Bethesda, Maryland

June 2, 2008


F. Daniel Armstrong PhD., (Chair), University of Miami, M.A. Bender,MD., PhD, Fred Hutchinson Cancer Research Center, Frans Kuypers, MD., CHORI, Eugene Orringer MD., University of North Carolina, Susan Perrine, MD., (Boston University School of Medicine.

Committee Members Participating by Telephone:

Ms. Shirley Miller, Southwestern Comprehensive Sickle Cell Center.

Committee Members Absent:

Punam Malik, MD., Cincinnati Children's Hospital Medical Center, Yogen Saunthararajah, MD., Cleveland Clinic/Case Western Reserve, Wally Smith, MD., Virginia Commonwealth University, R. Blaine Moore, PhD (NIH).

Ex- Officio Members Present:

David McCune, MD, MPH, Madigan Army Medical Center, Tacoma, WA.

Ex- Officio Members Absent:

Marie Mann, MD., HRSA, Joseph DeSimone, PhD., Veterans Administration, ILL, Dr. Marie Earley, MD, CDC.

NIH Staff Present:

(NHLBI) Greg Evans PhD, Ellen Werner PhD, Susan Shurin MD, and Kathryn Hassell, MD; (NICHD) James Hanson, MD.

Other Persons Present:

Willarda Edwards MD MBA, (SCDAA), Judy Hagopian, HRSA, Althea Grant, PhD, CDC, Hani Atrash, MD, MPH, CDC, Melissa Creary, MPH, CDC, Vamsee Pamula, PhD, Advanced Liquid Logic, Inc, Oswaldo Castro, MD, Howard University, William Winter, PhD, Howard University, Mammah Borbor, MBA, MSHCA, DHHS Emerging Leader Intern.

The meeting was held in room 9112/9116 of 6701 Rockledge Dr. Dr. Evans opened the meeting at 8:30 am. He welcomed all of the participants, and reminded committee members that they are formally considered government employees, subject to all rules affecting government employees, during committee meetings. Dr. Evans commented that there would be a full agenda for the meeting, with many exciting changes to talk about. Dr. Evans then turned the meeting over to Dr. Armstrong, the Chair.

Dr. Armstrong also extended his welcome to everyone. Following his brief comments, everyone introduced themselves. The minutes for the previous meeting, October 29, 2007, were raised for discussion. A motion to approve the minutes was put forward, seconded and passed unanimously. Dr. Susan Shurin, the Deputy Director of NHLBI was introduced and invited to present the NHLBI Update and Acting DBDR Director's update.


    Dr. Susan Shurin welcomed everyone on behalf of Dr. Betsy Nabel, the Institute Director. Dr. Shurin described recent changes to the NHLBI sickle cell disease research program that have been proposed from a number of forums including, the ASPHO summit, the ASH meeting recommendations, the CSCC re-competition review, the NHLBI RFI and the consequent recommendations of the NHLBI Advisory Council.

    Dr. Shurin provided several handouts including the NHLBI Council report on the NHLBI sickle cell disease program (dated February 2008) which contains Council recommendations for changes to the NHLBI sickle cell program, the NHLBI Strategic Plan, a hard copy of her slides and the FACA rules of 1972 governing the Sickle Cell Disease Advisory Committee.

    While the morphology of sickle cells was first described in 1910 and the beta globin molecular defect published in the 1950s, real improvement in life expectancy was not realized until the 1970s. Major advances that have taken place include:

    • the PROPS I trial that demonstrated that the significant risk of death due to septicemia in infancy can be prevented
    • The STOP I trial that demonstrated that children who are at high risk of having a stroke can be identified and placed on therapy to prevent stroke
    • The MSH trial that demonstrated that hydroxyurea is a safe and effective drug in treating patients with sickle cell disease to reduce painful crises and improve life expectancy.

    To continue to accomplish these major advances in basic and clinical research and to continue to have an impact on health care in the United States, it is necessary to ensure that we facilitate the two translational components. First, the development of basic research into clinical studies and trials, Translation I, is necessary. Second, the translation of the results of sound clinical studies into health practice be implemented, Translation II.

