions within the Food and Drug Administration Amendments Act of 2007 (P.L. 110-85) required the creation of a registry for reportable information on foods with safety problems. It also allowed for the identification of the supply chain of the questionable food item. Adjusted for inflation, FDA's foods budget doubled between FY1980 and FY2007; the number of FTEs increased by 15.2% during the same period. Despite substantial increases in statutory .)58-011 .L.P( doof elbatroper eht fo niahc ylppus eht fo noitacifitnedi rof swolla taht smelborp ytefas htiw sdoof no noitamrofni elbatroper rof yrtsiger a fo noitaerc eht deriuqeR .)264-901 .L.P( noitagitsevni na rof dedeen ytirohtua noitcepsni dna stnemeriuqer gnipeek drocer dedivorp ;gurd noitpircserpnon ro tnemelppus yrateid a fo esu eht morf tluser taht stneve esrevda suoires yna fo ADF ot gnitroper eht deriuqeR .)853-801 .L.P( ydob eht ni diorets a ot detrevnoc eb dluow taht rosrucerp a ro diorets cilobana na gniniatnoc tcudorp yna secnatsbus dellortnoc sa deifissalceR .)282-801 .L.P( doof a ni tneserp era snegrella esoht fo yna nehw lebal eht no raeppa ot snegrella tneuqerf tsom tuoba tnemetats cificeps a deriuqeR .)881-701 .L.P( slamina ro snamuh ot htaed ro secneuqesnoc htlaeh esrevda suoires fo taerht a stneserp tcudorp a taht ecnedive elbiderc rof seitlanep dna ytirohtua noitneted evitartsinimda dedivorp ;setatS detinU eht otni detropmi gnieb stcudorp fo eciton roirp deriuqer ;detaretluda eb ot deveileb tcudorp yna rof noitcepsni rof sdrocer niatniam dna retsiger ot noitpmusnoc .S.U rof doof dloh ro kcap ,ssecorp ,erutcafunam taht seitilicaf ngierof dna citsemod lla deriuqeR .)511-501 .L.P( sdradnats yrotutats eht gnicuder tuohtiw smialc tnetnoc tneirtun dna htlaeh gnizirohtua rof serudecorp dednapxe ;tsoc s'ADF revoc ot gnidnuf no tnegnitnoc ssecorp noitacifiton a detutitsbus dna secnatsbus tcatnoc doof fo lavorppa tekramerp detanimilE .)071-401 .L.P( smargorp noitcepsni sti hguorht slevel ecnarelot ecrofne dna ecremmoc etatsretni ni detaluger ti sdoof no slevel eudiser edicitsep rotinom ot ADF deriuqeR .secnarelot fo ytimrofinu lanoitan dna ,wonk ot thgir eht ,gnitset enircodne deriuqer ;edaced a ni noitaulaveer slevel ecnarelot deriuqer ;snoitaloiv ecnarelot rof seitlanep livic dewolla dna stifeneb fo noitaredisnoc detimil ;nerdlihc dna stnafni rof sdradnats ytefas edicitsep laiceps dedivorp ;sdoof dessecorp dna war ni sedicitsep lla rof dradnats desab-htlaeh elgnis a deriuqeR .)714-301 .L.P( secitcarp gnirutcafunam doog dna ,stneidergni yrateid wen fo weiver dna ssecorp noititep ,noitamrofni noitirtun dna tneidergni ,troppus lanoitirtun fo stnemetats rof noitacifiton rof selur deriuqer ;tekram eht no ydaerla stcudorp rof ADF no ytefas rof foorp fo nedrub eht decalp dna stnemelppus yrateid etaluger ot ytirohtua cificeps dedivorP .)535-101 .L.P( noitamrofni gnilebal noitirtun fo stcepsa lla fo noitaluger eht ADF ot gnirrefsnart ,stnemeriuqer lacol dna etats detpmeerp ;smialc htlaeh dna tnetnoc tneirtun fo weiver dna gnilebal noitirtun detadnaM .)005-101 .L.P( snoitcepsni noitatropsnart doof htiw ecnatsissa deriuqeR .)953-69 .L.P( stnemeriuqer noitneter drocer dna gnitset lacigoloiborcim ,llacer lanoitidda rof dednema ;salumrof tnafni rof tnetnoc tneirtun dna gnilebal noitpmexe ,llacer ,lortnoc ytilauq ,gnitroper rof selur deriuqeR 7002 dna 0891 neewteB deddA seitirohtuA .)872-49 .L.P( stnemelppus yrateid fo noitomorp dna noitisopmoc eht etaluger ot ytirohtua detimiL .)795-19 .L.P( sgge gnidarg rof sdradnats mrofinu dehsilbatse dna stcudorp gge fo noitcepsni deriuqeR .)557-98 .L.P( stnetnoc fo ytitnauq ten rof stnemetats lebal tnenimorp ,elbigel eriuqer ot dna segakcap fo llif lanoitcnuf-non tneverp ot selur deriuqeR .)816-68 .L.P( scitemsoc dna ,sgurd ,doof ni desu sroloc rof metsys lavorppa tekramerp dehsilbatsE .)929-58 .L.P( secnatsbus gnigakcap dna evitidda doof wen rof metsys lavorppa tekramerp dehsilbatsE .)717-57 .L.P( detaretluda doof eht deredner taht secnatsbus fo noitidda eht dna gnisitrevda eslaf detibihorp ;gnilebal evitamrofni dna sdoof rof sdradnats dna snoitinifed deriuqeR .)526-76 .L.P( maerc dna klim fo noitatropmi rof stimrep dilav fo gniussi eht deriuqeR .)315-76 .L.P( duarf a dna htlaeh ot suoirujni ,detaretluda ti deredisnoc dna klim dellif denifeD .)483-95 .L.P( stcudorp gnidneffo fo seruzies dezirohtua dna snoitaloiv rof seitlanep lanimirc dedivorp ;stcudorp dednarbsim ro detaretluda ni ecremmoc etatsretni detibihorP 0891 ni seitirohtuA 7002 dna 0891 ni seitirohtuA yrotutatS sdooF . 2 elbaT unlike the other activity areas (discussed below). authority during the period, FDA's Foods activity did not gain the authority to collect user fees, ¢ ¢ ¢ ¢ In Figure 5, changes in the foods budget and FTEs reflect certain events and policy initiatives during the 28-year period. The budget was relatively flat through the 1980s with requests primarily for mandatory costs and no program increases. The increase in budget and FTEs in the early 1990s reflect the considerable amount of work required to implement NLEA and the simultaneous CFSAN reorganization. Food safety activities also contributed to the modest increase in FTEs and funding. The subsequent drop off of FTEs from FY1992 to FY1997 represents both deficit reduction efforts and a shift in FTEs to elsewhere in the agency as noted in the 2002 GAO report. The new CFSAN building opened in College Park, MD, in 2001; construction costs were part of the budget increases from 1997 until 2001. Increases in both funding and FTEs in the late 1990s also signaled President Clinton's food safety initiative. Increases in the FY2002 budget and FY2003 FTEs represent increased agency attention to the food supply following the domestic terrorist attacks and subsequent passage of the Public Health Security and Bioterrorism Preparedness and Response Act of 2002. However, the increases did not continue. The foods budget has remained flat, while the number of FTEs has decreased since FY2002. Another reorganization of the foods portion of the agency occurred after 9/11 as a result of a reordering of the Center's work and priorities. Recent concerns about food safety problems have drawn attention to both the foods budget and FTEs.79 79 For more information, CRS Report RS22779, Food Safety: Provisions in the Food and Drug Administration Amendments Act of 2007, by Donna V. Porter. ¢ ¢ )$ 0002YF tnatsnoC(sETF dna tegduB :sdooF .5 erugiF 7002YF .stnemucod seettimmoC snoitairporppA rof setamitsE fo noitacifitsuJ ADF ,6002YF-0891YF roF :secruoS ton od erofereht dna noitacifitsuJ 8002YF eht ni desu noituloser gniunitnoc miretni na no desab era atad ETF .L.P fo egassap retfa depoleved nalP gnitarepO eht tcelfer atad tegdub 7002YF .ssergnoC yb noitca lanif tcelfer .7002 ,noituloseR snoitairporppA gniunitnoC desiveR ,5-011 .$ ytirohtuA tegduB = $ leveL margorP .sETF ytirohtuA tegduB = sETF latoT :setoN No manufacturer may offer a prescription or over-the-counter drug for sale in the United States without first obtaining FDA's approval. The agency's Center for Drug Evaluation and Research (CDER) works with a manufacturer throughout the application process, from permitting human clinical trials of an Investigational New Drug (IND), to evaluating for evidence of safety and effectiveness the data from those trials that are part of a New Drug Application (NDA). Up to a drug's approval, CDER wields tremendous influence, as the law authorizes, on required studies for the decision to grant marketing approval (hence, known as "premarket approval" or "premarket review"), wording and layout of materials for the prescribing clinician and the patient, and other aspects of the drug's labeling. Once a drug is on the market--a period known as both "postmarket" and "postapproval"--FDA continues its activities to ensure the product's safety and effectiveness, although the law does not 80 This section was prepared by Susan Thaul, Specialist in Drug Safety and Effectiveness. ¢ ¢ provide the agency with postapproval authority equivalent to its preapproval function. FDA staff examine the results of studies conducted and submitted by manufacturers; review adverse event reports from manufacturers, clinicians, and consumers; follow the scientific literature regarding other drugs with similar mechanisms of action; and review labeling, packaging, and promotional items to both consumers and clinicians. CDER staff also analyze data that the manufacturer submits and look for trends in large databases of pharmaceutical use.81 Figure 6 illustrates the resource history of the FDA Human Drugs program from FY1980 through FY2007. Between FY1980 and FY2007, the total inflation-adjusted funding available for FDA human drug activities increased 234% (that is, it more than tripled) and the number of FTEs increased 34%.82 )$ 0002YF tnatsnoC( sETF dna tegduB :sgurD namuH .6 erugiF 7002YF .stnemucod seettimmoC snoitairporppA rof setamitsE fo noitacifitsuJ ADF ,6002YF-0891YF roF :secruoS ton od erofereht dna noitacifitsuJ 8002YF eht ni desu noituloser gniunitnoc miretni na no desab era atad ETF .L.P fo egassap retfa depoleved nalP gnitarepO eht tcelfer atad tegdub 7002YF .ssergnoC yb noitca lanif tcelfer .7002 ,noituloseR snoitairporppA gniunitnoC desiveR ,5-011 snoitacifitsuj tegdub decudorp-ADF eht dna stca snoitairporppa eht ,7891YF hguorht 3891YF morF :setoN ni kaep a swohs 6 erugiF ,eroferehT .slatot seitivitca gurd namuh eht ni seitivitca scigoloib rof gnidnuf dedulcni resU + sETF ytirohtuA tegduB = sETF latoT .scigoloib rof hguort tnatimocnoc a swohs 7 erugiF dna sraey esoht .$ seeF resU + $ ytirohtuA tegduB = $ leveL margorP .sETF eeF 81 For further information, see CRS Report RL32797, Drug Safety and Effectiveness: Issues and Action Options After FDA Approval, by Susan Thaul. 82 Table A-2 in the Appendix displays the actual numbers (not adjusted for inflation). Using the unadjusted numbers, FDA's budget increased almost eightfold (690%) between FY1980 and FY2007. When the dollar figures are adjusted to indicate comparable purchasing value, the increase diminishes to more than threefold (234%). ¢ ¢ Beginning in FY1994, user fees have made up an increasing proportion of FDA's budget for human drug activities. While total funding has increased over the period, this has been entirely due to the increase in user fees. Congressional appropriations have remained essentially flat. Separating FTEs by funding source shows that the overall increase in personnel comes solely from the user fees first collected in FY1993 and that the overall increase in FTEs obscures a 19% decrease in congressionally funded (budget authority) personnel from FY1992 to FY2007. The 1992 Prescription Drug User Fee Act, in providing FDA with an additional source of funding, explicitly stated that the funds were to supplement, not supplant congressional appropriations. The law included complex formulas, known as "triggers," to enforce that goal. FDA may collect and use fees only if the direct appropriations for the activities involved in the review of human drug applications and for FDA activities overall remain funded at a level at least equal to the pre-PDUFA budget, adjusted for inflation as specified in the statute.83 These triggers, in particular, and the relative contributions of appropriations and user fees to FDA's budget for human drugs have implications for budget planning both within the human drugs activity area and in agency-level decisions across all activities. The drug-related tasks for which FDA is responsible have evolved along with the social, economic, scientific, and technologic developments in the United States. Even before there was a Bureau of Chemistry in the Department of Agriculture (established in 1862, the ancestral origin of the current FDA), Congress passed legislation to "prevent the importation of adulterated and spurious drugs and medicines." The 1906 Food and Drugs Act heralded the future influence of the federal government on drug (and food) regulation to protect the public's health. Many laws followed (see brief descriptions in the Appendix, Table A-4). Among the most significant are: the 1938 FFDCA, which required that drugs be safe; and the 1962 Kefauver-Harris Amendments to the FFDCA, which required that drugs also be effective. Subsequent laws addressed many issues for FDA, such as aiming to boost pharmaceutical research and development; to speed the approval of new medicines, including by supplementing FDA resources with user fee revenue; and to encourage research in pediatric drugs.84 Between FY1980 and FY2007, Congress added to FDA's responsibilities new areas (or expanded existing ones) that involved scientific, legal, and enforcement expertise (see Table 3). Most recently, the FDA Amendments Act of 2007 (P.L. 110-85) amended dozens of FFDCA sections. These included human drugs provisions to reauthorize certain programs (such as the assessment, collection, and use of prescription drug user fees); to enhance FDA's authority in ensuring safety and effectiveness over a product's life (both pre- and postapproval). It required the Secretary to maintain an Internet website with extensive drug safety information. New authorities include civil monetary penalties for failure to comply with certain postmarket study, labeling, and television advertisement requirements; mandates and incentives for pediatric drug research and labeling; and requirements for making available to the public material such as minutes of agency-industry performance goal negotiations, pediatric assessment findings and reviews, reviews of adverse event reports, and advisory committee recommendations on action. 