Toward a New Research Paradigm: Building a New Sickle Cell Disease Research Agenda

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.

1. 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.
     
     
2. 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.
     
     
3. 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.
     
     
4. 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.
     
     
5. 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:

1. 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.
   
   
2. 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.
   
   
3. 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.
   
   
4. 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.
   
   
5. 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:

1. 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.
2. 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.