3
Clinical Research Funding and Infrastructure

About $22 billion (16.7 percent) of the estimated $132 billion currently invested in research and development (R&D) by all sectors in the United States is health-related (National Institutes of Health, 1993b; National Science Foundation, 1992). The federal government is generally regarded as the primary sponsor of biomedical research, but, in fact, funding comes from a myriad of public and private sponsors, each with their own objectives or missions. During the 1980s, however, the portion supported by the federal government plummeted, decreasing from 59 percent in 1980 to an estimated 41 percent in 1992 (Figure 3-1) (National Institutes of Health, 1993b). The most notable change in this ratio over the past decade has been the growing contribution by industry, which has grown from 31 to 48 percent over the same period. Of the remainder, private nonprofit organizations supported about 4 to 5 percent, and state and local governments supported a small amount of health research.

Although less well appreciated, the contributions by the academic health centers themselves cover many of the costs of performing research (Commonwealth Fund, 1985). For example, many centers sponsor a variety of research activities with their own funds, such as covering the costs of starting up newly independent investigators, providing bridging funds for ongoing, high-quality research activities that fell just short of the funding level because of limited federal funds, and funding other projects that for various reasons may not or cannot be funded by other sponsors. Private philanthropy is not easily quantified, because it can be derived from a variety of private sources and large gifts or commitments to build research infrastructure may not be included in the accounting for research.



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Careers in Clinical Research: Obstacles and Opportunities 3 Clinical Research Funding and Infrastructure About $22 billion (16.7 percent) of the estimated $132 billion currently invested in research and development (R&D) by all sectors in the United States is health-related (National Institutes of Health, 1993b; National Science Foundation, 1992). The federal government is generally regarded as the primary sponsor of biomedical research, but, in fact, funding comes from a myriad of public and private sponsors, each with their own objectives or missions. During the 1980s, however, the portion supported by the federal government plummeted, decreasing from 59 percent in 1980 to an estimated 41 percent in 1992 (Figure 3-1) (National Institutes of Health, 1993b). The most notable change in this ratio over the past decade has been the growing contribution by industry, which has grown from 31 to 48 percent over the same period. Of the remainder, private nonprofit organizations supported about 4 to 5 percent, and state and local governments supported a small amount of health research. Although less well appreciated, the contributions by the academic health centers themselves cover many of the costs of performing research (Commonwealth Fund, 1985). For example, many centers sponsor a variety of research activities with their own funds, such as covering the costs of starting up newly independent investigators, providing bridging funds for ongoing, high-quality research activities that fell just short of the funding level because of limited federal funds, and funding other projects that for various reasons may not or cannot be funded by other sponsors. Private philanthropy is not easily quantified, because it can be derived from a variety of private sources and large gifts or commitments to build research infrastructure may not be included in the accounting for research.

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Careers in Clinical Research: Obstacles and Opportunities Also intertwined in this labyrinth of clinical research funding is the role of third-party payers. Although third-party payers, particularly Medicare, have underwritten some of the costs of medical education, the costs of experimental or investigational therapies have not generally been allowed as reimbursable, even though the results of clinical studies will define future standards for medical care. The growing concerns about cost-containment and a shift toward managed care are having an effect on what insurers will cover, even in the use of standard therapy (Antman et al., 1988 and 1989; Wittes 1987b). The committee is concerned that these coverage decisions might not be based on the best and most up-to-date information. Furthermore, cost-containment decisions might encourage the use of outmoded therapies rather than foster the timely introduction of truly novel or innovative therapies that could lead to long-term savings. Some feel that insurers and other third-party payers have a fundamental interest in and responsibility for supporting evaluative, patient-oriented clinical research to engage in coverage decisions and to facilitate the adoption of more cost-effective care (leaf, 1989; Newcomer, 1990). The total costs of clinical research cannot be shifted to insurers, but they are participants in providing care and should support and promote definitive studies that will define standards of care, assess the effectiveness of current therapies, and provide new effective therapies. Thus, the committee includes here a section on the roles and responsibilities of third-party payers. Realizing how critical funding is to successful research careers, particularly the perception by clinical scientists of their inability to garner funds for patient-oriented studies, the committee devoted time to develop a clearer understanding of the research funding base. Many of the commissioned papers included some reference to the tenuous nature of research funding, and the committee sponsored an invitational workshop, "Clinical Research and Training: Spotlight on Funding," in June 1992. This chapter explores trends in research funding by the various sectors. Because of inadequate data collection methods by research sponsors, it was frequently impossible to disaggregate research funds devoted to patient-oriented clinical research from other research funds. When possible, however, the trends in funding for patient-related research are elaborated. Since academic research careers are closely intertwined with the investigator-initiated, peer-reviewed grant system in the Public Health Service, including the National Institutes of Health (NIH) (and previously the Alcohol, Drug Abuse and Mental Health Administration [ADAMHA]), the committee focused considerable attention on this process. THE BIG PICTURE Prior to World War II, health research was sponsored primarily by industry, academic institutions, and private individuals (Ginzberg and Dutka, 1989).