83 For further information, see CRS Report RL33914, The Prescription Drug User Fee Act (PDUFA): History, Reauthorization in 2007, and Effect on FDA, by Susan Thaul. 84 For further information, see CRS Report RL33986, FDA's Authority to Ensure That Drugs Prescribed to Children Are Safe and Effective, by Susan Thaul. ,tneidergni evitca wen a tekram ot noitacilppa na fo trap sa ssenevitceffe dna ytefas fo tnemssessa cirtaidep a eriuqeR .)371-801 .L.P ,783-601 .L.P( ].tnemeriuqer reggirt ot eud detnemelpmi toN[ .seirtnuoc cificeps morf sgurd noitpircserp decirp-rewol tropmi ot srelaselohw gurd dna stsicamrahp gniwolla margorp hsilbatsE .)58-011 .L.P ,901-701 .L.P yb dednapxe ;511-501 .L.P( nerdlihc ni esu fo seiduts detseuqer-ADF gnitelpmoc rof egnahcxe ni ytivisulcxe gnitekram fo shtnom xis lanoitidda na rerutcafunam a tnarG .)511-501 .L.P( stcudorp detaluger fo gnitekram eht etidepxe ot gnikees elihw elor noitcetorp htlaeh cilbup a niatniam ot ti etagilbo lliw taht tnemetats noissim a rednu snoitcnuf yrotaluger tcudnoC .)511-501 .L.P( scitemsoc dna sgurd noitpircserpnon fo noitaluger eht ni ytimrofinu lanoitan dna noitazinomrah lanoitanretni ,seipareht lanoitagitsevni ot ssecca tneitap ,ADF eht yb devorppa tey ton secived ro sgurd fo sesu "lebal-ffo" tuoba noitamrofni fo noitanimessid eht gnidrager stnemeriuqer denifer ecrofnE .)511-501 .L.P( seussi cifitneics laisrevortnoc gnivloser rof snaem a edivorp dna ssecorp weiver gurd eht enilmaertS .)511-501 .L.P( snoitidnoc gninetaerht-efil taert dluow taht sgurd rof ssecorp lavorppa kcart tsaf hsilbatsE .)58-011 .L.P ,881-701 .L.P ,511-501 .L.P ,175-201 .L.P( snoitacilppa gurd wen fo weiver sti troppus ot eunever gnitluser eht esu dna srerutcafunam lacituecamrahp eht morf seef tcelloc dna ssessA .)282-201 .L.P yb dednapxe ,392-001 .L.P( selpmas gurd fo noitubirtsid eht no snoitaluger decnahne ecrofne dna etaglumorP .)714-89 .L.P( snoitacilppa gurd cireneg weiveR .)721-89 .L.P( stcudorp remusnoc degakcap htiw gnirepmat etagitsevnI .)414-79 .L.P( snoitidnoc dna sesaesid erar fo tnemtaert eht rof secived lacidem dna ,stcudorp ygolonhcetoib ,sgurd poleved ot srerutcafunam lacituecamrahp rof sevitnecni edivorP 7002 dna 0891 neewteB deddA seitirohtuA .)315-19 .L.P( laitnetop esuba na htiw gurd a sevlovni noitacilppa gurd wen dettimbus a nehw lareneG yenrottA yfitoN .)557-98 .L.P( stnemeriuqer gnilebal decnahne ecrofnE .)47-98 .L.P( seettimmoc yrosivda trepxe tnioppa ot dezirohtua ;sgurd tnalumits dna tnasserped fo ,sllifer noitpircserp ,snoitcepsni ,gnipeekdrocer ,erutcafunam gnirevoc snoitaluger decnahne ecrofnE .)187-78 .L.P( scitoibitna lla etalugeR .)187-78 .L.P( gnisitrevda gurd noitpircserp etalugeR .)512-28 .L.P( ylno-noitpircserp sa sgurd niatrec etalugeR .stset dna sdradnats ,sgniht rehto gnoma ,gnirevoc snoitaluger etaglumorp ;ytirup dna ,ytilauq ,htgnerts rof )931-97 .L.P( nillicinep dna )663-77 .L.P( nilusni fo hctab hcae yfitrec dna tseT .)717-57 .L.P( stnemeriuqer gnigakcap dna gnilebal decnahne ecrofnE .)816-68 .L.P( esu efas erussa ot gnilebal dna ,sesu ,snoitidnoc no desab )stcudorp detaluger-ADF rehto ro( sgurd no ro ni sevitidda roloc fo gnitsil eht rof snoitaluger etaglumorp ;)717-57 .L.P( sevitidda roloc fo sehctab yfitreC .)712-38 .L.P yb dednapxe ,717-57 .L.P( gnilebal dna ,sreniatnoc ,slairetam ,tnempiuqe gnidulcni ,seitilicaf gnidloh ro ,gnikcap ,gnissecorp ,gnirutcafunam tcepsni ;stnempihs fo sdrocer eriuqeR .ecremmoc etatsretni rof gurd a gnivorppa erofeb )187-78 .L.P( ssenevitceffe dna )717-57 .L.P( ytefas fo ecnedive weiveR .)103-26 .L.P( tceffe cituepareht ro evitaruc fo stnemetats eslaf gnidulcni ,)483-95 .L.P( gnidnarbsim dna noitaretluda tibihorp ;stcudorp gurd dna ,knird ,doof ni ecremmoc etatsretni etalugeR .)tamrof gnirebmun wal cilbup tnerruc eht fo esu setaderp ;ssergnoC ht03( sesoprup lacidem rof ssentif dna ,ytirup ,ytilauq rof daorba morf sgurd tcepsnI 0891 ni seitirohtuA 7002 dna 0891 ni seitirohtuA yrotutatS sgurD namuH . 3 elbaT ¢ ¢ ¢ ¢ fi ,ro ,cigoloib ro gurd a rof noitartsinimda fo etuor wen ro ,nemiger gnisod wen ,mrof egasod wen ,noitacidni wen -011 .L.P yb dednapxe ,551-801 .L.P( cigoloib desnecil ro gurd devorppa na rof ,yrassecen ti sredisnoc yraterceS eht .)58 -801 .L.P( deriapmi yllausiv dna dnilb eht ot noitamrofni gurd noitpircserp edivorp ot seigolonhcet fo esu eht ydutS .)371 kcatta tsirorret a ni desu eb yam taht stnega raelcun dna ,lacigoloib ,lacimehc ot serusaemretnuoc fo weiver etidepxE .)672-801 .L.P( Biologics are medical preparations made from living organisms. Examples of such products include traditional biologics (such as vaccines, blood, blood products, antitoxins, and allergenics86) and human therapeutic agents produced by the biotechnology industry (such as insulin, interferon, growth hormone, and epoetin). FDA ensures the purity and effectiveness of biologics by (1) issuing a license for each new product that is shown to be safe, pure, and potent and (2) inspecting manufacturing facilities to assure the product continues to be safe, pure, and potent. Unlike most chemically synthesized drugs (e.g., aspirin) with a known structure, biologics are often complex mixtures that are not easily identified or characterized. Biologics might also be living entities, such as cells and tissues. Biologics may be isolated from a variety of natural sources (human, animal, or microorganism) or may be produced by biotechnology methods and other cutting-edge technologies. FDA is also responsible for the safety of the nation's blood supply and routinely examines blood bank operations for record keeping and testing of donations for contaminants. Regulatory responsibility for biologics was first delegated in the early 1900s to the Hygienic Laboratory, a precursor of the National Institutes of Health (NIH).87 In 1972, regulatory authority for biologics was transferred from the NIH Division of Biological Standards to the FDA Bureau of Biologics.88 During the early 1980s, the FDA merged the Bureau of Drugs and the Bureau of Biologics to form the National Center for Drugs and Biologics. In 1984, all of the "National Centers" within FDA were redesignated simply as "Centers." In 1987, the FDA's Center for Drugs and Biologics was split into the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER). CBER continues to use NIH facilities and buildings until the expected move in 2012 to the new FDA headquarters in White Oak, MD. Because biotechnology products frequently cross the conventional boundaries between biologics, drugs, and devices, determining the jurisdictional status of these new products has been difficult for both the FDA and industry. Some products have had characteristics that met multiple statutory and scientific definitions. In 1991, the FDA published an Intercenter Agreement between CBER and CDER. In general, the agreement stated that traditional biologics as well as most biotechnology products, would be regulated by CBER.89 In 2002, however, the FDA announced 85 This section was prepared by Judith A. Johnson, Specialist in Biomedical Policy. 86 Allergenics are extracts used to diagnose and treat allergic reactions such as hay fever. 87 The NIH Almanac--Historical Data: Chronology of Events, at http://www.nih.gov/about/almanac/historical/ chronology_of_events.htm. 88 Donna Hamilton, "A Brief History of the Center for Drug Evaluation and Research," FDA History Office, November 1997, at http://www.fda.gov/cder/about/history/Histext.htm. 89 Except for a small set of biologics (hormones, such as insulin, human growth hormone, and a few medical enzymes) that would continue to be regulated by CDER. These biologics have historically been regulated as drugs under the (continued...) ¢ ¢ its intention to reorganize review responsibilities, consolidating review of new pharmaceutical products under CDER; CBER retains review responsibility for vaccines, blood safety, gene therapy, and tissue transplantation.90 On June 30, 2003, responsibility for most therapeutic biologics was transferred from CBER to CDER.91 Remaining at CBER are traditional biologics such as vaccines, allergenic products, antitoxins, antivenins, venoms, and blood and blood products, including recombinant versions of plasma derivatives (clotting factors produced via biotechnology). Figure 7 shows the total FDA budget for Biologics, composed of budget authority and user fees, for FY1980 through FY2007, adjusted to FY2000 dollars. It also provides FTE data over the same years: FTEs funded by budget authority; and total FTEs funded at program level (budget authority plus user fees). The impact on funding and FTEs of the FDA reorganization in the 1980s can be clearly seen in Figure 7. Although budget authority and FTEs for biologics were rising in the late 1980s and early 1990s, the graph shows that both decline and then remain flat coincident with the introduction of user fees in 1993. Budget authority and FTEs increased between FY2001 and FY2003, coincident with increased emergency funding following the domestic terrorist attacks. The drop in biologics funding and FTEs from FY2003 to FY2004 is due to the reorganization of review responsibilities for therapeutic biologics. Following the reorganization, budget authority and FTEs for biologics have remained relatively flat. (...continued) Federal Food, Drug, and Cosmetic Act rather than licensed under the Public Health Service Act. 90 FDA Press Release, "FDA to Consolidate Review Responsibilities for New Pharmaceutical Products," September 6, 2002, at http://www.fda.gov/bbs/topics/NEWS/2002/NEW00834.html. 91 Federal Register, vol. 68, no. 123, June 26, 2003, pp. 38067-38068. Examples of products transferred to CDER include monoclonal antibodies; proteins intended for therapeutic use (interferons, thrombolytic enzymes); immunomodulators (other than vaccines and allergenic products); and growth factors, cytokines, and monoclonal antibodies intended to alter production of blood cells. See Transfer of Therapeutic Products to the Center for Drug Evaluation and Research http://www.fda.gov/cber/transfer/transfer.htm; Approved Products Transferring to CDER http://www.fda.gov/cber/transfer/transfprods.htm; and Therapeutic Biological Products http://www.fda.gov/cder/ biologics/default.htm. ¢ ¢ )$ 0002YF tnatsnoC( sETF dna tegduB :scigoloiB .7 erugiF 7002YF .stnemucod seettimmoC snoitairporppA rof setamitsE fo noitacifitsuJ ADF ,6002YF-0891YF roF :secruoS ton od erofereht dna noitacifitsuJ 8002YF eht ni desu noituloser gniunitnoc miretni na no desab era atad ETF .L.P fo egassap retfa depoleved nalP gnitarepO eht tcelfer atad tegdub 7002YF .ssergnoC yb noitca lanif tcelfer .7002 ,noituloseR snoitairporppA gniunitnoC desiveR ,5-011 eno ni seitivitca sgurD namuH dna seitivitca scigoloiB deganam ADF ,7891YF hguorht 3891YF roF :setoN ni dedulcni era hcihw ,srebmun ETF dna rallod denibmoc ylno edivorp sraey esoht rof snoitacifitsuJ ehT .retneC .sETF eeF resU + sETF ytirohtuA tegduB = sETF latoT .)scigoloiB( 7 erugiF ni ton dna )sgurD namuH(6 erugiF .$ seeF resU + $ ytirohtuA tegduB = $ leveL margorP FDA's responsibilities related to the approval and regulation of biological products have changed somewhat between 1980 and 2007 (see Table 4). In 1980, FDA's authority with respect to the approval of biological products was governed primarily by Section 351 of the Public Health Service Act (P.L. 78-410). In addition, because most biological products also meet the definition of "drugs," they are subject to regulation under the FFDCA (P.L. 59-384). FDA also regulates medical devices involving biologics under various medical device laws. Examples include devices used in blood banks to produce various blood products, such as automated cell separators, empty plastic containers and transfer sets, and blood storage refrigerators and freezers. By 2007, the passage of additional laws had created more responsibilities and authorities for FDA in the area of biologics. The Pediatric Research Equity Act of 2003 (P.L. 108-155) requires a pediatric assessment of safety and effectiveness as part of an application to license a new biologic, or, if the Secretary considers it necessary, for an already licensed biologic. The Project ¢ ¢ Bioshield Act of 2004 (P.L. 108-276) requires FDA to provide an expedited review of vaccines and other countermeasures to bioterrorism agents. Congress is also currently considering proposed legislation that would expand the agency's regulatory activities by opening a pathway for the approval of so-called follow-on biologics, which are similar, but not identical, to the brand-name products made by the pharmaceutical or biotechnology industry.92 The new regulatory pathway would be analogous to the FDA's authority for approving generic chemical drugs under the Drug Price Competition and Patent Term Restoration Act of 1984 (P.L. 84-417), often referred to as the Hatch-Waxman Act. FDA personnel have been actively involved for some time in working with Congress on this potential new responsibility. 4 elbaT 7002 dna 0891 ni seitirohtuA yrotutatS scigoloiB . 