Full Text HL-93-11

ASTHMA CLINICAL RESEARCH NETWORK

NIH GUIDE, Volume 21, Number 45, December 18, 1992

RFA:  HL-93-11-L

P.T. 34

Keywords: 
  Asthma 
  Treatment, Medical+ 
  Data Management/Analysis+ 


National Heart, Lung, and Blood Institute

Letter of Intent Receipt Date:  March 1, 1993
Application Receipt Date:  May 6, 1993

PURPOSE

The Division of Lung Diseases invites applications for four Clinical
Groups and one Data Coordinating Center to participate, with the
assistance of the National Heart, Lung, and Blood Institute (NHLBI),
in the establishment of a network of interactive asthma clinical
research groups designed to facilitate evaluation of novel treatment
methods and management strategies for asthma; and to rapidly
disseminate the findings from these clinical studies to the health
care community.  This request for applications (RFA) is to:  (1)
provide a mechanism to establish and maintain the infrastructure
required to perform multiple therapeutic trials of novel treatments
and management strategies for asthma using common protocols with the
requisite numbers of patients.  Support would be provided to maintain
the infrastructure with additional funds provided on a cost per
patient basis for conducting clinical protocols.  (2) Establish a
Data Coordinating Center for the network.  It is envisioned that the
Clinical Groups would have significant experience and a strong
history of basic and clinical research on the pathogenesis and
treatment of asthma, since the program infrastructure should be built
around existing research projects.

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,
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 "Healthy People 2000" (Summary
Report:  Stock No. 017-001-00473-1) through the Superintendent of
Documents, Government Printing Office, Washington, DC 20402-9325
(telephone 202-783-3238).

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 organizations
are not eligible to apply and domestic applications may not include
international components. Applications from minority individuals and
women are encouraged.

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

MECHANISM OF SUPPORT

The administrative and funding mechanism to be used to undertake this
program will be a cooperative agreement (U01), an assistance
mechanism.  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
Terms and Conditions of Award.

FUNDS AVAILABLE

An estimated four awards for Clinical Groups and one award for a Data
Coordinating Center will be made under this RFA.  A maximum of about
$17.4 million (including direct and indirect costs) over a five-year
period will be awarded for the Clinical Groups and the Data
Coordinating Center.  Approximately $2.5 million will be available
for the first year, $3.5 million for the second year, $3.6 million
for the third year, $3.8 million the fourth year and $3.9 million for
the last year.  It is anticipated that the award for each Clinical
Group will be about $475,000 total costs for the first year and the
award for the Data Coordinating Center will be about $600,000 total
costs for the first 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 redistributed based on the recommended protocols.

Awards and level of support are dependent on the receipt of a
sufficient number of applications of high scientific merit.  Although
this program is provided for in the financial plans of the NHLBI,
awards pursuant to this RFA are contingent upon the availability of
funds for this purpose.

The total project period for applications submitted in response to
the present RFA may not exceed five years.  The anticipated award
date is September 30, 1993.

At this time the NHLBI anticipates that there will be a renewed
competition after five years.  However, the final decision will
depend upon experience with the network during the first five years
as well as financial considerations.

RESEARCH OBJECTIVES

Background

Asthma is an increasingly serious cause of morbidity and mortality in
the United States.  There are approximately 12 million asthmatics in
this country.  The disease affects both sexes and impacts all
racial/ethnic groups.  It is now recognized that asthma is a complex
disease of varied etiology triggered by a number of factors such as
allergens, drugs, chemicals, exercise, cold dry air, infections and
emotions, making asthma therapy difficult and sometimes complicated.
Multiple drugs are often required, including medications to treat and
control symptoms (bronchodilator agents such as beta-2 adrenergic
agonists, theophylline, and anticholinergics), as well as drugs
thought to control the underlying process (anti-inflammatory agents
such as inhaled and systemic corticosteroids, cromolyn sodium and
nedocromil).

