Workshop on Sickle Cell Disease: Clinical Priorities and Clinical Trials

October 22–24, 2008
Doubletree Hotel and Executive Meeting Center
Bethesda, Maryland

• Executive Summary
  • STRUCTURE AND CONTENT OF THE WORKSHOP
  • WORKSHOP DISCUSSION THEMES
  • RECOMMENDATIONS FOR CLINICAL SCD RESEARCH PRIORITIES
• Presentation Summaries
  • OPENING REMARKS
• Keynote Address
  • BUILDING NETWORKS—OBSERVATIONS FROM ONCOLOGY AND NON-MEDICAL INDUSTRIES
  • CREATING THE INFRASTRUCTURE FOR CLINICAL TRIALS: LESSONS LEARNED AND FUTURE PLANS
  • NEXT STEPS
  • LIST OF ABBREVIATIONS

Executive Summary

On October 20-22, 2008, NHLBI convened a meeting to discuss later-stage translational research in SCD, with the goals of lessening the burden of disease and realizing the promise of multiple opportunities. The meeting had two major topics: scientific opportunities and clinical needs; and the advantages and disadvantages of different infrastructure mechanisms to support later-stage translational research. NHLBI identified six key principles to guide clinical research infrastructure:

• The research must be driven by the science.
• Infrastructure will be established to conduct studies designed to answer specific research questions.
• Community engagement and the active involvement of patients and families are essential.
• Access to care is the basis for participants to have access to research programs, and for investigators to be able to offer these to their patients.
• Accountability, efficiency, and partnering to exploit existing infrastructure are essential.
• Supporting the career development of early-stage investigators and attracting investigators with expertise in other fields are important for long-term success.

Meeting attendees identified high priority scientific areas which were felt to be appropriate for a network structure. Given the magnitude of the scientific and clinical problems, attempts were made to identify the highest priorities summarized below.

• The biology and management of pain are critical and should include non-pharmacologic as well as pharmacologic studies, with aggressive attempts to involve pain specialists, and patients and families in the design and conduct of such studies. Both chronic and acute exacerbations of pain need substantial investigation.
• Epidemiology and patient outcome studies are essential to ensure that all patients have access to the best available care and to inform the research agenda. Genomic studies need to be population-based to provide the greatest scientific value and expand understanding of pathophysiology, and to identify new drug targets. Accurate descriptions of phenotype are essential to obtain optimal information from genomic studies.
• Vascular biologic studies are needed to understand the interactions of the blood with endothelium and should evaluate thrombosis, inflammation, and the impact of hemolysis and secondary nitric oxide depletion.
• Studies of neurologic complications should include both functional and imaging measures, with the goal of improved interventional studies to prevent damage and preserve function.
• Studies of pulmonary complications should include acute chest syndrome, pulmonary hypertension and airway hyper-reactivity.
• Pharmacologic methods of increasing fetal hemoglobin are essential, including both new agent development and enhanced use of hydroxyurea in eligible subjects.

Sickle cell disease, the first molecular disease, remains a rich area for scientific investigation. Advances in care which have increased longevity have shifted research priorities and raised new challenges to the management of a life-long chronic disease. The research portfolio is broad; this workshop attempts to identify key issues for future exploration.

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STRUCTURE AND CONTENT OF THE WORKSHOP

As a component of the reorganization of its sickle cell disease (SCD) research program, the National Heart, Lung, and Blood Institute (NHLBI) convened a workshop in Bethesda, Maryland on October 22–24, 2008. The workshop brought together investigators, clinicians, patients and patient advocates, and other members of the SCD community to identify priorities for clinical research and to consider the infrastructure to support SCD clinical trials. Dr. Kwaku Ohene-Frempong, Professor of Pediatrics, University of Pennsylvania School of Medicine, and Dr. Barbara M. Alving, Director of the National Center for Research Resources, co-chaired the workshop.

