Toward a New Research Paradigm: Building A New Sickle Cell Disease Research
Agenda
Summary of Recommendations from the American Society of Hematology Workshop on Sickle
Cell Disease
Background
The molecular and cellular basis for sickle cell disease (SCD) has been understood for over half
a century, and advances in testing and supportive care have substantially improved life
expectancy for SCD patients. With the reduction in early mortality has come a substantially
increased burden of disease for those now surviving long enough to develop late disease
complications. New therapies have developed that modulate the clinical severity of SCD and
may affect the evolution of organ damage. However, the application of these therapies –
including hydroxyurea, acute and chronic transfusion, and hematopoietic stem cell transplantation
– has been hampered by the heterogeneity of the disorder. There is a very limited understanding
of the genetic modifiers and environmental factors governing the severity of disease
manifestations and the development of late end-organ complications. While most patients will
develop some complications, many of the most devastating disease-related manifestations – such
as infection, stroke, and pulmonary hypertension – affect only a subset of patients. Consequently,
individualized effective therapy awaits new and better prediction techniques and treatment
methods that can forecast the severity of illness, the response to therapy, and the likelihood of
developing serious complications.
The American Society of Hematology conducted a sickle cell workshop in May, 2007, aimed at
exploring new SCD research objectives and creating a real-world model to achieve those
objectives. The workshop participants used the National Institutes of Health (NIH) Roadmap initiative as the framework for
their discussion. The NIH Roadmap encourages a multi-disciplinary approach to scientific
research on common and persistent diseases and health conditions in the United States. This
document presents a synopsis of the new research priorities identified as well as a blueprint for a
new sickle cell research strategy.
New Research Priorities
Five research areas were identified and prioritized by workshop participants. In rank order, they
are: (1) Development of improved and new treatments, 2) Identifying predictors of SCD
outcomes, 3) Improved pain management and quality-of-life issues, 4) Elucidation of the
pathophysiology of organ complications (kidneys, brain, heart, and lungs), and 5) Initiation of
international strategies for worldwide disease initiatives.
- Improved and New Treatment Approaches:
- More and better drugs are needed that increase fetal hemoglobin with the aim of
identifying agents that can achieve fetal hemoglobin levels of 30 percent or more in every
red blood cell in every patient. We propose a “Manhattan project” strategy that would
engage the talents and resources of synthetic chemists, cell biologists, clinical
trialists, and health services researchers to implement this strategy.
- Increased study of stem cell transplantation in patients of all ages, using unrelated
donors and novel preparative regimens.
- Further study of hydroxyurea efficacy and transfusion therapies to allow
individualized application of standard therapies.
- Further research on gene therapy.
- Development of therapies and drugs targeting other pathophysiologic processes,
including adhesion, inflammation, coagulation, and platelet activation.
- Predictors of SCD and Risk of Later Disease Complications
- Development and validation of novel biomarkers that correlate with overall disease
severity or organ specific injury.
- Expansion of genetic and genomic research, including SNPs, haplotypes, and whole
genome analyses to identify genetic modifiers of disease severity.
- Better methods of collection and analysis of standard laboratory tests in sickle cell
disease patients.
- Improved techniques for imaging and other functional tests, such as transcranial
Doppler and echocardiography.
- Pain Management/Quality of Life
- Establishment and support of collaboration with pain specialists and investigators in
other disciplines.
- Continued collection of comprehensive patient data using a well-funded long term
database/registry to perform phenotypic studies and assist with risk prediction.
- Development of sickle cell disease-specific quality-of-life instruments.
- Implementation of clinical trials using new analgesics.
- Organ Disease and Complications
Renal
- Interventions to prevent end stage renal disease.
- Improved means of defining hypertension in the SCD population.
- Development of methods for measuring and detecting clinically meaningful changes
in renal function during longitudinal follow-up of SCD patients.
Brain
- Better definition of pediatric and adult patients at risk for stroke and neurocognitive
abnormalities.
- Development and testing of improved prophylactic strategies against stroke.
- Improved understanding of the pathophysiology of neurocognitive dysfunction and
stroke in adult SCD patients.
- Study of the molecular basis of stroke in SCD.
