PEDIATRIC ASTHMA CLINICAL RESEARCH NETWORK

Release Date:  January 22, 1999 (see NOT-HL-03-013)

RFA:  HL-99-006

National Heart, Lung, and Blood Institute

P.T.

Letter of Intent Receipt Date:  February 4, 1999
Application Receipt Date:  March 18, 1999

PURPOSE

The National Heart, Lung, and Blood Institute (NHLBI) invites applications to
participate in an interactive Pediatric Clinical Asthma Research Network that
will evaluate current and novel therapies and management strategies for children
with asthma.  It is anticipated that one outcome of the network will be to
promote rapid dissemination of the findings from these clinical studies to the
health care community.  The objective of this Request for Applications (RFA) is
to establish and maintain (1) the infrastructure required for a network of six
clinical centers to perform multiple therapeutic trials for children with asthma,
and (2) a Data Coordinating Center for the network.  This is a one time
solicitation to support a Pediatric Clinical Asthma Research Network for 5 years.

HEALTHY PEOPLE 2000

The Public Health Service (PHS) is committed to achieving the health promotion
and disease prevention objectives of "Healthy People 2000," a PHS-led national
activity for setting priority areas.  This RFA, Pediatric Asthma Clinical
Research Network, is related to the priority areas of chronic disabling
conditions and clinical prevention services.  Potential applicants may obtain a
copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0 or Summary
report: Stock No. 017-001-00473-1) through the Superintendent of Documents,
Government Printing Office, Washington, DC 20402-9325 (telephone 202-512-1800),
or at http://www.crisny.org/health/us/health7.html.

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic, for-profit and non-profit
organizations, public and private, such as universities, colleges, hospitals,
laboratories, units of State and local governments, and eligible agencies of the
Federal government.  Foreign institutions are not eligible to apply and domestic
applications may not include international components.

Racial/ethnic minority individuals, women, and persons with disabilities are
encouraged to apply as Principal Investigators.

All current policies and requirements that govern the research grant programs of
the National Institutes of Health (NIH) will apply to grants awarded under this
RFA.

Among the disciplines and expertise that may be appropriate for this program are
pediatrics, pulmonary medicine, allergy and immunology, epidemiology,
pharmacogenetics, therapeutic development, and clinical trials management.

Awards for a Clinical Center and a Data Coordinating Center under this RFA will
not be made to the same Principal Investigator to ensure that data analysis is
done independently of data acquisition.  The same institution may apply for both
a Clinical Center and the Data Coordinating Center award, but the applications
for each must be from different individuals.

MECHANISM OF SUPPORT

This RFA will use the cooperative agreement (U10) administrative and funding
mechanism of support.  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 under the
section entitled RESEARCH OBJECTIVES.

The total project period for applications submitted in response to this RFA may
not exceed 5 years. This RFA is a one-time solicitation. Although not co-
sponsoring this RFA, other Institutes (National Institute of Allergy and
Infectious Diseases, National Institute of Environmental Health Sciences, and
National Institute of Child Health and Human Development) have an interest in the
research area discussed in this RFA.  Future applications in this research area
will be assigned based on NIH referral guidelines.

The anticipated award date is September 30, 1999. It is anticipated that the
award for each Clinical Center will be about $600,000 total costs per year
depending on per patient costs, and the award for the Data Coordinating Center
will be about $1,200,000 total costs per year.

FUNDS AVAILABLE

An estimated six awards for Clinical Centers and one award for a Data
Coordinating Center will be made under this RFA.  A maximum of about $25 million
(total costs) over a five-year period will be awarded for the Clinical Centers
and the Data Coordinating Center.  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 recommended 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 outstanding scientific and
technical merit.  Designated funding levels are subject to change at any time
prior to final award, due to unforeseen budgetary, administrative, or scientific
developments.

RESEARCH OBJECTIVES

Background

Asthma is a complex disease that often starts early in life.  Exacerbations can
be triggered by a number of agents such as allergens, respiratory infections,
environmental tobacco smoke and pollutants, drugs, chemicals, exercise, cold air,
infections and strong emotion making asthma therapy difficult and sometimes
complicated.  Multiple medications are often required to treat symptoms
(bronchodilator agents such as beta-2 adrenergic agonists, theophylline, and
anticholinergics), as well the underlying disease process (anti-inflammatory
agents such as inhaled and systemic corticosteroids, cromolyn sodium and
nedocromil; and leukotriene modifiers).

