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Bethesda, Maryland

June 7, 2004


Dr. Gilda Barabino, Northeastern University; Dr. Oswaldo Castro, Howard University/NIH; Dr. Michael DeBaun, Washington University School of Medicine; Dr. Paul Frenette, Mount Sinai School of Medicine; Dr. Johnson Haynes, Comprehensive Sickle Cell Center; Ms. J. Hoxi Jones, Texas Department of Human Services; Dr. Dorothy Moore, UMDNJ/NJMS & SCDAA, Dr. Joseph Telfair, University of Alabama at Birmingham, Dr. Theodore Wun, University of California-Davis Cancer Center.


Dr. Russell Ware


Dr. Joseph Desimone, Dr. William Hannon, Dr. Marie Mann, Dr. Robert Sheffler.


Dr. Duane Bonds, DBDR/BDP, Dr. Gregory Evans, DBDR/BDP; Dr. Blaine Moore DBDR/BDP; Dr. Charles Peterson, OD/DBDR; Dr. Pankaj Qasba, DBDR/BDP; Ms. Sonya Ross, SCDAA, Dr. William P. Winter, Howard University.

Executive Secretary - Dr. Charles M. Peterson

Secretary - Ms. Petronella A. Barrow

Dr. Charles Peterson called the meeting to order at 8:30 am and referred members to the required notification regarding conflicts of interest. He reminded those present to sign in on the required sign-in sheets. The retiring members (Ms. Hoxi-Jones and Drs. Barabino, Castro, and Telfair) were presented a certificate of recognition signed by Dr. Barbara Alving, Acting Director, NHLBI.

  1. Dr. Ted Wun called for review of the minutes of November 3, 2003 and they were reviewed and approved.
  2. Dr. Wun welcomed the members and guests and introduced the Scientific Presentations.

    A. Dr. Mark Gladwin: “Intramural Research in Sickle Cell Disease” Dr. Gladwin reviewed the ongoing studies of sickle cell disease, hemolysis and associated pulmonary hypertension. The driving hypothesis of the work is that these and other factors including increasing blood pressure, renal insufficiency, cutaneous leg ulcers, are linked resulting in or as a result of chronic vasculopathy. Sudden death and pulmonary hypertension are now being recognized as being a major cause of death in patients with sickle cell disease. Current treatment approaches for pulmonary hypertension were reviewed including proastacyclin, Bosentan, slidenafil, and L-Arginine or NO gas delivery. A large scale treatment trial is being considered with sildenafil. Such an effort would require the collaboration of the intra- and extra-mural communities to assure adequate recruitment.

    B. Dr. Ted Wun “Neutrophil Activation and Possible Link Between Pyridoxine Levels and Endothelial Perturbation in Sickle Cell Disease” Dr. Wun reviewed the function and potential role of monocytes and neutrophils in sickle cell disease associated sequelae. These cells through a number of mechanisms including activated oxygen species, inflammatory pathways, interactions with platelets and endothelium, along with homocysteine metabolism have been implicated in both the initiation and propagation of sickle cell associated pathology.

  3. Chairman’s Report:: Dr Wun provided an update on the Sickle Cell Treatment Act now being considered by the House of representatives.

  4. DBDR Director’s Report:: Dr Peterson reviewed 30 years of NHLBI involvement in Sickle Cell Disease Research. Life expectancy has increased from the teens to the late forties for persons with sickle cell disease. One could therefore say that research toward treatment and cure has reached the “half way point.” Issues such as quality of life and issues of chronic disability have become increasingly important as life expectancy increases. These challenges will need to be addressed in an environment of constricting fiscal and human resources. The Institute is looking for new ways of increasing efficiency through partnerships, outreach, novel approaches, and leveraging existing resources. The hemoglobinopathy wider community is encouraged to think of and include other hemoglobin disorders in protocol development and implementation especially through the network systems of the Institute.

