Part I Overview Information


Department of Health and Human Services

Participating Organizations
National Institute of Health (NIH), (http://www.nih.gov)  

Components of Participating Organizations
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), (http://www.nichd.nih.gov)

Title:  Pediatric Pharmacology and Therapeutics Research Consortium (PPTRC) (U54)

Announcement Type
New

Update: The following update relating to this announcement has been issued:

Request for Applications (RFA) Number: RFA-HD-08-021

Catalog of Federal Domestic Assistance Number(s)
93.865

Key Dates
Release Date: October 21, 2008
Letters of Intent Receipt Date: February 28, 2009
Application Receipt Date: March 31, 2009
Peer Review Date(s):  June/July 2009
Council Review Date:  October 2009
Earliest Anticipated Start Date: December 1, 2009
Additional Information to Be Available Date (URL Activation Date): Not applicable
Expiration Date: April 1, 2009 - (Now Expired November 5, 2008 per NOT-HD-09-004)

Due Dates for E.O. 12372

Not Applicable

Additional Overview Content

Executive Summary

Table of Contents


Part I Overview Information

Part II Full Text of Announcement

Section I. Funding Opportunity Description
1. Research Objectives

Section II. Award Information
1. Mechanism(s) of Support
2. Funds Available

Section III. Eligibility Information
1. Eligible Applicants
    A. Eligible Institutions
    B. Eligible Individuals
2.Cost Sharing or Matching
3. Other - Special Eligibility Criteria

Section IV. Application and Submission Information
1. Address to Request Application Information
2. Content and Form of Application Submission
3. Submission Dates and Times
A.  Receipt, Review and Anticipated Start Dates
                     1. Letter of Intent
B.  Sending an Application to the NIH
            C. Application Processing
D.  Application Assignment
4. Intergovernmental Review
5. Funding Restrictions
6. Other Submission Requirements and Information

Section V. Application Review Information
1. Criteria
2. Review and Selection Process
    A. Additional Review Criteria
    B. Additional Review Considerations
    C. Resource Sharing Plan(s)
3. Anticipated Announcement and Award Dates

Section VI. Award Administration Information
1. Award Notices
2. Administrative and National Policy Requirements
     A. Cooperative Agreement Terms and Conditions of Award
         1. Principal Investigator Rights and Responsibilities
         2. NIH Responsibilities
         3. Collaborative Responsibilities
         4. Arbitration Process
3. Reporting

Section VII. Agency Contact(s)
1. Scientific/Research Contact(s)
2. Peer Review Contact(s)
3. Financial/ Grants Management Contact(s)

Section VIII. Other Information - Required Federal Citations

Part II - Full Text of Announcement


Section I. Funding Opportunity Description


1. Research Objectives

Purpose

This FOA issued by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) of the National Institutes of Health (NIH), solicits grant applications from institutions/organizations for the creation of Pediatric Pharmacology and Therapeutics Research Consortium (PPTRC) Nodal Centers to conduct comprehensive translational/basic and clinical research in pediatric therapeutics.  A major goal of the PPTRC Nodal Centers will be to conduct research that will fill gaps in knowledge that may be responsible for failed efficacy trials or that may prevent Food and Drug Administration (FDA) labeling of drugs in pediatrics. In addition, the Consortium will be expected to adopt a new paradigm of promoting personalized pediatric therapeutics and promote a greater understanding of the interrelationship among disease processes, and therapy across the developmental spectrum. Testing of new molecular entities, pediatric formulations, novel therapeutic approaches, new types of delivery systems and development and testing of biomarkers will be priorities for the consortium. The Consortium will also be a locus of training future leaders and researchers in pediatric clinical and developmental pharmacology.

This FOA is the result of the need to restructure the pediatric pharmacology research program to address knowledge gaps that may be responsible for failed efficacy trials and to accommodate the research needs of the future, while at the same time profiting from the experience and contributions made by the PPRU Network from 1994 through 2008.  A new consortium will be developed according to functional cores rather than a group of units that are similar in structure and function. A major realignment will be the expansion of translational research with linkage to basic research and the continued development of multidisciplinary teams.

Although this FOA stems from the previous initiative, the Pediatric Pharmacology Research Unit Network (RFA HD-03-001), the program structure and goals of the current FOA differ substantially from those of the original FOA. Consequently, all responses to this FOA will be considered new applications. Investigators who are or were members of the previous Network have developed strong collaborations over the years in the therapeutic areas addressed in this FOA and have made substantial contributions to development of pediatric pharmacology using a multi-investigator approach. Current and/or past members of the Pediatric Pharmacology Network and other experts in pediatric pharmacology are strongly encouraged to apply as PPRTC Nodal Centers.