0891 ni seitirohtuA ot seitilicaf gnirutcafunam stcepsni dna tnetop dna ,erup ,efas eb ot nwohs era taht stcudorp lacigoloib wen sesneciL .)014-87 .L.P( tnetop dna ,erup ,efas eb ot seunitnoc tcudorp eht erussa .)717-57 .L.P( scigoloib rehto ro stcudorp doolb gnivlovni secived lacidem setalugeR .)187-78 .L.P( stcudorp lacigoloib setalugeR .)187-78 .L.P( stcudorp lacigoloib fo gnisitrevda setalugeR 7002 dna 0891 neewteB deddA seitirohtuA wen fo weiver eht troppus ot eunever gnitluser eht sesu dna srerutcafunam scigoloib morf seef stcelloc dna sessessA .)881-701 .L.P ,511-501 .L.P ,175-201 .L.P( stcudorp cigoloib .)34-901 .L.P ,412-801 .L.P ,052-701 .L.P( weiver ecived tekramerp rof seef resu tcelloC eht fi ,ro ,cigoloib wen a esnecil ot noitacilppa na fo trap sa ssenevitceffe dna ytefas fo tnemssessa cirtaidep a seriuqeR .)551-801 .L.P( cigoloib desnecil a rof ,yrassecen ti sredisnoc yraterceS .)672-801 .L.P( kcatta tsirorret a ni desu eb yam taht stnega ot serusaemretnuoc fo weiver setidepxE The FDA Center for Veterinary Medicine (CVM) regulates animal feeds (such as livestock feeds and pet foods), and veterinary drugs and devices.94 CVM is responsible for premarket approval of veterinary drugs, based on a sponsor's demonstration of safety and effectiveness. CVM regulates veterinary devices, but does not require their premarket approval.95 Veterinary biologics are regulated by the USDA.96 Much of CVM's authority is based in FDA's general authorities in the FFDCA, such as the authority to take enforcement actions if a regulated product is adulterated, to 92 For further information, see CRS Report RL34045, FDA Regulation of Follow-On Biologics, by Judith A. Johnson. 93 This section was prepared by Sarah A. Lister, Specialist in Public Health and Epidemiology. 94 See http://www.fda.gov/cvm/. 95 FDA can take appropriate regulatory action if a veterinary device is misbranded, mislabeled or adulterated. Also, firms that manufacture radiation-emitting veterinary devices must register their products under the radiological health regulations, administered by the FDA Center for Devices and Radiological Health (CDRH). See FDA CVM, "How FDA Regulates Veterinary Devices," May 2003, at http://www.fda.gov/cvm/regofdevices.htm. 96 Veterinary biologics, such as vaccines and clinical laboratory tests, are regulated by the USDA, Animal and Plant Health Inspection Service, Center for Veterinary Biologics. See http://www.aphis.usda.gov/animal_health/ vet_biologics/. ¢ ¢ require facility registration, and to conduct inspections. For example, animal feed is included in the definition of "food" in Section 201 of the FFDCA, and must meet the same general standards of safety as human food, pursuant to Sections 401 et seq. of the act. Additional specific requirements may also be applied to CVM-regulated products. Though USDA and FDA-CFSAN have primary responsibility for the safety of products intended for human food,97 CVM is responsible for some specific aspects of the safety of human foods derived from animals, such as determining tolerances (safe levels) of certain chemicals in meat and poultry, and evaluating the food safety aspects of animal clones and their offspring. Also, before CVM approves an animal drug, its use in animals must be shown to be safe for humans as well. Drug sponsors must demonstrate that a method is available to detect and measure any drug residues left in edible tissues of food-producing animals. Farmers and veterinarians who use drugs on food-producing animals must adhere to guidelines about how much time must elapse before a treated animal can be slaughtered, or before its milk can be marketed, and any other constraints or warnings that are stated on the drug label. Figure 8 shows the total FDA budget for animal drugs and feeds, composed of budget authority and user fees, for FY1980 through FY2007, adjusted to FY2000 dollars.98 Figure 8 also provides FTE data over the same period: FTEs funded by budget authority; and total FTEs funded at program level (budget authority plus user fees). During that time, the budget in adjusted dollars increased from $46.7 million in FY1980 to $87.6 million in FY2007. FTEs totaled 516 in FY1980, and 619 in FY2007, though there were fewer than 500 FTEs for most of the intervening years. Drug user fees provided a small portion of CVM's overall budget between FY2004 and FY2007, and made up about 11% of the FY2007 total. (FDA did not have authority to collect user fees for new animal drug reviews until FY2004.) The budget for animal drugs and feeds, in adjusted dollars, almost doubled in the three-year period from FY1999 to FY2002, from $44.3 million to $82.4 million. FTEs increased from 393 to 570 in the same period. (The budget was relatively stable in the years before and after this period of growth, when adjusted for inflation.) The funding increases largely paralleled increasing budget requests for those years. Increases were requested to support new statutory requirements as well as several initiatives, some of which were agency-wide. These initiatives included activities in food safety, antimicrobial resistance, and postmarket surveillance of drug safety, as well as efforts to reduce drug review times. They also included a bioterrorism preparedness initiative, and the expansion of feed safety programs to protect against Bovine Spongiform Encephalopathy (BSE, or "Mad Cow disease"). In each case, funding was expanded prior to a related high-profile incident, namely the 2001 anthrax attacks, and the 2003 emergence of BSE in North America. Prior to 1980, CVM was responsible for evaluating veterinary drugs for approval based on demonstrations of safety and efficacy, and for assuring the safety of animal feeds and feed additives. Several laws enacted since 1980 were aimed at improving the availability of veterinary drugs (which are typically not as lucrative for sponsors as are human drugs), clarifying the use of human drugs in animals, or streamlining the drug approval process. FDA's authority for animal 97 See CRS Report RS22600, The Federal Food Safety System: A Primer, by Geoffrey S. Becker and Donna V. Porter. 98 Though CVM was called the Bureau of Veterinary Medicine prior to 1984, the Center and the Animal Drugs and Feeds budget line have, for practical purposes, encompassed the same activities for several decades, and references to each are used interchangeably. ¢ ¢ products generally begins with the same statutes as those that regulate human drugs and foods (see Table 2 and Table 3), with additional specific requirements applied in some cases.99 This is consistent with FDA's long-standing obligation to assure that veterinary drugs and animal feeds are manufactured and used in ways that are safe for both animals and humans. )$ 0002YF tnatsnoC(sETF dna tegduB :sdeeF dna sgurD laminA .8 erugiF 7002YF .stnemucod seettimmoC snoitairporppA rof setamitsE fo noitacifitsuJ ADF ,6002YF-0891YF roF :secruoS ton od erofereht dna noitacifitsuJ 8002YF eht ni desu noituloser gniunitnoc miretni na no desab era atad ETF .L.P fo egassap retfa depoleved nalP gnitarepO eht tcelfer atad tegdub 7002YF .ssergnoC yb noitca lanif tcelfer .7002 ,noituloseR snoitairporppA gniunitnoC desiveR ,5-011 resU + $ ytirohtuA tegduB = $ leveL margorP .sETF eeF resU + sETF ytirohtuA tegduB = sETF latoT :setoN .$ seeF Major laws affecting CVM's regulation of animal drugs and feeds are summarized in Table 5.100 In 1988, the Generic Animal Drug and Patent Term Restoration Act (P.L. 100-670) authorized abbreviated applications for generic new animal drugs. In 1994, the Animal Medicinal Drug Use 99 An exception to this general rule is the Dietary Supplement and Health Education Act (DSHEA) of 1994, which requires that FDA not designate substances added to "food for humans" as food additives or drugs if the product meets the definition of a dietary supplement. FDA has interpreted that DSHEA does not apply to products added to animal feeds. Consequently, CVM regulates any animal feed supplement as either a food, food additive, or animal drug, depending on the intended use, and does not apply the additional dietary supplement category. 100 The Center's statutory authorities are discussed in greater detail on a public website, "Chronological History of CVM," at http://www.fda.gov/cvm/chronological.htm. ¢ ¢ Clarification Act (P.L. 103-396) permitted veterinarians to prescribe, for animals, extra-label uses of certain approved animal and human drugs, under certain conditions. In 1996, the Animal Drug Availability Act (P.L. 104-250) granted FDA more flexibility in evaluating and approving new animal drugs by amending the definition of substantial evidence of effectiveness. Among other provisions, the law also permitted the use of veterinary drugs in animal feeds, with veterinary prescription. In 2002, the Public Health Security and Bioterrorism Preparedness and Response Act (P.L. 107- 188) required the registration of all domestic and foreign facilities that manufactured, processed, packed or held animal feeds.101 In 2003, the Animal Drug User Fee Act (P.L. 108-130) authorized FDA to collect fees for the review of certain animal drug applications.102 In 2004, the Minor Use and Minor Species Animal Health Act (P.L. 108-282) authorized, along with other approaches and incentives for limited-market drugs, the conditional approval for drugs to treat minor animal species and uncommon diseases in major animal species,103 which allows the sponsor to make a drug available before collecting all necessary effectiveness data, but after proving that the drug is safe. In 2007, the FDAAA (P.L. 110-85) required, for pet foods, the development of ingredient, processing and labeling standards, and a surveillance system to detect disease outbreaks. Additional provisions that apply to both human foods and animal feeds require, among other things, that FDA establish a reportable food registry, and that persons in charge of FDA-registered food facilities report any instances of tainted foods that may harm humans or animals. 5 elbaT 7002 dna 0891 ni seitirohtuA yrotutatS sdeeF dna sgurD laminA . 0891 ni seitirohtuA seruzies sezirohtua dna snoitaloiv rof seitlanep lanimirc sedivorp ;sdeef dednarbsim dna detaretluda ni ecremmoc etatsretni stibihorP .)483-95 .L.P( stcudorp gnidneffo fo .gurd lamina na gnivorppa erofeb )187-78 .L.P( ssenevitceffe dna )717-57 .L.P( ytefas fo ecnedive weiveR .)993-09 .L.P( slamina gnicudorp-doof ni esu rof ytefas gnidulcni ,esu dednetni rof sgurd lamina fo ssenevitceffe dna ytefas weiveR 7002 dna 0891 neewteB deddA seitirohtuA .)076-001 .L.P( sgurd lamina cireneg rof snoitacilppa detaiverbba rof ytirohtuA niatrec rednu ,sgurd namuh dna lamina devorppa niatrec fo sesu lebal-artxe ,slamina rof ,ebircserp ot snairaniretev rof ytirohtuA .)693-301 .L.P( snoitidnoc detnarG .ssenevitceffe fo ecnedive laitnatsbus fo noitinifed dednema na gnidulcni ,sgurd lamina wen gnivorppa ni ytilibixelf deddA .)052-401 .L.P( noitpircserp yraniretev htiw ,sdeef lamina ni sgurd yraniretev fo esu eht rof ytirohtua niatniam dna retsiger ot noitpmusnoc citsemod rof deef lamina dloh ro ,kcap ,ssecorp ,erutcafunam taht seitilicaf rof stnemeriuqeR .)881-701 .L.P( sdrocer .)031-801 .L.P( snoitacilppa gurd lamina niatrec rof seef resu tcelloc ot ytirohtuA yrassecen lla tuohtiw ytefas fo noitartsnomed no desab ,seiceps ronim ro sesu ronim rof sgurd yraniretev fo lavorppa lanoitidnoC .)282-801 .L.P( atad ssenevitceffe tceted ot metsys ecnallievrus a dna ,sdradnats gnilebal dna gnissecorp ,tneidergni fo tnempoleved eht ,sdoof tep rof ,deriuqeR yrotadnam dna ,yrtsiger doof elbatroper a fo tnemhsilbatse eht ,sdeef lamina dna sdoof namuh htob rof ,deriuqeR .skaerbtuo esaesid .)58-011 .L.P( sdoof detniat fo secnatsni fo gnitroper 101 The law applied similarly to human food facilities. 102 The law is similar to the Prescription Drug User Fee Act (PDUFA) and the Medical Device User Fee and Modernization Act (MDUFMA) for human products. 