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Executive Summary The nature of biomedical research has been evolving in recent years. Relatively small projects initiated by single investigators have tra- ditionally been and continue to be the mainstay of cancer research, as well as biomedical research in other fields. Recently, however, techno- logical advances that make it easier to study the vast complexity of bio- logical systems have led to the initiation of projects with a larger scale and scope (Figure ES-1. For instance, a new approach to biological experi- mentation known as "discovery science" first aims to develop a detailed inventory of genes, proteins, and metabolites in a particular cell type or tissue as a key information source. But even that information is not suffi- cient to understand the cell's complexity, so the ultimate goal of such research is to identify and characterize the elaborate networks of gene and protein interactions in the entire system that contribute to disease. This concept of systems biology is based on the premise that a disease can be fully comprehended only when its cause is understood from the mo- lecular to the organismal level. For example, rather than focusing on single aberrant genes or pathways, it is essential to understand the comprehen- sive and complex nature of cancer cells and their interaction with sur- rounding tissues. In many cases, large-scale analyses in which many pa- rameters can be studied at once may be the most efficient and effective way to extract functional information and interactions from such complex biological systems. The Human Genome Project is the biggest and best-known large- scale biomedical research project undertaken to date. Another project of that size is not likely to be launched in the near future, but many other

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2 LARGE-SCALE BIOMEDICAL SCIENCE Conventional small-scale research ~ Large-scale ~ Very large-scale collaborative research Smaller, more specific goals Short-term objectives Relatively shorter time Dame Lower total cost, higher unit cost Hypothesis driven, undefined deliverables Broad goals (encompassing an entire field of . . Inquiry Requires long-range strategic planning Often a longer time Fame Higher total cost, lower unit cost Problem-directed with well-defined deliverables and endpoints Small peer review group approval sufficient ~ Acceptance by the field as a whole important Minimal management structure Minimal oversight by Finders Single principal investigator More dependent on scientists in training Generally Ended by unsolicited, investigator-initiated (Ret) grants Larger, more complex management structure More oversight by Finders Multi-investigator and multi-institutional More dependent on technical staff Often funded through solicited cooperative agreements More discipline-oriented ~ Often interdisciplinary Takes advantage of infrastructure and technologies generated by large-scale projects May or may not involve bioinformatics Develops scientific research capacity, infrastructure, and technologies Data and outcome analysis highly dependent on bioinformatics FIGURE ES-1 The range of attributes that may characterize scientific research. There is no absolute distinction indeed there is much overlap between the characteristic of small- and large-scale research. Rather, these characteristics vary along a continuum that extends from traditional independent small-scale projects through very large, collaborative projects. Any single project may share some characteristics with either of these extremes. projects that fall somewhere between the Human Genome Project and the traditional small projects have already been initiated, and many more have been contemplated. Indeed, the director of the National Institutes of Health (NIH) recently presented to his advisory council a "road map" for the agency's future that includes a greater emphasis on "revolutionary methods of research" focused on scientific questions too complex to be addressed by the single-investigator scientific approach. He noted that the NIH grant process will need to be adapted to accommodate this new large-scale approach to scientific investigation, which may conflict with traditional paradigms for proposing, funding, and managing science projects that were designed for smaller-scale, hypothesis-driven research.