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Careers in Clinical Research: Obstacles and Opportunities Following the war, policy changes initiated by Vannevar Bush, then head of the Office of Scientific Research and Development, began the surge of federal investment in university-based fundamental research. Bush and his colleagues formulated a set of proposals intended to sustain the nation's wartime research momentum and direct it toward civilian goals. These policies, outlined in his report to the President, "Science—the Endless Frontier" (Bush, 1945), proposed a coordinated federal policy of investing in research and the training of new researchers that would be driven by scientific merit rather than by political or geographical interests. This approach became the cornerstone of the peer-reviewed, academically based system now in place for federally sponsored, competitive extramural research grant programs. From the end of the war to the mid-1960s, the federal government invested heavily in health research and allocated resources to build health research facilities and to create programs to train health researchers (Institute of Medicine, 1990). Moreover, the synergism between federally sponsored research and research sponsored by industry and the private nonprofit sectors thrust the United States into the forefront of biomedical research. In the 1960s, increasing allocations for the war in Southeast Asia and the Cold War buildup began to constrain the federal resources available for domestic programs, including health research. In the 1970s, the health research budget plateaued, and high inflationary pressures further reduced the purchasing power of research funds. Over the past decade, the nation's expenditures for health research have tripled when measured in current dollars. After adjusting for inflation, which was relatively low throughout the 1980s, this investment grew by 65 percent (Figure 3-1). The health research enterprise has been highly successful, but the system has become increasingly stressed in recent years. The most significant reason is the concern over growing federal debt and recent legislation attempting to reduce the huge annual federal budget outlays. The 1980's policy of increased spending but decreased taxes has put the U.S. government in a precarious financial position and has mortgaged the country for many years to come. There are anticipated decreases in defense spending, but expectations for increased funding in other categories of the federal budget remain low. Recent attempts to reduce federal deficits have increased the competition for scarce funds for all federally financed programs. State funds and those from private sector sources have been unable to compensate for the slower growth of available federal funds. The increasing competition among worthy projects has often resulted in concessions to short-term needs rather than longer-term investments. The combination of increasing research costs and increasingly constrained funding has sent shock waves throughout the academic research community (Lederman, 1991; Movsesian, 1990). The broad array of research sponsors and the decentralized nature of the research of thousands of individual investigators are responsible for the success of health research over the past half-century.

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Careers in Clinical Research: Obstacles and Opportunities FIGURE 3-1 U.S. Support for health research and development by source of funds from 1977 to 1993. (Source: National Institutes of Health, 1993b.)

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Careers in Clinical Research: Obstacles and Opportunities FEDERAL SUPPORT FOR HEALTH SCIENCES R&D As a result of the postwar policy changes, the federal government became the largest single sponsor of health research, and programs that support health research can be found in numerous federal agencies (U.S. Congress, Office of Technology Assessment, 1991). About three fifths of these funds now come from programs in the U.S. Department of Health and Human Services (DHHS), including those in the Public Health Service (PHS) (Figure 3-2) (National Institutes of Health, 1993b). Within the PHS, NIH—which now includes the National Institute of Alcohol and Alcohol Abuse, the National Institute of Drug Abuse, and the National Institute of Mental Health—allocate the largest percentage of federal funds for health-related research (Figure 3-2). Research funds are also appropriated for the Centers for Disease Control and Prevention (CDC); the Health Care Financing Administration; the Health Resources Administration; the Food and Drug Administration (FDA); the Health Services Administration; the Office of Health Research, Statistics, and Technology; the Agency for Health Care Policy and Research; and the Office of the Assistant Secretary for Health in PHS. Other federal departments and agencies have budgets for health sciences research as well, most notably the Departments of Agriculture, Defense, Education, Energy, and Veterans Affairs and the National Science Foundation (see Figure 3-2). Even though some agencies have only a minimal role in sponsoring clinical research, they may require highly talented clinical investigators to carry out their mission, such as investigators at FDA and CDC. Thus, the committee sought to determine the fraction of federally sponsored research that involved human subjects. National Institutes of Health Of the nearly half of all financial support for health research that comes from federal sources, about three quarters is disbursed through NIH. The postwar policy decision to support fundamental research in academic institutions stimulated steady increases in NIH's budget (Figure 3-3). The most rapid growth in the NIH budget occurred between 1955 and 1965. From the late 1960s to 1980, budget growth for NIH leveled off. During the 1980s, however, congressional appropriations to NIH increased an average of 10 percent a year, resulting in a 2 percent per annum real growth in the NIH budget (National Institutes of Health, 1991). Many of the increases over the past few years can be attributed to the growth in funding for AIDS research. The new initiative for research into women's health issues has not yet stimulated growth in the NIH budget, but the Clinton administration and U.S. Congress have the opportunity to make these changes.

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Careers in Clinical Research: Obstacles and Opportunities FIGURE 3-2 Source of federal support for health research and developmentby agency for 1992. (Source: National Institutes of Health, 1993b.)

