MINUTES OF THE NINETY-FIFTH SICKLE CELL DISEASE ADVISORY COMMITTEE

March 26, 2010

COMMITTEE MEMBERS PRESENT

Edward Benz, Jr., M.D. (Chair), Dana-Farber/Harvard Cancer Center Michael A. Bender, M.D., Ph.D., Fred Hutchinson Cancer Research Center Thomas Coates, M.D., University of Southern California, Keck School of Medicine Elaine K. Gallin, Ph.D., Doris Duke Charitable Foundation Nigel Key, M.D., University of North Carolina at Chapel Hill Roberto F. Machado, M.D., University of Illinois Chicago Punam Malik, M.D., Cincinnati Children’s Hospital Medical Center Leslie Parise, M.D., University of North Carolina at Chapel Hill Susan Perrine, M.D., Boston University School of Medicine Yogen Saunthararajah, M.D., Cleveland Clinic/Case Western Reserve University Wally Smith, M.D., Virginia Commonwealth University Alexis A. Thompson, M.D., M.P.H., Children’s Memorial Hospital

NIH STAFF PRESENT

National Heart, Lung, and Blood Institute (NHLBI): Susan B. Shurin, M.D., Acting Director, NHLBI W. Keith Hoots, M.D., Director, DBDR Petronella Barrow, Administrative Assistant, DBDR Jonathan Goldsmith, M.D., Program Director, Blood Diseases Branch, DBDR Liana Harvath, Ph.D., Special Advisor to the Director, DBDR Kathryn Hassell, M.D., Program Director (IPA), Blood Branch, DBDR Joylene John-Sowah, M.D., DARD Edward Donnell Ivy, M.D., DARD Annie Joseph, Committee Management Pankaj Qasba, Ph.D., Program Director, Blood Diseases Program, DBDR

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Terry Bishop, Ph.D.

STAFF FROM OTHER FEDERAL AGENCIES

R. Lorraine Brown, HRSA

COMMUNITY

Sonya J. Ross, Consumer

INTRODUCTION

The Sickle Cell Disease Advisory Committee (SCDAC) convened on March 26, 2010 in Bethesda, Maryland. Edward Benz, Jr., M.D. of the Dana-Farber/Harvard Cancer Center, served as Chair. SCDAC members were reminded of NHLBI’s conflict of interest policy. No conflicts were declared.

Following remarks from Dr. Benz and Susan Shurin, M.D., Acting Director of NHLBI, the SCDAC reviewed and discussed the Division of Blood Diseases and Resources (DBDR) programs. The committee ended the day by summarizing its discussion and offering recommendations regarding research emphasis, gaps, challenges, and opportunities.

OVERVIEW/COMMENTS FROM ACTING DIRECTOR SUSAN SHURIN

Dr. Shurin welcomed SCDAC members and thanked them for their participation. She summarized the history, challenges, and opportunities in SCD research and provided a charge to the committee.

NHLBI has supported sickle cell disease (SCD) research for almost 40 years. In 2008, NHLBI, in collaboration with its Advisory Council, reassessed its SCD research and training programs and their accomplishments. This reassessment included input from investigators, patients, and other stakeholders. The review and recommendations were summarized by Dr. Shurin and former NHLBI Director Elizabeth Nabel, M.D. (Blood. 2008;111:4852-3). Dr. Shurin charged the SCDAC to help DBDR set priorities to achieve the goals outlined in the Blood editorial. She cautioned the Committee not to focus on mechanisms of support. NHLBI sets goals and determines the mechanisms needed to achieve them, and strives to encourage investigator-initiated research, which has generated the most clinically significant advances in SCD. The opportunities must be clearly defined to attract younger investigators and investigators from disciplines outside hematology.

Although the NHLBI does not support all NIH-funded SCD research, it supports the majority of basic, translational and clinical NIH-funded SCD research. NHLBI conducts stroke studies with the National Institute of Neurological Diseases and Stroke; works closely with the National Center of Minority Health and Health Disparities; and collaborates with the Health Resources and Services Administration (HRSA), the Centers for Medicare and Medicaid Services (CMS), the Centers for Disease Control and Prevention (CDC), the Food and Drug Administration (FDA), and the Agency for Healthcare Research and Quality (AHRQ). NHLBI is also exploring the use of Clinical and Translational Science Award (CTSA) mechanisms. Along with United Healthcare, NHLBI is developing a global health program focused on non-communicable diseases. In partnership with the National Human Genome Research Institute, and funded in part by the Common Fund, NHLBI is conducting genomics education in Africa. NHLBI also is working with CDC on a hemoglobinopathy surveillance program and is holding discussions with CMS about what constitutes good care for patients with SCD.

