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MINUTES OF THE SEVENTY-NINTH MEETING OF THE SICKLE CELL DISEASE ADVISORY COMMITTEE

Bethesda, Maryland
June 4, 2001

COMMITTEE MEMBERS PRESENT
Dr. Gilda Barabino, Dr. Oswaldo Castro,  J. Hoxie Jones-Carranza, Dr. Peter Lane, Dr. Herbert Meiselman, Ms. Sonya Ross, Dr. Jeanne Smith, Dr. Marie Stuart,  Dr. Paul Swerdlow, Dr. Joseph Telfair, Dr.  Tim Townes.

COMMITTEE MEMBERS ABSENT
None

EX-OFFICIO MEMBERS PRESENT
Ms. Barbara Adam for Dr. William Hannon, Dr. Joseph DeSimone, Dr. Marie  Mann, Dr. Robert Sheffler, Dr. Martin Steinberg

EX-OFFICIO MEMBERS ABSENT
None

PROGRAM STAFF AND AFFILIATED ORGANIZATION REPRESENTATIVES:
Mrs. Michelle Allen, Mr. Larry Allen, Dr. Barbara Alving, DBDR;  Dr. Duane Bonds, DBDR/SCDSRG; Dr. Carlo Brugnara, Childrens’s Hospital, Boston; Ms. Kristi Cooper, NHLBI; Dr. Gregory Evans,  DBDR/SCDSRG; Dr. Rebecca Haley, American Red Cross; Dr. Liana Harvath, DBDR/BRP;  Dr. Paul R. McCurdy; Dr. Helena Mishoe DBDR/BDP;  Dr. Charles Peterson, DBDR/BDP; Ms. Betsy Poindexter, FDA; Ms. Susan Pucie DBDR, Dr. Martin Ruta, FDA,  Dr. John Thomas DBDR/BDP, Dr. Virginia Wanamaker, DHHS; Dr. Ellen Werner, DBDR/BDP; Dr. William P. Winter, Howard University.

Executive Secretary  - Dr. Charles M. Peterson
Secretary  - Ms. Petronella A. Barrow

I. Dr. Paul Swerdlow called the meeting to order at 9:10 AM.
Dr. Charles Peterson read the required notification regarding conflicts  of interest and reminded those present to sign in on the required sign-in  sheets.

II.  The Minutes of November 13, 2000 were reviewed and approved.

III.  Dr. Swerdlow introduced the Scientific Presentations.

 A. Dr. Martin Steinberg reviewed Hemoglobin SC Disease.
He noted that approximately 1/800 African Americans has the genotype but the clinical expression varies from extremely mild to severe. In general, complications are about one half those seen in individuals with Hb SS. He reviewed the data on the use of hydroxyurea in patients with Hb SC. There are 3 phase I-II studies with patient numbers ranging from 5 - 8 subjects. There has been minimal toxicity reported to date in these trials all of which used relatively low doses. There have been no studies of clinical effectiveness or detailed studies of potential mechanisms of action of efficacy in this population. Another problem is the lack of data regarding who with Hb SC becomes ill and what predictors of clinical course may be valid in designing a trial. The data regarding clinical severity may be present in the data base for the Cooperative Study of Sickle Cell Disease but this has not been analyzed.

 B. Dr. Carlo Brugnara reviewed “Therapies to Prevent Dehydration of Sickle Erythrocytes”. There are a number of approaches being utilized to increase red cell hydration that include the Gardos, Cl, and KCL cotransport channels. Clotrimazole has been shown to block dehydration in cells, the SAD mouse and humans. The problem with the drug in humans is that hepatic toxicity is found in persons with sickle cell disease at doses above 20 -30 mg/kg/24 hours. Other compounds including Mg pindolate, and compounds identified by industry (Icogen and NeuroSearch) are being evaluated in preclinical and planned clinical trials.  A combined trial of magnesium and hydroxyurea is also being planned.

IV. Drs. Liana Harvath, Martin Ruta (FDA), and Rebecca Haley (American Red Cross) presented the issue of leukoreduction problems. On June 15, 2001, there will be a Blood Products Advisory Meeting convened by the FDA to explore the problem of leukofiltration failures. Leukoreduction has been advocated for all units of red cells in that this procedure is associated with a decrease in alloimmunization and febrile reactions in recipients. Approximately 1% of units are lost due to filtration problems usually associated with clots in the unit. There has been some concern that units from persons with sickle trait do not filter well. While a technical solution to the problem is being sought, FDA has proposed screening of blood donors for sickle cell trait.

The Committee felt that screening blood donors for sickle hemoglobin would be counterproductive and deliver the wrong message to a community where the shortage of donors presents tremendous problems. Dr. Jeanne Smith volunteered to represent the Sickle Cell Advisory Committee opinion to the FDA meeting on leukoreduction and report back to the Committee. Dr. Swerdlow would also convene an ad hoc committee to draft a statement on behalf of the Committee prior to the next meeting.

