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Special Reviews |
1 From the Department of Diagnostic Radiology, College of Medicine, and Division of Radiation Sciences, College of Health Sciences, University of Kentucky, Lexington, Ky (A.B.W.); and the Departments of Radiology, Radiation Oncology, Biophysics, and Community and Public Health, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226 (W.R.H.). Received July 13, 2005; revision requested September 19; revision received October 27; accepted November 23; final version accepted March 2, 2006; final review and update by W.R.H. July 20. Address correspondence to W.R.H. (e-mail: whendee{at}mcw.edu).
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONTHE NIHTHE NIBIBLIFE CYCLE OF AN...DISCUSSIONCONCLUSIONESSENTIALSReferences |
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© RSNA, 2007
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONTHE NIHTHE NIBIBLIFE CYCLE OF AN...DISCUSSIONCONCLUSIONESSENTIALSReferences |
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Created by the U.S. Congress in 2000, the National Institute of Biomedical Imaging and Bioengineering (NIBIB) (4) is the newest of NIH's 27 institutes and centers (ICs, as they are termed at NIH), and its primary objective is rather different from that of the rest of the ICs. (Expressions and acronyms that have special meaning at NIH will be introduced in italics.) Most ICs promote basic and clinical research on a specific cluster of organs or diseases and tend to support the development of associated technologies, primarily as related to their own central mission (5). The National Cancer Institute, for example, funds some activities that lead to improvements in positron emission tomography (PET), because it is an important tool for the detection of neoplasia; similarly, the National Heart, Lung, and Blood Institute and the National Institute of Mental Health support PET research as it relates to cardiac and mental health issues, respectively. NIBIB, in contrast, takes the position that advances in PET are likely to be brought about at least as efficiently through research and development focused on the science and technology of PET itself. The resulting advances in PET will then be adopted in radiology and nuclear medicine, oncology, cardiology, psychiatry, neurology, psychology, and other fields. NIBIB holds this principle to be valid across the spectrum of biomedical imaging and bioengineering technologies.
This review will describe the procedures by which investigators may obtain research funding from NIBIB and other NIH ICs (6–11). The intended audience includes radiologists, radiation oncologists, medical physicists, research scientists and engineers, and others involved in the development and use of imaging technologies—especially those with limited experience in the complexities of obtaining NIH grant support. It may be helpful to have copies of the relevant forms and instructions, which can be found online (12–15), available while reading it.
Virtually everything discussed here may be found on the Internet, but that material is widely scattered and generally highly detailed. Our intention is to provide a unified linear overview of the process, a user-friendly road map that describes many of the places of interest along the way and that also provides numerous references to sites where the topics are presented more fully (16).
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THE NIH |
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Ten percent of the total NIH budget is expended on what is referred to as intramural research by the 6000 researchers in its own laboratories, most of whom are on the Bethesda campus (18). These investigators focus on basic and clinical biomedical research that is of interest to the specific IC to which they have been appointed, and their facilities offer an unparalleled opportunity for researchers interested in improving patient care through translational and clinical research. One of the objectives of such a substantive intramural program is to attract the best people to serve as institute directors and senior scientists responsible for conducting all aspects of the NIH's operations. The chance to work in an environment resembling that of a great university, but without the headaches of having to struggle continuously for research funding, is a strong incentive.
The lion's share of the NIH budget (
80%) supports some 200 000 researchers through 50 000 highly competitive awards to 2800 universities, academic medical centers, hospitals, and other extramural sites for research in every state and in many countries (19). Each year, between a third and a quarter of the awards are newly initiated or competitively renewed, and a comparable number are retired; the rest support ongoing work, the typical grant being 3 or 4 years in duration. While a small part of this money is distributed in the form of cooperative agreements and procurement contracts, $9 of every $10 awarded is distributed in the form of grants in response to unsolicited or solicited applications.
In addition, administrative costs consume 8% of the NIH budget. The cost of peer review managed by the NIH CSR, which includes travel support to Bethesda for large numbers of expert consultants who serve on the numerous SRGs that assess applications for funding, is less than 1%.
The pool of applications for extramural support continues to grow steadily, and NIH is now receiving some 80 000 applications per year (20). As many as 30% have been chosen for support through a competitive peer-review process in some years, but more recently the number has been closer to 20%. The number actually funded at any time depends strongly on the current NIH budget approved by Congress and the president, the number of applicants, and the number of applications per investigator, which is increasing.
The 27 ICs differ somewhat in their main objectives (Table 1). Some ICs focus their resources on a specific set of diseases or organ systems (eg, National Cancer Institute; National Institute of Mental Health; National Heart, Lung, and Blood Institute). Others, such as the CSR or the National Library of Medicine, largely provide services to all of NIH. Each IC has its own budget and establishes its own approaches to setting funding priorities. The size of the budget for every IC is determined by Congress, with recommendations from the director of NIH (Fig 1).
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An RFA is a public announcement of an NIH initiative to fund research in a particular scientific area of special interest to the issuing IC(s). One particular category, known as NIH Roadmap Initiative RFAs, is generated by the office of the director of NIH rather than by any individual IC.
An RFA is an invitation to apply for a one-time competition in which the participating IC(s) sets aside a stated amount of money specifically earmarked to support its awardees. If a particular application is not funded, there is generally no resubmission opportunity (as there is for most other types of applications); it is always possible, however, to revise the title, take advantage of the reviewers' comments in modifying the text, and submit the application as a fresh but unsolicited proposal. The funding IC specifies the award mechanism for the RFA, such as R01, R21, or R43; sets a specific receipt date; and generally manages the peer-review process rather than rely on the CSR to do it.