Dr. Shurin highlighted several issues:

• Pain is the major problem for patients with SCD.
• Most primary care physicians and patients with SCD have limited knowledge about SCD.
• More translational research capacity is needed in the United States and globally.
• Although NHLBI can disseminate messages about SCD and care for patients with SCD, assimilation of these messages is limited.

Dr. Shurin concluded her remarks by announcing that a symposium will be held in November 2010 to honor the one-hundredth anniversary of Herrick’s description of SCD. The symposium is supported by a partnership of eight NIH Institutes and Centers.

COLLINS’ FIVE AREAS OF OPPORTUNITY AND THE NHLBI STRATEGIC PLAN

In January 2010, the NIH Director, Francis Collins, M.D., outlined five areas of opportunity (Science. 2010;327:36-37):

• High-throughput technologies
• Translational medicine
• Benefiting healthcare reform
• Focusing more on global health
• Reinvigorating and empowering the biomedical research community

In considering these areas, Dr. Benz remarked that even though fundamental discoveries in SCD are still needed, the NHLBImust balance its portfolio with projects that present translational opportunities. With new advances in molecular technologies and increased appreciation of disease phenotypes, SCD has proven to be complex, and there are now several research areas that must be prioritized. It is important to attract researchers from other disciplines to work in SCD. Dr. Shurin briefly discussed the NHLBI Strategic Plan which focuses on common themes and establishes goals for basic, translational, and clinical science. Although the plan is broad, NHLBI envisions epidemiological and population-based studies will inform basic and clinical science. Each NHLBI program area has its own strategic plan and set of goals that will be aligned with Dr. Collins’ five areas of opportunities.

PROGRAM SUMMARIES AND REVIEW

Jonathan Goldsmith, M.D. presented a summary and overview of each program, and the primary SCDAC reviewers commented on their assigned topics. Programs not reviewed by the committee were:

• Neuropsychological Dysfunction and Neuroimaging Abnormalities in Neurologically Intact Adults with SCD, a phase II pilot study supported by a cooperative agreement
• The Thalassemia Clinical Research Network (TCRN), initiated in 1999 and completed in 2010
• Career development awards through the K01, K08, K12, K23, K25, and K99/R00 mechanisms

Dr. Goldsmith also announced several upcoming workshops and meetings:

• Framing the Research Agenda for Sickle Cell Trait, June 3–4, 2010, Natcher Auditorium
• Annual Sickle Cell Clinical Meeting, August 25–27, 2010, Natcher Auditorium
• NIH Symposium Recognizing the 100th Anniversary of Herrick’s Report of SCD, November 16-17, 2010, Natcher Auditorium

Clinical Trials
Baby HUG

The Pediatric Hydroxyurea Phase III Clinical Trial (Baby HUG), a double-blind, placebo-controlled trial, determined whether daily oral hydroxyurea (HU) is safe, protects spleen and kidney function, and improves clinical and laboratory findings. Although the primary end points were not reached, favorable effects were found for spleen and kidney function. HU reduced complications such as pain, acute chest syndrome (ACS), need for transfusions, and hospitalizations. The trial is currently in an initial 2-year follow-up phase. NHLBI will present to the Board of External Experts a proposed observational follow up study through the first decade of the subjects’ lives. Members of SCDAC suggested adding parameters that were not included in the initial Baby HUG design, such as mutagenicity and long-term effects on growth and fertility. The SCDAC recommended collecting and banking serum, DNA, and RNArom trial participants.

The SCDAC members agreed that Baby HUG is an important study that presents a research opportunity that will also educate providers and patients about HU use. SCDAC members recommended that the observational follow up be extended as long as possible.

IMPROVE

The Improving Pain Management and Outcomes with Various Strategies of Patient Controlled Analgesia (IMPROVE) trial is one of two studies conducted by the SCD Clinical Research Network (SCD CRN). The trial compares the effects of high-demand/low-infusion dosing versus low-demand/high-infusion dosing on daily average pain intensity in patients aged 10 years or older who are hospitalized for severe pain. The study opened in January 2010. Funding for SCD CRN will end in April 2011.