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Careers in Clinical Research: Obstacles and Opportunities FIGURE 3-3 NIH appropriations from 1945 to 1992 in current and constant 1992 dollars. (Source: U.S. Department of Health and Human Services, Public Health Service, 1991e.) Allocations among extramural and intramural NIH programs and program management have not changed significantly since the late 1970s (Figure 3-4). Only about 10 to 12 percent of NIH budget is allocated for research conducted intramurally. Nearly 80 percent of the NIH budget is allocated to extramural programs for research and training at universities and other research institutions both in the United States and abroad (National Institutes of Health, 1993b). Most of these extramural research funds are allocated through peer review processes for research grants and cooperative agreements. A small fraction of these funds are allocated for research contracts as well. Nevertheless, since the expansion of NIH extramural programs began in the mid-1940s, R&D grants have been, and continue to be, the cornerstone of NIH and ADAMHA extramural support for health research. Intramural Research Although the intramural research program at NIH includes a broad portfolio of activities such as basic research, training, communication of scientific findings, development of policies on biomedical research priorities, and

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Careers in Clinical Research: Obstacles and Opportunities FIGURE 3-4 Allocation of the NIH budget from 1977 to 1992. (Source: National Institutes of Health, 1993b.) translation of research findings into more effective medical care, the committee was most concerned about the research activities and training at the Warren Grant Magnuson Clinical Center. The clinical center was established in 1953 on the Bethesda, Maryland, campus of NIH to facilitate research using human subjects that could not be conducted at academic medical centers for various reasons (Ahrens, 1992). The clinical center currently has about 500 patient beds, or about 50 percent of all the research beds in the country. The remaining 50 percent are located throughout the country in academic health centers that are largely supported by NIH institutes and centers. Since its inception, the clinical center has served as a training ground for clinical investigators, may of whom are now on the faculty at academic health centers around the country. Resource limitations precluded the committee from undertaking a comprehensive assessment of the clinical center, but the committee drew upon several studies done in the 1980s that examined the structure of NIH (Institute of Medicine, 1985), the intramural program (Institute of Medicine, 1988b), and research at the clinical center (Ahrens, 1992; Institute of Medicine, 1987; National Institutes of Health, 1986).

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Careers in Clinical Research: Obstacles and Opportunities There are two primary advantages for scientists who conduct research at the clinical center: (1) they do not have to compete for resources through the extramural peer review system and (2) they are not distracted from their research by obligations to teach or provide clinical services to the general public like their counterparts at academic medical centers are (Ahrens, 1992). Many criticisms of the intramural program have surfaced over the past decade suggesting that the quality of intramural research has declined. Some have suggested that peer review of the intramural research community is not as rigorous as that of the extramural research community. Further, it has recently been suggested that the organization of research groups has stifled cutting-edge investigations. It has been argued, on the other hand, that scientific oversight within NIH is as rigorous for intramural research scientists as peer review is for the extramural research community. The intramural research budget has not grown in real terms over the past decade, and intramural research scientists are therefore competing internally for scarce resources. The clinical center has accredited training programs in some fields, increasing the teaching requirements of the staff physician-scientists. Although the NIH campus served as a primary training ground for health scientists in the 1950s and 1960s, there were signs in the 1980s that NIH was beginning to have difficulty attracting and retaining scientists, including clinical investigators. During the 1980s, there was speculation that the intramural research program was not performing at the same level of quality demonstrated in the past. The relatively low government salary scales, noncompetitive fringe benefits, and the other bureaucratic constraints of working in a federal agency are thought to be contributory (Institute of Medicine, 1988b). It also has been postulated that the military draft may have been a driving force encouraging research-oriented scientists to pursue research training there during the mid to late 1960s. In response to these concerns and to the suggestion that the intramural program could benefit by shifting to the private sector, the Institute of Medicine (IOM) conducted an in-depth review of the program in 1988 (Institute of Medicine, 1988b). The IOM study committee concluded that the intramural program has made, and continues to make, valuable contributions to understanding basic biological and disease processes. For example, an analysis by Ahrens of 36 physician-scientists at the clinical center revealed that intramural scientists publish more papers on both clinical and nonclinical research than their counterparts in medical schools do (Ahrens, 1992). Moreover, the first gene therapy protocols have been carried out at the clinical center. Despite difficulties in effectively coordinating activities across institutes and responding efficiently to new challenges or crises, the IOM study committee concluded that the federated organizational structure of NIH has helped meet the nation's biomedical research goals. To maintain the intramural program's excellence and credibility and to improve in areas which it is deficient, the study committee recommended some changes in NIH administration as well as in the

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Careers in Clinical Research: Obstacles and Opportunities scope of responsibilities of scientific administrators directing the intramural programs (Institute of Medicine, 1988b). Beyond the general problems associated with the intramural program, the clinical center presents specific problems because of its role and position in the federation of institutes. According to the an NIH report, the center has struggled with an identity problem (National Institutes of Health, 1986). In one sense, the center might be viewed as a hospital with all the requisite responsibilities associated with patient care. In another sense, the center appears to be a collection of the clinical research fiefdoms of the activities of each separate institute, where ''The Clinical Center per se has very little power in determining its practical management, its clinical research program, or its fiscal decisions." (National Institutes of Health, 1986). Indeed, the clinical center budget is determined by the individual institutes on the basis of their research involvement and previous bed allocation. Although a medical board composed of the clinical directors from each institute help guide policy at the clinical center, some believe that an external advisory board should be constituted along the lines of the institute advisory councils to review protocols to ensure appropriate allocation of clinical center resources and an appropriate level of research activity for each institute. Although the committee understands that there are problems with the physical infrastructure of the clinical center and intramural clinical investigators share the same career obstacles, the committee did not feel that it had enough information or insight to make recommendations concerning the intramural program. Furthermore, a recent report on the NIH intramural program by an ad hoc panel has proposed a new, yet smaller (about 200 bed) clinical center (Marshall, 1994). Extramural Programs at NIH R&D grants, particularly investigator-initiated research project grants (R01), are the cornerstone of the extramural research program at NIH. To more clearly understand the support base for clinical research, the committee felt that it would be useful to recap some of the problems and policy changes that have affected the entire extramural research community over the past decade. When possible, the committee's analysis focused on patient-oriented clinical research. As growth in the NIH budget slowed during the mid-1970s, competition for grants intensified, and the number of new and competing renewal grants awarded by NIH fluctuated annually (Institute of Medicine, 1979; Seggel, 1985). Through the 1970s the number of funded new and competing proposals ranged from as few as 3,500 in 1976 to as many as 5,900 in 1979. The number funded annually did not follow any particular pattern, but depended on the cumulative grant portfolio and funds appropriated for a particular institute. These erratic patterns meant that