A PA also describes an ongoing or new research opportunity, but it tends to be broader in scope than an RFA, typically covering a wide area of research. Unlike an RFA, applications in response to a PA are commonly reviewed in the CSR, not in an IC; have multiple receipt dates, perhaps over the course of several years; and usually allow up to two resubmissions if the first attempt is not successful. Also unlike the case of an RFA, money is generally not reserved in advance for the announced work.
Categories of Grants: Award Mechanisms
The NIH and other Department of Health and Human Services agencies promote health-related research, training, conferences, and other activities by means of hundreds of formally established types of grants, commonly known as award mechanisms (25). The variety of award mechanisms reflects differences in their purposes, sizes, intended recipients, origins, and other factors.
The research award mechanisms commonly employed by NIBIB and the other ICs of NIH are of three general categories: research (with an R prefix), cooperative agreement (with a U prefix), and program (with a P prefix) awards, all of which are commonly called research project grants (Table 3). For example, about 60% of NIBIB's nearly 800 research grants (new and continuing) in fiscal year 2004 were standard R01 grants; another quarter were smaller higher-risk R21 grants. Other types included R03 grants for small research projects, R13 grants to support research-related conferences, R43 and R44 grants (Small Business Innovation Research phase I and II, respectively) for small businesses, and P41 grants (Biomedical Technology Resource Center Grant) for large centers.
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An application will be either investigator initiated or submitted in response to an NIH public solicitation, such as an RFA or a PA. If it is not successful in the first attempt, two subsequent revised resubmissions are usually allowed, unless the application is in response to an RFA.
Although the PI writes the grant application and is responsible for the conduct of the research, the award is actually made to the PI's employer, not to the PI personally. A grant may be awarded to organizations of all types (eg, universities, colleges, small businesses, not-for-profit organizations, domestic and foreign institutions, faith-based organizations), unless noted otherwise. If the PI moves to another institution or organization, an R01 grant is generally transferable.
A proposal from a foreign applicant must be for a project that "presents special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions in other countries that are not readily available in the U.S., or that augment existing U.S. resources" and that "has specific relevance to the mission and objectives of [NIBIB] and has the potential for significantly advancing the health sciences in the U.S." (26).
Grant money may be used to pay for direct costs, such as partial or total salary and fringe benefits for the PI and other technical personnel (27); equipment and supplies; some laboratory alterations and renovations; consultant and consortium costs and contract services; and travel, publication, and miscellaneous expenses.
Most award mechanisms will also support facilities and administration costs, also known as indirect, overhead, or institutional costs. These are assessed as a percentage of the modified direct costs of the grant; they can be a considerable fraction of the total, occasionally even approaching the amount awarded as direct costs. The term modified indicates that only certain of the direct costs are included in the calculation of the facilities and administration costs—namely, salaries and wages, fringe benefits, materials, supplies, services, travel, and subcontracts up to $25 000. Direct costs excluded from the computation of facilities and administration costs are those for equipment, capital expenditures, patient-care charges, tuition remission, off-campus rental costs, scholarships and fellowships, and subcontracts in excess of $25 000. The percentage that is used for facilities and administration costs computations is negotiated between the awardee's institution and the federal government.
With regard to the application itself, the proposed research plan, which covers Specific Aims, Background, Significance, Preliminary Studies, and Research Design and Methods, must follow the instructions provided in the grant application kit for the Public Health Service Grant Application (PHS398), which is the form currently required for application for an R01 grant (but, see later in this review regarding ongoing replacement of PHS398 with the new Standard Form 424 [SF424] Research and Related form) (13). This can be a long and complicated process, and an applicant new to the system may find it helpful to seek advice or, better yet, active support from an experienced investigator. It is also a very good idea to contact the relevant program director (PD), also called a program officer, at the IC most likely to fund the application. The PD is a PhD or MD degree–level official at the IC who is responsible for the programmatic oversight of a specific category of grants (eg, ultrasonography [US] and nuclear medicine, magnetic resonance [MR] imaging) and who will be able and willing to provide a great deal of useful guidance on all aspects of the grants process.
Finally and most important, for any type of award the work proposed should be innovative and of considerable potential importance to medicine. The technical approach to the research should be well thought out and effectively presented. The application itself should be clear and have a straightforward logical flow. It should be easy to follow by both generalist and specialist reviewers, and it should be written in excellent English. Preparation of an application to NIH takes months of concerted effort in writing, rewriting, and rewriting yet again. Such is the price of success.
R01 research project grant.—The R01 research project award mechanism was the earliest instrument established by NIH to support health-related research and development. It is still the fundamental, and by far the most widely used, funding vehicle (28).
An R01 grant is awarded for a discrete, specific biomedical research project that is related to the stated program interests of one or more of the ICs. It is meant to advance important research that seems, partly on the basis of submitted preliminary data, to have a high likelihood of success. While there is no fixed dollar limit, the average R01 grant provides around $300 000 per year for 4 years for direct costs (along with associated funds for indirect costs) and thereafter may be renewable through recompetition. Standard receipt dates for new R01 grant applications are listed in Table 4 (29).
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R13 conference grant.—An R13 conference grant is the most widely used mechanism for supporting research-related conferences (31). An R13 grant provides one-time-only funding for a recipient-sponsored and -directed international, national, or regional meeting, conference, or workshop; for subsequent meetings, the sponsors must recompete. NIBIB tends to award R13 grants to help defray travel expenses for high school, undergraduate, and graduate students' and postdoctoral fellows' and junior investigators' attendance at a meeting. At present, NIBIB generally limits R13 grants to $10 000 when it is asked to serve as the primary funding source, and $3000 when NIBIB agrees to act as secondary source to another IC that serves as the primary source. The dollar amounts may not be large, but lending the NIH name to an effort as a sponsor can be of value.