    The NHLBI report from its Advisory Council on the renewal of a Sickle Cell Disease Program made recommendations for goals in basic research, translational research and clinical research. In goal 1, a number of basic research areas were highlighted including: the study of disease mechanisms, new treatment approaches, understanding gene regulation and genetics, the role of vascular biology, the identification of new biomarkers and the further study of hemoglobin polymerization and therapies that can intervene, the study of erythropoiesis and the further development and studies of animal models. To achieve goal 2, the translation of research into clinical studies and into health care, we must develop infrastructure and resources to assist researchers in the progression of their accomplishments. At this time, we have in place facilities to produce cell therapies for clinical use (PACT), a resource to develop rapid access to interventional development (RAID), facilities to develop clinical grade vectors for gene therapy (GTRP), and clinical research units (CTSAs) to facilitate clinical research at all phases. In goal 3, we must consider the clinical research areas that are most important to study, that will be most feasible and will improve the health care of sickle cell persons in the US. Some of the areas recommended include: the prediction, prevention and management of organ damage, the management of pain, the study of new interventional therapies and finally, the development of curative therapies.

    Training and Career Development is considered a major component in the success of the future sickle cell disease research program. Updated guidelines and educational materials need to be developed. Finally, interdisciplinary programs involving researchers, educationists and physicians from varied backgrounds must be encouraged to assemble and address the pressing issues at hand.

    Dr. Shurin finished her presentation by reviewing the establishment and rules governing the Sickle Cell Disease Advisory Committee enacted in 1972.

    After Dr. Shurin's presentation, Dr. Edwards expressed her concerns that care for SCD patients will decrease due to the phase-out of the NHLBI Comprehensive Sickle Cell Centers (that provided care) and to the fact that only four centers are funded under the SCD Treatment Act (Talent Bill). Dr. Shurin responded that it is her hope that NIH's DHHS sister agencies (HRSA in particular) will fill this need to provide care for SCD patients. It is not formally within the Congressional mandate of NIH to support clinical services. The primary mission of the NIH is to support research. She also said she thinks healthcare for SCD patients might improve if we had non-fragmented healthcare centers that specialize in blood diseases (coagulation disorders, white blood cell disorders, hemoglobinopathies). Such centers would command greater attention from hospital administrators and the healthcare system.

    Dr. Bender commented that it is valuable to keep the Scholar training component and high school education component from the CSCC program, but he wondered who would serve as mentors given that only a few investigators are funded within each BTRP program. Dr. Werner commented that there is an NHLBI K12 training program for benign hematology and within that program there are currently only a few sickle cell trainees, and none at some sites. A motion was made and seconded to come back to discuss this K12 program later in the day.

    Dr. Castro commented that in the BTRP program the NHLBI is asking the investigators to do more, but with less resources. Dr. Shurin responded that the overall NHLBI sickle cell budget has not shrunk, but has been reallocated. A comment was made that the new clinical care guidelines will be very valuable. One concern raised about expanding the clinical network was that having more sites will not necessarily guarantee more enrollment as past experience has shown that most of the enrolled patients on any given study will come from only a few very strong sites. Dr. Shurin commented that the new expended network will leverage the resources of the NCRR-supported CTSA programs as much as possible.

    Dr. Armstrong commented that NIH's sister agencies (HRSA, CDC) that we would like to pull in to these new SCD research efforts are very resource-poor in contrast to NIH. They also need specific Congressional mandates and fund earmarks to support increased activity in sickle cell disease. This will require an extensive lobbying effort.

    Dr. Armstrong asked Dr. Shurin to address changes in DBDR staffing, given the departure of Drs. Peterson and Evans and what looks like a significant increase in sickle cell work scope. Dr. Shurin responded that a new DBDR Director has been identified but cannot be named publicly until the individual's current institution is notified. In addition, Dr. Jonathan Goldsmith has just been hired as a Medical Officer in the Blood Disease Branch, and a new PhD-level HSA will be hired to handle the basic science part of the new NHLBI SCD program.


