5
Academic-Industry Relationships

There is a long tradition of industry support for biomedical research, and there have been numerous types of academic-industry relationships. As noted in Chapter 3, industry funded more than half of all health sciences research in the United States before World War II, largely in the area of pharmaceutical research and development (R&D). Following the war, however, federal support for health research, primarily from the National Institutes of Health (NIH), grew at very rapid pace and soon eclipsed the investment by industry. Through the 1960s and early 1970s, industry support for research, in-house as well as sponsored research in academic institutions, slowed. The reasons for this waning of research investment have never been confirmed, but possibly include disappointing returns on overly optimistic expectations of the role and potential returns of broadly conceived basic research by industry, cost-accounting approaches to management that tended to put lower priority on long-range activities like fundamental research, and economic recessionary periods limiting corporate investment in research (National Science Board, 1981). The decline of in-house research was paralleled by a perception of slackening industrial support for academically based research. It has even been hypothesized that the Vietnam war aggravated antibusiness ideology on college campuses, further suppressing industry investment in academic research (National Science Board, 1981). However, industrial support, when measured in constant dollars, remained steady. As a result of these many forces, the proportion of funding from industry declined, and by the end of the 1970s, industry-supported only 29 percent of the total national investment in health sciences research.



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Careers in Clinical Research: Obstacles and Opportunities 5 Academic-Industry Relationships There is a long tradition of industry support for biomedical research, and there have been numerous types of academic-industry relationships. As noted in Chapter 3, industry funded more than half of all health sciences research in the United States before World War II, largely in the area of pharmaceutical research and development (R&D). Following the war, however, federal support for health research, primarily from the National Institutes of Health (NIH), grew at very rapid pace and soon eclipsed the investment by industry. Through the 1960s and early 1970s, industry support for research, in-house as well as sponsored research in academic institutions, slowed. The reasons for this waning of research investment have never been confirmed, but possibly include disappointing returns on overly optimistic expectations of the role and potential returns of broadly conceived basic research by industry, cost-accounting approaches to management that tended to put lower priority on long-range activities like fundamental research, and economic recessionary periods limiting corporate investment in research (National Science Board, 1981). The decline of in-house research was paralleled by a perception of slackening industrial support for academically based research. It has even been hypothesized that the Vietnam war aggravated antibusiness ideology on college campuses, further suppressing industry investment in academic research (National Science Board, 1981). However, industrial support, when measured in constant dollars, remained steady. As a result of these many forces, the proportion of funding from industry declined, and by the end of the 1970s, industry-supported only 29 percent of the total national investment in health sciences research.

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Careers in Clinical Research: Obstacles and Opportunities The availability of rapidly increasing federal funds for academic scientists possibly contributed to a weakening of the interactions and channels of communication between academic research institutions and industry through the 1950s and 1960s (White House Science Council, 1986). Industrial support of health R&D grew from 29 percent in 1979 to 48 percent in 1992. Of the estimated $13.5 billion that industry invested in health R&D in 1992, less than $1 billion went toward research at institutions of higher education (National Institutes of Health, 1993b). During the late 1970s and throughout the 1980s several factors led to renewed interest in partnerships between academic institutions and industry. The rapid pace of technological change and the lack of U.S. competitiveness in world markets stemming from a relative decline in productivity and quality required a greater awareness by U.S. industry of academic research developments (National Science Foundation, 1987b and 1988b; U.S. Congress, Office of Technology Assessment, 1984). There was a growing sense that the lines between basic knowledge and its application were becoming blurred in a number of areas and an awareness that fundamental research often provides solutions to industry's challenges (Low, 1983). The declining rate of increase in federal funding for research at a time of unprecedented scientific opportunities exist encouraged academic institutions to seek other sources of funding, notably from industry. Additionally, predictions of impending shortages of scientific and engineering talent in many fields led industry to reconsider their linkages with academic institutions (White House Science Council, 1986). A growing interest in the results of research by the public, particularly as it relates to their own health and welfare, also has been a driving force for innovation and more scientific investigation in the health arena. These and many other factors have influenced a renewed interest in academic-industry relationships. Legislation that also stimulated increased interactions between academic institutions and industry was passed. The Stevenson-Wydler Technology Innovation Act of 1980 established a federal policy for increasing the pace of translation of research results from federal laboratories into commercial products and directed federal agencies with research funds to allocate 0.5 percent of the research funds for technology transfer. In 1982 the Small Business Innovation Development Act required that all federal agencies with research budgets in excess of $100 million award 1.25 percent of their research funds to small, for-profit companies to encourage innovation and stimulate economic competitiveness through the translation of fundamental research into commercial products. These goals were reinforced by the passage of the Federal Technology Transfer Act in 1986, which provided incentives for collaboration between industry and the federal agencies. It authorized government laboratories to develop Cooperative Research and Economic Development Agreements with other federal agencies, state and local governments, and nonprofit and profit-making organizations. Finally, the federal government provided tax incentives

