ASTHMA CLINICAL RESEARCH NETWORK
RELEASE DATE: July 15, 2002
RFA: HL-02-029
National Heart, Lung, and Blood Institute (NHLBI)
(http://www.nhlbi.nih.gov)
LETTER OF INTENT RECEIPT DATE: September 24, 2002
APPLICATION RECEIPT DATE: October 24, 2002
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 Submitting an Application
o Peer Review Process
o Review Criteria
o Receipt and Review Schedule
o Award Criteria
o Required Federal Citations
PURPOSE OF THIS RFA
The National Heart, Lung, and Blood Institute invites applications to compete
for participation in a cooperative research network to evaluate current and
novel therapies and management strategies for adult asthma. One anticipated
outcome will be rapid dissemination of the findings to the medical community.
The objective of this Request for Applications (RFA) is to establish (1) a
network of 6 to 7 clinical centers to design and perform multiple therapeutic
trials for treatment of adult asthma, and (2) a Data Coordinating Center for the
network. This is a one time solicitation to support clinical research centers
and the Data Coordinating Center for 5 years.
RESEARCH OBJECTIVES
Background
Asthma is a chronic inflammatory disease of the airways. Over the past 15
years, the number of Americans afflicted with asthma has more than doubled to
over 14 million. Symptoms not severe enough to require a visit to the emergency
room or to a physician can still substantially impair quality of life. Asthma
results in many lost nights of sleep, disruption of family and caregiver
routines, and restricted activities for over one third of people with the
disease. It imposes financial burdens on patients and their families, including
lost work days and income. Asthma is the leading work-related lung disease,
accounting for at least 21 percent of all adult onset asthma. Asthma has great
impact in the U.S. economy, currently costing $18 to $20 billion yearly, with
the majority of the expense attributed to emergency room visits and
hospitalization.
There is an urgent need to rapidly evaluate new and existing therapeutic
approaches for patients with asthma, and to disseminate the findings to health
care professionals, patients and the public. In order to address this major
public health problem, the NHLBI established an Asthma Clinical Research Network
(ACRN) in 1993 to conduct short-term (e.g. 12 to 18 months) trials to evaluate
therapeutic approaches to asthma.
The current ACRN consists of six clinical centers and one Data Coordinating
Center. To date, the ACRN has completed six clinical trials. There are
currently three trials underway and two more are expected. Since its
establishment the ACRN has published 24 papers and 12 abstracts. Some of the
completed and ongoing trials include: The Addition of Regular-Use to
Intermittent Rescue Beta-Agonist for Patients with Mild Asthma, Colchicine In
Moderate Asthma, Salmeterol Off Corticosteroids, Salmeterol plus or minus
Inhaled Corticosteroids, Dose of Inhaled Corticosteroids with Equisystemic
Effects, Measuring Inhaled Corticosteroid Efficacy, Beta Adrenergic Response by
Genotype, Improving Asthma Control Trial, and Smoking Modulates Outcomes of
Glucocorticoid Therapy in Asthma. Additional information on these trials can be
found at the ACRN website http://www.acrn.org
The results from the ACRN studies have had a major impact on the treatment and
management of asthma. For example, in the mid 1990s several small studies
demonstrated that regularly scheduled use of inhaled beta agonists compared to
as needed use was associated with a deleterious effect on asthma control. In an
attempt to resolve the controversy surrounding the most commonly prescribed
asthma medication, the ACRN conducted a clinical trial on the comparison of
regularly scheduled with as needed use of the beta agonist albuterol in mild
asthma. The results showed that in patients with mild asthma, the regularly
scheduled use of inhaled albuterol was not associated with either a beneficial
or deleterious effect.
An NHLBI-supported asthma network is the ideal environment to address the above
and many other timely clinical topics. As the list of possible future studies
changes over time, the opportunity to collaborate in a network provides
flexibility to rapidly respond to new and emerging concepts. There are several
reasons why an asthma clinical research network will accelerate clinical
research to meet this need, some of these are: (1) to accumulate a large number
of comparable patients that otherwise would be difficult for one center to
recruit, (2) to standardize treatment protocols, which may result in reduction
of the number of patients needed at each clinical center, (3) to combine the
necessary clinical expertise and administrative resources to facilitate multiple
trials in a timely and efficient manner, and (4) to promote rapid dissemination
of research findings to health care professionals and the public.
