PROGRAMS OF EXCELLENCE IN GENE THERAPY

Release Date:  December 1, 1999

RFA:  HL-00-008 (see NOT-HL-04-110)

National Heart, Lung and Blood Institute

Letter of Intent Receipt Date: January 14, 2000
Application Receipt Date: April 26, 2000

PURPOSE

The major goal of this RFA is to facilitate clinical gene therapy studies by 
establishing comprehensive Programs of Excellence in Gene Therapy (PEGT) that 
encourage the multidisciplinary collaboration of investigators skilled in the 
application of gene therapy for any one or combination of cardiovascular, 
pulmonary and hematologic diseases.  To accomplish this goal, this initiative 
seeks to create an environment that rapidly translates basic science advances 
into clinical application by providing shared access to specialized services, 
such as preclinical toxicology testing, generating vectors for preclinical and 
clinical use, producing large scale amounts of biological reagents (e.g. 
cytokines), providing biostatistical support and establishing a high quality 
training program for M.D., M.D./Ph.D. and Ph.D. scientists.  Both the 
specialized services, and training program will be available to NHLBI-supported 
investigators and investigators within the PEGTs.   

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 Request for Applications (RFA), 
APrograms of Excellence in Gene Therapy, is related to one or more of the 
priority areas.  Potential applicants may obtain a copy of "Healthy People 2000" 
at http://odphp.osophs.dhhs.gov/pubs/hp2000.

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 for receiving awards 
under this solicitation.  However, under exceptional circumstances, a foreign 
component critical to a PEGT may be included as a part of the program.  
Racial/ethnic minority individuals, women, and persons with disabilities are 
encouraged to apply as Principal Investigators.

MECHANISM OF SUPPORT

This RFA will use the National Institutes of Health (NIH) cooperative agreement 
(U01)award 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 Apartner@ 
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 TERMS AND CONDITIONS OF THE AWARD. 

The total project period for an application submitted in response to this RFA 
may not exceed 5 years.  A one-time competitive renewal, for the existing 
awardees, may be accepted for an additional five (5) years, for a maximum of ten 
(10) years of support.  This RFA is a one-time solicitation.  The anticipated 
award date is September 29, 2000.

FUNDS AVAILABLE

The National Heart, Lung, and Blood Institute intends to commit approximately 
$15,000,000 in FY 2000 to fund up to 5 new grants in response to this RFA. An 
applicant may request a project period of up to 5 years and a budget for total 
costs (direct costs plus facilities and administrative -F & A-costs) of up to 
$3,000,000 per year, including F & A costs on consortium arrangements.  The 
three million dollars total cost per PEGT per year will include up to $600,000 
restricted funds for services provided to NHLBI-supported investigators.  Not 
included in the three million dollars per year is an additional $200,000 direct 
cost per year that will be awarded to the Institution serving as the 
Coordinating and Data Core for all the PEGTs. Because the nature and scope of 
the research proposed may vary, it is anticipated that the size of each award 
will also vary. Although the financial plans of the National Heart, Lung and 
Blood Institute provides support for this program, awards pursuant to this RFA 
are contingent upon the availability of funds and the receipt of a sufficient 
number of applications of outstanding scientific and technical merit. 

Applicants from institutions that have a General Clinical Research Center (GCRC) 
funded by the National Center for Research Resources may wish to identify the 
GCRC as a resource for facilitating the proposed research.  If so, a letter of 
agreement either from the GCRC program director or principal investigator should 
be included with the application.

RESEARCH OBJECTIVES

Background

Gene therapy is a powerful technology that has the potential for novel medical 
applications.  Considerable progress has been made in vector design and 
therapeutic strategies have emerged.  Within the next five to ten years, gene 
therapy is likely to reach clinical importance, particularly in monogenic 
diseases where the replacement of one mutated single gene may be curative, and 
in some pathological conditions, such as restenosis or acute lung injury, that 
require only a temporary expression of the transferred gene to achieve a 
beneficial biological effect.  However, in order to make the leap from basic 
studies to the clinical arena, there must be carefully designed human clinical 
studies that critically and objectively evaluate both the safety and potential 
of gene therapy. 								