Dr. Susan Shurin, NHLBI Deputy Director, Dr. Willarda B. Edwards, President and Chief Operating Officer of the Sickle Cell Disease Association of America, Dr. Frempong, and Dr. Alving presented opening remarks. Dr. Alving described the changing face of clinical research, with particular focus on the Clinical and Translational Science Award program. Co-chairs of eight subcommittees presented summaries of clinical research priorities based on pre-workshop meetings. The research priority subcommittee topics were: vascular biology/pathophysiology; pain, pulmonary/cardiac complications; neurological complications; kidney complications; stem cell transplantation; fetal hemoglobin; and epidemiology and patient outcomes. Breakout groups focused on these areas to refine and develop priorities for clinical research, reporting to the full group. The keynote address by Dr. David Dilts, Director of the Center for Management Research in Healthcare, Professor of Operations Management, and Director of the Engineering Management Program at Vanderbilt University addressed the principles of successful networks, using examples from the NCI Oncology Program as well as from businesses such as General Motors, FTD and Starbucks. His presentation emphasized flexibility, value to the customer, involvement of all stakeholders in improving processes, and the use of process mapping to identify which steps add value.

Discussion of the infrastructure required for successful clinical research drew from examples of existing networks. Dr. Kathryn Hassell, of the Colorado Sickle Cell Center and the Division of Blood Diseases and Resources, NHLBI, discussed the attributes of an optimal clinical trials framework for sickle cell disease. Dr. Clinton Joiner, of the Cincinnati Children's Hospital Medical Center, provided a report from the Sickle Cell Disease Task Force. Ms. Judith Manola, Dr. James Neaton, and Dr. Gail Weinmann described lessons learned from oncology, HIV/AIDS, and asthma clinical trials, respectively.

Care providers, patients, parents, and other members of the SCD community asked researchers to involve the patients as they design and conduct clinical research and critiqued what they had heard in the public comment section. Dr. Shurin summarized and discussed the next steps and concluded the workshop.

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WORKSHOP DISCUSSION THEMES

• Enrollment in SCD clinical research is challenging for multiple reasons, including: poor access to care for many patients; poor reimbursement for care delivered, which reduces institutional and investigator resources to invest in SCD research; relative lack of potential profitability for industry; few studies which are community-based; and competing studies for those subjects willing and available to participate in research.
• SCD clinical research must include the SCD patients, their families, and community organizations in each step of the design and conduct of clinical trials.
• Successful SCD clinical research requires the use of study end points which are clinically and scientifically meaningful to ensure that both efficacy and effectiveness are being assessed.
• SCD clinical research should include epidemiology, decision-making, and cost-effectiveness research.
• SCD clinical research should address lifespan and disease manifestation differences between children and adults.
• Clinical research networks should support investigator-initiated, peer-reviewed studies. Historically, investigator-initiated studies have been the most successfully planned and conducted, and have been the means by which scientific data have been obtained and clinical care has improved. Networks should provide input on study feasibility and adaptability to the network infrastructure.
• Clinical research networks should reward enrollment of participants and submission of data using a pay-for-performance model.
• Clinical research networks should be able to prepare and launch study protocols rapidly and effectively, and serve as training grounds for the next generation of investigators.
• Protocol development should be efficient, including steps that contribute value and eliminating unnecessary repetition.

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RECOMMENDATIONS FOR CLINICAL SCD RESEARCH PRIORITIES

Vascular Biology / Pathophysiology

1. Vascular imaging should be a high priority for investigating pathophysiology, defining new clinical end points, and discovering new therapeutic targets. Collaboration with radiologists and biomedical engineers is necessary to develop techniques that can be used in research and patient care. Studies are needed to correlate vascular changes with acute painful crisis and identify better surrogate or quantitative markers for crisis.
2. Ancillary studies should assess anti-platelet therapy and address biologic mechanisms underlying platelet activation, such as hemolysis, adenosine diphosphate release, nitric oxide scavenging, microparticles, and endothelial dysfunction.
3. Biomarker studies should be conducted and include markers for platelet activation, endothelial activation/dysfunction, oxidant stress, nitric oxide status, coagulation and thrombosis, and inflammation.
4. Genome wide association studies should include robust vascular phenotyping.

Pain

1. The development and validation of outcome measures is the highest priority because few of such instruments exist to assess SCD-associated pain, and new treatments cannot be evaluated without them. Outcome measures should define specific pain phenotypes and create or extend measures of pain based on etiology, domains of pain, and chronicity. Patient reported measures, functional status from pain, and compatibility with existing measurement standards are of prime importance. These measures should also take the settings in which treatment occurs into account. Patients, the U.S. Food and Drug Administration, NIH, researchers in SCD and other diseases, and payers should be involved in the development of outcome measures.
2. Studies should test efficacy of single interventions for palliation and remission. Comparative effectiveness studies should compare standard of care with multimodal, individualized treatment plans. Studies should include adult patients severely affected by chronic pain. Brain effects should be measured through functional imaging. Pediatric trials should focus first on prevention and acute pain. Studies should then test the ability to prevent brain remodeling or chronic pain as a long-term outcome.

