Previous Section || Go to Beginning || Next Section
Cross-Cutting and Policy Issues
The following sections deal with scientific issues that cut across programmatic lines and policy issues related to the operational processes, external factors, and resources that affect the overall accomplishment of the goals and objectives in this report. They have been highlighted here as endorsement by the National Advisory Eye Council (NAEC) of their importance to the programs of the National Eye Institute (NEI) and the vision research community and as an indication of future need.
CROSS-CUTTING ISSUES
Aging Research
Many of the most significant causes of blindness and visual disability are associated with the aging process. While improvements in nutrition and health in this country have increased the average lifespan, many Americans are unable to fully enjoy their increased longevity due to visual impairment and its subsequent effect on their quality of life. Indeed, there were approximately 33.9 million Americans age 65 or older in 1995. By the year 2030, that number is expected to double. Improved prevention, diagnosis, and treatment of eye diseases and disorders for this country's older citizens is, therefore, of great importance.
Within each program discussed in this report, the research objectives, needs and opportunities, and research strategies related to many of these diseases and disorders have been identified. In the Retinal Diseases Program, age-related macular degeneration (AMD) and diabetes are the major causes of vision loss in the elderly. Although a highly effective treatment exists for diabetic retinopathy, research indicates only half of those individuals who need treatment currently receive it, and treatment for AMD is available for only the small minority of the cases with the wet form of the disease. Objectives in these areas seek to explore the pathophysiological heterogeneity of AMD and investigate the pathogenesis of these and other vascular diseases of the retina and choroid with the aim of developing better methods of diagnosis, prevention, and treatment.
Diseases that affect the tear film on the surface of the eye, such as Sjögren's Syndrome, are also of concern, particularly among women. An objective within the Corneal Diseases Program is to improve the understanding of ocular surface physiology in hope of finding more treatments for diseases that affect it. Although a highly effective surgical treatment exists for treatment of cataract, the Medicare costs alone are approximately $3.5 billion per year in this country. Objectives in the Lens and Cataract Program are aimed at finding the genes that cause age-related cataract, and determining if there are genetic factors that interact with environmental factors to confer susceptibility to age-related cataract. Likewise, presbyopia (the inability of the lens to focus or accommodate on near objects as we age) represents a significant economic cost to society. One of the objectives is to understand the basis of lens accommodation and presbyopia at the molecular and mechanistic levels.
The most common types of glaucoma mainly affect older people and increase in prevalence with each decade over age 40. Because those with glaucoma often do not seek medical attention until irreversible loss has occurred, objectives in the Glaucoma Program seek improved methods of early diagnosis and identification of the genes and genetic loci that contribute to glaucoma. Because of the susceptibility of the elderly to these major causes of visual impairment, many of the objectives within the Visual Impairment and Its Rehabilitation section of this report are of special importance to the aging population. These include understanding normal visual functioning so that this knowledge can be extended to treating the problems experienced by people with low vision, and developing effective assistive devices and techniques that will maximize residual vision or substitute for visual information.
Technological advances may also provide the tools for understanding the effect of aging on the levels of expression of the genes in the eye that are normally maintained in balance. Genetic disease research has suggested that in diseases in which only one copy of a pair of genes is defective, there may be a level of expression below which normal function is lost. In normal cells, there may be a similar decline in expression during the aging process, but the threshold at which the normal function is lost may not be reached until later in life. Intramural researchers will be using microarray technology, a new technology that allows comparison of large numbers of genes. This will allow these researchers to search for genes whose relative levels of expression in the eye decrease or increase disproportionately during normal development, disease, or aging.
In addition to these areas of aging research, the NAEC encourages consideration of the eye as a model of the aging process. The Council feels that collaboration between the NEI and the National Institute on Aging on projects related to the processes involved in aging, as exemplified in eye tissues, would hasten understanding of these processes and development of the means to slow or prevent them.
Genetic Research
Hereditary and congenital diseases are significant causes of blindness and visual disability in the United States. Because the visual impairment often begins early in life, the economic, societal, and personal impact can be enormous. Research is aimed at early diagnosis, development of effective treatments, and ultimately the prevention of these diseases. In addition to known diseases with genetic components, such as retinitis pigmentosa, gyrate atrophy, the corneal dystrophies, and hereditary cataracts, genetic research has also recently identified genes associated with AMD and several forms of glaucoma. The NAEC recommends continuation of the search for genes and genetic loci related to these and other eye diseases and disorders throughout the NEI research program.
Developmental Biology and Regeneration Research
The development and assembly of the visual system have long been an essential part of the neurobiological investigations within the NEI research program. Early investigations into the structure and function of the central visual pathways and how they are modified by early visual experience have been exceedingly important in beginning to understand the plasticity of the central nervous system (CNS) and how the brain selectively responds to stimuli. Among the objectives for the Strabismus, Amblyopia, and Visual Processing Program are gaining an understanding of how the visual system is assembled during development, how its assembly is influenced by endogenous and exogenous factors, and the factors that are involved in its regeneration after injury. Understanding how the myriad neural connections necessary for a proper visual picture are developed may also lead to the appropriate treatments when these systems are damaged by disease or during the development process.
Regeneration of neural and other ocular tissues is also an area of extreme importance throughout the NEI research program. The adult retina is incapable of regeneration following damage, injury, ischemia, or degenerative disease, as is the case in the visual centers of the brain and other areas of the CNS. Similarly, in glaucoma, damage to the retinal ganglion cells in the optic nerve is irreversible. Research recommended in the Glaucoma Program section of this plan focuses on identifying neuroprotective strategies that could prevent retinal ganglion cell death, promote survival, or stimulate regeneration. The Council believes that research in these areas is important not only to diseases of the eye and visual system, but also for neurodegenerative diseases or damage to CNS tissues, for which regeneration of damaged or diseased neurons would be beneficial.