Background

Federal law and the regulations of the FDA require that drugs be tested for safety and efficacy before they are approved for clinical use.  This testing must take place in all populations in which the drug will be employed.  Since both the qualitative and quantitative aspects of pharmacodynamics and pharmacokinetics are different in immature individuals, studies must be conducted in infants and children before a drug can be approved for their use. 

Up to 1994 most drugs (75-80%) were not labeled as either safe or effective for infants and children and off label use was the norm for these therapeutic orphans. There was little awareness among practitioners that prescribing for children was not evidence-based.  In 1994, the FDA implemented a regulation (Pediatric Rule of 1994) that allowed labeling of drugs for pediatric use based on appropriate studies in adults and additional pharmacokinetics, pharmacodynamics, and safety studies in pediatric patients if the course of the disease and drug effects is similar in children and adults.  This regulation was designed to encourage pediatric labeling. 

In response to the need for appropriate drug therapy studies in pediatric patients, the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) established the Pediatric Pharmacology Research Unit (PPRU) Network in 1994.  As noted, at the inception of the PPRU Network, off label use of drugs in children was the norm and there was a dearth of pharmacokinetic (PK) information from which to determine pediatric dosing. Since 1994, the PPRU researchers have performed a variety of studies, including (but not limited to) pharmacokinetic studies (phases I and II of drug development), pharmacokinetic-pharmacodynamic investigations, studies of trial design, studies of drug metabolism, and pharmacogenetics evaluations.

The FDA issued new regulations in August 1997 (Final Rule of 1997), requiring pediatric studies of certain new drugs.  Also, in 1997 the FDA Modernization Act (FDAMA) was enacted. This legislation contained a provision (Section 111) that provided exclusivity incentives for the pharmaceutical industry (six months of additional patent exclusivity) to conduct pharmaceutical trials in children. The pediatric provisions of FDAMA expired in December 2001.The Best Pharmaceuticals Act for Children (BPCA), enacted in January 2002, extended the exclusivity incentives for five years. The BPCA also provides a mechanism for the study of off-patent drugs and identifies the need to conduct studies in the newborn population.

The 2007 reauthorization of the BPCA and the Pediatric Research Equity Act (PREA) increased FDA’s authority to require studies. These acts strengthened adverse event surveillance, and improved the transparency, oversight and administration of both Acts. Importantly, the role of the NIH in examining needs in pediatric therapeutics increased and the inclusion of pediatric pharmacologists in existing NIH career development programs was provided. The implementation of the FDAMA and the BPCA resulted in an impressive increase in the number of pharmaceutical industry-sponsored pediatric studies.  Performance of these studies uncovered the need to provide the scientific underpinnings of drug trials in children.  Along with these regulatory and legislative developments, the explosion of knowledge in pharmacogenomics has provided tools to decipher the mechanisms responsible for changes in drug biodisposition during development and the effects of ontogeny on both drug disposition and drug effects. 

Despite the advances in legislation, several practical problems discouraged the testing of drugs in children.  These include the unforeseeable nature of some clinical responses in immature individuals; the possibility of catastrophic unanticipated reactions; the threat of effects on growth or health long after completion of the drug administration; the difficulty in predicting dose-response relationships by extrapolation from data obtained in adults; the ethical problems of conducting non-therapeutic research in children; the awkwardness of procedures for obtaining informed parental permission and children's assent; and the lack of a suitable infrastructure for the conduct of pediatric drug studies. 

Pediatric labeling of drugs

As a result of the studies conducted under FDAMA, PREA and BPCA, there is an improved understanding of the pharmacokinetics of a number of drugs which has led to significant changes in drug labeling for pediatric patients. There is, however, concern about the significant number of failed pediatric trails because efficacy could not be demonstrated. According to the FDA, up to 50% of pediatric effectiveness trials are uninterpretable. (http://www.fda.gov/cder/pediatric/Sumaryreview.htm)

A recent study of antihypertensive trials under FDAMA and BPCA revealed that the Phase III trials failed mostly because of dosing issues. (Hypertension 2008; 51(4):834-840). A number of other factors may contribute to the high failure rate, including small sample size, feasibility issues, lack of well defined endpoints and differences in drug sensitivity between adult and pediatric patients. Because of these factors, there is an important need for model-based advice prior to the design of efficacy trials.

