The National Institute of Neurological Disorders and Stroke (NINDS) convened the Stroke Progress Review Group (PRG) in 2001 with the charge to identify and prioritize the scientific opportunities and needs in stroke research and to develop a plan addressing them. The PRG, composed of prominent scientists, clinicians, patient advocates, and industry representatives, convened a Roundtable meeting in July 2001. At this meeting, the PRG assembled 140 leading members of the stroke research and advocacy communities to identify key scientific questions and priorities for the next five to ten years in each of fifteen topic areas, ranging from cerebrovascular biology to health services implementation. Out of this meeting came a set of scientific and resource recommendations, which were assembled into the Report of the Stroke Progress Review Group, published in April 2002.
In reviewing these recommendations, the PRG highlighted five broad research/scientific priorities that represent a consensus of the scientific goals identified for many of the topic areas. In order to successfully prevent and treat stroke in the future, each priority must be implemented by strong bi-directional interactions between basic and clinical stroke researchers. They are:
The PRG also identified seven resource priorities that will be necessary to achieve the research/scientific priorities. These resources will aid researchers in generating and testing hypotheses important to understanding all basic and clinical aspects of stroke, and in advancing the prevention, diagnosis, prognosis, treatment, and rehabilitation of stroke patients. They are:
With the publication of the Report of the PRG, the NINDS began to implement the overall scientific/research and resource priorities identified in this document. The Institute has formed a NINDS Stroke Working Group (SWG) consisting of program, review, policy/planning staff and intramural scientists, all of whom have a shared interest and expertise in stroke research. This group meets on a biweekly basis to review recent progress and to discuss and plan for future activities. One of the first undertakings of the SWG was to map the FY2001 NINDS stroke grant portfolio and current and planned initiatives to the overall scientific and resource priorities of the Report, in order to identify research gaps and future priorities.
The results of the grant portfolio mapping (see Appendix) indicated that, while NINDS has funded a number of grants in each of the five scientific/research priority areas, there have been significant gaps in the grant portfolio in many of the resource priority areas. With the exception of brain imaging capabilities, clinical trial technology, and databases priorities, only a small number of grants addressed each of the identified resource priorities.
Results of the initiative mapping (see below) indicated that most of the scientific/research and resource priorities have been addressed by recent or current initiatives. While some of these are specific for stroke, others (especially those addressing the resource priorities) are applicable to a number of neurological disorders, including stroke. A listing of these initiatives follows for each of the scientific and resources priorities.
In January 2003, NINDS met with the PRG to present the results of the mapping exercise, report on activities to date to implement the PRG recommendations, and discuss future needs and opportunities as identified by the mapping exercise. After considering the results of the grant portfolio and initiative mapping for each of the research and resource priorities, PRG members were then asked to identify their top three priorities for implementation. Participants offered a number of comments, which could be grouped into six general themes:
Overall, the PRG was supportive of the actions NINDS is taking to implement the scientific priorities. However, they also emphasized the need for more research on the neurovascular unit and on prevention, and indicated that the resource priorities identified in the PRG Report should be a top priority.
As the implementation of the PRG recommendations continues, it is important to note that the success of each depends on several factors, including community commitment, scientific opportunity, the availability of funding, and the availability of staff resources. Some of the PRG's recommendations (e.g., those concerning review) can only be addressed at the NIH level.
The PRG identified research on the cellular and functional interactions among the capillaries, glia, and neurons of the brain, termed the "neurovascular unit", as a top priority for future research. The term "neurovascular unit" is intended to focus attention on the interactions of the cerebral microvessel and the neurons it serves.
Little is known about the interactions of microvessels with the specific neurons they supply, but their integrated function is essential to the proper functioning of the brain. In addition, much is known about neuronal and circulatory development, but the relationship between these structures during this highly dynamic period is not clear. Similarly, the role that the neurovascular unit plays in establishing the blood-brain barrier (BBB) is another area that has not been extensively studied. A better understanding of these relationships may potentially change our perspective of how the brain works under normal and disease conditions, and contribute to new and novel approaches to neuroprotective therapies for many CNS diseases.
Recently, the NINDS, together with NIA, have published a Program Announcement with set-aside funds (PAS-04-072) to encourage research focused on the neurovascular unit. Specifically, the PAS will encourage studies focused on improving our understanding of the normal and pathological interactions of the brain microvascular endothelium, glia, neurons and extracellular matrix in health and disease.