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Careers in Clinical Research: Obstacles and Opportunities even outstanding grant proposals often were not funded. Scientists began to feel that obtaining funding from NIH was unpredictable and had no regard for an investigator's previous research accomplishments or the significance of one's research. Moreover, the decreasing proportion of research grants being awarded to physicians raised concerns that the number of physician-investigators was declining and that measures must be taken to turn this situation around (Kelley, 1980; Thier et al., 1980; Wyngaarden, 1979). The 1979 and 1980 reports by Institute of Medicine for the DHHS Steering Committee for the Development of a Health Research Strategy reexamined these concerns about the future of federal support for new and ongoing health research in light of impending federal budget constraints. The Steering Committee called for five-year plans and evaluative procedures to be established for all of the health-related agencies in DHHS and emphasized the need to stabilize the science base by making investigator-initiated research projects the first priority in NIH and ADAMHA research budgets (Institute of Medicine, 1979 and 1980). The 1979 Steering Committee report suggested that the minimum number of competitive research grant awards for fiscal year 1981 be 5,000 for NIH and 569 for ADAMHA (Seggel, 1985). Although NIH was able to fund the recommended number of new and competing awards, appropriations for 1981 allowed ADAMHA to fund only 284 new and competing awards that year—only half the recommended level. As a result, U.S. Congress and the executive branch agreed on a policy that specified the minimum number of new and competing grants NIH and ADAMHA would be required to fund each year—a "stabilization policy." Thus, establishing the number of new and competing proposals to be funded became an integral part of the federal budget policy that remained in place through fiscal year 1988 (Institute of Medicine, 1990). The stabilization policy prevented erosion of the nation's scientific base by maintaining minimum annual numbers of investigator-initiated research grants. The total number of research project grants sponsored by NIH grew from 15,500 to 20,867 between 1977 and 1988. Research project grants increased from 51 percent of the total NIH extramural budget in 1978 to 67 percent in 1989 (Figure 3-5). Funding for research project grants grew from $ 2.5 billion in 1977 to $ 3.9 billion by 1989, when measured in constant 1988 dollars. Along with this growth, the expectation of funding may have encouraged scientists to submit more grant applications, which increased from 14,142 in 1980 to 20,154 by 1990 (Figure 3-6) (National Institutes of Health, 1993b). It should also be noted, however, that the number of amended applications grew significantly over the same period and now makes up nearly 30 percent of the application pool. By 1987, the number of new and competing awards made annually reached a peak of 6,400 for NIH and 600 for ADAMHA. Other forces were affecting the available pool of funds for scientists competing for funding in 1990. Despite added appropriations from Congress throughout the 1980s, the funds available were never adequate to fund fully the

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Careers in Clinical Research: Obstacles and Opportunities research accounts for only 5 percent (National Science Foundation, 1988b). There is another way to view investment; that is, approximately one third of a pharmaceutical firm's R&D investment is devoted to discovery and new product development, one third is spent on existing product improvement and expansion of current business, and one third is directed toward process improvement for defending current market shares of products (Institute of Medicine, 1990). Whatever the measure or matrix of investment, a large portion of pharmaceutical R&D is spent on clinical evaluation of drugs in phases I through IV of clinical evaluation (Table 3-7). Biotechnology is one subcategory of industrial biomedical R&D of particular importance to this committee (Blumenthal et al., 1986a, 1986b). The ability to synthesize proteins and peptides, new biological approaches to drug delivery such as the use of liposomes to encapsulate drugs, and other biological advances are rapidly expanding opportunities for finding and testing new biological therapies (Telling, 1992). The private sector, however, is not the exclusive investor in biotechnology. Whereas the federal government, primarily NIH, has been the primary source of R&D funds for biotechnology, the commercial markets for new biologicals is encouraging increased investment in biotechnology by industry. NIH reported that nearly 22 percent, or $1.02 billion, of its 1988 R&D budget was allocated to research on developing biotechnology techniques or employing the biotechnology (Institute of Medicine, 1990). The size of NIH investment in biotechnology reflects the importance of molecular and cellular biology in biomedicine. CLINICAL RESEARCH AND THIRD-PARTY PAYERS A chapter on the resources of funding for clinical research would not be complete without a discussion of the contributions to clinical research by third-party payers. In the United States, the relationship among insurers, subscribers, employers, and providers is unique. For many with employer-based health coverage, the employer establishes the contract of coverage, the employee pays part of the premium for the health coverage that the employer has established, and the third-party payer is the steward of the funds. The policy for those with federally supported coverage, such as Medicare or Medicaid, has been not to cover investigational or experimental therapies. The sad irony is that the 35 million or more people who have no health care coverage have more freedom to enroll in clinical studies or receive experimental therapy because they have no stake in who pays, and no third-party questions their decision. Unfortunately, very little is known about the amount of support actually contributed by third-party payers. There are no databases that track this investment, and in many instances, it is believed that the less known, the better. Another variable in this equation is the amount of unreimbursed care provided by