Pulmonary/Cardiac Complications

1. A cohort study of cardiopulmonary disease in children and young adults with SCD is needed to determine the meaning and implications of abnormal parameters and biomarkers related to pulmonary hypertension (PH) including tricuspid regurgitant jet velocity (TRV), Brain Natriuretic Protein (BNP), diastolic dysfunction and asthma. This study would require a large sample size.
2. Placebo-controlled clinical trials of pharmacotherapy for PH in adults with SCD are needed. These trials should have adequate statistical power to assess responses in subgroups with Pulmonary Arterial Hypertension versus PH with diastolic dysfunction. Treatment of PH with oral agents such as PD5 inhibitors and ET1RA would be considered.
3. Placebo-controlled trials in ACS should be conducted and include the development and validation of biomarkers that predict ACS, as well as therapeutic trials that evaluate prevention and early intervention. Establishing a study mechanism to identify high-risk subjects and test interventions could attract industry interest. Potential interventions include leukotriene modifiers, nitric oxide, steroids, and lung recruitment maneuvers such as bilevel positive airway pressure (BiPAP) and continuous positive airway pressure (CPAP).
4. A study of the prevalence and associated morbidity of airway hyper reactivity should be conducted and include rigorous diagnosis using methacholine bronchoprovocation and controls. It should examine interactions with PH, ACS, vaso-occlusive crises, and steroid complications, and it should identify effective therapeutic interventions.

Renal Complications

1. Where feasible, all SCD trials should consider including renal mechanistic, prognostic, and/or therapeutic observations, and subspecialists should be included in study design. Studies could clarify the pathologic role of inflammation and vascular injury and its resolution (using biomarkers) the accuracy and consistency of assessment of renal function (creatinine vs. cystatin-C vs. isothalamate vs. others); and microalbuminuria vs. proteinuria selectivity and significance regarding progression of glomerular dysfunction.
2. All primary SCD renal disease studies must collect data that will address mechanistic questions.
3. SCD studies should take advantage of indicated biopsy data for more sophisticated analysis of renal pathology. Consider creating a centralized pathology repository with ancillary data.
4. Conduct a full-spectrum analysis of United States Renal Data System data of chronic kidney disease and end stage renal disease.
5. Continue the losartan trial under development by the SCDCRN. Additional renal data might be obtained by including data on renal function in ongoing/upcoming trials, e.g. sildenafil for pulmonary hypertension or transfusion/hydroxyurea for pulmonary hypertension. Data on the impact of hydroxyurea on renal dysfunction is desperately needed.
6. Encourage further use of renal transplantation in SCD renal failure. Studies are needed to optimize sickle cell-related management (transfusion, erythropoietin, hydroxyurea) for those awaiting transplant and in the peri- and post-transplant period to generate and implement broad care guidelines.

Neurological Complications

1. Further study is needed on the prevalence and natural history of SCD-associated neurologic disease, including outcomes and end points, early brain development, stroke and event rates, Moya Moya syndrome, variant phenotypes, and the relationship between brain disease and other organ damage.
2. Studies of etiologic factors, including hypoxemia, endothelial dysfunction, cellular adhesion, non-vascular injury, traditional risk factors for stroke, and prenatal and perinatal events, should be built into clinical trials.
3. Studies are needed to assess the effects of prevention and treatment options, such as transfusions, hydroxyurea, aspirin, dipyridamole, clopidogrel, and statins, on the central nervous system in SCD patients.
4. Proposed phase II/III clinical trials include:
   1. A large pediatric trial assessing whether hydroxyurea prevents vascular disease, as measured by transcranial Doppler (TCD)
   2. A companion adult trial assessing hydroxyurea treatment following stroke
   3. A study of aspirin as preventive therapy, a trial that could pave the way for similar studies of other potentially vasoprotective agents
   4. A study of the safety and efficacy of surgical bypass procedures

