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Report of the National Heart, Lung, and Blood Advisory Council Subcommittee Review of the NHLBI Sickle Cell Disease Program
February 29, 2008
Sickle Cell Disease (SCD) affects millions of people around the world and is one of the most common inherited disorders of man. In the United States, SCD affects about 70,000 Americans most of whom are of African descent. It is a genetic blood disorder in which abnormal hemoglobin damages and deforms red blood cells (RBCs). The abnormal RBCs result in anemia and blood vessel occlusion causing pain and multi-organ damage.
Clinical severity in SCD can range from asymptomatic states to severe symptoms requiring hospitalization. Stroke is a common cause of morbidity and mortality in SCD, with eleven percent of children having a stroke by age 18. The adult years of a person with SCD are increasingly burdened by co-morbidities and disability.
Since the establishment of the National Sickle Cell Disease Program in 1972, the NHLBI has committed more than $1 billion to research on SCD. The Institute supports an extensive research program to improve understanding of the pathophysiology of SCD and to identify effective approaches for its management and treatment and for prevention of complications. Areas of current interest include genetic influences on disease manifestations, regulation of hemoglobin synthesis, discovery of drugs to increase fetal hemoglobin production, transplantation of blood-forming stem cells, gene therapy, and development of animal models for preclinical studies. The NHLBI supports this research through investigator-initiated projects and special initiatives.
Selected Examples of Institute-Initiated Research
Selected Examples of Investigator-Initiated Research
There have been significant returns on this public investment in SC disease research, ranging from understanding fundamental biological and pathological processes to translating basic discoveries and clinical observations into clinical applications. Some examples of clinical benefit include:
Despite such advances, no universal cure is currently available and the limited therapies that are available do not benefit all patients. The morbidity a SCD patient endures throughout his/her lifetime remains a significant problem. However, new and exciting opportunities for future research that will allow us to increase our understanding of the disease and its complications, to expand upon and improve our options for treatment, and to develop a safe and effective cure will flow from a wealth of relatively new resources and approaches. These include a rich array of clinical, molecular, physiological, and pathophysiological data, and such novel technologies and methodologies as genomics, proteomics, global gene expression profiling, epigenetics, gene transfer, micro-RNA, systems biology, and biological and informatics resources.
The Comprehensive Sickle Cell Centers (CSCCs) have been in place for 35 years and are undergoing competitive renewal. This provides an opportunity to assess the Institute's return on investment and to consider whether adjustments in the program are appropriate. The NHLBI initiated a rigorous assessment of the NHLBI SCD program to formulate the next stage in the campaign to eradicate the mortality and devastating morbidities associated with SCD. To help develop an appropriate course of action, the Institute published a Request for Information (RFI) in the NIH Guide to Grants and Contracts (Attachment 1). Respondents were asked to address four questions. There were 81 unique responses, including responses from basic and clinical investigators, patients, advocacy groups, health care providers, and organizations. Most replies contained concise responses to the four questions in the RFI, but some were very extensive and detailed. The responses were analyzed to identify major themes and recommendations.
As a next step, the Institute convened a subcommittee of the National Heart, Lung, and Blood Institute Advisory Council to:
A complete list of the materials used in the deliberations is provided in Attachment 2. The subcommittee roster is provided in Attachment 3. Attachment 4 lists the NHLBI staff involved.
The subcommittee met on January 30-31, 2008, and after a comprehensive evaluation of the information provided (listed in attachment 2), made recommendations in the following areas: Basic Research, Translational Research, Clinical Research, Program Structure, Training and Career Development, and Practice Guidelines and Educational Materials. These recommendations are summarized below.
Basic Research Recommendations
A continuous flow of basic science discoveries is needed to develop new treatments and to target treatments more effectively. Areas of exceptional promise include:
The best way to encourage SCD basic research in these areas is through the use of investigator-initiated R01s and program project grants (P01s), which could be stimulated by program announcements (PAs). These programs should emphasize and foster cutting-edge, creative, and innovative ideas. For example, in the area of new treatment approaches, applications could address novel therapeutic technologies, such as using pluripotent stem cells (including genetically modified) in cell treatment studies in animals; developing new approaches for genetically modifying HSCs or hematopoietic progenitor cells; and developing gene addition and gene correction methodologies (e.g., chromatin remodeling using aptamer technology; gene correction using zinc finger nucleases). In addition, these programs should encourage the involvement of scientists in areas other than hematology, including, but not limited to, investigators with interests in cell adhesion, inflammation, and pain physiology.
