and Human Services (HHS)
EXPIRED
SPECIALIZED CENTERS FOR CELL-BASED THERAPY (SCCT) FOR HEART, LUNG, AND BLOOD DISEASES
AND DATA AND COORDINATING CENTER (DCC)
RELEASE DATE: May 10, 2004
RFA: RFA-HL-04-017 (see NOT-HL-04-113)
EXPIRATION DATE: September 22, 2004
Department of Health and Human Services (DHHS)
PARTICIPATING ORGANIZATION:
National Institutes of Health (NIH)
(http://www.nih.gov)
COMPONENT OF PARTICIPATING ORGANIZATION:
National Heart, Lung, and Blood Institute (NHLBI)
(http://www.nhlbi.nih.gov/)
CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBERS: 93.837, 93.838, 93.839
LETTER OF INTENT RECEIPT DATE: August 21, 2004
APPLICATION RECEIPT DATE: September 21, 2004
THIS RFA CONTAINS THE FOLLOWING INFORMATION
o Purpose of this RFA
o Research Objectives
o Mechanism of Support
o Funds Available
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Special Requirements
o Where to Send Inquiries
o Letter of Intent
o Pre-Submission Meeting
o Submitting an Application
o Supplementary Instructions
o Peer Review Process
o Review Criteria
o Receipt and Review Schedule
o Award Criteria
o Required Federal Citations
PURPOSE OF THIS RFA
The primary objective of the Specialized Centers of Cell-based Therapy (SCCT)
programs is to foster multidisciplinary research on clinically relevant questions
thereby enabling basic science findings to be more rapidly applied to clinical
problems. Recent discoveries provide new and unprecedented opportunities for the
therapeutic use of stem, progenitor, and differentiated cells for new treatments.
Stem cell research, coupled with regenerative medicine, offers the potential to treat
major diseases of interest to the National Heart, Lung, and Blood Institute (NHBLI).
The objective of this program is to establish and maintain (1) Specialized Centers
for Cell-based Therapy (SCCT) to perform preclinical and clinical studies for cell-
based therapy and (2) a Data & Coordinating Center (DCC) for the program. The
clinical and basic research supported through this Request for Applications (RFA)
will be related to cell-based therapy for the treatment of heart, lung, and blood
diseases.
RESEARCH OBJECTIVES
The National Heart, Lung, and Blood Institute (NHLBI) revised the Specialized Centers
of Research (SCOR) in Hematopoietic Stem Cell Biology program, based primarily on
recommendations from the National Heart, Lung, and Blood Advisory Council. The new
program is called the Specialized Centers of Cell-based Therapy (SCCT) program. The
original SCOR program required both basic and clinical research, but the
preponderance of funded projects tended to be in the basic science arena. The new
program reflects the Institute's desire to capitalize on basic research advances by
encouraging their translation to the clinical arena. The guiding principle of the new
SCCT program is the central focus on clinically relevant research. The number of
funded clinical research projects in each NHLBI SCCT must be equal to or greater than
the number of basic science projects. However, a key feature of the new SCCT program
is the ability to precede clinical projects with preclinical studies, which can be
conducted in year one or in year one and two of the program, in order to meet the
requirements for an Investigational New Drug (IND) application prior to initiating
clinical studies. However, by the beginning of the third year of the program, a
Center’s clinical projects should initiate clinical studies. The specific components
of the new SCCT program are detailed below in this RFA.
Cell-based Therapy for Heart, Lung, and Blood Disorders
Recent discoveries provide new and unprecedented opportunities for the therapeutic
use of stem, progenitor, and differentiated cells for new treatments of heart, lung,
blood, and sleep disorders. Stem and progenitor cells have the potential to replace
cells that are damaged or diseased, restore vital functions, and offer the promise of
curing disease and ending disabilities. The potential for safe new treatments can
only be realized if preclinical and clinical research programs provide the basis to
establish the new therapy.
In August 2001 the National Heart, Lung, and Blood Institute (NHLBI) formed the Cell-
based Therapy Group in order to address stem cell and cell-based therapy issues, to
track human embryonic stem cell applications and grants, and to formulate a strategic
plan for the development of research programs leading to new cell-based therapeutics.
The Cell-based Therapy Group has formulated an Institute-wide implementation plan
integrating basic and translational research programs to support the development of
new cellular therapies including these Specialized Centers for Cell-Based Therapy
(SCCT) for Heart, Lung, and Blood Diseases.
Potential cell-based therapies involve a variety of cell sources. Bone marrow,
peripheral blood, and cord blood stem cells have been used to treat serious blood
disorders, malignant disease, and inherited diseases. Hematopoietic stem cells give
rise to all blood cells but may also differentiate into other cell lineages. For
example, the capacity of bone marrow derived cells to engraft as alveolar type 1
epithelial cells or as bronchial epithelial cells has been demonstrated. Bone marrow
and cord blood are also being used as a source of endothelial progenitor cells for
exploratory treatments for cardiac, limb ischemia, and for the regeneration of the
microvasculature and pre-capillary arterioles in experimental pulmonary arterial
hypertension (PAH). Mesenchymal stem cells from bone marrow have been demonstrated
to differentiate into a variety of non-hematopoietic tissues including bone,
cartilage, tendon, fat, skeletal and cardiac muscle, and early progenitors of neural
cells. Interesting preliminary data suggests mesenchymal stem cells may promote
hematopoietic stem cell engraftment and foster tolerance and facilitate
transplantation of heart, lung, or blood tissues from allogeneic donors.
Bone marrow cells have been reported as a source of cells for repairing various
tissues, including blood vessels, heart muscle, skeletal muscle and nervous tissue. A
novel multipotent adult progenitor cell isolated from bone marrow is reported to
differentiate into cells associated with all three germ cell layers and the potential
of these cells is just beginning to be explored. Adult skeletal muscle cells are
being utilized and cultured as a potential cell source for cellular cardiomyoplasty
for the treatment of heart disease. In addition, it has been speculated and there is
preliminary evidence that cardiovascular and lung tissues may contain one or more
progenitor or stem cells that could be induced to proliferate and repair cellular
damage.
This SCCT program is designed to address the need for facilities where basic and
clinical investigators can transform validated hypotheses into clinical applications.
Some of the preclinical tasks include the qualification and testing of reagents,
scale-up of methods, high-end cell selection and culturing, development of standard
operating procedures, ongoing process validation, and the provision of controlled
good manufacturing practice (GMP) infrastructure. An additional consideration is the
need for controlled studies to monitor the delivery of cells and the use of
appropriate controls. Is the effect of a cell-based therapy the result of the use of
a specific type of cell or are similar results obtained using other cells or a
placebo? For example, in cell transplantation studies in the heart, the injection of
skeletal muscle cells has been reported to improve function. However, the question
remains, would cardiac function also be improved using non-muscle cells such as
fibroblasts or hepatocytes?
With the initiation of clinical studies in cell-based therapies, there
will be special concerns for patient safety and data integrity. Current regulation,
policies and procedures in place for data and safety monitoring will be critical for
clinical studies and trials of cell-based therapies.
Blood Diseases
One of the goals required for cell-based therapies is investigating the role of the
immune system to understand how it regulates cell function, contributes to stem cell
and progenitor cell repair, or results in highly specific cellular subset
engraftment. It will be important to determine if a cell-based therapy enjoys immune
tolerance and, if not, how to develop an immune-tolerant pool of donor stem cells. An
evaluation of the immunogenicity of mesenchymal stem cells compared to hematopoietic
stem cells, or of differentiated cells within organ allografts, as well as, the
interplay with dendritic cells could reveal whether some stem cell populations have
alternative mechanisms for inhibiting or evading alloresponsive T cells, such as
those operating in the developing fetus. It is critical to bear in mind that clinical
translation to heart, lung and blood disorders will require knowledge of the
fundamental processes involved in the immune aspects of cell-based therapy and
regenerative medicine.