103 For more information on minor uses and minor species, see http://www.fda.gov/cvm/minortoc.htm. ¢ ¢ FDA is responsible for ensuring the safety and effectiveness of medical devices and eliminating unnecessary human exposure to man-made radiation from medical, occupational, and consumer products.105 There are thousands of types of medical devices, from heart pacemakers to contact lenses. Radiation-emitting products regulated by the agency include microwave ovens, video display terminals, and medical ultrasound and x-ray machines. FDA reviews requests to research or market medical devices; collects, analyzes, and acts on information about injuries and other experiences in the use of medical devices and radiation-emitting electronic products; sets and enforces good manufacturing practice regulations and performance standards for radiation- emitting electronic products and medical devices; monitors compliance and surveillance programs for medical devices and radiation-emitting electronic products; and provides technical and other nonfinancial assistance to small manufacturers of medical devices. The agency's current activities related to devices and radiological health (DRH) are primarily conducted by its Center for Devices and Radiological Health. As previously noted, CBER regulates some devices-- specifically those associated with blood collection and processing procedures, as well as with cellular therapies (e.g., stem cell treatments). In FY1980, after adjusting for inflation, FDA's DRH budget was $97,427,000, which supported 1,399 FTEs (see Figure 9). At that time, the agency's responsibilities with respect to devices were governed primarily by the Medical Device Amendments of 1976 (MDMA, P.L. 94-295). MDMA was the first major legislation passed to ensure the safety and effectiveness of medical devices, including diagnostic products, before they could be marketed. The amendments required manufacturers to register with FDA and follow quality control procedures in their manufacturing processes. They also required FDA to conduct premarket review of some products, and to generate performance standards that devices had to meet before they could be marketed. Between FY1980 and FY2007, several major pieces of device legislation were passed (see Table 6). Some of these added new types of responsibilities. In 1990, Congress gave FDA the authority to enforce postmarket requirements for devices, to act on postmarket adverse event reports, and to recall unsafe devices (P.L. 101-629). In 1992, Congress gave FDA the authority to require that manufacturers of defective products implement certain consumer accommodations and pursue penalties for postmarket surveillance noncompliance (P.L. 102-300). In 1997, Congress passed the Food and Drug Administration Modernization Act (FDAMA), major FDA reform legislation that tasked the agency with accelerating its premarket review and regulating unapproved uses of approved devices (P.L. 105-115). Other legislation contained provisions that could reduce or minimize, rather than simply increase, the regulatory burden on FDA. For example, while the Mammography Quality Standards Act (MQSA) added the responsibility of requiring the agency to certify mammography facilities, it also provided the authority to collect associated certification fees, creating a new revenue stream (P.L. 102-539). MQSA also allowed certain accredited third-parties to conduct inspections in order to relieve FDA of some of that responsibility. 104 This section was prepared by Erin D. Williams, Specialist in Public Health and Bioethics. 105 For further information, see CRS Report RL32826, The Medical Device Approval Process and Related Legislative Issues, by Erin D. Williams. ¢ ¢ In 2002, Congress passed the largest revenue-generating, non-appropriations legislation for FDA's DRH-related activities in the 28-year period under examination: the Medical Device User Fee and Modernization Act (MDUFMA, P.L. 107-250).106 The law gave FDA the authority to collect user fees for premarket device review, creating another significant source of revenue. It also accredited third-parties to conduct inspections, a measure designed to reduce FDA's regulatory burden. To preclude user fees from supplanting direct appropriations, MDUFMA contained a "trigger," requiring a certain amount of DRH-related direct appropriations for the collection of user fees to continue. In 2005, direct appropriations did not meet the trigger amount. Congress subsequently reduced the trigger amount so FDA could continue to collect the user fees (P.L. 109-43). Between FY1980 and FY2007, congressional appropriations for DRH-related activities generally followed the agency's budget requests. As Figure 9 indicates, the number of FTEs and budget remained relatively flat through the 1980s. Both then increased in the early 1990s. Beginning in the late 1990s, the budget and FTEs began to track somewhat differently than they had in the past.107 The flat budget in the late 1990s did not occur with a fairly constant number of FTEs as it had in the 1980s, but rather with a decrease in FTEs. Likewise, the budget increases that have occurred thus far in the 2000s have increased the number of FTEs, but not by as much as with similar budget increases in the early 1990s. Readers should note that the drop in FTEs between FY2006 and FY2007 apparent in Figure 9 is misleading, as the FTE numbers are based upon a continuing resolution (which had no allowance for user fees), while the budget numbers are based upon a cost estimate (which did include user fees). 106 For further information about medical device user fees, see CRS Report RL34571, Medical Device User Fees and User Fee Acts, by Erin D. Williams. 107 For a general discussion of the relationship between FTE data and budget data, see "Overall FDA Budget" and "FDA Activity-Area Budgets" sections of this report. ¢ ¢ )$ 0002YF tnatsnoC( sETF dna tegduB :htlaeH lacigoloidaR dna seciveD .9 erugiF 7002YF .stnemucod seettimmoC snoitairporppA rof setamitsE fo noitacifitsuJ ADF ,6002YF-0891YF roF :secruoS ton od erofereht dna noitacifitsuJ 8002YF eht ni desu noituloser gniunitnoc miretni na no desab era atad ETF .L.P fo egassap retfa depoleved nalP gnitarepO eht tcelfer atad tegdub 7002YF .ssergnoC yb noitca lanif tcelfer .7002 ,noituloseR snoitairporppA gniunitnoC desiveR ,5-011 resU + $ ytirohtuA tegduB = $ leveL margorP .sETF eeF resU + sETF ytirohtuA tegduB = sETF latoT :setoN .$ seeF The net result of the changes described above was that, over the 28-year period studied, FDA's budget and its number of FTEs dedicated to DRH-related activities increased, although by different amounts. Adjusted for inflation, the total DRH-related budget has increased by 124.5%. The number of FTEs increased by 7.1%. Over the same 28-year period, adjusting for inflation, the budget authority for DRH-related activities increased by 94.2%, while the number of FTEs supported by the budget authority decreased by 5.1%. User fees, which comprised none of the device-related budget in FY1980, comprised 13.5% of it in FY2006. User fee-funded FTEs, which comprised none of the FY1980 budget, comprised 11.3% of the FY2006 budget. See http://www.fda.gov/nctr/. 108 activities. Agreements, CRADAs, informal collaborations, and visiting scientists to advance its research technical advice and training to support FDA regulatory activities. NCTR uses Interagency responsibilities.108 NCTR conducts peer-reviewed scientific research and provides expert Order in 1971, does not have an explicit authority in law, and does not have direct regulatory Toxicological Research (NCTR), in Jefferson, AR. NCTR, which was established by Executive FDA's activities related to toxicological research are conducted by the National Center for ¡ provided a brief description of each one below. activities). While an in-depth analysis of these areas is not included in this report, we have Commissioner) or whose funding is included within each activity area budget (e.g., FDA's field within these categories (e.g., toxicological research, and headquarters and office of the FDA responsibilities. However, certain components of FDA's budget and responsibilities do not fall The above analysis focuses on areas in which FDA has product-specific regulatory .)052-701 .L.P( secived esu-elgnis dessecorper rof stnemeriuqer yrotaluger wen secrofnE .)052-701 .L.P( snoitcepsni tcudnoc ot seitrap driht stiderccA .)34-901 .L.P ,412-801 .L.P ,052-701 .L.P( weiver ecived tekramerp rof seef resu stcelloC .)511-501 .L.P( secived devorppa fo sesu devorppanu setalugeR .)511-501 .L.P( weiver tekramerp setareleccA .)563-801 .L.P ,842-501 .L.P ,935-201 .L.P( seef detaicossa stcelloc ,seitilicaf yhpargommam seifitreC .)003-201 .L.P( ecnailpmocnon ecnallievrus tekramtsop rof seitlanep seusruP .)003-201 .L.P( srerutcafunam tcudorp evitcefed yb snoitadommocca remusnoc niatrec sredrO .)926-101 .L.P( secived efasnu sllaceR .)926-101 .L.P( stroper tneve esrevda tekramtsop no stca ,sevieceR .)926-101 .L.P( stnemeriuqer tekramtsop secrofnE 7002 dna 0891 neewteB deddA seitirohtuA .)592-49 .L.P( yrtsiger rerutcafunam sniatniaM .)592-49 .L.P( serudecorp lortnoc ytilauq gnirutcafunam secrofne ,setaerC .)592-49 .L.P( gnitekram ot roirp ssenevitceffe ,ytefas serusnE .)557-98 .L.P( ycarucca ,ssenlufhturt lebal secrofnE .)717-57 .L.P fo noitaterpretni truoC( sgurd sa secived setalugeR 0891 ni seitirohtuA 7002 dna 0891 ni seitirohtuA yrotutatS htlaeH lacigoloidaR dna seciveD . 6 elbaT ¢ ¢ ¢ ¢ The FDA Commissioner has broad authority and responsibility to conduct research to support the agency's mission.109 The Office of the Commissioner (OC) is made up of several components, including the Ethics Program, Good Clinical Practice Program, History Office, Office of Combination Products, and Office of Crisis Management, among others.110 As reported in the FY1982 budget Justification, FY1980 funding for the OC was included in FDA's Program Management budget line. This line also included funding for the Associate Commissioners and the general management personnel responsible for the central program direction and administrative support functions of the agency. As reported in the FY2008 budget Justification, funding for the OC in FY2006 was included under the title FDA Headquarters and Office of the Commissioner. It consisted of agency-wide program direction, and administrative services to ensure that FDA's consumer protection efforts were managed and that available resources were put to the most efficient use. ¢ The lead office for FDA's inspection and enforcement activities (which FDA calls "field activities") is the Office of Regulatory Affairs (ORA). ORA is comprised of its Headquarters, the Office of Resource Management, the Office of Regional Operations, the Office of Enforcement, and the Office of Criminal Investigations.111 In almost every Justification, field activity budget and FTEs are included in each activity area. This report provides information on changes in FDA's resources, both budget and FTEs, as well as the evolution of its statutory responsibilities. Resources and responsibilities are juxtaposed because, as Congress requires more from the agency, it is important to assess whether FDA has the necessary financial resources to meet all those statutory responsibilities. The report is intended to assist Members and their staff in evaluating whether FDA's resources have fallen short, and, if so, how to enhance FDA's performance. The status of FDA resources and agency performance is important to Congress because each day FDA-regulated products touch the lives of every American citizen as well as people around the world. As stated previously, about 25% of American consumer dollars are spent on these FDA- regulated products. Among the industries that FDA regulates are some of the most successful and innovative in the U.S. economy. The agency regulates a wide range of products valued at more than $1 trillion. Problems with their safety or effectiveness could affect anyone, as is evident from the following sample of things FDA regulates: · the calorie and fat content information on food labels; · permissible and required information in televised prescription drug ads; 109 21 U.S.C. § 393(d)(2)(C). 110 See http://www.fda.gov/oc/. 111 See http://www.fda.gov/ora/about/default.htm. ¢ ¢ · the coloring in foods, medicines, and cosmetics; · the purity of ingredients in prepared foods--for people and animals; · inspection requirements for mammography and MRI equipment; and · antibiotics in the feed fed to animals bred for human consumption. The data in this report, assembled from the annual material that each President submits to Congress for the next year's appropriation, indicate some year-by-year variation, but mostly illustrate a few trends. For FDA as a whole, comparing FY2006, the most recent year for which we have parallel data sources for both dollars and FTEs, to FY1980 yields these inflation- adjusted findings (see Figure 1): FDA Budget: · almost a doubling of direct congressional appropriations (budget authority); · more than an 10-fold increase in other funds, mostly user fees; · resulting in an overall budget in FY2006 almost 2-1/2 times that in FY1980. FDA FTEs: · less than a 1% increase in budget authority-funded FTEs; · an almost fourfold increase in FTEs funded by other sources, mostly user fees; · resulting in an overall 19% increase from FY1980 to FY2006. Similar relationships are observed in each of the major activity areas that receive user fees (the Foods program does not have user-fee funds) and are discussed in this report. The human drugs program, along with biologics, was the first to include user fee revenue in its budget and is a good example to illustrate the relationship over time between congressionally appropriated dollars and user fee generated dollars. Again from FY1980 to FY2006, the data show that the human drugs total budget (program level), which included user fee revenue, more than tripled (a 231% increase) although the direct congressional appropriations (budget authority) increased by 78%. The effect of user fees is even more evident in comparing the number of FTEs. The budget authority funded FTEs decreased by 14%, but the overall human drug FTE level increased by 40% because of user fee funding. For the human drug program in FY2006, user fees contributed 46% of the budget and funded 39% of the FTEs. In general, Congress has either kept direct appropriations in line with inflation (FY1980-FY1988, FY1994-FY1997, and FY2002-2007) or increased them gradually (FY1989-FY1993 and FY1998-FY2001). The exception is FY2002, when Congress increased direct appropriations to FDA by 23%, along with increases to other public safety agencies in response to the attacks of September 11, 2001, and the anthrax mailings soon after. Congress