SEVERE ASTHMA RESEARCH PROGRAM

Release Date:  January 17, 2001

RFA:  RFA-HL-01-012 (Notice of limited competion request for competing 
applications, see NOT-HL-05-125)

National Heart, Lung, and Blood Institute

Letter of Intent Receipt Date:  February 9, 2001
Application Receipt Date:       March 12, 2001

PURPOSE

The National Heart, Lung, and Blood Institute (NHLBI) invites applications to
participate in an interactive Severe Asthma Research Program.  Severe asthma 
affects a small subset of asthma patients but uses a disproportionate amount 
of health care resources. It is also responsible for a significant amount of 
the morbidity and mortality associated with asthma.  The purpose of this RFA 
is to establish a collaborative program to investigate the mechanistic basis 
for severe asthma and how it differs from mild-to-moderate asthma.  The 
objective of this Request for Applications (RFA) is to establish a 
collaborative program to perform research investigating the pathophysiology 
of severe asthma.

HEALTHY PEOPLE 2010

The Public Health Service (PHS) is committed to achieving the health 
promotion and disease prevention objectives of "Healthy People 2010," a PHS-
led national activity for setting priority areas.  This Request for 
Applications (RFA), Severe Asthma Research Program, is related to one or more 
of the priority areas.  Potential applicants may obtain a copy of "Healthy 
People 2010" at http://www.health.gov/healthypeople/.

ELIGIBILITY REQUIREMENTS

Applications may be submitted by foreign and 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.  Racial/ethnic minority individuals, 
women, and persons with disabilities are encouraged to apply as Principal 
Investigators.

Among the disciplines and expertise that may be appropriate for this program 
are pulmonary medicine, molecular and cellular biology, allergy and 
immunology, pharmacogenetics, genetics, and imaging.

MECHANISM OF SUPPORT

This RFA will use the National Institutes of Health (NIH) regular research 
project (R01) award mechanism.  The total project period for an application 
submitted in response to this RFA may not exceed five years.  This RFA is a 
one-time solicitation.  Future unsolicited competing continuation 
applications will compete with all investigator-initiated applications and be 
reviewed according to the customary peer review procedures.  The anticipated 
award date is September 30, 2001.

FUNDS AVAILABLE

The NHLBI intends to commit approximately $4.5 million dollars in FY 2001 to 
fund up to eight awards in response to this RFA.  An applicant may request a 
project period of up to five years and a budget for direct costs of up to 
$350,000 per year.  Facilities and Administrative (indirect) costs will be 
awarded based on the negotiated rates.  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 may also vary in all years.  Future year costs may be 
distributed based on the final projects agreed upon by the principal 
investigators.

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 meritorious applications.  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

A small percentage of asthma patients (10 percent or less) has severe disease 
that is refractory to conventional treatment modalities, including treatment 
with systemic corticosteroids.  Although severe asthmatics represent only a 
small percentage of the asthmatic population, their disease has a major 
impact on the health care system, consuming resources disproportionately, in 
terms of time and health care dollars.   In addition, this patient subgroup 
bears the most significant burden in relation to poor quality of life, high 
risk for mortality, and a high investment of health care costs for marginal 
management.  Yet, we have very little knowledge of the pathophysiology of 
severe asthma and how it differs from mild-to-moderate asthma.  This 
information is critical for the development of effective treatment modalities 
for severe asthma patients.

Although there has been a considerable increase in our understanding of the 
mechanisms involved in the inception and maintenance of mild-to-moderate 
asthma over the past 20 years, a paucity of clinical, physiologic, and 
pathologic data exists on severe asthma.  While there is overwhelming 
evidence to indicate that airway inflammation underlies the pathophysiology 
of asthma, its relationship to disease severity remains unclear.   Although 
atopy is one of the strongest risk factors for the development of asthma in 
childhood, it is not an associated finding in severe asthma, thus its role in 
the pathology of severe asthma requires clarification.  Virtually nothing is 
known of the genetic, environmental, and other factors that are associated 
with disease progression and severity.  Once established, it is not known 
whether severe asthma can be completely reversed.  Corticosteroids are highly 
effective anti-asthma drugs acting to reduce airway inflammation.  However, 
there are many patients with severe asthma in whom only partial improvement 
is achieved even at high doses.  Although very few long term longitudinal 
epidemiologic studies exist, the scant evidence available suggests that 
severe and poorly controlled asthma progresses to an increasingly 
irreversible component.  Severe and prolonged inflammation is almost always 
accompanied by tissue remodeling, however, the mechanism(s) involved and 
their contribution to the pathophysiology of severe asthma remain poorly 
understood.  The functional importance of remodeling to airway narrowing, or 
for the development of airways hyperresponsiveness, remains unclear, as well 
as the potential ramifications of these changes for airway function and 
therapeutic management.  Given the recent findings demonstrating the 
persistence of inflammation in patients with severe asthma despite high dose 
glucocorticoid treatment, a comprehensive assessment of severe asthma is 
clearly warranted to define the cellular and molecular events underlying the 
pathophysiology of severe asthma.