Organization of the Asthma Clinical Research Network
The Asthma Clinical Research Network will be a cooperative network of 6 to 7
adult asthma Clinical Centers, one Data Coordinating Center, and the Division of
Lung Diseases, NHLBI. Clinical Centers will be responsible for proposing and
prioritizing protocols, participating in protocol development, conducting the
research, and disseminating research findings. All individual Clinical Centers
will be required to participate in a cooperative and interactive manner with one
another and with the Data Coordinating Center in all aspects of the network.
The Data Coordinating Center will support protocol development and provide
sample size calculations, statistical advice, common questionnaires, data
analysis, coordinating the activities of the Steering Committee, Protocol Review
Committee, Data and Safety Monitoring Board, and overall study coordination and
quality assurance.
A Steering Committee composed of the principal investigators of the Clinical
Centers and the Data Coordinating Center and the NHLBI Project officer will be
the main governing body of the ACRN. Each Clinical Center, the Data
Coordinating Center and the NHLBI will have one vote. The Steering Committee
may meet as often as three to six times in the first 12 months of the project
period and two to four times per year 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 network, finalizing common clinical protocols, facilitating the conduct
and monitoring of the studies, and reporting study results. Topics for the
protocols will be proposed and prioritized by the Steering Committee. For each
protocol, one Clinical Center will take the lead responsibility for drafting the
protocol, although the entire Steering Committee will provide input and will be
responsible for assuring development of a common protocol to be implemented by
the Clinical Centers.
Subcommittees of the Steering Committee will be established as necessary, for
example, it is envisioned that a Publications and Presentations Committee will
prioritize, facilitate and supervise preparation and review of manuscripts prior
to submission for publication. 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.
An independent Protocol Review Committee, established by NHLBI with input from
the Steering Committee, will provide peer review for each protocol. A Data and
Safety Monitoring Board (DSMB), similarly established, will monitor patient
safety and review 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 boards (IRBs.)
It is required that each protocol will be conducted in at least four or more of
the Clinical Centers. As specific protocols are developed, support will depend
on the availability of funds and will be provided on a per patient basis. All
the Clinical Centers must be willing to pursue this funding arrangement for each
new protocol conducted. Clinical protocols must be approved by the local IRBs
and the Protocol Review Committee before initiation. The exact number of
protocols supported in the 5-year program will depend on the nature and extent
of the investigations proposed by the Steering Committee and the availability of
funds.
Research Scope
The overall goal of this program is to establish a Clinical Research Network to
identify the best possible asthma therapies with original ideas and improve
overall asthma control. The emphasis will be on clinical trials 12-18 months in
duration that help identify optimal therapy for patients with different asthma
phenotypes, genotypes, ethnic background and asthma severity. Therapeutic
trials may involve investigational drugs, drugs already approved but not
currently used, and drugs currently used in treatment of asthma. All projects
must be completed within the 5-year duration of this research program.
Examples are provided to indicate the range of research areas appropriate for
this RFA. They include, but are not limited to the following:
o Evaluation of novel treatments such as anti-cytokine, anti-IgE, or other
innovative approaches of specific immunotherapy in asthma.
o Evaluation of the role of macrolides altering the progression of asthma.
o Development of management strategies and characterization of particular asthma
phenotypes (e.g. steroid-resistant severe asthma, sudden onset and severe
exacerbations in otherwise mild asthma, cough variant asthma, adult onset
asthma, non-atopic asthma, nocturnal asthma, obesity and asthma).
o Exploration of the implications of genotype-phenotype correlations in
determining a patient"s response to a particular pharmacologic agent.
o Evaluation of markers of inflammation appropriate for clinical practice to
monitor patient"s response to treatment.
o Evaluation of the effectiveness of various medications (e.g. theophylline,
anti-histamines) in combination with other asthma drugs for controlling,
preventing and altering the progression of asthma.
o Identification of optimal management strategies in different ethnic and
cultural settings, as well as in elderly patients.
THESE ARE EXAMPLES ONLY. APPLICANTS SHOULD NOT FEEL LIMITED TO THE SUBJECTS
MENTIONED ABOVE AND ARE ENCOURAGED TO SUBMIT OTHER TOPICS PERTINENT TO THE
OBJECTIVES OF THE RFA.
It is not the intent of this network to provide support for only one or two
protocols that run for the entire 5 years. Multiple trials will need to be
conducted, possibly 2 to 4 a year. It is anticipated that in the initial year,
trials will be selected from the studies proposed by the successful applicants.