Drug Delivery
The Council also encourages continued improvement in delivery of drug treatments for ocular disease. Development and testing of devices such as the ganciclovir implant, which demonstrated a significant effect in delaying the progression of retinitis in AIDS patients with cytomegalovirus (CMV) retinitis, may ultimately yield improved treatments for a wide variety diseases, including bacterial and viral infections, uveitis, glaucoma, and retinal degenerations.
Trauma
Another cross-cutting area closely linked to regeneration is trauma or injury. Because it is the most exposed ocular tissue, the cornea is highly susceptible to trauma from a variety of mechanical, chemical, and environmental insults, in addition to being exposed to a host of microbes capable of inflicting damage to the ocular surface. Retinal tissues, the optic nerve, and the visual pathways and centers in the brain are less exposed, but they too are susceptible to trauma or injury. Although traumatic damage to tissues can be devastating, often it is the wound healing process itself that upsets the delicate and unique properties of the ocular tissues. For that reason, research throughout the NEI research program is focused on the complex cell-cell interactions and cellular and molecular events associated with wound healing. The hope is that careful evaluation will help identify the key processes that ultimately may be regulated to preclude further damage to vision. Research is also aimed at determining how ocular tissues themselves protect themselves from damage.
Systemic Diseases (Immune Disorders and Diabetes)
Systemic diseases, such as diabetes, can have some of their most devastating consequences in the eye. Diabetes exerts its most harmful ocular effects on the retina, where it causes progressive breakdown of the normal vessels in the eye, a condition called diabetic retinopathy. Diabetics are also at increased risk for other serious eye problems, such as cataract and glaucoma. Studies such as the Diabetes Control and Complications Trial and its followup have made a significant a contribution to patient welfare and quality of life by showing that tight control of glycemic levels could delay the onset and possibly prevent diabetic eye disease. Although advances have provided identification and characterization of factors and proteins that may play a critical role in the management of diabetic retinopathy, research is now being focused on testing new therapeutic approaches suggested by the results of this research, as well as newer, more potent aldose reductase inhibitors. Research is also aimed at discovering genetic factors involved in diabetic retinopathy. The Council feels strongly that this research may be beneficial to the entire field of diabetes research and encourages collaboration with the National Institute of Diabetes and Digestive and Kidney Diseases.
Immune disorders of the eye also cut across programmatic lines. Not only does the immune system protect the eye, it must also maintain a delicate balance between protection and overreaction, which can adversely affect the surrounding tissues. Many ocular structures, such as the cornea, lens, and vitreous, do not normally have blood vessels and therefore do not have typical responses to foreign substances, microbes, or transplanted tissues. Within the eye, autoimmune responses such as uveitis can have blinding consequences. Other autoimmune diseases like Sjögren's Syndrome and Graves' disease can also have sight-impairing consequences. Within the Retinal Diseases Program, objectives seek to identify the factors that dictate the unique properties of intraocular immunity and inflammation and alter systemic immunity to intraocular antigens and to develop diagnostic methods that distinguish among infectious, immunopathogenic, and autoimmune responses. In the Corneal Diseases Program, the focus is on understanding immune regulation at the cellular and molecular levels, which could provide researchers with new medical interventions to control or reverse autoimmune phenomena, such as Sjögren's Syndrome.
POLICY ISSUES
Funding Policies and Priorities
The funding priorities for NEI support are based primarily on the scientific and technical merit of competitive applications as determined by peer review. In making funding decisions, however, issues of program relevance, program balance, and the availability of funds must also be taken into consideration by the NEI. In this regard, the Council reaffirms the value of its designating some applications as having "high program relevance." These applications, which address critical program objectives identified, in most cases, through the planning process, have been judged by scientific review groups to have significant scientific merit. Nonetheless, due to overall constraints on funds, these applications would likely not be funded if priority scores for scientific merit were the sole determinant. The Council's designation of an application as having "high program relevance" is a formal recommendation to the NEI Director to give the application special consideration in making a funding decision. In practice, the NEI has awarded most applications so designated by the Council. During the Fiscal Year (FY) 1992 through FY 1996, approximately 6 percent of all competing awards received the Council designation of "high program relevance."
Laboratory Research
Mechanisms of Support.The Council strongly endorses the NEI's emphasis on maximizing funding opportunities for individual investigators. For support of laboratory research, the NEI's first funding priority should continue to be the individual investigator-initiated research project grant (R01-type), not program project grants or any other type of "umbrella" mechanism of support. Moreover, the Council continues to urge great restraint in the use of formal Requests for Applications to solicit applications in targeted areas of laboratory research.
Length of Award.The Council believes that the National Institutes of Health (NIH) decision to mandate an average length of 4.0 years for all research project grants should be reconsidered. Throughout most of the 1980's, the NEI had the longest average length of a research project grant award and the highest "success rate" at the NIH. The relative distribution of competing and noncompeting NEI grants was kept remarkably constant in the process. Thus, the NEI managed to keep the "window of opportunity" open for investigators who submitted competing grant applications during the transition to longer awards. The current mandate decreases overall productivity and creativity as a result of more scientists having to spend valuable time writing and reviewing grant applications. The NEI should be permitted to make longer awards when appropriate.