R21 exploratory grant.—Unlike an R01 grant, an R21, or exploratory, grant focuses on promising but higher-risk, high-reward work (32). A total of $275 000 of seed money is available, to be used over 2 years at most, to demonstrate proof of principle; as with an R03 grant, few or no initial data are needed. In its first few years, NIBIB offered combined R21/R33 grants, in which a phase I R21 grant could rapidly lead to a much larger phase II R33 developmental grant similar to an R01, so long as the PI met certain prearranged quantitative milestones. The R33 vehicle is used infrequently now, but a successfully completed R21 project leaves the investigator in a good position to apply afterwards for an R01 or other award.
R43 and R44 Small Business Innovation Research grants.—A pair of award mechanisms is available to encourage qualified small domestic businesses to expand their technologic potential (33,34). The R43/R44 sequence of Small Business Innovation Research (SBIR) grants is designed for U.S.-owned, for-profit companies with fewer than 500 employees. Under the R43, or phase I, SBIR award, a business establishes the technical merit and feasibility of an idea that may ultimately lead to commercial products or services and receives typically $100 000 for a 1-year period. If the R43 effort is successful, a longer (eg, 2-year) and larger (up to $750 000 per year) R44, or phase II, grant may follow to support the subsequent work needed to bring the products or services to fruition. A variation on this theme is the fast-track R43/R44 that NIBIB occasionally uses to speed up the progress of a few unusually promising projects.
R41 and R42 Small Business Technology Transfer grants.—A Small Business Technology Transfer, or R41/R42, award pair also provides funding, comparable to that of an R43/R44 grant, to a small domestic for-profit operation—in this case, however, to one that is establishing a formal collaborative research and development relationship with a university or other nonprofit institution. As with an R43 grant, an R41 grant encourages demonstration of the technical merit and feasibility of an idea that has potential for commercialization.
P41 Biomedical Technology Resource Center grant.—A Biomedical Technology Resource Center acts as a large, focused, and publicly available service-oriented national resource for the scientific community. Supported by a P41 award, the grantee is expected to not only undertake an extensive research program but also provide cutting-edge technical assistance, including hands-on laboratory experience, short courses, and other types of training, to any qualified investigator carrying out scientific research related to the center's activities (35,36). Funding for a P41 grant is typically $1 million per year for 5 years, after which recompetition is required. NIBIB supports about 20 such centers, including the Electron Paramagnetic Resonance facility at the Medical College of Wisconsin (Milwaukee, Wis).
A P01 research program project award, by contrast, provides funding to a relatively large but integrated interdependent research group to pursue a set of coordinated collaborative activities with a central research focus.
Cooperative agreements.—A cooperative agreement, or U-type research award, is somewhat like an R grant, except that the funding IC plays an active role as a partner in the project, including having a say in how the project is managed (22). NIBIB does not currently have any U-type grants in its portfolio, but it recognizes their potential usefulness (eg, a U13 grant in support of a major conference).
Fellowship, career development, and training awards.—Apart from research and conference awards, the other general category of NIBIB support is for various forms of training and career development (37). Some fellowships and training awards are made to grantee organizations, and others go to individual recipients (38). Those employed relatively commonly by NIBIB include the F32 National Research Service Award (39) postdoctoral fellowship, K01 Research Scientist Career Development Award (40), K25 Mentored Quantitative Research Career Development Award (40), T32 institutional training grants (40), and several others.
Sketch of the Funding Process
The process of applying for a research grant is demanding for an applicant and, not infrequently, leads initially to disappointment. But an idea that is novel, potentially of substantial importance, and well and appropriately presented has a good chance of ultimate success.
Regardless of the IC(s) that might eventually fund it, every application goes through essentially the same process (Fig 2, Table 5). Although this is not the official NIH view, one can think of the life cycle of a grant as consisting of seven stages, as outlined below.
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2: Application.—The PI prepares the application and makes the initial submission to the NIH CSR. The CSR is the central office for receipt of all applications for research and training support (41).
3: Classification.—The CSR classifies the subject matter of the research or training and determines which IC is most appropriate for it. The CSR also then selects an SRG to judge the application and, thus, also, the SRG's permanent PhD- or MD degree–level Scientific Review Administrator, who manages the review process.
4: Assessment.—An SRG, commonly but not always under the direction of the CSR, assesses the application's scientific merit and gives it a priority score. Within several weeks of the SRG meeting, the applicant and the IC are informed of the merit evaluation; a month or so after that, both will receive the summary statement, which discusses the scoring decision in detail.
5: Award.—The IC makes the funding decision regarding the application, which depends on its priority score relative to the scores of other applications, the availability of financial resources from the IC, and the internal priorities of the IC. The complete award process can take from several months to a year from the time of submission to that of the final decision. If a grant is not forthcoming, the applicant can generally resubmit up to two times, starting back at the application step.
6: Report.—To continue to be funded annually throughout a multiyear award period, the grantee must demonstrate successful performance of the research by means of an annual progress report.
7: Renewal or termination.—The project is completed or the PI submits a competitive renewal application for its continuation.
These seven stages are discussed in greater detail in subsequent sections.
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THE NIBIB |
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TOPABSTRACTINTRODUCTIONTHE NIHTHE NIBIBLIFE CYCLE OF AN...DISCUSSIONCONCLUSIONESSENTIALSReferences |
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In response to several decades of concerted effort by the affected communities (42), NIBIB came into existence on December 29, 2000, when President Clinton signed the authorizing legislation into law (43). This new institute was designed to concentrate on promoting biomedical imaging and bioengineering technologies that have the potential for broad application to multiple diseases or biologic processes. NIBIB stands at the convergence of the physical sciences and engineering with biology and clinical medicine, and a major part of its mission is the development of novel technologies and tools that support advances in basic research and health care.