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Careers in Clinical Research: Obstacles and Opportunities hospitals and medical centers for individuals enrolled in clinical studies or trials; for example, those covered under Medicare. The committee was clearly aware of the problems of assessing the level of involvement of third-party payers in clinical research, but it felt strongly that the relevant policy issues should be explored. Thus, while this section is short on data, it draws upon presentations by executives from the insurance sector given at the workshop "Clinical Research and Training: Spotlight on Funding" (see Appendix D). An unwritten understanding previously promoted, or at least did not discourage, the participation of patients in clinical studies or trials in which third parties contributed patient care costs, whether or not they were cognizant of it. For example, an extra computed tomography scan or other test might be performed to collect longitudinal data, and the claim would be covered without question. Changes in health care coverage in the past 15 years—with the emphasis on reigning in costs by cutting hospital stays and other care not proven to be cost-effective or efficacious—have altered this fragile relationship. The move to prospective payment based on diagnostic-related groups may also have affected the enrollment of patients in clinical studies. With computerized technology, third-party payers are able to scrutinize how patients are being treated and question why they should be supporting experimental studies. Government programs, both Medicare and state Medicaid programs are having the same difficulties that the science agencies are experiencing—scrambling for scarce resources in the federal budget. The for-profit private insurers must be equally concerned with covering the soaring costs for standard therapies and paying dividends to shareholders. Even the nonprofit insurers like Blue Cross and Blue Shield must be concerned with balancing their cash flow. Thus, most third-party payers probably believe that clinical research falls far outside of their boundaries of responsibility. Old therapies that may or may not be effective are not being adequately assessed, and new medical technologies and therapies are evolving very rapidly. At the same time, biomedical scientists are becoming increasingly sophisticated in understanding the biological bases of disease processes and the heterogeneity of patient populations. This synergism stokes the engine for even more scientific inquiry to define more precise fits between treatments and specific patient populations, not only for the good of science, but certainly for the benefit of the patients. Coupled to this is the public's expectation for increasingly sophisticated health care with cascades of tests and procedures and without concern for how the costs will be covered. Patients with incurable diseases also expect to have access to the best possible care or optimal therapy—even if that involves enrolling in a clinical study for testing an unproven therapy. Viewed purely on a cost basis, standard therapy may be the least expensive in the short run. A well-designed clinical trial, however, may uncover an improved therapy to reduce morbidity or mortality and, it is hoped, improve quality of life, despite the high initial costs. The conundrum that has arisen is that an adversarial situation has

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Careers in Clinical Research: Obstacles and Opportunities developed between the patients and their doctors, on the one hand, and the patients and the third-party payers, on the other, because the affected parties cannot agree on what portion of clinical investigation is reimbursable (Newcomer, 1990). The bottom line is that reimbursement of costs is essential. Someone must ultimately pay for the costs associated with experimental therapy as well as the costs of standard medical care, whether it is the federal government (Health Care Financing Administration, NIH, and the like), the third-party payers, the institutions, or other sponsors of research. Following the paradigm of the past, clinical investigators expected that insurers would reimburse the costs of legitimate care associated with sponsored research of the highest quality. At the same time, it was believed that the sponsor of the research should bear the cost associated with the research. Nevertheless, it is frequently difficult to separate the care costs from the research costs, and most of the disagreement focuses on this gray area. This is particularly evident in the treatment of cancer, where almost all treatment is some form of experiment, often using class C (cancer) drugs or combining two or more types of therapies (Antman et al., 1988; Wittes, 1987b). Another point of contention is the refusal by a payer to allow reimbursement for any care if a covered patient is enrolled in a study Wittes 1987b and 1988). Patients, however, are suing their insurers to allow them to enroll in clinical studies and receive coverage for both the standard care and the experimental therapy, especially when standard therapies are not much improved over no treatment. Although this puts pressure on third-party payers to cover the costs associated with the standard care and those associated with the experimental therapy, moving these controversies into the courts may not be the best way to encourage participation in clinical research. After prolonged legal procedures, as well as high legal costs for the patient and the patient's family, the decision is usually left in the hands of a jury, which is unlikely to have the requisite expertise in experimental medicine. The result fails to serve good medicine, appropriate patient care, or sound reimbursement policy. Furthermore, it ties up everyone's time and resources and prolongs the potential benefit a patient might receive from the investigational therapy. A better route would be to have clinicians, in collaboration with payers, make sound decisions based on clear clinical research data about whether to provide care under an experimental protocol. One example of growing cooperation among the affected parties is the use of autologous bone marrow transplantation for treating metastatic breast cancer. This is a developing technology that is costly, effort-intensive, and somewhat toxic, but it has shown some promise over standard therapy. Briefly, it consists of harvesting autologous bone marrow from a patient, administering very high doses of chemotherapy or radiation therapy to inactivate the metastatic cells, and then reconstituting the normal hematopoietic elements from the harvested bone marrow. Hospitalization is necessary for anywhere from a few days to several weeks, and the cost for such treatment has been in the range of $75,000 to