    The first presenter was Vamsee Pamula, PhD, from Advanced Liquid Logic Inc. in Research Triangle Park, NC. Dr. Pamula was introduced by Dr. Evans. Dr. Pamula's talk was entitled, "Digital Microfluidic Lab-on-a-Chip for Multiplexing Diagnostics- Possible Applications in Sickle Cell Disease." Dr. Pamula is an electrical engineer by trade, and is Chief Technology Officer and Co-Founder of his company, which has received SBIR awards from many institutes at NIH. Dr. Pamula talked about his company's electrowetting-based digital microfluidics technology, a new chip-based platform for applications such as immunoassays, clinical chemistry, newborn screening, pathogen detection, DNA sequencing, protein crystallization, and coagulation assays. The advantages of this platform are that it uses very small amounts of liquid, which means that everything can take place on a much faster time scale. It is automated- all of the liquid handling is programmable via software. With this technology, tiny droplets of liquid containing biological samples of interest are precisely moved from place to place on a chip in order to complete an assay of interest. This is a very flexible platform, allowing for many types of DNA-based or protein-based assays. After the presentation, Dr. Hanson from NICHD pointed out that this technology has great potential for public health applications, in that it has the following features:

    • low cost
    • great flexibility in the types of assays it can run simultaneously (multiplexing)
    • low sample volume requirement
    • high throughput
    • low personnel requirement and thus low personnel costs

    The second presenter was Althea Grant, PhD from CDC. Her title was "Introduction to Activities at the U.S. Centers for Disease Control- Highlighting Sickle Cell Disease." Dr. Grant presented information regarding the mission of the CDC and its overall organization. Under the Coordination Center for Health Promotion is the National Center for Birth Defects and Developmental Disabilities. This Center is principally responsible for evaluating New Born Screening, mortality and morbidity, genomics, and collaborative activities for a number of diseases. Within the Center is the Division of Blood Disorders which is subdivided into three sections: 1. Epidemiology and Surveillance; 2. Prevention Research; and 3 Laboratory Analyses. A number of blood diseases have been undergoing surveillance by CDC. They include: hemophilia (1992), thalassemia (2004), thrombosis 2005 and Diamond-Blackfan anemia (2006). Plans are now underway to develop an interagency agreement with the National Heart Lung, and Blood Institute that will create a surveillance system for sickle cell disease. The CDC hopes to develop further ties with NIH and HRSA over the next several years to provide services to sickle cell patients and patients in other diseases.

  3. CHAIRMAN'S REPORT     Dr. Daniel Armstrong

    Dr. Armstrong expressed his interest in having this committee support and monitor three key areas of the new NHLBI SCD program as we move forward:

    • ensuring that the new, expanded SCD clinical network structure serves both pediatric and adult patients. The pediatric focus should be prevention, while the adult focus should be state-of-the-art treatment of end-organ damage.
    • keeping translational research vibrant and building bridges between the BTRP program and the new clinical network.
    • finding ways to better communicate the NHLBI SCD research agenda to patients and community groups.

    CDC       Dr. Althea Grant

    The agency has active projects in the genomics of SCD trait, outcomes of pregnancy for mothers with SCD, and the economics of health care utilization claims. The agency is also organizing a partners meeting for all federal agencies with an interest in SCD, as well as the American Society of Hematology and the Sickle Cell Disease Association of America. Individual states will not come to this meeting, but will be brought into a national discussion of SCD needs at a later stage.

    HRSA     Judy Hagopian

    There are 17 new SCD newborn screening grants as of May 31. Ten of these are returning grants, and seven are new. The agency is piloting products developed in the last funding cycle. Two such products are the Newborn Baby Tool Kit, and the SCD Trait Notification Tool Kit for Providers. Four demonstration programs are funded under the Talent Bill. They are addressing issues related to SCD primary care and subspecialty care. The agency expects to have by September a minimum data set from the last funding cycle of newborn screening grants.