Stem Cell Transplantation

1. A phase II trial should be conducted to assess the use of bone marrow transplantation (BMT) for young adult subjects with SCD. Study questions include the safety and effectiveness of reduced-intensity regimens, the impact of mixed chimerism, and acceptable toxicity rates. Study design should address optimal conditioning regimens, appropriate eligibility criteria and clinical end points (survival, organ-specific outcomes, or both).
2. Studies should be done to assess the safety and efficacy of BMT in preventing stroke in children and the regenerative capacity of cord blood for treating neurovascular injury.
3. The utilization of BMT as a treatment option should be evaluated, particularly with respect to the decision-making process used by patients and their families.

Fetal Hemoglobin

1. A sickle cell patient registry, including a DNA biorepository with annotations about patient phenotypes, should be established. Such a registry, which would be a national program based on the Centers for Disease Control and Prevention (CDC) Hemophilia Treatment Centers model, would facilitate genome-wide association studies, adult and pediatric studies comparing subjects who do and do not take hydroxyurea, and comparing subjects who respond with those who do not respond to hydroxyurea.
2. A standard pathway for clinical trial development, based on lessons learned from oncology and HIV/AIDS clinical trials networks, should be established in SCD. Such a mechanism would include a process for moving from phase I to phase II/III trials and include studies to measure pain, quality of life, organ function, and hemolysis.
3. Near-term clinical trials should include a phase II trial examining decitabine, a phase II trial examining combinations of hydroxyurea and butyrate, and a phase I trial of other single agents such as histone deacetylase inhibitors or pomalidomide. These studies would likely be restricted to severely ill adult patients.

Epidemiology and Patient Outcomes

1. NHLBI should continue its work with CDC to quantify and characterize the SCD population. An NHLBI-CDC data system should include assessments of neonatal testing and outcomes through early childhood and transition from pediatric to adult care. The system should be designed to detect changing demographics (for example, immigration) of the SCD population and underserved patients not in the health care system.
2. Identify access and barriers to care, including systems issues such as insurance, specialized versus primary care, geography, and state-specific variations in benefits.
3. Assess quality of life, including stigmatization and its effects on patient outcomes. These studies should examine the relationship between quality of life and clinical course.
4. Examine the knowledge, attitudes, and beliefs of physicians who treat adults with SCD and the relationship of these variables to patient outcomes and clinical course.
5. Explore bioethical issues related to study participation and DNA collection.
6. Explore sociodemographic factors and health care variables associated with different treatments, clinical outcomes, and diagnostic regimens.
7. Future studies should be cross- and multi-disciplinary. For example:
   1. Which patient provider and health system factors are associated with use of specific treatments?
   2. What is the association between gene variants and specific patient outcomes?
   3. What factors are associated with up-to-date vaccinations, educational attainment, work status, and socioeconomic status as both correlates and outcomes?
8. Behavioral epidemiology studies should examine the utilization of and adherence to treatments, including hydroxyurea, chronic transfusion, and penicillin prophylaxis; and patient acceptance of and adherence to diagnostic procedures, such as monthly laboratory tests.
9. The effectiveness of TCD as a modality in the prevention of stroke should be studied.
10. Studies should explore effects of SCD on other conditions, for example comparing children who have SCD with a reference population such as that in the Third National Health and Nutrition Examination Survey, or assessing how children with SCD are affected by the obesity epidemic.
11. Studies should assess the role of cognitive deficit in clinical on quality-of-life outcomes.

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Presentation Summaries

OPENING REMARKS

Elizabeth G. Nabel, M.D., Director, National Heart, Lung, and Blood Institute

The object of the reorganization of the Sickle Cell Disease program is to invest in programs that yield returns and enhance inclusivity. NHLBI wants to ensure that physicians and their patients have maximal access to NHLBI sponsored studies.