- Long term studies of the effects of chronic transfusions.
Lung
- Longitudinal studies aimed at understanding the pathophysiology, natural history, and
predictors of early pulmonary hypertension (treatment and prevention).
- Improved diagnosis and prediction of the natural history of chronic sickle cell lung
disease.
- Improved understanding of the role of asthma as a predictor of acute chest syndrome
and chronic lung disease in SCD patients.
Heart
- Longitudinal studies to understand the development and natural history of cardiac
complications, such as diastolic dysfunction and left ventricular hypertrophy.
- Studies focused on the causes of sudden death in SCD patients.
- Enhanced knowledge about the role of iron and reactive oxygen species in
myocardial damage in SCD patients.
- International Research Perspectives
- Better studies of the natural history of the disease in Africa and use of hydroxyurea
and other treatment approaches in developing countries.
- Study of local treatment remedies employed in Africa.
- Increased interaction with Western European investigators treating SCD.
Barriers To a New Research Agenda
During the workshop, the participants acknowledged the psychosocial, economic, and clinical
care delivery barriers that affect persons with sickle cell disease, especially adults. Furthermore,
current NIH funding and organizational structure does not support multi-disciplinary approaches
to complex diseases such as SCD. The lack of cohesive efforts among the many SCD
stakeholders also hampers new research initiatives. Specifically, workshop participants made the
following recommendations to overcome key barriers to changing the SCD research paradigm:
- The National Heart, Lung, and Blood Institute (NHLBI), which has borne the responsibility for providing primary oversight of NIH supported
research involving SCD, should examine, evaluate, and consider
modifying its existing national infrastructure for clinical investigation. Current NHLBI
structure -- which consists of ten comprehensive sickle cell centers, a clinical research
network involving eight centers, and other research initiatives and collaborations focusing on
particular age groups or organ-related complications – may not be the best means of
achieving the research agenda’s goals.
- Partnerships between NHLBI with other institutes at NIH, such as the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institue of Neurological Disorders and Stroke, etc., and
other governmental agencies within the Department of Health and Human Services
(DHHS), especially the Health Resources and Services Administration (HRSA), the Centers for Disease Control and Prevention (CDC), the Centers for Medicaid and Medicare Services, and the Agency for Healthcare Research and Quality, must be forged to develop a collaborative
framework to ensure that clinical research is conducted in a milieu where federally funded
comprehensive care programs include a much larger proportion of children and adults with
sickle cell disease than is currently served by existing centers, networks, and other
governmental support programs.
- Meaningful participation will be required from non-governmental institutions, organizations,
foundations, and individuals whose mission involves improved access to and provision of
care for persons with SCD.
- Persons with SCD and their families, who are ultimately the beneficiaries of the
new sickle cell research group executing the proposed agenda, are important stakeholders in
the SCD research enterprise. It is critical that the research agenda be enthusiastically
supported by patients, through attendance at designated sickle cell treatment and research
centers, participation in clinical trials, and involvement in fundraising and advocacy efforts
undertaken by others on their behalf.
- The establishment of a new infrastructure for translational and clinical research in sickle cell
disease must be created in parallel with continued and expanded support of basic research
and other individual investigator initiated studies through RO1s and other mechanisms.
Recommendations
Blueprint for a New Sickle Cell Disease Collaborative Research Group
In an effort to avoid fragmentation and disengagement, workshop participants recommended that
the NIH assemble a single national DHHS-funded multi-center collaborative research group. Its
aims should be to establish a new clinical research infrastructure to conduct the clinical trials
necessary to answer key research questions while fostering improved care of patients with SCD. Affected children and adults residing in areas of the United States not served by
current governmental funded programs or who do not have access to care for financial or other
reasons must be included. They described two models for the NHLBI and other agencies to
consider:
- Cooperative Clinical Trials Groups supported by the National Cancer Institute (NCI): One of the best models for access
to and coordination of care in the setting of cutting-edge research is enrollment of patients
with uncommon, serious, and/or complex disorders in clinical trials. For 40 years this has
been the accepted norm in pediatric cancer research, with a prominent example being the
NCI-supported Children’s Oncology Group (COG). Over 200 institutions broadly dispersed
throughout the United States are COG members, and physician investigators within the
network work together to design and conduct clinical and translational research to improve
the lives of children with cancer. Over 90 percent of children with cancer in the United States are
followed at COG institutions and participate in COG research studies. It is estimated that
over 75,000 children and adolescents with cancer are currently followed in these centers,
with widely recognized successful results. However, cancer care for children and many
adults is readily accessible and reimbursed by payers. By contrast, sickle cell providers and
investigators are few in number, and reimbursement for sickle cell services is modest at best.