    No report at this meeting. A representative from the Veteran's Administration was unable to attend due to a conflict.


    The SCD cases Dr. McCune sees as an internist in active duty military hospitals are pediatric only, as there are no adults in the Army with SCD. Only trait cases are allowed into the Army. Dr. McCune is sending his fellows out for specialty SCD training, in an effort to improve the SCD education of Army providers. He is also involved in NCI Clinical Oncology Group (COG) trials, and he expressed his view that the new expanded SCD network should connect to the COG group.

    Active military hospitals are not connected to the veteran's Administration (VA) system at present.


    1. SCD Clinical Research Networks- Old and New     Dr. Kathy Hassell
      (Plans for Workshop)

      The Sickle Cell Disease Clinical Research Network (SCDCRN) is the third year of its first funding cycle and will field two interventional trials by the end of 2008. The first is the study of the use of transfusion therapy to prevent acute chest syndrome, as detected by an elevated phospholipase A2 level. The second is the use of Lorsartan to reduce the deterioration of kidney function in individuals with sickle cell disease who have protein in their urine. An ancillary study of systemic hypertension during this trial is planned. A third study involves collaboration with the Bone Marrow Transplantation Network to study the use of unrelated donor for stem cell transplantation for children with sickle cell disease. The SCDCRN was asked to participate in an ongoing United Kingdom study to examine the benefits of transfusion before low-to-moderate-risk surgeries, but it was considered to be of a lower priority for NHLBI and will not be performed by the SCDCRN. Two sites (Virginia Commonwealth University and Duke) are Outcomes Core Sites, and will analyze economic endpoints for in the interventional studies. The SCDCRN is also developing an acute pain management study. In order to complete these studies, a need to include additional research sites has been anticipated by the initial program, and funding set aside to recruit and support these sties. An SCDCRN subcommittee is developing a request for proposals (RFP) to solicit these sites. A workshop is planned for October, 2008 to obtain input and feedback into the development of a broad-based, inclusive clinical trials system for sickle cell disease.

    2. Basic and Translational Research Program in SCD      Dr. Ellen Werner, Dr. Kathy Hassell, Dr. Greg Evans

      Dr. Werner read, and displayed on a projector, the letter that will be sent to the new BTRP Principal Investigators to inform them of the new program, and schedule of activities. A total of 32 four-year research projects have been funded, in the following categories:

      Basic research 6
      Translation I 6
      Translation II 7
      Clinical (single center) 1
      Scholar and High School Training 12

      The goals of the BTRP are:

      • Development and completion of basic and translational (I and II) research in sickle cell disease.
      • Advancement of NHLBI's research agenda through collaborative interaction to identify, define and prioritize important areas in sickle cell disease.
      • Enhancement of training in hematology, with an emphasis on sickle cell disease, through the high school and Sickle Cell Scholars programs.
    3. Proposed Interagency Agreement with CDC: Registry     Dr. Ellen Werner
      and Surveillance System in Hemoglobinopathies (RuSH)

      Dr. Werner has been meeting with the CDC since September, 2007, to plan and develop an initiative for a new data system and repository in hemoglobinopathies. The overall purpose of the NHLBI-CDC Registry and Surveillance System in Hemoglobinopathies (RuSH) is to develop and implement a national data system and biospecimen repository that will provide data to describe the epidemiologic and clinical characteristics of people with all genotypes of sickle cell disease, Thalassemias, and other hemoglobinopathies. The system will be developed, tested, evaluated, and implemented in phases.