Successful gene therapy requires both the identification of therapeutic genes 
applicable to the correction of a genetic defect or amelioration of symptoms in 
inherited or acquired diseases, and the design of suitable vehicles for 
effective gene delivery and appropriate transgene expression.  While the 
conventional approach calls for testing of experimental gene therapies in animal 
models of human disease, it is sometimes not possible to establish the safety 
and efficacy of experimental therapies in such animal models.  Indeed in some 
cases, such as cystic fibrosis, animal models do not completely mimic all major 
manifestations of the corresponding human disease.  In these cases, clinical 
studies represent not only practical implementation of basic discoveries, but 
also critical experiments which refine and define new questions to be addressed 
by pre-clinical investigation.  Thus, it is important to create environments 
that enable rapid translation of preclinical studies into human pilot 
experiments and provide training for the transition from basic science to 
clinical application.

Research Scope

The overall goal of this initiative is to promote clinical research on gene 
therapy for any one or combination of heart, lung, and blood diseases.  The 
development of successful gene therapy approaches necessitates involvement of 
multiple research and clinical disciplines.  Such success relies on the quality 
of the underlying science, the care with which the clinical protocols are 
designed, the merging of different disciplines and strategies into a cohesive 
approach, the Ashared@ core resources, and the capacity to train investigators 
that are able to integrate the translational and clinical concepts into clinical 
trials. In addition, it is of critical importance that as the field moves from 
the bench into the clinical arena that the safety of human subjects be assessed 
and monitored in a rigorous manner.  It is anticipated that this initiative by 
requesting preclinical and clinically oriented projects will address the safety 
and appropriateness of gene therapy interventions in human subjects. 

Program Structure

Organizational Structure: A PEGT should be an identifiable organizational unit 
formed by a single institution or a consortium of cooperating institutions.  
Recognizing that the desired expertise and technologies may not necessarily 
reside at a single institution or even within a particular region, the PEGT may 
have projects and cores situated in different geographical areas. Each PEGT must 
provide a multidisciplinary structure that will coordinate activities between 
basic science investigators and clinicians in order to enable the rapid 
translation from basic research to clinical application.  This structure will 
facilitate gene therapy research in cardiovascular, pulmonary and hematologic 
diseases by providing researchers with access to highly specialized technology 
and research tools, and clinical facilities.  Each PEGT must consist of 
preclinical projects and two or more clinically oriented research projects 
(Phase I and/or Phase II studies) as well as shared core facilities that would 
enhance research productivity and increase the functional capacity of the PEGT. 
 While each project or core will have a specific expertise, they must be 
integrated to work towards a common goal. Each PEGT must have a Training Program 
to advance gene therapy into the clinical arena.  An Internal Advisory Committee 
must be established by the PEGT for the internal governance and operations of 
each PEGT.  In order to facilitate some of the functions that are common to each 
PEGT, one of the PEGTs will have the additional function of being a Coordinating 
and Data Core for all PEGTs.  Each PEGT must include a plan delineating the 
function of this Core and how it will successfully accomplish integrating PEGT 
interactions.  The funds ($200,000 direct cost per year plus associated F & A 
costs) do not count toward the total cost limit set for these gene therapy 
applications.  An Inter-Program Steering Committee (with membership from all the 
PEGTs) will be appointed that will have scientific management oversight and 
responsibility for developing collaborative interaction among the PEGTs. In 
addition, there will be an External Scientific Panel that will be responsible 
for reviewing applications requesting services from the PEGTs.

Preclinical Projects, Clinically Oriented Research Projects and Clinical Core:  
Each PEGT may contain a combination of preclinical and clinical projects but 
must have a minimum of two clinically oriented research projects (Phase I and/or 
II) focusing on any one or combination of cardiovascular, pulmonary and 
hematologic diseases.  Phase III studies will not be considered.  However, it is 
anticipated that results from Phase I and II studies will permit investigators 
to obtain support for Phase III studies through separate, independent 
applications.  In designing each clinically oriented study, applicants should 
aim for generating sufficient data to support the movement of the project to the 
next clinical phase.  Importantly, the quality of the proposed studies will 
figure prominently into the evaluation of all PEGT applications.  The clinically 
oriented research projects do not need to extend for the full five year funding 
period.  New clinically oriented research projects may be proposed to replace 
those that terminate.  The monitoring and selection of these new projects will 
be through the Inter-Program Steering Committee.  Each clinically oriented 
research project would support up to two training positions for either M.D., 
M.D./Ph.D or Ph.D. scientists who need to acquire the necessary skills for 
conducting clinical studies for gene therapy.  

