Report of the National Heart, Lung, and Blood Advisory Council Subcommittee Review of the NHLBI Sickle Cell Disease Program

Background

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

• Sickle Cell Disease Clinical Research Network -- initiated in FY 2006 to facilitate translation of results from basic studies and phase I/II clinical trials into phase III trials in patients with SCD; funding will continue through FY 2010.
• Phase II/III Trial of Sildenafil for Sickle Cell Disease-Associated Pulmonary Hypertension -- initiated in FY 2006 as a complement and extension of an NHLBI intramural trial to test the effects of sildenafil therapy on exercise endurance and pulmonary artery pressure in SCD patients who have pulmonary hypertension; funding will continue through FY 2009.
• Pediatric Hydroxyurea Phase II Clinical Trial (BABY HUG) -- initiated in FY 2000 to assess the effectiveness of hydroxyurea in preventing chronic organ damage in young children with SCD; funding will continue through FY 2009.
• Comprehensive Sickle Cell Centers -- initiated in 1972 to support multidisciplinary research and expedite development and application of new knowledge for improved diagnosis and treatment of SCD; 10 centers are funded through FY 2007.

Selected Examples of Investigator-Initiated Research

• Stroke with Transfusions Changing to Hydroxyurea (SWITCH) - Initiated in FY 2005 to compare standard therapy (transfusions and chelation) with alternative therapy (hydroxyurea and phlebotomy) for the prevention of secondary stroke and management of iron overload in children with sickle cell anemia.
• Stroke Prevention in Sickle Cell Anemia (STOP) - initiated in FY 1994 to determine whether periodic blood transfusions were more effective at preventing stroke than standard supportive care
• Sibling Donor Cord Blood Banking and Transplantation - initiated in FY 2001 to collect cord blood from sibling donors in families who have children with sickle cell disease or thalassemia with the intent of future transplantation
• Stroke Prevention in Sickle Cell Anemia (STOP 2) - initiated in FY 2000 to determine if transfusions must continue or could be stopped and when

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:

• The life expectancy of SCD patients doubled between 1972 and 2002
• Prophylactic penicillin from birth to 5 years of age significantly reduces sepsis and mortality; and can be safely discontinued at age 5.
• Transcranial Doppler (TCD) screening identifies children at an increased risk for stroke.
• Periodic transfusions prevent first time and recurrent stroke in SCD children at high risk.
• Hydroxyurea therapy in adults with SCD reduces by 50% the frequency of pain, acute chest syndrome, hospitalizations for painful symptoms, and units of blood transfused.
• Allogeneic bone marrow transplantation can cure the clinical symptoms of SCD.

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:

• Review the major advances in sickle cell (SC) research, diagnosis, and treatment during the past 25 years and identify the advances that were the direct outputs of the NHLBI SC Centers program.
• Review the past performance of the NHLBI SC Centers, ascertain the progress to date in the NHLBI SC networks, and assess their return on investment to SC patients and taxpayers.
• Review public comments on the NHLBI SC program and assess the recommendations for their incorporation into the NHLBI SC program.
• Recommend future directions for the NHLBI SC Program
  • Research needs and questions
  • Research approaches and opportunities
  • Research structures

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:

• disease mechanisms (e.g., contribution of inflammatory and hemostatic mediators, genetic modifiers, pain biology and pharmacology)
• new treatment approaches (e.g., new drugs to increase fetal hemoglobin, allogeneic human stem cell (HSC) transplantation, genetically modified autologous HSCs, gene therapy)
• genes/genetics (e.g., genetic variability that underlies phenotypic heterogeneity, new factors that modify the SCD phenotype, mechanisms by which genetic modifiers act, sophisticated models of computational genetics, genomic approaches including genome-wide association studies, innovative gene transfer strategies)
• molecular biology and biomarkers (e.g., small molecules that disrupt hemoglobin polymerization, proteomics to identify new biomarkers, inflammation- or hemostatic-based biomarkers)
• vascular biology (e.g., the role of angiogenesis, molecular basis for interaction of abnormal red blood cells with the vasculature, endothelial cell heterogeneity in vascular complications, effect of sickle cells on the endovascular environment)
• erythropoiesis and red blood cell (RBC) biology (e.g., vasoactive genes to prevent sickle cell crises, epigenetics of globin gene regulation, molecules that silence embryonic and fetal hemoglobin, RBC membrane components that affect variability)
• animal models (e.g., develop an animal model that more faithfully recapitulates human disease, test treatments for ischemic stroke and thrombosis)

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:

• NHLBI Production Assistance for Cellular Therapies (PACT) (http://www.pactgroup.net)
  PACT supports the development of novel somatic cell therapy products by providing production assistance to the cell therapy community, as well as educational training via web seminars and at meetings. Production assistance is provided through the funded contract manufacturing of therapeutic cell products at PACT processing facilities. These facilities offer scale-up capability and expertise in the translational development needed to produce cell therapy products under cGMP and cGTP regulations. PACT manufactures quality cell therapy products on behalf of investigators with funded clinical trials requiring support in product development and approval. PACT's educational training focuses on three general areas: translational development/scale-up and manufacture of cell therapy products; and quality assurance and regulatory issues.
   