and various administrations have allowed FDA's research program to diminish and its many data systems are not meeting the agency's needs. The context of this report does not allow a distinction between program decisions made by budget constraints and those made by policy intent. The focus of this report is the FDA budget. The discussion does not, therefore, explore other possible constraints on FDA's meeting its responsibilities and the public's expectations. Such ¢ ¢ factors could include the agency's lack of strong advocates, both externally (such as NIH has with its patient advocacy groups) and internally (because of chronic vacancies in key leadership positions, including the Commissioner). Independent of whether the FDA budget is sufficient to cover agency responsibilities is how FDA manages the resources it does have. The influence of non-budgetary factors likely complicates agency actions, though analyzing that is beyond the scope of this report. From 1980 through 2007, 36 new major statutes were enacted that address FDA activities.112 This report does not evaluate the impact of individual statutory requirements on the workload and resources needs of the agency. However, an examination of the FDA Amendments Act of 2007 (FDAAA, P.L. 110-85) provides examples of the funding issues discussed in this report. Some news coverage of FDAAA hailed it as "the most sweeping overhaul of the Food and Drug Administration in a decade."113 In addition to the widely expected reauthorization of drug and device user fees and pediatric drug research incentives, FDAAA, among other things, authorized demonstration grants, including ones for improving pediatric device availability; established mechanisms for public-private partnerships to support FDA's mission to accelerate medical product innovation, translational therapeutics, and enhanced medical product safety; required an expanded clinical trial registry databank; and strengthened FDA's authority to require studies and labeling changes for drugs already on the market. Implementation of these and other provisions is to involve the development of new regulations and extensive communication with industry and the public. Carrying out these new responsibilities will require time and resources. To fund all these provisions, FDAAA authorized annually an additional $250 million in appropriations and $32 million in user fee revenue.114 Absent appropriations, these authorizations remain congressional statements of intent. This report has focused on the presentation of FDA's financial and human resources and statutory responsibilities over time. In presenting that information in context, the report also identifies actions--other than a straightforward increase in direct appropriations--that others have suggested as possible steps to help FDA's budget situation. These propose to: · Restructure the PDUFA trigger mechanism to minimize its unintended effect of pulling resources from non-PDUFA activities. · Authorize FDA to bypass the HHS and OMB budget offices in submitting its request for appropriations to Congress. · Require, in addition to the OMB-processed budget request, that the FDA Commissioner submit to Congress a Professional Judgment budget based on his or her personal expertise and experience. 112 This number is held down by the concatenation of many introduced bills into large packages passed as single items. For example, FDAAA of 2007 is counted once although it included the Prescription Drug User Fee Amendments of 2007, the Medical Device User Fees Amendments of 2007, the Pediatric Medical Device Safety and Improvement Act of 2007, the Pediatric Research Equity Act of 2007, and the Best Pharmaceuticals for Children Act of 2007, among many other items. 113 Drew Armstrong, "Major Elements of the FDA Overhaul," CQ Weekly: Health, September 24, 2007, p. 2767. 114 FDAAA included other provisions that could (but do not necessarily) affect FDA's total program level. These are direction to transfer appropriated funds for specified purposes, authority to assess certain civil penalties, and authority to appropriate funds for certain grants and contracts. ¢ ¢ · Move FDA appropriations from the appropriations subcommittees on agriculture to the Labor-HHS subcommittees, which handle most other agencies involved in protecting the public's health. ¢ ¢ ¡ ¢ This report tracks, as consistently as possible with publicly available material, the FDA budget numbers and employee numbers (FTEs) from FY2007 back to FY1980. The goal was to provide about 25 years of budget and FTE history accompanied by changes in the agency's statutory responsibilities. Only limited budget and FTE data are available from bills and reports of the congressional appropriations committees. Citing constraints on its staff time, FDA indicated that it would only be able to provide data for recent years. Therefore, this report used data prepared annually by FDA for Congress at the beginning of each budget cycle and presented in the Justification documents. The Justifications are prepared initially by FDA and transmitted through HHS to OMB, often with adjustments made by HHS and OMB. These documents provide detailed budget and FTE data along with an extensive narrative. Over the years, changes in agency organization, accounting methods, definitions, and other conditions resulted in variations in data presentation in the Justification documents. Although some data inconsistencies found in the documents could be explained, other inconsistencies could not. This section of the report provides the basic approach used to calculate historical budget and FTE numbers, highlights inconsistencies among the Justification documents, and describes the steps taken to make the data as consistent as possible. There may be additional data inconsistencies that were not found because they were less readily apparent. The annual Justification documents present first the overall FDA information (narrative, and budget and FTE data) followed by information for the various activity areas within the agency. Except as noted below, this report uses data from the Actuals column in tables labeled: All Purpose Table--Total Program Level; All Purpose Table--Budget Authority; and All Purpose Table--User Fees. These tables are found at the beginning of each Justification document. The report also uses activity-specific data from similar tables that are included at the beginning of the Justification's narrative section on each activity area. The FDA's total budget, also called the program level, consists of (1) direct congressional appropriations, referred to by FDA as budget authority, and (2) funds collected or transferred from other sources, which this report refers to as other funds and which FDA lists under user fees in recent Justifications. Other funds include all of the financial and FTE resources that are available to FDA as itemized in the Justifications that are from sources other than direct congressional appropriations. In recent years, the largest component of other funds comes from user fees collected under the authority of the Prescription Drug User Fee Act, the Medical Device User Fee and Modernization Act, and the Animal Drug User Fee Act. Grouped separately in some years' Justifications are other fees obtained under the Mammography Quality Standards Act, and fees collected for color certification, export certification, and Freedom of Information Act (FOIA) requests. Additional sources itemized in the Justifications include advances and reimbursements; Parklawn Computer Center FTEs; CRADAs; and P.L. 83-480 (Agricultural Trade Development and Assistance Act of 1954) funds. Note that overall FDA budget authority includes appropriations for both "Salaries and Expenses" and "Buildings and Facilities." (In contrast, as indicated below, activity-area budgets include only "Salary and Expenses.") ¢ ¢ ¢ This report follows the order in the FY2008 Justification document in presenting information on FDA's five major activity areas: Foods, Human Drugs, Biologics, Animal Drugs and Feeds, and Medical Devices and Radiological Health. For each activity area, the Justification provides the amount given by direct congressional appropriations (budget authority) and user fees (a narrower category than other funds), the total of which is the program level. The Justification documents do not allocate an amount for Buildings and Facilities to each activity-area. Buildings and Facilities is recorded as a separate line within the overall FDA budget. Activity area amounts in this report's tables and graphs are for Salaries and Expenses. The report groups remaining FDA activities (Toxicological Research), agency-wide responsibilities (Headquarters and Office of the Commissioner) and expenditures (Rent, Buildings and Facilities) into an "Other Activities" category. Tables A2 and A3 in the Appendix of this report include budget and FTEs for Other Activities within the FDA Total columns, but do not provide a separate Other Activities column. Budget amounts for Other Activities are included in Figure 1 and Figure 3, which present overall FDA data. Data in Table A-2 in the Appendix are as reported in the Justifications and have not been adjusted for inflation. For Figures 1 and 2 as well as Figures 4-9, data have been adjusted for inflation using "Total Non-Defense" deflators from Table 10.1, Gross Domestic Product and Deflators Used in the Historical Tables: 1940-2012, found on pages 192-193 in: Office of Management and Budget, Historical Tables, Budget of the United States, Fiscal Year 2008. As stated above, this report uses data found in the Actuals column of tables in the Justification documents.115 Budget and FTE information for each activity area found in the overall summary tables at the front of the Justification document was compared with information found in the tables within the activity-area sections of the same document for confirmation. When a Justification included inconsistent information, Justification documents from the preceding and succeeding fiscal years were used to resolve the problem. The steps taken to resolve specific inconsistencies are described below in Table A-1 in the Appendix. The reporting format that FDA has used within the Justification documents to describe both its overall budget and those of its various activities has changed over the past 28 years. The format in this report was kept as consistent as possible with the format found in the FY2008 Justification. 115 Actuals data for a specific fiscal year can be found in the Justification document proposing the agency's budget two fiscal years later. For example, the Actuals data for FY2001 come from the FY2003 Justification. latoT" delebal tnuoma eht sa emas eht ton si tnuoma "sesnepxE margorP" ehT morf elbat yrammuS noitairporppA ADF eht ni "ytirohtuA lanoitagilbO .ytirohtua tegdub ot lauqe ton si "sesnepxE margorP" delebal tnuoma eht ,revewoh ;level 1991 latoT" delebal tnuoma eht gnitcartbus yb detaluclac erew sdnuf rehtO margorp ot lauqe si "latoT" delebal tnuoma eht ,elbat "elbaliavA secruoseR latoT" eht nI -9891 .tseuqer eht ot roirp sraey owt raey eht rof tnuoma lautca na sa dna raey gnidecerp eht dna raey tseuqer eht rof setamitse sa detroper era stnuoma esehT .ADF ot elbaliava sdnuf rehto detroper elbat "elbaliavA secruoseR latoT" ehT .level margorp ro sdnuf rehto rof stnuoma edivorp ton did dna stnuoma .sdnuf rehto etaluclac ot desu ton erew elbat "elbaliavA )ytirohtua tegdub( snoitairporppa tcerid ylno deniatnoc snoitacifitsuJ3991YF-1991YF 1991 secruoseR latoT" eht ni lautcA delebal stnuoma eht ,evoba ot tsartnoc nI eht ni selbat yrammuS noitairporppA eht ,selbat esopruP llA 8002YF eht ot tsartnoc nI -9891 .elbat yrammuS noitairporppA ADF eht ni "ytirohtuA lanoitagilbO latoT" ro "noitairporppA latoT" delebal tnuoma eht sa emas eht si tnuoma "sesnepxE margorP" .slatot level ehT .ytirohtua tegdub lauqe si "sesnepxE margorP" delebal tnuoma eht dna level margorp niatbo ot dedda erew stnuoma ytirohtua tegdub dna sdnuf rehtO margorp ot lauqe si elbat "elbaliavA secruoseR latoT" eht ni "latoT" delebal tnuoma ehT .tseuqer eht ot roirp sraey owt raey eht rof slautca sa dna raey gnidecerp eht dna raey tseuqer eht rof setamitse sa detroper era stnuoma esehT .ADF ot elbaliava sdnuf rehto detroper elbat "elbaliavA secruoseR latoT" ehT .level margorp ro sdnuf rehto rof stnuoma edivorp ton did dna stnuoma .sdnuf rehto etaluclac ot desu )ytirohtua tegdub( snoitairporppa tcerid ylno deniatnoc snoitacifitsuJ0991YF-8891YF 8891 erew elbat "elbaliavA secruoseR latoT" eht ni lautcA delebal stnuomA eht ni selbat yrammuS noitairporppA eht ,selbat esopruP llA 8002YF eht ot tsartnoc nI -6891 .sraey eseht rof stnuoma tegdub dna ETF scigoloiB dna sgurD namuH .sraey eseht rof secruoser sgurD namuH ni pmuj eht dna atad scigoloiB fo denibmoc stroper snoitacifitsuJ .REBC dna REDC mrof ot 7891 ni tilps hcihw scigoloiB 7891 ecnesba eht gninialpxe setontoof edulcni troper siht ni serugif dna selbaT dna sgurD rof retneC eht mrof ot 3891 ni degrem seitivitca scigoloiB dna sgurD namuH -3891 .slatot level .slautca ro setamitse era stnuoma eht rehtehw etacidni ton did margorp niatbo ot dedda erew stnuoma ytirohtua tegdub dna sdnuf rehtO slebal elbat ehT .raey gnidecerp eht dna raey tseuqer eht rof ylno detroper era stnuoma sdnuf rehto esehT .ADF ot elbaliava sdnuf rehto detroper