V. Dr. Swerdlow gave the Chairman’s report. He noted that there was a pending FDA Notice of Meeting on Anesthetic and Life Support Drugs Advisory Committee. The meeting had been postponed from its original time of June 14 and 15. The committee will discuss the medical use of opiate analgesics in various patient populations including pediatric patients and patients with chronic pain of nonmalignant etiology, as well as the risk to benefit ratio of extending opiate treatment into these populations. Dr. Swerdlow noted the importance of pain therapy for patients with sickle cell disease and volunteered to attend the FDA meeting of the Anesthetic and Life Support Drugs Advisory Committee and coordinate a response of the Sickle Cell Disease Advisory Committee as necessary. He passed out the notice of meeting to the Committee.

VI.  Action Items from previous meeting were completed or discussed as follows:

 A. It was recommended by the committee that the Sickle Cell Disease Research Group distribute a list of ongoing clinical trials and brief progress reports on each as well as potential studies and current priorities  prior to the Committee Meeting. This was done by Dr. Bonds.

 B. Speakers for the next meeting should be sought who could address the issues of clinical trials that increase cellular hydration with magnesium and feasible clinical trials in SC disease. This was accomplished.

 C. 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. Since DSMB deliberations are ongoing, this discussion was postponed until the next meeting.

 D. The issue of sickle cell trait as a public health problem as well as  a problem for the military will be considered in future meetings. The committee  will continue to try and see if someone from the military can address the  issue at a future meeting. To date it has not been possible to get a person. Dr. Alving will contact the Army Surgeon General to see if she can find someone to address the committee. In response to these efforts, Lieutenant Colonel Robert Sheffler Consultant to the Surgeon General for Hematology/Oncology and Chief of the Hematology /Oncology Service at Brooke Army Medical Center will be attending the meetings. He reported on the history of screening for sickle cell disease in the military. After a great deal of activity in the 1960s and 1970s with the Kark Report, changes in procedure were introduced such that there were no deaths in the subsequent 10 years. In 1996 it was recommended that the army not screen. Each service has its own policy. The Air Force screens and offers those found positive the option to opt out of service. The Navy screens and identifies those positive with a special neck tag and a red belt during heavy exercise sessions. The marines screen but do not alter routine. The routine for marines during training is to pay strict attention to protocol for hydration and electrolyte restoration. The army had 8 deaths in the years 1999-2000 during basic training. Of these, 5 were screened for presence of hemoglobin S and 3 were found positive. In view of the higher than expected prevalence, the Army is reviewing its procedures with respect to screening.

The following motion was moved, seconded and unanimously approved by the Committee.

Measures to prevent exertional heat illness eliminate the disparity in sudden death during military basic training between persons with sickle cell trait and persons without sickle cell trait and reduce the risk of death in both groups. The Sickle Cell Disease Advisory Committee recommends:
 1. All military services should systematically implement measures to prevent exertional heat illness and monitor compliance with such measures.
 2. Routine screening of recruits for sickle cell trait is unnecessary, potentially stigmatizing and discriminatory, and should be discontinued.
 3. Screening for sickle cell trait may be appropriate prior to participation in selected activities that involve predictable exposure to environmental hypoxia. In such circumstances, screening should be universal and education and counseling should be provided to persons identified as hemoglobinopathy carriers.

VII.  Dr. Alving gave the Director's Report from the Division of  Blood Diseases and Resources.
The progress on the book Management and Therapy of Sickle Cell Disease was reviewed and the list of contents distributed.  Each member of the Sickle Cell Disease Advisory Committee was encouraged to review the entire book and forward comments to Dr. Alving by June 28, 2001.

Dr. Alving distributed a number of letters that she had received regarding a need for a network to perform clinical studies in sickle cell research.  She noted that within the current framework, the goal of NHLBI is to develop a clinical research network through the sickle cell centers.   Plans for workshop on Adults with Sickle Cell Disease - to be held in conjunction with HRSA.  Received names of those who wished to work in this area were planned.

VIII.  Agency Reports

A. Department of the Army. Dr. Sheffler’s report is summarized above (IV. D.)

B. Centers for Disease Control. Ms. Barbara Adam gave the report.  She had a number of questions regarding Hb SC disease in response to a letter from a patient with the condition. Notable among the issues raised include that few physicians or emergency rooms know of the condition much less follow guidelines for care.  Thus there appears to be under reporting, miscoding, and misdiagnosis of the condition.  There are no studies known regarding quality of life issues for individuals with Hb SC.  The Committee concurred on the lack of data regarding quality of life issues and encouraged development of a workshop in the area.  It was further pointed out that the ICD 9 codes for both SC disease and sickle beta thalassemia make no sense and are confusing to health care providers.  It was noted that to change an ICD 9 code, one must work with the American Medical Association.  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.