Clinically, cell-based therapies may utilize cell infusion, cell mobilization from
tissues, in situ cell regeneration, or tissue engineering to repair or replace
tissues and organs. Reparative or regenerative approaches could use autologous or
allogeneic cells that may or may not be from a specific cell lineage subset or be
manipulated through genetic modifications. Therapeutic candidates include new
reconstitution strategies to establish or enhance immunological function or replenish
and rejuvenate quiescent or senescent multi-potential stem cell or lineage-specific
cellular growth, expansion and maturation. With the anticipation that allogeneic
cellular products will be required for replacement, repair or regenerative purpose,
the mechanism of immune tolerance will need further exploration and definition, as
well as, discovery of effective means for tolerance induction, manipulation, and
maintenance. Basic and translational studies could explore directed differentiation,
cell subset function and characterization, and subset cellular modification.
However, research plans aimed at full hematopoietic reconstitution, for example,
standard hematopoietic stem cell transplantation, using known stem cell sources will
not be considered responsive.
Heart Disease
Ventricular remodeling and ultimately heart failure are the inexorable consequences
of substantial myocardial infarction. Current options for treatment of myocardial
infarction and subsequent failure suffer from specific limitations. In light of the
limited efficacy and co-morbidity of these current treatment options, alternative,
additional long-term therapeutic strategies are needed. Cardiac repair is one
potential new therapeutic option. Through cellular therapies, the concept of
"growing" heart muscle and vascular tissue and manipulating the myocardial cellular
environment has revolutionized the approach to treating heart disease. In the heart,
cellular repair strategies can include (1) therapies that prompt the body to
regenerate damaged tissue, (2) tissue engineering techniques for the development of
replacement tissue, and (3) direct transplantation of cells into damaged
environments.
The regeneration of damaged heart tissue may include the mobilization of progenitor
or stem cells to the damaged area or stimulation of a regenerative program within the
organ. Recent studies have suggested that stem cells resident within the bone marrow
or peripheral blood can be recruited to the injured heart. In addition, there is now
evidence accumulating that the heart contains resident stem cells that can be induced
to develop into cardiac muscle and vascular tissue. Two of the most widely used cell
types for cardiac repair today are skeletal muscle-derived progenitors, or myoblasts,
and bone marrow-derived progenitors. Both cell types share advantages over other
cells proposed for cardiac repair in that they are readily available, autologous, and
easily expanded in vitro. A limitation to the efficacy of myoblasts is their
apparent inability to transdifferentiation into cardiac or endothelial cells. In
contrast, bone marrow-derived stem cells are currently gaining favor because of their
seeming plasticity, which could allow them to alter their phenotype in response to
cues from the target organ, and the possibility of using the patient’s own cells. A
few recent clinical studies advocate the simple extemporaneous reinjection of
unfractionated bone marrow cells in patients with acute myocardial infarction.
However, since such studies have been performed at the acute stage of the ischemic
insult, their relevance to chronically infarcted myocardium remains uncertain.
Vascular Diseases
Pathologies of the peripheral vasculature are responsible for a wide variety of
clinical conditions associated with considerable mortality and particularly high
morbidity. Leg pain, impaired mobility, and even amputation are frequent
consequences of peripheral arterial disease (PAD), with serious effects on functional
capacity and quality of life. Many patients with ischemic limbs experience reduced
blood flow to those limbs. Current treatment options are inadequate, particularly
when revascularization has failed or is not an option. Infusion of endothelial
progenitor cells has been shown to induce angiogenesis in animal models of limb
ischemia. Preliminary studies have shown that patients with ischemic legs benefited
form injection of autologous bone marrow mononuclear cells. There was a significant
increase of capillary formation in the injected limbs. Cell-based therapies offer a
means of stimulating blood vessel formation to improve blood flow to ischemic limbs.
Loss of blood supply to nerves results in diabetic neuropathy, a complication of
diabetes. Similar to PAD, leg pain, impaired mobility, and amputation are frequent
consequences of diabetic neuropathy and treatment options are limited. Angiogenesis
induced by gene transfer have shown promise to resolve some of these consequences.
Cell-based therapies offer another option.
Drug eluting stents have reduced the rate of restenosis significantly. However,
restenosis continues to be a problem after revascularization. Re-edothelialization
reduces restenosis. The origin of the endothelial cells in re-edothelialization is
not clear. It is important to understand whether the new endothelial layer results
from proliferation of the adjacent endothelial cells, or is contributed by bone
marrow derived, resident or circulating endothelial progenitor cells. Some studies
suggest that bone marrow derived stem cells contribute to neovascularization by
providing the necessary growth factors, and the host tissue provides the cells
forming the vessel. Understanding the origin of stem cells that contribute to
neovascularization, as well as the origin of cells that form the new vessels is an
area of great interest.
Lung Diseases
The unique properties of the lung provide inherent obstacles, but also opportunities
for a cell-based therapy strategy for diseases of this organ. One major obstacle is
the slow turnover of lung cells. As a result, lung engraftment may require prior
treatments to create space for exogenously administered cells. It is notable that
the growing lung has heightened cell turnover, and thus, may be a more amenable
therapeutic target than its adult counterpart. Another limitation is conceptual: a
more complete understanding of the factors and cues that control lung cell
differentiation would provide additional tools for a cell-based therapeutic strategy.
The multitude of cell types that comprise the intact lung contribute to the
complexity of this issue. Defining marrow cell subtypes that have the capacity to
differentiate into particular lung cell lineages is another key issue. The
appropriate homing and insertion of exogenously delivered precursor cells to specific
parenchyma sites require migration through vessel walls, basement membranes, and the
extracellular space.
Organ injury may improve engraftment efficiency, in part, by breaching the integrity
of anatomical barriers, and by causing release of local inflammatory chemoattractant
substances. Hence, migration of marrow cells into an acutely injured heart or lung
will likely be facilitated. Indeed, distal injury to lung or heart appears to
significantly enhance homing, engraftment and differentiation of marrow cells into
alveolar T1 or myocardial cells in mice. The unique anatomical configuration of the
lung, however, suggests the possibility of direct airway delivery in conditions that
are not associated with significant inflammation or alterations in barrier function.
Moreover, the lung has a very extensive capillary network and receives the entire
cardiac output. Thus, the overall delivery of cells to the lung may not be limiting.
Rather, targeting and migration into specific micro-anatomical compartments is likely
to be a formidable limitation.
Organization of the Specialized Centers for Cell-based Therapy
Specialized Centers for Cell-based Therapy (SCCT) will be a cooperative program of
three or more Specialized Centers, one Data & Coordinating Center, and the National
Heart, Lung, and Blood Institute (NHLBI). The number of funded clinical research
projects in each SCCT application must be equal to or greater than the number of
basic science projects. However, a key feature of this SCCT program is the ability
to matriculate a clinical project, beginning with preclinical studies conducted in
year one or in year one and two, in order to complete an Investigational New Drug
(IND) application required for the initiation of Phase I II clinical studies. By
the beginning of the third year of the program, clinical projects should commence
clinical studies. The specific components of the new SCCT program are detailed below
in this RFA.
With the establishment of a Data & Coordinating Center (DCC), important and novel
research issues can be addressed which would not be possible with the individual
resources available at any one individual Specialized Center for Cell-based Therapy.