The significant number of failed pediatric trials requires concentrated efforts to address issues of study design, appropriate dosing, development of biomarkers of response to therapy and toxicity across disciplines and therapeutic areas. The need to provide the scientific basis for the performance of efficacy and safety trials applies to both academic research studies and studies to support pediatric labeling.

Molecular Medicine and Personalized Therapeutics

Advances in decoding the genome have led to an expanded understanding of disease pathogenesis and identification of molecular drug targets. Molecular medicine (genomics, proteomics and metabolomics) has emerged as a powerful engine that is providing the tools to characterize changing disease states and uncover pathways for possible individualized therapeutic interventions. 

Molecular markers represent a vision for the future that has been incorporated into the FDA’s Critical Path but this approach remains largely unexplored particularly in current clinical pediatric practice. Gene-based molecular diagnostics, however, is changing the practice of medicine. Molecular profiling of various diseases using genomic or proteomic approaches holds great promise. The use of molecular markers as clinical correlates of disease progression, risk quantification and prognostic indicators will form the basis of individualized medicine in years to come.

Completion of the Human Genome Project opened new areas of research and expansion of the fields of functional genomics, bioinformatics, and proteomics and the bioinformatics essential to interpreting the complex information generated by these techniques. These technologies and new areas of knowledge markedly expand the potential of pharmacogenomics, receptor biology, and molecular pharmacodynamics.

The genomic research revolution has resulted in an explosion of knowledge that made the development of multidisciplinary researchers in developmental pharmacology essential. There is a need to form multidisciplinary teams with participation of investigators with expertise in developmental biology, systems biology, bioinformatics, pharmacogenomics, metabolomics, biomarker development and pediatric subspecialists. There is a limited appeal for developmental pharmacology outside the small pediatric pharmacology community.  Without an increase in the pool of investigators trained in new “omics” technology, the necessary integration and synergistic interaction will not be possible.

Pediatric Therapeutics: a changing discipline

Pediatric pharmacology has been the mainstay of pediatric therapeutics with emphasis on the effect of development on the biodisposition and response to specific drugs in children. The interrelationship between disease processes, development and therapy is beginning to be appreciated. Disease processes in children often differ from those similar disorders in adults, and different phenotypes are being identified in children at various developmental ages. Until recently asthma was considered to be basically similar in adults and children, differing primarily in clinical severity. Therefore, successful treatment was believed to require only different dosage regimens or routes of administration to control the disease. Asthma is now recognized as a heterogeneous disease with a number of distinct phenotypes. The course of asthma may also vary based on age, with marked variations possible between young children, older children, adolescents and adults. While developmental processes can modulate phenotypic expression, the latter may also be influenced by therapy.

The explosion in biomedical knowledge and the growing number of disease targets dictate the need to reevaluate traditional approaches to pediatric pharmacology. There is a pressing need for innovation in pediatric therapeutics and the adoption of disease-oriented and patient-oriented approaches. This new paradigm will require a multidisciplinary approach in which pharmacologic expertise is integrated with knowledge of disease expression in children compared to adults and with in depth knowledge in physiology and pathophysiology of disease processes.

Research Objectives and Scope

The goals of the PPTRC are to:

General Description and components of the PPTRC 

PPTRC Nodal Centers must involve investigators at two or more research sites and at different institutions.  Each responding applicant team must include researchers from at least two different institutions. The Nodal Centers will work together to develop a consensus-based program in Pediatric Pharmacology and Therapeutics.

For the purpose of this FOA, a programmatic pathway is defined as a research area of interest within a pediatric therapeutic area that is considered a top research priority for the NICHD and that lends itself to a series of concurrent or sequential research projects. The type of studies will vary according to the research needs of the NICHD and may include basic and translational research including preclinical (in vivo animal models, in vitro and or in silico studies), and clinical studies. A systems biology approach will be used by forging links and collaborations with basic scientists in developmental biology, pharmacology and informatics.

Each of the PPTR nodal centers will include clusters (programmatic pathways) that will focus on only one of the following therapeutic areas:

Other therapeutic area groupings may be included if adequate rationale for the grouping is provided and the proposed group fulfills the overall goals of the consortium.  It is expected that the implementation of programmatic pathways within and across therapeutic areas will maximize knowledge acquisition and generate multi-investigator and interdisciplinary teams to address knowledge gaps. The programmatic pathways are not limited by, but must be congruent with, NICHD priorities for the BPCA program. Please refer to the following website for the BPCA list of needs in pediatric therapeutics:  http://bpca.nichd.nih.gov .