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EXECUTIVE SUMMARY 3 The recent interest in adopting large-scale research methods has gen- erated many questions, then, as to how such research in the biomedical sciences should be financed and conducted. Accordingly, the National Cancer Policy Board determined that a careful examination of these issues was warranted at this time. The purpose of this study was to (1) define the concept of "large-scale science" with respect to cancer research; (2) iden- tify examples of ongoing large-scale projects to determine the current state of the field; (3) identify obstacles to the implementation of large- scale projects in biomedical research; and (4) make recommendations for improving the process for conducting large-scale biomedical science projects, should such projects be undertaken in the future. Although the initial intent of this study was to examine large-scale cancer research, it quickly became clear that issues pertaining to large- scale science projects have broad implications that cut across all sectors and fields of biomedical research. Large-scale endeavors in the biomedi- cal sciences often involve multiple disciplines and contribute to many fields and specialties. The Human Genome Project is a classic example of this concept, in that its products can benefit all fields of biology and biomedicine. The same is likely to be true for many other large-scale projects now under consideration or underway, such as the Protein Struc- ture Initiative (PSI) and the International HapMap Project. Furthermore, given the funding structures of NIH, the launch of a large-scale project in one field could potentially impact progress as well as funding in other fields. Thus, while this report emphasizes examples from cancer research whenever feasible, the committee's recommendations are generally not specific to the National Cancer Institute (NCI) or to the field of cancer research; rather, they are directed toward the biomedical research com- munity as a whole. Indeed, it is the committee's belief that all fields of biomedical research, including cancer research, could benefit from imple- mentation of the recommendations presented herein. Ideally, large-scale and small-scale research should complement each other and work synergistically to advance the field of biomedical research in the long term. For example, many large-scale projects generate hypoth- eses that can then be tested in smaller research projects. However, the new large-scale research opportunities are challenging traditional aca- demic research structures because the projects are bigger, more costly, often more technologically sophisticated, and require greater planning and oversight. These challenges raise the question of how the large-scale approach to biomedical research could be improved if such projects are to be undertaken in the future. The committee concluded that such improve- ment could be achieved by adopting the seven recommendations pre- sented here to address these issues. The first three recommendations suggest a number of changes in the

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4 LARGE-SCALE BIOMEDICAL SCIENCE way scientific opportunities for large-scale research are initially assessed as they emerge from the scientific community, as well as in the way specific projects are subsequently selected, funded, launched, and evalu- ated (Table ES-1. Although the procedures of NIH and other federal agencies have a degree of flexibility that has allowed some large-scale research endeavors to be undertaken, a mechanism is needed through which input from innovators in research can be routinely collected and incorporated into the institutional decisionmaking processes. Also needed is a more standard mechanism for vetting various proposals for large- scale projects. For example, none of the large projects initiated by NCI to date has been evaluated in a systematic manner. There is also a need for greater planning and oversight by federal sponsors during both the ini- tiation and phase-out of a large-scale project. Careful assessment of past and current large-scale projects to identify best practices and determine whether the large-scale approach adds value to the traditional models of research would also provide highly useful information for future en- deavors. Recommendation 1: NIH and other federal funding agencies that support large-scale biomedical science (including the National Sci- ence Foundation [NSF], the U.S. Department of Energy [DOE], the U.S. Department of Agriculture [USDA], and the U.S. Department of Defense [DOD]) should develop a more open and systematic method for assessing important new research opportunities emerg- ing from the scientific community in which a large-scale approach is likely to achieve the scientific goals more effectively or efficiently than traditional research efforts. This method should include a mechanism for soliciting and evaluating proposals from individuals or small groups as well as from large groups, but in either case, broad consultation within the relevant scientific community should occur before funding is made available, perhaps through ad hoc public con- ferences. Whenever feasible, these discussions should be NIH- wide and multidisciplinary. An NIH-wide, trans-institute panel of experts appointed by the NIH director would facilitate the vetting process for assessing sci- entific opportunities that could benefit from a large-scale approach. Once the most promising concepts for large-scale research have been selected by the director's panel, appropriate guidelines for peer review of specific project proposals should be established. These guidelines should be applied by the institutions that oversee the projects.