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Careers in Clinical Research: Obstacles and Opportunities $150,000 per patient. That this therapy is available is a tribute to the sponsors of fundamental research, including the National Cancer Institute, the American Cancer Society, and the American Leukemia Society. More interesting, however, is the paradigm for supporting a large, multicenter clinical trial on the therapy. After losing several suits forcing various payers to cover the costs of this therapy, a coalition of third-party payers, including some of the individual Blue Cross and Blue Shield plans, have agreed to fund a demonstration project in which they will accept some responsibility for paying the clinical care costs associated with these particular national studies. This may signal a new paradigm for sharing the costs of clinical research in which payers, clinical investigators, and patients all cooperate to further understanding of novel and innovative therapies. Third-Party Payers' Perspective It has become increasingly necessary for plans to serve their subscribers while striving for access to quality health care at an affordable price. Inextricably bound to those objectives are the processes of technology assessment and coverage determination. Medical technology committees, frequently including physicians and subscribers, have become increasingly sophisticated and have established sets of criteria to guide coverage, including cost-effectiveness, legal, ethical, and cultural differences, and distributive justice (Whether the technology is available to all subscribers.). These criteria have been delineated after some years of study to help determine when a technology has reached a stage at which it is no longer considered investigational and can be accepted as eligible for coverage. Once the criteria have been satisfied and the committee has determined that a critical mass of evidence is available to show that a procedure or technology is established as standard care, most will agree that it is eligible for coverage determination (Leaf, 1989). The bigger concern, however, appears to be over who should pay for the initial studies to collect the requisite primary data and how the data should be collected, shared, and analyzed (Antman et al., 1988; Wittes 1987b). For example, FDA approval of a drug or device for a given condition often, although not always, meets the criteria for coverage (Wittes, 1987a). Another problem arises, however, when an approved drug is used to treat a disease for which it is not approved (off-label use) (Moertel, 1991; U.S. Government Accounting Office, 1991). In some instances, there may be compelling evidence that a particular drug is effective, but the pharmaceutical manufacturer does not choose to add this information to the label because of the costs associated with additional FDA approval or the short time remaining on a sole-source patent. Patients and the provider are often left with few options. At the same time, third-party payers see their role as that of gatekeepers preventing overutilization and expansion of technology beyond its intended use or the continued use of outmoded technology. This scenario presents a serious gap in

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Careers in Clinical Research: Obstacles and Opportunities the U.S. system of who should pay for what. For example, pharmaceutical patents are time-limited. When an already approved therapy shows promise for another condition and a manufacturer is unable or unwilling to cover the costs associated with gaining approval for the use of the drug in the treatment of that other condition, who should pay for the investigations? Should the government allocate funds for the trials? Should the third-party payers be obligated to participate? Would a coalition of all concerned parties resolve this conundrum? During the early 1980s, a modification of coverage determination was designed to cover certain therapies that were not yet established, but had demonstrated promising success rates at particular institutions—selective coverage. For example, a payer might determine that a procedure in the hands of skilled physicians looks promising and would cover the associated costs at a particular medical center (for example, the early days of heart transplantation). Thus, a body of evidence might have accumulated demonstrating a procedure had positive outcomes and that it might no longer be considered investigational when performed at that institution. Although this late-stage coverage is appreciated, many resources that were not reimbursed were consumed to reach this stage. Third-party payers are also concerned about the proliferation of clinical trials for any one condition. Because many of these trials are investigator-initiated, one might find five or six different research groups, each treating patients on a different protocol for the same disease. Depending on the available patient populations, many of these trials might not be able to accrue enough patients to achieve statistical validity. Moreover, the third-party payers may not be able to determine which ones should be covered and which ones should not. Another problem cited is the varied perspectives of the investigators, even those collaborating on one project. By the time one gets through compromising with 5 or 10 very aggressive investigators, each one altering the study design in his or her own way, a study may be misguided and not answer the original question, or perhaps answer questions that were not very germane about the disease in question to society as a whole. These difficulties are not very appealing to insurers and make them disinclined to sponsor clinical studies. Involvement in Study Design and Data Analyses If third-party payers are to become significant collaborators in clinical studies and trials, their roles in experimental design and data analysis should be fully elucidated. As a stakeholder, the question arises as to how much of a role the insurer should have in creating the study design. Would it constitute a conflict of interest if an insurer supports a study with a design that could be potentially biased at the outset because of company participation? How can participation be assured without compromising the scientific validity of the investigation?