NIBIB acquired official grant-making authority with passage of the NIH appropriations budget for fiscal year 2002; 1 month later it issued its first grant announcement, an RFA. On May 7, 2002, Roderic I. Pettigrew, PhD, MD, was appointed the first permanent NIBIB director. He oversees a budget that has grown from $112 million in that year to nearly three times that amount for fiscal year 2006 (44).
Imaging Research Areas That NIBIB Supports
While some established imaging technologies have neared their theoretic limits of contrast, noise reduction, and spatial and temporal resolution, others have considerable room for further improvements (45). Even a relatively small modification can sometimes open up a new world of opportunity. In addition, radically new modalities appear from time to time. These opportunities and challenges, as well as similar ones in bioengineering, are of particular interest to NIBIB.
The general research areas that NIBIB supports (46) are listed in Figure 3. Those involved primarily with imaging can be partitioned roughly into groups that deal with improvements in currently established imaging technologies and methods, new and multiple-imaging modalities and instruments, imaging at the cellular and molecular levels, convergence of diagnosis and therapy, and computer applications. Other topics that do no fit readily into any of these "boxes" are still welcomed. The following list contains typical examples, but it is not all-inclusive.
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Nuclear medicine.—These grants, most of which are for PET and single photon emission computed tomographic (SPECT) applications in oncology and nuclear cardiology, cover improvements in scintillation crystals and collimator design; novel receptor-specific radiopharmaceuticals; dual-isotope imaging; the fusion of SPECT or PET images with those of CT or MR imaging; micro-PET and other small-animal systems for use in molecular imaging; novel methods of data acquisition, image processing, and quantitative imaging; radionuclide dosimetry; and other areas.
MR imaging and related areas.—NIBIB has funded methods to reduce image acquisition time without loss of image quality, such as through special radiofrequency and gradient pulse sequences or combination of signals obtained from multiple radiofrequency coils simultaneously; high-field-strength devices; MR angiography, MR microscopy, and diffusion imaging; devices for special applications, such as MR imaging of the breast; functional MR imaging and other approaches to physiologic imaging; MR spectroscopy, including that of carbon 13, fluorine 19, and phosphorus 31; and instruments for in vitro and in vivo electron paramagnetic resonance and electron spin resonance imaging and spectroscopy and proton-electron double-resonance imaging, or PEDRI, which involves simultaneous electron paramagnetic resonance and nuclear MR imaging.
Ultrasonics, photoacoustics, and thermoacoustics.—Awards in these areas encompass the design of miniaturized very-high-frequency piezoelectric and capacitive two-dimensional–array micromachined ultrasound transducers, which have potential applications in imaging of the eye, the skin, the interiors of narrow vessels, and perhaps even cells; novel contrast agents and the exploitation of harmonic frequency information generated through nonlinear interactions of ultrasound energy with contrast agents and even tissues; coded-excitation pulse trains and matched filters; elastography, which directly reveals the elasticity parameters of different tissues rather than just the boundaries between them; focused ultrasound for therapy; and mechanisms of biologic damage.
Molecular imaging.—One of the more rapidly evolving research areas is molecular imaging, the in vivo sensing and characterization of biologic processes at the cellular and molecular levels. Molecular imaging contributes to the exploration of gene expression and protein-protein interactions, the monitoring of apoptosis (as a predictor of therapeutic response), the assessment of tumor growth, and other areas. NIBIB funds innovations in the synthesis of molecular agents such as "quantum dots"—semiconductor nanoparticles coated with antibodies or other agents that can attach with high specificity to proteins or with other biomolecular targets; quantum dots are detectable by using various imaging methods, including PET, MR, and optical imaging technologies such as quantitative fluorescence imaging, multiphoton and near-infrared microscopy, and optical coherence tomography. NIBIB also supports research on personalized treatment based on image-guided tissue analysis and on scaled-down CT, MR, SPECT, PET, optical bioluminescence, fluorescence molecular tomographic, and other devices for the study of mice and rats rather than people.
Biomagnetic and bioelectric effects.—Diagnostic technologies based on biomagnetic and bioelectric effects include the analysis and modeling of data from electrocardiography, magnetocardiography, electroencephalography, magnetoencephalography, electric impedance tomography, and others.
Image-guided intervention.—NIBIB is interested in minimally invasive image-guided intervention technologies and in the technical integration of diagnosis and therapy, as in imaged-guided interventions. Among the technologies that have been supported are US- and MR imaging–guided radiofrequency ablation of tumors and endoscopic procedures; surgical planning and treatment; and robotics and haptics (interfacing tactile sensation and control devices with computers).
Computer applications.—Computers are essential for tomographic reconstruction and many other imaging processes, and they have become ubiquitous in radiology. NIBIB funds work in image processing, display, and perception, such as registration and segmentation techniques, virtual reality technologies, and observer performance measurement methods; bioinformatics; mathematic modeling, simulation, and analysis, including systems and multiscale modeling, computer-aided detection, computer-aided diagnosis, and other forms of knowledge-based models; picture archiving and communication systems and other software and hardware infrastructure, image compression, and multiple domain applications; and telehealth (electronic delivery of health care services and information).
For these and other modalities, moreover, NIBIB encourages the development of low-cost and readily portable medical devices to benefit underserved communities in this country and elsewhere. Of course, some good imaging ideas that might appeal to NIBIB may not fit neatly into any categorization scheme and are considered on an ad hoc basis.
Establishing and Maintaining a Focus for NIBIB
In its earliest days, NIBIB inherited responsibility for $67 million worth of ongoing grants from other ICs, largely from the National Cancer Institute, along with the resources needed to fund them. It was critically important that these inherited projects be related clearly to the NIBIB mission, as suggested by the categories listed in Figure 4.