      The purpose of this current initiative is to conduct the first phase of pilot studies in 7 to 10 states. The pilot studies will test specific data collection methods, procedures and organizational structures, and determine the feasibility of implementing RuSH on the national level. RuSH is an interagency agreement between the NHLBI and CDC. NHLBI is taking the lead on this initiative because of our 35+ years of experience in hemoglobinopathies research; our commitment to set a data-driven research agenda and priorities; and our recognition of the need for data for evidence-based medicine in hemoglobinopathies. The work will be carried by the Centers for Disease control and Prevention (CDC) in order to take advantage of its experience and infrastructure in data systems, and its work with states, states' IRBs, and health care systems. NHLBI is working with CDC on the scope of work, and organizational structure. CDC will submit a Technical Proposal that will be peer-reviewed for scientific merit under the auspices of the NHLBI Review Branch. For the proposal, and throughout the pilot studies, NHLBI and CDC will meet with outside experts to get their input on scientific direction of the program.

      A proposal for this initiative was approved by the NHLBI Board of Extramural Experts at its May 7, 2008 meeting, and will be presented to the NHLBI Advisory Council at its meeting on June 11, 2008.

    4. Proposed Initiative- Neurobiology of Sickle Cell Pain    Dr. Kathy Hassell

      In 2007, Dr. Luksenburg conducted a workshop with brought together specialists in sickle cell disease and the area of basic and clinical pain research. The considerable enthusiasm generated by the interaction and recognition of the large potential for collaboration has resulted in the development of the potential Request for Applications (RFA) to support cross-disciplinary research in the neurobiology of sickle cell pain. Approval is being sought for NHLBI and other Institutes' support of this RFA.

    5. NIH Consensus Development Conference: HU in SCD     Dr. Ellen Werner
      (Possible future) State of Science: Management of SCD Putting Prevention into Practice

      Dr. Werner presented the Panel Statement from the NIH Consensus Development Conference on Use of Hydroxyurea in Sickle Cell Disease. It is due to be published in the June 17, 2008 issue of Annals of Internal Medicine. Attendees at the Consensus Conference identified gap areas in the NIH research portfolio. Dr. Werner is working with these attendees on a list of those gap areas, with the idea of releasing a PAR in the future.

      The prospect of another conference, such as one on the State of the Science will be discussed in the future.

    6. Proposed Initiative: Assessing Guidelines for     Dr. Ellen Werner
      SCD Management

      Dr. Werner iterated that the NHLBI is committed to funding research that will generate data for evidence-based guidelines. However, the organizational unit responsible for guidelines and dissemination research is the NHLBI Division of Application of Research Discoveries. Therefore, any work on sickle cell guidelines will be administered by DARD.

    7. Adult Sickle Cell Quality of Life Measurement Information     Dr. Ellen Werner
      System (ASCQ-Me)

      The purpose of ASCQ-Me is to develop, validate, and disseminate a measurement information system for adult sickle cell patients to report on their quality of life, and the impact of sickle cell on their physical, social role, and emotional functioning.

      ASCQ-Me is the only disease-specific partner of the NIH Roadmap Patient-Reported Outcomes Measurement Information System (PROMIS), and as such, has benefit and is benefiting from this collaboration.

      Later this summer, ASCQ-Me will be field tested in five sites across the country. The site coordinators will undergo centralized training on August 25, 2008 at the NIH. The project contractor's IRB has approved the study. The contractor is the American Institute for Research (AIR). Four sites have their own IRBs; the fifth site will use the AIR IRB. Dr. Werner has requested that the NIH Privacy Officer and Project Clearance Branch approve a Clinical Exemption for ASCQ-Me since the project does not meet the criteria for OMB clearance. Field tests of ASCQ-Me and selected PROMIS items will start in September, 2008.

    8. BABY HUG Phase 3 Clinical Trial    Dr. Greg Evans

      Baby HUG is double-blind, randomized, placebo-controlled trial to determine if hydroxyurea, given to infants with sickle cell disease at about 1 year of age, can prevent damage to the spleen and kidneys. The study was initiated in 1999 to conduct a pilot phase of 40 patients to determine if a phase 3 trial was warranted. 10 sites were awarded through contracts to initiate the study. In 2005, upon completion of the pilot phase and analysis of the initial data, it was decided to implement the full trial with a final recruitment goal of 200 patients (i.e. another 160 patients). Since recruitment had been slow, it was recommended that additional sites be added. In this regard 4 additional sites were funded through subcontracts from one of the main sites at University of Texas Southwestern. Despite a brief hold on the trial, 193 patients were recruited by 2008 at which point accrual was ended. The last patient is expected to complete the study in July 2009. A 2 year follow-up study has received approval for funding and is in the process of obtaining NHLBI and IRB approvals of the consent forms. The need for a new IND for hydroxyurea to cover the follow-up study is being examined.