However, a decision to fund a particular Clinical Center will not commit the
ACRN to develop that group"s clinical protocol.
MECHANISM OF SUPPORT
This RFA will use the cooperative agreement (U10) award mechanism. Under the
cooperative agreement mechanism, the Principal Investigator retains the primary
responsibility and dominant role for planning, directing, and executing the
proposed project, with NIH staff being substantially involved as a partner with
the Principal Investigator, as described under the section "Cooperative
Agreement Terms and Conditions of Award." The anticipated award date is
September 30, 2003.
This RFA uses just-in-time concepts. It also uses the modular as well as the
non-modular budgeting formats
(see https://grants.nih.gov/grants/funding/modular/modular.htm). Specifically,
if you are submitting an application with direct costs in each year of $250,000
or less, use the modular format. Otherwise follow the instructions for
non-modular research grant applications.
The NIH (U10) is a cooperative agreement award mechanism in which the Principal
Investigator retains the primary responsibility and dominant role for planning,
directing, and executing the proposed project, with NIH staff being
substantially involved as a partner with the Principal Investigator, as
described under the section "Cooperative Agreement Terms and Conditions of
Award."
FUNDS AVAILABLE
A maximum of up to seven awards for Clinical Centers and one award for a Data
Coordinating Center will be made under this RFA. A maximum of about $43.4
million (total costs) over a five year period will be awarded for the Clinical
Centers and the Data Coordinating Center. An applicant for a Clinical Center
may request a project period of up to five years and a budget for total costs of
up to $823,000 per year. An applicant for a Data Coordinating Center may
request a project period of up to five years and a budget for total costs of up
to $1,332,000 per year. Because the nature and scope of the research proposed
in response to this RFA may vary, it is anticipated that the size of an award
will also vary in all years. Future year costs will be distributed based on the
final approved protocols.
Although the financial plans of the NHLBI provide support for this program,
awards pursuant to this RFA are contingent upon the availability of funds and
the receipt of a sufficient number of applications of appropriate scientific and
technical merit. Designated funding levels are subject to change at any time
prior to award, due to unforeseen budgetary, administrative, or scientific
developments. It is not known if competing renewal applications will be
accepted or if this RFA will be re-issued.
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
INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS
Any individual with the skills, knowledge, and resources necessary to carry out
the proposed research is 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.
Among the disciplines and expertise that may be appropriate for this program are
pulmonary medicine, allergy and immunology, pharmacology, pharmacogenetics,
molecular and cellular biology, biostatistics, therapeutic development, and
clinical trials management.
SPECIAL REQUIREMENTS
Studies contemplated in this program require a significant number of patients be
enrolled in a uniform manner before individual research studies are initiated.
Thus, this program is designed to be a collaborative effort. Applicants will be
responsible for proposing research studies and common guidelines that will be
shared across the program for patient diagnosis, enrollment, testing, sampling,
and data collection. All individual investigators/centers will be required to
participate in a collaborative and interactive manner with one another in all
aspects of the program. This mechanism should include common definitions,
common procedures for patient selection and enrollment, standardization of
common procedures, tests and reporting forms.
Terms and Conditions of Award
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" role, 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 will serve on the Steering Committee, he/she or
another NHLBI scientist may serve on other study committees, when appropriate.
The NHLBI Project Scientist (and the other cited 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 potential
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 and the NHLBI Project Scientist. 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, MD. A NHLBI staff person
(other than the NHLBI Project Scientist) shall serve as Executive Secretary to
the Board. An independent Protocol Review Committee, established by the NHLBI,
will provide peer review for each protocol.
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 (i.e.,
cooperative agreement awardees).
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. Awardees are encouraged to publish and publicly to release and disseminate
results, data and other products of the study, concordant with the study
protocol and governance and the approved plan for making data and materials
available to the scientific community and the NHLBI. However, during or within
three years beyond the end date of the project period of NHLBI support,
unpublished data, unpublished results, data sets not previously released, or
other study materials or products are to be made available to any third party
only with the approval of the Steering Committee and in accordance with
paragraph 6.
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, quality control, or other major breach
of the protocol, (c) substantive changes in the agreed upon protocol with which
NHLBI cannot concur, (d) reaching 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, the Data Coordinating Center is expected to
put all study 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:
Hector G. Ortega, M.D., Sc.D.
Division of Lung Diseases
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 1008, MSC795
Bethesda, MD 20892
Telephone: (301) 435-0202
FAX:(301) 480-3557
Email: ortegah@nhlbi.nih.gov
o Direct your questions about peer review issues to:
Anne P. Clark, Ph.D.