• National Cancer Institute Rapid Access to Intervention Development (RAID) 
  RAID is a program designed to facilitate translation to the clinic of novel, scientifically meritorious therapeutic interventions originating in academia. RAID accomplishes this goal by making resources for the pre-clinical development of drugs and biologics available to the academic research community on a competitive basis. RAID is intended to remove the most common barriers between laboratory discoveries and clinical trials of new molecular entities. The goal is clinical "proof of principle" that a new molecule or approach is a viable candidate for expanded clinical evaluation. Examples of tasks supported by RAID include: definition or optimization of dose and schedule for in vivo activity; development of pharmacology assays; conduct of pharmacology studies with a pre-determined assay; acquisition of bulk substance (GMP and non-GMP); scale-up production from lab-scale to clinical-trials lot scale; development of suitable formulations; development of analytical methods for bulk substances; production of dosage forms; stability assurance of dosage forms; range-finding initial toxicology; IND-directed toxicology, with correlative pharmacology and histopathology; planning of clinical trials; and regulatory affairs, so that FDA requirements are likely to be satisfied by participating investigators seeking to test new molecular entities in the clinic; and IND filing advice.

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:

• curative therapies (e.g. genetically modified autologous bone marrow transplantation or allogeneic transplants)
• major interventional trials (e.g., compare hydroxyurea vs. elective transfusion vs. best supportive care)
• prediction, prevention, and management of organ damage (e.g., pulmonary hypertension, acute chest syndrome, end-stage renal disease, stroke, neurocognitive function, and reproductive health, including the effect of SCD on maternal and fetal health, menopausal outcomes, and research on management of priapism)
• pain management
• new fetal hemoglobin inducers
• Interruption of pathophysiology (e.g. anti-inflammatory, anti-oxidant, anti-adhesion therapies)
• early predictors of complications and disease severity later in life

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:

• Provide appropriate structures for several kinds of research studies, including pilot studies of early phase testing of novel therapeutic approaches; larger studies of therapeutic interventions (a key issue is access to large populations to facilitate rapid enrollment); and small and large scale studies of standard interventions to prevent late consequences of disease.
• Ensure open access of the trials network, so that investigators from a wide range of centers are eligible for funding, with the level of funding contingent on numbers of subjects enrolled. The trials network should be structured so that an investigator with a compelling idea for a clinical study would have full access to lead and carry out studies.
• Establish field centers that provide the largest pool of patients and provide access to a broader portion of the SCD patient population.
• Establish an oversight group that assures all proposed trials are considered and reviewed objectively leading to a fair prioritization. The oversight group should have broad expertise, including, but not limited to, cardiology, pulmonary medicine, nephrology, and pain management, to help refine protocols and prioritize studies for funding.
• Fund multi-center trials on a per capita basis per enrolled subject. These funds should reimburse for clinical investigators' time, clinical coordinators, research nurses, and other reasonable personnel and trial-related expenses.
• Consider including international sites in situations where insufficient patients are available in the USA, or to speed recruitment, or for observational studies.

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.

Summary

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.

Attachments

1. Request for Information (RFI): Defining a Research Agenda for Sickle Cell Disease and Other Hemoglobinopathies

Notice Number:  NOT-HL-08-108

Key Dates

Release Date:     December 13, 2007
Response Date:  January 14, 2008

Issued by

National Heart, Lung, and Blood Institute

Purpose

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.

Background

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.

Information Requested

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.

Inquiries

Susan B. Shurin, M.D. 
Deputy Director 
National Heart, Lung, and Blood Institute 
Building 31, Room 5A48 
9000 Rockville Pike 
Bethesda, MD 20892- 2486
Telephone: (301) 496-1078 
Fax: (301) 402-0818 
Email: Shurinsb@nhlbi.nih.gov(link sends e-mail)

2. Materials for Subcommittee Deliberations

• Request for Information
  • NIH Guide Notice
  • Analysis of Request for Information Responses
  • Unedited Documents
    • Responses from Individuals
    • Responses with multiple authors or from organizations or professional societies
      • Toward a new Research Paradigm: Building a New Sickle Cell Disease Research Agenda - Summary of Recommendations from the American Society of Hematology Workshop on Sickle Cell Disease
      • Vision For a National Comprehensive Sickle Cell Disease Research Program - Current Sickle Cell Center Investigators - authored by Drs. Clinton H. Joiner and Peter A. Lane
      • Letter from the American Society of Pediatric Hematology/Oncology
      • Joint Response From Members of the Sickle Cell Disease Community
      • Sickle Cell Disease Association of America (SCDAA) Joint Response
      • American Academy of Pediatrics (AAP) Joint Response
      • American Society of Hematology (ASH) Letter
      • Joint Response from Sickle Cell Community Advisory Council of California
      • Response from Sickle Cell Patients
      • Response from Division of Hematology at Children's Hospital in Philadelphia
• Portfolio Analysis
• Research Support
• Most Highly Cited SCD Publications Over the Past Ten Years
• Major Basic and Translational Advances Over the Past Ten Years
• Major Clinical Advances Over the Past 25 Years
  • Major Published Clinical Studies
  • Impact of Major Advance Publications
  • CSCC Publications in Process
  • Major Multicenter Clinical Studies Outside the CSCCs
  • Bone Marrow Transplantation Protocols
  • Single Center Studies Outside of the NIH Clinical Center
  • Types and Primary Funding of Ongoing Clinical Studies
• Major Population-based Advances from Published and Ongoing Studies Over Previous Ten Years
• Outreach Activities
• CSCC Publications and Impact Factors Over the Past Ten Years
• CSCC Midcourse Evaluations, 2000 and 2005
• Funding Cycles of the Hemoglobinopathy Networks (1998 to 2012)
• Conference Summary -- New Directions for Sickle Cell Therapy in the Genome Era (November 19-21, 2003)