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EXECUTIVE SUMMARY TABLE ES-1 Summary of the Challenges Associated with Large-Scale Biomedical Research Projects, and the Committee's Recommendations to Overcome These Difficulties 5 Difficulties Associated with Large-Scale Projects Potential Paths to Solutions No systematic method for assessing large-scale biomedical research opportunities exists. Carefully planning and orchestrating the launch as well as the phase out of a large-scale project is difficult, but imperative for its long term success and efficiency. There are very few precedents to guide the planning and oversight of large- scale endeavors in biomedical science. It is difficult to recruit and retain quali- fied scientific managers and staff for large-scale projects. It can be costly and difficult for investi- gators to maintain reagents produced through large-scale projects and to share them with the research community. Licensing strategies can affect the availability of research tools produced by and used for large-scale research projects. A seamless transition between discovery and clinical application is lacking. Develop an NIH-wide mechanism for soliciting and reviewing proposals for large-scale projects, with input from all relevant sectors of biomedical science. Clear but flexible plans for entry into and phase out from projects should be developed before funding is provided. NCI and NIH should commission a thorough analysis of their recent large- scale initiatives to determine whether those efforts have been effective and efficient in meeting their stated goals and to aid in the planning of future large-scale projects. Institutions should develop new ways to recognize and reward scientific col- laborations and team-building efforts. NIH should provide funding to preserve and distribute reagents and other research tools once they have been created. NIH should examine systematically the impact of licensing strategies and should promote licensing practices that facilitate broad access to research tools. Consideration should be given to pursuing projects initiated by academic scientists in cooperation with industry to achieve large-scale research goals. Collaborations among institutes could encourage participation by smaller institutes that may not have the resources to launch their own large-scale projects. NIH should continue to explore alternative funding mechanisms for large-scale endeavors, perhaps including approaches similar to those used by NCI's Unconventional Innovations Program, as well as funding collaborations with industry and other federal funding agencies.

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6 LARGE-SCALE BIOMEDICAL SCIENCE International collaborations should be encouraged, but an ap- proach for achieving such cooperation should be determined on a case by case basis. Recommendation 2: Large-scale research endeavors should have clear but flexible plans for entry into and phase out from projects once the stated ends have been achieved. It is essential to define the goals of a project clearly and to monitor and assess its progress regularly against well-defined milestones. Carefully planning and orchestrating the launch of a large-scale project is imperative for its long-term success and efficiency. NIH should be very cautious about establishing permanent infra- structures, such as centers or institutes, to undertake large-scale projects, in order to avoid the accumulation of additional Institutes via this mechanism. Historically, NIH has not had a good mechanism for phasing out established research programs, but large-scale projects should not become institutionalized by default simply because of their size. If national centers with short-term missions are to be established, this should be done with a clear understanding that they are temporary and are not meant to continue once a project has been completed. - Leasing space is one way to facilitate downsizing upon comple- tion of a project. - Phase-out funding could enable investigators to downsize over a period of 2-3 years. Recommendation 3: NCI and NIH, as well as other federal funding agencies that support large-scale biomedical science, should com- mission a thorough analysis of their recent large-scale initiatives once they are well established to determine whether those efforts have been effective and efficient in achieving their stated goals and to aid in the planning of future large-scale projects. NIH should develop a set of metrics for assessing the technical and scientific output (such as data and research tools) of large- scale projects. The assessment should include an evaluation of whether the field has benefited from such a project in terms of increased speed of discoveries and their application or a reduc- tion in costs. The assessment should be undertaken by external, independent peer review panels with relevant expertise that include academic, government, and industry scientists. To help guide future large-scale projects, the assessment should pay particular attention to a project's management and organiza-

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EXECUTIVE SUMMARY tional structure, including how scientific and program managers and staff were selected, trained, and retained and how well they performed. The assessment should include tracking of any trainees involved in a project (graduate students and postdoctoral scientists) to deter- mine the value of the training environment and the impact on career trajectories. The assessment should examine the impact of industry contracts or collaborations within large-scale research projects. Industry has many potential strengths to offer such projects, including efficiency and effective project management and staffing, but intellectual property issues represent a potential barrier to such collaborations. Thus, some balance must be sought between providing incentives for producing the data and facilitating the research community's access to the resultant data. In pursuing large-scale projects with industry, NIH should care- fully consider the data dissemination goals of the endeavor be- fore making the funds available. To the extent appropriate, NIH should mandate timely and un- restricted release of data within the terms of the grant or con- tract, in the same spirit as the Bermuda rules adopted for the release of data in the Human Genome Project. The committee has formulated four additional recommendations aimed at improving the conduct of possible future large-scale projects. These recommendations emerged from the committee's identification of various potential obstacles to conducting a large-scale research project successfully and efficiently. To begin with, human resources are key to the success of any large-scale project. If large-scale projects are deemed worthy of substantial sums of federal support, they also clearly warrant the highest-caliber staff to perform and oversee the work. But if qualified individuals, especially at the doctoral level, are expected to participate in such undertakings, they must have sufficient incentives to take on the risks and responsibilities involved. In particular, effective administrative management and committed scientific leadership are crucial for meeting expected milestones on schedule and within budget; thus the success of a large-scale project is greatly dependent upon the skills and knowledge of the scientists and administrators who manage it, including those within the federal funding agencies. However, it may be quite difficult to recruit staff with the skills to meet this need because of the unusual status of such managerial positions within the scientific career structure, and because scientists rarely undergo formal training in management. Young investi- gators and trainees also need recognition for their efforts that contribute