The SCDAC reviewers noted the design of the trial which involves comparative effectiveness research (CER) of two strategies that are commonly used for pain management. They also noted potential gains from the study: identification of the typical opioid dose required for customary inpatient management at a given age and the use of IMPROVE as a template for other trials of SCD and pain. However, the reviewers expressed concerns about the lag in enrollment. SCDAC members suggested performing pharmacogenetic, pharmacokinetic, and pharmacodynamic analyses and comparing results in patients who respond versus those who do not respond. Ancillary mechanisms were suggested as a mechanism to support such analyses.

The SCDAC agreed that this study may change practice. They noted that the study could assess specific tools to measure pain and when those tools should be used by the provider or patient. They further suggested summarizing findings in guidelines.

Stem Cell Transplantation for SCD

NHLBI supports several protocols investigating stem cell transplantation in patients with SCD:

• Evaluating the Safety and Effectiveness of Stem Cell Transplants from Unrelated Donors in Children with SCD (SCURT), an extramural study that evaluates the safety and effectiveness of bone marrow or umbilical cord stem cell transplants from unrelated donors in children who have severe SCD and receive a reduced-intensity conditioning regimen before transplantation. The study seeks to enroll 45 participants; 15 have enrolled as of March 2010.
• Nonmyeloablative Haploidentical Peripheral Blood Mobilized Hematopoietic Precursor Cell Transplantation for Severe Congenital Anemias, including SCD and??-Thalassemia, which plans to enroll 192 patients aged older than 18 years.
• Nonmyeloablative Allogeneic Peripheral Blood Mobilized Hematopoietic Precursor Cell Transplantation for Severe Congenital Anemias, including SCD, Thalassemia, and Diamond Blackfan Anemia, a trial co-supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). This study seeks to enroll 25 patients younger than 16 years of age.
• Collection and Storage of Umbilical Cord Stem Cells for Treatment of SCD, also co-supported by NIDDK. This is an observational study to determine the optimal collection and storage of cord blood from babies with SCD, sickle cell trait (SCT), or no trait or disease.
• Screening of Subjects to Determine Eligibility to Safely Participate in Blood Disorders Studies, co-supported by NIDDK. This is an observational study that collects history and physical data, blood, urine, and buccal swabs from individuals greater than 8 years and bone marrow aspirates from individuals greater than 18 years.

SCDAC reviewers noted that evaluation of results from the SCURT trial would depend on the need for long-term, possibly lifelong, immunosuppressive therapy. More unrelated donor transplantation studies are needed in young adults. SCDAC members suggested that the issue of graft rejection should be a high priority because graft rejection is frequent among patients with SCD and the causative factors are not well understood.

SCDAC reviewers stressed the importance of long-term follow-up to determine if stem cell transplantation eliminates the SCD phenotype. They suggested following organ function, fertility, growth, effects of chimerism, and financial costs. The SCDAC expressed concern about the lag in enrollment.

The SCDAC agreed that transplantation trials are important and suggested a balance between exploring general transplantation issues such as immunosuppressive therapy and hapoloidentical transplantation, and SCD-specific issues such as nutrition and the high level of graft rejection.

PROACTIVE Feasibility

The second study conducted by the SCD CRN, the Preventing Acute Chest Syndrome by Transfusion Feasibility Study (PROACTIVE) is a multicenter study to determine whether secretory phospholipase A2 (sPLA2) levels can be used to predict and prevent acute chest syndrome (ACS) in patients with SCD. Enrollment has proven challenging; only eight participants have been randomized. The lag in enrollment may result from technical problems with the sPLA2 test at multiple clinical sites.

SCDAC reviewers noted that the designers of the sPLA2 test should be consulted. Other SCDAC members also noted the challenges of identifying patients on the brink of complications: the time to give consent and undergo the necessary tests for enrollment is limited.

The Committee agreed that PROACTIVE is a valuable feasibility study with the potential to change practice. SCDAC members noted that this is the only ACS study in the NHLBI sickle cell portfolio.

SWiTCH

The Stroke with Transfusion Changing to Hydroxyurea (SWiTCH) study is supported by a cooperative agreement and conducted under an investigational new drug (IND) application. It is a Phase III non-inferiority study comparing standard treatment (transfusions and chelation) with an alternative treatment (hydroxyurea and phlebotomy) for the prevention of secondary stroke and the management of iron overload in children with sickle cell anemia (SCA). All subjects have been enrolled and 35% have completed the study. The remaining participants are continuing in active follow up.