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Careers in Clinical Research: Obstacles and Opportunities Data Sharing and Analysis Once a third-party payer decides to support a study, another question arises; that is, how much access should they have to the data? On the one hand, the insurer will have access to the claims data, from which it could draw certain conclusions. On the other hand, how much access to the scientific data should the insurer be allowed? Again, as a stakeholder, the third-party payer probably believes that it should have complete access to medical information on patients covered under its policies. In the appropriate conduct of randomized clinical trials, however, the study is blinded and the codes cannot be broken until the statistical considerations are met. Other types of clinical studies may warrant other arrangements of data sharing. In addition to the issues surrounding access of data by the third-party payers, access to third-party payer databases by investigators also raises several issues. The insurers maintain the massive databases required for accounting purposes in the U.S. health care system. Such data bases could be utilized for continuous evaluation of medical practice. Studies of such data might not only provide a sounder basis for reimbursing new and experimental interventions but also could allow reevaluation of older, potentially obsolete or ineffective technologies that should no longer be employed. Numerous deficiencies in these databases, however, preclude this use. For example, each insurer has a claim form that collects and codes information differently. Without a standard type of data collection, comparison of data sets from different sources becomes impossible. Moreover, many of the claims data are probably not complete enough to draw conclusions about the effectiveness or outcomes of different therapies. Possible Solutions From the perspective of third-party payers, direct funding of clinical research is not possible. Viewing themselves as custodians of subscribers' funds, they do not have the reserves or the authority to devote resources to underwriting all clinical research, particularly that in which a third-party payer has a commercial interest. However, as custodians of those funds, third-party payers make coverage decisions that affect the health and well-being of their subscribers. Thus, payers have an obligation to find out what works and what does not. Nevertheless, possible solutions that will serve the interests of all parties can be developed without allowing costs to continue to soar (Antman, 1989; Wittes, 1988). The committee believes that high-quality care at a reasonable cost can be retained, while at the same time advancing new and unproven therapies that could potentially improve quality of life. Much can and should be done to ensure, encourage, and enhance the cooperative investment of time and interest that all parties have in clinical

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Careers in Clinical Research: Obstacles and Opportunities research, clinical research training, and the responsible utilization of new approaches to the diagnosis and treatment of disease. New approaches must encourage, not discourage, the responsible use of emerging technologies and therapies and the development of new uses for accepted interventions. To increase the quality of life and the effectiveness of health care, all parties need to foster continued innovation, not only in academic and industrial research laboratories but also at the bedside. There must be a true partnership that meets the goals and expectations of all participating parties and ensures the timely and cost-effective application of the findings of clinical research or the application of new technologies. Meaningful partnerships and coalitions need to be created. These coalitions could include not only university academic health centers but also private foundations, federal and state agencies, the pharmaceutical and biomedical technological industry, and those in the health insurance industry. For example, an interdisciplinary, interorganizational group could be created to help establish guidelines and provide recommendations for the use of, and payment for, therapies that have gone beyond the early investigational phase or for therapies over which there is a degree of controversy. Membership for such a group could be drawn, for example, from the Institute of Medicine, the Agency for Health Care Policy and Research, NIH, the health insurance sector, health-related private foundations, and representative consumers. This group would develop and maintain guidelines and criteria and decide what new procedures, therapies, or devices should or should not be reimbursable. One form of cooperation might be to adopt a uniform policy of paying for experimental therapies for all patients on approved protocols by NIH. Another might be to establish a diagnosis-related group-style prospective payment system that would ensure that adequate numbers of patients were enrolled in a trial to answer a question with adequate statistical power. The potential advantages of increased cooperation are obvious. By working together rather than through the courts or other judgmental bodies, the committee believes that the appropriateness and effectiveness of care for patients can be improved. Improved outcomes for patients may result in economic savings for the patients and the payers. Thus, knowledge of how best to provide care will be expanded and transmitted to a broad base of qualified providers and, of great importance, to the next generation of practitioners. Of course, any changes need to occur in a climate that recognizes that the resources for health care are under greater stress and pressure than in any other time in U.S. history, whether it be in the academic health centers, pharmaceutical and biotechnology industry, or the insurance industry.

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Careers in Clinical Research: Obstacles and Opportunities MODELS OF COOPERATION Undeniably, the U.S. system of health research has been highly successful largely because of the unhindered ability of investigators to pursue intriguing and pertinent questions ranging from very fundamental basic biology to clinical studies requiring the participation of human subjects. Previously, the separation of who should pay for what was of little concern because of plentiful resources and fairly well-established areas of responsibility. Simplistically, NIH and other federal agencies funded investigator-initiated human studies and other clinical studies deemed necessary by advisory bodies or Congress to fill gaps in certain areas, industry has been motivated by the potential for-profits and clinical studies are driven by regulatory concerns, the insurance industry may or may not cover certain aspects of investigational care, and academic health centers and hospitals have underwritten significant portions of unrecovered clinical research expenses out of their own reserves. With the growing attention to health care cost-containment and increasing constraints on the federal research budget, however, the committee fears that fundamental human research may be inadvertently squeezed out of the research portfolio. Clearly, the potential for return on investment continues to be a strong incentive for industry to sponsor clinical trials of test substances, chemical or biological. A large amount of the knowledge base upon which new therapeutic agents may be founded, however, is derived from investigator-initiated preclinical research and studies of human biology and disease that are likely to have no immediate or long-term commercial interest. Thus, the committee believes that new models of cooperation among all parties with a vested interest in health care are necessary for continued progress in human research to further improve modern health care. To explore these opportunities for increased cooperation among industry, government, academic health centers, and third-party payers, the committee sought examples in other scientific areas to serve as models or prototypes. One notable example is SEMATECH, which was formed during the 1980s in response to the intense international competition in the semiconductor industry. SEMATECH is a consortium of U.S. semiconductor manufacturers working with government and academia; it sponsors and conducts precompetitive cutting-edge research in semiconductor manufacturing technology for U.S. manufacturers. It was originally created out of a concern that the U.S. manufacturers were losing market share and may be forced out of the global market altogether, therefore risking the national security if the U.S. military were reliant on foreign manufacturers for vital computer chips. The annual budget for SEMATECH is $200 million—far above the ability of many firms to shoulder independently. Half of the budget is raised through corporate memberships, with a ceiling of $15 million to prevent single-company domination and a floor of $1 million. The remaining $100 million is provided through the U.S. Department of Defense through the Advanced Research Projects