The number of severe asthma patients at any one site, along with differing 
diagnosis guidelines make it difficult to obtain clear data on the 
pathophysiology of severe asthma.  There is a critical need to evaluate a 
significant population of patients in a uniform manner to elucidate how the 
pathophysiology of severe asthma differs from that of mild-to-moderate 
asthma.  Because of the small number of patients with severe asthma at any 
one institution, meaningful comparison and investigation into the underlying 
causes of severe asthma necessitate recruitment of patients through a 
collaborative research program.  Investigators in this program will agree on 
a definition of severe asthma and diagnosis guidelines in order to obtain a 
sufficiently homogeneous patient population to answer research questions that 
may require more patients than can be recruited at any one institution.  In 
addition, the collaborative nature of the program will help pool the 
necessary expertise and resources to facilitate the conduct of novel research 
in a timely and efficient manner.

Research Scope

The objective of this RFA is to establish a Severe Asthma Research Program in 
order to accelerate research on the pathophysiology of severe asthma.  The 
fundamental question to be addressed by each investigator is how the 
pathophysiology of severe asthma differs from that of mild-to-moderate 
asthma.  The final definition of severe asthma, for the purposes of this RFA, 
will be decided upon by a steering committee composed of the principal 
investigators from each institution and the NHLBI Project Officer.  Each 
applicant must propose a research project in humans characterized with severe 
asthma.  Applicants should provide a definition of severe asthma in the 
application along with standard diagnosis guidelines for patients.  All 
investigators must agree to utilize the common guidelines developed by the 
Steering Committee for all investigator-initiated studies performed under 
this RFA.   Animal models, intervention-based clinical studies and long-term 
epidemiology studies are not appropriate for this RFA.  Robust disease 
definitions will need to be developed and used as entry criteria for research 
studies to enable meaningful comparisons between groups of patients in the 
program.   Studies may be combined or patients pooled to address common 
questions.  Comparisons with mild-to-moderate asthmatics should be included 
as controls.  Emphasis should be placed on research that will help elucidate 
the underlying pathophysiologic mechanisms that contribute to the initiation 
and progression of the severe asthma phenotype. 

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

o   Investigation of the risk factors for severe asthma versus mild-to-
moderate asthma.  This may include investigation into environmental, genetic, 
pharmacogenetic and other factors that may predispose a patient towards the 
development of severe asthma as compared to mild-to-moderate asthma.  
Determine whether disease begins in early life and progresses or whether 
there is a defining event(s) that changes the course of illness.

o   The genetics and pharmacogenetics of severe asthma.

o   Determination of whether there are physiologic abnormalities that are 
specific to severe asthma.  Evaluate the relationship between progressive 
remodeling and declining FEV1 and lack of reversibility.  Definition of the 
morphologic and histologic findings of patients with severe asthma as 
compared with those who have mild to moderate asthma and to those with airway 
remodeling.

o   Investigation of the role of infection and atopy in severe asthma.  The 
role of both respiratory infections and allergy in the development and 
exacerbation of mild-to-moderate asthma has been established.  However, their 
roles in the initiation and/or progression of severe asthma is unclear and 
needs to be clarified.

o   Definition of the immune, inflammatory and neuroregulatory mechanisms 
that contribute to the pathogenesis of severe asthma and their impact on lung 
function.  Particular attention needs to be given to how these mechanisms 
differ in severe asthmatics as compared to patients with milder disease.  The 
relationship between the innate and acquired immune systems of the airways 
and their relationship to severe asthma needs to be established.  The 
relationship of lymphocytes (e.g., neutrophils) and their effector functions 
as they relate to ongoing inflammation and airway remodeling specifically in 
severe asthma needs to be more fully explored.

o   Establish the effect of inhaled and/or oral corticosteroids on basic 
pathophysiologic manifestations of severe asthma, e.g., modulation of airway 
cell function, disease progression, airway remodeling and lung function.

o   Application of new technologies to study the composition and dynamics of 
the airways in chronic severe disease with increased discrimination and 
resolution.