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8 LARGE-SCALE BIOMEDICAL SCIENCE to elaborate, long-term, and large multi-institutional efforts. Thus, the committee concluded that both universities and government agencies need to develop new approaches for assessing teamwork and manage- ment, as well as novel ways of recognizing and rewarding accomplish- ment in such positions. Recommendation 4: Institutions should develop the necessary in- centives for recruiting and retaining qualified scientific managers and staff for large-scale projects, and for recognizing and reward- ing scientific collaborations and team-building efforts. Funding agencies should develop appropriate career paths for indi- viduals who serve as program managers for the large-scale projects they fund. Academic institutions should develop appropriate career paths, including suitable criteria for performance evaluation and promo- tion, for those individuals who manage and staff large-scale col- laborative projects carried out under their purview. Industry and The National Laboratories may both serve as in- structive models in achieving these goals, as they have a history of rewarding scientists for their participation in team-oriented research. It is important to establish guiding principles for such issues as equitable pay and benefits, job stability, and potential for advance- ment to avoid relegating these valuable scientists and managers to a "second-tier" status. Federal agencies should provide adequate funding to universities engaged in large-scale biomedical research projects so that these individuals can be sufficiently compensated for their role and contribution. Universities, especially those engaged in large-scale research, should develop training programs for scientists involved in such projects. Examples include courses dealing with such topics as managing teams of people and working toward milestones within timelines. Input from industry experts who deal routinely with these issues would be highly valuable. The committee also identified potential impediments to deriving the greatest benefits from the products of large-scale endeavors in terms of scientific progress for biomedical research in general. Large-scale projects are most likely to speed the progress of biomedical research as a whole when their products are made widely available to the broad scientific community. However, concerns have been raised in recent years about the willingness and ability of scientists and their institutions to share data, reagents, and other tools derived from their research. Since a pri-

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EXECUTIVE SUMMARY 9 mary goal of many large-scale biomedical research projects is to produce data and research tools, NIH should facilitate the sharing of data and the distribution of reagents to the extent feasible. Currently, NIH grants gen- erally do not provide funds for this purpose, making it difficult for inves- tigators to maintain reagents and share them with the research commu- nity. This obstacle could be reduced if NIH provided such funds for large-scale research projects. Recommendation 5: NIH should draft contracts with industry to preserve reagents and other research tools and distribute them to the scientific community once they have been produced through large-scale projects. The Pathogen Functional Genomics Resource Center, established through a contract with the National Institute of Allergy and Infec- tious Diseases, could serve as a model for this undertaking. The distribution of standardized and quality-controlled reagents and tools would improve the quality of the data obtained through research and make it easier to compare data from different investi- gators. Producing the reagents and making them widely available to many researchers would be more cost-effective than providing funds to a few scientists to produce their own. An issue closely related to the sharing of data and reagents is the licensing of intellectual property. Many concerns have been raised in re- cent years about the challenges and expenses associated with the transfer of patented technology from one organization to another. Innovations that can be used as research tools may offer the greatest challenge in this regard because it is difficult to predict the future applications and value of a particular tool, and because a number of different tools may be needed for a single research project. Since many large-scale projects in the bio- sciences aim to produce data and other tools for future research, this subject is especially salient for large-scale research. The committee con- cluded that NIH should continue to promote the broad accessibility of research tools derived from federally funded large-scale research to the extent feasible, while at the same time considering the appropriate role for intellectual property rights in a given project. However, in the absence of adequate information and scholarly assessment, it is difficult to deter- mine how NIH could best accomplish that goal. Thus, the committee recommends that such an assessment be undertaken, and that appropri- ate actions be taken based on the findings of the study. Recommendation 6: NIH should commission a study to examine systematically the ways in which licensing practices affect the avail-