    9. SWiTCH Phase 3 Clinical Trial    Dr. Kathy Hassell

      The Stroke With Transfusion Changing to Hydroxyurea Trial which compares continued use of transfusion to prevent recurrent stroke in children with sickle cell disease, using chelation therapy to control iron overload, with hydroxyurea therapy to prevent recurrent stroke, using phlebotomy to control iron overload. The study opened in November 2006 and has enrolled 110 subjects, 87 of which have completed initial study procedures and have been randomized. The enrollment goal is 130 randomized subjects. The trial is running smoothly.

    10. Walk-PHaSST: Treatment of Sickle Cell Disease-Associated     Dr. Greg Evans, Dr. Kathy Hassell
      Pulmonary Hypertension with Sildenafil

      Walk-PHaSST is a two-part study designed to screen 1,000 SCD subjects (aged 12 and up) for pulmonary hypertension, and then to enroll 132 subjects in a 16-week interventional comparison of sildenafil versus placebo. The primary endpoint is exercise capacity measured by 6-minute walk distance. Contracts for this trial were issued to 9 clinical sites and a Data Coordinating sender in September 2006. Among the 9 clinical sites are the NHLBI intramural program, and one in the UK, a site that involves 3 hospitals in London. The current status of the study is that 115 subjects have been screened, and 7 subjects have been randomized for the interventional study.

    11. Best Practices in Transfusion Medicine     Dr. Kathy Hassell

      In September, 2007, Dr. Ted Wun conducted a conference to discuss best practices in transfusion medicine for adults with sickle cell disease. This cross-disciplinary conference which included transfusion specialists, sickle cell disease experts and representation from blood bank organizations was support by an R-13 awarded to Dr. Wun, representing the Sickle Cell Adult Provider Network (SCAPN). An executive summary outlining specific recommendations is under review by participants, and a full document is in preparation. Results will be made available through the NHLBI, on the SCAPN website, and through publication. This was the second in a series of best practices conferences convened by members of SCAPN to bring attention to important issues for adults with sickle cell disease. The next conference will be held by adult consumers in September, 2008, to discuss successful strategies in self-management, navigation of the healthcare system and other key issues from the adult community perspective, as well as to provide feedback to SCAPN about how providers can better serve their patients. SCAPN will provide financial support for participants and is seeking additional sources of funding for this meeting. The Sickle Cell Disease Association of America has facilitated meeting space for this conference, scheduled to occur just prior to their annual national meeting in New Orleans.


    Sickle Cell Disease Association of America (SCDAA) REPORT

    Dr. Edwards commented that she had already expressed what she wanted to say to the committee, especially the concerns and decreased care for sickle cell patients in the context of the closing of the Comprehensive Sickle Cell Centers. The next SCDAA annual meeting will be held September 24-27, 2008, in New Orleans.


    The SCDAC voted to recommend that the NHLBI add two (2) slots for Sickle Cell Scholars to the currently funded six sites in the K12 Program in Clinical Hematology. The current sites are: Duke/UNC, Harvard Medical School, Johns Hopkins Medical School and School of Public Health, University of Pennsylvania School of Medicine, University of Washington School of Medicine, and Washington University School of Medicine.

    VI. FUTURE MEETING DATES (November 3, 2008 and June 1, 2009)

    R. Blaine Moore, Ph
    SCDAC Executive Secretary

    F. Daniel Armstrong, PhD
    SCDAC Chair

Last updated: May 4, 2010

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