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In addition, there are several NIH partnerships in which NIBIB participates actively. Prominent among them is the Bioengineering Consortium, in which a number of ICs joined together in 1997 to orchestrate and support biomedical engineering projects; in 2001, NIBIB assumed administrative responsibility for the group (47). The Bioengineering Consortium introduced several specialized award mechanisms such as the Bioengineering Research Grant, the Exploratory Bioengineering Research Grant, and the Bioengineering Research Partnership Grant. The Bioengineering Research Grant is an R01 grant, but since it is directed largely to imaging or bioengineering projects, it uses a more appropriately tailored set of considerations for its review process. The Exploratory Bioengineering Research Grant is similar but employs the R21 mechanism. Bioengineering Research Partnership Grants are R01 grants that tend to be very large (as much as $2 million in total costs per year for up to 5 years) and support multiple institutions working together in close synergy, somewhat like a P01 award. Finally, some of these bioengineering grants are of the Small Business Innovation Research (R43/R44) type. While most BECON projects deal directly with traditional bioengineering topics, NIBIB contributes funding to several that concern image-guided interventions, biomedical computation, and small-animal imaging.
NIBIB also belongs to the Bioinformation Science and Technology Initiative Consortium (48), another group of ICs with a structure similar to that of the Bioengineering Consortium but with a different set of priorities—namely, the application of bioinformatics and computer science approaches to biomedical problems.
The director of NIH recently introduced and published, by means of RFAs, a set of NIH Roadmap initiatives—biomedical challenges of substantial scientific importance and clinical relevance that cannot be resolved by one or a few ICs alone but that NIH as a whole might address effectively (49). The projects fall into three broad general areas. "New Pathways to Discovery" is concerned with the advancement of basic approaches to complex biologic systems and with the development of the toolbox of needed research technologies. "Re-engineering the Clinical Research Enterprise" focuses on translating the results of basic research into useful clinical applications through better training of the clinical research workforce. It also supports the establishment of national clinical research networks, including biomedical informatics systems with interoperable infrastructures. "Research Teams of the Future" is concerned with ways to strengthen the increasingly diverse and interdisciplinary teams that will provide the basis for success with the other two areas—such as through establishment of public-private partnerships among the government, research-oriented corporations, and universities and other not-for-profit research centers. The NIH director has dedicated more than $2 billion to the road-map initiatives for the decade of 2004 through 2013, and NIBIB is actively involved with a number of them in areas such as nanobiomedicine, molecular imaging, biomedical informatics, interdisciplinary training, and public-private partnerships (see Fig 4).
Setting NIBIB Priorities
The NIH is a very large organization, and the funding policies of its various ICs have a tremendous impact on the directions that biomedical research and development take in this country. Apart from the directives it receives from the director of NIH, such as the road-map initiatives, how does NIBIB, for instance, go about making its own prioritization decisions?
The senior management and PDs of NIBIB have been considering such matters for as long as the institute has been in existence. They have a PhD or MD degree, and sometimes both, along with considerable research experience, and they tend to be highly knowledgeable in their fields. They stay in close contact with the leaders of academic and private research groups, professional societies, and device manufacturers, who frequently provide useful input, and they are continually learning about what is happening at the cutting edge through frequent interactions with applicants and grantees.
In selecting areas of emphasis and specific topics for RFAs and PAs, NIBIB also makes extensive use of feedback from its own National Advisory Council for Biomedical Imaging and Bioengineering, from focused workshops, and from other special-purpose advisory groups drawn from the extramural population that NIBIB serves. In addition, more than half of all research projects funded by NIBIB are initiated by PIs, rather than in response to NIH announcements of money available for specific research projects or project areas—and by tracking these unsolicited grant applications from the biomedical community, NIBIB can acquire another perspective on what the most interesting, important, and immediate scientific challenges are. So, by submitting a grant application, an investigator actually becomes part of the priority-setting process, indicating where he or she believes the agency should be expending its research and educational resources.
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LIFE CYCLE OF AN R01 GRANT |
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TOPABSTRACTINTRODUCTIONTHE NIHTHE NIBIBLIFE CYCLE OF AN...DISCUSSIONCONCLUSIONESSENTIALSReferences |
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Starting Off: Discussions between PI and PD
Suppose that a new assistant professor of radiology has an idea for a research project that falls within her area of competence, that clearly could have a great impact in the technology of medical imaging, and that her institutional environment is well suited to support.
She is fairly certain that her concept is original and in an area that has not been explored in depth by others. She confirms this with an exhaustive literature search, and she also consults CRISP (Computer Retrieval of Information on Scientific Projects), a publicly accessible Web-based NIH database that includes abstracts and other technical information about federally funded biomedical research (50). CRISP allows searches according to scientific area, investigator, and other terms to facilitate identification of emerging trends or to provide information on specific projects, and it may help her get a better sense of the nature of the competition—or perhaps thoughts on possible collaborators or consultants. She also signs up for the NIBIB e-mail list (NIBIB LISTSERV), through which notices of NIBIB funding opportunities, workshops, and symposia are sent (51).
The applicant determines, from the NIBIB Web site or a phone call, the name of the PD in her field (10) and discusses the project at length with him or her for several reasons—to confirm that the institute encourages the submission of her application, to solicit relevant advice on how to proceed, and to begin a professional relationship with someone with whom she may have a fair amount of contact in the future. The PD deals with scientific and technical aspects of her application and can also be a valuable source of information on how to get things done, pitfalls to avoid, and so on. (A PD also stays in close contact with the relevant research communities, initiates new areas of special funding by NIBIB through RFAs and PAs, sets up and runs workshops, makes policy recommendations to the institute, interfaces with the ICs and other organizations with related interests, etc.) The PDs at NIBIB and the other ICs consider interacting with their applicants to be an important and satisfying part of the job, so the applicant need not feel shy about getting, and remaining, in touch.