Downward Negotiations.Downward negotiations are essentially across-the-board cuts to individual grant awards made because of budgetary, not scientific or programmatic considerations. The Council finds the costs awarded on typical NEI grants to be reasonable and not out of line with the costs of biomedical research in today's environment. Rigorous NEI staff review of individual budget requests, conducted on a grant-by-grant basis subsequent to Initial Review Group and Council recommendations, eliminates unnecessary and unreasonable costs before awards are made. This practice has helped contain the average costs of NEI grants. The Council, therefore, supports the strategy of funding grants at the full levels recommended by NEI staff. It is important that the NEI continue to work toward eliminating the problem of downward negotiations.
Multiple Grants.The Council reviewed data on the distribution of NIH research grant funds, excluding training grants and research and development contracts. For the NIH as a whole, approximately 23 percent of funded investigators held two or more grants. In comparison, the NEI tended to be more conservative regarding multiple awards, with approximately 13 percent of NEI-funded investigators holding two or more grants.
The Council believes that it is reasonable for a principal investigator (PI) to be awarded a second R01-type NIH research project grant when this represents an opportunity for the NEI to support high-quality, programmatically relevant research. The Council expects that, in these cases, the second project would be in a new area of research or be significantly different from that supported by the first grant, and that the PI would have a sufficient level of effort to devote to each project.
The Council recommends that funding a third R01-type NIH research project grant to an individual investigator should occur only in exceptional circumstances and requests that these competing applications be brought to its attention for special consideration. The existence of significant sources of other research support should continue to be among the factors that the NEI considers when making funding decisions. In addition, the Council encourages NEI staff to continue their careful grant-by-grant preaward review of all applications, both competing and noncompeting, to eliminate any scientific and budgetary overlap.
Interactive Research Project Grants.The NIH has traditionally relied on multicomponent awards, such as program projects or center grants, to encourage multidisciplinary collaboration. The NEI does not fund program projects or center grants, but it does support several collaborative research projects. These collaborative projects are funded through individual research project grants to each of several collaborating investigators.
The NIH Interactive Research Project Grant (IRPG) program was first announced in 1993 and later revised. An IRPG group consists of two or more investigator-initiated applications for independent research on related topics, with a formalized agreement to collaborate in specific ways to enhance the accomplishment of the goals of all of the projects. The PIs may be from one or more institutions. The IRPG, therefore, offers a means of promoting collaborative efforts between or among projects that are scientifically related, while providing a record of independently obtained awards and retaining the research autonomy of each PI. Because each research project is an independent application, it must be prepared with the same detail and thoroughness that is required of any other application. The NEI is encouraged to explore the use of the IRPG as an additional, more formal way of facilitating collaborative laboratory research.
Clinical Research
Mechanisms of Support.Unlike many other institutes, the NEI does not use funds contained in the research project grant (R01-type) category of the budget to support clinical research projects like clinical trials and other large epidemiological studies. These types of projects are typically funded as cooperative agreements or cooperative clinical research grants, which appear in the "Other Research" budget category. As these clinical projects are crucial to the NEI's mission, it must be emphasized to the NIH, the Administration, and the Congress that NIH nonresearch project grant budget categories are important and need to be protected. The distribution of funds among the various budget categories is discussed each year by the Council, and its recommendations are considered by the NEI in setting overall funding policies. At the operational level, this distribution can be fine-tuned to some extent, as funds can be reprogrammed from one category to another, depending on the number, scientific merit, and cost of the different types of applications received in any particular fiscal year.
Cooperative Agreements (U10).The NEI supports investigator-initiated multicenter clinical trials and other large clinical studies using cooperative agreement awards. This mechanism of support is used because NEI staff will be substantially involved with the investigators during the conduct of the clinical trial or study. The role of the NEI is that of a partner, but not a dominant one—the PI has prime responsibility for the project. NEI staff contribute to protocol development, recruitment, data analyses, and dissemination of results. They serve as members of steering committees and participate in a number of activities, including monitoring performance, working closely with data and safety monitoring committees, identifying and selecting additional participating clinics, and preparing and reviewing study publications. They assist in monitoring for quality control and they help coordinate the activities of diverse groups of investigators. The Council strongly supports continued use of cooperative agreements for supporting these types of large-scale clinical studies.
Clinical Study Planning Grant (R21).Investigators who submit applications for large-scale clinical studies for consideration by the NEI are expected to provide detailed information regarding the study rationale, design, protocols and procedures, analytical techniques, facilities and environment, administrative procedures, and collaborative arrangements. This information is best presented in a well-documented Manual of Procedures (MOP), which is submitted as part of the application. However, preparing an MOP is a time-consuming and expensive activity. The Clinical Study Planning Grant helps support this activity and provides other related assistance. This nonrenewable grant provides a maximum of $50,000 in direct costs for a period of 1 year.
An important question that each applicant must face is whether to submit a Clinical Study Planning Grant prior to submitting a full-scale, detailed application. The advice given by NEI staff depends on a number of factors, including the relevant experience of the investigators, the resources available to them, the complexity of study protocols, and the extent of preliminary data. The Council recommends that the NEI give further consideration to increasing the maximum amount allotted under this mechanism and extending the length of the grant period beyond 1 year.
Small Research Grants for Data Analysis (R03).The NEI Small Research Grants for Data Analysis provide support for secondary analyses of existing research data that have been generated by clinical trials and other large-scale clinical vision research projects that have been supported by the NEI. The grants can also be used to support analyses of similar types of data derived from other sources, but secondary analyses of data derived from NEI-supported studies are of higher programmatic interest. Applicants may request up to $50,000 (direct costs) per year for a maximum 2-year grant period for technical assistance, supplies, computer usage, and limited travel for collaborative effort required by the project. This mechanism of support, however, appears underutilized. One explanation may be that the current guidelines for this mechanism permit salary support for the PI "only in unusual circumstances." Another related explanation may be that the $50,000 ceiling is too low, and equipment purchases are not allowed. Other issues relate to the relative accessibility of data from NEI-supported studies. The guidelines for this mechanism should be reconsidered as part of an overall NEI review of the accomplishments and status of this program.