Despite major advances in understanding the etiology and
pathophysiology of asthma and the development of new therapeutic
modalities, the prevalence, severity, and mortality from asthma have
increased over the past decade in all age groups.  In addition to the
rise in morbidity and mortality, hospitalizations for asthma have
doubled in adults and increased fivefold for children over the past
20 years.  Mortality rates appear to be particularly high in urban
and rural minority populations. Asthma continues to place a heavy
burden on patients and their families, the health care system, and
society as a whole. Therefore, new approaches are needed to help
alleviate this growing problem.

One important need is to establish a mechanism to allow rapid
evaluation of new and existing therapeutic approaches for asthma, and
for dissemination of laboratory and clinical findings to the health
care community.  This program seeks to accomplish this through a
network of interactive asthma Clinical Groups that conduct clinical
research in a coordinated and multidisciplinary setting.  There are
several key reasons why establishment of an asthma network would
greatly accelerate clinical research:  (1) The sometimes complicated
clinical picture often makes it difficult to accumulate a large
number of comparable patients in any one center.  (2) The
distribution of underlying disease processes may vary between
populations and influence outcome independent of experimental
treatment.  (3) Uniformity in treatment protocols would decrease the
variability of data and decrease the numbers of patients needed for
each clinical study.  (4) Results from the basic and clinical
research laboratories can be rapidly disseminated to health care
professionals for optimal care of the asthmatic patient.
Availability of a coordinated asthma network would ensure appropriate
patient categorization and bring together the necessary clinical
expertise and administrative resources to conduct multiple
therapeutic trials.  Centralized protocols will promote high quality
design, decrease the variability in supportive modalities, and reduce
unnecessary or redundant support for conducting multiple independent
clinical studies.  A separate Data Coordinating Center will support
protocol development, sample size calculations, common
questionnaires, complete data analysis and overall study
coordination.

Objectives and Scope

The objective of this program is to establish a network of
interactive asthma clinical research groups to rapidly assess novel
treatment methods and to ensure that these findings on optimal
management of asthmatic patients are rapidly disseminated to
practitioners and health care professionals.  This program is
intended to provide a mechanism to establish and maintain the
required infrastructure to perform multiple therapeutic trials in
asthmatic patients.  The therapeutic trials may involve
investigational drugs, approved agents not currently used, or drugs
currently used in treatment of asthma.  It will be advantageous for
groups to have had substantial previous basic and/or clinical
research experience in asthma and asthma related fields, since it is
anticipated that the program infrastructure will be built around
existing research projects.

Although some of the characteristics of the network and experimental
protocols are specified, the specific selection, prioritization and
design of the various protocols remain in the hands of the
investigators.  A number of possible examples are listed purely for
illustrative purposes.

In order to rapidly conduct multiple clinical protocols to test novel
therapeutic approaches for asthma, a collaborative effort will be
required by approximately four Clinical Groups and one Data
Coordinating Center.  Participating institutions will develop and
then follow uniform study protocols and use standardized data
collection procedures.

The collaborative protocols will be developed by a Steering
Committee, composed of the Principal Investigators and the NHLBI
Project Scientist.  The various protocols will be subject to peer
review by an uninvolved expert group.  The clinical trials will
proceed into their second (or implementation) phase only with the
concurrence of both the awardees and the NHLBI.

Study Design and Population

It is envisioned that over the five year period several multicenter
clinical trials will be developed and implemented by the Principal
Investigators.  The individual Clinical Groups within the network
should emphasize clinical research that can be conducted under
mutually agreed upon protocols.  The study population is envisioned
to be asthmatic patients encompassing a broad range of age groups and
consisting of appropriate gender and minority representation with
clearly defined and documented asthma.  At a minimum, one third of
the patient population at each clinic should be minority individuals
and one half women.  It is expected that each Clinical Group would
have the ability to access at least 400 patients for various
protocols over the five year period, but it is not envisioned that
all 400 patients would necessarily be enrolled in research protocols
at any one time, and it is possible that an individual patient may be
involved in more than one study.  Patient access may be accomplished
by establishing strong links with community health groups such as
HMOs, asthma clinics, or private practice physicians to ensure
adequate numbers of patients for initiation of the clinical trials.
Of the total patients accessible, investigators should include
substantial numbers from a broad age range, as well as a description
of the age distribution and characteristics of the population that
they might recruit into potential clinical trials.  Also, it is
expected that Clinical Groups will develop plans to establish
partnerships with the practicing physicians responsible for primary
patient care.