Examples of preclinical projects: 1)experiments addressing the safety and 
evaluation of the vector and the toxicity of the expressed protein(s); 2) 
experiments verifying that the administration route successfully transports the 
gene of interest to the target site; 3) experiments evaluating the immune 
response against the gene therapy product; and 4) experiments evaluating the 
biodistribution of the gene of interest.

Examples of clinically oriented research projects are: 1) experiments in humans 
that will clearly establish proof-of-concept for the use of a specific gene 
therapy vector/protocol for a specific disorder; 2) experiments in humans 
designed to safely and ethically study specific technical problems that 
currently stand as barriers to successful treatment of disease by gene therapy; 
and 3) experiments in humans designed to test refinements in specific aspects of 
therapeutic approaches (e.g. tissue-specific and inducible gene expression) that 
will have a significant impact on the development of successful gene therapy for 
a specific disorder or disorders.  

In addition, each PEGT would be required to set up a Clinical Core that would 
support personnel to provide necessary services to the clinically oriented 
research projects.  This core, for example, would include a clinical research 
nurse, a study coordinator and a statistician that would service each project.  
It would also oversee the quality assurance and compliance of each study.  Each 
PEGT would have an Internal Advisory Committee to monitor and allocate personnel 
between projects. In addition, applicants are encourage to identify a GCRC as a 
resource for facilitating the proposed clinical studies. 

Specialized Resource Facilities and Services: The advancement of gene therapy 
into the clinical arena depends on multiple resources for generation of vectors 
for clinical use, for preclinical toxicology studies, for large scale production 
of biological reagents (e.g. cytokines), and for animal facilities.  For 
example, the difficulty in producing research and clinical grade viral vectors 
in large enough quantities that meet good manufacturing practice (GMP) standards 
is a major obstacle to the initiation of clinical protocols.  Therefore, the 
establishment of shared vector production cores for both PEGTs and NHLBI-
supported investigators would significantly accelerate the incorporation of the 
latest vectors into preclinical and clinical studies. 

Each PEGT must include in its application a description of all the proposed 
cores (of the typed cited above) and how they could serve as resource and 
service facilities for all PEGTs and NHLBI-supported investigators.  For those 
applications that are in the funding range, the NHLBI will determine which cores 
will be selected as common cores so as to have no duplication of cores among all 
the PEGTs.  NHLBI-supported investigators from both within and outside of the 
PEGTs would be eligible to submit a request for a service that any of the PEGT 
cores provide.  The service would be at no cost to the requestor.  The 
Coordinating and Data Core would coordinate the review of the requests through 
the External Scientific Panel and distribute them among the appropriate PEGTs.  
The External Scientific Panel made up of outside experts would rank the request 
in priority order based on scientific merit.  Subsequently, the NHLBI staff 
would review the prioritization of these requests with regards to: 1)scientific 
merit as judged by the External Scientific Panel; 2)NHLBI program relevance; and 
3) core availability.  Restricted funds would be awarded to each core facility 
to offset the cost of these services to the requesting investigators. 

Training Program for Career Development Opportunities:  Full implementation of a 
nationwide effort in translational research for gene therapy requires 
availability of trained M.D., M.D./Ph.D. and Ph.D. scientists.  These 
individuals must be knowledgeable about the molecular aspects of gene therapy 
and able to integrate the translational and clinical concepts necessary for the 
development of successful clinical trials.  One unique feature of the PEGT is to 
function as a program for advanced training by establishing various mechanisms 
such as training positions and specialized short courses that will focus on the 
training of M.D., M.D./Ph.D and Ph.D. scientists in translational research for 
gene therapy.  Both PEGT and NHLBI-supported investigators would be eligible for 
these training opportunities. 

As mentioned above, training opportunities for M.D., M.D./Ph.D. and Ph.D. 
scientists will be available within each clinically oriented research project. 
These trainees will be supported by the PEGT for up to two years during which 
time it will be expected that the trainee apply for NIH training or research 
grants to continue supporting the research initiated through the PEGT.  In this 
way, PEGT training funds will be available for new trainees on a continuous 
basis to optimize the number of M.D., M.D./Ph.D. and Ph.D. scientists trained 
through the program.