Preparation and Submission of the Application
Unsolicited applications are processed in three batches each year, with a new review cycle beginning every 4 months; the appropriate receipt dates depends on the type of grant (Table 4). The PI thus plans her work accordingly.
After talking with several colleagues experienced in obtaining NIH funding, our investigator brings together a solid team of collaborators and mentors with a range of technical, clinical, and grant-writing expertise broad enough to cover all aspects of the proposed work. The team begins by clarifying, to the extent possible, the basic aims of the work, the novelty and significance of the project, the issues it addresses, the aims of the work, the hypotheses and rationales underlying the project, the gaps in scientific and/or technical knowledge that it should help to fill, and so on. The PI is sensitive to the need to be not too ambitious—a mistake common among applicants early in their careers—and sticks to a manageable project.
The PI and her team then turn to the long and demanding task of developing an explicit technical approach to the project, in particular the experimental design. This has to be worked out in enough detail to convince reviewers that the methods are sensible and likely to succeed in accomplishing the stated objectives. In putting pen to paper, the team decides to enhance clarity by dividing the section on each aim into parts, with subtitles such as Rationale, Methods (including Statistical Analysis), Anticipated Results, and Potential Problems and Their Resolution.
As the work progresses, the group prepares the first draft of the technical description of the proposed research, recognizing that the draft will have to be refined a number of times, and perhaps largely be rewritten, before it is finished. They estimate that the effort will cost $200 000 per year for 4 years and decide to apply for an R01 grant. Although several members think that they could make good headway for less money and over only 2 years with an R21 grant, the PI prefers to take a greater risk in the hopes of gaining more support. A request of $250 000 or less in direct costs each year must be submitted in modular budget format (52). Their expected cost is lower than the $500 000 per year cut-off level, above which level they would be required to obtain a letter of preapproval from the likely IC before submitting the application (53).
As soon as possible, the team begins to acquire preliminary data, which are required for an R01 (but not for an R21) grant. The reviewers will consider these data to be illustrative of what would be generated if a grant were awarded; therefore, the work must be of very high quality. The accompanying analysis and discussion must clearly lead a reader through all the important steps of the experiments and calculations and demonstrate that these studies and those planned for later are focused on the overall objective.
Our applicant reads several descriptions on the Web of the application process and grantsmanship and downloads the Public Health Service grant application form PHS398, which has long been the starting point for virtually all applications to NIH. She goes over the instructions carefully, noting the fine-print instructions on font size, margins, page numbering and limits, and other such tedious but requisite matters (54) and makes sure that her budget and timeline are credible.
Criteria for scoring an application.—Five criteria are employed by most SRGs in assessing the scientific merit of applications (Fig 5). These deal with the significance of the proposed work, its level of innovation, the appropriateness of its technical approach, the qualifications of the investigators, and the suitability of the scientific and technical environment (55). Individual SRG members may tend to ascribe greater importance to one or another of these, but all five criteria are generally considered to be critical. In any case, the PI and her group emphasize the ways in which the application goes well beyond merely satisfying the five criteria.
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A project is viewed as innovative if it presents a challenge to existing paradigms, develops original concepts or methods, or employs existing ideas or technologies in novel ways.
The approach is considered sound if the conceptual framework, design, methods, and analyses are adequately developed, well integrated, and appropriate to the objectives of the project and if the applicant has set appropriate milestones and evaluation procedures. If called for, as for an R01 grant, there should be preliminary data directly related to the specific aims of the proposal, and the meaning of these data should be clearly discussed. The proposed experimental design should be logical, focused, and described in sufficient detail to paint a clear picture. On the other hand, it should not contain too many minutiae: A general "data dump" or "fact dump" definitely does not impress reviewers favorably. The application should acknowledge potential problem areas and present alternative strategies if difficulties do arise.
It should be demonstrated that the lead investigator and other researchers have the ability, training, and experience needed to coordinate, manage, and conduct a project on the scale of the one proposed. What are the strengths of the team, and what suggests that they are (perhaps uniquely?) qualified to bring the work to a successful conclusion? To what extent is this an extension of work with which the PI and team members are already familiar, and how much have they published in the field?
The physical and intellectual environment in which the work will be performed must be seen to be conducive to success; it should allow sufficient access to the necessary resources such as laboratory space, equipment, computer facilities, and potential collaborative arrangements. Ideally, the PI can report that her own institution has already agreed to provide some financial support to supplement the award.
To summarize, the levels of significance and innovation relate to the importance of the project; the assessment of investigator and environment provide an indication of the likelihood of its success; and the approach describes the engine that drives the whole project forward. These five review criteria may be modified somewhat in some announcements for RFAs, PAs, fellowships, and career development awards, but the general idea is standard.
Animal and Human Subjects
Many NIH grants involve the use of animal or human subjects, and this requires additional thought and paperwork (56–62).
A quarter of all applicants to NIBIB propose the use of animals in studies, and the NIH Office of Laboratory Animal Welfare insists on ensuring their proper handling and care (63). Detailed plans for the management of research animals must be presented, together with documentation of approval by the Institutional Animal Care and Use Committee (IACUC) at the applicant's institution. Some applications are rejected at the outset simply because of animal care issues. NIH does permit an investigator to send an application without IACUC approval, however, and will grant an award in these situations, though no funds will be released until the appropriate documentation arrives at NIH and is approved. An applicant's institutional grants and contracts office can be helpful here.