Future planning for SCD trials will encompass the following principles:

• Research must be driven by the best science. The SCD community must first determine the scientific priorities and then decide on the resources will be needed.
• Community engagement is essential. NHLBI considers patients, their families, and the community to be co-investigators in its SCD research.
• NHLBI wants every patient with SCD in the United States to have access to NHLBI-sponsored clinical trials. The patients' input will help the research community to determine scientific priorities.
• Care will improve if participation in research becomes part of the standard of care. The conduct of clinical research must involve as many caregivers and investigators as possible.
• Accountability is essential. Clinical research is a team sport, and study participants, investigators, the health care team, and NHLBI must be involved in its conduct. Expectations must be transparent, and partners must hold each other accountable.
• Efficiency is essential. The research community must be flexible, form partnerships, make use of established infrastructure, and take advantage of new opportunities. Use of centers that have received CTSAs will be emphasized.
• Support for the development of early-stage investigators is essential in continuing SCD research. NHLBI will try to attract bright, junior, talented individuals, as well as individuals from other disciplines, into SCD research to keep momentum going. NHLBI must provide training opportunities.

Susan B. Shurin, M.D., Deputy Director, National Heart, Lung, and Blood Institute

Most patients born with SCD now survive into middle age because of newborn screening and extensive follow-up that extends life. However, SCD research continues to face challenges posed by an uneven system of access to care and by economic challenges many patients with SCD experience. Although NHLBI cannot solve these structural problems, it can work with the SCD community to improve access to care and to enhance the infrastructure necessary for research.

NHLBI is adjusting several aspects of its SCD research program, based on the principles discussed by Dr. Nabel, to enable the field to exploit rapidly evolving scientific opportunities. Feasibility is critical to the success of this reorganization, as clinical research projects must be doable. Workshop participants will help NHLBI to determine what those projects are and NHLBI will establish metrics to evaluate their outcomes.

Each partner has responsibilities. NHLBI serves as the organizer, convener, and sponsor of programs such as that devoted to SCD research, and it has a responsibility to the citizens and to Congress as a steward of federal funds. It is also responsible for oversight and governance. Scientific investigators and medical providers are responsible for identifying clinical and scientific questions for study. They must create a community of trust, invite and support the participation of colleagues, and move study teams forward. Professional societies and home institutions are also critical to success. Likewise, advocacy organizations must play a major role in encouraging participation in clinical studies, advocating for research funds, and ensuring families have access to high-quality care.

Willarda Edwards, M.D., M.B.A., President, Sickle Cell Disease Association of America (SCDAA)

SCD remains a major health problem for more than 100,000 citizens and their families. More support for research is needed, as is greater participation in SCD research by investigators, patients, the community that supports patients, and the research and medical establishments.

The SCDAA recognizes the challenges NHLBI faces as it seeks to reorganize SCD programs developed over the past 36 years. The SCDAA hopes that previously allocated funding to comprehensive SCD programs is not lost or reduced, research scientists are not discouraged because SCD is viewed as an unstable area of research, research for better treatments and a cure is not further delayed, and NHLBI and NIH do not retreat from their commitments to SCD research.

The SDCAA advocates for development of and involvement in a larger, well-funded, and more efficient clinical trials network that quickly tests new treatments and monitors medium and long-term outcomes. Efforts are needed to address barriers to the effective use of hydroxyurea therapy.

The SCDAA can assist in community education, recruiting patients, and monitoring the conduct and outcome of clinical research. It also can address some issues of access and insurance and evaluate quality-of-life issues related to SCD.

Barbara Alving, M.D., Director, National Center for Research Resources, NIH

A new model is needed to conduct clinical trials implement the findings the trials into clinical practice.

The Clinical and Translational Science Awards (CTSA) program was designed to create a more efficient highway from the laboratory to the clinic by speeding up the translation of research into clinical trials and by transforming how science is done. Each CTSA institution serves as a home for clinical and translational science. This home includes such components as trial design, advanced degree-granting programs, regulatory support, biostatistics, clinical resources, biomedical informatics, and clinical research ethics. Participant and community engagement is a vital component of CTSA institutions, which interact with NIH and other government agencies, industry, and health care and community organizations.

Changes in public policy, through Congressional mandates, may be necessary to bring about adaption of this new model. Five principles of optimizing clinical practice through research were outlined:

• The research agenda should be determined by the needs of the patients and populations, not the needs of the researchers.
• The agenda should address contextual and implementation issues, including delivery and accountability systems.
• The research agenda should determine the methods.
• Researchers and clinicians should collaborate to define the research agenda, allocate resources, and implement findings.
• Research funding must accommodate the magnitude of the task.

Research and care in SCD should address several considerations.