In addition, in the past year, NINDS, together with NIMH and NIA, have published a PAS (PAS-03-165) to encourage further study of the BBB. BBB research is particularly critical for the translation of therapies, since many treatments will need to cross this barrier in order to be effective. This initiative will focus on improving our understanding of the BBB through molecular, cellular and genetic approaches. For example, research focused on cerebrovascular endothelial cell biology and genomics may provide insight into the neurovascular unit.Future Goals for NINDS
At the 2001 PRG meeting, participants recommended: 1) an exploration of methods to increase implementation of stroke prevention guidelines by individuals, health care providers, and health care systems; 2) improvements in existing stroke assessment methods; and 3) testing of novel stroke prevention therapies. At the subsequent implementation meeting, PRG members suggested that stroke prevention research could be integrated with stroke care, including acute stroke treatment and stroke rehabilitation. A greater focus on these issues could potentially be accomplished within the comprehensive clinical research network currently being planned by NINDS (see the "Clinical Trials" section below).
NINDS funds a number of large epidemiological studies to better understand what risk factors contribute to the stroke, especially in minority communities. These include one study, Reasons for Geographic and Racial Differences in Stroke (REGARDS), which is examining stroke disparities in the Stroke Belt, an area of the southeastern US which has a high stroke mortality rate.
The NINDS, together with NHLBI, have collaborated with the Center for Disease Control and Prevention (CDC) to draft a "National Action Plan for Cardiovascular Health: A Comprehensive Public Health Strategy to Combat Heart Disease and Stroke." The plan was released at a national health summit in Baltimore on April 15-16, 2003. NINDS is also one of several federal partners participating with the American Heart Association in a Memorandum of Understanding to work together on the heart disease and stroke goals in Healthy People 2010. Finally, NINDS is the lead NIH Institute for the FY2004 NIH Government Performance and Results Act (GPRA) goal: "By FY2010, identify culturally appropriate, effective stroke prevention programs for nationwide implementation in minority communities."
NINDS has also made progress toward improving methods for stroke risk assessment and expanding its stroke prevention portfolio from secondary prevention to include primary prevention trials. In January 2004, the Institute brought together a group of experts in stroke risk assessment and stroke prevention to review the current state of knowledge on stroke risk assessment methods. These methods incorporate recent findings on stroke risk factors, and can be used both in medical practice and for identification of potential participants in primary stroke prevention clinical trials. The availability of a simple and reliable way to determine the risk level in an individual patient may enhance the likelihood that medical providers will implement prevention therapy and that at-risk individuals will adhere to their prescribed regimens. Another closely related purpose of the workshop was to review current guidelines for primary stroke prevention and to identify the needs and opportunities in primary prevention of stroke and heart disease. Representatives of NHLBI participated in this workshop, and it has been agreed in principle that any future primary stroke prevention trial would be developed as a joint initiative between NINDS and NHLBI.Future Goals for NINDS
Creation of Networks and Facilitation of Collaborative Research
Participants at the PRG implementation meeting recommended enhancing collaborations among investigators, contributions made by centers for clinical and basic research, and multidisciplinary teams to attack large or complex issues. Similar recommendations had also emerged from the original PRG report as part of the Resource Priorities section, and as goals in the clinical trials section. Several members of the 2003 PRG implementation panel suggested that the Specialized Program of Translational Research in Acute Stroke (SPOTRIAS) centers might be used for this purpose. Others suggested that these goals might be achieved through the development of large clinical trials, including the expansion of stroke care sites. Although most recommendations focused on clinical efforts, the members encouraged multidisciplinary research projects to examine the five scientific priorities from the original PRG Report.
The development of research networks has been an interest of many advisory groups, Congress, and lay organizations. Such networks could enable NINDS and NIH to broadly address specific diseases, conduct clinical trials, and/or foster collaboration and cross-disciplinary projects. In addition, the NIH director has recently addressed the complexity of biomedical research in his vision for an NIH Roadmap. Based on input from extramural advisors, the NIH has developed several strategies to improve these networks, including the creation of multi-disciplinary teams in basic and clinical research, and the strengthening of the NIH clinical enterprise as a system, rather than as individual projects on specialized disorders. Recommendations from the Stroke PRG are on target with this overall vision, and will be incorporated into future NINDS planning.
SPOTRIAS. In May 2001, NINDS initiated the SPOTRIAS, to facilitate translation of basic research findings into clinical practice in settings where patients with acute ischemic and hemorrhagic stroke are evaluated and treated very rapidly after onset of their symptoms. Broader goals of this program include career development opportunities for new investigators, sharing of human tissue resources, and encouragement of collaborations among investigators across institutions. As of March 2004, four extramural SPOTRIAS centers have received funding, and the intramural acute stroke program is a member of the growing SPOTRIAS network.Future Goals for NINDS
Clinical Trials. Participants in the 2003 PRG meeting made several recommendations relevant to Clinical Research Collaboration Networks, Networks for Clinical Trials, or a Clinical Infrastructure for Stroke Care. NINDS currently supports approximately 30 clinical trials in stroke, and each is typically run by a group of investigators who collaborate for that particular study. Phase III trials in stroke often include a coordinating center funded separately from the clinical sites. Other models to support clinical trials exist at NIH within NCI, NIAID and NHLBI. NINDS supports a research consortium in Parkinson's disease to perform several pilot trials aimed at eventually mounting a large efficacy trial, as well as a contract to support pilot clinical studies in neurological disorders. The PRG's recommendation for regional networks of collaborating academic and community practitioners poised to implement clinical trials is comparable to this infrastructure. We hope that such networks will meet trial recruitment goals more rapidly and disseminate stroke research in community hospitals, critical for implementation of effective treatment.