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10 LARGE-SCALE BIOMEDICAL SCIENCE ability of research tools produced by and used for large-scale bio- medical research projects. Whenever possible, NIH and NCI should use their leverage and resources to promote the free and open exchange of scientific knowledge and information, and to help minimize the time and expense of technology transfer. Depending on the findings of the proposed study, NIH should promote licensing practices that facilitate broad access to research tools by issuing licensing guidelines for NIH-funded discoveries. In addition to the role of federal funding agencies, the committee considered the role of industry and philanthropies in conducting large- scale biomedical research. Public-private collaborations provide a way to share the costs and risks of innovative research, as well as the benefits. Philanthropies and other nonprofit organizations can play an important role in launching nontraditional projects that do not fit well with federal funding mechanisms. Pharmaceutical and biotechnology companies also make enormous contributions to biomedical research worldwide. Tradi- tionally, the role of independent companies has been to pursue applied research aimed at producing an end product; however, the distinction between "applied" and "basic" research has blurred in recent years, in part because of novel approaches used for drug discovery and develop- ment. A recent focus by academic scientists on translational research, which aims to translate fundamental discoveries into clinically useful practices, has further obscured the distinction. Several recent projects initiated and funded by industry or carried out in cooperation with industry and nonprofit organizations clearly demonstrate the potential value of contributions by these entities to large-scale research endeavors. The Single Nucleotide Polymorphism, or SNP, consortium is a prime example of how effective these sectors can be when involved in a large-scale research projects. Industry in particular has many inherent strengths that could be brought to bear on large-scale biomedical research efforts, such as experience in coordinat- ing and managing teams of scientists working toward a common goal. Combining the respective strengths of academia and industry could optimize the pace of biomedical research and development, potentially leading to more rapid improvements in human health. Thus, the com- mittee recommends that cooperation between academia and industry be encouraged for large-scale research projects whenever feasible. Recommendation 7: Given the changing nature of biomedical re- search, consideration should be given to pursuing projects initiated by academic scientists in cooperation with industry to achieve the

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EXECUTIVE SUMMARY 11 goals of large-scale research. When feasible, such cooperative ef- forts could entail collaborative projects, as well as direct funding of academic research by industry, if the goals of the research are mutu- ally beneficial. Academia is generally best suited for making scientific discoveries, while the strength of industry most often lies in its ability to de- velop or add value to these discoveries. Establishing a more seamless connection between the two endeav- ors could greatly facilitate translational research and thus speed clinical applications of new discoveries. Great strides in biomedical research have been made in recent de- cades, due largely to a robust investigator-initiated research enterprise. Recent technological advances have provided new opportunities to fur- ther accelerate the pace of discovery through large-scale research initia- tives that can provide valuable information and tools to facilitate this traditional approach to experimentation. Recent large-scale collaborations have also allowed scientists to tackle complex research questions that could not readily be addressed by a single investigator or institution. The current leadership of NIH and many scientists in the field clearly have expressed an interest in integrating the discovery approach to biomedical science with hypothesis-driven experimentation. As a result, at least some large-scale endeavors in the biomedical sciences are likely to be under- taken in the future as well. But because the large-scale approach is rela- tively new to the life sciences, there are few precedents to follow or learn from when planning and launching a new large-scale project. Moreover, there has been little formal or scholarly assessment of large-scale projects already undertaken. Now is the time to address the critical issues identified in this report in order to optimize future investments in large-scale endeavors, what- ever they may be. The ultimate goal of biomedical research, both large- and small-scale, is to advance knowledge and provide society with useful innovations. Determining the best and most efficient method for accom- plishing that goal, however, is a continuing and evolving challenge. Fol- lowing the recommendations presented here could facilitate a move to- ward a more open, inclusive, and accountable approach to large-scale biomedical research, and help strike the appropriate balance between large- and small-scale research to maximize progress in understanding and controlling human disease.