The primary objectives of the DCC will be to (1) establish and maintain a database
for cell-based therapy including cellular characteristics and preclinical and
clinical outcome data collected at SCCT sites, (2) assess availability and potential
use of existing databases and how they could be incorporated or made compatible, (3)
provide instruction and data quality control across all participating sites, (4)
provide assistance to SCCT investigators in planning and conducting research studies
using the database, (5) provide regulatory guidance and facilitate interactions with
regulatory authorities, (6) make available virtual catalog of cellular products
developed by SCCT studies for use in SCCT clinical studies, (7) coordinate activities
of the Steering Committee, Protocol Review Committee, and Data and Safe Monitoring
Board including meetings and teleconference calls, and (8) administer SCCT funds for
clinical studies.
A Steering Committee will be the main governing body of the program and, at a
minimum, will be composed of the principal investigator and one co-investigator from
each Specialized Center, the principal investigator from the Data & Coordinating
Center (DCC) and the NHLBI project scientists. The Steering Committee may be
assisted by other members of SCCT staff, DCC staff, representatives from the stem
cell research community, and special consultants. The Steering Committee
Chairperson, who will be someone other than an NHLBI staff member and may be someone
other than a principal investigator, will be selected by NHLBI. The Specialized
Centers, the Data & Coordinating Center, and NHLBI each will have one vote on the
Steering Committee. The Steering Committee may meet once or twice a year in
Bethesda, MD and may meet as often as monthly by telephone conference call in the
first 12 months of the program, and every other month thereafter. All major
scientific decisions will be determined by majority vote of the Steering Committee.
The Steering Committee will have primary responsibility for the general organization
of the program, facilitating the conduct and monitoring of protocols and studies, and
reporting study results. The Committee will be responsible for evaluating clinical
protocols, participating in their overall development, conducting the research, and
disseminating research findings. All clinical projects submitted by applicants,
that receive Center awards, will be considered for implementation and reimbursement
by the Steering Committee.
Subcommittees of the Steering Committee will be established as necessary; for
example, it is envisioned that a Publications Committee will prioritize, facilitate
and supervise preparation and review of manuscripts prior to submission for
publication. Subcommittees to oversee reporting of outcomes, e.g. clinical benefits,
toxicities, adverse events, and graft versus host disease are also envisioned. Data
collections will be monitored in a manner consistent with Guidelines for Data Quality
Assurance in Clinical trials and Observational Studies
http://www.nhlbi.nih.gov/funding/policies/dataqual.htm.
A Protocol Review Committee (PRC), established by NHLBI, will conduct a protocol
review before each clinical study is initiated and will monitor patient safety and
data analysis. The DSMB will review the performance of each study approximately
semi-annually. As a part of its monitoring responsibility, the DSMB will submit
recommendations to NHLBI regarding the continuation of each study and prepare a
report for principal investigators to provide to their Institutional Review Board
(IRB.)
Research Topics
The objective of the SCCT for Cell-Based Therapy for Heart, Lung, and Blood Diseases
is to stimulate clinically relevant, multidisciplinary collaborations leading to
clinical and basic science research efforts on important public health problems for
individuals with heart, lung, and blood disease. The translation of knowledge into
clinical practice should be a goal of applications submitted in response to this
initiative. Recent advances in the understanding of stem cell and progenitor cell
biology, transplantation of autologous and allogeneic cells for the treatment of
disease, the development of cellular and molecular imaging tools and markers, and the
management of immune reconstitution after stem cell transplantation offer potential
novel approaches to clinical problems in heart, lung, blood systems, and sleep
disorders. Centers are encouraged to undertake multi-disciplinary approaches, to
include projects that address more than one therapeutic area, and to propose clinical
research projects leading to early Phase clinical trials.
Projects outside of the scope of this announcement are:
o studies that are not focused on a cell-based therapy;
o studies that exclusively focus on gene therapy or gene transfer rather than
cellular therapy;
o studies that do not address heart, lung, and blood diseases, or sleep disorders;
o studies that use bone marrow stem cells in known protocols rather than in novel
treatments for the regeneration of lineage-specific cellular replenishment, immune
recovery to establish broad immune competence, or for establishment of allogeneic
tolerance to cellular therapeutics.
It is highly recommended that prospective applicants discuss possible applications
with program staff to ensure that proposed projects are appropriate to this SCCT
program. The following examples of research topics are intended to provide a
perspective on the scope of research that would meet the objectives of this program.
It is not required that all or any of these topics be included. Applicants are
encouraged to consider other topics that are relevant to the goals of the new SCCT
program for Cell-based Therapy. A unified program of clinical and basic research is
needed to address such topics as:
o Develop cellular neovascularization strategies for the treatment of chronic
myocardial ischemia, pulmonary arterial hypertension, peripheral vascular disease,
stroke, or the cardiovascular complication of diabetes such as diabetic neuropathy;
o Cell-based approaches to the treatment of vascular disease including stimulating
revascularization, tissue engineering approaches to treating various vascular
diseases, and therapies involving stem cell differentiation relevant to vascular
disease;
o Novel cell-based therapies and tissue engineering approaches for treating diseased
and damaged cardiac tissue, including contractile dysfunction or failure,
arrhythmias, myocardial remodeling, or developmental abnormalities;
o Cellular therapies for the myocardium to treat myocardial infarction by providing
myocardial myocyte protection, stimulating myocyte regeneration during the peri-
infarct period, and by preventing chronic heart failure during the post-myocardial
infarct period;
o Studies to compare sources of cells and to increase understanding of cell
distribution and delivery routes including adherence or trapping of cells in the
lungs that may lead to acute lung injury reactions;
o Characterization of resident lung or circulating stem and progenitor cells,
understanding the signals that determine how these cells may be marginated from the
pulmonary blood stream into the pulmonary interstitium, and activated to replace the
pulmonary epithelium;
o Cell-based approaches including the expansion of genetically engineered lung
progenitor cells to treat of degenerative lung diseases, e.g., emphysema, pulmonary
or alveolar hypoplasia, or pulmonary fibrosis;
o Studies to understand the contribution of endogenous or circulating stem or
progenitor cells to lung tissue maintenance, regeneration, or disease;
o Novel approaches to developing marrow-derived cell therapies such as stem cell
expansion pathways and applications for mesenchymal stem cells;
o Bioengineering of cellular devices that prevent thrombogenesis;
o Studies addressing safety of cell-based therapy including tumorgenesis;
o Identify genotype-phenotype correlations, modifier genes, pharmacologic
manipulation, and genetic variation that influences therapeutic success of cell-based
therapy, as well as the incidence of adverse clinical events;
o Develop imaging and biomarker tools which can aid in the evaluation of clinical
cell-based treatments;
o Novel uses of peripheral blood or marrow cells for the regeneration of immunity or
for establishment of tolerance to cellular transplantation;
o Basic research on stem cell differentiation, proliferation, and interactions during
development to enable the use of highly specific cells as sources of therapeutic cell
products to treat disease.
o Understanding the origin of stem cells that contribute to neovascularization, as
well as the origin of cells that form the new vessels;
o Characterization of bone marrow derived, resident or circulating endothelial
progenitor cells;
o Development of novel cell-based therapies for diseases with heart, lung, or blood
complications, e.g., diabetes, congenital disorders, or enzyme deficiencies.