Clinical Vision Research Development Award (R21).This award helps institutions acquire the staff and other resources needed to enhance programs of clinical vision research through the application of epidemiologic and biostatistical methodology to clinical problems. These activities may range from strengthening biostatistician-clinical investigator interactions in the design and conduct of clinical research to developing coordinating center capabilities. A maximum of $75,000 in direct costs per year for 5 years will be provided. Funds may be requested, for example, for the support of a biostatistician (up to 75 percent effort), for other staff, for computer charges, for supplies, and for equipment. The NEI also supports these kinds of activities through Biostatistics Modules on Core Grants for Vision Research. The Council recommends that the NEI review the accomplishments of the Clinical Vision Research Development Award.
Mentored Clinical Scientist Development Award (K08).The NIH career development mechanisms of support were revised extensively in mid-1995. Applicants were advised that some of the Institutes and Centers would be offering different award provisions, such as salary and research expenses. In the fall of 1995, following discussions with the vision research community and the Council, the NEI revised its Mentored Clinical Scientist Development Award (K08) program. First, the NEI alerted clinical investigators that it had broadened the guidelines of its program to specifically include the disciplines of biostatistics and epidemiology. Second, although grant recipients are subject to a legislatively imposed salary cap (currently $125,000), the NEI indicated that it would not impose any special cap on salary requests. Salary requests should be reasonable and conform to the established, consistently applied policy of the institution for other staff members of equivalent qualifications, rank, and responsibilities, and reflect no more than the percentage of time actually devoted to the project.
In FY 1995, the NEI supported 20 K-awards at a total cost of $1,651,000; in FY 1997, the NEI supported 37 K-awards at a total cost of $4,110,000. In the future, some additional growth in the NEI K08 portfolio seems likely, because the response from the clinical departments has been very enthusiastic. Applications remain of very high quality overall, and for the first time the NEI has begun to attract clinicians in certain subspecialty areas, such as corneal diseases. The Council reaffirms its strong support for the K08 program and the steps that the NEI has taken to improve and strengthen it.
Core Grants for Vision Research
The primary objective of Core Grants for Vision Research is to provide groups of investigators who have achieved independent NEI funding with additional, shared support to enhance their own and their institution's capability for conducting vision research. Secondary objectives of this program include the facilitation of collaborative studies and the attraction of other scientists to research on the visual system.
Core Grants are subdivided into discrete units or modules, each devoted to a specific activity that would be impractical or less efficient to support on an individual research project grant. The primary purpose of each module is to support a service or resource that enhances or facilitates the research efforts of a group of investigators, each having independent NEI funding. This can include the purchase and maintenance of a shared instrument. Examples of such modules include electron microscopy, tissue and cell culture, a hybridoma facility, laboratory animal resources, and image analysis. Some sharing of Core Grant resources and services with other NIH-funded collaborators and with investigators new to vision research is encouraged.
The Council reviewed both the number and size of NEI Core Grants. Consistent with Council recommendations contained in the last plan, the NEI was able to provide some much-needed increases to offset inflation. The number of Core Grants has increased from 30 in 1994 ($8.1 million in total costs) to 32 in 1997 ($9.8 million in total costs). This mechanism of support currently utilizes approximately 3.4 percent of the NEI's total extramural research budget. The NEI provides up to $1,200,000 in direct costs over a 5-year period in support of a Core Grant. The level and duration of support for individual Core Grants are determined on the basis of peer review recommendations and administrative considerations. When considering the vastly increased new opportunities in vision research, the Council has concluded that there is still a clear need to increase further both the number and size of Core Grants. At a minimum, the Council recommends that the NEI continue to increase the size of Core Grants to help offset inflation. If the overall funding situation improves, the Council recommends that the current Core Grant budget ceilings be increased to allow the support of additional modules and to increase the total number of such awards.
Research Training
Introduction
Much of the outstanding progress in every field of vision research has been made possible by a cadre of well-trained laboratory and clinical scientists. It is clear that, to continue this progress, the NEI must train outstanding scientists in individual disciplines who are interested in applying their knowledge and expertise to the study of the visual system and sight-threatening diseases and disorders of vision. As part of the NEI's overall strategy, innovative techniques must be developed for recruiting, nurturing, and training outstanding vision scientists. Applicants for vision training programs should be of the highest quality, and predoctoral and postdoctoral trainees should not be solely admitted to meet the workforce needs of the research laboratories. The strategies of developing a well-trained pool of laboratory and clinical scientists for the future must include the achievement of scientific literacy through innovative science education programs at the elementary level through high school for all students regardless of age or gender or cultural, racial, or ethnic background. The NEI must take full advantage of the changes in the demographic patterns of the workforce and make special efforts to foster the scientific careers of women and minority groups, who will make up the majority of new workers by the year 2000. Programs of support for specific training in visual sciences at graduate and postgraduate levels must convince students that their educational endeavors will be rewarded with opportunities for productive careers and research support. Therefore, the NEI's emphasis on individual investigator-initiated research project grants must continue to be given high priority.