  5. Action Items from previous meeting were completed. It was noted that rather than receive a handbook, the committee will receive a copy of “the charter of the committee” in each meeting packet in future meetings. The statement is:


    The Sickle Cell Disease Advisory Committee (Committee) provides advice and guidance concerning the Sickle Cell Disease Program, Division of Blood Diseases and Resources (DBDR), National Heart, Lung, and Blood Institute (NHLBI). Sickle cell anemia, a chronic inherited disease estimated to occur in one of every 400 Black births in the United States, has a major medical and sociological impact on the affected populations. In addition, sickle cell trait, a related but usually benign condition, occurs in about 10 percent of Black Americans. Sickle cell anemia and related variants also occur among other racial and ethnic groups, including individuals from sub-Saharan Africa, the Middle East, the Caribbean and South America, as well as people from countries in the Mediterranean.


    42 U.S.C. 282(b)(6), section 402(b)(6) of the Public Health Service (PHS) Act, as amended. The Committee is governed by the provisions of the Federal Advisory Committee Act, as amended (5 U.S.C. Appendix 2), which sets forth standards for the formation and use of advisory committees.


    The Committee advises the Director of the National Institutes of Health (NIH); the Director, NHLBI; and the Director (DBDR), on the Sickle Cell Disease Program, NHLBI; recommends priorities within the Program; identifies research opportunities and needs; and makes recommendations concerning the planning, execution, and evaluation of the program.

    As necessary, the Committee and subcommittees may call upon special consultants; assemble ad hoc working groups; and convene conferences, and workshops, or other activities.


    The Committee shall consist of 10 members including the Chair, appointed by the Director, NIH. Eight members shall be selected from authorities knowledgeable in the fields related to sickle cell disease such as hematology, pediatrics, family practice, health education, and behavioral science, and two public members shall be selected with demonstrated leadership in programs related to sickle cell disease. In addition, there will be the following ex officio members: the Director, NIH; the Director, Centers for Disease Control and Prevention; the Administrator, Health Resources and Services Administration; the Chief Medical Director, Department of Veterans Affairs; and the Assistant Secretary of Defense (Health Affairs), or their designees.

    A quorum for the conduct of business by the full Committee shall consist of a majority of currently appointed members. A quorum for each subcommittee shall be three members.

    Members shall be invited to serve for overlapping terms of up to four years; terms of more than two years are contingent upon renewal of the Committee by appropriate action prior to its expiration. A member may serve after the expiration of that member's term until a successor has taken office.

    As necessary, standing and ad hoc subcommittees, composed of members of the parent committee, may be established to perform specific functions within the Committee's jurisdiction. The Department Committee Management Officer shall be notified upon the establishment of each standing subcommittee and shall be provided information on its name, membership, function, and estimated frequency of meetings.

    Upon approval by the Chair, the advice of a subcommittee shall be considered the advice of the Committee.

    A member of one subcommittee may serve as a voting member of other subcommittees when that member’s expertise is required. However, that member shall not be counted in determining the presence of a quorum.

    Management and support services shall be provided by the Division of Blood Diseases and Resources, NHLBI.


    Meetings of the full Committee shall be held approximately two times a year at the call of the Chair, with the advance approval of a Government official who shall also approve the agenda. A Government official shall be present at all meetings.

    Meetings shall be open to the public unless as determined otherwise by the Secretary of Health and Human Services. Notice of all meetings shall be given to the public.

    Meetings shall be conducted and records of the proceedings kept, as required by applicable laws and Departmental policies.

  6. Update on Program Activities

    A. The New NHLBI Strategic Plan for Hemoglobin Disorders was reviewed by Dr. Evans. In response to the outcome of the NHGRI-led workshop, “New Directions in Sickle Cell Therapy in the Genome Era,” held in November, 2003, a Trans-NIH Working Group for New Therapies for Sickle Cell Disease has been formed. Starting with the over 30 workshop recommendations, this group identified 10 priority areas for the NIH to address, comprising a new NHLBI Strategic Plan for Hemoglobin Disorders from which initiatives may be developed in the future. Some of the priority areas overlap with those proposed and endorsed in 2000 by NHLBI as part of its Strategic Plan for a Gene-Based Cure for Beta-Chain Hemoglobinopathies, and some overlap with key areas or initiatives previously recommended by the NHLBI Sickle Cell Disease Advisory Committee. The 10 priority areas are:

      1- E-Mail listserv for sickle cell disease research This is available now by sending an e-mail to . Type as the body of the message: subscribe SCDR-L and your name.