The treatment of human participants in research is an even more sensitive issue (64). One-fifth of the applications to NIBIB involve human participants in research, and these applications must be consistent with the requirements of the NIH Office of Extramural Research (65,66). NIBIB is rarely involved in clinical trials, but even tasks as seemingly innocuous as examination of images, tissues, or pathology slides obtained earlier in an unrelated study and bearing no patient identification code may require approval from an institutional review board at the applicant's institution. An institutional review board is required and is authorized to ensure that both federal regulations and local institutional policies are carried out properly (67). Whether or not a study is considered to involve human participants depends, in complicated and somewhat nonintuitive ways, on the extent of involvement of the provider of the data or specimens, the role of the recipient investigator, and the nature of what is being obtained. If in doubt, contact NIH for clarification.
In any study involving humans, an Inclusion Enrollment Report Table that demonstrates an equitable distribution of subjects by sex and race must be filled out completely. It is important that children be included in studies unless their exclusion is medically or legally justified, but there may need to be special provisions for them or for certain groups in whom the research may pose an undue risk. Funds will not be issued until an enrollment table is submitted.
For studies that expose human participants to known or possible risk, an additional review by a Data Monitoring Committee or the closely related Data Safety Monitoring Board at the applicant's institution may be needed.
Completing the Application
After accounting for all of the above issues, the prospective PI carefully edits her application, rewriting parts of it, and does this again and again until she believes that it is technically correct, complete, perspicuous, well organized, and well written. She attempts to make her discussion comprehensive but, at the same time, as concise as is reasonable. She uses the active voice, separates the sections of her discussion with helpful headings and subheadings, makes sure that every term is fully understandable to a prospective reviewer and that all acronyms are defined when introduced. In presenting her plans and preliminary data, she checks that the tables, graphs, and figures and captions all are intelligently thought out, self-explanatory, and meticulously prepared and that every parameter and variable in every equation is unambiguously defined.
She then asks several generalist and specialist colleagues—preferably ones who write well—to go over the application and provide detailed comments. They are happy to help, knowing that she will reciprocate at a future date.
While all of this may seem obvious, many researchers miss an essential point: An application that is scientifically meritorious can easily be rejected because of a poorly organized or sloppily prepared written presentation. Reviewers are busy people with limited time and many applications to examine, and they will not be pleased by an application that they have to struggle through; there are enough good ones being submitted that are relatively easy to appreciate. The written English does have to be excellent—not only the grammar and spelling but also the overall style of writing. The organization and presentation should progress smoothly, as with any other good story, and the table of contents and sequence of section headings should provide a meaningful overview of the entire application.
Having agonized through this process for several months or more, the applicant prepares a one- or two-page cover letter that describes the project in a few sentences. In the cover letter she may suggest the primary IC that she hopes will provide funds, as well as one or more secondary ICs if shared interests exist among the ICs; identify an NIH grant mechanism suitable for funding her research; propose an SRG she thinks will be most appropriate; identify the type of expertise the SRG will need to review her application; and name scientists in her field who she thinks would be inappropriate reviewers because of a conflict of interest or a long-standing dispute that could bias the review. After she reviews a recent listing of the study group membership (68,69), she may come to believe that some technical areas need better representation—so without mentioning names, she asks that reviewers with the needed scientific expertise be added. She also sketches her anticipated timetable and milestones. NIH takes all of this information into consideration. It is important to note that applicants are not permitted to suggest the names of researchers they think should review their applications. Doing so would prevent these researchers from being considered.
She notes that she has never previously served as PI on any Public Health Service–supported research project other than an R03, R15, or R21 grant and that she should therefore be considered a new investigator. This will provide her with an advantage (see below) at the time that NIBIB makes its funding decisions. There is a corresponding box to check on the face page of the PHS398 form. As a new investigator, she sees the wisdom of also asking several senior-level well-known researchers to submit letters of recommendation on her behalf.
She passes the completed application on to her organization's responsible program office, in her case the university's director of grants and contracts, who can sign financial documents. The program office then completes the paperwork and submits the application to NIH.
The preparation of a grant application is an arduous business, and the larger the grant, the greater the amount of preparation required. The heart of the application is the description of the proposed research. This must be presented lucidly enough for a generalist to understand the main points, but there must also be enough sophistication and detail to convince a specialist in the field that the project is novel and important and has a good chance to succeed. This balance may be difficult to achieve, but it is quite important.
Transition from PHS398 to SF424.—Starting in 2006 and continuing through 2007, NIH has been phasing in a new system whereby application has to be made by way of the new SF424 instead of the PHS398. The form must be submitted electronically through the Web portal (http://www.grants.gov) rather than by mail (70). The change occurred because 26 federal grant-making agencies combined forces to create a single grants access point for all of them (71,72), and the SF424 followed as a single form for research and research-related funding.
After the transition date, current estimates for completion of which (73) are shown in Table 6, application must be made by way of the SF424; before then, however, one still has to use the PHS398. The start date for R01 grants, in particular, is February 1, 2007. Another NIH notice describes the need for some responses to Funding Opportunity Announcements (ie, PAs and RFAs) to employ version 2 of the SF424 form (74). Instructions on how actually to obtain or use an SF424 are available at http://era.nih.gov.
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Sometimes there is overlap in the research areas that two ICs are willing to fund, and they decide together what to do on a case-by-case basis. NIH encourages multi- and interdisciplinary research, and, when appropriate, the CSR may direct an application to multiple ICs as potential cofunders. If several agree that it should be supported, then one will assume the role of primary IC and assume administrative and principal financial duties, and the secondary IC(s) will transfer funds to the primary IC.
The application identification number.—The CSR assigns the proposal a unique application number, which will be retained as its grant number if it is funded. A typical number might read "1 R01 EB001234-01A2."
The leading 1, an indication of the grant type, reveals that this is either a new application or a funded project in its 1st year of support. Other possibilities are listed in Table 7. A type-5 application is a multiple-year grant that is now beyond its 1st year. A type-2 application is one in which a grant has nearly run through its allotted duration but the PI wishes to continue the same work by competing for a renewal. This grant-type number is primarily for NIH bookkeeping purposes.