Chief Review Branch
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 7178, MSC 7924
Bethesda, MD 20892
Telephone: (301) 435-0270
FAX: (301) 480-0730
Email: clarka@nhlbi.nih.gov
o Direct your questions about financial or grants management matters to:
Ray Zimmerman
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 7156
Bethesda, MD 20892
Telephone: (301) 435-0171
Email: zimmermr@nhlbi.nih.gov
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 IC 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 Dr. Anne Clark at the address
listed in the inquiries section.
SUBMITTING AN APPLICATION
Applications must be prepared using the PHS 398 research grant application
instructions and forms (rev. 5/2001). The PHS 398 is available at
https://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format.
For further assistance contact Grants Info, Telephone (301) 710-0267,
Email: GrantsInfo@nih.gov.
SUPPLEMENTAL INSTRUCTIONS:
Clinical Center Applicants:
o Qualifications and experience. Participation in this Network will be a
complex and time-consuming undertaking. Applicants for Clinical Centers must
have the necessary experience and expertise to conduct clinical studies in
patients with asthma. Prospective Clinical Centers must have an established
research program in asthma, and demonstrated access to a sufficient number of
patients to accomplish their portion of the proposed protocols. An appropriate
time commitment is expected from the investigator leadership (Principal
Investigator and any Co-investigators) at each Clinical Center.
o Study population. The application should include a description of the pool of
potential study participants, including the age range, ethnic/racial and gender
distribution (approximately 50 percent women and 25 percent minorities), and
recruitment sources. It is not anticipated that all eligible patients will be
enrolled in research protocols at any one time, and it is possible that an
individual patient may be enrolled in more than one study. Patient access may be
accomplished by establishing links with other groups in addition to the
applicant"s institution. If this is planned, there must be a well-described and
documented plan to link the individual Clinical Centers with other community
health care providers, such as pulmonary/allergy practices, general
practitioners, pediatricians, and health maintenance organizations, as
appropriate, to ensure adequate numbers of patients for clinical studies.
o Applicants from institutions that have a General Clinical Research Center
(GCRC) funded by the NIH National Center for Research Resources may wish to
identify the GCRC as a resource for conducting the proposed research. In such a
case, a letter of agreement from either the GCRC Program Director or Principal
Investigator should be included with the application.
o Willingness to participate in the Asthma Clinical Research Network.
Applicants should state their general support of collaborative research, any
special expertise they can offer and willingness to interact with other Clinical
Centers, the NHLBI, and the Data Coordinating Center through this Network
concept. Applicants should discuss their willingness, and that of the
institutions involved, to pursue a per-patient basis (capitation) of operational
costs for each protocol. Clinical Center applicants must be able to interact
with the Data Coordinating Center to transmit and edit data and should discuss
their capability to participate in a distributed data entry system.
o Research Plan:
Each Clinical Center applicant should propose a research plan that includes two
protocols. These two protocols must be short-term (12-18 months) clinical
trials on asthma patients and involve sufficient subjects to require the use of
a network with multicenter participation. The research plan should follow the
instructions in the PHS 398 application form
(revised 5/2001, https://grants.nih.gov/grants/forms.htm), and should include: a
one page overview of the proposed two investigations that presents the key
research objective of each investigation and a diagram depicting the initiation
and duration of the two investigations, a description of each of the two
protocols that includes the rationale, research aims, outcome measures, and
study design, a description of the patient populations with an estimate of the
expected distribution of minority and female patients, ages, and levels of
asthma severity, and assurances of the applicant"s access to the patient
populations. Applicants are encouraged to explore, within the context of their
proposed protocols, new technologies that could lead to improved treatments,
monitoring of disease progression, predicting or evaluating response to therapy.
It will also be important to include strategies to assure adherence to therapy
as part of the protocol.
The applicant should indicate for each protocol how many patients are available
in the applicant"s center and how many will be required for the entire Network.
In the discussion of outcome measures, it will be important to indicate
appropriate objective measures of primary and secondary outcomes.
