MINUTES OF THE SEVENTIETH MEETING OF THE SICKLE CELL DISEASE ADVISORY COMMITTEE Bethesda, Maryland July 22, 1996 COMMITTEE MEMBERS PRESENT Dr. Samuel Charache Dr. Jessica Davis Dr. James Eckman Dr. Mary Fabry Dr. Cage Johnson Dr. William Mentzer Ms. June Vavasseur Dr. Charles Whitten COMMITTEE MEMBERS ABSENT Dr. Faye Belgrave Dr. Iris Buchanan EX-OFFICIO MEMBERS PRESENT Dr. Jane Lin-Fu Dr. Martin Steinberg EX-OFFICIO MEMBERS ABSENT Dr. William Hannon Dr. Scott Wegner PROGRAM STAFF AND AFFILIATED ORGANIZATION REPRESENTATIVES: Dr. Clarice D. Reid, DBDR; Duane Bonds,SCRG; Dr. Junius Adams, SCRG; Dr. Carol Letendre, DBDR; Ms. Susan Pucie, DBDR; Dr. Bertram Lubin, Children's Hospital Oakland, Dr. Seigo Ohi, Dr. Oswaldo Castro, Ms. Julia Siteman, Howard University; Mr. Donald Tankersley, Consultant; Ms. Patricia Penn, Maryland, DHMH, Office of Hereditary Diseases; Dr. Doris L. Wethers, St. Lukes-Roosevelt; Dr. Harold Davis, FDA, Office of Epidemiology; Ms. Chanda Chhay, Caset Associates, Ltd., Mr. Mervin A. Talyor, Alpha Therapeutics Corp., Ms. Lisa Douglas, Georgetown University. Executive Secretary - Dr. Clarice D. Reid Secretary - Ms. Petronella A. Barrow I. CALL TO ORDER Dr. Cage Johnson, Chairman, called the 70th meeting of the Sickle Cell Disease Advisory Committee to order at 9:00 am. Il. ANNOUNCEMENTS Dr. Clarice Reid, Executive Secretary, reviewed the mandatory confidentiality and conflict of interest procedures. She expressed thanks to the retiring committee members present, Dr. Samuel Charache and Dr. Charles Whitten for their service to the committee. Ill. CONSIDERATION OF MINUTES The minutes of the last meeting were unaminously approved as submitted. IV. CHAIRMAN'S REPORT Dr. Johnson briefly summarized the major points from the last meeting, highlighting the work presented by Dr. Brugnara on clotrimazole which seems to prevent dehydration of red blood cells. He stressed the importance of another issue before the committee of how different states are dealing with the information on infants identified with sickle cell trait through the newborn screening programs. The committee will receive a full report later on this topic from the ad hoc committee appointed at the last meeting. Dr. Johnson reported that a recent recommendation of a Special Emphasis Panel on the use of hydroxyurea in pediatric patients suggested that the prevention of end organ damage would be an appropriate outcome for examining efficacy. He indicated that additional information and discussion on this issue will be provided during the meeting. V. DIRECTOR'S REPORT Dr. Clarice Reid, DBDR Director, provided an update on budget issues and indicated that the NHLBI reached a payline of 18.7% for funding investigator-initiated grants for fiscal year 1996. This was much better than initially anticipated. The House Appropriations Committee voted a 6.9% increase in the overall NIH budget. This has not been acted on by the Senate and the final budget is expected to be less generous. A number of important activities related to the Division of Research Grants (DRG) have occurred since the last meeting. A report from a committee on peer review has recommended several changes including the use of three basic criteria for assessing scientific merit of research grant applications. These are approach, significance and feasibility of the proposed research. Comments from the scientific community have been solicited and can be made directly to DRG via the World Wide Webb before October 1, 1996. The NIH has recently announced a policy that grants exceeding $500,000 in direct costs will not be accepted by DRG unless there is evidence that the applicant has communicated with the appropriate program official and there is agreement of interest in the application. DRG also has published that research grant applications will not be accepted after two amendments. The NHLBI presented three exciting Institute-wide initiatives to the Council in May. One deals with mitochondrial mutations in heart, lung. Blood and blood vessel diseases. The second addresses gene transfer and the third is aimed at improving gene vector design and development using the small business technology transfer mechanism of support. DBDR presented one initiative entitled, "Homing Receptors of Hematopoietic Stem and Progenitor Cells" which was approved by the Council and has subsequently been released. The issue of genetic testing was raised and Dr. Jessica Davis reported that the Genetic Diseases Act was undergoing discussion from a number of view points. A major concern is how to protect individuals from indiscriminate use of genetic information when applying for health or life insurance. Another major item under discussion is the provision of information from genetic testing and counseling. The Human Genome Project has published an interim "Principles of Genetic Testing" which is available on the World Wide Web. Dr. Davis highlighted the ongoing issue of informed consent for genetic testing and noted its special relevance to newborn screening for sickle cell disease. Vl. PRESENTATIONS Dr. Harold Davis, Food And