The prevalence of asthma is increasing in all age groups, but most particularly
in children under the age of 18 years.  In 1992, the prevalence of self-reported
asthma among persons under 18 years of age was 7.2 percent, compared to 5.1
percent among all persons.  The most rapid increase in asthma has occurred in
children under 5 years old, with rates increasing over 160 percent over the past
15 years.  Among all ages, over 450,000 hospitalizations, 5,000 deaths, and more
than 100 million days of restricted activity are due to asthma every year.  Yet
the burden of asthma disproportionately affects children.  For example, asthma
hospitalization rates are highest among persons age 0-4 years, and have increased
over 28 percent in the last 15 years; mortality rates increased faster among
those aged 5 to-12 years than among those age 15-34 years and neither changes in
disease coding nor improved recognition of asthma fully explain these increases. 
Nearly one third of children restrict their activities due to asthma, including
participation in physical education and sports.

Despite major advances in understanding the etiology and pathophysiology of
asthma and the development of new therapeutic modalities to control symptoms and
prevent exacerbations, effective therapies are not widely used in the pediatric
health care community.  Further, the long term effects and side effects of asthma
medications in children, especially children under the age of 12 years, are not
well understood.  Much remains to be learned about the impact of asthma therapy
at different ages and at different points in the natural history of the asthma
in altering the progression, chronicity, or severity of the disease.

There is an urgent need to rapidly evaluate new and existing therapeutic
approaches for children with asthma, and to disseminate the findings to health
care professionals, patients and the public.  There are several reasons why a
pediatric asthma clinical research network will accelerate clinical research and
meet this need.  The highly variable and sometimes complicated clinical
manifestations of asthma often make it difficult to accumulate a large number of
comparable patients in one center.  Further, uniformity in treatment protocols
may reduce the number of patients needed at each clinical center.  Also, the
network mechanism will help pool the necessary clinical expertise and
administrative resources to facilitate the conduct of multiple and novel
therapeutic trials in a timely, efficient manner.  This, in turn, would promote
rapid dissemination of research findings to health care professionals.

Organization of the Pediatric Asthma Clinical Research Network

The Pediatric Asthma Clinical Research Network will be a cooperative network of
six pediatric asthma Clinical Centers, one Data Coordinating Center, and the
Division of Lung Diseases, NHLBI.  Clinical Centers will be responsible for
proposing common protocols, participating in their 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.  A
separate Data Coordinating Center will support protocol development and provide
sample size calculations, statistical advice, common questionnaires, data
analysis, and overall study coordination and quality assurance.

A Steering Committee will be the main governing body of the Pediatric Asthma
Clinical Research Network and, at a minimum, will be composed of the principal
investigators of the Clinical Centers and the Data Coordinating Center and the
NHLBI Project Scientist.  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 study, and two to four times per year
thereafter.  All major scientific decisions will be determined by majority vote
of the Steering Committee.  The Chairperson, who will be someone other than an
NHLBI staff member and may be someone other than a principal investigator, will
be selected by the end of the second meeting of the Steering Committee.  The
first meeting of the Steering Committee will be convened by the NHLBI Project
Scientist.  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 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 facilitate and
supervise preparation of manuscripts prior to submission for publication.

An independent protocol review committee, established by the NHLBI, will provide
peer review for each protocol.  A Data Safety Monitoring Board (DSMB), also
established by the NHLBI with input from the Steering Committee, will monitor
patient safety and review performance of each protocol.  As a part of its review,
the DSMB will submit recommendations to the NHLBI regarding the continuation of
each protocol.

Each protocol will be implemented in two or more of the Clinical Centers,
depending on the numbers of children needed for the study.  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 capitation of operational costs for each new protocol conducted.  Clinical
protocols must be approved by local institutional review boards and the Pediatric
Asthma Clinical Research Network 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 Pediatric Asthma Clinical
Research Network Steering Committee.