Research Resources
The SCCT organizational structure provides both the incentive and the structure to
maintain critical collaborative cores or other resources necessary for translational
research. In addition, the SCCTs are encouraged to establish collaborative
relationships with other NHLBI programs in order to utilize the considerable
resources already available. These NHBLI programs include:
o Center applicants are encouraged to work with small businesses to develop medical
devices, tests, drugs or biologics required to safely initiate new cell-based
therapies. The recipient of NIH SBIR Phase I and Phase II awards may receive up to a
total of $850,000. The NHLBI program Competing Continuation Awards of SBIR Phase II
Grants for Heart, Lung, Blood, and Sleep Disorders (PA-04-028) provides Phase II
competing continuation support to small businesses for up to $1,000,000 total costs
per year and time periods up to 3 years for additional Phase II research to address
clinical issues, and other important issues relevant to regulatory approvals by
agencies such as the FDA
(http://grants.nih.gov/grants/guide/pa-files/PA-04-028.html).
o Programs Of Excellence In Gene Therapy (PEGT) for Heart, Lung, and Blood Diseases
with National Service Cores for Pre-Clinical Grade Vector Production, Cell
Morphology, Hematopoietic Cell Processing, and Non-Human Primate Hematopoietic
Transplantation (http://www.med.cornell.edu/pegt/).
o Programs for Genomic Applications (PGA) which include resources for animal modeling
and phenotyping, clinical and physiological studies, databases and software tools,
bioinformatics, expression profiling, mutagenesis, proteomics, SNP’s and genotypes,
comparative sequence analysis, educational programs, biomedical topics, and
biochemical pathways (http://www.nhlbi.nih.gov/resources/pga/).
o NHLBI Proteomics Centers
(http://www.nhlbi.nih.gov/resources/medres/proteomics/index.htm).
o The Centers for Fetal Monkey Gene Transfer for Heart, Lung, and Blood Diseases at
the California National Primate Research Center
(http://www.cfmgt.ucdavis.edu/).
o NHBLI Somatic Cell Therapy Processing Facilities (RFP under BAA-HB-03-06) and the
Somatic Cell Therapy Processing Administrative Centers (RFP under NHLBI-HB-03-07) for
the development of clinical, Good Manufacturing Practices (GMP) grade cell products
(http://www.nhlbi.nih.gov/funding/inits/archive/hb03-06a1.htm).
In addition, new non-invasive imaging technologies to be developed by the program for
Cellular and molecular imaging of the cardiovascular, pulmonary, and hematopoietic
system would also support SCCT activities
(http://grants.nih.gov/grants/guide/rfa-files/RFA-HL-04-003.html).
MECHANISM OF SUPPORT
This RFA will use the NIH U54 cooperative agreement award mechanism. All applications
received in response to this RFA will be considered as new applications and must meet
the requirements for the SCCT program. Under the cooperative agreement, the NIH
assists, supports, and/or stimulates, and is substantially involved with recipients
in conducting a study by facilitating performance of the effort in a "partner" role.
Details of the responsibilities, relationships, and governance of a study funded
under a cooperative agreement are discussed later in this document. The anticipated
award date is September 2005.
Each NHLBI SCCT program is limited to 10 years of support. Under this policy, a
given SCCT grant is awarded for a 5-year project period following an open
competition. Only one 5-year competing renewal is permitted, for a total of 10 years
of support.
The NHLBI comprehensive evaluation of the Specialized Centers For Cell-Based Therapy
for Heart, Lung, and Blood Diseases program will be conducted during the second
project period according to the following timetable:
Program Announced: FY 2004
Project Period (First Competition): FY 2005 through FY 2009
Program Re-announced: FY 2007
Project Period (Second Competition): FY 2010 through FY 2014
Letter to Principal Investigators
Regarding SCCT Evaluation Plans: FY 2011 (mid-way through year 02
of 2nd project period)
SCCT Evaluation Meeting: FY 2012
of 2nd project period
The NHLBI does not limit the number of applications for Specialized Centers or for
the DCC from one institution. However, each SCCT and DCC application must have a
different principal investigator, must be self-contained, and independent from any
other application from the same institution. Institutions envisioning more than one
application are strongly encouraged to discuss their plans with the program contact
listed under Inquiries.
FUNDS AVAILABLE
The NHLBI intends to commit approximately $7,450,000 in FY 2005 to fund three or more
grants for Specialized Centers for Cell-based Therapy (SCCT) and one grant for a Data
& Coordinating Center (DCC).
Specialized Centers for Cell-based Therapy (SCCT) applicants should request a 5 year
budget and may propose an annual budget of up to $2,330,000 in total costs for the
initial year. These total costs include facilities and administrative (F&A) costs.
Total costs for the SCCT budget may be escalated at 3 percent for future years.
Funds for SCCT clinical studies will be administered by the Data & Coordinating
Center.
Data & Coordinating Center (DCC) applications must be submitted separately from
Specialized Centers for Cell-Based Therapy (SCCT) applications. The Data &
Coordinating Center (DCC) should request a project period of five years and may
request up to $450,000 total costs in year one and two and up to $750,000 in total
costs in years three, four, and five. The DCC will also administer the clinical
research funds for SCCT clinical studies. All applications will be considered as new
applications. Because the nature and scope of the proposed research will vary from
application to application, it is anticipated that the size of each award will also
vary. Although the financial plans of the NHLBI provides support for this program,
awards pursuant to this RFA are contingent upon the availability of funds and the
receipt of a sufficient number of meritorious applications.
Consortium Arrangements
If a grant application includes research activities that involve institutions other
than the grantee institution, the application will be considered a consortium effort.
Such applications are permitted, but it is imperative that the application be
prepared so that the programmatic, fiscal, and administrative considerations are
explained fully. At least 50 percent of the projects (including at least one
clinical project) and 50 percent of the cores must be located at the applicant
institution. The NIH published policy governing consortia is available in the
business offices of institutions that are eligible to receive Federal grants-in-aid
and should be consulted before developing the application. For clarification of the
policy, contact Ms. Ryan Lombardi, Grants Operations Branch, NHLBI, (301) 435-0177.
Applicants for SCCT grants should exercise great care in preserving the interactions
of the participants and the integration of the consortium project(s) with those of
the parent institution, because synergism and cohesiveness can be diminished when
projects are located outside the group at the parent institution.
ELIGIBLE INSTITUTIONS
You may submit (an) application(s) if your institution has any of the following
characteristics:
o For-profit or non-profit organizations
o Public or private institutions, such as universities, colleges, hospitals, and
laboratories
o Units of State and local governments
o Eligible agencies of the Federal government
o Domestic institutions/organizations
o Foreign institutions are not eligible to apply.
o Faith-based or community-based organizations
INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS
Individuals with the skills, knowledge, and resources necessary to carry out the
proposed research are invited to work with their institution to develop an
application for support. Individuals from underrepresented racial and ethnic groups
as well as individuals with disabilities are always encouraged to apply for NIH
programs.
Awards for a Specialized Center and a Data & Coordinating Center under this RFA will
not be made to the same Principal Investigator to ensure that data analysis is
conducted independently of data acquisition. The same institution may apply for both
a Specialized Center and the Data & Coordinating Center award, but the applications
for each must be from different individuals and must be self-contained and
independent of the other application for the same institution.
SPECIAL REQUIREMENTS
1. The overall concept of a SCCT program focuses on clinical and basic scientific
issues related to diseases and disorders relevant to the mission of the NHLBI. To be
considered responsive to this announcement, all applications must include both
clinical and basic research. In addition, interactions between clinical and basic
scientists are expected to strengthen the research, enhance the translation of
fundamental research findings to the clinical setting, and identify new research
directions. Translation of findings from basic to clinical studies is an important
focus of the SCCT program.
2. In order for a project to be considered clinical research for the purposes of
responsiveness to this RFA, the research must be patient-oriented research. Patient-
oriented research is research in which an investigator (or colleague) directly
interacts with patients having a disease or condition of interest. Normal healthy
subjects may be included, but only in combination with studies involving patients.