Summary of Previous Recommendations and Implementation
The 1994-1998 national plan set forth the following recommendations: (1) bring young scientists of the highest caliber with expertise in molecular genetics, cell biology, immunology, biostatistics, and epidemiology into vision research; (2) support postdoctoral training primarily by individual fellowships, with the possibility of a short transitional period of support on an institutional training grant as a means to make a transition to another training mechanism of training (i.e., National Research Service Award [NRSA] individual postdoctoral fellowship [F32] or Physician Scientist Award [K11]); (3) support the Physician Scientist Award (K11) as an effective tool for training clinical researchers; (4) support the First Independent Research and Transition (FIRST) award (R29) and use funds that would have been spent on the discontinued small grants program for these awards; (5) support the need to increase stipends for K11 grant mechanisms and for all NRSA grant mechanisms; and (6) support efforts to recruit and retain women and minorities in science. These recommendations were set forth to ensure that outstanding laboratory and clinical scientists would be trained and available in adequate numbers and in specific scientific disciplines to study the visual system and its diseases.
As a result of these recommendations, a number of changes were made to the NEI research training program. The NEI supported targeted predoctoral training programs, which were developed to assure that outstanding scientists were being trained in molecular biology, genetics, and immunology. Three predoctoral training programs were supported in molecular biology and genetics, three in immunology, and one in molecular biology and biophysics. The program was designed to provide basic science training in specific disciplines and to expose trainees to opportunities in vision research. Overall, these programs provided outstanding research training and supported high-caliber predoctoral trainees.
In addition, the NEI has developed two predoctoral and postdoctoral training programs in biostatistics and epidemiology to train scientists to take leadership roles in designing and conducting clinical trials and epidemiological studies related to ocular diseases. The NEI has also broadened the guidelines on the Mentored Clinical Scientist Award grant mechanism to include training in epidemiology and biostatistics. A course in visual science developed and supported by the NEI in 1992, 1994, and 1996 at the Marine Biological Laboratories (MBL) at Woods Hole, Massachusetts, was aimed at attracting young investigators who were well trained in cellular and molecular biology into vision research. Recruitment was specifically targeted to predoctoral and postdoctoral trainees who were either outside of, or newly entered into, vision research. Early evaluation of this course has shown that outstanding young scientists have attended the course, and some have gone on to apply and receive NEI grant support. The NEI continues to use institutional training grants to support predoctoral trainees and individual fellowships to support postdoctoral trainees. This policy continues to shift the balance of training positions on institutional training grants (T32s). In 1997, more than 82 percent of the training positions on institutional training grants were occupied with predoctoral trainees, and 77 percent of the postdoctoral trainees supported by the NEI received individual postdoctoral fellowships. The shift toward individual postdoctoral fellowships has resulted in trainees who have the skills necessary to develop into independent investigators.
In 1995, the grant mechanisms to support the development of clinician research scientists was modified, resulting in changes in NIH guidelines. The Physician Scientist Award, the K11 award, became the K08 award, the Mentored Clinical Scientist Award. This is a very similar award to its predecessor, which provides an intensive period of mentored research training. Concurrently, the NEI changed its salary policy for this award and eliminated the salary restriction of $50,000 per year. Although NEI grantees are subject to a legislatively imposed salary cap (currently $125,000), the NEI does not impose any additional special cap on salary requests. As a result of this change, the NEI has doubled both the number of K08 grant applications received and supported. There was a noticeable increase in K08 grant applications supporting corneal, epidemiology, and biostatistics research training. Evaluation of these programs revealed that the K08 seems to be an effective grant mechanism for attracting clinicians interested in laboratory and clinically based research careers and provides some advantage to the grantee in subsequently competing for grant support.
The FIRST award grant mechanism (R29) continued to provide 5 years of initial support to new investigators and allowed them to develop an independent laboratory. The NEI continued to support the FIRST award for 5 years, even under the NIH policy of an average of 4 years for grant support. There is an NIH-wide effort to review and evaluate NIH research support and grant mechanisms for new investigators, and it has been recognized that the total direct costs of $350,000 for a 5-year period are limiting. Recently, the NIH developed a new policy for new investigators, and will no longer accept applications for the R29 grants mechanism. The most significant reason for this policy change was the dollar limitation on the R29. In making this change, the NIH has committed to supporting the same number of new investigators and, if necessary, directing more resources to them.
The NEI continued to support NIH-wide increases in NRSA stipends for institutional training grants and individual postdoctoral fellowships. In 1994 and 1997, stipends increased for predoctoral and postdoctoral trainees supported by NRSA grant mechanisms.
The NEI participated in NIH-wide programs to continue to attract, recruit, and retain women and minorities in research. These included: providing research supplements for underrepresented minorities, promoting reentry into biomedical and behavior research careers, and supporting a predoctoral fellowship program for minority students and students with disabilities. The NEI strongly supported these supplements, and evaluation has shown that excellent candidates have been supported and trained in strong research environments.
Recommendations for 1999-2003
Train high-caliber predoctoral trainees to study the visual system and sight-threatening diseases and disorders of vision.There is a continued need to train vision scientists in basic science areas of immunology, molecular biology, genetics, and cell biology. As part of an overall strategy, the NEI must develop innovative techniques for recruiting, nurturing, and training outstanding vision scientists to study the visual system and its disorders. Applicants for vision training programs should be of the highest level. Graduate programs should allow each applicant's skills to be developed in effective oral and written communication, be completed in no more than 5 or 6 years, and be reviewed annually for progress. The institutional training grant mechanism is seen as the most effective tool for predoctoral training. Even in disciplines that presently are well represented in visual sciences (e.g., neuroscience), it is important to support predoctoral training programs to continue to train highly qualified candidates.