The entire Research Plan, including protocols, should not exceed the Form 398
Research Plan instructions of 25 pages.
o Clinical Research Skills Development Core:
The NHLBI is interested in ensuring that the full potential of clinical research
networks and multicenter clinical studies foster the clinical research careers
of new investigators. The Clinical Skills Development Core presents a rich
environment for young clinical investigators to be exposed to and develop
additional research skills. The individual centers can be expected to include
among their research staffs clinical personnel who are newly trained and
relatively inexperienced in research. To assist the centers in enhancing the
developmental environment for their new clinical investigators, the NHLBI will
permit applicants to request up to $100,000 in direct costs per year for a
Clinical Research Skills Development Core. The objective of the Core is to
support activities to assist new clinical investigators in progressing to more
senior status by enhancing their research skills. This support is in addition
to the infrastructure and protocol costs for the network mechanism. A Clinical
Research Skills Development Core is not required, however, and its absence will
not disadvantage an applicant. The priority score of the Core will have no
effect on the overall score of an application.
Developmental opportunities that provide experience with new technologies and
skills are encouraged for inclusion in the Core. Innovative strategies should
be proposed for cross-disciplinary career development to achieve the goal of
exposing new clinical investigators to additional research techniques and
opportunities. Examples include a program of seminars focusing on scientific
topics that involve translational research. In addition to developing the
research skills of new clinical investigators, the Cores must ensure that the
participating new clinical investigators receive the mentoring they need to
foster their research careers. The Clinical Research Skills Development Core is
intended for staff investigators with limited clinical research experience,
including fellows and junior faculty members. Investigators who have had a
previous K series award are not eligible to participate as new investigators
under this program. Individuals with an active K grant can participate until
the end of the award period for the K grant. The Core should also address other
skills necessary for a successful research career, such as grant writing,
ethical conduct of research, biostatistics, and clinical trial design.
If a Clinical Research Skills Development Core is proposed, it must be directed
by an investigator with strong educational and mentoring credentials who will
devote a minimum of 5 percent effort as its Leader. To facilitate mentoring and
multidisciplinary developmental activities, active involvement by the principal
investigator and other senior investigators within the program is strongly
encouraged.
An application for a Clinical Research Skills Development Core will be evaluated
in terms of its potential effectiveness in developing the skills and research
capabilities of new clinical investigators as reflected in the following
required elements of the application:
1. A summary of the types of skills that would be developed and a description of
proposed project-specific activities,
2. A detailed discussion of how mentoring and the professional development of
the new clinical investigators will be achieved, including their progression to
more independent status,
3. The credentials and track records of the Clinical Research Skills Development
Core Leader, the Principal Investigator, and other participating senior staff in
developing new investigators,
4. A plan for coordinating the activities of participating senior investigators,
5. A plan for monitoring the progress of the new clinical investigators,
6. A description of existing opportunities within the applicant"s institution
for supporting investigator development and steps taken to avoid overlap with or
duplication of these efforts, and
7. A detailed development plan for each proposed new investigator (or a
representative plan and proposals for tailoring it to the needs of multiple new
investigators) including required course work and scientific enrichment
activities such as special lectures, visiting scientist symposia, seminars, and
workshops.
Costs allowable for inclusion within the $100,000 direct costs per year limit
for the Clinical Research Skills Development Core include salary support for the
Core Leader and other participating senior investigators and staff, travel costs
for new investigators, supplies and equipment to be used in support of
developmental activities, and costs for courses, seminars, workshops, and other
activities directly related to the development plan. All costs requested in
this Core must be justified with respect to developmental activities and may not
be used to supplement the costs of research proposed in the rest of the
application.
Since the Core is intended to serve new clinical investigators who occupy
positions and receive salary support from other sources, salary support for the
new investigators is neither needed nor allowable as a Core cost. All new
clinical investigators supported by any grant are eligible to participate in
Core-sponsored activities so long as they have not attained independent status.
However, attaining independent status should be an objective of the Core
activities so participating new investigators should be encouraged to apply for
either a Career Development Award, a patient-oriented regular research grant, or
any other source of independent research or career development support.
Although the participating new investigators will be expected to devote
essentially full-time effort to research during this period, they may devote an
appropriate percentage of their time to maintaining clinical skills.