Thus, this model is not perfect for SCD but deserves consideration so that its
best components could be adapted to a SCD clinical research group.
- Comprehensive Hemophilia Centers supported by the Maternal and Child Health Bureau (MCHB) / HRSA and CDC: In the late
1970’s hemophilia diagnosis and treatment centers were established, and more than 130 are
presently distributed throughout the United States. The centers, which serve pediatric and
adult patients, were not specifically designed to conduct “research”. Their primary emphasis
is instead on patient care services and prevention of complications. However, MCHB and
CDC funding supports the personnel (primarily nurses, social workers, and administrative
staff) who assure optimal patient care and also facilitate investigator initiated and
collaborative multi-center research trials funded by other sources. Approximately 70 percent of the
estimated 20,000 patients in the United States with hemophilia and other clinicallysignificant
hereditary bleeding disorders are followed in these federally-funded centers and
are thus readily available for participation in hypothesis-driven research. For example, over
80 percent of hemophilia patients are participating in the CDC-sponsored ongoing Universal Data
Collection Surveillance Study. The substantial involvement of industry in hemophilia care
and research is obviously a confounder, which makes this model imperfect with regard to
SCD, but elements of this strategy should be considered.
A New Funding Model
ASH believes that some combination of these two funding models best fits the needs of the
SCD research community. Therefore, strong consideration should be given to
developing a Sickle Cell Disease Clinical Research Group structure similar to that employed by
the Children’s Oncology Group. Participating institutions (perhaps between 30 and 70 in number),
primarily based in academic medical centers serving sizeable populations of patients with sickle
cell disease, should be chosen by means of competitive peer review to serve as Group member
institutions. Each participating institution would designate a principal investigator and
individual members who are sickle cell investigators in adult hematology, pediatric hematology,
and other disciplines. Every center would be responsible for demonstrating that its patient
population, prior track record in SCD research, and organizational structure
warrants Group participation. Funding from NIH should provide salary support for investigators
and key research staff, as well as the specific costs of conducting individual studies. According
to the hemophilia program organizational model, CDC, MCHB, and other governmental and
non-governmental organizations should provide support for the companion infrastructure
necessary to assure access to and provision of excellent care to patients participating in research
projects.
Operation of the research Group would be directed by an executive committee and chair, elected
by the PI’s of the Group’s member institutions. A single group-wide statistical and data
management center, chosen through peer review, would have representation on the executive
committee. Scientific, discipline, and protocol specific committees would be assembled in order
to implement the scientific agenda. Oversight would be provided collaboratively by NIH,
HRSA, and CDC, along with a new Sickle Cell Disease Advisory Committee with representation
for all relevant stakeholders.
Summary
There remains a critical need for research strategies to improve SCD treatment. New research
should focus on multi-disciplinary approaches to characterize the genetic and environmental
factors that contribute to the heterogeneity of disease phenotype and response to therapy.
Continued improvement in drug therapies and pain management techniques remains a high
priority. Additional research must also focus on preventing and reducing organ complications for
those with SCD. Finally, the U.S. research community should take the lead in improving the
diagnosis and treatment of sickle cell disease worldwide while benefiting from the power that
larger geographically broad research studies can offer.
To achieve these ends, emphasis should be placed on aligning the efforts of SCD stakeholders,
including government entities, physicians, scientists, foundations, community advocates and
SCD patients and their families. Consequently, ASH recommends the creation of a new Sickle
Cell Research Group. This Group would be comprised of clinicians and scientists at academic
medical centers that serve a large number of SCD patients. Working together, the Group’s
members would work to pursue the common goal of providing excellent individualized care for
patients with SCD.
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