Workshop on Sickle Cell Disease:
Clinical Priorities and Clinical Trials
October 2224, 2008
Doubletree Hotel and
Executive Meeting Center
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
- 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
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
- 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
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 2224, 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
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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
- 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
- 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
Vascular Biology / Pathophysiology
- 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.
- 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
- Biomarker studies should be conducted and include markers for
platelet activation, endothelial activation/dysfunction, oxidant stress, nitric
oxide status, coagulation and thrombosis, and inflammation.
- Genome wide association studies should include robust vascular
- 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.
- 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.
- 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.
- 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.
- 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
- 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.
- 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.
- All primary SCD renal disease studies must collect data that will
address mechanistic questions.
- 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.
- Conduct a full-spectrum analysis of United States Renal Data System
data of chronic kidney disease and end stage renal disease.
- 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.
- 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.
- 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
- 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
- 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.
- Proposed phase II/III clinical trials include:
- A large pediatric trial assessing whether hydroxyurea prevents
vascular disease, as measured by transcranial Doppler (TCD)
- A companion adult trial assessing hydroxyurea treatment
- A study of aspirin as preventive therapy, a trial that could
pave the way for similar studies of other potentially vasoprotective
- A study of the safety and efficacy of surgical bypass
Stem Cell Transplantation
- 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).
- 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.
- The utilization of BMT as a treatment option should be evaluated,
particularly with respect to the decision-making process used by patients and
- 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.
- 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.
- 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
- 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.
- Identify access and barriers to care, including systems issues such
as insurance, specialized versus primary care, geography, and state-specific
variations in benefits.
- 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.
- 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.
- Explore bioethical issues related to study participation and DNA
- Explore sociodemographic factors and health care variables
associated with different treatments, clinical outcomes, and diagnostic
- Future studies should be cross- and multi-disciplinary. For example:
- Which patient provider and health system factors are associated
with use of specific treatments?
- What is the association between gene variants and specific
- What factors are associated with up-to-date vaccinations,
educational attainment, work status, and socioeconomic status as both
correlates and outcomes?
- 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.
- The effectiveness of TCD as a modality in the prevention of stroke
should be studied.
- 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.
- Studies should assess the role of cognitive deficit in clinical on
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Elizabeth G. Nabel, M.D., Director, National Heart, Lung, and Blood
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
Future planning for SCD trials will encompass the following
- Research must be driven by the best science. The SCD community must
first determine the scientific priorities and then decide on the resources will
- 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
- 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
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
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
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
Barbara Alving, M.D., Director, National Center for Research Resources,
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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BUILDING NETWORKSOBSERVATIONS 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-centralizedeach 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
Kathryn Hassell, M.D., Colorado Sickle Cell Center and Division of
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 Forcethe American
Society of Pediatric Hematology/Oncology (ASPHO) Summit
Clinton Joiner, M.D., Ph.D., Cincinnati Children's Hospital Medical
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
- A clinical research network for SCD will likely require 50 sites or
- Network funding should reward successful patient accrual in clinical
- 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
- Evaluate protocols for practicality, feasibility, and
cost-effectiveness at the same time they are evaluated for scientific
- Use a central IRB.
- Monitor accrual through a data monitoring committee and tracking
- 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
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
- 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 registeredit 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
- 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
- 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
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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
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
Asthma Clinical Research Network
acute chest syndrome
Acute Respiratory Distress Syndrome Network
American Society of Pediatric Hematology/Oncology
bilevel positive airway pressure
bone marrow transplant
brain natriuretic peptide
Childhood Asthma Research and Education Network
Community Clinical Oncology Program
Centers for Disease Control and Prevention
continuous positive airway pressure
Clinical and Translational Science Award
Eastern Cooperative Oncology Group
U.S. Food and Drug Administration
General Clinical Research Centers
International Network for Strategic Initiatives in Global HIV
institutional review board
National Cancer Institute
National Heart, Lung, and Blood Institute
National Institute of Allergy and Infectious Diseases
National Institutes of Health
sickle cell disease
Sickle Cell Disease Association of America
tricuspid regurgitant jet velocity
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