The combined resources of the PEGTs should make these centers excellent training 
grounds for any scientists interested in acquiring the skills and experience 
necessary to advance gene therapy into the clinical arena.  PEGTs may consider 
developing high quality programs that would compete well for National Research 
Service Institutional Training Grant Awards (T32) and the Short-Term 
Institutional Research Training Grants (T35).

In summary, a PEGT application is expected to include:

Preclinical projects
Two or more clinically oriented research projects
Shared Core Facilities or Resources 
Clinical Core
Training Program for M.D., M.D./Ph.D. and Ph.D scientists
Internal Advisory Committee (see special requirements)
Coordinating and Data Core (see special requirements)

SPECIAL REQUIREMENTS

Inter-Program Steering Committee: Because of the PEGTs diverse scientific 
agendas and tasks to be accomplished, an Inter-Program Steering Committee will 
be established.  The Inter-Program Steering Committee will be comprised of 
representatives from each PEGT, outside non-PEGT investigators appointed by the 
NHLBI, and NHLBI program staff.  The designated program officer for the PEGTs 
will be the NHLBI voting representative on the Inter-Program Steering Committee. 
This Committee will have the responsibility of overseeing the collaborative 
efforts of all the PEGTs, facilitating the conduct and monitoring of studies, 
and establishing policies and procedures for NHLBI investigators applying to the 
resources offered by the PEGTs. The Inter-Program Steering Committee will also 
be involved in the review of new clinical protocols brought forth by the PEGTs. 
Also, the Inter-Program Steering Committee will discuss and advise NHLBI on 
emerging scientific opportunities and on needs or impediments that are relevant 
to the goals of the PEGTs. For example, the Committee will develop plans to 
integrate into the PEGTs any new vectors or related technologies that will 
optimize systems for gene therapy in humans for diseases of interest to the 
NHLBI.

Coordinating and Data Core: The Coordinating and Data Core will serve a range of 
functions common to each PEGT such as arranging meetings, conference calls, and 
also will administer the provision of PEGT services to PEGT investigators and 
the wider NHLBI research community.  Applications for services from NHLBI- 
supported investigators both outside and within a PEGT will be processed through 
the coordinating and data core. The Coordinating and Data Core will administer 
the review of each application for services through an External Scientific Panel 
made up of nominees generated by the Steering Committee and the NHLBI.

Another function of the Coordinating and Data Core will be to establish a PEGT 
Intranet web site to compile and manage a range of information that will be 
generated by the PEGTs. Such information may include: patient information, 
technical information with updates on vectors and protocols for vector 
production and purification; results of toxicology studies for a particular 
construct; adverse effects; information on seminars and short courses being 
offered at various centers; and other types of information that the steering 
committee determines should be compiled and maintained.

Internal Advisory Committee: Each PEGT will have an Internal Advisory Committee 
to facilitate internal governance and operations, and to oversee the 
collaborative arrangements among investigators.  This Committee should be 
comprised of the PEGT Director and Principal Investigators of its various 
projects and cores.

External Scientific Panel: The External Scientific Panel will consist of non-
PEGT affiliated scientists appointed by the Steering Committee and NHLBI.  This 
panel would rank in priority order the applications requesting services from the 
PEGT Resources and Cores from NHLBI-supported investigators including PEGT 
investigators.  The review will be based on scientific merit and core 
availability  Subsequently, the NHLBI program staff would review the 
prioritization of these requests with regards to NHLBI program relevance.

Terms and Conditions of Award

The cooperative agreement is an award instrument establishing an Aassistance@  
relationship (in contrast to an Aacquisition@ 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 Apartner@ 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 the study, 
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 Inter-Program Steering Committee.    

2. The NHLBI Project Scientist will serve on the Inter-Program 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 Inter-
Program 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 an Inter-Program     
Steering Committee. Inter-Program Steering Committee voting membership shall    
consist of the principal investigators (i.e., cooperative agreement awardees) 
and the NHLBI Project Scientist.  Meetings of the Inter-Program Steering    
Committee will ordinarily be held by telephone conference call or in the 
metropolitan Washington D.C. 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 Inter-
Program 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 datasets 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 Inter-program Steering Committee (i.e., cooperative 
agreement awardees). 