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Careers in Clinical Research: Obstacles and Opportunities for R&D investment in the 1981 Economic Recovery Act, which provided a 20 percent tax credit for incremental increases in R&D spending. Similar research investment incentives to encourage research activity and the translation of research into products have been used since that time. During the 1980s there was also increased interest in the commercialization of the results of academic research. The 1980 Patent & Trademarks Act stipulated that inventions made by academic scientists on federally funded research projects were subject to institutional policies and were not the property of the government. In effect, academic institutions were granted the authority and incentive to protect the intellectual property of their faculty who were supported by federal research funds, own patents resulting from federally sponsored research, and seek industrial partners to transfer technology to the marketplace (Waugaman and Porter, 1992). The U.S. General Accounting Office, an investigative arm of U.S. Congress, reports that large numbers of faculty have linkages with for-profit companies, and the control of inappropriate access to federally funded research results is causing growing uneasiness in many sectors (U.S. Government Accounting Office, 1992b). This was particularly evident in the Scripps Institute/Sandoz Company agreement announced recently in which Sandoz was to have exclusive rights to license the research results of scientists at Scripps even when the research was underwritten by U.S. taxpayers. This agreement has subsequently not materialized. In the worst light, this has been described as "science for sale" (Malone, 1992). The increased interaction between academic institutions and industry has also stimulated an increase in technology transfer, which some would argue has reached its highest level of expression in the biotechnology industry. Biotechnology is defined as "any technique that uses living organisms [or parts of organisms] to make or modify products to improve plants or animals or to develop micro-organisms for specified uses" (U.S. Congress, Office of Technology Assessment, 1988b). These methods were revolutionized during the 1980s, and there has been a huge investment by the federal government in such research. This explosion of biological knowledge, together with the ability to apply the knowledge to increasing the understanding of disease states and the development of biotechnology products to modify diseases, led to intensive activity in the academic community to commercialize the discoveries. This activity has led to the formation of hundreds of biotechnology companies, which often represent a positive interaction between the academic community and the investment community (Blumenthal et al., 1986a and 1986b). These dramatic changes have created unprecedented opportunities for innovative new product development to improve health care, but the new developments have also led to novel situations that must be dealt with by industry, government, and academic institutions. Clearly, innovation and the translation of fundamental research to improved health care rely on the interdependent relationships of research institutions, government, and industry.

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Careers in Clinical Research: Obstacles and Opportunities The cultural differences and frequent misperceptions between academia and industry have clouded their complementary relationships and the opportunity for positive collaborations between them. Cooper and Novitch (1992) have described the long-range needs of industry from academic medical centers, which include the following: patients, prestige, patents, publications, and personnel. The committee sought to explore these relationships in general terms as well as from the perspective of clinical research. In the development of these opportunities, the clinical investigator plays a key role in transferring the technology to improved patient care. The extent, consequences, and management of these new academic-industry relationships in the life sciences have been reviewed recently by Blumenthal (1992). This chapter discusses the relationships between research institutions and industry and the implications of the changing patterns of interactions. OBJECTIVES OF ACADEMIC-INDUSTRY RELATIONSHIPS Linkages between academic institutions and industry are often viewed with suspicion and disdain because the motivations and cultures of the two participants are quite different. Knowledge for its own sake is the accepted and desired output from academic research, and industry is motivated by the potential for the efficient production of goods and services in a competitive marketplace (Low, 1983). According to Cooper and Novitch (1992), there is nothing inherently corrupting about the presence of industrial funding in academic medical centers because all research funding has economic components and determinants. They also posit that regulatory rules and requirements to gain Food and Drug Administration (FDA) approval, not industry's profit-making orientation, are the major impediments to academic-industry collaborations. Academicians, on the other hand, perceive that research structured to gain regulatory approval removes the freedom to pursue their own research paths and is not highly regarded by promotion committees. Although academic norms are founded on the open communication and publication of research findings, industry must protect proprietary information to remain competitive. Nonetheless, there are also many common objectives and common needs by both parties. Industry needs a continuous stream of highly skilled talent to work at the cutting-edge of research and product development. Academicians may be better prepared to teach and perform cutting-edge research with potential practical applications through close ties to industry (Low, 1983). Melding the unique contributions each can make to positive research collaborations can facilitate the rapid and efficient transfer of new knowledge to medical care.

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Careers in Clinical Research: Obstacles and Opportunities TWO CULTURES In the past the two very different cultures of industrial research and academically based research have defined the interactions between them. Some of these cultural differences have had the unfortunate effect of unnecessarily inhibiting open and full interaction between academic scientists and industry (National Academy of Sciences, 1991). The notion that each sector has its own well-delineated and isolated role in the R&D process is outmoded in today's research environment. The longstanding paradigm that new fundamental knowledge that is discovered in academic settings flows to industry, where it is transformed into useful commercial applications, is no longer entirely valid. However, too much emphasis has been placed on the dichotomy between the ''pure" basic research performed in academic settings and the applied research considered the province of industry (Varrin and Kukich, 1985). Universities are largely recognized as the marketplace of ideas where knowledge is pursued following the norms of free discussion and free access to and exchange of information in concert with the uninhibited freedom to publish scholarly works. Such an environment relies on trust and openness and a clear understanding of a set of principles governing scholarly pursuit. Simply stated, these principles include the following: the academic institution and the faculty pledge themselves to the open, unimpeded, and objective pursuit of ideas; to the exchange of ideas openly and without deceit; and to the full and wide dissemination of knowledge through teaching and written publication of the results of scholarly inquiry (Giamatti, 1983; Merton, 1942). Largely through publication in peer-reviewed journals faculty submit their research findings to the critical scrutiny of their peers to ensure that there has been completeness in investigation and citation and that rigorous and logical conclusions have been applied in the process. Whereas industrial research may be subjected to the same rigor during the research process, the primary driving force is the commercial potential of products and processes derived from new knowledge, basic or applied. Commercial application of new knowledge typically requires substantial investment in applied R&D to bring products or processes to market. Companies will make such investments and take the associated risks only when they can expect a reasonable return on investment (Giamatti, 1983). Thus, the opportunity for generating profit provides the incentive for companies to develop socially beneficial applications of new knowledge. However, to realize profits from technological innovation and remain competitive in the marketplace, companies strive to protect their proprietary knowledge from other companies. This emphasis on protecting trade secrets, often through limiting the exchange of information, is antithetical to those investigators in academia. As a result, industry-sponsored research has often been perceived as being of lower intellectual caliber than investigator-initiated investigations of the type supported

