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
.