Once responses to PAs are received, the NHLBI should ensure that applications get suitable consideration in peer review by adding appropriate expertise to existing, relevant study sections in the Center for Scientific Review and/or by using Special Emphasis Panels. In addition, responses to PAs should be brought to the attention of Council for special consideration.
Translational Research Recommendations
The NHLBI should strengthen the translational portion of its SCD program by developing and focusing resources needed to conduct translational phase I clinical trials of novel therapeutic approaches. In order to accomplish this important task, it is critical for the Institute to help remove hurdles to early phase clinical testing. Frequently, scientists making clinically relevant discoveries lack experience in developing them to the point where they are ready for clinical trials. The Institute can help overcome this hurdle by facilitating their interaction with investigators who can perform preclinical development, generate the data that supports testing a new drug in humans, and successfully complete the FDA's application for an Investigational New Drug (IND). Two NIH programs serve as models for providing access to key resources and services that significantly catalyze the movement of basic science discoveries to clinical testing:
In an effort to develop a more effective interface between basic and translational investigators, the NHLBI should foster interactions between basic and translational scientists to create a bridge between animal models research and clinical investigation and practice. One strategy would be to convene a 2 day conference each year, perhaps in conjunction with the American Society of Hematology, with basic and translational investigators scheduled to present.
Additional priority activities for translational efforts include: developing a co-operative multi-center database and repository with genotype-phenotype data and biological samples; fostering resource-sharing among investigators; assuring that research is conducted on pain pathophysiology and pain management; and identifying early predictors of complications and disease severity later in life.
Clinical Research Recommendations
In order for the NHLBI to stimulate and support the conduct of major efforts in clinical research, it is essential to establish an infrastructure that creates a larger pool of potential subjects for interventional and observational studies and includes investigators in geographic regions where the largest groups of patients reside. In addition, the Institute should expand access to participation in trials, for both investigators and patients, and assure open access to a wide network of clinical investigators. When making decisions about funding clinical sites, the NHLBI should consider access to potential subjects, track record in enrolling subjects and completing data collection, availability of resources (e.g., from a local Clinical and Translational Sciences Awardee), and the presence of critical staff, including physicians with expertise in SCD, research nurses, and social work specialists.
Areas of exceptional promise include:
NHLBI SCD Program Structure Recommendations
As mentioned above, the Institute should continue and expand basic research support through investigator-initiated grant mechanisms.
Thorough analysis indicates that the current structure of the CSCCs may no longer be optimal for supporting SCD research. Other mechanisms of support are now yielding better returns in clinical research and only five percent of the US SCD population is covered by existing CSCCs. Hence, there are special considerations that require careful attention in order to effectively establish and manage the support for clinical research. These include:
As a final point, it is recommended that the NHLBI take the lead in convening discussions with other federal agencies (e.g., Centers for Medicare and Medicaid Services, Centers for Disease Control and Prevention, Health Resources and Services Administration, Agency for Healthcare Research and Quality), who can increase the funds available to support SCD programs and provide unique capabilities and activities that do not fall under the NIH's mandate (e.g., health care delivery; patient services; surveillance of disease prevalence, severity, and mortality).
Training and Career Development Recommendations
In order to effectively pursue the high priority research described above, it is essential for the NHLBI to attract, develop, and retain creative and innovative investigators of the highest caliber. In particular, there is a need to attract investigators to study SCD in adult patients. Therefore, the Institute is strongly encouraged to utilize its full range of training, career development, and skills development mechanisms, from pre-doctoral through independent investigator, to insure that new talents and fresh perspectives are brought to the field. In addition, SCD investigators are eligible for the Loan Repayment Program (LRP) in the category of health care disparities research and in the category of pediatric research. Hence, making sure that investigators are aware of LRP eligibility could serve as a viable tool for attracting and developing talent in SCD research.
Practice Guidelines and Educational Materials Recommendations
The NHLBI should improve educational programs to conduct health care education for physicians, other health care providers, and patients. Translating clinical research advances into medical practice that will benefit patients requires the development and implementation of evidence-based guidelines. Once evidence-based guidelines are developed, the Institute should use a systematic campaign to disseminate them. Strategies include involving professional organizations (e.g., American Society of Hematology, American Academy of Pediatrics, American College of Physicians, and American Academy of Family Physicians) and coordinated outreach efforts among centers caring for large numbers of patients. Because it is important to ensure that improved benefit to patients extends beyond academic medical centers, the NHLBI should also consider involving community-based and faith-based organizations in its plans for disseminating guidelines.