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Careers in Clinical Research: Obstacles and Opportunities by the federal government or nonprofit organizations. Because of the close linkages between academic clinical researchers and industry in conducting clinical trials for pharmaceutical development, this type of research frequently has been regarded with disdain in the academic community. One notable contrast between the cultures of industry and academia is the different approaches to performing research between the two. In academia, investigators are expected to conduct scholarly research in an area of investigation to gain recognition, climb the academic ladder, and, in many cases, achieve tenure. Thus, academic scientists frequently tend to work independently, or in small collaborative units, to achieve their scholarly goals. Whereas companies stifle the flow of proprietary information among competitors, research within companies frequently is undertaken by a team approach (testimony to the committee by Dr. Louis Sherwood of Merck Sharp & Dohme Laboratories, 1991). Teams involve not only a wide spectrum of scientists in various fields but also others who are actively involved in the development process, such as marketing and regulatory affairs personnel. The committee drew the corollary that clinical researchers in academia often combine the attributes of the independent scholarly achievement of the academic setting with the team approach common to corporate researchers. TYPES OF ACADEMIC-INDUSTRY LINKAGES Over the past decade substantial efforts have been made by federal, state, and local governments to foster greater and more effective ties between academic institutions and industry through mechanisms such as cooperative programs, research centers, and research parks (National Academy of Sciences, 1986). The globalization of research and the pressure of international competition have introduced a critical time dimension into the stream of product development (National Academy of Sciences, Government-University-Industry Roundtable, 1992; President's Council of Advisors on Science and Technology, 1992). Whereas the United States has enjoyed a competitive advantage in many high technology fields, other countries have developed effective means for the direct translation of new knowledge into commercial products. As inferred by a report by the Task Force on the Health of Research of the House Committee on Science, Space, and Technology, it is likely that federal funding for research will become increasingly tied to societal goals (U.S. House of Representatives, Committee on Science, Space, and Technology, 1992). The same emphasis has been echoed by the Carnegie Commission on Science, Technology, and Government (1992). As a result of these legislative forces and the initiative of the academic institutions and industry, many varieties of mechanisms for industry support of academic research have evolved (National Academy of Sciences, 1986; Price,

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Careers in Clinical Research: Obstacles and Opportunities 1985). According to Waugaman and Porter (1992) there are five critical elements in academic-industry collaboration including: (1) contract research, (2) consultantship, (3) employment, (4) technology transfer, and (5) gifts. These elements lead to a number of relationships that satisfy industry's needs, but they also raise conflicts with the investigators and academic institutions. Blake (1994) has outlined "a spectrum of relationships" that the academic clinical investigator can have with one or more companies, including: consultant, sponsored research basic, sponsored research clinical trials, patent licensing, and company founder. All of these relationships can provide financial gain for the investigator and each has a particular set of issues related to conflict of interest and conflict of commitment. The type and magnitude of gain vary as do the potential conflict with obligations to the investigator's employer, the academic institution, but some distinctions should be recognized. A consulting fee or support of salary through a research grant provides concurrent reimbursement for research services rendered. In this case, no direct future financial benefit ensues to the investigator other than the potential for a continuation of the consultantship or continued research support. Although these future potential benefits are valuable, they are not unique to relationships with industry. Indeed, future continuous support from NIH for grant recipients depends largely on achieving a certain level of research productivity. In addition, if industry did not reimburse academic organizations for the effort of their faculty and staff, the academic institution in effect would be subsidizing the R&D program of a for-profit company. Independent fee-for-service consulting and salary support under sponsored research agreements traditionally have been accepted by academic institutions, government, and public representatives, particularly in areas such as law, business, and engineering schools, long before they arose in schools of medicine. However, the concern in the health sciences arena reflects, in part, the unique element that health research sometimes involves patients whose welfare might conceivably be compromised in the service of corporate-sponsored investigations (Blumenthal, 1992). The doctor-patient relationship is built on a foundation of trust and respect, and any compromise of this relationship to further the interests of business or financial gain runs counter to medical ethics and academic principles. As recently stated by David Kessler, FDA Commissioner, FDA could not do its job without complete trust in the clinical trials of medical products performed by academic clinical investigators (St. George's Society Lecture, Johns Hopkins University, 1992). The special concern about the clinical investigator in the setting of a randomized clinical trial (RCT), the core of clinical investigation, is ironic in that this is rigorously designed research that is subjected to substantial scrutiny by committees and government agencies. The clinical investigator in a multicenter RCT, with oversight by a separate data and monitoring group, has virtually no opportunity to bias the results.