In studies involving the use of human specimens, the investigators must have direct
interaction with the patient from whom the specimen is obtained and relate the
research results to the patient status or outcome for this to be considered a
clinical project. It is intended that the requirement for investigator interaction
with the study participants will eliminate research involving archived tissue.
3. The number of funded clinical research projects in each NHLBI SCCT must be equal
to or greater than the number of basic science projects. In addition, preclinical
studies can be conducted in year one or in year one and two of a clinical project in
order to meet the requirements for an Investigational New Drug (IND) application
prior to initiating clinical studies. Beginning in the third year of the 5-year
project period, each clinical project must initiate clinical studies. For example,
if an application has a total of three projects, two must be clinical projects that
begin clinical research studies by the third year. Neither a clinical component in a
basic science project nor a clinical core fulfills the requirement for a clinical
project. However, a single project can integrate basic and clinical research. If
the majority of the research within a project is clinical, it will be considered a
clinical project; if the majority of the research within a project is basic, it will
be considered a basic project. Applicants will indicate whether a proposed project
is basic or clinical. Questions should be discussed prior to submission with
program staff listed under WHERE TO SEND INQUIRES. Because a SCCT grant is a 5-year
program, an applicant should submit a 5-year plan for all the projects.
Applicants are encouraged to pursue patient-oriented research on topics related to
health disparities and the translation of this research to clinical practice for
affected minority populations. At a minimum, clinical research projects must include
women and minorities in the study population in representative numbers, unless such
inclusion can be demonstrated to be inappropriate. Clinical studies involving
interventions or treatments must give consideration to including sufficient numbers
of women and minorities to conduct valid analyses of subgroup effects. Human
biomedical and behavioral studies of etiology, pathogenesis, prevention and
prevention strategies, diagnostic approaches, and treatment of cardiac diseases,
disorders or conditions are responsive. However, epidemiologic studies or Phase III
clinical trials will be considered unresponsive to this RFA.
4. Each awarded SCCT must consist of three or more projects, all of which are
directly related to the overall clinical focus of the SCCT. At least 50 percent of
the projects and 50 percent of the cores must be located at the applicant institution
and at least one of the clinical projects must be at the applicant institution.
Component projects not located at the applicant institution may be at a foreign
institution, but must conform to NIH policy regarding the protection of human
subjects. Each component project, whether clinical or basic, requires a well-
described clinically relevant hypothesis, preliminary data, and a time-table for
conducting the proposed investigations.
5. Each SCCT may include one or more cores. The relationship of each core to each
component project should be described. A core must provide services to two or more
projects.
6. Each Specialized Center must have a well-delineated organizational structure and
administrative mechanism that foster interactions between investigators, accelerate
the pace of research, enable translation of basic research findings to clinical
applications, and ensure a productive research effort. The structure must include
administrative support for protocol development.
7. Specialized Center applicants should provide a detailed data and safety monitoring
plan for the clinical research proposed; the monitoring plan will be considered as
part of the peer review of the application. This plan should address informed
consent, recruitment, reporting of adverse events, patient safety, oversight of
clinical issues in the protocols, storage and analysis of confidential data, and
dissemination of any research results. After a decision has been made regarding SCCT
awards, the Institute will determine whether to convene a Data and Safety Monitoring
Board (DSMB) to oversee one or more clinical projects in a SCCT program.
8. The principal investigator should be an established research scientist with the
ability to ensure quality control and the experience to administer both clinical and
basic research effectively and integrate all components of the program. A minimum
time commitment of 25 percent is required for this individual. The principal
investigator must be the project leader of one of the component research projects.
If this project is not recommended by peer review, the overall SCCT application will
not be considered further. If this project is judged by peer review to be of low
scientific merit, this will markedly reduce the overall scientific merit ranking
assigned to the entire application.
9. Project leaders should have significant research experience and must agree to
commit at least 20 percent effort to each project for which they are responsible.
Leaders of clinical projects should have experience in clinical research as defined
in Item 2, above. Investigators with minimal research experience, but promising
credentials, may participate; however, it is expected that most of the project
leaders will be investigators with significant research experience.
10. Applicants are encouraged to establish links and utilize existing resources,
including the NHLBI Programs Of Excellence In Gene Therapy (PEGT), Program in Genomic
Applications (PGA), NHLBI Proteomics Centers, NHLBI Centers for Fetal Monkey Gene
Transfer, NHBLI Somatic Cell Therapy Processing Centers, NHLBI clinical research
networks, and General Clinical Research Centers (GCRC), as feasible and appropriate.
If applicants propose to utilize such resources, a letter of agreement from the
program director or principal investigator of the resource should be included with
the application.
11. Upon initiation of the program, the sponsoring Institute will arrange annual
meetings to encourage the exchange of information among investigators who participate
in this program. In the preparation of the budget for the grant application,
applicants should include travel funds for one meeting each year to be held in
Bethesda, Maryland. Applicants should also include a statement in the applications
indicating their willingness to participate in such meetings.
12. Applicants for the Data & Coordinating Center (DCC) should present a description
of plans to (1) develop and maintain a common data set of cellular products aimed at
repair and regeneration of damaged and/or dysfunctional heart, vascular, lung, and
blood systems (2) survey existing database structures and integrate common variables
and index non-conforming variables in a central database (3) develop and implement a
web-based system to coordinate SCCT center activities, and collect data and adverse
events on SCCT studies (4) develop an interactive web-based virtual catalog of
cellular products developed by SCCT sites (5) provide consultation on study design and
statistical analysis to SCCT centers (6) provide regulatory guidance and facilitate
interactions with regulatory authorities, and (7) provide coordination of meetings and
reports including the Steering Committee, Data & Safety Monitoring Board (DSMB),
Protocol Review Committee (PRC), and federal regulatory agencies. The DCC will also
administer SCCT funds for clinical studies.
13. The DCC staff should have appropriate expertise and capability in biostatistics,
web-based data management, data analysis, and project management. Prior experience in
complex large-scale collaborative studies is desired. The DCC Principal Investigator
or other key staff should have knowledge of cell-based therapy research and experience
in interacting with federal regulatory agencies.
COOPERATIVE AGREEMENT STATEMENT TERMS AND CONDITIONS
The cooperative agreement is an award instrument establishing an "assistance"
relationship (in contrast to an "acquisition" relationship) between NHLBI and a
recipient, in which substantial NHLBI scientific and/or programmatic involvement with
the recipient is anticipated during performance of the activity. The NHLBI purpose
is to support and/or stimulate the recipient's activity by involvement in and
otherwise facilitating the activity in a "partner", but avoiding a dominant role,
direction, or prime responsibility. The terms and conditions, below, elaborate on
these actions and responsibilities, and the awardee agrees to these collaborative
actions with the NHLBI Project Scientist toward achieving the project objectives. It
is anticipated that these terms and conditions will enhance the relationship between
the NHLBI staff and the principal investigator(s), and will facilitate the successful
conduct and completion of the study. These agreements will be in addition to, and
not in lieu of, the relevant NIH procedures for grants administration. The terms
will be as follows:
1. The awardee(s) will have lead responsibilities in all aspects of their protocols,
including any modification of study design, conduct of the study, quality control,
data analysis and interpretation, preparation of publications, and collaboration with
other investigators, unless otherwise provided for in these terms or by action of the
Steering Committee.
2. The NHLBI Project Scientist (Dr. John Thomas) will serve on the Steering
Committee; he/she or other NHLBI scientists may serve on other study committees, when
appropriate. The NHLBI Project Scientist (and the other NHLBI scientists) may work
with awardees on issues coming before the Steering Committee and, as appropriate,
other committees, e.g., recruitment, intervention, follow-up, quality control,
adherence to protocol, assessment of problems affecting the study and possible
changes in the protocol, interim data and safety monitoring, final data analysis and
interpretation, preparation of publications, and development of solutions to major
problems such as insufficient participant enrollment.