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The –01 suffix indicates either that this application has not yet been funded or, if it has, that it is in the 1st year of funding; an –03 suffix would mean that the grant is in its 3rd year of operation. (Only in the particular case of a new application or grant are the leading 1 and the –01 suffix redundant.) The final A2 signifies that the original submission and the first resubmission were not successful and that the application or grant is now a second amendment.
Assignment to an SRG and Scientific Review Administrator.—The CSR uses specific review guidelines to assign an application to the appropriate SRG, also known as a Study Group or Study Section, which will carry out the assessment of its scientific and technical merit (Fig 7). The SRG may be either a permanently established Standing Study Section or an ad hoc Special Emphasis Panel set up temporarily for a particular group of applications (eg, those responding to a specific RFA or PA with receipt). Either way, the SRG consists of successful technical experts with research experience, several of whom may work in the same subfield as the applicant.
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Approximately 6 weeks after an application arrives at NIH, the applicant should receive a notice from the CSR containing the application number, the SRG and Scientific Review Administrator assignments, the name of the relevant PD at NIBIB—with whom the applicant has probably already interacted—and a CSR representative to contact if there are any problems to address or last-minute changes to the application.
Because several months may have passed since submission, an applicant may wish to include some recently generated supplementary materials to be considered in the review. The method of doing so depends somewhat on the SRG, and the best approach is to contact the Scientific Review Administrator.
Finally, before the application undergoes review, a copy is sent to its potentially awarding IC for some further processing. Those that are sent to NIBIB are assigned an internal Program Class Code to assist staff by identifying the NIBIB division involved, the scientific area, and the PD.
Peer Review Assessment of the Application by an SRG
Of the 80 000 applications NIH receives each year, a large number describe work that is clearly worthy of support. But the agency has resources to fund only a fraction of these applications, regardless of the potential medical benefits of the others; so, it is called on to make extremely difficult decisions. NIH attempts to do the painful but necessary culling of applications in as wise, scientifically productive, and equitable a manner as possible.
The NIH review process is designed to give each application a fair and open hearing within an appropriate SRG (78). A typical SRG consists of 20–40 established researchers—primarily academics, but also scientists from national laboratories, business, and elsewhere, all drawn from a pool of 15 000 established and widely recognized experts—who are highly qualified in areas directly or indirectly related to those of the application (79). It is their job to evaluate the scientific merit of 50–100 applications at an SRG meeting.
Application scoring process.—About 6 weeks before the meeting of an SRG and after attempting to ensure that there are no conflicts of interest, the CSR mails to each SRG member a compact disk containing copies of all the applications to be considered. In addition, for each application the Scientific Review Administrator asks one member to serve as the primary reviewer and two or more others to be secondary reviewers, to examine the application in depth. Before the meeting, each of the three or more reviewers provides the study group with a written critique that describes the application in detail, expresses opinions on its technical strengths and weaknesses, and assigns it a preliminary rating of between 1.0 (for outstanding) and 5.0 (for the other extreme). In scoring an application, an SRG member is always to use the same five standard criteria (Fig 5).
Meetings normally occur three times a year, several months after a submission deadline. At any of these meetings, the SRG members convene around a large conference table for 1 or 2 days, with the SRG chairperson and the Scientific Review Administrator jointly conducting the proceedings. Federal Advisory Committee Act rules apply (80), and the meeting is confidential and closed to the public; however, an IC with applications being judged may send a PD to keep track of how their applications fare. An SRG member for whom there may be a conflict of interest with a particular application leaves the room while it is being discussed.
For every application, the primary and secondary reviewers and the discussant orally state the scores they have given and then present their critiques, each for a few minutes or more, to justify their numeric assessments. After they have finished, the group members discuss it, occasionally for up to a half hour or so and sometimes in a rather impassioned manner. The reviewers then openly either retain their initial numeric assessments or modify them, and every SRG member anonymously submits his or her own number. The average of these values, multiplied by 100, is the priority score. The SRG then turns to other matters related to the application, ensuring that any legally required approvals regarding the care of animals or protection of human subjects or the environment are in order and that the proposed budget and timeline are suitable.
Before the meeting, the SRG members are called on to submit to the Scientific Review Administrator a list of those R01 applications that they consider to be noncompetitive—that is, applications that do not, on the basis of scientific merit, fall within the stronger half of those being considered. A reviewer or the chair will then, near the beginning of the meeting, move to unscore each such application; if the decision on the application is unanimous, the SRG does not consider it further. A single member can prevent unscoring from occurring for a specific application, however, thereby ensuring full discussion of it. This streamlining process frees up time for discussion of the more favored applications. The recipient of an unscored result can rethink and, by carefully responding to the written comments of the reviewers in the Summary Statement, resubmit the application like any other unsuccessful applicant.
The SRG may also defer action on an application if, for example, additional information is required. Rarely, the SRG may decide that the application has virtually no scientific merit or that there are egregious ethical concerns over the treatment of human or animal subjects and recommend that it never be given any future consideration.
An R01 application that goes to a chartered standing study group receives not only an absolute score but also a relative percentile measure of how it compared with the other R01 applications being assessed. The percentile is the application's rank, on a scale of 0.1 (best) to 100.0, that indicates the percentage of applications with a priority score that is equal to or better than it. The comparison base for chartered SRGs and some Special Emphasis Panels consists of all R01 applications reviewed by that study group over the current and previous two review rounds. The advantage of this approach is that because some SRGs may tend to give substantially higher or lower priority scores than do others, such bias is removed by means of the percentile process. This is shown in Table 8 for one particular SRG, but the scale may differ considerably for other groups.
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