<>SCDAC members noted the importance of this study and commended its progress. They also emphasized the need to evaluate the etiologies of stroke and the impact of iron overload in patients with SCD. Committee members also noted that the composite primary end point may make interpretation of the results more challenging.

TWiTCH

TWiTCH is a multicenter Phase III non-inferiority study comparing 24 months of hydroxyurea versus 24 months of transfusions for prevention of primary stroke in children with SCA and abnormal TCD velocities. Sites have been identified, regulatory documents filed, and an investigator meeting has taken place, but the study has not yet begun.

SCDAC reviewers felt that the study was feasible and offered great potential for translation into practice. The Committee commented that hydroxyurea and transfusions are the only viable treatments for patients with SCD. Committee members cautioned that the long-term effects of hydroxyurea are not completely understood. SCDAC members agreed that more effort is needed to address a preventive approach, rather than waiting for stroke to occur. It was suggested that other agents, including anticoagulants, be explored.

Walk-PHaSST

The Treatment of Pulmonary Hypertension (PH) and SCD with Sildenafil Therapy (walk-PHaSST) study was a placebo-controlled, double-blind, multicenter study examining whether sildenafil could improve exercise capacity in patients with SCD and PH. This study was stopped in July 2009 following a safety review by the Data and Safety Monitoring Board. The number of serious adverse events (SAEs) was excessive among patients taking sildenafil, and exercise capacity did not improve. These results were contrary to those observed in pilot studies. Reviewers noted that walk-PHaSST highlighted the difficulty of conducting large-scale studies with cardiopulmonary-related end points in adults with SCD. The trial also illustrated the need to consider the feasibility of a study, potential recruitment challenges, and the infrastructure needed to provide eligible patients. Despite its early termination, the study has provided a cohort of ~700 patients that have a well characterized cardiovascular phenotype. Serum, plasma, and DNA have been collected, and linked clinical data have been obtained to facilitate long term follow up of these patients.

The majority of SAEs reported in the sildenafil group were hospitalizations for pain. The relation to baseline pain rate was not part of the trial. Nitric oxide signaling was suggested as a potential factor in the pain events. The study’s SAEs are important because they might offer clues about the pathophysiology of pain in SCD. SCDAC members emphasized the importance of refining study designs, studying specific populations, and characterizing the stabilization of SCD in patients prior to their enrolling in a study.

Surveillance/Epidemiology/Health Services Research

ASCQ-Me

The Adult Sickle Cell Quality of Life Measurement Information System (ASCQ-Me) is a corollary to the NIH Patient-Reported Outcomes Measurement Information System (PROMIS). ASCQ-Me can be used to describe the broader effects of SCD on adult functioning and well-being by facilitating enhanced characterization of clinical trial results and by informing therapy design and health care policy. This system also can aid in comparative effectiveness research by facilitating the evaluation of health care outcomes.

SCDAC lauded the establishment of this system. Reviewers noted that the quality of life for SCD patients is roughly that of patients on dialysis and that, although SCD patients often provide anecdotes regarding treatment quality, societal stigmatization, social interactions, and daily motivations, have not been addressed by investigators. ASCQ-Me will provide validated, patient-oriented outcome measures for future trials; because of its strong links to PROMIS, the measures will be available to investigators outside SCD. Reviewers emphasized that ASCQ-Me and PROMIS would be valuable tools in identifying better end points for SCD studies.

SCDAC members noted that by collecting information on outcomes most important to patients, ASCQ-Me can provide feedback on whether SCD studies are addressing the most important issues. SCDAC emphasized the importance of incorporation of ASCQ-Me into any NHLBI-supported clinical trials. Members also stressed the need to combine these measures with biological measures and suggested that both be used to assess study participants at baseline. SCDAC reviewers commended the American Institutes for Research for its standardized use of qualitative methods in conducting the initial ASCQ-Me studies.