3. Awardee(s) agree to the governance of the study through a Steering Committee.
Steering Committee voting membership shall consist of the principal investigators
(i.e., cooperative agreement awardees), the NHLBI Project Scientist, and the
Chairperson. Meetings of the Steering Committee will ordinarily be held by telephone
conference call or in the metropolitan Washington Area.
4. A Data and Safety Monitoring Board will be appointed by the Director, NHLBI to
provide overall monitoring of interim data and safety issues; the Steering Committee
will nominate members for this Board. Meetings of the Data and Safety Monitoring
Board will ordinarily be held in Bethesda. An NHLBI scientist other than the NHLBI
Project Scientist shall serve as the Executive Secretary to the Board. An
independent Protocol Review Committee, established by the NHLBI, will provide peer
review for each center protocol. Because the Board serves as an independent group
advisory to the NHLBI, study investigators will not communicate with Board members
regarding study issues, except as authorized by the Board’s Executive Secretary.
5. Awardees will retain custody of and have primary rights to their data developed
under these awards, subject to Government rights of access consistent with current
HHS, PHS, and NIH policies. The collaborative protocol and governance policies will
call for the continued submission of data centrally to the coordinating center for a
collaborative database; the submittal of copies of the collaborative data sets to
each principal investigator upon completion of the study; procedures for data
analysis, reporting and publication; and procedures to protect and ensure the privacy
of medical and genetic data and records of individuals. The NHLBI Project Scientist,
on behalf of the NHLBI, will have the same access, privileges and responsibilities
regarding the collaborative data as the other members of the Steering Committee.
6. Support or other involvement of industry or any other third party in the study --
e.g., participation by the third party; involvement of project resources or citing
the name of the project or the NHLBI support; or special access to project results,
data, findings or resources -- may be advantageous and appropriate. However, except
for licensing of patents or copyrights, support or involvement of any third party
will occur only following notification of and concurrence by NHLBI.
7. Study investigators are encouraged to publish and to release publicly and
disseminate results and other products of the study, in accordance with study
protocols and governance. Within three years of the end of the period of NHLBI
support for the project, data not previously released and other study materials or
products not previously distributed, are to be made available to individuals who are
not study investigators, provided such release is consistent with the study protocol
and governance and with paragraph 6. In addition, study investigators must establish
a plan for making data sets and materials available to the scientific community and
to the NHLBI immediately upon completion of the three year period following the end
of the period of NHLBI support.
8. The NHLBI reserves the right to terminate or curtail the study (or an individual
award) in the event of (a) failure to develop or implement a mutually agreeable
collaborative protocol, (b) substantial shortfall in participant recruitment, follow-
up, data reporting, or quality control, (c) major breach of the protocol or
substantive changes in the agreed-upon protocol with which NHLBI cannot concur, (d)
attaining of a major study endpoint substantially before schedule with persuasive
statistical significance, or (e) human subject ethical issues that may dictate a
premature termination.
9. Upon completion of the project, awardees are expected to put their intervention
materials and procedure manuals into the public domain and/or make them available to
other investigators, according to the approved plan for making data and materials
available to the scientific community and the NHLBI, for the conduct of research at
no charge other than the costs of reproduction and distribution.
10. Any disagreement that may arise in scientific/programmatic matters (within the
scope of the award), between award recipients and the NHLBI may be brought to
arbitration. An arbitration panel will be composed of three members--one selected by
the Steering Committee (with the NHLBI member not voting) or by the individual
awardee in the event of an individual disagreement, a second member selected by
NHLBI, and the third member selected by the two prior members. This special
arbitration procedure in no way affects the awardee's right to appeal an adverse
action that is otherwise appealable in accordance with the PHS regulations at 42 CFR
part 50, Subpart D and HHS regulation at 45 CFR part 16, or the rights of NHLBI under
applicable statutes, regulations and terms of the award.
11. These special terms of award are in addition to and not in lieu of otherwise
applicable OMB administrative guidelines, HHS Grant Administration Regulations at 45
CFR part 74, and other HHS, PHS, and NIH grant administration policy statements.
WHERE TO SEND INQUIRIES
We encourage inquiries concerning this RFA and welcome the opportunity to answer
questions from potential applicants. Inquiries may fall into three areas:
scientific/research, peer review, and financial or grants management issues:
o Direct your questions about scientific/research issues to:
John W. Thomas, Ph.D.
Division of Blood Diseases and Resources
National Heart, Lung, and Blood Institute
Rockledge II, Room 10154, Mail Stop 7950
Bethesda, MD 20892-7950
Telephone: (301) 435-0065
FAX: (301) 451-5453
Email: [email protected]
Mary Anne Berberich
Division of Lung Diseases / NHLBI
6701 Rockledge Drive, Room 10102, Mail Stop 7952
Bethesda, MD 20892-7952
Telephone: (301) 435-0222
FAX: (301) 480-3557
Email: [email protected]
John Fakunding, Ph.D.
Division of Heart and Vascular Diseases
National Heart, Lung, and Blood Institute
Rockledge II, Room 9170, Mail Stop
Bethesda, MD 20892
Telephone: (301) 435-0544
FAX: (301) 480-1336
Email: [email protected]
o Direct your questions about peer review issues to:
Valerie L. Prenger, Ph.D.
Chief, Review Branch
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Dr., Room 7214, MSC 7924
Bethesda, MD 20892-7924 (20817 for express/courier service)
Telephone: (301) 435-0270
FAX: (301) 480-0730
Email: [email protected]
o Direct your questions about financial or grants management matters to:
Ms. Ryan Lombardi
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
Rockledge II, Room 7157, Mail Stop 7926
Bethesda, MD 20892-7926
Telephone: (301) 435-0177
Email: [email protected]
LETTER OF INTENT
Prospective applicants are asked to submit a letter of intent that includes the
following information:
o Descriptive title of the proposed research
o Name, address, and telephone number of the Principal Investigator
o Names of other key personnel
o Participating institutions
o Number and title of this RFA
Although a letter of intent is not required, is not binding, and does not enter into
the review of a subsequent application, the information that it contains allows
Institute staff to estimate the potential review workload and plan the review.
The letter of intent is to be sent by the date listed at the beginning of this
document. The letter of intent should be sent to The Chief of Review at the address
listed under WHERE TO SEND INQUIRES.
PRE-SUBMISSION MEETING
The NHLBI intends to hold a pre-submission meeting at 9:00 AM on Monday, May 24, 2004
to which all prospective applicants are invited. The meeting will be held in Room
9104 of Two Rockledge Centre located at 6701 Rockledge Drive, Bethesda, MD 20817.
Program staff & staff from the Division of Extramural Activities (DEA) will make
presentations that explain their goals and objectives for the Centers and answer
questions from the attendees. FAQs and other information from this meeting will be
available by contacting Dr. John W. Thomas at the address listed under Where to Send
Inquiries .
SUBMITTING AN APPLICATION
Applications must be prepared using the PHS 398 research grant application
instructions and forms (rev. 5/2001). Applications must have a DUN and Bradstreet
(D&B) Data Universal Numbering System (DUNS) number as the Universal Identifier when
applying for Federal grants or cooperative agreements. The DUNS number can be
obtained by calling (866) 705-5711 or through the web site at
http://www.dunandbradstreet.com/. The DUNS number should be entered on line 11 of the
face page of the PHS 398 form. The PHS 398 document is available at
http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format.
For further assistance contact GrantsInfo, Telephone (301) 710-0267, Email:
[email protected].