The PRG also recognized a need for greater participation of non-academic medical centers in stroke clinical trials. A comprehensive clinical research network could approach stroke care from primary/secondary prevention to acute therapy, and recovery/rehabilitation. In the past year, NINDS has issued a Request for Proposals (RFP) (NOT-NS-03-006) to create a clinical research collaboration facility to facilitate these types of clinical research networks. In terms of short-term goals, the PRG recommended consideration of a large, randomized, community-based trial combining an effective means of primary prevention with acute stroke treatment.Future Goals for NINDS
Facilitation of Translational Research
The development of effective stroke treatments continues to be an urgent priority, and the successful translation of vascular approaches (e.g., tPA Trial, PROACT II, Ancrod) has demonstrated that stroke is treatable in the acute stage of the disorder. The promise of these successes is tempered by the continued failure of neuroprotective agents to be successfully translated from animal models to clinical studies in humans. Further analysis of both pre-clinical and clinical parameters is needed.
The PRG considered these challenges and offered several suggestions, including the development of a consortium of pre-clinical investigators and clinical trialists to address the complexities of animal model studies that result in promising leads for therapies. The pre-clinical consortium could address the PRG priorities on combination and sequential therapies, and treatments targeting recovery after stroke. The NINDS has several grant and contract mechanisms available for developing such a consortium. The consortium could also evaluate compounds developed for acute stroke therapy, interventions for improving chronic behavioral outcomes, and single agents affecting multiple factors in stroke. PRG participants suggested that incentives for academia and the pharmaceutical industry to screen and develop new stroke pharmacotherapies would help facilitate translational research. To this end, NINDS has already made support available for drug screening through the NINDS Translational Program, which includes the NINDS Cooperative Program in Translational Research and NINDS Exploratory/Developmental Projects in Translational Research. The goal of these specific initiatives is to implement a program of cooperative agreements that will support milestone-driven projects focused on the identification and pre-clinical testing of new therapeutics. The intent of this program is to facilitate the effective review and research administration of translational research projects and accelerate the translation of discoveries in basic research to treatment in the clinic.Future Goals for NINDS
Addressing Review Issues
Several PRG members suggested improvements in the process of identifying highly meritorious stroke grants in the review process. For example, inclusion of expertise in animal modeling and pharmacology would facilitate translational research. NINDS will evaluate the composition of its own study sections to ensure that the expertise of the reviewers is appropriate.
In addition, some members of the PRG expressed concern about the review of innovative ideas, specifically that the current process of review may discourage applicants from proposing new approaches. To address this issue, it is incumbent upon all reviewers to become advocates for innovative ideas with great potential.
The PRG also suggested improvements in the review of projects that involve clinical research, and recommended the addition of practicing physicians to the review process. NINDS includes practicing neurologists in its NINDS Clinical Trials Review committee (NSD-K); however, many of the problems with clinical applications are methodological, and not disease-specific. To address the range of issues that affect clinical trial design, the NSD-K Review Committee has twenty permanent members, including experts in clinical trial methods, statistics, neurology, and neurosurgery (especially those neurologists and neurosurgeons who have some experience participating or managing clinical trials). Inclusion of other disciplines (e.g., radiology, specialized neurosurgical and neurological expertise, emergency medicine, and epidemiology) is conducted on an ad hoc basis.
PRG members also suggested that NINDS develop a more expeditious review process for clinical trials, including rapid, interactive discussion with NIH officials, and this has begun to be achieved. Investigators meet with NINDS clinical trial program directors to seek advice about problems with their applications prior to submission. To date, approximately 80 investigators have consulted with the clinical trials group prior to submitting an application, 24 of these concerned proposed stroke trials. To facilitate a more expeditious review process, NINDS has also implemented a procedure for the R34 Planning Grant which allows investigators to submit an application just six weeks before the review committee meeting. This process gives the applicant and the Institute an opportunity to review the concept of a trial and weigh its relative importance to possible areas of interest, before the applicants expend considerable effort in the preparation of an application.