Over the past 35 years, the NHLBI has stimulated and supported research responsible for significant advances in morbidity and mortality of SCD patients. By releasing the RFI and convening this subcommittee, it is clear that SCD research remains a high priority for the Institute. By careful review of the responses to the RFI, the portfolio analysis, and the other materials provided, this committee has made recommendations for activities in basic research; translational research; clinical research; program structure; training and career development; and practice guidelines and educational materials. Implementing these recommendations will enable the NHLBI to optimally pursue a vibrant and robust spectrum of research, training, and outreach activities that provide greater access to patients and investigators that will fulfill the opportunities and promise to further improve outcomes that will prolong and enhance the quality of life for patients with SCD.
1. Request for Information (RFI): Defining a Research Agenda for Sickle Cell Disease and Other Hemoglobinopathies
Notice Number: NOT-HL-08-108
Release Date: December 13, 2007
This request for information (RFI) seeks comments on the current and evolving scientific opportunities for investment in research that will lead to improved understanding of sickle cell disease (SCD) and other hemoglobinopathies and enable improved methods of treatment for the major clinical problems of those affected with the diseases.
The National Heart, Lung, and Blood Institute (NHLBI) at the National Institutes of Health (NIH) has recently completed a Strategic Plan that will guide the Institute's research investments in the areas of heart, lung, and blood diseases. The Institute is now examining how it will address the goals defined in the Strategic Plan across its broad research portfolio.
The mission of the NIH is to conduct and support research and research training. The NHLBI is uniquely positioned to catalyze changes that transform new scientific knowledge into measures that can improve the public health, and to communicate advances in knowledge to the individuals and institutions directly engaged in disease prevention and healthcare delivery. Research in the field of SCD is supported by multiple Institutes at the NIH. The NHLBI supports basic and clinical research in SCD and other hemoglobinopathies. Over the past decade, several therapies (e.g., hydroxyurea, chronic transfusion, and hematopoietic stem cell transplantation) have been developed that are known to be effective in mitigating various complications of SCD. Many of them have implications for other hemoglobinopathies as well. Earlier studies supported by the NHLBI demonstrated the efficacy of prophylactic antibiotics for prevention of early death in affected children. The results of those studies led to widespread neonatal screening and greatly increased the lifespan of people born with SCD. We now seek input from the scientific community in the major scientific opportunities in basic and clinical research for SCD, which we aligned with the NHLBI Strategic Plan.
Please respond by identifying what you consider to be the major scientific opportunities for advancing understanding of SCD and other hemoglobinopathies, and providing suggested approaches to best exploit them.
This RFI is for planning purposes only and should not be construed as a solicitation for applications or as an obligation on the part of the Government to provide support for any ideas identified in response to it. Please note that the United States Government will not pay for the preparation of any information submitted or for its use of that information. Responses will be compiled and shared internally and with the National Heart, Lung, and Blood Advisory Council, with one or more subcommittees of the Council, and with scientific working groups convened by the NHLBI, as appropriate. In all cases where responses are shared, the names of the respondents will be withheld.
We look forward to your input and hope that you will share this document with your colleagues. Thank you very much for your help.
Susan B. Shurin, M.D.
2. Materials for Subcommittee Deliberations
3. Subcommittee Roster
NHLBI Advisory Council Member
Shaun R. Coughlin, M.D., Ph.D.
Charles T. Esmon, Ph.D.
Katherine A. High, M.D. (Chair of Subcommittee)
J. Hoxi Jones
Jeffrey McCullough, M.D.
4. NHLBI Staff
Gregory L. Evans, Ph.D.
Kathryn Hassell, M.D.
Harvey S. Luksenburg, M.D.
Stephen C. Mockrin, Ph.D.
Blaine Moore, Ph.D.
Robert A. Musson, Ph.D., M.B.A.
Elizabeth G. Nabel, M.D.
Rachel Permuth-Levine, Ph.D., M.P.H.
Charles M. Peterson, M.D., M.B.A.
Susan B. Shurin, M.D.
Ellen M. Werner, Ph.D.