Applicants should propose two examples (conducted either concurrently
or sequentially) of clinical protocols requiring multicenter
participation that they consider important.  For each example
applicants should submit concept documents not more than four pages
long, that briefly outline the rationale and background of the
proposed clinical trials, study design, type of patients to be
included in the protocols, eligibility criteria, and baseline and
outcome measures.  These examples should represent clinical trials
that the investigators are interested in conducting, keeping in mind
that the network mechanism allows using specific non-approved
investigational drugs.  For each of the clinical protocols,
applicants should discuss the characteristics and numbers of
potential patients that would be available from their own geographic
area.

Examples of clinical protocols appropriate to the program may
include, but are not limited to:

o  long term evaluation of safety, efficacy, and side effects of high
dose inhaled steroids in the treatment of moderate to severe asthma,
including the effects on airways responsiveness, growth, bone
density, pituitary and adrenal axis function;

o  efficacy of alternative anti-inflammatory therapies (e.g.,
methotrexate, gold) in the treatment of chronic asthma; the role of
5-lipoxygenase inhibitors and other new agents that inhibit the final
pathways in the treatment of asthma;

o  comparison of leukotriene antagonists and 5-lipoxygenase
inhibitors with inhaled steroids;

o  efficacy of long acting beta-2 agonists and their interaction with
inhaled steroids.

The topics for the network protocols will be proposed and prioritized
by the steering committee, but the actual number of clinical trials
conducted will be dependent upon availability of funds.  It is
anticipated that many of the initial network protocols will be
selected from among those proposed by the successful applicants.

Timetable

The timetable for the study may be roughly subdivided into three
phases over a five year period.  There may be some overlap of
functions within each of the phases, and the time estimates are only
approximations.  The purpose of the phases is to provide broad
guidelines of the total scope of work to be accomplished for this
RFA.

Phase I:    Planning and development of the network
            infrastructure, protocol development               0-12
months

Phase II:   Patient recruitment, protocol implementation,
            further protocol development                      12-60
months

Phase III:  Data analysis, report preparation, protocol
            development and recruitment for next studies      24-60
months

The first twelve months of the study may be devoted to planning and
development of the network infrastructure and committee structure.
Possible objectives for the planning and development stage are to
select a steering committee chairperson; determine patient
eligibility criteria for initial clinical trials; train staff in
diagnostic procedures; help set up data acquisition and consent
forms; define terms and outcome measures; develop a manual of
operations, questionnaires, procedures for quality control, determine
priorities for protocol development and begin to develop specific
protocols.  The Principal Investigators, through the Steering
Committee, will lead the planning effort, with the assistance of the
Project Scientist at NHLBI.  Key Clinical Group staff may also be
involved in the planning.  Subcommittees of the Steering Committee
may be formed to help in this effort.

The Data Coordinating Center will also play a key role in the
planning and development stage.  Possible objectives for the planning
and development stage for the Data Coordinating Center, in addition
to assisting Clinical Groups in their planning and organization of
the network, are to help develop study protocols, randomization and
analytic plans; select a data acquisition, transfer, and management
system; plan for any subcontracts for chemical analysis; develop
procedures for quality control, training, and certification; print
the protocols and data forms; develop and produce a Manual of
Operations, and take the lead for the orderly accumulation and
transmission of data for the network.

In Phase II, the Clinical Groups will select and prioritize common
protocols for the network, proceed with subject recruitment and
protocol implementation for the first studies and concurrent
development of additional protocols.  Possible objectives for Phase
II for the Data Coordinating Center are to assist the Clinical Groups
with respect to completing protocol development, patient recruitment,
randomization, data acquisition, and ongoing quality control.