elbat "elbaliavA secruoseR .tnuoma latoT" ehT .level margorp ro sdnuf rehto rof stnuoma edivorp ton did dna stnuoma sdnuf rehto na tcurtsnoc ot desu erew snoitacifitsuJ 6891YF-1891YF )ytirohtua tegdub( snoitairporppa tcerid ylno deniatnoc 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'srohtuA lairetaM ecruoS ni noitatimiL raeY lacsiF snoitatimiL ataD tegduB ADF sserddA ot nekaT snoitcA .1-A elbaT .shparg yna ni dedulcni ton era .ssergnoC yb noitca lanif yna tcelfer ton od ,erofereht ,dna dna selbat xidneppA eht ni "tseuqeR" delebal era 8002YF rof stnuomA ,tseuqeR tegduB s'tnediserP eht era noitacifitsuJ 8002YF ADF eht ni 8002YF rof stnuomA 8002 .srebmun ETF niatnoc ton did tub 7002 ,noituloseR snoitairporppA gniunitnoC desiveR eht ,5-011 .L.P rednu slevel gnidnuf lanif eht detcelfer )7002 hcraM detad( 7002YF rof nalP gnitarepO ADF nA .detcane saw noituloseR snoitairporppA gniunitnoC desiveR a ,retaL .atad ETF fo ecruos eht sa desu saw noitacifitsuJ 8002YF .emit eht ta tceffe ni noituloser gniunitnoc a morf stnuoma 7002YF desu noitacifitsuJ ehT .atad tegdub fo ecruos eht sa desu saw nalP gnitarepO ADF ehT 8002YF ehT .llib snoitairporppa erutlucirgA na fo egassap tuohtiw dedne 7002YF 7002 .desu erew noitacifitsuJ 8002YF eht morf stnuoma ,)htlaeH .scigoloiB lacigoloidaR dna seciveD lacideM dna ,sdeeF dna sgurD laminA ,sdooF( dna sgurD namuH rof tpecxe seitivitca lla rof tamrof suoiverp eht ot detrever ADF seitivitca gniniamer eht roF .sraey rehto htiw tnetsisnoc meht ekam snoitacifitsuJ , 8002YF dna 7002YF eht nI .tner edulcni did tub ,sriaffA yrotalugeR fo eciffO ot tner gnitcartbus dna stnuoma sriaffA yrotalugeR fo eciffO ni gnidda rof stnuoma edulcni ton did slatot ytivitca ,raey tahT . snoitacifitsuJ rehto naht tnereffid yb detcurtsnocer erew srebmun 4002YF ,scigoloiB dna sgurD namuH roF tamrof a ni--4002YF rof atad lautcA gnidulcni--atad dezinagro noitacifitsuJ 6002YF ehT 4002 .desu saw ytirohtuA tegduB--elbaT esopruP llA eht morf 000,170,093,1$ fo tnuoma ytirohtua tegdub ADF llarevo ehT .snoitaleR tneutitsnoC .000,972,8$ fo ecnereffid a ,leveL margorP & lanoitanretnI dna snoitaleR lanretxE fo seciffO eht rof stnuoma latoT--elbaT esopruP llA eht ni 000,053,893,1$ dna ,ytirohtuA tegduB--elbaT esopruP tcerrocni deniatnoc ylekil leveL margorP latoT--elbaT esopruP llA llA eht ni 000,170,093,1$ si ytirohtua tegdub ADF llarevo ehT .selbaT esopruP llA eht delebal elbat eht taht detacidni noitacifitsuJ 5002YF eht ni snoitces rehtO ni stnuoma ytirohtua tegdub ADF llarevo tnereffid owt detroper noitacifitsuJ 5002YF ehT 3002 .tegdub aera ytivitca rehto yna ro ,scigoloiB ,sgurD namuH fo yrogetac seef resu eht ni dedulcni ton saw tnuoma eef resu AFUDP eht ,seef AFUDP .)8002YF hguorht 4991YF rof esac eht si sa( scigoloiB ro sgurD eht rof atad level-ytivitca fo ecnesba eht nI .tegdub ADF llarevo eht namuH fo tegdub eht ni dedulcni ton si yrtne elbarapmoc a tub ,seef )AFUDP( tcA eeF fo yrogetac sdnuf rehto eht ni dedulcni saw tnuoma eef resu AFUDP ehT resU gurD noitpircserP ni 000,949,8$ sedulcni sdnuf rehto rof tnuoma ADF llarevo ehT 3991 . snoitacifitsuJ 9991YF dna 8991YF eht ni "tseuqeR tegduB lanoissergnoC ADF" dna snoitacifitsuJ 7991YF dna 6991YF eht ni "ytivitcA yb ytirohtuA tegduB ADF" deltit era selbat ehT . snoitacifitsuJ 8002YF-0002YF eht ni "selbaT .ecruos atad eht sa desu erew selbat "tseuqeR tegduB lanoissergnoC esopruP llA" eht ot ralimis noitamrofni dna stamrof evah ,hcus sa delebal ton hguohtla 7991 ADF" eht dna selbat "ytivitcA yb ytirohtuA tegduB ADF" ehT ,taht tnemucod eht fo gninnigeb eht ta selbat deniatnoc snoitacifitsuJ 9991YF-6991YF ehT -4991 snoitacifitsuJ . 8002YF-0002YF eht ni dedivorp sa "leveL margorP--esopruP llA" ro "ytirohtuA tegduB--esopruP llA" rehtie ot tnelaviuqe yrammus a gnittimo dna ;yrogetac snoitacifitsuJ . 8002YF-0002YF eht ni "selbaT esopruP llA" eht "eeF resU" 'sraey tnecer eht morf smeti lareves gnidulcxe :yltnereffid noitamrofni ni noitatneserp rieht htiw tnetsisnoc rennam a ni seirogetac "sdnuf rehto" eht ezirogetac snoitacifitsuJ 5991YF dna 4991YF eht ni selbat eht ,revewoH .8002YF dna ",ytirohtua tegdub" ",level margorp" ni decalp erew selbat "ytivitcA -0002YF fo "selbaT esopruP llA" eht ni detneserp taht ot ralimis noitamrofni deniatnoc 3991 yb ytirohtuA tegduB ADF" 5991YF dna 4991YF eht morf smeti laudividnI snoitacifitsuJ 5991YF dna 4991YF eht ni elbat "ytivitcA yb ytirohtuA tegduB ADF" ehT -2991 .elbat "elbaliavA secruoseR latoT" eht ni "latoT" delebal tnuoma eht .elbat yrammuS noitairporppA ADF eht ni "ytirohtuA lanoitagilbO noitatneserP tropeR rof noisiceD 'srohtuA lairetaM ecruoS ni noitatimiL raeY lacsiF 106,21 656,751 0 395,94 485,43 331,601 696,59 835,512 407,972 438,561 941,840,1 389,312,1 0002 812,31 097,541 0 352,34 243,92 320,59 678,77 324,002 861,532 417,441 972,589 399,921,1 9991 673,11 923,441 0 453,14 335,72 974,59 960,36 975,991 942,602 614,811 388,139 992,050,1 8991 944,21 273,741 0 612,63 483,62 652,69 633,35 970,102 381,191 262,611 347,088 500,799 7991 755,8 717,341 0 418,63 199,92 513,78 368,05 420,202 149,002 418,89 725,988 143,889 6991 0 120,751 0 486,14 156,52 311,401 314,84 049,712 893,612 830,97 032,968 862,849 5991 0 953,951 0 813,04 348,61 847,011 801,32 558,412 410,312 777,44 869,578 547,029 4991 0 520,921 0 710,83 0 182,89 0 746,112 096,402 632,72 968,697 501,428 3991 0 137,611 0 000,93 0 135,09 0 835,891 403,602 020,61 038,167 058,777 2991 0 877,401 0 652,53 0 680,38 0 204,671 998,381 570,91 293,886 764,707 1991 0 563,98 0 076,03 0 142,37 0 915,641 280,161 275,01 979,006 155,116 0991 0 754,87 0 254,42 0 174,06 0 512,131 112,141 401,01 343,245 744,255 9891 0 119,47 0 604,52 0 973,15 0 231,711 104,621 745,8 405,774 150,684 8891 0 279,07 0 668,42 0 b-- 0 246,151 944,021 702,01 441,744 153,754 7891 0 165,56 0 877,22 0 b-- 0 906,921 357,901 000,8 163,404 163,214 6891 0 362,76 0 724,32 0 b-- 0 699,031 145,011 095,9 543,414 539,324 5891 0 865,26 0 319,32 0 b-- 0 533,411 000,611 358,7 946,293 205,004 4891 0 638,85 0 110,22 0 b-- 0 274,801 492,301 905,6 783,193 698,793 3891 0 463,35 0 994,12 0 471,32 0 482,27 352,401 732,21 426,143 168,353 2891 0 812,85 0 000,12 0 836,12 0 674,67 373,29 478,41 024,133 492,643 1891 0 530,94 0 894,32 0 741,22 0 911,27 701,59 530,51 928,423 468,933 0891 seeF ytirohtuA seeF ytirohtuA seeF ytirohtuA seeF ytirohtuA ytirohtuA sdnuF ytirohtuA aleveL raeY resU tegduB resU tegduB resU tegduB resU tegduB tegduB rehtO tegduB margorP lacsiF .loidaR & seciveD sdeeF scigoloiB sgurD namuH sdooF ADF & sgurD laminA )sdnasuoht ni sra llod( noitalfnI rof detsujdanU ,8002YF hguorht 0891YF ,gnidnuF rehtO dna ytirohtuA tegduB ,margorP rojaM yb dna llarevO ,snoitairporppA ADF .2-A elbaT ¢ ¢ .slevel tseuqer noitartsinimdA eht era stnuoma 8002YF .c .scigoloiB ni ton dna sgurD namuH ni dedulcni era hcihw stnuoma rallod denibmoc ylno edivorp sraey esoht rof snoitacifitsuJ ehT .retneC eno ni seitivitca sgurD namuH dna seitivitca scigoloiB deganam ADF ,7891YF hguorht 3891YF roF .b .)seef resu ,.g.e( gnidnuf rehto + )snoitairporppa tcerid( ytirohtua tegdub = level margorp latoT .a .5-011 .L.P rednu slevel gnidnuf gnitcelfer )7002 hcraM detaD( 7002 rof nalP gnitarepO si 7002YF ehT .detacolla erew seef resu AFUDP 3991 woh raelcnU .seeF noitacifitreC--dnuF gnivloveR sulp AFUDP era 3991 ni seeF resU .seeF noitacifitreC--dnuF gnivloveR era 2991 ni seeF resU .2891 dna ,1891 ,0891 rof dedda erew stcudorP lacigoloidaR dna seciveD .eunever eef resu edulcni ton seod tegdub margorp sdoof s'ADF :setoN .stnemucod seettimmoC snoitairporppA rof setamitsE fo noitacifitsuJ ADF :secruoS 452,54 221,042 325,11 908,49 267,06 370,551 853,232 834,423 627,664 099,344 956,046,1 946,480,2 c8002 732,24 017,032 735,9 947,49 837,56 745,441 832,552 831,513 501,754 335,334 491,475,1 727,700,2 7002 874,43 365,022 462,8 085,98 191,95 815,831 091,112 517,792 127,834 411,963 085,394,1 496,268,1 6002 023,92 269,412 835,7 484,09 575,74 901,321 056,091 484,192 715,534 002,523 472,254,1 474,777,1 5002 363,03 341,191 389 854,38 266,44 453,221 474,761 811,292 250,704 096,772 412,104,1 409,876,1 4002 539,32 053,391 0 956,78 811,84 813,541 577,921 370,472 428,604 585,732 170,093,1 656,726,1 3002 596,31 269,971 0 346,58 732,93 506,831 446,901 007,452 652,393 395,281 663,453,1 959,635,1 2002 952,21 603,561 0 070,46 729,83 303,801 569,301 515,812 405,782 638,871 113,990,1 741,872,1 1002 seeF ytirohtuA seeF ytirohtuA seeF ytirohtuA seeF ytirohtuA ytirohtuA sdnuF ytirohtuA aleveL raeY resU tegduB resU tegduB resU tegduB resU tegduB tegduB rehtO tegduB margorP lacsiF .loidaR & seciveD sdeeF scigoloiB sgurD namuH sdooF ADF & sgurD laminA ¢ ¢ 374,1 54 824,1 244 0 244 140,1 552 687 535,2 117 428,1 544,2 989,8 481,1 508,7 1002 274,1 64 624,1 604 0 604 199 112 087 905,2 176 838,1 683,2 038,8 201,1 827,7 0002 084,1 84 234,1 393 0 393 989 891 197 654,2 016 648,1 933,2 019,8 950,1 158,7 9991 555,1 84 705,1 193 0 193 720,1 681 148 924,2 074 959,1 932,2 409,8 128 380,8 8991 766,1 84 916,1 283 0 283 070,1 902 168 515,2 644 960,2 622,2 171,9 718 453,8 7991 646,1 34 306,1 304 0 304 010,1 602 408 954,2 153 801,2 843,2 271,9 586 784,8 6991 138,1 0 138,1 864 0 864 211,1 851 459 375,2 592 872,2 095,2 462,9 354 118,8 5991 997,1 0 997,1 594 0 594 301,1 621 779 094,2 87 214,2 576,2 253,9 983 369,8 4991 386,1 0 386,1 584 0 584 969 0 969 944,2 0 944,2 596,2 931,9 002 939,8 3991 406,1 0 406,1 605 0 605 898 0 898 093,2 0 093,2 397,2 490,9 203 297,8 2991 284,1 0 284,1 384 0 384 428 0 428 362,2 0 362,2 736,2 054,8 381 762,8 1991 233,1 0 233,1 834 0 834 577 0 577 620,2 0 620,2 574,2 418,7 581 926,7 0991 362,1 0 362,1 414 0 414 476 0 476 319,1 0 319,1 773,2 893,7 071 822,7 9891 282,1 0 282,1 144 0 144 485 0 485 249,1 0 249,1 641,2 012,7 171 930,7 8891 832,1 0 832,1 144 0 144 a-- a-- a-- 324,2 0 324,2 170,2 369,6 961 497,6 7891 712,1 0 712,1 144 0 144 a-- a-- a-- 604,2 0 604,2 190,2 100,7 961 238,6 6891 952,1 0 952,1 624 0 624 a-- a-- a-- 644,2 0 644,2 461,2 212,7 881 420,7 5891 112,1 0 112,1 854 0 854 a-- a-- a-- 822,2 0 822,2 693,2 772,7 881 980,7 4891 852,1 0 852,1 054 0 054 a-- a-- a-- 653,2 0 653,2 752,2 603,7 481 221,7 3891 161,1 0 161,1 644 0 644 014 0 014 307,1 0 307,1 694,2 583,7 473 110,7 2891 573,1 0 573,1 994 0 994 094 0 094 320,2 0 320,2 913,2 239,7 473 855,7 1891 993,1 0 993,1 615 0 615 705 0 705 201,2 0 201,2 804,2 281,8 663 618,7 0891 latoT eeF resU AB latoT eeF AB latoT eeF AB latoT eeF AB latoT latoT sdnuF AB raeY resU resU resU rehtO sETF htlaeH sETF sETF scigoloiB sETF sgurD namuH sETF sETF ADF lacigoloidaR & seciveD sdeeF & sgurD laminA dooF 8002YF hguorht 0891YF ,dednuF-rehtO dna dednuF-ytirohtuA tegduB ,margorP rojaM yb dna llarevO ,stnelaviuqE emit-lluF .3-A elbaT ¢ ¢ .tseuqer noitartsinimdA no desab 8002YF .b .scigoloiB ni ton dna sgurD namuH ni dedulcni era hcihw sETF denibmoc ylno edivorp sraey esoht rof snoitacifitsuJ ehT .retneC eno ni seitivitca sgurD namuH dna seitivitca scigoloiB deganam ADF ,7891YF hguorht 3891YF roF .a .eunever eef resu edulcni ton seod tegdub margorp sdoof s'ADF :etoN .stnemucod seettimmoC snoitairporppA rof setamitsE fo noitacifitsuJ ADF :ecruoS 935,1 081 953,1 916 85 165 101,1 362 838 130,3 502,1 628,1 207,2 988,9 209,1 789,7 b8002 962,1 43 532,1 205 0 205 199 512 677 528,2 221,1 307,1 316,2 930,9 925,1 015,7 7002 894,1 071 823,1 295 45 835 979 942 037 749,2 641,1 108,1 477,2 896,9 508,1 398,7 6002 615,1 941 763,1 016 93 175 140,1 372 867 819,2 180,1 738,1 349,2 019,9 927,1 181,8 5002 515,1 931 673,1 595 3 295 830,1 642 297 949,2 279 779,1 280,3 141,01 475,1 765,8 4002 584,1 35 234,1 695 0 695 922,1 282 749 696,2 677 029,1 761,3 752,01 713,1 049,8 3002 454,1 74 704,1 075 0 075 631,1 242 498 715,2 007 718,1 437,2 864,9 751,1 113,8 2002 latoT eeF resU AB latoT eeF AB latoT eeF AB latoT eeF AB latoT latoT sdnuF AB raeY resU resU resU rehtO sETF htlaeH sETF sETF scigoloiB sETF sgurD namuH sETF sETF ADF lacigoloidaR & seciveD sdeeF & sgurD laminA dooF ¢ ¢ rehto ro nam fo ydob eht fo noitcnuf yna fo erutcurts eht tceffa ot dednetni ... selcitra" edulcni ot noitinifed eht dednapxe rehtruf dna ;esaesid fo tnemtaert dna sisongaid eht ni esu rof dednetni selcitra edulcni ot esaesid fo noitneverp dna ,noitagitim ,eruc eht ni desu eb ot dednetni secnatsbus dnoyeb gurd fo noitinifed eht dednapxe tca ehT .sevitidda roloc fo sehctab fo noitacifitrec eht rof snoitaluger deriuqer dna ;gnilebal dna ,sreniatnoc ,slairetam ,tnempiuqe sti gnidulcni ,)stcudorp detaluger-ADF rehto dna( sgurd sdloh ro ,skcap ,sessecorp ,serutcafunam taht ytilicaf a fo noitcepsni dezirohtua ;stnempihs fo sdrocer deriuqer ;duarfed ot tnetni na devlovni gnidnarbsim fi seitlanep desaercni ;gurd a hcus fo tpiecer eht dna ,ecremmoc etatsretni otni gurd a hcus fo noitcudortni eht ,gurd a fo gnidnarbsim dna noitaretluda eht detibihorp ;ecremmoc etatsretni ni dlos eb dluoc yeht erofeb efas nevorp eb sgurd taht deriuqer snoisivorp gurd ehT .secnatsbus hcus rof dedivorp erew slevel seciveD ecnarelot efas sselnu ,detaretluda doof eht redner dluow taht secnatsbus fo noitidda eht dna gnisitrevda eslaf detibihorp ti ,noitidda nI .gnilebal ,laminA ,scigoloiB evitamrofni dna sdoof rof sdradnats dna snoitinifed etaglumorp ot ADF deriuqer yllacificeps snoisivorp doof ehT .dedda neeb evah setutats ,sgurD ,sdooF tneuqesbus hcihw no wal gurd dna doof tnerruc fo noitadnuof yramirp eht deredisnoc si 8391 fo tcA citemsoC dna ,gurD ,dooF laredeF 717-57 .ADF yb sgurD detaluger esiwrehto stcudorp