6. Support or other involvement of industry or any other third party in the 
study -- e.g., participation by the third party; involvement of study resources 
or citing the name of the study or NHLBI support; or special access to study 
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.  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
Inter-Program Steering Committee and in accordance with paragraph 6.

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

9. 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 Inter-Program 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.

10.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.

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 
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 read the 
"NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical 
Research," which was published in the Federal Register of March 28, 1994 (FR 59 
14508-14513) and in the NIH Guide for Grants and Contracts, Vol. 23, No. 11, 
March 18, 1994, available on the web at: 
https://grants.nih.gov/grants/guide/notice-files/not94-100.html. 

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: 
https://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 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 IC staff to estimate the 
potential review workload and avoid conflict of interest in the review.

The letter of intent is to be sent to Dr. C. James Scheirer listed under 
inquiries by January 14, 2000.

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 301/710-0267, email: 
GrantsInfo@nih.gov.

Packaging of the PEGT Application

Each application to establish a PEGT will be submitted as one application by a 
PEGT Director, who will be responsible for organizing and maintaining effective 
integration and interaction of the Program.  A clear description of the 
relationship among the various components, plans for communication, interaction, 
collaboration and sharing among investigators in the PEGT should be included.  
The PEGT Director should also indicate the mechanisms for handling day-to-day 
administrative details, program, coordination, planning, and evaluation.  A PEGT 
Director will be required to be the principal investigator of one project at a 
minimum of 20% level of effort.  Each PEGT project will be directed by a 
Principal Investigator with a minimum of 20% level of effort. The PEGT Director 
has the responsibility of oversight and coordination of all projects or 
component of the PEGT, whether or not they are at his/her institution.  

Each PEGT must include a description of a Coordinating and Data Core that will 
facilitate functions common to all PEGTs, administer the PEGT services to PEGT 
and NHLBI-supported investigators and manage a PEGT intranet web site.  However, 
upon review of the proposed Coordinating and Data core, only one PEGT will be 
selected for this core.  In addition, each PEGT must describe a Clinical Core to 
support personnel to provide necessary services to clinically oriented research 
projects.  A Training Program is another integral part of each PEGT.  Selection 
and monitoring of trainees must be described.  Each PEGT application must also 
describe an Internal Advisory Committee for internal governance and operations 
and must clearly outline the proposed administrative and organizational 
structure of their PEGT, including integration, collaborative arrangements, and 
roles for key investigators from all Institutions. The applicant must also state 
willingness to participate in Inter-Program Steering Committee and abide by its 
governance.

Budget and Related Issues 

In order to fully achieve the major goal of this initiative, up to 5 PEGTs are 
proposed for support.  The cost of each PEGT could be up to $3.0 million (total 
cost) per year (a three percent escalation per year may be included as long as 
the $3.0 million per year is not exceeded in any one budget period), depending 
upon the scope of the program, in the initial phase of the program.  Included in 
the $3.0 million is $600,000 restricted funds for services provided to NHLBI-
supported investigators.  The PEGTs will be initially funded for five years, 
with an additional five years contingent upon successful competitive peer 
review.

During the course of the project period, it is anticipated that technologies 
such as vector development, gene expression and cell targeting will improve and 
the proposed studies may change.  Accordingly, it is expected that the principal 
investigators will be allowed adjustments in their scientific projects to 
accomodate such changes.  During the course of the award, the principal 
investigators will be invited to meet with NHLBI staff and the Steering 
Committee to review progress of their studies.  Budget requests should include 
travel funds for an annual principal investigator=s meeting in Bethesda, MD.

Applications should present five budget periods of 12 months each.  Applicants 
should provide adequate budget justification and all applicable direct and 
facilities and administrative costs should be included.  Estimates of staffing 
needs, including the principal investigators, other professional and support 
staff must be included.  The minimum level of effort for Program Directors and 
Key Investigators (Project Director, Core Director)is 20 percent each.  Travel 
costs for Inter-Program Steering Committee meeting and PEGT Program Coordinating 
and Data Committee meetings, as detailed under the section title ASpecial 
Requirements@ must be budgeted, along with statements indicating willingness to 
participate in these meetings.