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Careers in Clinical Research: Obstacles and Opportunities Probably the most common model in the clinical research realm is funding provided by industry as direct support to individual academic investigators to perform clinical trials on a specific drug or device under development utilizing their access to patient populations. A few industry programs support basic research without specified commercial product or process development. These fund research programs or centers that support many research projects and that are closely tied to general academic research and teaching activities. An existing model of industry involvement in academically based research is several collaborative relationships that emerged during the 1980s. For example, the Monsanto Corporation established a collaborative research effort with Washington University in St. Louis to conduct basic research into peptides and proteins. Monsanto initiated the relationship in 1982 to support research in areas in which the company lacked expertise. Although the funding allows uninhibited pursuit of fundamental knowledge, the company reserves the right to review research results 30 days prior to submission for publication in order to have adequate time to decide on exclusive licensing to develop commercial products (National Academy of Sciences, Government-University-Industry Research Roundtable, 1986). A similar collaborative arrangement was established between Hoechst AG and the Massachusetts General Hospital to fund facilities and provide research support to the hospital's Department of Molecular Biology. Another kind of academic-industry interaction is a focus project, which involves well-defined practical objectives and intellectual goals. This arrangement often uses the research of both academic and corporate scientists. An example of this type of arrangement is Becton Dickinson Corporation support for research in the infectious diseases section of the Department of Medicine at Wake Forest University's Bowman Gray School of Medicine (Waugaman and Porter, 1992). Various consortia of academic institutions have been formed to combine the strengths of the various institutions to focus on a specific problem or set of problems (Low, 1983). One notable example in the arena of clinical research is the Consortium of Teaching Hospitals that was recently formed to facilitate the efficient conduct of clinical trials. As numerous small clinical trials companies have begun to siphon away some multicenter clinical studies from academic institutions, this consortium provides a central access point for companies to negotiate multicenter trials through one organization. Thus, companies will be able to negotiate one agreement for many centers rather than dealing with the different rules and committees of numerous institutions to conduct their trials. In some fields industry has also formed cooperatives when the entire industry perceives a need for more research and research personnel. Although these types of relationships may be uncommon in the medical field presently, they have been formed in other fields such as in semiconductor R&D. These

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Careers in Clinical Research: Obstacles and Opportunities cooperatives, like SEMATECH raise funds through membership fees and award research funds to academic institutions in response to specific proposals. Many institutions have formed affiliate programs by which companies can acquire access to an institution's or a department's research results through conferences, mutual visits, and publications. Often these results are available to affiliates prior to public release, and thus may enable them to gain a competitive edge. The relationships are frequently bidirectional, in which the academic institution receives important advice on the needs of the marketplace. Universities and state and local governments have also been creating incubators and research parks to facilitate technology transfer. In many instances, these start-up ventures are provided inexpensive space, scientific advice, and laboratory and library services. The benefits include a mutually supportive environment for industry and the academic institution, with the potential for collaboration that may spawn new ideas and the synergism for a dynamic academic-industry enterprise. An evolving paradigm of academically based research with significant involvement of industry might be the creation of centers of excellence focusing on a specific research theme combining the support of academic institutions, industry, the federal government, and other sources. One example of a center with such a funding portfolio is the Transplantation Biology Research Center at the Massachusetts General Hospital that was formed to bring together a critical mass of basic scientists and clinical investigators to move fundamental research results more efficiently into clinical practice. As federal research support becomes ever more constrained, these collaborative efforts may become important means of leveraging scarce resources and achieving high-quality research. Industry also may provide operating or capital funds for academic institutions in terms of gifts. Such gifts do not obligate the investigator or the academic institution to provide anything in return. Support for training is another important contribution to the academic sector. Some companies directly sponsor fellowships for trainees both in industrial laboratories and in academic laboratories. Others may contribute to a common fund for training that is overseen by a third-party such as Merck's support for clinical research fellowships offered by the American Federation for Clinical Research. PROGRAMS TO HELP COMMERCIALIZE FACULTY RESEARCH Many academic institutions have developed expertise in patenting the novel findings of their scientists with the hope that the patents will yield products and return capital to the academic institution. In the past, academic institutions

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Careers in Clinical Research: Obstacles and Opportunities generally have not had the resources for or the experience of transforming novel research discoveries into marketable products. Thus, academic institutions have licensed these patents to industry to develop them into products. Some institutions have had nonprofit affiliates for some time such as the Wisconsin Alumni Research Foundation formed at the University of Wisconsin in 1925 and the MIT Development Corporation founded by the Massachusetts Institute of Technology in 1972 to facilitate the transfer of technology. Others have created for-profit buffer corporations to develop real and intellectual property on behalf of the institution. For example, the Dome Corporation was established by the Johns Hopkins University and the Johns Hopkins Health System with a cadre of professional technology transfer managers, many of whom thrive on the compensation arrangements of the private sector, to facilitate technology transfer. The Dome Corporation, in turn, created another for-profit corporation, Triad Investors, to provide venture capital for start-up companies. Although the latter does not have more access to faculty than other venture capital firms, and is free to work with nonacademic personnel, these firms allow an avenue for commercial development by faculty (Blake, 1994). The committee believes that patenting and licensing will continue to play an increasing role in academic institutions, and faculty need to be apprised of the process. For example, the growing area of biological therapies derived from investigator-initiated research such as genetically engineered proteins and peptides might lead to a novel therapy for a disease with a low incidence rate or may not have significant commercial interest at the outset. Not unlike the provisions for developing orphan drugs in the private sector, such findings might not capture the interest of industry if the market is small and the potential for an adequate return on investment is marginal. Thus, academic institutions may be placed in the position of working through their own buffer corporations to bring these therapies to market themselves. In fact, a new therapy developed by University of California researchers for systemic lupus erythematosus is, for various reasons, being brought to market by the institution. PREVALENCE OF ACADEMIC-INDUSTRY RELATIONSHIPS According to Blumenthal (1992), information on the prevalence and outcomes of academic-industry relationships in the health sciences is outdated. However, it is useful to recap results of earlier studies to gain an appreciation of the involvement of faculty and students in these relationships. In 1985 a survey by the Harvard Project on University-Industry Relationships of 800 faculty at 40 of the top 50 U.S. universities involved in biotechnology research revealed that 47 percent provided consultant services to industry, 23 percent participated as principal investigators on at least one industry funded project, and 8 percent owned equity in a privately traded company that marketed products that were