      2- Clinical research network focused on Phase III clinical trials for sickle cell disease (RFP or RFA)

      3- International, prospective registry and sample repository to support large scale human genetic studies for sickle cell disease (RFP or RFA)

      4- Training program for application of high-throughput genomic/proteomic technologies to hemoglobin disorders (RFA)

      5- Chemical genomics for sickle cell disease (RFA; leverages related portion of the NIH Roadmap effort)

      6- Research on ethical, legal, and social implications of human genetic studies for subjects with sickle cell disease (Notice in the Guide as addendum to existing Program Announcement)

      7- Novel idea grants for sickle cell disease (PA with special review)

      8- Genetic modifiers of sickle cell disease (RFP or RFA; dependent on registry, with clinical phenotypes linked to DNA samples)

      9- Late stage drug development for hemoglobin disorders (RFP or RFA; will leverage related portion of the NIH Roadmap effort to the extent feasible)

      10- Gene therapy for hemoglobin disorders (RFA)

    The clinical research network and registry (#s 2 and 3 above) have been combined and developed into a single initiative that was presented to the NHLBI Board of Extramural Advisors (BEA) in April, 2004. The BEA rated it highly. This initiative was subsequently presented to the NHLBI Advisory Council in May, 2004, where again it received favorable reviews. This initiative has been approved for funding in fiscal year 2006, and for immediate development and release by the Acting Director, NHLBI, and is now being written by Dr. Blaine Moore, Director of the Blood Diseases Program. The chemical genomics initiative (#5 above) will be implemented by NHGRI in fiscal year 2005, with co-sponsorship by NHLBI.

    B. Comprehensive Sickle Cell Centers Integration Committee Report, and High School Student Summer Program: Dr. Evans reviewed the progress made by the centers, the protocols under consideration and the training programs in the context of other training opportunities. A new training supplement has recently been made available to the Sickle Cell Centers that will allow recruitment of individuals from high school level to young investigators. Dr. Qasba gave an update on the Summer for Sickle Cell Science Program, that provides Summer research experiences for high school students. Last summer, 26 students were supported at 9 Centers in the first year of this program. Applications appear to be even greater for this coming summer.

    C. MSH Patients’ Follow-up:

    This follow-up study is a five year longitudinal epidemiologic study of the patients who participated in the Multicenter Study of Hydroxyurea in Sickle Cell Anemia (MSH Trial) to ascertain long term toxic effects of hydroxyurea usage in the sickle cell anemia patient population who participated in MSH. The patients will be followed annually to determine health status, quality of life, incidence of malignancies, and birth defects in their offspring.

    Since hydroxyurea has been proven to be efficacious in adults, it may have a profound effect on the chronic organ damage and decreased life expectancy of this patient population. Sickle cell anemia patients who experience 3 or more crises per year were observed in the Cooperative Study of Sickle Cell Disease (CSSCD) to die 10 to 15 years earlier than those patients who suffer fewer crises per year. In addition, before MSH, hydroxyurea was used primarily as a cancer chemotherapeutic agent so its long term effects on the sickle cell anemia patient population are unknown. If patients who take this drug live longer, they may be at risk for developing diseases that are currently seen in the normal African American population. In addition, this agent may be mutagenic in humans so a longitudinal study of sickle cell anemia patients who reproduce and their offspring may yield valuable information. The cohort of patients who participated in MSH are unique, and the incidence of medical problems that they develop will be compared to the adult cohort of the CSSCD. In 1991, the National Heart, Lung, and Blood Advisory Council advised the Division of Blood Diseases and Resources to set up a mechanism for following these patients for a minimum of 10 years after the end of the efficacy trial.

    During the current 5 - year contract, East Coast subjects will be seen at the NIH Clinical Center to undergo the work-up for pulmonary hypertension that is supervised by Dr. Mark Gladwin. In addition, West Coast patients followed at the Northern California Comprehensive Sickle Cell Center will receive the same work-up outlined in Dr. Gladwin’s protocol. It is hoped that since this is a large cohort of adult patients who are well characterized in terms of hydroxyurea usage, it will provide invaluable information about the impact that hydroxyurea therapy may or may not have on this life threatening complication.

    Dr. Bonds noted that the follow-up study continues. There was discussion of when the follow-up study will have contributed as much as can be scientifically helpful in view of the difficulty of non-randomized follow-up. The committee felt that the study was still providing useful information and should be continued for this funding cycle.