The award will be subject to administrative review annually.

APPLICATIONS NOT CONFIRMING 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.  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: 
https://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. James Scheirer
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
Two Rockledge Center
6701 Rockledge Drive, Room 7220, MSC 7924
Bethesda, MD  20892-7924

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 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 Division of Extramural Affairs, NHLBI, in accordance with the review 
criteria stated below.  As part of the initial merit review, a process will be 
used by the initial review group in which applications receive a written 
critique and undergo a process in which only those applications deemed to have 
the highest scientific merit, generally the top half of the applications under 
review, will be discussed, assigned a priority score, and receive a second level 
review by the National Heart, Lung, and Blood Advisory Council.
Review Criteria

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 apply the five standard review 
criteria (see below) to each of the following components of the program in order 
to judge the likelihood that the proposed research will have a substantial 
impact on the pursuit of these goals:

(1) The overall goals and mission of the PEGT in meeting the major objectives of 
this RFA.

(2) The quality of the proposed preclinical and clinically oriented projects.

(3)The plans for integration of projects and shared cores; the plans for the 
accessibility of cores and resources to PEGTs and NHLBI-supported investigators; 
the plans for establishing an education/training program; and the plans for 
organization, oversight and administration of a PEGT.

The five standard review criteria are:

(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:  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 other researchers (if any)?

(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?

The program will also be evaluated with regard to synergy and interaction:

6) Synergy and interaction: Is the overall synergy of the component parts of the 
program apparent? Is there an expressed willingness to interact both within and 
between programs?  Is the infrastructure appropriate to allow and foster synergy 
and interaction?

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.

Additional scientific/technical merit criteria specific to the objectives of the 
RFA and the mechanism used must be included if they are to be used in the 
review.

Each project or component within the program will be individually evaluated 
according to the review criteria listed above and assigned a priority score. The 
program as a whole will also receive a priority score that will reflect its 
synergy and interaction.  Projects or components may be deleted if they are 
duplicative of other PEGTs.

Schedule

Letter of Intent Receipt Date: January 14, 2000
Application Receipt Date: April 26, 2000
Peer Review Date: June/July 2000
Council Review: September 2000
Earliest Anticipated Start Date: September 29, 2000


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 strongly encouraged.  Potential applicants 
should request a copy of the special instructions package.  The opportunity to 
clarify any issues or questions from potential applicants is welcome.

Direct inquiries regarding programmatic issues to:

Cardiovascular:

Sonia I. Skarlatos, Ph.D.
Division of Heart and Vascular Diseases
National Heart, Lung and Blood Institute 
Two Rockledge Center
6701 Rockledge Drive, Room 10186 (MSC 7956)
Bethesda, MD  20892-7956
Phone: (301) 435-1802
FAX: (301) 480-2858
E-mail: ss90g@nih.gov

Pulmonary:

Susan Banks-Schlegel, Ph.D.
Division of Lung Diseases
National Heart, Lung and Blood Institute
Two Rockledge Center
6701 Rockledge Drive, Room 10018 (MSC 7952)
Bethesda, MD 20892-7952
Phone: (301)435-0202
FAX: (301) 480-3557
E-mail: schleges@nih.gov

Hematology:

Greg Evans, Ph.D.
Division of Blood Diseases and Resources
National Heart, Lung and Blood Institute
Two Rockledge Center
6701 Rockledge Drive, Room 10152 (MSC 7950)
Bethesda, MD 20892-7950
Phone: (301)435-0055
FAX: (301) 480-0868
E-mail: evansg@nih.gov

Direct inquiries regarding review matters to:

C. James Scheirer, Ph.D.
Division of Extramural Affairs
National Heart, Lung and Blood Institute
Two Rockledge Center
6701 Rockledge Drive, Room 7220 (MSC 7924)

Bethesda, MD 20892-7924
Phone: (301) 435-0266
Fax: (301) 480-3460
e-mail: js110j@nih.gov

Direct inquiries regarding fiscal matters to:

Jane Davis
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
Two Rockledge Center
6701 Rockledge Drive, Room 7174 (MSC 7926)
Bethesda, MD  20892-7926
Telephone: (301) 435-0166
FAX: (301) 480-3310
Email: davisj@nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No. 
93.837, (use appropriate program number).  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 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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	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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