Another important suggestion was to explore methods to approve applications conditionally, pending modifications. For example, PIs whose unfunded applications were scored highly meritorious, and with minimal issues to correct would have the opportunity to submit clarifications or amendments to the program director. Subsequently, an expedited review process could be accomplished via a mail review by a subset of the study section, which would avoid the need to resubmit through the lengthy amended application route. This concept has generated considerable interest throughout NIH. The advent of electronic submission and review is expected to accelerate the entire submission/review process.Future Goals for NINDS
Promoting Training Opportunities
Issues raised by PRG members for training young investigators included: 1) training of physicians to conduct clinical research and clinical trials; and 2) training of Ph.D. scientists to conduct stroke research. NIH can stimulate some training activities, while other ideas can be best accomplished through neurology training programs in the academic community. Basic science training in stroke could be addressed through requests for training support on Program Project Grants. To expand clinical training, NINDS included a core component on training in one its large stroke initiative, the SPOTRIAS program. In addition, several K awards (career development awards) are available for physicians and non-physicians to conduct stroke or translational research, learn statistics and/or epidemiology, as well as clinical trial methodology. Nevertheless, NINDS could further encourage the addition of fellows to clinical trial grants to learn clinical trial design, statistics, and trial management.
Further training opportunities are included in the NINDS "Cooperative Program in Translational Research," a broad program for the development of animal models for neurological diseases and therapeutics which encourages the translation of these discoveries into new treatments for neurological disease. Specifically, these awards will support training of postdoctoral fellows in basic or translational aspects of stroke research.
Another possibility for short-term training of stroke fellows could be patterned after the annual Tahoe Seminar, a cooperative two-week seminar series supported by the National Heart, Lung, and Blood Institute and the American Heart Association. This program brings together cardiology fellows and others interested in heart disease in an intensive environment to learn and work together. The program is currently funded through the NIH T15 mechanism (Continuing Education Training Grants); however the R25, which is designed to support the development of programs in education or training could also be used, and NINDS already supports this mechanism. There is strong interest among some members of the stroke community to provide this type of training to individuals interested in risk factors, epidemiology, statistics, and clinical trial methodology as applied to stroke.
At large academic training centers for neurology and stroke, research training could be further integrated into stroke fellowships, and a clinical research culture could be developed that would include neurologists, emergency department personnel, nurses, and clinical Ph.D.'s. Such clinical research workforce training issues are a focus of the current NIH Roadmap effort. It is also of note that the AHA has fellowships in stroke research.Future Goals for NINDS
Database Tools and Data Sharing Issues
The PRG expressed a need for standardized data collections and facilitated access to data. The field of data sharing is an integral component of the current vision of the NIH policy on resource sharing. Consistent with this philosophy, participants recommended that both clinical and research databases be made available generally for the evaluation of data subsets. Such transparency would allow investigators around the country to benefit from the experiences of "positive" and "negative" clinical trials and studies.
Several suggestions referred to specific data management tools and systems. Those included consideration of the Southwest Oncology Group (SWOG) as a paradigm for clinical trial surveillance and data management which could be useful in stroke clinical trials. SWOG, which was formed in the late 1950s, is an unincorporated association of approximately 4000 investigators at a variety of academic and non-academic universities, hospitals and other health care institutions and providers. It is supported in part by the National Cancer Institute (NCI). Another model may be the Parkinson's Study Group, a non-profit group of over 350 physicians and other health care providers from approximately 85 medical centers in the United States and Canada, experienced in the care of Parkinson's patients and dedicated to clinical research of Parkinson's disease.
Participants also suggested specific software modalities, including database and mining tools such as Extensible Markup Language (XML) and Structured Query Language (MySQL). XML is a text format originally designed for use in large-scale electronic publishing, and is now playing an increasing role in web-based data exchange. The MySQL database server is an open source database with architecture designed to allow customized data collection and data subset analysis.
An NINDS initiative related to database infrastructure include the Human Genetic Resource Center: DNA and Cell Line Repository. In addition, the NIH Roadmap exercise has as one of its goals of interest the creation of a national electronic clinical trials and research network. As proposed, this network would link current and emerging clinical research information systems together to facilitate the sharing of data and resources in order to accelerate the translation of clinical research findings into practice.Future Goals for NINDS
NINDS convened the Stroke Progress Review Group to work together with the stroke community in developing a long-range research agenda for stroke research, and the Institute is committed to implementing its recommendations. With the publication of the PRG Report in April 2002, the NINDS has begun to implement the scientific/research and resource priorities identified in this document. While all the priorities are important, the Institute cannot implement them all, and encourages the stroke community to work together with NINDS to initiate responses to these priorities. The January 2003 PRG meeting provided an opportunity to review implementation progress and to focus efforts on the most important current priorities. NINDS plans to convene these PRG meetings periodically in order to review progress and continue the prioritization of the PRG recommendations.
In addition to specifically addressing those items identified as being of highest priority, NINDS will also work to implement the priorities by encouraging investigator-initiated research, ensuring that stroke is part of any trans-Institute initiatives (e.g., for resources or training), and collaborating with other agencies and organizations that have a shared interest in stroke research.
Last updated March 10, 2014