    D. Pediatric Hydroxyurea Phase III Clinical Trial (BABY HUG) :

    The objective of the BABY HUG clinical trial is to determine if hydroxyurea therapy is effective in the prevention of chronic end organ damage in the spleen and kidney in pediatric patients with sickle cell anemia (HbSS). This clinical trial will involve the cooperation of pediatric clinical centers with expertise in treating sickle cell anemia, and a medical coordinating center which will supervise drug distribution, central laboratory functions, and data collection. In 1995, the Multicenter Study of Hydroxyurea (MSH Trial) demonstrated that hydroxyurea is effective in decreasing the frequency of painful crises, hospitalizations for crises, acute chest syndrome, and blood transfusions by 50%. The recently completed phase II study of hydroxyurea in children (PED HUG) demonstrated that children have a response to hydroxyurea similar to that seen in adults in terms of increasing fetal hemoglobin levels and total hemoglobin, and decreasing complications associated with sickle cell anemia. In addition, this study demonstrated that the drug does not adversely affect growth and development between the ages of 5 and 15. A recently completed pilot study of hydroxyurea given to children between the ages of 6 months and 24 months (HUSOFT) demonstrated that the drug is tolerated well by small infants, and that the fetal hemoglobin switch can be forced to remain in the 'on position' by hydroxyurea administration.

    A Special Emphasis Panel (SEP) met on April 12, 1996 to review the results of the MSH Trial and the progress to date of the PED HUG study. The SEP recommended to the National Heart, Lung, and Blood Institute that a randomized, double blind, placebo controlled trial be undertaken in young children to test the hypothesis that hydroxyurea can prevent the onset of chronic end organ damage in children recruited before two years of age. Surrogate markers of end organ damage were suggested to be used to evaluate brain, pulmonary, renal, and splenic function as well as developmental milestones. The proposed clinical trial responds to that recommendation and was reviewed and approved by the National Heart, Lung, and Blood Advisory Council on October 22, 1998.

    The Pediatric Hydroxyurea Phase III Clinical Trial will involve the recruitment of 200 children with sickle cell anemia. The children will be followed at clinical sites around the country with expertise in the care of young children with sickle cell anemia.

    Dr. Bonds noted that this trial has begun patient recruitment in the Feasibility and Safety Pilot which aims to enroll 40 subjects by August 31, 2004. The BABY HUG DSMB will evaluate safety parameters obtained during the pilot study to determine if recruitment should be opened up to the full sample size of 200 subjects. The next meeting of this trial’s DSMB will be on June 21, 2004.

    E. STOP II:

    Without intervention, approximately 10% of children with sickle cell anemia will sustain a stroke before the age of 20. The Stroke Prevention Trial in Sickle Cell Anemia (STOP) which was completed in September, 1997, showed that patients at high risk for stroke could be identified using transcranial Doppler ultrasound, and that the incidence of stroke could be reduced by 90% in those high-risk children using periodic blood transfusions for 36 months. However, periodic blood transfusions are cumbersome, expensive and associated with morbidity from iron overload. In addition, despite the impressive reduction in stroke in the STOP trial, many patients refuse this treatment. STOP 2 hopes to address these issues.

    The purposes of the STOP 2 Trial are: 1) To determine how long transfusions are needed for primary stroke prevention. 2) To determine what is the duration of risk associated with abnormal transcranial doppler (TCD) measurements. 3) To determine the specificity of the stroke risk model developed in STOP in patients with abnormal transcranial doppler (TCD) measurements.

    STOP II is now entering its 5th year of funding. Dr. Bonds reported that although recruitment has been slower than originally anticipated, the investigator group has now enrolled 69 subjects. It is hoped that the trial will be extended for 2 years beyond the originally planned end of funding so that observations on the planned sample size of 100 can be obtained.

    F. The CSSCD Cohort Study and DNA Repository Samples were discussed. Over 4,000 subjects were enrolled during the 20 years of the Cooperative Study of Sickle Cell Disease (CSSCD). The CSSCD was a prospective, epidemiologic cohort study whose main goal was to describe the natural history of sickle cell disease. During the course of the CSSCD, over 2,000 DNA samples were obtained from the subjects. Since the end of the CSSCD, various investigators have requested access to DNA samples from this cohort so that genetic modifiers of clinical severity could be investigated. Unfortunately, the CSSCD DNA repository has a large number of empty vials that represent samples obtained from subjects with a high rate of severe sickle cell disease related clinical events. Thought has been given to expanding the genomic DNA available in these samples to provide an ongoing resource. It was felt that the effort to preserve the samples should be pursued.

