MINUTES OF THE SEVENTY-SECOND MEETING OF THE SICKLE CELL DISEASE ADVISORY COMMITTEE Bethesda, Maryland June 9, 1997 COMMITTEE MEMBERS PRESENT Dr. Kenneth Bridges Dr. Jessica Davis Dr. Joseph DeSimone Dr. James Eckman Dr. Mary Fabry Dr. Cage Johnson Dr. Vipul Mankad Dr. William Mentzer Ms. June Vavasseur COMMITTEE MEMBERS ABSENT Dr. Iris Buchanan EX-OFFICIO MEMBERS PRESENT Dr. Jane Lin-Fu Dr. Martin Steinberg Dr. Scott Wegner EX-OFFICIO MEMBERS ABSENT Dr. William Hannon PROGRAM STAFF AND AFFILIATED ORGANIZATION REPRESENTATIVES: Dr. Clarice D. Reid, DBDR; Duane Bonds,SCRG; Dr. Junius Adams, SCRG; Dr. Carol H. Letendre, DBDR; Ms. Susan Pucie; Dr. Helena Mishoe, Ms. Sonya I. Ross, Maryland, DHMH, Office of Hereditary Diseases ; Ms. Patricia Penn, Maryland, DHMH, Office of Hereditary Diseases, Ms. Lisa Douglas, Georgetown, Ms. C. Siegal, Alpha Therapeutics, Dr. John Boucher, RTL. Executive Secretary - Dr. Clarice D. Reid Secretary - Ms. Petronella A. Barrow I. INTRODUCTORY REMARKS Dr. Cage Johnson, Chairman, called the 72nd meeting of the Sickle Cell Disease Advisory Committee to order at 9:00 am. He welcomed the new member, Dr. Vipul Mankad, Chairman and Professor of Pediatrics, University of Kentucky, Louisville. He thanked the outgoing member, Ms. June Vavasseur for her service to the committee. II. ANNOUNCEMENTS Dr. Clarice Reid, Executive Secretary, read the mandatory conflict of interest statement and reminded members to sign and return forms to Ms. Barrow. III. CONSIDERATION OF MINUTES The minutes of the last meeting were unanimously approved without modification. IV. CHAIRMAN'S REPORT Dr. Johnson briefly summarized highlights of activities since the last meeting. The Special Emphasis Panel on Bone Marrow Transplantation for Sickle Cell Disease held in April considered a number of research and social issues. Of particular interest was the discrepancy between the large number of patients on the clinical center rosters of the national collaborative study supported by the NHLBI and the relative small number of transplants. This led to a discussion regarding eligibility criteria, lack of available matched sibling donors, and how physicians provide education about transplantation as a potential therapeutic option. The financing of bone marrow transplants has not been a major problem, although reimbursement differs in states. DIRECTOR'S REPORT Dr. Clarice Reid, presented information on the latest cycle of grant funding at the recent meeting of the NHLBI Advisory Council. While grants were funded to the 23rd percentile, there were fewer investigator-initiated grants submitted in the Blood Division during the entire year. This translates to fewer grants to identify for select pay, in addition to a smaller number of fundable grants within the established payline. Hopefully, this is a one time occurrence and not a trend for future years. The DBDR presented two program initiatives that were approved by Council. One encourages clinical research for Cooley's anemia in areas of oral chelators, non-invasive techniques for measuring body iron and other therapeutic approaches. The second program presented focused on platelet storage. Dr. Reid reviewed with the committee several updates on pending legislation, Dr. Varmus's testimony on setting priorities, and the new peer review grading system that includes a consideration of innovation. In closing, the committee was reminded of the 50th anniversary of the NHLBI and the upcoming September Conference highlighting NHLBI and the 25th anniversary of the National Sickle Cell Disease Program. VI. Hemostatic Factors and Sickle Cell Diseases - Dr. Jay Degen, Children's Hospital Research Foundation, Cincinnati,OH. Dr. Degen's research is based on an accumulation of indirect evidence that hemostatic factors participate in sickle cell disease pathology. He presented studies that will be carried out in transgenic mouse animal models. The sickle cell animal model is the SAD mouse, which has a human beta-globin transgene containing the mutations for Hb S, Hb Antilles, and Hb D Punjab. These animals develop severe sickling problems under ambient oxygen tension, especially in the spleen and bone marrow. The SAD mouse line will be crossed with each of three transgenic mouse lines which have recently been developed in Dr. Degen's laboratory: 1) no circulating fibrinogen due to disruption of the Aalpha-chain gene; 2) a truncation of the fibrinogen gamma-chain, which ablates platelet aggregation; and 3) no circulating plasminogen due to gene disruption. If fibrinogen-dependent functions (fibrin clot formation and platelet aggregation) contribute to the vasoocclusive process in sickle cell disease, the pathological manifestations of sickle cell disease in SAD mice should be ameliorated in that have both the SAD gene and either of the genes that result in decreased fibrinogen function. In contrast, the SAD mice with the plasminogen mutation will reveal the postulated role of coagulation in sickle cell disease by manifesting worsened vasoocclusive pathology due to deficiency in fibrinolysis. The results of these genetic manipulations of coagulation on sickle cell disease pathology in the SAD mouse should elucidate the role of thrombosis in sickle cell vasoocclusion and will provide a foundation for the application of new anticoagulant, antiplatelet, and thrombolytic therapies to the treatment of sickle cell patients. Thrombotic Markers in Vasoocclusive Crises - Dr. James Eckman Emory University School of Medicine. Dr. Eckman and colleagues have shown that individuals with sickle cell disease exhibit enhanced thrombosis in vivo, and that thrombosis is substantially increased during painful episodes. Furthermore, in a controlled clinical study evaluating n-3 fatty acids in individuals with frequent painful episodes, thrombosis decreased to near basal control levels, and the frequency of painful episodes decreased significantly. However, the changes in laboratory values were somewhat less dramatic. These encouraging preliminary results suggest that more extensive studies with more patients should be carried out to determine whether or not the beneficial effects of n-3 fatty acid administration are due to changes in blood coagulation. Dr. Eckman suggested that these studies should include intervention trials with a preventive component, as well as acute intervention with anti-thrombin therapy during acute painful episodes. VII. COMMITTEE REPORTS Sickle Cell Trait Results Dr. Eckman reviewed with the committee the guidelines developed by the Council of