An application for a Clinical Research Skills Development Core will be evaluated
in terms of its potential effectiveness in developing the skills and research
capabilities of new clinical investigators as reflected in the required
application components identified above. Additional information is available at
http://www.nhlbi.nih.gov/funding/policies/ntwk_skill.htm.
o Budget:
Clinical Center applicants should consider the following issues regarding
budgets. The underlying concept of the Asthma Clinical Research Network is that
a group effort is essential to maintain the infrastructure required to perform
multiple clinical trials. Based on this approach, it is estimated that the
individual Clinical Centers will require a minimum level of effort to sustain
the organizational aspects of the Asthma Clinical Research Network. Therefore,
individual Clinical Centers should submit requests for a CORE BUDGET not to
exceed $175,000 total costs per year. It is anticipated that this budget will
cover a minimum of 25% total effort for the combined physician leadership
(Principal Investigator and any Co-investigators), appropriate percentages of
effort for other key personnel (e.g., clinical coordinator, data entry clerk),
and travel costs for approximately six trips each year to attend Steering
Committee meetings in Bethesda, MD, and other travel related to Network
operations. These costs should include appropriate justification. Total costs
for the core budget can be escalated at three percent annually for future years.
It should be noted that funds would not be provided for the purchase of
expensive equipment.
In addition to the core budget, each Clinical Center will be provided funds for
implementation of protocols. This support will be provided for each protocol on
a per-successfully-enrolled-patient basis. The precise number of protocols
conducted over the five years will be determined by the Asthma Clinical Research
Network Steering Committee and will depend on a number of factors including
availability of funds, length of the protocols, and ease of recruitment. It is
anticipated that after the first year, two to four protocols may be active each
year. Clinical Centers should request protocol enrollment funds as PATIENT CARE
costs not to exceed $648,000 per year. This amount should be placed in the
patient care category. Patient care costs can be escalated at three percent
annually for future years. Maximum allowable total costs for each clinical
center (core costs, costs per patient to conduct the protocols, and facilities a
nd administrative costs) will be $823,000 a year.
Applicants for the Clinical Centers should present the following information:
o For each year, the Clinical Centers should include the core budget costs (not
to exceed $175,000 total costs) and patient care costs (not to exceed $648,000
total costs). Estimated protocol implementation costs for Year 1 should be based
on the two proposals presented in the applicant"s research plan. A table should
be included showing estimated costs per patient for conducting each protocol.
o The budget for each clinical protocol in the PATIENT CARE category should be
developed on a cost-per-patient-basis and include all direct costs and the
associated protocol facilities and administrative costs at a rate not to exceed
28%. Costs of drugs or laboratory tests that are not clinically indicated
(i.e., are not eligible for third-party reimbursement as part of routine
clinical care) should be part of the per-patient cost of conducting a protocol.
Applications should identify the potential source(s) for any drugs or substances
that are being considered for clinical protocols that are currently unavailable
commercially. If either of the protocols proposed by a Clinical Center
applicant includes obtaining blood or tissue samples, the applicant should
delineate how such specimens will be handled and analyzed. In the event that a
central laboratory is required to analyze specimens, the Clinical Centers will
be responsible for obtaining the sample(s) and the cost of obtaining them will
be part of the Clinical Center"s per-patient expense. The cost of shipping,
analyzing, and storing them, as well as training of personnel and quality
control will be the responsibility of the Data Coordinating Center.
o Investigators should prepare budgets only for their own Clinical Center to
conduct the proposed trial, and not for the entire Asthma Clinical Research
Network. The applicant should state the total number of patients required by
the entire Network to complete each proposed trial. The yearly budget for the
applicant"s Center should include the number of patients available for the
proposed protocol at the applicant"s Center. A budget based on the costs per
patient for recruiting and maintaining the specified number of subjects at the
applicant"s Center should be included for each protocol.
Note that ongoing annual budgets for protocols will be based on the protocols
approved by the Protocol Review Committee and the Asthma Clinical Research
Network Steering Committee. The individual Clinical Centers will be expected to
project patient enrollment for a specific protocol during a specified time
frame, continuation and level of funding for each Clinical Center will be based
on actual recruitment and overall performance.
Awards will be subject to administrative review annually.
Data Coordinating Center Applicants:
o Qualifications and experience. Applicants for a Data Coordinating Center must
demonstrate experience in asthma and in coordinating multi-center clinical
studies in all phases: protocol and manual of operations development, data
collection and management, data safety and confidentiality, quality assurance,
data entry, data analysis, electronic communications, administrative management
and coordination. A significant commitment is expected from the Principal
Investigator of the Data Coordinating Center.
o Study design and management. Data Coordinating Center applicants should
discuss various aspects of study design that would be important in developing
clinical protocols, for example: eligibility criteria, baseline and outcome
measures, methods of randomization, important considerations for making sample
size and power calculations, methods and frequency of data collection and entry,
monitoring accuracy of data collection, quality control procedures including
training and certification for multiple protocols, some of which may occur
simultaneously, managing labeling and handling of specimens (see below), and
plans for statistical analysis. Applicants should also describe their
experience with asthma patients and their ability to provide leadership in this
field to support the clinical studies envisioned under this RFA. In addition,
they should describe their plans for administrative management of the DSMB, the
Protocol Review Committee, the Steering Committee, and associated subcommittees.