SUPPLEMENTARY INSTRUCTIONS:
The Data & Coordinating Center (DCC) applications should include (1) a description of
capabilities and experience of the key personnel, (2) a description of data
coordination experience, (3) a budget with justification of expenses. For item 1,
the description of capabilities and experience should include (a) a description of
the applicant organization's facilities, resources, and how the staff's strengths in
biostatistics, web-based data management, data analysis, and project management
skills have been used in previous, successful large-scale collaborative research, (b)
a description of the knowledge and experience of the Principal Investigator and other
staff in cell-based therapy research and complying with federal regulatory
requirements in this type of research including preparation of regulatory submissions
for the Food and Drug Administration (FDA) in cell-based therapy studies or product
development, (c) description of the experience of the key personnel in assisting
protocol design, manual preparation, and data quality control in web-based data
collection systems for previous large-scale, complex research projects. For item 2,
a description of data coordinating experience include (a) a presentation of the
applicant's record in generating reports on data collection and monitoring
performance in previous large-scale collaborative projects, including preparation of
manuscripts, (b) a description of how logistical services and organizational support
have been utilized in managing resources and monitoring performance in previous
large-scale, collaborative research and propose an administrative and management
structure that would support the SCCT centers, and (c) a describe the platform for
the web-based data collection system and propose a structure for developing,
maintaining, and coordinating a minimal data set; and integrating common variables
and indexing non-conforming variables in a central database, and (d) a description of
procedures for maintaining data integrity across centers to assure confidentiality of
subjects in SCCT clinical studies. Applications must include documentation of the
ability to properly acquire clinical data. The NIH brochure entitled "Research on
Human Specimens: Are You Conducting Research Using Human Subjects?
(http://www.cdp.ims.nci.nih.gov/policy.html) and OHRP guidance on Repositories, Tissue
Storage Activities and Data Banks (http://www.hhs.gov/ohrp/humansubjects/guidance/reposit.htm) are
available for guidance on these topics. For item 3, a budget with justification of
expenses, all proposals should request and provide justification for five years of
support. The total costs requested for applications may not exceed $450,000 in years
one and two, and $750,000 in years three through five. These costs should include
those for logistical arrangements for the Steering Committee, the Protocol Review
Committee (PRC), and the Data & Safety Monitoring Board (DSMB) meetings including
meeting room rental and audio video expenses plus additional teleconferences.
Steering Committee meetings will be held twice each year, PRC and DSMB meetings will
be held once in years 1 and 2 and twice in years 3 to 5. Funds for SCCT clinical
studies will be awarded in addition to the above ceilings.
USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 5/2001) application
form must be affixed to the bottom of the face page of the application. Type the RFA
number on the label. Failure to use this label could result in delayed processing of
the application such that it may not reach the review committee in time for review.
In addition, the RFA title and number must be typed on line 2 of the face page of the
application form and the YES box must be marked. The RFA label is also available at:
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf.
SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of the
application, including the Checklist, and three signed, photocopies, in one package
to:
Center for Scientific Review
National Institutes of Health
6701 Rockledge Drive, Room 1040, MSC 7710
Bethesda, MD 20892-7710
Bethesda, MD 20817 (for express/courier service)
At the time of submission, two additional copies of the application must be sent to
The Chief of Review at the address listed under WHERE TO SEND INQUIRES.
Please note that applications delivered by individuals are no longer accepted; all
applications must either come via courier delivery or the USPS
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-012.html).
APPLICATION PROCESSING: Applications must be received by the application receipt
date listed in the heading of this RFA. If an application is received after that
date, it will be returned to the applicant without review.
The Center for Scientific Review (CSR) will not accept any application in response to
this RFA that is essentially the same as one currently pending initial review, unless
the applicant withdraws the pending application. However, when a previously unfunded
application, originally submitted as an investigator-initiated application, is to be
submitted in response to an RFA, it is to be prepared as a NEW application. That is,
the application for the RFA must not include an Introduction describing the changes
and improvements made, and the text must not be marked to indicate the changes from
the previous unfunded version of the application.
Principal investigators should not send supplementary material without first
contacting the Scientific Review Administrator (SRA). The SRA will be identified in
the letter sent to you indicating that your application has been received. If you
have not received such a letter within three weeks after submitting the application,
contact The Chief of Review at the address listed under WHERE TO SEND INQUIRES.
PEER REVIEW PROCESS
Upon receipt, applications will be reviewed for completeness by the CSR and
responsiveness by the NHLBI. Incomplete and/or non-responsive applications will be
not be reviewed.
Applications that are complete and responsive to the RFA will be evaluated for
scientific and technical merit by an appropriate peer review group convened by the
NHLBI in accordance with the review criteria stated below. As part of the initial
merit review, all applications will:
o Undergo a process in which only those applications deemed to have the highest
scientific merit, generally the top half of the applications under review, will be
discussed and assigned a priority score
o Receive a written critique
o Receive a second level review by the National Heart, Lung, and Blood Advisory
Council.
REVIEW CRITERIA
REVIEW CRITERIA FOR SPECIALIZED CENTERS
The goals of NIH-supported research are to advance our understanding of biological
systems, improve the control of disease, and enhance health. Factors to be
considered in the evaluation of each application will be similar to those used in the
review of traditional clinical and basic research grant applications and, in
addition, will include overall proposed interactions between clinical and basic
research projects. The review panel will include a majority of clinical researchers
who will receive special instructions to place emphasis on strong clinical
components. Major factors to be considered in the evaluation of applications
include:
o Scientific merit of the proposed clinical and basic research projects including
significance, importance, clinical relevance and appropriateness of the theme;
innovation, originality, and feasibility of the approach; adequacy of the
experimental design; and potential for clinical research projects to lead to early
Phase clinical trials.
o Leadership, scientific expertise, experience, and commitment of the principal
investigator; competence of the investigators to accomplish the proposed research
goals and their time commitment to the program; clinical research experience among
the investigators; and the feasibility and strength of consortium arrangements.
o Collaborative interaction between clinical and basic research components, the
required number of clinical projects, and plans for transfer of potential findings
from basic to clinical studies.
o Adequacy of the environment for performance of the proposed research including
clinical populations and/or specimens; laboratory facilities; quality of the support
cores; proposed instrumentation; quality controls; administrative structure;
institutional commitment; and, when needed, data management systems.
o Adequacy of the data and safety monitoring plan for the clinical research proposed.
Each project will receive a priority score. Each core will be Recommended or Not
Recommended based on whether the core is essential for the proposed research and has
the capability to fulfill the proposed function. Reviewers will evaluate the number
of projects serviced by the core; strengths and weaknesses of the proposed
approaches, resources, and interactions; whether the investigators are qualified for
their role(s) in the core; and whether the proposed budget for the core is
appropriate. Each application will receive an overall priority score based on the
review criteria listed above.
REVIEW CRITERIA FOR DATA & COORDINATING CENTER
o COORDINATING EXPERIENCE: Documentation of the specific competence and previous
experience of professional, technical, and administrative staff pertinent to the data
center. Prior experience should be demonstrated in similar programs, for the
collection of data from multiple locations using a web-based data collection system,
as well as experience in monitoring the quality and timeliness of such data. Also
the ability to monitor and distribute clinical study funds should be demonstrated.
o CLINICAL RESEARCH EXPERIENCE: Documentation of the specific competence and
previous knowledge of professional staff with cell-based therapy research and
complying with federal regulatory requirements in this type of research.
o APPROACH TO DATA HANDLING: Merit and suitability of the proposed approach to
developing, managing, and coordinating a web-based database and data collection
system for cell-based therapies as outlined in the RFA and the adequacy of the
proposed facility and technical hardware and appropriateness of the budget for the
work proposed. Suitability of plans for maintaining data integrity across centers to
assure confidentiality of subjects in SCCT clinical studies and for collecting
clinical data.
o MANAGEMENT PLAN AND ORGANIZATION: Merit and suitability of the proposed
administrative and management structure that would support the coordination of the
SCCT centers, including evidence of the degree of commitment and support of the
organization or institution for the proposed program.