Research Scope

The objective of this RFA is to establish a Pediatric Asthma Clinical Research
Network that will accelerate research in the management of childhood asthma.  The
emphasis will be on clinical trials that help identify optimal therapy for
children with different asthma phenotypes, genotypes, and ethnic background and
children at different developmental stages.  Although research in children from
ages birth to 18 years is within the scope of this RFA, emphasis is placed on
research involving infants and young children (ages 0-5 years).  Therapeutic
trials may involve investigational drugs, drugs already approved but not
currently used in childhood asthma, and drugs currently used in treatment of
asthma.  All projects must be completed within the 5 year duration of this
research program.

Some examples of research areas appropriate for this RFA include, but are not
limited to the following:

o  Comparison of the effectiveness (in altering the progression of the disease,
or in controlling and preventing asthma symptoms) and side effects of different
medications or different dosing regimens of the same medication;

o  Evaluation of novel treatments (e.g. anti-IgE therapies) or novel uses in
asthma of medications currently used for other conditions (e.g. antibiotics);

o  Examination of management strategies for particular asthma phenotypes (e.g.
steroid-resistant severe asthma; sudden onset and severe exacerbations in
otherwise mild asthma);

o  Exploration of the implications of genotype-phenotype correlations in
determining a patient's response to a particular pharmacologic agent.

o  Assessment of a child's developmental stages on the therapeutic response, and
the influence of medications on children's development.

o  Determination of the optimal timing for the introduction of anti-inflammatory
therapy in children.

o  Identification of optimal management strategies for infants and young
children, or adolescents in various ethnic and cultural settings.

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 be conducted, possibly 2-4 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 Pediatric Asthma Clinical Research Network to develop that group's
clinical protocol.

Each Clinical Center applicant should propose a research plan that includes two
protocols.  One must be a short term (one year or less) and one a long term (one
to three year) investigation of pediatric asthma.  Furthermore, one of the
protocols must involve infants and young children (age 0-5 years).  The research
plan should follow the instructions in the PHS 398 application form (revised
4/98; http://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 over a 5 year period; a description (within
the total page limits designated in the PHS 398 application form) 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. 
In the discussion of outcome measures, it will be important to indicate
appropriate objective measures of lung function in young children.  Applicants
are encouraged to explore, within the context of their proposed protocols, new
technologies such as biochemical markers of inflammation to monitor disease
progression and response to therapy.  It will also be important to include
strategies to assure adherence to therapy as part of the protocol.

SPECIAL REQUIREMENTS

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
(i.e., cooperative agreement awardees) and the NHLBI Project Scientist.  Meetings
of the Steering Committee will ordinarily be held by telephone conference call
or in the Washington DC Metropolitan 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.  The NHLBI Project
Scientist shall serve as Executive Secretary to the Board.

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. Awardees are encouraged to publish and to publicly 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.  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.

9. 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.

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.

INSTRUCTIONS FOR INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH STUDIES

It is the policy of the NIH that women and members of minority groups and their
subpopulations must be included in all NIH supported biomedical and behavioral
research projects involving human subjects, unless a clear and compelling
rationale and justification is provided 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 research involving human subjects should follow the
"NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical
Research," which have been published in the Federal Register of March 28, 1994
(FR 59 14508-14513), and in the NIH Guide for Grants and Contracts of March 18,
1994, Volume 23, Number 11 and available on the web at:
http://grants.nih.gov/grants/guide/notice-files/not94-105.html.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of the NIH 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.  This
policy applies to all initial (Type 1) applications submitted for receipt dates
after October 1, 1998.

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 was published in the NIH Guide for GRANTS and
Contracts, March 6, 1998, and is available at the following URL address:
http://grants.nih.gov/grants/guide/notice-files/not98-024.html.

Investigators also may obtain copies of these policies from the program staff
listed under INQUIRIES.  Program staff may also provide additional relevant
information concerning the policy.

LETTER OF INTENT

Prospective applicants are asked to submit by February 4, 1999, a letter of
intent that includes a descriptive title of the proposed research, the name,
address, and telephone number of the Principal Investigator, the identities of
other key personnel and participating institutions, and the number and title of
the RFA in response to which the application may be submitted.  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 NHLBI staff to
estimate the potential review workload and avoid conflict of interest in the
review.