The proposed Data Coordinating Center budgets should stipulate and justify the
amount included for managing the DSMB and other Committees. Travel expenses for
the clinical center PI to attend the Steering Committee will be included in the
budgets prepared by the Clinical Centers.
o The Data Coordinating Center should describe how laboratory specimens (e.g.,
blood or tissue samples) will be handled. Laboratories responsible to the Data
Coordinating Center will manage specimens and laboratory studies as required by
the Steering Committee. The costs of performing specific laboratory tests that
are not clinically indicated (i.e., will not be reimbursed through third-party
payers as part of routine clinical care) will be budgeted as a part of the
per-patient costs of each Clinical Center. The costs of specimen shipment as
well as laboratory data acquisition and management will be a part of the budget
of the Data Coordinating Center. Estimated shipping and handling expenses for
specimens should be justified and included in the budget of the Data
Coordinating Center. For the purposes of planning, the Data Coordinating Center
should assume about 2,000 patients over the course of the 5-year study period.
o The Data Coordinating Center will be responsible for one or more central labs
that will analyze data from clinical testing. It is understood that the
specific central lab(s) needed will depend on the protocols ultimately selected.
However, for purposes of the application, Data Coordinating Center applicants
should describe in detail how they will identify and secure the necessary
central lab(s) once specific protocols are approved. The costs of performing
specific tests (i.e., tests that are not eligible for third-party reimbursement)
will be budgeted as a part of the per-patient costs of each Clinical Center. The
format of transfer of data to the Data Coordinating Center should be specified.
The expense of transferring the data on the clinical studies to the central
lab(s), training technicians to obtain the data in a uniform manner, and
instituting quality control measures (e.g., provision for re-reading a
proportion of the studies to determine accuracy of interpretation) will be
included in the Data Coordinating Center budget.
o Budget:
Applicants for the Data Coordinating Center should prepare budgets for five
12-month periods that roughly correspond with the standard coordinating center
responsibilities outlined elsewhere in this RFA. Data Coordinating Center
applicants may request a project period of up to five years and a budget for
total costs of up to $1,332,000 per year. Total costs can be escalated at three
percent annually for future years. For budget purposes, Data Coordinating
Center applicants should assume that in the first year, all administrative
aspects of the Asthma Clinical Research Network will be organized and at least
one protocol will be developed and started. For subsequent years, applicants
may assume that two to four protocols a year will be active, i.e., either in the
protocol development, implementation, or analysis and writing phase. Data
Coordinating Center applicants should include costs for managing the DSMB, the
Protocol Review Committee, and the Steering Committee including the cost of DSMB
meetings two times per year in Bethesda, the cost of Protocol Review Committee
conference calls and meetings, and the administrative expenses of Steering
Committee conference calls and meetings. Travel of Steering Committee members
will be budgeted by Clinical Centers. The Data Coordinating Center also should
include costs for site visits of each of the Clinical Centers over the five-year
study period, assuming seven Clinical Centers throughout the U.S., and a
five-member site visit team, for purposes of budget preparation.
The award will be subject to administrative review annually. It is expected
that all protocols will be performed in a manner consistent with United States
Food and Drug Administration guidelines.
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:
https://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 as well as
five collated sets of Appendix material must be sent to Dr. Anne P. Clark at the
address listed in the inquiries section.
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. The CSR
will not accept any application that is essentially the same as one already
reviewed. This does not preclude the submission of substantial revisions of
applications already reviewed, but such applications must include an
Introduction addressing the previous critique.
Principle 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 your application has been
received. If you have not received such a letter within three weeks after
submitting the application, contact Dr. Anne Clark at the address listed under
Where to Send Inquiries.
PEER REVIEW PROCESS
Upon receipt, applications will be reviewed for completeness by the CSR and
responsiveness by the Institutes and Centers (IC). Incomplete and/or
non-responsive applications will be returned to the applicant without further
consideration.