As the NEI develops a strategy for training vision researchers, the Council encourages the NEI to examine and realize economic trends. These trends indicate that, from 1985 to 1995, there was an increase of more than 50 percent in the number of biomedical Ph.D. degrees awarded by U.S. institutions; nearly 70 percent of this increase can be attributed to the increase in the number of noncitizens receiving their Ph.D. degrees in the United States. Even though at the present time there is low unemployment among U.S. citizens with biomedical Ph.D. degrees, the number of biomedical scientists has grown, while the number of faculty positions has remained stable. Therefore, faculty positions have declined as a percentage of total employment for biomedical scientists. In the future, academic jobs may not be the most prevalent form of employment for U.S. biomedical scientists (FASEB Conference on Graduate Education). The impact of these data on training of vision scientists must be considered in setting the NEI's future training initiatives.
Utilize the individual postdoctoral fellowship for postdoctoral training.Since obtaining an NEI individual postdoctoral fellowship is a competitive process, it is believed that this competition will assure the support of high-quality postdoctoral applicants and research training. A limited number of postdoctoral trainees can be supported on institutional training grants for a short transitional period as a means of attracting promising candidates to vision research and enabling them to make a transition to another mechanism of training or career support.
Encourage training of scientists at the predoctoral and postdoctoral level in the area of corneal, lens and cataract, and glaucoma research. The number of individuals being trained or seeking training in these scientific areas is still inadequate. It is important that the NEI continue to emphasize predoctoral and postdoctoral research training in these areas, always demanding high-quality mentors with outstanding research training experience and environments. The Council recommends continuing the NEI-sponsored vision course at MBL as a means of attracting outstanding young scientists into these scientific disciplines.
Support efforts to increase the stipend level for all NRSA training grant mechanisms.In spite of the recent 1997 NIH increase in stipend levels, they are still low, and well below the recommendations on stipends included in the 1994 National Academy of Sciences report, "Meeting the Nation's Needs for Biomedical and Behavioral Researchers." Predoctoral NRSA stipends are below the estimated salary amounts of NIH-supported graduate research assistants on research grants, as are stipends available from other competitive training programs. In addition, postdoctoral NRSA stipends remain below house staff salaries and salary levels for NIH intramural postdoctoral fellows. Low postdoctoral stipends are frequently cited as a reason for declining an individual NIH NRSA postdoctoral fellowship offer. Raising the stipend levels is especially important to the postdoctoral trainee, who may be faced with financial and family obligations.
Encourage the use of the Mentored Clinical Scientist Award as an effective tool for training clinician-scientists.The small number of health professionals choosing research careers has been well established. The Mentored Clinical Scientist Award can provide the clinician with an intensive, fulltime research training program in laboratory science and clinical research that is directly relevant to eye diseases. A 4- to-5-year commitment by the applicant is considered necessary to achieve both the applicant's training goals and his or her establishment as an independent clinician-scientist who can compete successfully for independent grant support. The Council believes mentors should be carefully chosen to select the best research and training environment and role model for clinician-scientists. It is hoped that this type of training will increase the number of clinicians who participate in laboratory and clinically based vision research. The well-trained clinician-scientist can be instrumental in translating advances in the laboratory to clinics for patients with ocular diseases.
Establish epidemiological and biostatistical training programs housed in departments of biostatistics, epidemiology, and public health, that have close collaborative arrangements with ophthalmology and optometry departments.The Council supports the development of additional Ph.D. training programs in epidemiology, biostatistics, and clinical trials, with an emphasis on eye diseases. The shortage of trained biostatisticians and epidemiologists impacts the availability of trained personnel for designing, conducting, and managing clinical trials. This would include the training of ophthalmologists and optometrists, with additional quantitative and hands-on training in biostatistics, epidemiology, and clinical trials. Currently, there are only a few formal training programs in the area of clinical trials methodology.
At this time, the NEI is supporting two training programs—one in biostatistics and the other in epidemiology. The goal of the ophthalmological biostatistics training program is to educate predoctoral and postdoctoral trainees in statistical theory and methods applied in laboratory, clinical, and epidemiological studies. The goal of the epidemiology training program is to provide research training via formal coursework and practical hands-on experience in the design, management, and analysis of data in clinical trials. It is hoped that these two training programs will begin to meet the needs of persons trained to perform leadership roles in conducting and coordinating clinical trials related to eye diseases. In addition, these programs would be designed to foster the development of health professionals into independent investigators capable of designing, conducting, and managing clinical trials.
Develop predoctoral and postdoctoral training programs that provide the opportunity to gain expertise in the methods of health services research and knowledge of the important issues in eye health and disease.There is a severe shortage of individuals with appropriate training to lead efforts in health services research (HSR) in the area of eye health and disease. The changing healthcare system has created a demand for accurate information in many areas that require the methods of HSR, such as access to and utilization of eye care; cost-effectiveness of various approaches to prevention and treatment of eye disease; the outcomes of management strategies for prevention and management of major eye and vision problems; the impact of those outcomes on patients; and the satisfaction of patients with their clinical management. Only a small number of medical doctors have chosen careers in research, and very few have received any training in the methods and approach of HSR. Within the field of health services research, few with Ph.D. degrees have sufficient background and interest in the area of eye care to lead investigations. In addition, very few academic institutions have the resources to provide comprehensive training in both areas. The Council recommends developing training programs that integrate the fields of HSR and eye care. Training should be located in an environment that maximizes the advantages of collaborative relationships of ophthalmologists, optometrists, and vision scientists with those having expertise in HSR. Whether the training program is based in a school of public health or a school of medicine, there should be a close relationship among faculty members. Training programs should involve a continuing effort, stable and committed faculty, and a core of set courses. There should be several ongoing investigations using HSR approaches to problems in health care so that trainees are exposed to a wide array of methodologic approaches. Training opportunities should be coursework and hands-on experience in design, conduct, and analysis of studies in HSR as applied to eye care.