Drug Administration, presented data on the epidemiological aspects of sickle cell disease in the United States. The source of the information was obtained from databases of the National Center for Health Statistics. The estimated annual cost of sickle disease in the United States was reported at $475 million. Using these databases, it was not possible to estimate the individual per patient cost or cost in relation to other diseases. The databases also indicated that there was a significant improvement in the mortality associated with sickle cell disease between years 1968 to 1992. Although a continual improvement in the mortality of sickle cell disease due to more comprehensive care and newborn screening followed by penicillin prophylaxis was strongly suggested by the Cooperative Study of Sickle Cell Disease, this study is the first to provide good evidence for improved mortality in the earlier time periods. Dr. Davis used Medicaid data reporting the availability of penicillin to assess compliance with the prophylactic penicillin protocol for pneumococcal infections in three states (New York, Michigan and Missouri) with large at-risk populations. Overall compliance tended to be highest during the first two years. Dr. Bertram Lubin, the Director of Children's Hospital Research Institute in Oakland, California presented data on the quality of care and litigation issues in the management of pediatric patients with sickle cell anemia. It is clear that providing comprehensive care for individuals with sickle cell disease will be much more difficult with the new emphasis of managed care.. It is important that appropriate guidelines for the care of individuals with sickle cell disease be developed and that a mechanism be in place to assure that these guidelines are being followed by the Health Maintenance Organizations (HMOs). Dr. Lubin indicated that there is limited communication between HMOs and primary health care providers who are experienced in the management of sickle cell disease. Several cases in Northern California have led to litigation when the care of patients has been compromised in areas ranging from lack of timely intervention for fever resulting in death from bacterial sepsis to a failure to recognize or properly treat central nervous system complications. It is incumbent upon the sickle cell community to become proactive in the area of standards of care. The Northern California Sickle Cell Center has overcome some of the problem by hiring a general pediatrician who is an expert in sickle cell disease. The referral by the HMOs to this generalist has resulted in decreased emergency room visits and increased clinic visits. The problems that are emerging with the advent of managed care are not unique to sickle cell disease. Thus, efforts directed toward improving managed care for sickle cell disease should be part of a larger movement that will improve care for all individuals receiving care through these mechanisms. Dr. Doris Wethers, the Director of the Sickle Cell Program at St. Luke's Roosevelt Hospital in New York, and Dr. James Eckman, Director of the Emory Comprehensive Sickle Cell Center, reported on the ad hoc committee's efforts to address guidelines for the follow up of hemoglobin trait carriers identified through newborn screening programs. It was pointed out that the approach to handling thalassemia is difficult since most state newborn programs are not equipped to identify either the phenotype or genotype of thalassemia heterozygotes (thalassemia trait). Therefore, thalassemia was not included in the report. There were concerns that insufficient emphasis was given to sickle cell disease, particularly since the parents of the infant with disease are obligate carriers and should receive adequate genetic counseling. The two main priority areas identified by the committee are to provide guidelines that will assist states in meeting there obligations to the sickle hemoglobin trait carriers and to assure that there are trained and qualified individuals to provide the necessary counseling information. There were five basic statements presented from the committee: 1) Education about newborn screening and informed consent should be obtained during the prenatal care well in advance of the time of delivery. 2) State newborn programs should have a mechanism in place to assure that all results of newborn screening for sickle cell disease are made available to the parents of all infants that are tested. 3) The parents of all infants who are detected as carriers of hemoglobin variants should be offered appropriate education, counseling, and testing. 4) The training and credentialing of counselors should be available to assist and maintain quality of services. 