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Careers in Clinical Research: Obstacles and Opportunities Agency. The funds are used to conduct research at SEMATECH by staff and scientists from the member companies. SEMATECH also awards research contracts to small semiconductor research firms and universities. For member companies to conduct cooperative research through such consortia, they must file for antitrust exemptions with the U.S. Department of Justice. Whereas SEMATECH may appear to be an anomaly in U.S. R&D sector, more than 380 such filings have been recorded. In sum, SEMATECH serves as one prototype that could be duplicated in the health research arena to support fundamental human research (precompetitive) and clinical research training. In the policy arena, the Government-University-Industry Research Roundtable (GUIRR) of the National Academy of Sciences is a forum of senior-level government science managers, leaders in industrial research, and leaders in university leadership who meet to discuss broad science policy issues affecting all groups. The formation of GUIRR is unique in its own sense because it required approval by the White House Office of Management and Budget to allow senior government managers to meet in closed sessions with industry leaders. Although by its charter GUIRR is prohibited from making recommendations, it serves as a unique forum for science policy discussions and a means to bridge gaps among the federal government, industry, and the academic community. Some health fields are already taking the initiative to assemble funds through consortia of industry and private philanthropy to promote research and training in specific areas. For example, the Alliance for Aging Research has proposed a National Geriatrics Development Fund to create Leadership Centers in Geriatrics at various academic medical centers with geriatric medicine programs. The Alliance, with the support of the Commonwealth Fund, hopes to raise matching funds from industry and nonprofit foundations to carry out this mission. Awards will be made through a peer-reviewed competition. Although business as usual has brought the United States to the pinnacle of health research, the committee feels that new paradigms for research cooperation and support are warranted. The committee believes that models of cooperation that could be applied in the area of human research already exist. All parties—industry, academia, government, and third-party payers—need to recognize that clinical research is not someone else's responsibility, but is the collective responsibility of all. One proposal would be to form an alliance or consortia of all parties, similar to SEMATECH, so that critical, fundamental human research can be supported to the benefit of all parties and, most importantly, improve the health of the U.S. public. Thus, funds from government, industry, third-party payers, nonprofit organizations, special interest groups, and academia could be pooled and available for peer-reviewed competition to close gaps of knowledge in particular areas or provide special emphasis in others deemed appropriate or urgent.

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Careers in Clinical Research: Obstacles and Opportunities CONCLUSIONS The committee concluded that patient-oriented clinical research is supported by a diverse, yet interlocking network of federal agencies, industry, and private nonprofit organizations that share many common goals. Of these, the federal government is the single largest sponsor of health research in the United States. Of the more than $75 billion the federal government invested in R&D during fiscal year 1993, nearly $11 billion was health-related. Contributions by health-oriented corporations are roughly equal in magnitude, but they are devoted largely to product application developments rather than fundamental discovery research. Contributions by private nonprofit sponsors favor fundamental discovery research, generally in somewhat restricted fields of interest, but represent only about four to five percent of the total U.S. investment in health research. In light of this investment and the continuing budget limitations, the scientific community must reexamine its resource base to improve its effectiveness and efficiency. Federally sponsored health research by the various agencies is generally mission oriented. Whereas NIH is the primary agency that disburses federal health research funds for investigation into fundamental biological discovery, other agencies such as VA and AHCPR are key players in health research, particularly patient-oriented research. Thus, the committee emphasizes that all types of health research expand the boundaries of knowledge for improving health care and should be considered crucial parts of the realm of health research. Although industry has been playing an increasingly important role in health research, focusing primarily on product development, it relies heavily on university research programs for fundamental knowledge (both basic and clinical) and talent. Cooperative ventures between universities (or government) and industry provide a unique mechanism for sharing knowledge and for technology transfer, a central policy of the federal government for increasing U.S. economic competitiveness. Foundations, voluntary health agencies, and other nonprofit organizations have played a very important role in sponsoring health research. The committee believes that these organizations have been particularly helpful by providing crucial support in filling gaps in the nation's research agenda and sponsoring new initiatives. Although the federal government rapidly eclipsed the investment by these organizations following World War II, these organizations have continued to supply a steady stream of research dollars. These funds are used for individual research project, supporting career development awards in specific research fields, equipment, facilities, and various programs of knowledge dissemination. The committee anticipates that these organizations will continue to provide support for the health sciences. The health insurance industry also is a stakeholder in the realm of clinical research. Third-party payers need to recognize their responsibility to subscribers

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Careers in Clinical Research: Obstacles and Opportunities and society as a whole for improving health care. The committee does not imply that insurers should foot the entire costs for experimental or investigational therapy, but that they should work with the medical scientific community to determine what works and what does not. To facilitate cooperation to uncover new knowledge about human disease and improve health care, the committee recommends the formation of an alliance that will bring all parties with a vested interest to the table in support of patient-oriented clinical research. New paradigms of cooperation are warranted to continue to improve the health of the U.S. public.