• Existing infrastructures, such as the CTSA program can be used to support research and patient care.
• The SCD research community also should identify successful efforts and determine how to maintain them, determine whether there are academic health centers that provide excellent care, and what steps should be achieved in the advance toward a cure.
• The SCD research community should determine how it can maximize the training and knowledge of patients and care providers. For example, telemedicine or a Web-based informatics system could be used to connect providers with others who have more expertise. Social networking can maximize knowledge exchange among patients and their families.
• The SCD research community should examine economic models and work with business schools to identify the economic benefit of such a research.

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Keynote Address

BUILDING NETWORKS—OBSERVATIONS FROM ONCOLOGY AND NON-MEDICAL INDUSTRIES

David Dilts, Ph.D., M.B.A., Vanderbilt University

Dr. Dilts noted that successful organizations understand the importance of value to the customer, determine how to integrate diverse systems, transfer lessons learned from other domains, and establish a balance between a rigid structure and flexibility. These organizations also acknowledge that they will make mistakes and must therefore be able to effect rapid change.

Some lessons for biomedical research network building were highlighted: a distribution of rewards, not money, is a primary motivation for research networks; customers must be convinced that they need the network; the reasons are known for delays in the process of initiating clinical trials; flexibility and continuous adaptation to new conditions are important; and a critical mass of sites must be enlisted to provide the required numbers of subjects to complete trial. Clinical trials networks may be centralized or de-centralized—each has advantages and disadvantages.

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CREATING THE INFRASTRUCTURE FOR CLINICAL TRIALS: LESSONS LEARNED AND FUTURE PLANS

Attributes of an Optimal Clinical Trials Framework for Sickle Cell Disease

Kathryn Hassell, M.D., Colorado Sickle Cell Center and Division of Blood Diseases

Patients and their families must work with the sponsors of research to set priorities. They need to be included in collaborative relationships with researchers and trust that their needs will be heard. The broader community, including philanthropic organizations, can support research financially, but also by providing education to the community and to researchers, and by providing services, such as transportation and other resources needed for attendance at research visits.

To optimally implement clinical studies, a clinical research network in SCD should be open, flexible, and nimble, with an established infrastructure to facilitate and influence the conduct of clinical studies. Networks should be stable, with centralized data coordination, safety monitoring and a large pool of individual sites that are paid for performance. They should provide maximum opportunity for participants and qualified investigators, be able to conduct different types of studies, and be ready to implement studies once they are developed. Studies should be well developed and ready to begin once they enter the network, though networks should adapt aspects of studies to facilitate conduct within network sites. The timeline by which network performance for study conduct is judged should not begin until a developed protocol, ready for implementation, is delivered to the network.

Dr. Hassell analyzed 14 SCD studies conducted independent of a clinical research network. These studies involved a median of 23 centers and 235 study participants, with a median time of 44 months to enroll. This requirement was fairly consistent across all types of studies, except for pediatric studies, which required fewer sites. Even sites that provide only five or six patients were needed in order to complete enrollment. There was no relationship between the number of study sites and the time to enrollment, however, there was a trend to more rapid enrollment with more available sites.

Approximately 75 institutions are conducting SCD trials across the United States; there are 50 others that have conducted clinical trials in the past 15 years which are not listed as active in the open trials in SCD. Only 3 clinical studies in SCD were completed in the Comprehensive Sickle Cell Centers' Clinical Trials Consortium; two others were closed before completion. No trials have yet opened in the SCD Clinical Research Network. The majority of open SCD clinical studies are not conducted within a network framework. An optimal clinical research network offers the opportunity for efficient and effective study conduct, but needs to identify and incorporate all available resources and sites.

Report from the Sickle Cell Disease Task Force—the American Society of Pediatric Hematology/Oncology (ASPHO) Summit

Clinton Joiner, M.D., Ph.D., Cincinnati Children's Hospital Medical Center

The SCD Task Force arose from the ASPHO SCD Summit and identified opportunities in access to clinical care, population-based surveillance, and basic, translational, clinical, and health services research. Challenges unique to SCD include the lack of access to care and of financial support for routine clinical care activities, involvement of multiple organs in SCD, differing manifestations of SCD in children and adults, and the lack of appropriate clinical end points for SCD research. The SCD Task Force outlined the following organizing principles for a clinical research network:

• Investigator-initiated protocols are the most dynamic.
• Review and prioritization of clinical research protocols should be based on scientific merit assessed by peer review.
• Membership should be based on the site's ability to conduct clinical research.
• A clinical research network for SCD will likely require 50 sites or more.
• Network funding should reward successful patient accrual in clinical trials.
• An NHLBI sickle cell research program should integrate its network with basic research, translational research, and training programs.