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Careers in Clinical Research: Obstacles and Opportunities based on the faculty member's academic research (Blumenthal at al., 1986a). More recently, Krimsky et al. (1991), have shown that nearly one third of the faculty in selected life sciences departments had some link to private firms. Gluck et al. (1987) also surveyed 700 graduate students and postdoctoral fellows in the life sciences departments of six research universities and found that 19 percent received some research or educational support from industry. The level of industry participation in academic research relationships is also worthy of mention. Although research-intensive pharmaceutical companies have had longstanding relationships with academic institutions, the relative importance of these relationships could be measured by the escalation of arrangements with biotechnology firms. A 1984 survey by Blumenthal et al. (1986b), of 106 firms conducting research in biotechnology revealed that nearly half supported research in universities. Thus, it can be inferred that there are many positive aspects of academic-industry linkages that are important to the successful translation of this new technology to commercial products and applications. BENEFITS FOR INDUSTRY Access to Fundamental Scientific Advances The boundaries of the earlier paradigm of developing new knowledge and theoretical concepts in academia and the transformation of this knowledge into practical application by industry are becoming more blurred. Although the pharmaceutical and biotechnology industries conduct fundamental research in many areas, they are still highly dependent on the results of the discovery process, which is embedded in the biomedical research laboratories of academia and certain government agencies such as NIH. Development and the clinical application of new discoveries are, on the other hand, highly dependent on the interest of the pharmaceutical and biotechnology industries. This interdependence became even more relevant when universities, academic medical centers, and government agencies obtained the right to protect their intellectual property through the patent process. Nonetheless, the R&D process works best for the health of the public when there is a rapid and facile pace of discovery, disclosure, and technology transfer. Some scientific fields have evolved in such a manner that commercial applications derive more readily and rapidly from academically based research than was previously the norm. In the health research arena, biotechnology could be cited as a prime example. Not only is industry involved in developing technology for end-use patient care, but, in cooperation with academic institutions, is also actively involved in commercializing midstage fundamental knowledge into commercial products such as recombinant DNA procedures and

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Careers in Clinical Research: Obstacles and Opportunities transgenic animals. Thus, the shrinking interval between fundamental research and industrial applications also is serving to foster linkages between academic institutions and industry. In an earlier survey, the factors perceived to be benefits by the majority of industrial respondents from biotechnology firms included the following: the likelihood of the collaboration resulting in product or process licenses, the ability of the company to keep current with important research, reduction in the costs of mounting R&D programs in a new field, enhancement of the firms' public image, and training and staff development for company scientists (U.S. Congress, Office of Technology Assessment, 1987). There are certainly many other benefits too numerous to cover in this section. However, it is evident that collaborations with academic institutions allow companies to tap into existing pools of scientific talent and resources to increase their competitive edge without having to duplicate efforts already in place. Thus, academic-industry relationships enable both parties to achieve research objectives that neither could accomplish alone. Access to Academic Personnel Historically, industry has needed access to scientific personnel employed in academia to conduct research, basic as well as applied, on potentially marketable products. In the clinical research arena this has involved clinicians in the design and execution of clinical studies or trials during the various phases of the drug or device approval process. The unique contributions of academic clinical investigators have been access to sufficiently large patient populations and the objective assessment of the compound or device under investigation. Although some of these studies have merely involved clinicians as data collectors, others have provided the opportunity for clinical investigators to learn methods of conducting large-scale clinical investigations while they have participated in the design, execution, and subsequent data analysis of these studies. With the growing interrelationships between industry and academia, old paradigms of collaboration are being reinforced or remodeled, and new ones are being shaped. The various types of faculty-industry relationships were discussed above in more detail in the section on types of academic-industry relationships.

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Careers in Clinical Research: Obstacles and Opportunities Human Resources Needs The pharmaceutical and biotechnology industries not only need highly qualified investigators in academia to catalyze the discovery process and conduct research on behalf of the corporate sector, but they also need academia as a source of corporate talent. Industry needs access to highly trained personnel who can undertake basic research and health professionals to run clinical trials, including physicians, pharmacists, nurses, and other professionals, such as biostatisticians, who are essential for the design and execution of clinical trials. For example, many biotechnology companies are just bringing their first products into the clinical trial stage; thus, a substantially greater number of personnel probably will be needed both in the companies and in academic medical centers. In addition, corporate leadership often comes from academia. Thus, industry is highly dependent on the preparation of highly skilled individuals from academia. BENEFITS FOR ACADEMIC INSTITUTIONS, FACULTY, AND STUDENTS With the increasing competition for and the reduced rate of growth of the available federal funds for research, academic institutions have actively sought other sources of support, particularly from industry. Universities and their faculty generally would prefer that industry provide unrestricted funds for both basic research and clinical trials. Nevertheless, industry is most likely to invest large amounts of money in work with potential for product development. The U.S. pharmaceutical industry spent over $2 billion on clinical research in 1991, making it one of the largest sources of support for patient-oriented clinical research. Although many of these financial resources are viewed as contractual research with prescribed outcomes, participation in industry research also can spin off some investigator-initiated studies simultaneously. Thus, the exposure of faculty to these opportunities can enhance their scholarly pursuits. Just as industry benefits from access to academic talent, academic institutions can also benefit by interaction with scientific personnel in the private sector. Exchanges of scientific talent with industry allows the infusion of new ideas into the academic realm in the same fashion as academics provide advice to industry. Students can benefit from academic-industry relationships by participating in industry-sponsored research. Such experiences can open up new opportunities for investigation and career opportunities. However, students should not be beholden to industrial support for their thesis research and certain precautions should be taken to insulate students from any negative consequences of industrial support.