In Phase III, after the last patients in the first study have
completed their follow-up measurements, Clinical Groups will review
their data and assist the Data Coordinating Center in the closeout of
the initial study.  Initiation of patient accrual will begin for the
next studies and protocol development continues for subsequent
trials.  The Data Coordinating Center will continue with its
activities in data management, editing, data analysis and protocol
development.  It will also support manuscript preparation through
data analysis, statistical consultation, editorial tasks, and
coordination of meetings.  It is anticipated that the main results
paper for each network clinical trial will be collaboratively
prepared by the investigators and submitted for publication.

SPECIAL REQUIREMENTS

Additional Material to Include in the Application

To promote the development of a collaborative program among the award
recipients, a number of issues discussed below need to be addressed
in each application for a Clinical Group.  Each application should
discuss the qualifications and experience of the investigators.  It
is envisioned that the Principal Investigator will be an established
investigator with experience in conducting multicenter trials that
include patients, physicians, and the community.  It is anticipated
that the program infrastructure will be built around existing
research projects.  Therefore, applicants should have a substantial
base of funded research in asthma or asthma related fields.  The
level of this current research support (direct costs per year) and
past record of achievement in research related to the pathogenesis
and treatment of asthma should be discussed as well as the
laboratory/clinical facilities available at their institutions, and
the facilities at any proposed participating subcontracting
organizations.  For any subcontracts, especially for access to asthma
patients, there should be a description of the organization of that
facility including the means of assuring quality control of patient
care as well as data entry, plans for coordination, and a process for
filing patient assurances.  Also, plans for accessing at least 400
asthmatic patients encompassing a broad range of age groups, and
consisting of appropriate gender and minority representation with
clearly defined and documented asthma for use over the five year
period should be detailed in the application.  These plans should
outline links between individual Clinical Groups and community health
groups.  In addition, applicants should provide a brief description
of the patient characteristics, age distribution, and any other
relevant baseline information of the patient population.  It is
anticipated that the patient population will consist of about one
third minority groups and one half women.  The patient population
available to investigators should be recruited primarily from within
a clinic's immediate geographic area, and include a substantial
number of patients covering a broad age range.  As part of these
community based contacts, clinics should discuss potential approaches
to disseminate new knowledge gained from these clinical studies to
various health care groups.

Applicants should also discuss their willingness, and that of the
institutions involved, to pursue capitation of operational costs for
each protocol, and general support of collaborative research through
this network concept.

Clinical Group applicants must be able to interact effectively with
the Data Coordinating Center to transmit and edit data and should
discuss their capability to participate in a distributed data entry
system if this approach is selected.  Clinical Group applicants
should also state their willingness to participate in a cooperative
and interactive manner with other Clinical Groups, the NHLBI and the
Data Coordinating Center within the context of the network.

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.  If so, a letter of agreement from either the
GCRC Program Director or Principal Investigator should be included
with the application.

Data Coordinating Center applicants should discuss various aspects of
study design that would be important in developing asthma clinical
protocols; their familiarity with asthma and other pulmonary
diseases, eligibility criteria, methods of randomization, important
considerations for making sample size and power calculations,
baseline and outcome measures, other relevant measures including
objective outcome measures of asthma, methods and frequency of data
collection and entry, monitoring accuracy of data collection, methods
of data acquisition and transfer, quality control procedures
including training and certification, chemical analysis of blood
samples, and plans for statistical analysis of results.

Budget and Related Issues

The underlying concept of this network is that a core effort is
essential to maintain the infrastructure required to perform multiple
therapeutic trials in asthma.  Based on this approach we estimate
that the individual Clinical Groups will require a minimum level of
effort to sustain the organizational aspects of the network.
Therefore, individual Clinical Groups should submit requests for a
BASE BUDGET, not to exceed $125,000 total costs per year, for the
organizational aspects of the network over five years.  The suggested
level of commitment to maintain the infrastructure for each year may
be in the order of 10 percent for the Principal Investigator, five
percent for the co-investigator, 25 percent for a secretary, 100
percent for a clinical coordinator, and travel costs for
approximately four trips to Bethesda for two people.  Additional
support (in the range of $350,000 total costs for the first year per
clinic) will be provided on a per patient basis for conducting the
actual clinical protocols.