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 Division of Extramural Affairs, NHLBI in accordance with the review criteria
stated below. The roster of the initial review group will be posted on the
NHLBI home page approximately two weeks prior to the review. As part of the
initial merit review, all applications will:
o Receive a written critique
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 second level review by the National Heart, Lung and Blood Advisory
Council.
REVIEW CRITERIA
Upon receipt, applications will be reviewed for completeness by the CSR and
responsiveness by the NHLBI. Incomplete and/or non-responsive applications will
be returned to the applicant without further consideration. 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 receive a written critique and 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,
assigned a priority score, and receive a second level review by the National
Heart, Lung, and Blood Advisory Council.
Review Criteria for Core Clinical Center Applications
o Research plan. Appropriateness of proposed protocol(s), need for the network
to accomplish the proposed protocol, relevance and importance of the research
questions, preliminary results that justify the proposed end points and sample
size, and likelihood that accrual could be accomplished on time.
o Qualifications and experience. The expertise, training, and experience of
the investigators and staff in asthma clinical trials, evidence of understanding
of randomized, multi-center trials, administrative abilities of the Principal
Investigator, study nurse and/or data coordinator, and the level of commitment
to the program for the effective function of the Asthma Clinical Research Network.
o Patient access and study population. The access to at least 200 patients
with asthma, plans for the recruitment and retention of subjects, plans to
ensure appropriate representation by ethnic group, age, and gender, the
description of competing protocols, and the strategy for allocating patients
between them.
o Willingness and ability to participate in the Network. Applicant
institution"s history of collaborative research, depth of commitment,
willingness to randomize patients, and ability to work with other Network
Centers and NHLBI.
o Institutional resources for patient care and follow-up. Adequacy of
institutional resources including personnel, space, and special laboratory
facilities.
Review Criteria for Data Coordinating Center Applications
o Research plan. Demonstrates understanding of the scientific, statistical,
logistical, and technical issues underlying multi-center studies, including
issues relating to assessment of outcomes relating to use of novel treatments of
patients with asthma, and demonstrates leadership in study design and
statistics, data acquisition and management, data quality control, data
analysis, handling and quality control of laboratory specimens, and network
coordination.
o Qualifications and experience. The expertise, training, and experience of
the investigators and staff, including the administrative abilities of the
Principal Investigator, co-investigator, and the time they plan to devote to the
program for the effective coordination of the Network.
o Study management. The administrative, supervisory, and collaborative
arrangements for achieving the goals of the program, including willingness to
cooperate with the participating Clinical Centers and the NHLBI. This includes
the ability to assist Core Clinical Centers with recruitment problems to meet
accrual goals.
o Willingness and ability to participate in the Network. Applicant
institution"s history of collaborative research, depth of commitment, and
ability to work with other Network Centers and the NHLBI.
o Environment. Facilities, equipment, and organizational structure to
effectively coordinate Clinical Research Network activities and assist Clinical
Centers in implementing the Clinical Research Network protocols, providing for
specialized laboratory testing, and collecting data. This includes but is not
limited to development of repositories, conduct of lab tests and studies, and
obtaining study drugs or investigational agents or products.
In addition to the above criteria, in accordance with NIH policy, all
applications will also be reviewed with respect to the following:
o The adequacy of plans to include both genders, minorities and their
subgroups, and children as appropriate for the scientific goals of the research.
Plans for the recruitment and retention of subjects will also be evaluated.
o The reasonableness of the proposed budget and duration in relation to the
proposed research.
o The adequacy of the proposed protection for humans, animals or the
environment, to the extent they may be adversely affected by the project
proposed in the application.
RECEIPT AND REVIEW SCHEDULE
Letter of Intent Receipt Date: September 24, 2002
Application Receipt Date: October 24, 2002
Peer Review Date: February/March 2003
Council Review: May 29-30, 2003
Earliest Anticipated Start Date: September 1, 2003
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
MONITORING PLAN AND DATA SAFETY AND MONITORING BOARD: Research components
involving Phase I and II clinical trials must include provisions for assessment
of patient eligibility and status, rigorous data management, quality assurance,
and auditing procedures. In addition, it is NIH policy that all clinical trials
require data and safety monitoring, with the method and degree of monitoring
being commensurate with the risks (NIH Policy for Data Safety and Monitoring,
NIH Guide for Grants and Contracts, June 12, 1998:
https://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
(https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html), a complete
copy of the updated Guidelines are available at
http://grants1.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.
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
https://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.
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
https://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm.
Applicants may wish to place data collected under this RFA 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. 93.838 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 https://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.