Mechanisms for supporting a clinical research network include philanthropic organizations, the pharmaceutical industry, CTSAs, and community-based organizations. Partnerships could be formed with nonprofit organizations, similar to the partnership between COG and the National Children's Cancer Foundation. CTSAs offer several benefits, including the ability to augment study capacity and to stretch research dollars. However, not all network sites will have access to CTSAs, and CTSAs are likely to charge for services. Community organizations will play a vital role in advocating for research and clinical care funding, form partnerships with health care organizations, provide support services for patients on clinical trials, educate the community about clinical research, and facilitate enrollment.

The SCD Task Force envisions a national SCD research program in which a clinical research network interacts bi-directionally with community organizations, basic and translational researchers, clinical care providers, and surveillance mechanisms. The training of new clinicians and investigators will underlie all these activities.

Lessons Learned: Clinical Trials in Oncology

Judith Manola, M.S., Dana-Farber Cancer Institute

The NCI Clinical Trials Cooperative Group Program, established in the 1950s, allows researchers to jointly develop and conduct cancer treatment clinical trials in multicenter settings. The program includes: disease-oriented groups; high-tech, single-modality groups; groups with particular expertise, such as the Children's Oncology Group; and multimodality groups such as the Eastern Cooperative Oncology Group (ECOG), which consists primarily of academic centers but includes community hospitals as affiliates. ECOG also includes community clinical oncology programs (CCOPs), separately funded institutions that conduct clinical trials in a community setting.

Group structure and funding is permanently in place, not linked to specific clinical trials. Funding primarily comprises capitation payments, cooperative agreement U10 grants to participating sites, and funds from the NCI Division of Cancer Prevention to CCOPs. Governance mechanisms are specified in a constitution and by-laws subject to the policies and procedures of the Department of Health and Human Services, NIH, NCI, the Office of Human Research Protections, FDA, and the Office of Research Integrity. Although funding for NCI overall has been flat in recent years, cooperative groups receive approximately $180 million, which covers accrual for about 25,000 patients per year. Forty-five percent of that funding covers per-case reimbursement.

NCI has implemented successful strategies to patient accrual and completion of clinical trials including:

• Develop recruitment videos and brochures that explain clinical trials.
• Evaluate protocols for practicality, feasibility, and cost-effectiveness at the same time they are evaluated for scientific merit.
• Use a central IRB.
• Monitor accrual through a data monitoring committee and tracking programs.
• Develop clear and concise case report forms, instructions for using them, and remote data capture systems.
• Conduct conference calls, face-to-face meetings, training, and use interactive networking tools.
• Involve patient advocates by assigning advocates to all committees within the cooperative group structure to review protocols, encourage accrual, and recommend future research directions.
• Include patient-reported outcomes which minimize the number of data elements, instruments and time points for data collection.

Lessons Learned: Clinical Trials in HIV/AIDS

James Neaton, Ph.D., University of Minnesota

The International Network for Strategic Initiatives in Global HIV Trials (INSIGHT) is a merger of two older networks sponsored by the National Institute of Allergy and Infectious Diseases (NIAID). It aims to evaluate strategies for the optimization of treatment and, ultimately, to prolong disease-free survival in a demographically, geographically, and socioeconomically diverse population of individuals with HIV. Its emphasis is primarily on phase III/IV trials. The network does not provide funds or infrastructure to the sites except for minimal up-front costs. Instead, money comes primarily from reimbursement for enrollment and follow-up visits. In addition, some infrastructure funds are available to site coordinating centers for training and on-site monitoring.

INSIGHT boasts many accomplishments. It has engaged hundreds of investigators in clinical trials in a cost-effective way, and it has included many scientists from fields other than HIV. The network has engaged the community at several levels, formed several collaborations with NIH intramural scientists, and enabled co-funding by other governments. The Community Programs for Clinical Research in AIDS, one component merged into INSIGHT, completed 35 trials, many of which changed guidelines regarding opportunistic infection prophylaxis and antiretroviral therapy. The network recently completed the SMART trial, which involved over 5,000 patients; 17 papers on SMART have been published since it ended in 2006. The network has carried out the two largest HIV/AIDS treatment trials to date. A trial of early HIV treatment ("when to start") that will involve 4,000 patients will begin enrollment in early 2009.