Applications for the Clinical Groups and Data Coordinating Center
should present five budget periods of 12 months each.  For the
Clinical Groups, budgets for the first twelve months should include
the base costs and a budget for only one of the proposed clinical
trials that is outlined in the application for the duration of the
proposed trial.  The budget for the clinical protocol should be
developed on a cost per patient basis and include all direct and any
applicable indirect 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.  Applicants 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 Group and not for the
entire network.  Applicants should also indicate whether the
capitation costs for the second protocol included in the application
will be similar or markedly different (if so by how much) from the
sample budget.

Only the base budget should be escalated four percent for the
remaining future years.  It is not the intent of this network to
provide support for only a single protocol that runs for the entire
five years.  Ongoing annual budgets of the Clinical Groups within the
asthma network will be based on individual recommended protocols that
will be funded through a capitation funding mechanism.  Each Clinical
Group will be given base costs as defined above and in addition, a
flat fee per patient successfully enrolled and completed as defined.
Future year costs will be redistributed based on the recommended
protocols.  The individual clinics will be expected to project
patient enrollment for a specific protocol during a specified time
frame; continuation and level of funding will be based on actual
recruitment and overall performance.

Applicants for the Data Coordinating Center should prepare budgets
that roughly correspond with the standard coordinating center
responsibilities related to the above mentioned network phases.

These awards will be subject to administrative review annually.

It should be recognized that not all clinical protocols proposed or
recommended may be done, and it is possible that not all clinics
would be participating equally in all protocols.  Given the current
resources and range of anticipated costs, it is possible that the
network may be able to simultaneously conduct between two and four
simple protocols per year.  However, availability of funds and
ability to recruit the required patients will determine the actual
numbers of protocols that can ultimately be accomplished through the
network.

The protocols of successful applicants will be submitted to the
Steering Committee for further consideration once the cooperative
agreements have been awarded.  It is anticipated that many of the
initial network protocols will be selected from among those highly
meritorious studies proposed by the successful applicants.  However,
a decision to fund a particular Clinical Group will not commit the
network to develop that group's clinical protocol.

Study Organization

Steering Committee

The Steering Committee will be the main governing body of the network
and, at a minimum, will be composed of the PIs of each Clinical
Group, the Principal Investigator of the Data Coordinating Center,
and the NHLBI Project Scientist (Branch Chief, Airways Diseases
Branch, Division of Lung Diseases).  Each Clinical Group, the Data
Coordinating Center and the NHLBI will have one vote.  The Committee
may meet as often as four 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, should 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 developing
common clinical protocols, facilitating the conduct and monitoring of
the studies, and reporting the study results.  Topics for the
protocols will be proposed and prioritized by the Steering Committee.
In certain instances, FDA cooperation may be sought in protocol
development, especially if unconventional interventions are being
considered.  Subcommittees of the Steering Committee will be
established as necessary.  The NHLBI will have one voting
representative on each subcommittee.

The collaborative protocols will be developed by the Steering
Committee.  With data submitted centrally to the Data Coordinating
Center, the protocols will define rules regarding access to data and
publications.  An independent Data and Safety Monitoring Board, to be
appointed by NHLBI, will review progress at least annually and report
to NHLBI.

Terms and Conditions of Award

The administrative and funding mechanism to be used to undertake this
project will be cooperative agreements (U01), an assistance
mechanism.  Under the cooperative agreement, the NIH assists,
supports and/or stimulates, and is involved substantially with
recipients in conducting a study by facilitating performance of the
effort in a "partner" role.  Consistent with this concept, the tasks
and activities in carrying out the studies will be shared among the
awardees and the NHLBI Project Scientist.  The tasks or activities in
which awardees have substantial responsibilities include protocol
development, participant recruitment and follow-up, data collection,
quality control, interim data and safety monitoring, final data
analysis and interpretation, preparation of publications,
collaboration with other awardees, and collaboration with the NHLBI
Project Scientist.  The NHLBI Project Scientist will have substantial
responsibilities in protocol development, quality control, interim
data and safety monitoring, final data analysis and interpretation,
preparation of publications, collaboration with awardees, and
coordination and performance monitoring.