5) The programs for follow-up of carriers of hemoglobin variants should have a mechanism of ongoing assessment that document the effectiveness, outcome, and cost of providing the services. Dr. Eckman requested comments from members of the committee by August 15, 1996. Vll. AGENCY REPORTS Department of Veterans Affairs (VA) Dr. Martin Steinberg reported that the VA had successfully launched a program of collaborative research between the VA and historically black colleges or universities (HBCUs). The VA is in the process of reorganizing its research program and the major change is to target research toward diseases that are prevalent in the veteran population. Only 20% of the total research budget will be devoted to other research. The sickle cell trait counseling program is still active at the VA; however, the funds for this program are part of each hospital's general budget and are no longer separate. Health Resources and Services Administration (HRSA) Dr. Jane Lin-Fu indicated that funds were not available to support new grants in fiscal year 1996. Some of the existing grants were terminated. The agency is currently in the process of a reorganization and it is not apparent at this exactly how a new structure will be implemented. Centers for Disease Control (CDC) No representative was present. Department of Defense (DoD) No representative was present. Vlll. PROGRAM ACTIVITIES Dr. Junius Adams provided an update on the status of recent program solicitations, noting that two Requests for Applications (RFAs) have been issued. One, entitled " Sickle Cell Disease Therapy," addresses research on basic approaches to therapy for sickle cell disease. Applications received in response to this RFA were reviewed by a Special Emphasis Panel (SEP) on June 20-21, 1996. Dr. Adams discussed the streamlining review process that identified 19 of the 40 applications as non-competitive. The remaining 21 applications received a full committee discussion and scoring. The 21 scored applications range in priority score from 119 to 256 with a mean of 172. The most meritorious applications included improved methods for gene transfer, ribozyme mediated correction of the abnormal gene, computer generated anti-sickling compounds, removal of pathological iron from sickle red blood cells, reactivation of the gamma-globin gene, transgenic animal models of sickle cell disease, and sickle red blood cell hydration. The second RFA. was a renewal of the Comprehensive Sickle Cell Centers program. Applications are due September 18, 1996. In closing, Dr. Adams noted that the agenda for the upcoming workshop on "Approaches to Therapy of Sickle Cell Disease" scheduled for August 19 and 20, 1996 had been completed. Dr. Duane Bonds reported on the results of a Special Emphasis Panel(SEP) meeting on the topic of hydroxyurea for pediatric patients with sickle cell disease. Data from the Multicenter Study of Hydroxyurea (MSH) and from the pediatric hydroxyurea dosing and safety study were reviewed noting that the pediatric dosing study will end in early 1997. There were three major recommendations from the SEP. First, based on the results of the adult trial and the fact that the pathophysiology of sickle cell painful crisis in children is not different from that seen in adults, there is no scientific benefit to be obtained by doing a randomized double blind placebo controlled trial of hydroxyurea with painful episodes as the primary endpoint. Second, if a Phase lll clinical trial is deemed feasible, it should be a randomized double blind placebo controlled trial using markers of chronic end organ damage as the primary endpoint. Finally, the study would be a pilot study with approximately two and a half years of follow-up designed to have 50 percent power to detect a 50 percent reduction in selected markers of chronic end organ damage. If at the end of two and a half years of follow-up there was a statistically significant difference in these markers, the study would end, and hydroxyurea would be recommended for widespread use in children beginning at one year of age. A motion was made and seconded to endorse the concept of this as an initiative. The motion was unanimously approved. Dr. Bonds reported that the Stroke Prevention Trial (STOP) and the Cooperative Study of Sickle Cell Disease (CSSCD) are continuing as described in the minutes of the previous meeting. The MSH follow-up trial is enrolling patients. A survey has been mailed to participants to assess the feasibility of enrolling non-MSH patients in this trial. IX. PROGRAM NEEDS AND OPPORTUNITIES AND FUTURE AGENDA ITEMS Dr. Johnson emphasized that the Workshop on Approaches to the Treatment of Sickle Cell Disease on August 19-20 would be an excellent forum for identifying potential opportunities for future research initiatives. Other areas suggested for initiatives by committee members included transfusion therapy, immune dysfunction and the inflammatory process in sickle cell disease. Xl. FUTURE MEETING DATE The next meeting date was tentatively scheduled for November 8, 1996. Several members indicated a conflict with that date. The meeting was adjourned at 3:00 pm. I hereby certify that to the best of our knowledge, the foregoing minutes are accurate and complete. _________________ _________ Date Cage Johnson, M.D. Chairman Sickle Cell Disease Advisory Committee ____________________ __________ Date Clarice D. Reid, M.D. Executive Secretary Sickle Cell Disease Advisory Committee .