The letter of intent is to be faxed or mailed to Dr. C. James Scheirer at the
address listed under INQUIRIES.

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 4/98) is to be used in applying
for these grants.  These forms are available at most institutional offices of
sponsored research and may be obtained from the Division of Extramural Outreach
and Information Resources, National Institutes of Health, 6701 Rockledge Drive,
MSC 7910, Bethesda, MD 20892-7910, telephone 301-435-0714, E-mail:
GrantsInfo@nih.gov.  The PHS 398 application kit is also available on the
Internet at http://grants.nih.gov/grants/funding/funding.htm.

Additional Material to Include in the Application

Clinical Center Applicants:

To promote development of a collaborative program among the award recipients, the
issues discussed below need to be addressed in each application for a Clinical
Center.  This material is in addition to the submission of a research plan, as
described in the section entitled Research Scope.

o  Qualifications and experience.  Applicants for Clinical Centers must have
experience and expertise to conduct clinical studies in children with asthma. 
Prospective Clinical Centers must have an established research program on the
pathogenesis and treatment of asthma.  A minimum of three (3) funded asthma
research projects, at least one in children, (minimum aggregate research support
of $400,000 in direct costs per year at the time of submission of an application
in response to this RFA) will be among the eligibility criteria.

o  Study population.  Clinical Center applicants must have the ability to enroll
over the 5 years at least 300 children with asthma or, for younger children, at
risk of developing asthma.  The pool of potential study participants in the
Pediatric Asthma Clinical Research Network should include children ages 0-18
years and consist of appropriate gender (approximately 50 percent women) and
minority (approximately 30 percent) representation. Children who are currently
(1998-1999) enrolled in an asthma intervention clinical study are not eligible
as potential study participants.  The application should include a description
of the pool of potential study participants--the age range, ethnic/racial
distribution, estimated distribution of patients with different levels of asthma
severity, and recruitment source.  Access to at least 300 patients for various
protocols over the 5 year period is expected, but it is not anticipated that all
300 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
besides the applicant's institution.  There must be a well described plan to link
the individual Clinical Centers with community health care providers such as
HMOs, asthma clinics, or private practice physicians to ensure adequate numbers
patients for clinical studies of therapeutic agents and management strategies for
pediatric asthma.

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 Pediatric Asthma Clinical Research Network. 
Applicants should state their general support of collaborative research and
interaction 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 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.

Data Coordinating Center Applicants:

o  Qualifications and experience.  Applicants for a data coordinating center must
demonstrate experience and demonstrated expertise coordinating multi-center
clinical trials in all phases: protocol and manual of operations development,
staff training in study procedures, research instrument development, data
collection and management, quality assurance, data analysis, distributed data
entry, electronic communications, administrative management and coordination.

o  Study design and management.  Data Coordinating Center applicants should
discuss various aspects of study design that would be important in developing
pediatric asthma clinical protocols, for example: eligibility criteria; baseline
and outcome measures, including objective measures of asthma; 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 chemical and genetic analysis of blood samples; and plans for
statistical analysis.  Applicants should also describe their familiarity with
asthma in children and other pulmonary diseases.

BUDGET AND RELATED ISSUES

Applicants should complete the budget information as directed in the PHS 398
application form. Sample budgets and justification page will be provided upon
request from Mr. Raymond Zimmerman at the number listed under INQUIRIES.

Clinical Center Applicants:

Clinical Center applicants should consider the following additional issues
regarding budgets.  The underlying concept of the network is that a core effort
is essential to maintain the infrastructure required to perform multiple clinical
trials in childhood asthma.  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 network.  Therefore, individual Clinical Centers
should submit requests for a CORE BUDGET not to exceed $150,000 total costs
(direct costs plus facilities and administration) per year.  It is anticipated
that this core budget will cover a minimum 10% effort for the principal
investigator, and a small percent effort for other key personnel (nurse,
technician, clinic coordinator, secretary), and travel costs for two people to
attend three Pediatric Asthma Clinical Research Network meetings a year in
Bethesda, MD.  These costs may be distributed in their application and include
appropriate justification.  Total costs for the core budget may be escalated at
3 percent for future years.