It is anticipated that awardees will have lead responsibilities in
study design, protocol development, final data analysis and
interpretation, and the preparation of most publications.  It is
anticipated that the NHLBI Project Scientist will have lead
responsibilities in quality control and catalyzing interim monitoring
of data and safety and may, consistent with publication policy to be
adopted by the Steering Committee, have lead responsibilities in the
preparation of some publications. The NHLBI Project Scientist will
have voting membership on the Steering Committee, and as appropriate,
its subcommittees.

Awards resulting in response to this RFA are for five years for the
Clinical Groups and Data Coordinating Center.

Awardees will retain custody of and have primary rights to their data
developed under these awards, subject to Government, e.g., NHLBI,
NIH, or PHS, rights of access consistent with current HHS, PHS, and
NIH policies.

The NHLBI reserves the right to terminate or curtail the study (or an
individual award) in the event of (a) substantial shortfall in
participant recruitment, follow-up, data reporting, quality control,
or other major breech of the protocol, (b) substantive changes in the
agreed-upon protocol to which the NHLBI does not agree, (c) reaching
a major study endpoint substantially before schedule with persuasive
statistical significance, or (d) human subject ethical issues that
may dictate a premature termination.

Any disagreement that may arise in scientific matters 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.

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.

STUDY POPULATIONS

SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH
POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL
RESEARCH STUDY POPULATIONS

NIH policy is that applicants for NIH clinical research grants and
cooperative agreements are required to include minorities and women
in study populations so that research findings can be of benefit to
all persons at risk of disease, disorder, or condition under study;
special emphasis must be placed on the need for inclusion of
minorities and women in studies of diseases, disorders, and
conditions which disproportionately affect them.  This policy is
intended to apply to males and females of all ages.  If women or
minorities are excluded or inadequately represented in clinical
research, particularly in proposed population-based studies, a clear
compelling rationale must be provided.

The composition of the proposed study population must be described in
terms of gender and racial/ethnic group.  In addition, gender and
racial/ethnic issues must be addressed in developing a research
design and sample size appropriate for the scientific objectives of
the study.  This information must be included in the form PHS 398
(rev. 9/91) in Sections 1-4 of the Research Plan, and summarized in
Section 5, Human Subjects.  Applicants are urged to assess carefully
the feasibility of including the broadest possible representation of
minority groups.  However, NIH recognizes that it may not be feasible
or appropriate in all research projects to include representation of
the full array of United States racial/ethnic minority populations
(i.e., Native Americans [including American Indians or Alaskan
Natives], Asian/Pacific Islanders, Blacks, Hispanics).

The rationale for studies on single minority population groups should
be provided.

For the purpose of this policy, clinical research includes human
biomedical and behavioral studies of etiology, epidemiology,
prevention (and preventive strategies), diagnosis, or treatment of
diseases, disorders or conditions, including but not limited to
clinical trials.

The usual NIH policies concerning research on human subjects also
apply.  Basic research or clinical studies in which human tissues
cannot be identified or linked to individuals are not subject to
these policies.  However, every effort should be made to include
human tissues from women and racial/ethnic minorities when it is
important to apply the results of the study broadly, and this should
be addressed by applicants.

If the required information is not contained within the application,
the application will be returned.

Peer reviewers will address specifically whether the research plan in
the application conforms to these policies.  If the representation of
women in a study design is inadequate to answer the scientific
question(s) addressed AND the justification for the selected study
population is inadequate, it will be considered a scientific weakness
or deficiency in the study design and will be reflected in assigning
the priority score to the application.

All applications for clinical research submitted to NIH are required
to address these policies.  NIH funding components will not award
grants or cooperative agreements that do not comply with these
policies.

LETTER OF INTENT

Prospective applicants are asked to submit, by March 1, 1993, 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 subsequent applications, the information
that it contains is helpful in planning for the review of
applications.  It allows NHLBI staff to estimate the potential review
workload and to avoid conflict of interest in the review.