Continue to attract strong minority scientists into vision research using the NIH-wide program for research supplements for underrepresented minorities.New vision researchers must come in greater measure from members of ethnic minority groups. Members of minorities are markedly underrepresented in science in this country and, therefore, are an increasingly important source of talent for maintaining leadership in this area. Since the NAEC's last major planning effort, lack of marked success to increase the numbers of underrepresented minorities in biomedical science, including vision research, clearly makes the case for the need for new strategies. The NEI has enthusiastically participated in NIH-wide special programs for underrepresented minorities. The Council reaffirms its recognition that progress in this area can come only if potential laboratory and clinical scientists seek and obtain sufficient grounding in fundamental levels of biological, physical, and mathematical sciences. This means that programs must begin at the elementary school and junior high school levels. The vision community must become involved in vision science programs at local schools, sharing the excitement and enthusiasm of science. Vision research organizations may be able to assist with these outreach programs nationwide. A school program called "Vision," for children in grades 4 through 8, was developed by the NEI in cooperation with The Association for Research in Vision and Ophthalmology. This program is a series of three lessons that was designed for vision researchers and eyecare professionals for school classroom visits.
Long-term programs involving promising students, combined with individual mentoring preparing for a career in vision science, should have a positive impact on encouraging minority students to pursue careers in vision research. It is hoped that this will continue to attract and encourage minority individuals to enter and pursue careers in vision research. The Council encourages the use of the research supplement program for underrepresented minorities to provide outstanding research training opportunities for these individuals to develop into independent vision scientists. The Council recommends that mentors be selected who can provide an excellent training environment.
Continue to develop strategies to retain and promote women in vision research careers.Recruitment of women in the field of science has improved steadily, with women being better represented in graduate degree programs, such as medical schools and doctoral studies. Women are not, however, represented well in scientific and academic leadership positions. The commitment to children and other home responsibilities often interrupts a woman scientist's career, especially if she chooses to leave for a period of time, or to work part time, so she can raise her children or attend to other family responsibilities, such as caring for aging parents. In addition, a woman scientist who chooses to reenter a scientific career after fulfilling these obligations often has a difficult time. The Council strongly urges consideration of these factors in designing and implementing training and reentry opportunities for women scientists. The Council supports efforts by the NIH to facilitate full participation by women in all aspects of biomedical research, including developing special strategies that may be necessary to help women combine research training with child rearing and other family responsibilities. There seems to be a disparity in the number of women receiving NRSA research training and the number of recipients of NIH research grants. The Council recommends that the NEI continue to assist women scientists in establishing themselves in productive careers as vision scientists. New ways to retain and promote women in these vision research careers must be identified and implemented.
Support new investigators in vision research and the grant mechanisms that are targeted for vision scientists beginning their independent research careers.There is a continuing concern that increased competition for grants will make it more difficult for new investigators to obtain independent research funding. Analysis of the success rates for first-time grantees and more experienced scientists seeking new grants shows that new investigators continue to fare well in the NIH system. There is no evidence that new investigators have been selectively disadvantaged in obtaining their first research grants. The Council feels that it is extremely important to send a strong signal to new investigators that there is a place for them in the system. Because of the importance of new investigators to the advancement of biomedical and behavioral research, the Council recommends that the NEI support NIH-wide initiatives into the evaluation and development of several mechanisms with the intent of facilitating the entry and retention of new investigators in vision research. The NEI is initiating a new career development program that is designed to provide an opportunity for new investigators to receive high-quality research training in the NEI intramural program. This program will also facilitate the transition of new investigators to an independent position by offering a research grant. New investigators who provide new ideas and approaches are critical to continuing the progress in vision research.
Evaluate the NEI's training initiatives and programs.The success of the NEI's training programs should be assessed by examining program goals and mission with career outcomes of the trainees. This information should be provided to the trainees, program directors of the institutional training grants, and the Council.
Summary
There is a continuing need for training highly skilled and talented vision researchers who will participate in laboratory and clinical investigations, ultimately leading to new and improved diagnosis, treatment, and prevention of eye diseases. The availability of research funding, employment opportunities, and research costs must be considered in developing future NEI training programs.
Use of Animals in Vision Research
The NAEC strongly endorses the use of animals in research and teaching. Most of the major advances made over the past several decades in the prevention, diagnosis, and treatment of eye diseases and blindness, as well as most of the increases in knowledge about the structure and function of the visual system, have resulted from the study of animals and animal models. Many of these advances have saved or restored the vision of hundreds of thousands of people. Ongoing research offers hope for those still suffering from diseases of the eye.
The Council shares the conviction that animal experiments must be performed humanely, using methods that comply with applicable laws, standards, and policies. Indeed, the Council will not recommend funding any application unless there is a complete and careful justification of the appropriateness of the animal model. The Council applauds the efforts of NEI staff members in helping vision researchers stay abreast of new developments in animal care by organizing workshops and issuing policy statements about experimental procedures commonly used in studies of the visual system. Vision researchers are encouraged to consult with NEI staff members when issues arise about animal care or experimental procedures.
The Council strongly encourages the vision research community to become familiar with the "Guide for the Care and Use of Laboratory Animals," published by the Institute of Laboratory Animal Resources of the National Research Council. Vision researchers should be familiar with the policies on the use of animals published by professional societies such as The Association for Research in Vision and Ophthalmology and the Society for Neuroscience, as well as informational guidelines in publications such as Preparation and Maintenance of Higher Mammals During Neuroscience Experiments.