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.  Applications utilizing animals, clinical 
interventions or long-term epidemiology studies will be judged non-
responsive.

SPECIAL REQUIREMENTS

In order to gain insight into the pathophysiology of severe asthma it is 
critical that a significant number of patients be evaluated in a uniform 
manner before individual research studies are initiated.  Thus, this program 
is designed to be a collaborative effort.  Applicants will be responsible for 
proposing  research studies and  common guidelines that will be shared across 
the program for patient diagnosis, enrollment, testing and sampling and 
sharing of materials and data.   All individual investigators will be 
required to participate in a collaborative and interactive manner with one 
another in all aspects of the program, including sharing of patients, samples 
and data. The investigators in the Program will be responsible for 
collaboratively developing a common mechanism by which patient data, samples 
and materials can be collected and shared as needed for the research studies 
proposed.  This mechanism should include common definitions, common 
procedures for patient selection and enrollment, standardization of common 
procedures, tests and reporting forms.  

A Steering Committee will coordinate the efforts of the Severe Asthma 
Research Program and will be composed of the principal investigators of the 
Program and the NHLBI Project Officer.  The Steering Committee may meet as 
often as three to six times in the first 12 months of the study, and two 
times per year thereafter.  Meetings will be held in the greater Baltimore-
Washington area.  The Steering Committee will have primary responsibility for 
the general organization of the program, finalizing the common definitions, 
common measures, standardization of common procedures and common reporting 
formats, so that studies are comparable and complementary, to be implemented 
at each institution, facilitating the conduct and monitoring of the studies.  
Definitions and procedures must be agreed upon by the Steering Committee 
before research studies are initiated.  Research funds will be restricted 
until such agreement is reached.  Subcommittees of the Steering Committee may 
be established as necessary.

Applicants must include sufficient travel funds in order for the principal 
investigator, at a minimum, at each institution to attend all meetings of the 
Steering Committee.  Designated funds will be restricted for travel to 
Steering Committee meetings only.  Applicants must also include sufficient 
funds for shipment of samples.

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of the NIH that women and members of minority groups and 
their sub-populations must be included in all NIH-supported biomedical and 
behavioral research projects involving human subjects, unless a clear and 
compelling rationale and justification are provided indicating that inclusion 
is inappropriate with respect to the health of the subjects or the purpose of  
the research.  This policy results from the NIH Revitalization Act of 1993 
(Section 492B of Public Law 103-43). 

All investigators proposing research involving human subjects should read the 
UPDATED "NIH Guidelines for Inclusion of Women and Minorities as Subjects in 
Clinical Research," published in the NIH Guide for Grants and Contracts on 
August 2, 2000 
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html), 
a complete copy of the updated Guidelines are available at  
http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm:  The 
revisions relate to NIH defined Phase III clinical trials and require: a) all 
applications or proposals and/or studies to provide a description of plans to 
conduct analyses, as appropriate, to address differences by sex/gender and/or 
racial/ethnic groups, including subgroups if applicable, and b) all 
investigators to report accrual, and to conduct and report analyses, as 
appropriate, by sex/gender and/or racial/ethnic group differences.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of 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.

URLS IN NIH GRANT APPLICATIONS OR APPENDICES

All applications and proposals for NIH funding must be self-contained within 
specified page limitations.  Unless otherwise specified in an NIH 
solicitation, internet addresses (URLs) should not be used to provide 
information necessary to the review because reviewers are under no obligation 
to view the Internet sites.  Reviewers are cautioned that their anonymity may 
be compromised when they directly access an Internet site.

LETTER OF INTENT

Prospective applicants are asked to submit 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 plan the review.

The letter of intent is to be sent to Dr. Deborah Beebe at the address listed 
under INQUIRIES by February 9, 2001.

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 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, email: 
GrantsInfo@nih.gov.

Because we expect that there will not be any applications requesting less 
than $250,000 in direct costs for every year, applications should be in the 
standard (non-modular) format with a detailed budget.

Additional Material to Include in the Application

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

o  Willingness to participate in the Severe Asthma Research Program.   
Applicants should provide a written statement describing their general 
support of collaborative research and interaction with other institutions 
participating in the Program and specifically state their willingness to 
implement common guidelines developed by the Steering Committee as well as 
share patients, samples and data when appropriate as determined by the 
Steering Committee.