The letter of intent is to be sent to:

C. James Scheirer, Ph.D.
Review Branch, Division of Extramural Affairs
National Heart, Lung, and Blood Institute
Westwood Building, Room 648
Bethesda, MD  20892
Telephone:  (301) 496-7363
FAX:  (301) 402-1660

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 9/91) is to be used
in applying for these grants.  These forms are available at most
institutional offices of sponsored research; from the Office of
Grants Inquiries, Division of Research Grants, National Institutes of
Health, 5333 Westbard Avenue, Room 449, Bethesda, MD 20892, telephone
(301) 496-7441; and from the NIH Project Scientist named below.

The RFA label available in the 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, the RFA title and number must be typed in line 2a of the
face page of the application form and the YES box must be marked.
Send or deliver the original, signed application and three legible
complete photocopies to:

Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892**

Send two additional copies of the application to:

C. James Scheirer, Ph.D.
Review Branch, Division of Extramural Affairs
National Heart, Lung, and Blood Institute
Westwood Building, Room 648
Bethesda, MD  20892
Telephone:  (301) 496-7363

It is important to send these two copies at the same time as the
original and that three copies are sent to the Division of Research
Grants.  Otherwise, the NHLBI cannot guarantee that the application
will be reviewed in competition for this RFA.

Applications must be received by May 6, 1993.  If an application is
received after this date it will be returned to the applicant without
review.  The Division of Research Grants (DRG) will not accept any
application in response to this announcement that is essentially the
same as one currently pending initial review, unless the applicant
withdraws the pending application.  The DRG 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 reviewed, but such applications must include an
introduction addressing the previous critique.

REVIEW CONSIDERATIONS

General Considerations

All applicants will be judged on the basis of the scientific merit of
their proposed protocols and their documented ability to conduct the
essential study components as broadly outlined in the RESEARCH
OBJECTIVES of this RFA.  Although the technical merit of the protocol
is important, it will not be the sole criterion for selection of a
Clinical Group.  Other considerations such as the importance and
timeliness of the proposed clinical trials, access to patients, and
multidisciplinary nature of the studies will be part of the
evaluation criteria.

Review Method

Upon receipt, applications will be reviewed by the DRG for
completeness and by NHLBI staff for responsiveness to this RFA.
Incomplete applications will be returned to the applicant without
further consideration.  If the application is judged unresponsive,
the applicant will be contacted and given an opportunity to withdraw
the application or to have it considered for the regular,
investigator-initiated grant program of the NIH.  If the application
submitted in response to this RFA is substantially similar to a grant
application already submitted to the NIH for review, but has not yet
been reviewed, the applicant will be asked to withdraw either the
pending application or the new one.  Simultaneous submission of
identical applications will not be allowed, nor will essentially
identical applications be reviewed by different review committees.
Therefore, an application cannot be submitted in response to this RFA
that is essentially identical to one that has already been 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.

Applications judged to be responsive by NHLBI staff will be reviewed
for scientific and technical merit by an initial peer review group,
which will be convened by the Division of Extramural Affairs, NHLBI,
solely to review these applications.  The initial review will include
a preliminary evaluation to determine scientific merit relative to
the other applications received in response to this RFA (triage); the
NIH will remove from further consideration applications judged to be
noncompetitive and promptly notify the Principal Investigator and the
official signing for the applicant organization.  Those applications
judged to be competitive will be further evaluated for
scientific/technical merit by the usual peer review procedures,
including, if deemed appropriate, an applicant interview in or near
Bethesda at the applicant's expense. Subsequently, they will be
reviewed by the National Heart, Lung, and Blood Advisory Council.

Review Criteria

Applicants are encouraged to submit and describe their own ideas on
how best to meet the goals of the network and their specific
protocols, but they are expected to address issues identified under
SPECIAL REQUIREMENTS of this Request for Applications.  Applications
will be judged primarily on the scientific quality of the
application, the appropriateness, importance and timeliness of the
proposed clinical trials, facilities and access to patients,
multidisciplinary nature of the study, approach to cost containment,
the discussion of considerations relevant to this RFA, expertise of
the investigators, their capability to perform the work proposed, and
a demonstrated willingness to work as part of the network and with
the NHLBI Project Scientist.