Healthy People 2020

Healthy People (HP) objectives are objective public health measures that drive policy. Of the many objectives in HP2010, only one focused on non-malignant blood diseases. Through the concerted efforts of DBDR and others in public health, however, 12 HP 2020 objectives will focus on hemoglobinopathies:

• Increase the proportion of persons who donate blood.
• Reduce the proportion of persons who develop AEs resulting from the use of blood and blood products, including alloimmunization among persons with hemoglobinopathies.
• Increase the proportion of persons with hemoglobinopathies who receive care in a patient/family-centered medical home.
• Increase the proportion of persons with hemoglobinopathies who receive disease-modifying therapies.
• Increase the proportion of hemoglobinopathy carriers who know their own carrier status.
• Increase the proportion of persons with hemoglobinopathies who receive early and continuous screening for complications.
• Increase the number of community-based organizations that provide outreach and awareness campaigns for hemoglobinopathies.
• Increase the proportion of persons with hemoglobinopathies and their families who are referred for evaluation and treatment.
• Increase the proportion of persons with hemoglobinopathies who receive recommended vaccinations.
• Increase the proportion of children with SCD who receive penicillin prophylaxis from 4 months to 5 years of age.
• Increase the proportion of persons with a diagnosis of hemoglobinopathies who complete high school education or a general education development certificate by 25 years of age.
• Reduce hospitalizations due to preventable complications of SCD among children aged 9 years and younger.

The SCDAC noted that these objectives all focus on improving the management of patients with hemoglobinopathies, that some objectives can be addressed by research projects in the NHLBI portfolio, and that funding from other appropriate agencies can be used to assess how this research is translated into practice. Operations and health services research, registry and surveillance, and guidelines for appropriate treatment will be helpful in measuring the achievement of HP2020 objectives.

The SCDAC lauded the HP2020 objectives for establishing hemoglobinopathies as a public health priority, and they emphasized the need for NHLBI and the SCD research community to collaborate with other agencies and make a real-world impact. One member suggested holding a trans-agency scientific meeting to foster collaboration among NIH, CDC, HRSA, CMS, and AHRQ. Other members suggested the inclusion of population scientists, private funders, and nonprofits such as the Sickle Cell Disease Association of America. NHLBI should also explore ways to enhance recruitment and training of investigators focused on hemoglobinopathies. Although HP2020 objectives focus on the US, SCDAC reviewers also suggested that NHLBI explore global health, particularly in sub-Saharan Africa.

RuSH

Supported by a cooperative Inter-Agency Agreement, the Hemoglobinopathies Surveillance and Registry (RuSH) program focuses on surveillance in six States for the first 2 to 3 years, then will issue additional requests for proposals (RFPs) to develop a registry for longitudinal tracking. Surveillance, which will be conducted by CDC with NHLBI support, seeks to find both individuals screened as newborns and those who have not been screened. Collected information includes geographic distribution, age, gender, patterns of health care use and costs, complications, and chronic disease. The registry will include participants who have signed a RuSH-compliant consent, and NHLBI will build a biorepository in the registry phase.

Because RuSH is still in the planning stage, SCDAC reviewers had few comments. They did note, however, that because the ability to measure an objective is required for objectives to be included in HP2020, RuSH has already been emphasized. While the Committee agreed that surveillance is CDC’s area of expertise, they stressed that NHLBI should stay engaged in this effort because expectations are high. One Committee member suggested that NHLBI seek input from various communities on culturally acceptable conduct of surveillance. It was also suggested that NHLBI seek input for innovative techniques to reach populations.

DBDR staff clarified that most of the 4 years under this Inter-Agency Agreement will focus on surveillance, which in turn will inform design and construction of the registry. NHLBI plans to focus first on the six cooperative agreement States to ensure that data collection is robust, then possibly expand surveillance to other interested states. Drs. Hoots and Goldsmith stated that NHLBI will remain engaged in the process to facilitate planning of the registry and repository.

SCD Practice Guidelines

The NHLBI Division for the Application of Research Discoveries (DARD) is developing evidence-based guidelines on the management of SCD patients across the lifespan. Recommendations will be developed around five key questions (chapters) determined by an expert panel. The overall goal is to translate the current knowledge base about SCD into improved care. The expert panel has been convened, a methodology group contracted, and a plan and process outline created. Potential deliverables include an evidence summary document with tables, scientific publications on the recommendations, provider tools, and patient education materials.