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 5 years will be determined by the Pediatric Asthma Clinical
Research Network Steering Committee and will depend on availability of funds. 
It is anticipated that after the first year, 2-4 protocols may be active each
year.  Clinical Centers may request PATIENT CARE costs not to exceed $450,000 per
year.  This amount should be placed in the patient care category.  Patient care
costs may be escalated at 3 percent for future years.  Allowable total costs for
each clinical center (both core costs and costs per patient to conduct the
protocols) will be, on average, $600,000 a year.

Applicants for the Clinical Centers are requested to present the following
information:

o  For each year, the Clinical Centers should include the core budget costs (not
to exceed $150,000 total costs) and patient care costs (not to exceed $450,000
total costs).  Estimated protocol implementation costs for Year 1 should be based
on the two proposals presented in the applicants research plan.  A table should
be included showing estimated costs per patient for conducting each protocol.

The budget for the clinical protocol should be developed on a cost per patient
basis and include all direct and any applicable facilities and administration
costs.  Capitation costs should not include funds for investigational drugs. 
However, any approved drugs or laboratory tests 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.  Investigators should only
prepare budgets for their own Clinical Center to conduct the proposed trial, and
not for the entire network.  For example, after stating the total number of
patients required to complete each proposed trial, the applicant should prepare
a yearly budget for their own center based on the costs per patient for
recruiting and maintaining subjects into each protocol.

Note that ongoing annual budgets for protocols will be based on the protocols
approved by the Pediatric Asthma Clinical Research Network Steering Committee and
will be funded through a capitation funding mechanism.  The individual clinics
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:

Applicants for the Data Coordinating Center should prepare budgets for five 12
month periods that roughly correspond with the standard coordinating center
responsibilities outlined in other sections of this RFA.  For budget purposes,
Data Coordinating Center applicants should assume that in the first year, all
administrative aspects of the Pediatric Asthma Clinical Research Network will be
organized and one protocol will be developed and started.  For subsequent years,
applicants may assume that 2-4 protocols a year will be active, i.e. either in
the protocol development, implementation, or analysis and writing phase.

The award will be subject to administrative review annually.

APPLICATIONS NOT CONFORMING TO THESE GUIDELINES WILL BE CONSIDERED UNRESPONSIVE
TO THIS RFA AND WILL BE RETURNED WITHOUT FURTHER REVIEW.

The RFA label found in the PHS 398 application form must be affixed to the bottom
of the face page of the application.  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, to identify the application as a
response to this RFA, check "YES" in item 2 of page 1 of the application and
enter the title "Pediatric Asthma Clinical Research Network HL-99-006.

Submit a signed, typewritten original of the application 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 Dr. C. James Scheirer at the listing under INQUIRIES.

Applications must be received by March 18, 1999.  If an application is received
after this 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 an
application already reviewed, but such applications must include an introduction
addressing the previous critique.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by the CSR and for
responsiveness by NHLBI.  Incomplete and/or nonresponsive applications will be
returned to the applicant without further review.  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 available via the NHLBI home page.  As part
of the initial merit review, all applications will receive a written critique and
undergo a review 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

Clinical Centers:

The goals of NIH-supported research are to advance our understanding of
biological systems, improve the control of disease, and enhance health.  In the
written comments, reviewers will be asked to discuss the following aspects of the
application in order to judge the likelihood that the proposed research will have
a substantial impact on the pursuit of these goals.  Each of these criteria will
be addressed and considered in assigning the overall score, weighting them as
appropriate for each application.  Note that the application does not need to be
strong in all categories to be judged likely to have major scientific impact and
thus deserve a high priority score.  For example, an investigator may propose to
carry out important work that by its nature is not innovative but is essential
to move a field forward.

o  Significance:  Does this study address an important problem?  If the aims of
the application are achieved, how will scientific knowledge be advanced?  What
will be the effect of these studies on the concepts or methods that drive this
field?

o  Approach:  Are the conceptual framework, design, methods, and analyses
adequately developed, well-integrated, and appropriate to the aims of the
project?  Does the applicant acknowledge potential problem areas and consider
alternative tactics?

o  Innovation:  Does the project employ novel concepts, approaches or methods? 
Are the aims original and innovative?  Does the project challenge existing
paradigms or develop new methodologies or technologies?

o  Investigator:  Is the investigator appropriately trained and well suited to
carry out this work?  Is the work proposed appropriate to the experience level
of the principal investigator and key personnel?

o  Environment:  Does the scientific environment in which the work will be done
contribute to the probability of success?  Do the proposed experiments take
advantage of unique features of the scientific environment or employ useful
collaborative arrangements?  Is there evidence of institutional support?