htiw detaicossa gnisitrevda fo thgisrevo noissimmoC edarT laredeF eht ot dengissa 8391 fo tcA aeL-releehW 744-57 .yrtnuoc eht otni detropmi eb ot maerc dna klim rof secivreS namuH dna htlaeH fo yraterceS eht morf deniatbo eb timrep dilav a taht deriuqer tca ehT .htlaeh cilbup gnitcetorp dna yrtsudni sdooF yriad .S.U eht gnitomorp fo esoprup eht rof setatS detinU eht otni maerc dna klim fo noitatropmi eht detaluger 7291 fo tcA kliM tropmI 526-76 .cilbup eht nopu duarf a detutitsnoc elas sti taht dna htlaeh cilbup eht ot suoirujni ,doof ro elcitra detaretluda na si klim dellif taht deralced tca ehT .klim demmiks ro ,maerc ,klim fo noitatimi na si tcudorp gnitluser eht taht os taf klim naht rehto lio ro taf yna dednuopmoc sdooF ro ,dednelb ,dedda si hcihw ot ,mrof sti fo sseldrager ,klim demmiks ro maerc ,klim yna sa klim dellif denifed 3291 fo tcA kliM delliF 315-76 .deificeps stnuoma eht evoba scitocran esoht fo seititnauq fo gnisnepsid eht rof )euneveR lanretnI fo renoissimmoC eht yb dedivorp mrof a no( noitpircserp nettirw a deriuqer osla tI .sdrocer peek dna ,xat laiceps a yap ,eunever lanretni fo srotcelloc eht htiw retsiger ot scitocran rehto niatrec ro "muipo yawa sevig ro ,setubirtsid sgurD ,slles ,sesnepsid ,ni slaed ,sdnuopmoc ,serutcafunam ,stropmi ,secudorp ohw nosrep yreve" deriuqer 4191 fo tcA scitocraN nosirraH 322-36 sgurD .tceffe cituepareht ro evitaruc fo stnemetats eslaf edulcni ot gnidnarbsim fo noitinifed eht dednapxe 2191 fo tnemdnemA yelrehS 103-26 .stcudorp deliops fo esu eht dna ,stneidergni suoireteled fo noitidda eht ,ytiroirefni ro egamad fo tnemlaecnoc eht ,ytilauq decuder taht secnatsbus fo noitutitsbus ro erutximretni eht debircsed seitilareneg os ,detsixe sdradnats on esuaceb detimil saw noitaretluda dna ,lebal ro egakcap eht no stnemetats gnidaelsim ro eslaf gnikam ot denifnoc saw gnidnarbsim ,doof gnidrageR .ycarucca lebal dna ytirup gnigduj rof stnerefer sa yralumroF lanoitaN eht dna aiepocamrahP setatS detinU eht ni snoitpircsed gurd ot derrefer osla tca ehT .)scitocran niatrec dna lohocla fo seititnauq gnidulcni ,delebal sa ton stnetnoc( gnidnarbsim dna ,)ytirup ro ,ytilauq ,htgnerts fo sdradnats dehsilbatse morf gnireffid( noitaretluda ,)slamina rehto ro nam rehtie fo esaesid fo noitneverp ro ,noitagitim ,eruc eht rof desu eb ot dednetni ecnatsbus( gurd denifed tI .stcudorp gnidneffo fo eruzies eht dezirohtua laminA osla dna snoitaloiv rof seitlanep lanimirc dedivorp tI .dednarbsim dna detaretluda erew taht stcudorp gurd dna ,knird ,doof ni ecremmoc ,sgurD ,sdooF etatsretni tibihorp ot noisivid doof eht deriuqer ,yrtsimehC fo uaeruB ADSU-neht eht yb deretsinimda ,6091 fo tcA gurD dna dooF eruP 483-95 .sesoprup lacidem rof ssentif dna ,ytirup ,ytilauq rof daorba morf sgurd tcepsni ot )ecivreS smotsuC .S.U( yrusaerT eht fo tnemtrapeD eht deriuqer )932-732 ;8481 ;07 .tphC ,1 noisseS sgurD ,ssergnoC ht03 ,senicideM dna sgurD suoirupS dna detaretludA fo noitatropmI eht tneverP ot tcA nA( tcA noitatropmI gurD a ytivitcA waL fo noitpircseD feirB dna eltiT waL cilbuP seitivitcA ADF gnitceffA yltnacifingiS 8481 ecniS swaL cilbuP detceleS .4-A elbaT ¢ ¢ .scitemsoc dna ,secived ,sgurd ,doof rof snoitaluger etaglumorp ot yraterceS SHH eht detangised tI .segakcap fo llif lanoitcnuf-non eht tneverp ot snoitaluger tpoda seciveD ot ADF dezirohtua osla tca ehT .rotubirtsid ro ,rekcap ,rerutcafunam eht fo ecalp dna eman dna ,ytitnauq ,stnetnoc eht fo ytitnedi eht setats ,sgurD ,sdooF taht lebal tnenimorp ,elbigel a yalpsid ot ecremmoc ni tcudorp remusnoc degakcap yna deriuqer 6691 fo tcA gnilebaL dna gnigakcaP riaF 557-98 .seitlanep deificeps ti dna ;secnatsmucric niatrec rednu seettimmoc yrosivda trepxe tnioppa ot dna gurd a tpmexe ot yraterceS eht dezirohtua dna ,sllifer noitpircserp fo rebmun eht detimil wal ehT .seitilicaf tcepsni dna sdrocer yfirev ot yraterceS eht wolla dna sdrocer peek srehto dna ,srelles ,srerutcafunam taht deriuqer sgurD ;sgurd tnalumits dna tnasserped fo gnissecorp dna ,gnidnuopmoc ,erutcafunam eht detcirtser 5691 fo stnemdnemA lortnoC esubA gurD 47-98 .scitoibitna lla ot ytirohtua ADF dednapxe dedulcni dna noitartsinimdA gurD dna dooF eht ot noissimmoC edarT laredeF eht morf gnisitrevda gurd noitpircserp etaluger ot ytirohtua eht dengissaer osla wal ehT .ytefas sgurD sa llew sa stcudorp rieht fo ssenevitceffe eht evorp srekamgurd taht deriuqer ACDFF eht ot 2691 fo stnemdnemA gurD sirraH-revuafeK 187-78 .esu efas erussa ot gnilebal dna ,sesu ,snoitidnoc no desab scitemsoc dna ,sgurd ,doof no ro ni sevitidda roloc fo gnitsil eht rof snoitaluger etaglumorp yraterceS eht taht sgurD ,sdooF deriuqeR .scitemsoc dna sgurd ,doof ni desu sroloc rof metsys lavorppa tekramerp a dehsilbatse 0691 fo stnemdnemA evitiddA roloC 816-68 .secnatsbus laminA ,sdooF tcatnoc doof ynam dna stneidergni doof wen rof metsys lavorppa tekramerp a dehsilbatse 8591 fo stnemdnemA evitiddA dooF 929-58 sdooF .seitidommoc larutlucirga no sedicitsep rof secnarelot hsilbatse ot ytirohtua htiw ADF dedivorp 4591 fo tnemdnemA edicitseP relliM 815-38 .dedulcni dah wal 8391 eht hcihw ,noitcepsni rof ytilicaf eht retne ot noissimrep s'renwo na deriuqer regnol on noitces eht fo noisrev dednema ehT .snoitidnoc yrotcafsitasnu fo troper nettirw a yraterceS eht ot dnes dna sgurD renwo eht evig rotcepsni eht taht eriuqer ot noitcepsni yrotcaf no noitces ACDFF eht dednapxe 3591 fo tnemdnemA noitcepsnI yrotcaF 712-38 .htlaeh cilbup fo noitcetorp eht rof yrassecen ton si tnemeriuqer eht fi gurd a morf tnemeriuqer noitpircserp eht evomer ot yraterceS eht dezirohtua osla tI .renoititcarp desnecil a fo noisivrepus eht rednu tpecxe sgurD esu rof efas ton si taht ro gnimrof-tibah si taht gurd a fo elas eht ylno noitpircserp ot detcirtser 1591 fo tnemdnemA yerhpmuH-mahruD 512-28 .snoitaluger etaglumorp ASF eht taht dna ;ytirup sgurD dna ,ytilauq ,htgnerts rof nillicinep fo hctab hcae fo noitacifitrec eht rof edivorp ASF eht taht deriuqer 5491 fo tnemdnemA nillicineP 931-97 .snoitaloiv rof seitlanep lanimirc dna livic sedivorp dna ;htlaeh cilbup eht ot drazah tnenimmi na tneserp taht ro esnecil a tuohtiw stcudorp fo llacer eht dna ,stcudorp lacigoloib fo noitaraperp eht ni devlovni stnemhsilbatse gnirutcafunam fo noitcepsni eht sezirohtuA .stcudorp hcus rof esnecil a dloh scigoloiB ot ecremmoc etatsretni otni retne taht scigoloib erutcafunam ohw seinapmoc ro slaudividni deriuqer 4491 fo tcA ecivreS htlaeH cilbuP 014-87 .stset dna sdradnats ,sgniht rehto gnoma ,gnirevoc snoitaluger etaglumorp ot rotartsinimdA eht detcerid osla wal ehT .ytirup dna ,ytilauq ,htgnerts rof nilusni fo hctab hcae fo noitacifitrec dna gnitset eht rof edivorp )ycnegA ytiruceS sgurD laredeF eht ni dediser ADF ,3591 ot 0491 morf ;ASF( rotartsinimdA ytiruceS laredeF eht taht deriuqer 1491 fo tnemdnemA nilusnI 663-77 .secived lacidem ot snoitaluger gurd eseht ylppa ot ADF dewolla evah struoc ehT .srehto gnoma ,sgninraw dna ,esu rof snoitcerid ,ytitnauq ,gnigakcap ,gnilebal rof stnemeriuqer gnidulcni ,gnidnarbsim fo epocs eht dednapxe tI ".slamina a ytivitcA waL fo noitpircseD feirB dna eltiT waL cilbuP ¢ ¢ sdooF dna stcudorp doof tsom no slebal noitirtun etadnam ot ycnega eht rof ytirohtua dedivorp 0991 fo tcA noitacudE dna gnilebaL noitirtuN 535-101 .snoitcepsni noitatropsnart doof ni ecnatsissa edivorp ot ,SHH gnidulcni ,stnemtraped rehto htiw krow ot TOD deriuqer tca ehT .)TOD( noitatropsnarT fo tnemtrapeD laminA ,sdooF eht fo yraterceS eht fo noitcidsiruj eht rednu doof fo noitatropsnart eht no desucof yliramirp saw 0991 fo tcA tropsnarT dooF yratinaS 005-101 .gurd lamina wen a fo lavorppa laminA eht rof snoitacilppa detaiverbba ezirohtua ot ACDFF eht dednema 8891 fo tcA noitarotseR mreT tnetaP dna gurD laminA cireneG 076-001 .setats eht yb desnecil eb srelaselohw gurd taht deriuqer dna ;selpmas gurd rof sdradnats gnitnuocca sgurD dna ,gnildnah ,egarots detadnam ;selpmas gurd fo esahcrup dna ,edart ,elas eht dennab 7891 fo tcA gnitekraM gurD noitpircserP 392-001 .lavorppa ADF gnirud syaled yrotaluger tcelfer ot smret tnetap eman-dnarb gnidnetxe osla elihw ,sgurd cireneg fo yrtne tekram sgurD reilrae wolla ot wal tnetap degnahc )tcA namxaW-hctaH( 4891 fo tcA noitarotseR mreT tnetaP dna noititepmoC ecirP gurD 714-89 seciveD ,laminA ,scigoloiB .snoitaloiv etagitsevni ,sgurD ,sdooF ot ADF eht dezirohtua dna stcudorp remusnoc degakcap htiw repmat ot emirc a ti dekam 3891 fo tcA gnirepmaT-itnA laredeF 721-89 .snoitidnoc dna sesaesid erar fo tnemtaert eht rof secived sgurD lacidem dna ,stcudorp ygolonhcetoib ,sgurd poleved ot srerutcafunam lacituecamrahp rof sevitnecni dedivorp 3891 fo tcA gurD nahprO 414-79 .stnemeriuqer noitneter drocer dna gnitset lacigoloiborcim wen dna sllacer alumrof tnafni rof stnemeriuqer lanoitidda dedda )075-99 .L.P( 6891 fo tcA esubA gurD-itnA ehT .stnemeriuqer tneirtun dna gnilebal dna ,snoitpmexe ,stnemeriuqer llacer ,serudecorp sdooF lortnoc ytilauq ,stnemeriuqer gnitroper gnihsilbatse yb salumrof tnafni revo ytirohtua s'ADF degralne 0891 fo tcA alumroF tnafnI 953-69 .gnitekram erofeb sdradnats ecnamrofrep teem ot dah srehto elihw ,ADF yb weiver tekramerp ogrednu ot deriuqer erew stcudorp emoS .sessecorp gnirutcafunam rieht ni serudecorp lortnoc ytilauq wollof dna ADF htiw retsiger ot srerutcafunam deriuqer stnemdnema ehT .detekram eb dluoc yeht erofeb ,stcudorp citsongaid gnidulcni seciveD ,secived lacidem fo ssenevitceffe dna ytefas erusne ot dessap noitalsigel rojam tsrif eht saw wal sihT 6791 fo stnemdnemA eciveD lacideM 592-49 .doof htlaeh dna stcudorp lanoitirtun ycnetop hgih lortnoc ot troffe gnol-edaced s'ycnega eht fo noitcejer a gnikram sdooF ,stnemelppus yrateid fo noitomorp dna noitisopmoc eht etaluger ot ytirohtua s'ADF detimil 6791 fo tnemdnemA lareniM-nimatiV 872-49 .dednarbsim ro detaretluda era taht stcudorp gge dna sgge fo doof namuh ni esu rof elas ro tnemevom eht tneverp ot stcudorp gge dna sgge fo noitubirtsid dna gnissecorp fo noitaluger eht rof elbisnopser si ycnega eht ,noitidda sdooF nI .sgge gnidarg rof sdradnats mrofinu dehsilbatse dna stcudorp gge niatrec tcepsni ot ADF deriuqer 0791 fo tcA noitcepsnI stcudorP ggE 795-19 .laitnetop esuba na htiw gurd a sevlovni noitacilppa gurd wen dettimbus a nehw GA eht yfiton ot )ADF aiv( yraterceS eht deriuqeR .yraterceS SHH eht morf ecivda cifitneics tseuqer GA eht taht deriuqeR .sesu lacidem detpecca dna ,ecnedneped lacigolohcysp ro lacisyhp rof laitnetop ,esuba rof laitnetop rieht no desab seludehcs evif ssorca sgurd niatrec ezirogetac ot )GA( lareneG yenrottA sgurD eht dezirohtua )0791 fo tcA lortnoC dna noitneverP esubA gurD evisneherpmoC eht fo trap( tcA secnatsbuS dellortnoC 315-19 .slamina gnicudorp-doof ni esu rieht rof ytefas fo weiver a dedulcni dna ,esu dednetni rof sgurd lamina fo ssenevitceffe dna ytefas eht weiver ot ADF rof stnemeriuqer eht dednetxe laminA ,sgurd lamina fo lavorppa eht ot yllacificeps ylppa ot ACDFF eht fo 215 noitces wen a dehsilbatse 8691 fo stnemdnemA gurD laminA 993-09 a ytivitcA waL fo noitpircseD feirB dna eltiT waL cilbuP ¢ ¢ snoisivorp dedda dna ,sraey net ni noitaulaveer level ecnarelot deriuqer tca ehT .smargorp noitcepsni sti hguorht derotinom ti sdoof eht rof snoitaloiv ecnarelot rof seitlanep livic esopmi ot ADF dewolla dna ,stifeneb fo noitaredisnoc detimil ,nerdlihc dna stnafni rof snoisivorp ytefas laiceps dedivorp osla tI .sdoof dessecorp dna war ni sedicitsep rof sdradnats elpitlum yb desop smelborp gnidnatsgnol eht gnitanimile ,sdoof lla ni sedicitsep lla rof dradnats desab-htlaeh ,elgnis a dehsilbatse APQF ,ACDFF rednU .tcA edicitnedoR dna ,edicignuF ,edicitcesnI laredeF sdooF s'ycnegA noitcetorP latnemnorivnE eht dna ACDFF s'ADF eht htob fo snoisivorp edicitsep detceffa 6991 fo tcA noitcetorP ytilauQ dooF 071-401 .stnemelppus rof sPMG eht dezilanif ton tub ,desoporp ylno sah ADF raf os ;ycnega eht yb detaglumorp eb ot erew )sPMG( secitcarp gnirutcafunam doog ,yllaniF .esu fo snoitidnoc dednetni sti rednu ytefas fo ecnedive htiw ADF noititep ot tekram eht gniretne tneidergni yrateid wen a fo srerutcafunam deriuqer wal ehT .noitamrofni gnilebal noitirtun dna tneidergni edivorp ot deriuqer era stnemelppuS .snoitaluger gnilebal morf tpmexe eb ot troppus lanoitirtun fo stnemetats dna stnemelppus fo esu eht no erutaretil ytrap driht swolla wal ehT .devomer eb dluohs dna efasnu si tekram eht no ydaerla tnemelppus a taht etartsnomed ot ADF no foorp fo nedrub eht gnicalp dna ,stcudorp eht sdooF gninifed yb ,stnemelppus etaluger ot ycnega eht rof ytirohtua cificeps dedivorp 4991 fo tcA noitacudE dna htlaeH tnemelppuS yrateiD 714-301 .slamina gnicudorp-doof ni seudiser evitaloiv ni tluser ton tsum dna pihsnoitaler tneitap-tneilc -nairaniretev a fo txetnoc eht nihtiw nairaniretev a fo redro eht no ro yb eb tsum esu lebal-artxe yna ,stnemeriuqer rehto gnomA .)esu lebal -artxe( snoitcerid lebal devorppa eht htiw ecnadrocca ni ton si taht rennam a ni esu rof sgurd namuh dna lamina devorppa niatrec ,snoitidnoc laminA niatrec rednu ,slamina rof ebircserp ot snairaniretev dewolla )ACUDMA( 4991 fo tcA noitacifiralC esU gurD lanicideM laminA 693-301 .snoitacilppa scigoloib dna gurd wen fo weiver sti troppus ot eunever gnitluser eht esu ot dna srerutcafunam scigoloiB ,sgurD lacituecamrahp eht morf seef tcelloc dna ssessa ot ADF ,sraey evif rof ,dezirohtua )AFUDP( 2991 fo tcA eeF resU gurD noitpircserP 175-201 .)563-801 .L.P( 4002 fo tcA noitazirohtuaeR sdradnatS ytilauQ yhpargommaM eht dna )842-501 .L.P( 8991 fo tcA noitazirohtuaeR sdradnatS ytilauQ yhpargommaM eht yb dezirohtuaer dna dednema saw wal sihT .snoitcepsni fo stsoc eht revoc ot seef detadnam osla tI .seitilicaf deifitrec fo snoitcepsni launna tcudnoc ot yraterceS eht detcerid dna ,smargommam fo ycarucca dna ytefas eht erussa ot sdradnats detadnam tI .mlif yhpargommam fo gnissecorp eht rof edivorp ro ,tnempiuqe tcepsni ,smargommam terpretni ro mrofrep seciveD ot ytilicaf a rof redro ni noitacifitrec eriuqer ot tcA ecivreS htlaeH cilbuP eht dednema 2991 fo tcA sdradnatS ytilauQ yhpargommaM 935-201 .stnemeriuqer ecnallievrus tekramtsop htiw ylpmoc ot lasufer ro eruliaf a saw ereht fi dednarbsim tcudorp ecived yna demeed dna ,seitlanep livic dna lanimirc ot tcejbus tca detibihorp a ecnallievrus tekramtsop gninrecnoc ACDFF eht fo snoisivorp yb desopmi tnemeriuqer a htiw ylpmoc ot eruliaf edam tI .stnemeriuqer gnitroper desiver ;derutcafunam ro dengised ylreporpmi saw ecived eht nehw ,remotsuc eht ot ecirp esahcrup eht dnufer scigoloiB ,seciveD ro ,ecived a ecalper ro riaper ot rotubirtsid ro ,retropmi ,rerutcafunam a redro ot ADF dezirohtua 2991 fo stnemdnemA eciveD lacideM 003-201 .)sgurd cireneg rof ,.e.i( sgurD snoitacilppa gurd detaiverbba gnivlovni stca lagelli rof seitlanep rehto dna tnemrabed desopmi 2991 fo tcA tnemecrofnE gurD cireneG 282-201 .wal eht htiw ylpmoc ton did taht stcudorp rof ,sllacer tcudorp ecived sa hcus ,snoitca tnemecrofne niatrec tuo yrrac ot ADF dezirohtua tca ehT .tneitap a fo yrujni ro ,ssenlli suoires ,htaed eht ot detubirtnoc ro desuac evah dluoc ecived lacidem a taht detseggus taht tnedicni yna ADF ot troper ot seciveD secived lacidem esu taht seitilicaf deriuqer dna ,secived lacidem rof stnemeriuqer tekramtsop dehsilbatse 0991 fo tcA seciveD lacideM efaS 926-101 .noitamrofni gnilebal noitirtun fo stcepsa lla gnitaluger rof ytilibisnopser ADF gnivig ,detpmeerp erew gnilebal rof stnemeriuqer lacol dna etats tsoM .smialc htlaeh dna tnetnoc tneirtun wolla a ytivitcA waL fo noitpircseD feirB dna eltiT waL cilbuP ¢ ¢ snosrep detidercca yb detcudnoc eb ot snoitcepsni tnemhsilbatse dewolla ti )2( ;secived fo sweiver tekramerp rof seef resu dehsilbatse ti )1( scigoloiB ,seciveD :secived lacidem rof snoisivorp tnacifingis eerht tcane ot ACDFF eht dednema 2002 fo tcA noitazinredoM dna eeF resU eciveD lacideM 052-701 .margorp eef resu gurd noitpircserp eht dezirohtuaeR .slamina ro snamuh ot htaed ro secneuqesnoc htlaeh esrevda suoires fo taerht a stneserp tcudorp a taht ecnedive elbiderc si ereht erehw seitlanep dna ytirohtua noitneted evitartsinimda htiw ycnega eht dedivorp dna setatS detinU eht otni detropmi gnieb stcudorp fo ADF ot eciton roirp deriuqer osla tca ehT seciveD .slamina ro snamuh ot htaed ro secneuqesnoc htlaeh esrevda suoires fo taerht a gnitneserp ro ,detaretluda eb ot tcudorp a deveileb ylbanosaer ,laminA ,scigoloiB ti nehw noitcepsni ADF rof sdrocer niatniam dna retsiger ot setatS detinU eht ni noitpmusnoc rof doof dloh ro ,kcap ,ssecorp ,erutcafunam ,sgurD ,sdooF taht seitilicaf ngierof dna citsemod lla deriuqer 2002 fo tcA esnopseR dna ssenderaperP msirorretoiB dna ytiruceS htlaeH cilbuP 881-701 .yduts detseuqer-ADF na tcudnoc ot denilced rerutcafunam gnidloh-tnetap a hcihw rof stcudorp ni dna ,stnemeerga ytivisulcxe gnitekram rehto ro tnetap yb derevoc regnol on era taht stcudorp ni hcraeser cirtaidep egaruocne ot snoisivorp dedda osla tca ehT .stroper dna seiduts esu cirtaidep detseuqer-ADF rof nruter ni rerutcafunam a ot ytivisulcxe gnitekram sgurD fo doirep htnom-xis lanoitidda na evig ot )AMADF morf( ytirohtua s'ycnega eht dewener 2002 fo tcA nerdlihC rof slacituecamrahP tseB 901-701 ].detnemelpmi reveN[ .remusnoc naciremA eht ot stcudorp derevoc fo tsoc eht ni noitcuder tnacifingis a ni tluser dluow dna ,ytefas dna htlaeh s'cilbup eht ot ksir lanoitidda on esop dluow ti taht etartsnomed ,margorp eht gnitnemelpmi erofeb ,yraterceS eht taht deriuqer wal ehT .seirtnuoc cificeps morf sgurd noitpircserp decirp-rewol tropmi ot srelaselohw gurd dna stsicamrahp gniwolla margorp raey sgurD -evif a dezirohtua )llib snoitairporppa erutlucirgA 1002YF eht fo trap ,tcA SDEM( 0002 fo tcA ytefaS gurD dna ytiuqE enicideM 783-601 .sdradnats htiw ylpmoc ot eruliaf rof seitlanep yenom livic dna ,seitilicaf fo noitcepsni ,seidob noitatidercca rof sdradnats gnidulcni ,seitilicaf seciveD yhpargommam fo noitacifitrec eht ot gnitaler snoisivorp dezirohtuaer 8991 fo tcA noitazirohtuaeR sdradnatS ytilauQ yhpargommaM 842-501 .nerdlihc ni gurd a fo esu eht fo seiduts detseuqer-ADF gnitelpmoc rof egnahcxe ni ytivisulcxe gnitekram fo shtnom xis sgurD lanoitidda na rerutcafunam gurd a tnarg ot ADF ,sraey evif rof ,dezirohtua )AMADF fo trap( tcA nerdlihC rof slacituecamrahP retteB 511-501 .secived devorppa fo sesu devorppanu fo gnisitrevda ynapmoc etaluger ot dna secived fo weiver tekramerp etarelecca ot serusaem dedulcni snoisivorp ecived lacideM .dradnats yrotutats eht gnicuder tuohtiw smialc tnetnoc noitirtun dna smialc htlaeh ezirohtua nac ADF hcihw rednu serudecorp dednapxe noisivorp doof rehtonA .ycnega eht ot tsoc sti revoc ot snoitairporppa lanoitidda no tnegnitnoc si ssecorp noitacifiton eht fo noitatnemelpmI .tcudorp wen eht tekram ot deecorp dluoc rerutcafunam eht ,syad 021 nihtiw detcejbo ADF sselnu dna secnatsbus tcatnoc doof niatrec esu ot noitnetni sti tuoba ycnega eht yfiton ot rerutcafunam eht rof ssecorp a dehsilbatse wal eht ,daetsnI .tcudorp doof eht otni etargim yam dna doof htiw tcatnoc ni emoc taht secnatsbus rehto dna gnigakcap tsom rof lavorppa tekramerp s'ADF fo tnemeriuqer eht detanimile tI .snoitaluger doof ot cificeps snoisivorp fo rebmun detimil a deniatnoc AMADF .stcudorp detaluger fo gnitekram eht etidepxe ot gnikees elihw elor noitcetorp htlaeh cilbup a niatniam ot ti etagilbo lliw taht tnemetats noissim a rednu snoitcnuf yrotaluger sti tcudnoc ADF taht deriuqer dna ;scitemsoc dna sgurd noitpircserpnon fo noitaluger eht ni ytimrofinu lanoitan dehsilbatse dna stnemeerga noitazinomrah lanoitanretni degaruocne ;seipareht lanoitagitsevni ot ssecca tneitap dednapxe dewolla seciveD ;seussi cifitneics laisrevortnoc gnivloser rof snaem a edivorp dna ssecorp weiver gurd eht enilmaerts ot stnemucod ecnadiug deriuqer ;lavorppa ,laminA ,scigoloiB gurd rof stnemeriuqer niatrec desae ;snoitidnoc gninetaerht-efil taert dluow taht sgurd ot noitaredisnoc lavorppa kcart tsaf dedivorp ;sraey ,sgurD ,sdooF evif rof margorp eef resu gurd noitpircserp eht dezirohtuaer )AMADF( 7991 fo tcA noitazinredoM noitartsinimdA gurD dna dooF 511-501 .noitpircserp yraniretev a htiw ,sdeef lamina ni sgurd yraniretev fo esu eht dettimrep osla wal eht ,snoisivorp rehto gnomA .ssenevitceffe fo ecnedive laitnatsbus fo noitinifed eht gnidnema laminA yb ,sgurd lamina wen gnivorppa dna gnitaulave ni ytilibixelf erom ADF tnarg ot ACDFF eht dednema 6991 fo tcA ytilibaliavA gurD laminA 052-401 .noitpecxe na rof snoititep etats a sselnu ,secnarelot fo ytimrofinu lanoitan deriuqer dna ,wonk ot thgir eht ,gnitset enircodne rof a ytivitcA waL fo noitpircseD feirB dna eltiT waL cilbuP ¢ ¢ scigoloiB ,seciveD tegrat eunever eef laeper ,seef resu ecived lacidem tsujda ot ACDFF eht dednema 5002 fo tcA noitazilibatS eeF resU eciveD lacideM 34-901 .7002YF hguorht snoitairporppa detaler dezirohtua dna ;eettimmoC yrosivdA ecnarussA ytilauQ yhpargommaM lanoitaN eht gnidrager yraterceS eht fo stnemeriuqer niatrec edam ;secnatsmucric niatrec ni noitatiderccaer gnikees ytilicaf yhpargommam a ot etacifitrec lanoisivorp detimil a ro etacifitrec lawener yraropmet seciveD a eussi ot yraterceS SHH eht ezirohtua ot ASHP eht dednema 4002 fo tcA noitazirohtuaeR sdradnatS ytilauQ yhpargommaM 563-801 .ydob eht ni detrevnoc eb dluow taht diorets taht ot rosrucerp a ro diorets cilobana na deniatnoc taht stcudorp yna sdooF erew dedulcnI .secnatsbus dellortnoc sa stcudorp tnemelppus yrateid dna gurd niatrec deifissalcer 4002 fo tcA lortnoC dioretS cilobanA 853-801 .ytivisulcxe gnitekram fo sraey neves dna ,gnitset ssenevitceffe dna ytefas troppus ot stnarg gnidulcni ,)tcA gurD nahprO namuh eht ot ralimis( lavorppa rof sevitnecni niatrec )3( dna ;lavorppa lanoitidnoc a rednu neve ssecorp lavorppa eht fo stsoc eht troppus ot llams oot si gurd a rof tekram laitnetop eht nehw ,sgurd lamina wen devorppanu detekram yllagel fo xedni na ot gurd eht fo noitidda )2( ;efas si gurd eht gnivorp retfa tub ,atad ssenevitceffe yrassecen lla gnitcelloc erofeb elbaliava gurd a ekam ot rosnops eht swolla hcihw ,lavorppa lanoitidnoc )1( :ezirohtua ot ACDFF eht dednema wal ehT .)stac dna ,sgod ,sesroh ,syekrut ,snekcihc ,eniws ,elttac( seiceps lamina rojam ni sesaesid nommocnu dna laminA ,seiceps lamina ronim taert ot sgurd fo ytilibaliava eht decnahne )SMUM( 4002 fo tcA htlaeH laminA seicepS roniM dna esU roniM 282-801 .doof a ni tneserp era snegrella esoht fo yna nehw tcudorp doof a no raeppa sdooF snegrella tneuqerf tsom eht tuoba tnemetats cificeps a taht deriuqer 4002 fo tcA noitcetorP remusnoC dna gnilebaL negrellA dooF 282-801 .snoisivorp rehto gnoma ,kcatta tsirorret a ni desu eb yam taht stnega raelcun dna ,lacigoloib ,lacimehc ot serusaemretnuoc scigoloiB ,sgurD sa stnemtaert fo noitubirtsid dipar elbane ot serudecorp weiver sti etidepxe ot ADF dezirohtua 4002 fo tcA dleihSoiB tcejorP 672-801 .gnilebal cinortcele dna ,stnemeriuqer noitatidercca dna noitcepsni ytrap-driht ,seef resu secived lacidem gninrecnoc snoisivorp esiver ot )2002 fo scigoloiB ,seciveD tcA noitazinredoM dna eeF resU eciveD lacideM eht yb dednema sa( ACDFF eht dednema tcA snoitcerroC lacinhceT seciveD lacideM 412-801 .deriapmi yllausiv dna dnilb eht ot noitamrofni gurd noitpircserp edivorp ot seigolonhcet esu ot woh yduts ot yraterceS eht deriuqer osla tca ehT .setatS detinU eht otni sgurd noitpircserp fo noitatropmi eht no ssergnoC ot troper dna yduts ot yraterceS SHH eht detcerid osla ti ;sgnivas tsoc dna ytefas fo noitacifitrec s'yraterceS eht deriuqer osla taht noitces ralimis a htiw tcA sgurD SDEM eht morf snoisivorp noitatropmi gurd eht decalper 3002 fo tcA noitazinredoM dna tnemevorpmI gurD noitpircserP eracideM 371-801 .sksir tnacifingis esop dluoc lebal eht no noitamrofni esu cirtaidep gnivah ton hcihw ni snoitautis ni tnemssessa cirtaidep a timbus ot cigoloib desnecil ro gurd devorppa na fo rerutcafunam eht eriuqer ot yraterceS eht dezirohtua osla tca ehT .evitceffe dna efas si tcudorp eht hcihw rof noitalupopbus cirtaidep hcae rof noitartsinimda dna gnisod troppus ot dna ;snoitalupopbus cirtaidep tnaveler lla ni snoitacidni demialc eht rof tcudorp eht fo )noitartsinimda dna gnisod troppus ot atad dna( ssenevitceffe dna ytefas eht fo tnemssessa cirtaidep a ,cigoloib ro gurd a rof noitartsinimda fo etuor wen ro ,nemiger gnisod wen ,mrof egasod wen ,noitacidni wen scigoloiB ,sgurD ,tneidergni evitca wen a tekram ot noitacilppa na htiw gnola ,timbus ot rerutcafunam a deriuqer 3002 fo tcA ytiuqE hcraeseR cirtaideP 551-801 .8002 ,1 rebotcO retfa stesnus ytirohtua margorp AFUDA .AMFUDM dna AFUDP ot ralimis si wal ehT .sgurd lamina fo weiver eht fo troppus ni ,snoitacilppa gurd lamina devorppa ylsuoiverp dna eseht htiw detaicossa srosnops dna ,stcudorp ,stnemhsilbatse eht rof dna laminA ,snoitacilppa gurd lamina niatrec rof seef tcelloc ot ADF gnizirohtua ,ACDFF eht dednema )AFUDA( 3002 fo tcA eeF resU gurD laminA 031-801 .)34-901 .L.P( 5002 fo tcA noitazilibatS eeF resU eciveD lacideM eht dna ,)412-801 .L.P( tcA snoitcerroC lacinhceT eciveD lacideM eht yb deifidom saw tI .secived esu-elgnis dessecorper rof stnemeriuqer yrotaluger wen detutitsni ti )3( dna ;)seitrap driht( a ytivitcA waL fo noitpircseD feirB dna eltiT waL cilbuP ¢ ¢ .htlaeH lacigoloidaR dna seciveD = seciveD ;sdeeF dna sgurD laminA = laminA ;sgurD namuH = sgurD .a .cilbup eht ot elbaliava edam eb ot noitamrofni dna ,noissim ADF eht troppus seciveD ot ytitne tiforpnon wen a ,seitlanep yratenom livic ,sesabatad lairt lacinilc gninrecnoc esoht erew seitirohtua wen eht gnomA .secived lacidem ,laminA ,scigoloiB dna ,scigoloib ,sgurd noitpircserp ,)sdeef lamina gnidulcni( doof fo ytefas eht etaluger ot ytirohtua s'ycnega eht dednapxe dna ;)sevitnecni ,sgurD ,sdooF hcraeser cirtaidep ,seef resu ecived lacidem dna gurd noitpircserp( smargorp ADF gnitsixe dezirohtuaer 7002 fo tcA stnemdnemA ADF 58-011 .sdrocer detaler fo noitcepsni timrep dna niatniam dna ,noitamrofni puwollof yna troper ,tcudorp eht fo esu htiw detaicossa tneve esrevda suoires yna ,syad ssenisub 51 nihtiw ,ADF ot troper ot tnemelppus ro gurd noitpircserpnon a fo lebal eht no sraeppa eman esohw rotubirtsid ro ,rekcap sdooF ,rerutcafunam a eriuqer ot ACDFF dednema 6002 fo tcA noitcetorP remusnoC gurD noitpircserpnoN dna tnemelppuS yrateiD 264-901 .rerutcafunam eht seifitnedi ti sselnu ecived esu elgnis dessecorper yna dednarb sa meed dna ,stnemtsujda gnittes eef etanimile ,stnuoma a ytivitcA waL fo noitpircseD feirB dna eltiT waL cilbuP ¢ ¢ ¢ ¢ Judith A. Johnson, Coordinator Susan Thaul Specialist in Biomedical Policy Specialist in Drug Safety and Effectiveness jajohnson@crs.loc.gov, 7-7077 sthaul@crs.loc.gov, 7-0562 Donna V. Porter Erin D. Williams Specialist in Nutrition and Food Safety Specialist in Public Health and Bioethics dporter@crs.loc.gov, 7-7032 ewilliams@crs.loc.gov, 7-4897 ------------------------------------------------------------------------------ For other versions of this document, see http://wikileaks.org/wiki/CRS-RL34334