SCDAC reviewers noted that, dated as it is, the “Red Book” remains a critical resource in the SCD community and thus needs to be updated. They emphasized the need to leverage expertise to ensure that the updated guidelines are implemented. Refereed journals and professional societies were suggested as possible vehicles for disseminating updated guidelines. SCDAC members also noted that most patients with SCD are not seen by hematologists but by primary care providers. The treating physicians must be informed of the guidelines and involved in implementation. SCDAC cited a model in the hemophilia centers, which offer three tiers of care: primary care, general non-cancer hematology, and specialized hemophilia treatment centers. The SCDAC suggested that NHLBI support health services research or draw on existing research efforts, such as by the Robert Wood Johnson Foundation, to determine how to achieve vertical integration of care. One member suggested a trans-agency initiative in which AHRQ awards a grant for guidelines development, HRSA and CDC implement the grant, and CMS assists in funding it.

Requests for Applications (RFAs)

Neurobiology of Pain

The Neurobiology of Pain RFA fosters basic and translational research in the neurobiology of pain in SCD. Three grants have been awarded: one focused on calmodulin, one focused on the clinical implications of pain phenotypes in SCD, and one exploring nociceptive mechanisms underlying sickle cell pain.

One SCDAC reviewer expressed excitement about the calmodulin project, which uses the Berkeley mouse model to study assays focused on pain, then employs the assays in human study participants. SCDAC reviewers stressed the importance of the RFA and the need to establish a well-characterized pain phenotypes in SCD. They noted the benefit of an animal model to validate findings. They identified gaps including potential links between pain experience and later disease outcomes. SCDAC suggested that the RFA be reissued to potentially increase the number of investigators from the pain research community. They also noted the need for studies exploring pain in children and the opportunity to leverage phenotypic information, such as from the walk-PHaSST trial, and encourage NINDS investigators to use SCD as a model for pain.

R34 RFA

The R34 Mechanism to Advance Clinical Research in Hemoglobinopathies supports planning grants for the design of effective Phase II/III clinical trials to increase the chances that these trials will succeed. The mechanism allows up to 3 years of funding (up to $450,000 total direct costs) and provides an opportunity for a research team to build the infrastructure they will need for their studies, test that infrastructure, and conduct pilot studies. The RFA will be issued by June 2010, and NHLBI expects to make awards in 2011.

SCDAC reviewers viewed the R34 mechanism as recognition by NIH that the infrastructure for SCD research is not well developed, that few institutions provide the support needed to build that infrastructure, and that industry traditionally has been unwilling to provide support because SCD is an orphan disease. Although the reviewers lauded the mechanism and stressed its importance, they cautioned that the R34 should be used not only to foster more trials in hydroxyurea or transfusions, but also to provide opportunities to test new agents. Some committee members also speculated that by using the R34 to build infrastructure and drive innovation, NHLBI might establish an environment that garners industry interest and involvement.

Dr. Hoots explained that the R34 Mechanism to Advance Clinical Research in Hemoglobinopathies is designed to re-establish a pipeline of clinical trials. Successful R34 applicants will design a trial, identify their statistical design support and the types of scientific and regulatory advice they will need, and eventually obtain R01 or U01 support. NHLBI will issue a Request for Information (RFI) to identify CTSAs, contract research organizations, clinical trial specialists, statisticians, and others who can assist investigators in their studies.

Workshops and Working Groups

Inflammation, Thrombosis, Vascular Injury in SCD

SCDAC reviewers summarized themes and recommendations from this working group meeting, which had taken place on October 29, 2009. Working group participants agreed that inflammation and thrombosis are closely linked and that both processes are related to SCD. Although fetal hemoglobin switching has long been the “holy grail” of SCD treatment research, other targets should be explored. The working group discussed which agents to use, the use of phenotype/genotype correlations to determine which patients to target, and which end points would be most useful. Participants also discussed the possibility of bringing these two large fields of research together.

SCDAC members stressed the importance of cell-level imaging and discussed emerging technologies in this area. SCDAC members who attended the working group meeting also noted the complex knowledge base that exists outside of SCD and stressed the importance of bringing in high-level laboratories that are not currently focused on the disease. Other members suggested that modern technologies be exploited to examine old problems such as hemoglobin polymerization.

Translational II/III SCD Research

The major recommendations from a Workshop on Sickle Cell Priorities held in the Fall 2008 were summarized:

• Investigator-initiated trials have been most successful in moving the field forward.
• Enrollment in SCD clinical trials is extremely difficult, and work is needed to understand the many factors involved in this difficulty.
• Creating a community of trust is essential to success in SCD research. The CDC-supported Thalassemia Centers can be used as a model for building this kind of trust.
• Clinical research network trials have been less successful in completing enrollment than investigator-initiated SCD clinical trials.