The Council encourages and supports the development and use of nonanimal models for vision research. Research projects currently being funded by the NEI include experiments using tissue cultures of animal lens cells that could be instrumental in uncovering the genetic defects associated with human congenital cataracts, and the use of cultured human trabecular cells in glaucoma research.
While nonanimal models avoid the ethical concerns involved in experiments with humans or animals, the Council recommends them as procedures that complement, not replace, the use of animals for research purposes. These models may reduce the number of animals required for research purposes, but they can never eliminate the need for animal research. Simply stated, it is impossible to determine the effectiveness of a drug in reducing intraocular pressure or in slowing the development of cataracts in preparations that do not have eyes. When cell and tissue cultures are used as screening tests for pharmacological agents, results must be validated by animal experiments. Moreover, cells in culture cannot mimic the complicated interaction of physiological systems that occur in living animals. Neither computers nor mathematical models can serve as replacements for animal studies. Computer models that are based on the results of animal experiments and predictions made by these models usually must be verified by additional animal experiments.
An issue that continues to concern the Council is the choice of animal species to be used in research projects. The Council strongly advocates that the species that is best suited to answer the particular research question posed should be selected. Given the mission of the NEI to find new ways to prevent, diagnose, and treat human diseases of the visual system, in the absence of compelling scientific reasons for doing otherwise, preference should be given to using species generating data that will most readily generalize to the human visual system. Of particular concern are cases in which investigators choose species that will not yield results that generalize well, not for scientific reasons, but because of the additional cost of acquisition, housing, or care of the most appropriate species. In the long term, the savings realized by using a less expensive model disappear when the data obtained must then be replicated using the more expensive preparation. Nonhuman primates are the model system closest to the human, but species ranging from invertebrates, such as flies and worms, to nonprimate mammals, such as cats and rabbits, have and will continue to yield significant information on the fundamental mechanisms of vision common to all species, including humans. Thus, the Council encourages applicants to seek the advice of NEI staff when there are questions about the acquisition and animal care components of the budget, about which species is most appropriate for the planned experiments, and to explain the advantages of the particular species to be used in the grant application.
A related issue is the need to convey to the general public, the media, and policymakers an appreciation for how much important information about the human visual system is based on experiments using nonmammalian and invertebrate species. Most of what is known about the anatomical organization of the human retina, about the information processing that occurs in this structure, and about the neurotransmitters used for signal processing were first observed in experiments conducted on frogs, turtles, toads, salamanders, and horseshoe crabs. These animals were used in experiments not because their retinas or visual systems are exactly like the retina or visual system of humans, but because these animal models revealed principles that generalize to humans. Studying a particular photoreceptor type may be enhanced by using an animal that has only that type of photoreceptor. Also, with the use of techniques currently available, it is extremely difficult to record the electrical activity of certain cells in the mammalian retina. Thus, the role of these cells in processing information (e.g., determining the shape of objects or the direction and rate of movement of objects) must be studied in animals.
Animal activist groups have openly declared their goal of abolishing animal experimentation, and their efforts have been successful. Research projects on human and animal diseases have been delayed or halted by raids on animal laboratories, causing millions of dollars in damages. Efforts to recruit students into health-related careers are being hampered by the climate of fear caused by threats and acts of violence by animal rights activists. Research projects have been shut down and construction of animal facilities delayed by legal actions of the activist groups. New Federal regulations, sometimes passed without benefit of hearings or legislative debate, add tremendously to the cost of animal experimentation. For these reasons, the Council encourages the vision research community to become more active in communicating the value of animal research to the public.
Clinical Trials Database
The ultimate aim of laboratory and clinical research conducted by the NEI is to improve the visual health of the American people. Even though laboratory research may at times seem far removed from the patient's bedside, a tremendous amount of laboratory research must be conducted before new therapies for the prevention or treatment of disease can be developed and tested in a clinical trial setting. Clinical trials are the most effective means of comparing the benefits and risks of new eye disease treatments. Equally important, however, is disseminating the information gained through these clinical trials to researchers, educators, healthcare providers, and most importantly, the American public.
In recognizing the importance of this information, the NEI periodically publishes a book, Clinical Trials Supported by the National Eye Institute, which contains information on all of the clinical trials supported by the Institute since 1970. As a means of further disseminating and improving access to information on the results of completed trials, the status of ongoing trials, and the recruitment of patients for trials in progress, a new clinical trials database has been established and is available through the NEI's homepage on the World Wide Web (http://www.nei.nih.gov/). This site also provides a record of the progress and accomplishments in vision research since the Institute was created in 1968.
Resource Requirements
There has been considerable discussion of the Nation's investment in biomedical research in light of the changes in the economic outlook for the country since the publication of the last plan. To be sure, there are few who would argue against continued investment in meeting the health challenges that face us in the modern world; however, it is essential that the investment be made wisely, since choices must still be made between programs competing for the funds available in the discretionary budget.
Within this plan, the goals and objectives for vision research in this country over the next 5 years have been carefully prepared by those with special expertise in the areas of science represented in the NEI's programs. They are the priorities for vision research, representing areas of public health need and scientific opportunity, and are worthy of further investment of precious resources.
The NAEC recognizes that there must also be a careful appraisal of the level of funding that would be realistic and appropriate given the current level of resources (personnel, laboratory space, etc.). The Council feels that doubling the budget over the next 5 years, as proposed by many in Congress, is both a realistic and achievable goal, representing an annual increase of approximately 15 percent.