ADDITIONAL REVIEW CRITERIA FOR ALL APPLICATIONS
PROTECTION OF HUMAN SUBJECTS FROM RESEARCH RISK: The involvement of human subjects
and protections from research risk relating to their participation in the proposed
research will be assessed. (See criteria included in the section on Federal
Citations, below).
INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH: The adequacy of plans to
include subjects from both genders, all racial and ethnic groups (and subgroups), and
children as appropriate for the scientific goals of the research. Plans for the
recruitment and retention of subjects will also be evaluated. (See Inclusion Criteria
in the sections on Federal Citations, below).
CARE AND USE OF VERTEBRATE ANIMALS IN RESEARCH: If vertebrate animals are to be used
in the project, the five items described under Section f of the PHS 398 research
grant application instructions (rev. 5/2001) will be assessed.
SHARING RESEARCH DATA: Applicants requesting more than $500,000 in direct costs in
any year of the proposed research must include a data sharing plan in their
application. The reasonableness of the data sharing plan or the rationale for not
sharing research data will be assessed by the reviewers. However, reviewers will not
factor the proposed data sharing plan into the determination of scientific merit or
priority score.
BUDGET: The reasonableness of the proposed budget and the requested period of
support in relation to the proposed research.
RECEIPT AND REVIEW SCHEDULE
Letter of Intent Receipt Date: August 21, 2004
Application Receipt Date: September 21, 2004
Peer Review Date: January/February, 2005
Council Review: May 2005
Earliest Anticipated Start Date: September 2005
AWARD CRITERIA
Award criteria that will be used to make award decisions include:
o Scientific merit (as determined by peer review)
o Availability of funds
o Programmatic priorities.
REQUIRED FEDERAL CITATIONS
ANIMAL WELFARE PROTECTION: Recipients of PHS support for activities involving live,
vertebrate animals must comply with PHS Policy on Humane Care and Use of Laboratory
Animals (http://grants.nih.gov/grants/olaw/references/PHSPolicyLabAnimals.pdf), as
mandated by the Health Research Extension Act of 1985
(http://grants.nih.gov/grants/olaw/references/hrea1985.htm), and the USDA Animal
Welfare Regulations (http://www.nal.usda.gov/awic/legislat/usdaleg1.htm), as
applicable.
DATA AND SAFETY MONITORING PLAN: Data and safety monitoring is required for all
types of clinical trials, including physiologic, toxicity, and dose-finding studies
(phase I); efficacy studies (phase II); efficacy, effectiveness and comparative
trials (phase III). The establishment of data and safety monitoring boards (DSMBs)
is required for multi-site clinical trials involving interventions that entail potential
risk to the participants. (NIH Policy for Data and Safety Monitoring, NIH Guide for
Grants and Contracts, June 12, 1998:
http://grants.nih.gov/grants/guide/notice-files/not98-084.html).
INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: It is the policy of the NIH
that women and members of minority groups and their sub-populations must be included
in all NIH-supported clinical research projects unless a clear and compelling
justification is provided indicating that inclusion is inappropriate with respect to
the health of the subjects or the purpose of the research. This policy results from
the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43).
All investigators proposing clinical research should read the AMENDMENT "NIH
Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research -
Amended, October, 2001," published in the NIH Guide for Grants and Contracts on
October 9, 2001 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html);
a complete copy of the updated Guidelines are available at
http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm. The
amended policy incorporates: the use of an NIH definition of clinical research;
updated racial and ethnic categories in compliance with the new OMB standards;
clarification of language governing NIH-defined Phase III clinical trials consistent
with the new PHS Form 398; and updated roles and responsibilities of NIH staff and
the extramural community. The policy continues to require for all NIH-defined Phase
III clinical trials that: a) all applications or proposals and/or protocols must
provide a description of plans to conduct analyses, as appropriate, to address
differences by sex/gender and/or racial/ethnic groups, including subgroups if
applicable; and b) investigators must report annual accrual and progress in
conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group
differences.
INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS: The NIH
maintains a policy that children (i.e., individuals under the age of 21) must be
included in all human subjects research, conducted or supported by the NIH, unless
there are scientific and ethical reasons not to include them.
All investigators proposing research involving human subjects should read the "NIH
Policy and Guidelines" on the inclusion of children as participants in research
involving human subjects that is available at
http://grants.nih.gov/grants/funding/children/children.htm.
REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS: NIH policy
requires education on the protection of human subject participants for all
investigators submitting NIH proposals for research involving human subjects. You
will find this policy announcement in the NIH Guide for Grants and Contracts
Announcement, dated June 5, 2000, at
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.
HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research on hESCs
can be found at http://stemcells.nih.gov/index.asp and at
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html. Only research
using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry
will be eligible for Federal funding (see http://escr.nih.gov). It is the
responsibility of the applicant to provide, in the project description and elsewhere
in the application as appropriate, the official NIH identifier(s) for the hESC
line(s)to be used in the proposed research. Applications that do not provide this
information will be returned without review.
PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The Office of
Management and Budget (OMB) Circular A-110 has been revised to provide public access
to research data through the Freedom of Information Act (FOIA) under some
circumstances. Data that are (1) first produced in a project that is supported in
whole or in part with Federal funds and (2) cited publicly and officially by a
Federal agency in support of an action that has the force and effect of law (i.e., a
regulation) may be accessed through FOIA. It is important for applicants to
understand the basic scope of this amendment.
NIH has provided guidance at
http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm.
Applicants may wish to place data collected under this PA in a public archive, which
can provide protections for the data and manage the distribution for an indefinite
period of time. If so, the application should include a description of the archiving
plan in the study design and include information about this in the budget
justification section of the application. In addition, applicants should think about
how to structure informed consent statements and other human subjects procedures
given the potential for wider use of data collected under this award.
URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and proposals for NIH
funding must be self-contained within specified page limitations. Unless otherwise
specified in an NIH solicitation, Internet addresses (URLs) should not be used to
provide information necessary to the review because reviewers are under no obligation
to view the Internet sites. Furthermore, we caution reviewers that their anonymity
may be compromised when they directly access an Internet site.
HEALTHY PEOPLE 2010: The Public Health Service (PHS) is committed to achieving the
health promotion and disease prevention objectives of "Healthy People 2010," a PHS-
led national activity for setting priority areas. This RFA is related to one or more
of the priority areas. Potential applicants may obtain a copy of "Healthy People
2010" at http://www.health.gov/healthypeople.
AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal
Domestic Assistance No. 93.837, 93.838, 93.839, and is not subject to the
intergovernmental review requirements of Executive Order 12372 or Health Systems
Agency review. Awards are made under authorization of Sections 301 and 405 of the
Public Health
Service Act as amended (42 USC 241 and 284) and administered under NIH grants
policies described at http://grants.nih.gov/grants/policy/policy.htm and under
Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92.
The PHS strongly encourages all grant recipients to provide a smoke-free workplace
and discourage the use of all tobacco products. In addition, Public Law 103-227, the
Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases,
any portion of a facility) in which regular or routine education, library, day care,
health care, or early childhood development services are provided to children. This
is consistent with the PHS mission to protect and advance the physical and mental
health of the American people.
Weekly TOC for this Announcement
NIH Funding Opportunities and Notices
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