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Careers in Clinical Research: Obstacles and Opportunities RISKS, CONCERNS, AND CONFLICTS Increasing academic-industry relationships also raise the specter of the inherent risks involved in these collaborations. Low (1983) has summarized the principal concerns as the following: The possible erosion of basic academic values of the educational goals of teaching and research, of giving faculty members their choice of questions to pursue, and of maintaining the academic institution as a credible and impartial resource. The conflicts of interest that may arise when trade secrets interfere with the freedom to publish, or when managing one's investments interferes with one's commitment to teaching and scholarly work. The possible leakage of information from company to domestic or foreign competitors when research results are communicated openly in traditional academic fashion. Concerns about the commercialization of academic biomedical research and linkages with industry have been scrutinized throughout the past decade. This was reflected by hearings convened by the U.S. House of Representatives Committee on Science and Technology in 1981 that focused on two primary issues: whether academic-industry research relationships violated scientific and academic freedom and responsibilities, and whether these relationships best served the interests of the American public. A year later, then Congressman Albert Gore, Jr., stated, "We do not view such agreements as bad per se, but rather as a development that needs to be examined in detail" (U.S. Congress, Office of Technology Assessment, 1988). To date, few empirical data from few isolated studies have been generated and little evidence exists to confirm or refute the risks to academia as a result of academic-industry relationships (Blumenthal, 1992). Nonetheless, a slate of issues has emerged, and these issues need to be considered in developing positive interrelationships between academic institutions and industry (National Academy of Sciences, 1991). Scientific Communication and Proprietary Rights The apparent conundrum is one of preserving basic academic values while protecting the rights of ownership of commercially valuable products or processes (Low, 1983). As mentioned above, academic principles are generally understood to be the educational goals of teaching and research, in which the faculty have the uninhibited choice to pursue questions of their own choosing, while maintaining the academic institution as a credible and impartial resource. By contrast, commercial value is inherent in the competitive advantage gained

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Careers in Clinical Research: Obstacles and Opportunities through the application of new knowledge in the application of a process or the design of a product that is uniquely available to one company and not to its competitors. To this end, commercial value relies on the control of proprietary information or control of the use of the information (Low, 1983). Thus, the academic freedom of academia and the desire to advance knowledge for its own sake conflicts with the needs of both industry and the academic institution to develop products. Results of the survey reported by Blumenthal et al. (1986a) suggest that academic-industry relationships in the biotechnology research arena were associated with some potentially worrisome departures from the traditional Mertonian academic behaviors and norms (Merton, 1942). For example, approximately one third of faculty engaged in biotechnology research reported that their choice of research topics had been influenced by the likelihood that the research results would have commercial application, whereas less than 10 percent of those without industry support indicated that their choice had been so influenced. Moreover, biotechnology faculty with industrial support were more than four times as likely as their colleagues without such support to report that proprietary information had resulted from their investigations (Blumenthal et al., 1986a). Additionally, faculty involved in industry relationships were nearly five times as likely to report that their research results were the property of their industrial sponsors and could not be published without the sponsor's consent. These reports have raised concerns about the whether academic-industry linkages can potentially compromise the objective role of academic institutions in the development of fundamental biological knowledge (Blumenthal, 1992). The main commodity of the biomedical academic-industrial research enterprise is unique proprietary information that can be used to develop competitive products. Many research projects arrive at a crossroads—where following one path of investigation would provide interesting information with no near-term application to product development, whereas an alternate path may lead to more immediate product development. Industry that is funding research at academic institutions would prefer the strategy that leads to near-term product development; the academic investigator may have a different objective. Industry needs to protect this information to justify a large investment, and patents provide a way to protect the information. However, academic faculty, in the spirit of open and uninhibited communication of research findings, wish to present these findings at scientific meetings and publish scholarly works in peer-reviewed journals. Prompt publication of findings or presentation of findings at a scientific meeting may conflict with the need of industry to protect information and release it at a later time to limit competitor access as long as possible. Furthermore, academic institutions have now recognized the value of patents, and the timing of release of information from academic research is an emerging issue that needs further scrutiny.