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.

The initial review group will also examine the provisions for the protection of
human subjects and the safety of the research environment.

Applications will be judged primarily on the scientific quality of the
application, however, the scientific merit of the proposed research plan will not
be the sole criterion for selection of a Clinical Center.  Applicants are
encouraged to submit and describe their own ideas on how best to meet the goals
of the Pediatric Asthma Clinical Research Network, but they are expected to
address issues identified under APPLICATION PROCEDURES of the RFA.  Further
considerations for the review include: access to patients, multi disciplinary
nature of the proposed studies, the discussion of considerations relevant to this
RFA, and a demonstrated willingness on the part of the investigators to work as
part of the Pediatric Asthma Clinical Research Network and with the NHLBI Project
Scientist.

Data Coordinating Center:

Considerations for the review of Data Coordinating Center Applicants include the
following issues:

o  Understanding of the scientific, statistical, logistical, and technical issues
underlying multi center studies, including issues relate to treatment and
management of childhood asthma, and taking a leadership role in the area of study
design, statistics, logistics, data acquisition and management, quality control,
data analysis, and network coordination.

o  Adequacy of the proposed plans for acquisition , transfer, management, and
analysis of data, quality control of data collection and monitoring, and overall
coordination of network activities.

o  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  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.

o  Facilities, equipment, and organizational structure to effectively coordinate
network activities and assist Clinical Centers in implementing the network
protocols and collecting data.

o  Appropriateness of the budget for the work proposed.

Schedule

Letter of Intent Receipt Date:  February 4, 1999
Application Receipt Date:       March 18, 1999
Council Review:                 September 16 and 17, 1999
Anticipated Award Date:         September 30, 1999

AWARD CRITERIA

Factors that will be considered in making awards include: a) the scientific merit
of the proposed program as determined by peer review, the multi disciplinary
nature of the proposed studies, and the quality of meeting the special
requirements stated in this RFA; b) relevance to the overall programmatic balance
and priorities of the NHLBI and sufficient compatibility of features proposed in
the research plan and qualifications of the investigators to make a collaborative
program within the Pediatric Asthma Clinical Research Network a reasonable
likelihood; and c) the availability of funds.

INQUIRIES

Inquiries concerning this RFA are encouraged.  The opportunity to clarify any
issues or questions from potential applicants is welcome.

Direct inquiries regarding programmatic issues to:

James P. Kiley, Ph.D. or Virginia S. Taggart, M.P.H.
Division of Lung Diseases
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Suite 10018, MSC 7952
Bethesda, MD  20892-7952
Telephone:  (301) 435-0202
FAX:  (301) 480-3557
Email:  kileyj@gwgate.nhlbi.nih.gov
Email:  vt10s@nih.gov

Direct inquiries regarding review matters to:

James Scheirer, Ph.D.
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Suite 7220, MSC 7924
Bethesda, MD  20892-7924
Telephone:  (301) 435-0266
FAX:  (301) 480-3541
Email:  js110j@ nih.gov

Direct inquiries regarding fiscal matters to:

Ray Zimmerman
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Suite 7154, MSC 7926
Bethesda, MD  20892-7926
Telephone:  (301) 435-0171
FAX:  (301) 480-3310
Email:  Zimmermr@gwgate.nhlbi.nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance, No.
93.838.  Awards are made under authorization of the Public Health Service Act,
Title IV, Part A (Public Law 78-410, amended by Public Law 99-158, 42 USC 241 and
285) and administered under PHS grants policies and Federal Regulations 42 CFR
52 and 45 CFR Part 74.  This program is not subject to the intergovernmental
review requirements of Executive Order 12372 or a Health Systems Agency Review.

The PHS strongly encourages all grant and contract recipients to provide a
smoke-free workplace and promote the non-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.


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