Recommendations from this workshop covered several areas: vascular biology; pain; pulmonary, cardiac, renal, and neurologic complications; stem cell transplantation; fetal hemoglobin switching; and epidemiology. The SCDAC noted that although pain is the most important issue for patients with SCD, only 4% of the NHLBI SCD portfolio studies pain.

The Methods for Translational II/III Research in Sickle Cell Pain Management working group meeting, which occurred in September 2009 was discussed. The meeting brought together pain specialists, hematologists, and health services researchers. Patient-doctor interactions and what to do with early findings were highlighted as major issues. The working group stressed the need for interdisciplinary work, across the pain and hematology fields and across Federal agencies. Since most pain events occur at home, workshop participants suggested that more studies should evaluate pain in the home setting. New interventions, mechanistic trials, and improvements in delivery of existing therapy were suggested as important research areas to be studied in the home.

Basic and Translational Research Program (BTRP)

BTRP, the successor to the Comprehensive Sickle Cell Centers, supports 15 basic and translational research projects and 5 clinical projects. The Sickle Cell Scholars Program, which funds one scholar at each BTRP site for a total of 12 scholars overall, accompanies the BTRP.

SCDAC reviewers lauded the overall success of the BTRP projects and agreed that the program had achieved its goal. With minimal infrastructure, the BTRP supports investigators from several different disciplines. The SCDAC agreed that the success of the BTRP program illustrates the need to support research from the bench to bedside. They noted that this program was an interim program and questioned what would happen next. SCDAC members recommended more emphasis on the scholars to present and share their work experiences.

Issues and challenges remain to be addressed.

• Renal and cardiac complications related to SCD remain understudied.
• SCD is not a priority for the pharmaceutical industry.
• SCD researchers find it difficult to obtain study drugs because manufacturers are afraid that new AEs will be discovered or that SCD complications will be attributed to their drugs.
• SCD trials generally take longer than other trials because of social issues, problems with recruitment and accrual, and interruptions in funding. Frequent interruptions of funding pipelines for multicenter studies are destructive.
• There is a lack of patient advocacy or ownership of the field among the SCD population. SCDAC suggested that studies should focus on underlying mechanisms and inform efforts to prevent end-organ damage in patients with SCD. High-throughput technologies and animal models are important for such studies.

SCDAC RECOMMENDATIONS

1. Build the infrastructure needed to provide an adequate number of eligible patients to SCD research, or provide incentives for institutions to share existing infrastructure. NHLBI is talking with the National Center for Research Resources about possible links with the CTSA program, which includes several disciplines across schools of medicine, dentistry, and public health and supports the building of infrastructure that can be used by all parts of the NIH community.
2. Develop or collect best practices, which can be used as a set of prerequisites for future trials supported by NHLBI. Establish a mechanism to support the ability to collect the maximum amount of information on study participants, which will allow investigators to learn as much as possible from these trials.
3. Exploit the wide knowledge base outside SCD by bringing in high-quality laboratories from other fields.
4. Support more mechanistic studies and studies that explore new agents targeting upstream events in the pathophysiology of SCD.
5. Reward innovation, such as creative ways to identify new sources of study participants.
6. Support health services research, and collaborate with other agencies with expertise in health services research.
7. Enhance collaborations with other Federal agencies (CDC, HRSA, CMS, and AHRQ), private funders, the Sickle Cell Disease Association of America, and population scientists to advance research on SCD and other hemoglobinopathies.
8. Leverage the successes of the Comprehensive Sickle Cell Centers and the BTRP, such as the ability to bring together and provide incentives for interested investigators from different disciplines. The process for deciding how to move forward from BTRP should be thoughtful, transparent, and driven by science.
9. Basic and translational research on definitive therapies should include hemoglobin switching agents, pain management (including psychosocial research), prevention and treatment of stroke, acute chest syndrome, and other anti-sickling agents (red cell hydrators and anti-adhesion agents).
10. Distributed clinical trials infrastructure should include SCD Clinical Trials Network, leverage CTSAs, R34 mechanism, and trials should favor translational emphasis including biomarkers.
11. Basic and translational pathophysiology research should include outreach to other Institutes and Agencies, and include areas such as CNS changes, coagulopathy and vasculopathy, role of inflammation and immunity, and chest syndrome.

W. Keith Hoots, M.D.
SCDAC Executive Secretary

Edward Benz, M.D.
SCDAC Chair

Last Updated January 2011