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Careers in Clinical Research: Obstacles and Opportunities Ownership of Proprietary Rights for New Discoveries Questions arise about the ownership of novel discoveries made at academic institutions while performing investigations that are based on proprietary information from industry. Blake (1994) has suggested that the clinical investigator who discovers a useful new effect of a drug studied under the manufacturer's sponsorship should have patent rights. Most companies believe that because they own the patent they should also own any use patents if the discovery occurred during the performance of a study. Universities could argue that the patent belongs to the inventor (or the inventor's institution) because it is a reward for the inventor's creative effort. Is the academic clinical investigator an employee of the sponsor—without intellectual property rights—or an independent scholar whose creative talents can benefit the sponsor's R&D program? The matter of who should own the use patent if a clinical investigator discovers a new activity of the drug that the investigator is studying under manufacturer's sponsorship is a complex one. The ability of the investigator to make novel observations has been made possible by the company through its novel product and by support of the investigator's research. A company cannot be regarded in the same way as a publicly funded government agency. In drug development, investors have placed their money at risk in the hope that they will realize a return on their dollars. By the time the product is in clinical trials, tens of millions of dollars have already been invested by company shareholders. Many of these potential products fail at earlier stages, or even at the clinical trial stage. Industry will promote scholarship while commercializing products, but it is clearly in the context of shareholder risk. A company will not be willing to relinquish its rights to these discoveries. Regardless of the resolution of these issues, the public gains from the commercialization effort because it brings forth novel therapies that improve medical care. Exclusivity of Information Recently, growing concern has been voiced in many sectors regarding the exclusivity of scientific results stemming from federally supported research. Although academic institutions have the legal right to patent and license technologies derived from federally supported research, some of these arrangements call into question the inappropriate licensing of exclusive rights because of undisclosed conflicts of interest or other relationships (U.S. General Accounting Office, 1992). Particularly troublesome are arrangements that might stifle the release of important research results from research that has been underwritten by taxpayers for reasons of commercial or financial gain. Thus,

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Careers in Clinical Research: Obstacles and Opportunities some companies might gain an unfair advantage in commercializing the results of federally sponsored research. Probably even more troublesome is the involvement of foreign interests in gaining exclusive rights to federally sponsored research results emanating from U.S. research institutions. In some cases, this information can be bought freely, through membership fees paid to an institution, to obtain information prior to its public release. Thus, information is available to those people, domestic or foreign, who can afford to pay. In the extreme, foreign companies can develop relationships with research institutions to effectively gain the rights of exclusive licensing for all research performed at an institution or in a particular department without regard to the public sponsor. Although the committee is not aware of any documented case of abuse in these types of relationships, the potential exists for controlling information paid for by U.S. citizens and relationships of this sort require careful monitoring in the event that public policy changes need to be made. Conflicts of Interest The issue of conflicts of interest is a complicated one and is the subject of a book by Porter and Malone (1992). Most reports have focused on the clinical investigator, because the relationships of clinical investigators with industry (described above) create the setting for such conflicts. From the point of view of industry, there is a desire to avoid conflicts of interest that may inject bias into research results. Talented academic investigators with relevant special expertise, especially those who provide advice as consultants, are given incentives by industry to provide their best effort through remuneration. Some firms provide a basic modest consulting fee along with equity opportunities such as stock options. However, this kind of compensation is not provided for academic investigators who perform clinical trials with company products, because it might create an investigator bias in the interpretation of results. Such conflicts, which could lead to loss of objectivity, are counterproductive for the company as well as the academic stature of the investigator. Although investigator conflict of interest has received considerable scrutiny, institutional conflict of interest has begun to emerge, in which officers and managers of academic institutions own equity in companies whose success may be influenced by their faculty's research. The leadership of academic institutions is ultimately held responsible and accountable for the faculty's research and providing assurance of objectivity and integrity. The personal ownership or institutional ownership of equity in companies with which they have a professional research relationship raises the specter of improprieties and questions the ability of these institutions to manage their own academic-industry relationships (Blumenthal, 1992). With the relatively recent approach of

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Careers in Clinical Research: Obstacles and Opportunities patenting academic research discoveries, institutions that wish to take new discoveries from the laboratory to the clinic, such as was described above with the formation of the Dome Corporation and Triad Investors by the Johns Hopkins University, will have to take careful measures to avoid conflicts of interest. This is clearly a topic that needs careful monitoring and attention from a public policy standpoint. Clearly, bias created through conflicts of interest by investigators undermines the academic research process and the credibility of academic research institutions. The heterogeneity of academic research institutions and their affiliates suggests that there is no universally applicable standard or formula for dealing with conflicts of interest. Furthermore, according to Shipp (1992), the goal in managing conflicts of interest should not be to eliminate all potential sources of conflicts: rather, the objective should be to control the injection of inappropriate bias into research and other professional activities. Although investigators can be expected to exert some level of self-control over their outside interests, it is probably unreasonable and unwise to depend entirely on researchers to identify, disclose, and manage all of their own potential conflicts of interest (Shipp, 1992). Ambiguity in guidelines often makes distinguishing between acceptable and questionable practices difficult and requires oversight by institutions. Thus, institutions must have a role in aiding their researchers in identifying, monitoring, and controlling conflicts of interest. Whatever the policies of the institution, many would agree that avoiding conflicts of interest by the faculty requires full, timely, and public disclosure to avoid even the perception of impropriety (Blake, 1992). Conflict of Commitment With regard to academic-industry relationships, conflict of commitment is quite different from conflict of interest. Conflict of commitment pertains to whether a faculty member is fulfilling institutional obligations while subjected to competing demands for one's time (Porter, 1992). Conflicts of commitment frequently are more difficult to address and resolve than conflicts of interests, because they are often subtle and of varying degrees (Low, 1983). Resolution generally falls into one of two categories: discontinuing or reducing one's outside commitments in the commercial venture that caused the conflict or leaving the academic institution (Low, 1983). Because of the complexity of conflict of commitment, few policies exist, and those that do are generally vague and ambiguous. However, the Association of American Medical Colleges has suggested the following guidelines to obviate conflict of commitment: Ensure that research, teaching, and public service obligations to the academic institution are met.