Regional Networks (CORN) to assure follow up of individuals identified with sickle cell trait through newborn screening programs. The SCDAC officially approved this document as the official statement of the committee and discussed ways to disseminated the information. Dr.Jane Lin-Fu suggested sending the guidelines with a cover letter to all the state maternal and child health directors. It should also be included in the genetics Clearinghouse and placed on the MCH electronic superhighway. Dr. Davis emphasized the continued need for education of primary care providers with respect to hemoglobinopathies.The pilot project funded by HRSA to her center has confirmed the knowledge deficit and the ability to improve this through a well directed educational program. Update on Genetic Screening Dr. Jessica Davis reported on the Task Force, a subcommittee of ELSI, working on guidelines for genetic testing and screening. The first part of the report was a follow up to issues raised by the IOM on genetics in the early nineties regarding the pitfalls and problems of genetic testing. The final report will be forwarded to the Secretary level through Dr. William Raub whose office is coordinating the input from PHS agencies. . It includes a section on education, laboratory provisions and consumer and provider issues related to informed consent. One of the disturbing points was the lack of any federal laboratory regulations regarding genetic testing. Other issues that remain unresolved involve discrimination, not just in health and life insurance, but also in employment and educational opportunities. It is a challenge to the genetics community to work with Congress and others to assure that these problems are properly addressed. It was suggested that an entirely different group should examine the issue of public health and genetics. Pediatric Hydroxyurea Follow up (PED-HUG) Dr. Duane Bonds briefly reported on preliminary data from the PED-HUG study. It is designed to determine the maximum tolerated dose of hydroxyurea and overall safety in young children with sickle cell disease and overall safety. The children entered range in ages 5-15 years. The children had similar responses to hydroxyurea as the adults with increases in total hemoglobin, MC and MCHC. Fetal hemoglobin data are not available. There have been no significant changes in growth and development. The committee discussed the future follow up of these children and it was the consensus that pediatric patients in the study should be closely followed and evaluated. In addition, a registry with all the pediatric patients on hydroxyurea is needed to capture untoward effects of this drug. The possible mechanism would be to attach a pediatric component to the ongoing MSH adult follow up study. VIII. AGENCY REPORTS Department of Veterans Affairs Dr. Martin Steinberg reported that the VA screening and education program continues to function at a low level. In the area of research, there are few grants in red cell or sickle cell disease, however, the VA is still interested in supporting good basic and clinical research in the area of red cells and mechanisms of disease. Health Resources and Services Administration Dr. Jane Lin-Fu reported on the Genetic Services Program. The current budget is $9.2 million and the focus of grant solicitations is to integrate community health services, strengthen genetics in primary care and overcoming ethnocultural barriers. The overall goal is to improve genetic services nationwide. The largest number of applications were in the areas of sickle cell disease (12) grants and primary care (11) grants. There were very few in managed care. Dr. Lin-Fu discussed the managed care conference, convened by CORN, in April. A protocol was presented by Dr. Peter Lane that had been used successfully to negotiate with managed care organizations in Colorado for sickle cell children. It appears that other states are developing similar relationship with managed care organizations. Centers for Disease Control There was not a representative from the CDC. Department of Defense (DoD) Dr. Wegner indicated that the entire Department of Defense will be transitioned to managed care by the end of 1997. All beneficiaries will be in a managed care network, some operated by the military and others outside of the military. This will likely affect the pediatric population. IX. UPDATE ON PROGRAM ACTIVITIES Dr. Adams highlighted opportunities for research under the use of the Small Business mechanism with particular emphasis on collaborations with the academic community. He reported on new exciting areas of potential research with the zebrafish pointing out the advantages of this model from the standpoint of developmental biology and genetics. The program initiative on vascular biology in sickle cell disease has been updated to eliminate overlap with coagulation and input was requested from committee members. The initiative on lung disease will be reviewed by several committee members and discussed at the next meeting. Dr. Bonds gave a brief update of ongoing clinical trials. The CSSCD is in the last phase of the study and there are no plans for continuation. The major unanswered question is the lack of specific indices of clinical severity. The committee discussed the importance of even some "soft" outcome variables that would be helpful. Dr. Bonds introduced the concept of a pediatric clinical trial with hydroxyurea with surrogate markers of chronic end organ disease as the endpoints. There was considerable discussion by the committee of other potential therapies that could be used in younger asymptomatic children. One possible selection process for children could be based on genetic markers as haplotypes, alpha thalassemia genotype and F cell locus. Dr. Mankad shared with the committee his experience on the FDA committee that supports small clinical research studies through the orphan drug program. He pointed out the opportunity for research on sickle cell disease and suggested the possibility of inviting an FDA official to a meeting of this committee to provide an overview of this process. The meeting was adjourned at 3:15 pm . FUTURE MEETING DATES November 14, 1997 June 8, 1998 I hereby certify that to the best of our knowledge, the foregoing minutes are accurate and complete. ___________________________ _____________ Cage S. Johnson, M.D. Date Chairman Sickle Cell Disease Advisory Committee ___________________________ ______________ Clarice D. Reid, M.D. Date Executive Secretary Sickle Cell Disease Advisory Committee .