The review group will assess the scientific merit of the protocols
and related factors, including:

Clinical Groups

o  Importance and scientific merit of the proposed protocols,
including adequacy of the methodology to carry out the research and
utilization of the multicenter nature of the network.

o  Adequacy of the patient population and numbers of patients,
including appropriate representation of minorities and women.

o  Availability of adequate facilities and other resources including
a plan for the administrative structure within the Clinical Group.

o  Rationale and cost-effectiveness of the research approach
proposed.

o  Adequacy of data collection, preliminary analysis, and reporting
procedures, including adequacy to process the volume of data expected
within their Clinical Group and manage the individual study
databases.  Plans to ensure quality control of data.

o  Expertise, training, and experience of the investigators and
staff, including the scientific and administrative abilities of the
PI and co-investigators; their potential to accomplish the proposed
research goals; the time they plan to devote to the program for the
effective conduct of the study; their previous experience conducting
clinical research in asthma; their ability and experience to
participate in multicenter clinical trials; and willingness to work
collaboratively with other Clinical Groups, the Data Coordinating
Center, and the NHLBI in the manner summarized in the RFA, including
implementation of common protocols within the network framework.

o  Facilities, equipment, and organizational structure to effectively
implement the proposed research.

Data Coordinating Center

o  Understanding of the scientific, statistical, logistical, and
technical issues underlying multicenter studies, including issues
related to treatment and management of 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 and co-investigators, 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 Groups and the NHLBI.

o  Facilities, equipment, and organizational structure to effectively
assist Clinical Groups in implementing the network protocols and in
data collection procedures and in overall coordination of network
activities.

o  Appropriateness of the budget for the work proposed.

AWARD CRITERIA

Applications recommended by the National Heart, Lung, and Blood
Advisory Council will be considered for award based upon (a)
scientific and technical merit, importance of the proposed clinical
trial, timeliness, multidisciplinary nature of the study, and the
requirements explicitly stated in this RFA; (b) program balance,
including in this instance, sufficient compatibility of features to
make a successful collaborative program a reasonable likelihood; and
(c) availability of funds.

Letter of Intent:          March 1, 1993
Application Receipt Date:  May 6, 1993
Review by NHLBAC:          September 2-3, 1993
Anticipated Award Date:    September 30, 1993

INQUIRIES

Written and telephone inquiries are encouraged.  The opportunity to
clarify any issues or questions from potential applicants is welcome.

Inquiries regarding this announcement may be directed to:

James P. Kiley, Ph.D.
Chief, Airways Diseases Branch
Division of Lung Diseases
National Heart, Lung, and Blood Institute
Westwood Building, Room 6A15
Bethesda, MD  20892
Telephone:  (301) 496-7332
FAX:  (301) 496-9886

Inquiries regarding review and application procedures may be directed
to:

C. James Scheirer, Ph.D.
Review Branch, Division of Extramural Affairs
National Heart, Lung, and Blood Institute
Westwood Building, Room 648
Bethesda, MD  20892
Telephone:  (301) 496-7363
FAX:  (301) 402-1660

Inquiries regarding fiscal and administrative matters may be directed
to:

Mr. Raymond Zimmerman
Grants Management Officer, Lung Section
Grants Operations Branch
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
Westwood Building, Room 4A11C
Bethesda, MD  20892
Telephone:  (301) 496-4970
FAX:  (301) 402-1200

AUTHORITY AND REGULATIONS

This project is described in the Catalog of Federal Domestic
Assistance No. 93.837.  Awards are made under authorization of the
Public Health Service Act, Title IV, Part A (Public Law 78-410, as
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 74.  This project is not subject to the intergovernmental review
requirements of Executive Order 12372 or Health Systems Agency
review.

.

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	Office of Extramural Research (OER)			National Institutes of Health (NIH) 9000 Rockville Pike Bethesda, Maryland 20892			Department of Health and Human Services (HHS)
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