Dr. Neaton outlined several lessons learned:

• A strategic plan is important.
• It takes a long time to secure funding for large clinical trials. Funding from multiple mechanisms is critical.
• A network needs a large number of sites, and a phased initiation can be positive. Networks can include sites that enroll as few as 10 patients and as many as 50. Sites that enroll five or fewer patients have poorer follow-up and more protocol deviations.
• Sites should be appropriately compensated for enrolling and following patients in clinical trials.
• Funding algorithms must be transparent.
• Regional coordinating centers to support sites make the network work.
• The inclusion of many sites can facilitate rapid translation of results into practice.

Dr. Neaton also highlighted network pitfalls. The sponsor must clearly specify the level of available funding. Intensive studies are not feasible in a global network, though they might be possible in smaller sub-studies done by some of the sites. Study enrollment should not be initiated before a large number of sites are registered—it is best to begin with strong enrollment. Site expansion should not be delayed too long if enrollment is not going as planned by the participating sites.

Lessons Learned: Clinical Trials in Asthma

Gail Weinmann, M.D., National Heart, Lung and Blood Institute

NHLBI's asthma networks, the Asthma Clinical Research Network (ACRN) and the Acute Respiratory Distress Syndrome Network (ARDSNet), are the oldest networks supported by NHLBI. ACRN and the Childhood Asthma Research and Education Network (CARE) have conducted 24 protocols, with 18 sub-studies, 3 ancillary studies, and one collaborative study. These activities have resulted in 52 publications (seven are in press) as well as in changes in national and international guidelines for asthma management. ACRN and CARE have led to new science in pharmacogenetics, tested new trial designs, and trained new junior faculty. ARDSNet has conducted 10 protocols, with four ancillary studies, three funded collaborative studies, and one pending pediatric collaborative study. Activity in this network has led to 121 publications, with sub-studies in pathogenesis and epidemiology, and it has changed mechanical ventilation practice in intensive care units worldwide. DNA has been collected from all patients in this network.

In May 2007, NHLBI convened a workshop of experts in lung disease to evaluate the asthma networks. This workshop yielded several recommendations:

• Maintain a focus on improving clinical care, but allow more flexibility in research questions.
• Develop mechanisms to facilitate and promote scientific exchange across clinical research programs.
• Structure networks for maximum efficiency.
• Promote the shared use of resources and standardization among networks.
• Promote training.
• Facilitate rapid dissemination of research findings, which includes the adoption of new practices in the community.

The next NHLBI asthma network will address asthma management questions across the lifespan and have flexibility to conduct more proof-of-concept and mechanistic studies. The new network will collaborate with NHLBI's Division of Applied Research Discoveries to improve the dissemination of research findings. It also will harmonize and standardize phenotyping procedures, data elements, and outcomes for use across all programs; establish links with other NIH resources such as GCRCs and CTSAs; and build training collaborations across centers.

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NEXT STEPS

Susan Shurin, M.D., Deputy Director, NHLBI

As a sponsor of basic and clinical research, the NIH has the responsibility to: assemble a variety of partners, including investigators, and members of the community; establish priorities; and determine how best to leverage and support available resources.

Preparation and refinement of clinical protocols can take place within network structures or as investigator-initiated proposals. NHLBI will encourage the development of efficient processes that facilitate conduct of research and limit redundancy. A clinical research network cannot do everything. It must limit the complexity of its studies to successfully initiate and complete the studies.

NHLBI plans to use existing infrastructure to the extent possible. The Institute will reach out to investigators, patients and their families, and patient advocates to identify existing resources within institutions which can be adapted to support the conduct of research on SCD within academic institutions and in community settings. Infusion of additional resources to support research on SCD will enhance the existing infrastructure, and enhance the importance of SCD research within institutions and communities.

On the basis of recommendations from this workshop, NHLBI will issue a series of Funding Opportunity Announcements to address the highest priorities, while building on existing infrastructure that will enable the research.

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LIST OF ABBREVIATIONS

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