APPLICATIONS NOT CONFORMING TO THESE GUIDELINES WILL BE CONSIDERED 
UNRESPONSIVE TO THIS RFA AND WILL BE RETURNED WITHOUT FURTHER REVIEW.
The RFA label available in the PHS 398 (rev. 4/98) application form must be 
affixed to the bottom of the face page of the application.  Type the RFA 
number on the label.  Failure to use this label could result in delayed 
processing of the application such that it may not reach the review committee 
in time for review.  In addition, the RFA title and number must be typed on 
line 2 of the face page of the application form and the YES box must be 
marked.

The sample RFA label available at: 
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been modified to 
allow for this change.  Please note this is in pdf format.

Submit a signed, typewritten original of the application, including the 
Checklist, and three signed, photocopies, in one package to:

CENTER FOR SCIENTIFIC REVIEW
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040, MSC 7710
BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for express/courier service)

At the time of submission, two additional copies of the application must be 
sent to: Dr. Deborah Beebe at the listing under INQUIRIES.  

Applications must be received by the application receipt date listed in the 
heading of this RFA.  If an application is received after that date, it will 
be returned to the applicant without review.
  
The Center for Scientific Review (CSR) will not accept any application in 
response to this RFA that is essentially the same as one currently pending 
initial review, unless the applicant withdraws the pending application.  The 
CSR will not accept any application that is essentially the same as one 
already reviewed. This does not preclude the submission of substantial 
revisions of applications already reviewed, but such applications must 
include an introduction addressing the previous critique.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by the CSR and 
responsiveness by the NHLBI.  Incomplete and/or non-responsive applications 
will be returned to the applicant without further consideration.

Applications that are complete and responsive to the RFA will be evaluated 
for scientific and technical merit by an appropriate peer review group 
convened by the NHLBI in accordance with the review criteria stated below.  
As part of the initial merit review, all applications will receive a written 
critique and undergo a process in which only those applications deemed to 
have the highest scientific merit, generally the top half of the applications 
under review, will be discussed, assigned a priority score, and receive a 
second level review by the NHLBI National Advisory Council or Board.

Review Criteria

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.

(1) 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?

(2) 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?

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

(4) Investigator:  Applicants must have experience and expertise to conduct 
research studies in patients with severe asthma.  Prospective institutions 
must have an established clinical research program on the pathogenesis of 
asthma. 

(5) 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?

(6) Study population.  Applicants must have the ability to enroll over the 5 
years at least 25-50 patients with severe asthma.  The pool of potential 
study participants in the Severe Asthma Research Program should consist of 
appropriate gender and minority representation.  The application must 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 25-50 
patients for research studies over the 5 year period is expected, but it is 
not anticipated that all patients will be enrolled in research studies 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 institutions with community health 
care providers such as HMOs, asthma clinics, or private practice physicians 
to ensure adequate numbers patients.

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.

o  The adequacy of the proposed plan to share data, if appropriate.

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 successful applicants.  Applicants 
are encouraged to submit and describe their own ideas on how best to meet the 
goals of the Severe Asthma Research Program, but they are expected to
address issues identified under APPLICATION PROCEDURES of the RFA. 

Schedule

Letter of Intent Receipt Date:    February 9, 2001
Application Receipt Date:         March 12, 2001
Peer Review Date:                 July 2001
Council Review:                   September 6-7, 2001
Earliest Anticipated Start Date:  September 30, 2001

AWARD CRITERIA

Award criteria that will be used to make award decisions include:

o  scientific merit (as determined by peer review)
o  availability of funds
o  programmatic priorities.

INQUIRIES

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

Direct inquiries regarding programmatic issues to:

Patricia Noel, Ph.D.
Division of Lung Diseases
National Heart, Lung and Blood Institute
6701 Rockledge Drive, Room 10018, MSC7952
Bethesda, Maryland 20892-7952
Telephone: (301)-435-0202
FAX: (301)-480-3557
Email: noelp@nih.gov

Direct inquiries regarding review issues to:

Deborah Beebe, Ph.D.
Division of Extramural Affairs
National Heart, Lung and Blood Institute
6701 Rockledge Drive, Room 7418, MSC 7924
Bethesda, MD 20892-7924
Telephone: (301) 435-0270
FAX: (301)-480-3541
Email: (beebed@nhlbi.nih.gov)

Direct inquiries regarding fiscal matters to:

Tanya McCoy
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: mccoyt@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 Sections 301 and 405 of the 
Public Health Service Act as amended (42 USC 241 and 284) and administered 
under NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 
74 and 92.  This program is not subject to the intergovernmental review 
requirements of Executive Order 12372 or Health Systems Agency review.

The PHS strongly encourages all grant 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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