3. Subcommittee Roster

NHLBI Advisory Council Member

Shaun R. Coughlin, M.D., Ph.D.
Director
Cardiovascular Research Institute
University of California, San Francisco
San Francisco, CA 94143

Charles T. Esmon, Ph.D.
Lloyd Noble Chair in Cardiovascular Research
Oklahoma Medical Research Foundation
Howard Hughes Medical Institute
825 N.E. 13th Street, Room A205
Oklahoma City, OK 73104

Katherine A. High, M.D. (Chair of Subcommittee)
William H. Bennett Professor of Pediatrics
Investigator, Howard Hughes Medical Institute
Children's Hospital of Philadelphia
3615 Civic Center Boulevard
Philadelphia, PA 19104

J. Hoxi Jones 
Southeast Texas Public Information Officer
Texas Health and Human Services Commission
9703 Willow
Houston, TX 77088

Jeffrey McCullough, M.D. 
Professor, Department of Laboratory 
Medicine and Pathology
University of Minnesota
420 Delaware Street, S.E.
Minneapolis, Minnesota 55455

4. NHLBI Staff

Gregory L. Evans, Ph.D. 
Program Director
Blood Diseases Branch
Division of Blood Diseases and Resources
National Heart, Lung, and Blood Institute
National Institutes of Health 
6701 Rockledge Drive, MSC 7950 
Bethesda, MD 20892-7950 (20817 for courier service)

Kathryn Hassell, M.D.
Division of Blood Diseases and Resources
National Heart, Lung, and Blood Institute
National Institutes of Health 
6701 Rockledge Drive, MSC 7950 
Bethesda, MD 20892-7950 (20817 for courier service)

Harvey S. Luksenburg, M.D. 
Medical Officer
Division of Blood Diseases and Resources
National Heart, Lung, and Blood Institute
National Institutes of Health 
6701 Rockledge Drive, MSC 7950 
Bethesda, MD 20892-7950 (20817 for courier service)

Stephen C. Mockrin, Ph.D. 
Director 
Division of Extramural Research Activities 
National Heart, Lung, and Blood Institute 
National Institutes of Health 
6701 Rockledge Drive, MSC 7922 
Bethesda, MD 20892-7922 (20817 for courier service)

Blaine Moore, Ph.D. 
Chief, Blood Diseases Program
Division of Blood Diseases and Resources
National Heart, Lung, and Blood Institute
National Institutes of Health 
6701 Rockledge Drive, MSC 7950 
Bethesda, MD 20892-7950 (20817 for courier service)

Robert A. Musson, Ph.D., M.B.A. 
Director
Office of Staff Training and Communication
Division of Extramural Research Activities
National Heart, Lung, and Blood Institute
National Institutes of Health 
6701 Rockledge Drive, MSC 7922 
Bethesda, MD 20892-7922 (20817 for courier service)

Elizabeth G. Nabel, M.D.
Director
National Heart, Lung, and Blood Institute
National Institutes of Health
Building 31, Room 5A48
31 Center Drive, MSC 2486
Bethesda, MD 20892_2486 (20817 for courier service)

Rachel Permuth-Levine, Ph.D., M.P.H. 
Acting Director
Office of Strategic and Innovative Programs
Division of Extramural Research Activities 
National Heart, Lung, and Blood Institute
National Institutes of Health 
6701 Rockledge Drive, MSC 7922
Bethesda, MD 20892-7922 (20817 for courier service)

Charles M. Peterson, M.D., M.B.A. 
Director
Division of Blood Diseases and Resources
National Heart, Lung, and Blood Institute
National Institutes of Health 
701 Rockledge Drive, MSC 7950 
Bethesda, MD 20892-7922 (20817 for courier service)

Susan B. Shurin, M.D.
Deputy Director
National Heart, Lung, and Blood Institute
National Institutes of Health
Building 31, Room 5A48
31 Center Drive, MSC 2486
Bethesda, MD 20892_2486 (20817 for courier service)

Ellen M. Werner, Ph.D. 
Program Director
Blood Diseases Branch
National Heart, Lung, and Blood Institute
National Institutes of Health
6701 Rockledge Dr. MSC 7950
Bethesda, MD 20892-7950 (20817 for courier service)