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Careers in Clinical Research: Obstacles and Opportunities Abide by restrictions on the type and amount of outside activity, as determined by the academic institution or by subsequent agreements between faculty and the academic institution or hospital administration. Abide by commitments of effort as specified in the contractual research and grant applications. MANAGING ACADEMIC-INDUSTRY RELATIONSHIPS The management of academic-industry relationships poses challenges to both academic institutions and industry. It is imperative that these relationships not threaten the fabric of academic principles or freedoms nor compromise the proprietary information of industry. Varrin and Kukich (1985) have proposed a partial list of management guidelines for academic institutions to consider in these relationships that include the following: retain publication rights, retain ownership of all patents, minimize the use of proprietary information in research and do not require graduate students to sign confidentiality agreements, create research units with faculty, and hire full-time researchers to staff such units if necessary, do not permit faculty to consult with sponsors in the area of the sponsored research, do not permit a faculty entrepreneur's company to sponsor his or her research on campus, share personnel and resources with industry, which is beneficial for both parties, and prepare model research agreements for potential industrial sponsors. The preceding list is not exhaustive nor is it totally inclusive; it is merely intended to raise consciousness about several potential pitfalls in striving to develop fruitful academic-industry collaborations. To prevent improprieties, academic institutions could require full disclosure of the commercial interests of faculty, academic officers, and senior management in their institutions on a regular basis. Academic institutions could develop criteria or standards of what is and what is not acceptable in the various types of academic-industry relationships. This is particularly applicable in clinical research, in which the financial interests of the faculty or administration could cause bias to be injected into a study (Blumenthal, 1992). Academic institutions also need to be concerned about the balance of interdepartmental and intradepartmental resources. Whereas some departments may engender the interest of industry, financially as well as scientifically, other departments fear that they will be starved of resources (U.S. Congress, Office of Technology Assessment, 1987). Thus, institutions should take care to provide balance in the allocation of resources in light of some lucrative academic-industry collaborations.

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Careers in Clinical Research: Obstacles and Opportunities SUMMARY AND CONCLUSIONS In summary, academic-industry relationships are growing in number and frequency (Blumenthal, 1992). The real benefit from academic-industry research relationships is the potential to achieve results that neither partner could achieve alone (U.S. Congress, Office of Technology Assessment, 1987). The respect and objectivity inherent in academic research must not be compromised by academic-industry relationships. A clearer understanding of each others' motivations, responsibilities, and mechanisms to facilitate constructive relationships will undoubtedly allow each to contribute to research in mutually beneficial relationships. These collaborative arrangements should not be so rigidly uniform as to squelch creativity. Rather, each should be tailored individually to achieve objectivity, valid clinical ends, mutually agreeable financial results, and legally acceptable consequences. As the pattern of academic-industry research collaboration strengthens in the future, sound policies and respect for each others' interests will be major factors in determining the extent and fruitfulness of such relationships (Cooper and Novitch, 1992). Examining the overall picture of academic-industry interactions, many important advantages can be seen. The major winners are the American people, who benefit from the increasing pace of development of new products to improve health care. The relationships should provide more revenues to academic institutions and improved product development and profits for industry. Individual clinical investigators who have made important contributions can benefit financially from the evolution of their discoveries into products that improve health care. One of the most important contributions that a biomedical scientist can make is to improve the health care of millions of people. At the same time, the pitfalls of this new process are clear. Academic freedom and pursuit of knowledge for its own sake require protection at academic institutions. Academic faculty must continue to perform their faculty duties, despite the financial incentive of interacting with industry. Continued federal support of research is needed, because NIH-supported research has been an important incubator of new ideas and novel discoveries. A cohort of clinical investigators must also be trained to transfer technology between the laboratory bench and the bedside. They will oversee the transmission of new products and interventions to the clinic and, conversely, the transfer of clinical aberrancies to the laboratory for explanation. Highly trained individuals who can accomplish this in an efficient and cost-effective manner are needed. Incentives must be created to attract physicians and other health professionals to clinical investigations to ensure that new technology will generate new medical therapy. There continues to be debate about whether the current supply of individuals appropriately trained as clinical investigators is seriously deficient. There is nearly unanimous agreement that the explosion of new knowledge in

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Careers in Clinical Research: Obstacles and Opportunities molecular biology, medicine, and medical informatics will create a need in the future for substantially more expertise (Kelley, 1988). Fully trained physicians and other health professionals in academia, government service, and industry will be particularly crucial in the transformation of these discoveries into cost-effective treatments for human disease. Thus, clinical investigators trained in academia will also be needed in industry to help in the translation of advances in biomedical research to the development and application of new products. Given the monumental opportunities that will soon be available and the current nature of the enterprise, the critical human resource pool will be seriously deficient. The pharmaceutical and biotechnology industries have a special interest in facilitating training and in the initial discovery process, which often occurs in academia. The translation and application of advances in research to patient care require a strong partnership between the academic institutions and industry. Facilitation of technology transfer by both parties is important and deserves special support. The relationship among faculty, the academic institution, and industry is changing dramatically and represents a new paradigm. This will require new standards in the definition and resolution of conflicts of interest at all levels in support of this change. Issues related to conflicts of interest must be explicitly defined, and for the alleviation of both individual and institutional conflict of interest must be implemented at the local level.

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