    G. Upcoming Meetings and RFA’s:

    Dr. Bonds noted that applications had been received for the Pulmonary Complications of Sickle Cell Disease RFA. This RFA will be reviewed with a plan to present the most meritorious applications for funding in the fall of 2004.

    The Annual Sickle Cell Disease Clinical Meetings will be held at Natcher Conference Center on the main NIH campus from September 20-24. In addition to the Steering Committee meetings of the CSCC Network, BABY HUG, STOP II, and the MSH Patient’s Follow-up, other important meetings will occur. These meetings will be workshops on pain and iron overload sponsored by IASCNAPA on 9/21/04; RFA grantees meetings on 9/21, 9/22, and 9/23; and the Working Group on the Sickle Cell Disease Consultative Network on 9/21/04.

  7. Other
  8. Dr. Dorothy Moore noted that the Sickle Cell Disease Association of America is moving to Baltimore, MD. Ms. Sonya Ross distributed the SCDAA Federal Legislative Briefing Book for FY 2005.

  9. Suggestions for NHLBI from the Committee
  10. A. In view of the importance of quality of life issues, NHLBI should plan toward including these issues in all phase III clinical trials as well as integrating useful tools into health services and a longitudinal registry. Psychosocial issues are becoming an increasing issue for persons with sickle cell disease. NHLBI should consider studies of the prevalence as well as the treatment of these concomitant factors.

    B. Pediatric and Medical Comprehensive Care should be a criteria for evaluation in the next round of the Sickle Cell Centers Competitive Review.

    C. Increasing emphasis should be placed on studies of pulmonary vasculopathy with thought given to prevention. BABY HUG investigators may wish to consider serial ECHO studies in the expanded cohort. The Committee encouraged the development of intramural/extramural collaborations to answer questions of importance to people with sickle cell disease.

    D. Pilot Phase I pipeline drug studies should be encouraged. Mechanisms should also be sought that would encourage studies of already approved drugs for sickle cell disease indications.

    E. Partnerships that NHLBI should encourage could include the cell transplant communities, the Nursing Institute at NIH, Outreach to Clinical Care Centers for Sickle Cell Disease and Corporate America including the Pharmaceutical Industry.

    F. Additional thought needs to be addressed to encouraging non-clinical researchers to become interested in sickle cell disease. A forum for basic researchers interested in sickle cell disease that also put them in contact with clinicians and patients would be useful.

  11. Dates of Next Meetings
  12. November 1, 2004

    June 6, 2005

  13. Areas of Program Needs and Opportunities

    A. The issues of behavioral and psychosocial research were identified in particular with hopes expressed that the workshop on unmet needs will develop a strategic plan in these areas.

    B. Staff was asked to identify speakers for the next meeting who could address statistical approaches and issues of small N clinical trials in pain research and potential surrogate markers of eye and bone disease in patients with SC disease.

  14. Summary List of Action Items
  15. A. The Protocol Review/DSMB Committees of BABY HUG are requested to report to the Committee regarding development of the protocol, age of participants, and considerations of therapeutic endpoints and potential toxicities. This clinical trial is on hold pending completion of review by NHLBI.

    B. Dr. Swerdlow would also convene an ad hoc committee to draft a statement on behalf of the Committee prior to the next meeting. Dr. Swerdlow noted that he would coordinate an outreach for the Committee to the AMA regarding the ICD 9 codes for SC disease and sickle beta thalassemia disorders, Dr. Lane will assist.

    C. Dr. Marie Stuart will review the two SC initiatives with a critical eye and see whether there might be a way to merge the two SC initiatives.

    D. NHLBI will consider ways by which the utility of the CSSCD DNA resource can be prolonged and establish a minimum amount below which no more samples will be withdrawn thus anticipating a yet to be developed expansion technology.


    Theodore Wun, M.D.


    Sickle Cell Disease Advisory Committee


    Charles M. Peterson, M.D.

    Executive Secretary

    Sickle Cell Disease Advisory Committee

    Last updated: October 28, 2007

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