Ms. Adams noted the many changes occurring in the methods of testing being used for neonatal screening.  A number of gene based kits are beginning to appear as are new methods using tandem, MALDI, and ESI-mass spectroscopy for detecting hemoglobin variants.  There is still some interest on the part of the CDC in participating in or convening a workshop on new methods. The Committee felt that such a conference might attract international interest as well as interest from the many state screening programs.

C. Health Resources and Services Administration.  Dr. Marie Mann reviewed the agencies appoaches to newborn screening and the implications of new technologies for screening.  There has also been an increased interest in the ethical, legal and social issues that accompany screening programs.  Policies and procedures regarding the use and storage of blood spot samples used for screening are under evaluation.  The agency would like to develop model procedures that could be distributed.

D. Veterans Administration. Dr. Joseph DeSimone noted that the VA is developing new funding opportunities for those that historically treat minority populations. Details of these efforts will be forwarded to the Committee as they appear.

IX. Update on Program Activities

TIME LINE FOR RECOMPETITION OF NHLBI COMPREHENSIVE SICKLE CELL CENTERS  (CSCCs)

A. Comprehensive Sickle Cell Centers Renewal. Dr. Gregory Evans reviewed the time line for the renewal of the RFA for the Sickle Cell Centers and noted that suggestions from the committee were taken to incorporated in the new RFA.

Application Receipt:     September 25,  2001
Merit Review:      Spring 2002
Presentation of Proposed Funding Plan to NHLBI Advisory Council:      September 2002
Award:  April 2003

B.  Dr. Evans reported on a the Strategic Plan for a Gene-Based Cure for Beta-Chain Hemoglobinopathies.  The first 3 of 11 potential initiatives were presented to the Bureau of Extramural Advisors (BEA) and the Council.  These three initiatives dealt with approaches to increasing hemoglobin F.  One of the initiatives has been announced and two others are moving forward.

C. MSH Patients’ Follow-up Cohort Trial. Dr. Duane Bonds reviewed the status of trial and noted that an additional 5 years of follow-up was being planned by NHLBI. Dr. Steinberg mentioned that he and others were working on a report updating the follow up of these patients.

D. BABY Hug Phase 3 Clinical Trial. This protocol is under review by the DSMB at the present
time.

E.  Parvovirus B19 Study. Dr. Duane Bonds announced that this cumulative incidence epidemiologic study has been initiated through nine of the ten Sickle Cell Centers and recruitment of patients now exceeds 700.

F. STOP 2 Trial. Dr. Bonds reported that the trial was underway and 3 patients have been recruited.

G.  Additional Clinical Trials in Progress. Dr. Bonds reported that the Hip Core Trial continues to recruit patients and now has 32 patients in follow up.  This trial and a planned trial in Acute Chest Syndrome are being coordinated through the Oakland Sickle Cell Center.  The Cooperative Study of Sickle Cell Disease Cohort Study continues to encourage investigators to apply for ancillary funds to further evaluate data.  Interested investigators should contact Dr. Bonds.

H. A number of potential initiatives were discussed.  Dr. Bonds was encouraged to proceed with efforts in the following areas:
 1. Sickle Cell Disease and the Lung.
 2. Hydroxyurea and SC Disease.
 3. Membrane active agents and Hb SC and SS.

I. The Committee was reminded that the Sickle Cell Disease Meetings at NHLBI will be from August 24-27, 2001

X. Dates of Next Meetings

November 5, 2001
June 3, 2002

XI.  Summary List of Action Items

A. Dr. Jeanne Smith volunteered to represent the Sickle Cell Advisory Committee to the FDA meeting on leukoreduction and report back to the Committee.  Dr. Swerdlow would also convene an ad hoc committee to draft a statement on behalf of the Committee prior to the next meeting.

B. Dr. Swerdlow noted the importance of pain therapy for patients with sickle cell disease and volunteered to attend the FDA meeting of the Anesthetic and Life Support Drugs Advisory Committee and coordinate a response of the Sickle Cell Disease Advisory Committee as necessary.

C. 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.

D. The Committee concurred on the lack of data regarding quality of life issues and health services utilization and encouraged development of a workshop in the area.

E. 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.

F. Dr. Joseph DeSimone noted that the VA is developing new funding opportunities for those that historically treat minority populations.  Details of these efforts will be forwarded to the Committee as they appear.

G. Dr. Bonds was encouraged to proceed with efforts in the following areas:
 1. Sickle Cell Disease and the Lung.
 2. Hydroxyurea and SC Disease.
 3. Membrane active agents and Hb SC and SS.

___________________________                               ________________
Paul Swerdlow, M.D.                                                    Date
Chairman
Sickle Cell Disease Advisory Committee

___________________________                                 ________________
Charles M. Peterson, M.D.                                            Date
Executive Secretary
Sickle Cell Disease Advisory Committee
 
 

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