Although each PPTRC Nodal Center will spearhead research in a therapeutic area, all PPTRC Nodal Centers are expected to participate in pharmacologic studies requiring integration and collaboration beyond a single PPTRC Nodal Center, such as building a prior knowledge base to determine pediatric dosing or providing the scientific underpinnings for the study of drugs at different developmental stages. Other inter-Nodal Centers studies may address the effects of obesity or under nutrition on drug disposition, and effect, or the development of methodology applicable to all pediatric clinical trials e.g., determination of renal or hepatic toxicity. Cooperation from the Inter-Nodal Centers  will also include a mechanism to augment patient enrollment in clinical studies originating at individual PPTRC Nodal Centers.

The establishment of collaborations with established pediatric specialty networks with drug efficacy experience, (e.g., NICHD Newborn Research Network, the NHLBI Pediatric Heart Network, the Childhood Asthma research and Education Network), is highly desirable.  It is expected that the PPTRC will provide other NIH disease-specific pediatric networks and collaborations with industry, with pharmacologic support in the performance of novel pharmacologic approaches e.g., development of pharmacodynamic or toxicity biomarkers.  Participation and interaction with the Pharmacogenetics Research Network (PGRN), pharmacoepidemiology consortia and BPCA-related clinical trials network(s) are also encouraged. When expertise or capability not available in the PPRTC is needed for addressing a specific scientific question the PPRTC Steering Committee may recognize affiliate or associate membership of individual investigators or a group of investigators.

The awarded PPTRC Nodal Center will work jointly under the guidance of the Steering Committee of the PPRTC on the development, harmonization and prioritization of programmatic pathways within and across therapeutic areas and conditions.

The synergy, harmonization and integration of projects will be the responsibility of the PPRTC steering committee, and should be designed to have a multiplier effect with various other interrelated studies instead of developing common protocols projects. An overriding consideration will be the interrelationship of projects across programmatic pathways that may become the source of hypothesis generating ideas for consortium studies.  These ideas should allow for cross-fertilization of therapeutic areas and conditions, addressing knowledge gaps whose resolution will result in important generalizable knowledge for determining efficacy and safety in all pediatric subpopulations.

PPTRC Nodal Center Research Activities

Each PPTRC Nodal Center should be an incubator for innovation, hypothesis generation, and testing of proof of concept. In addition the PPTRC Nodal Centers will address gaps in knowledge and develop new approaches to solve feasibility issues that prevent the determination of safety and efficacy of drugs in pediatric patients.

Each PPTRC Nodal Center will consist of a consortium of clinical and translational science investigators, institutions and relevant organizations. The focus of each PPTRC Nodal Center is pharmacologic and disease-oriented research in a therapeutic area. Each PPTRC is designed to perform collaborative research in a synergistic and complementary manner with other PPRTC Nodal Centers.

Overall research goals:

Each Center Node will have a translational, a pharmacometric and a clinical research core and an administrative unit.

1)  Translational Core.

2) Pharmacometrics Core.

Applicants responding to this FOA must:

3) Clinical Research Core.

Projects within the Clinical Core may include:

Pediatric efficacy trials are not part of this FOA. However, interaction between pharmacometric and translational researchers, pediatric pharmacology investigators of the PPTRC, and pediatric specialists involved in pediatric clinical trials networks, is strongly encouraged.  The proposed research project(s) should address problems in pediatric therapeutics within the PPTRC Nodal Center therapeutic area that requires substantial collaboration. Applicants are strongly encouraged to use a multidisciplinary team approach rather than a large number of small projects that can be addressed outside the U54 cooperative mechanism. It is expected that activities may require collaboration with other institutions or other PPTRC Nodal Centers. By using an interdisciplinary approach, the PPTRC Nodal Center can conduct activities that are beyond the capabilities of individual investigators or institutions.

The description of the three cores must not exceed 10 pages.

Administrative Unit

The Nodal Center Administrative Unit must be headed by the Project Director (PD) of the Nodal Center who ensures a mutually supportive interaction between scientists conducting translational, pharmacometric or clinical investigations. The qualifications of the PD for this role and the plan to promote clinical and translational research should be described. The description of the administration need must not exceed five pages.

Training, Education and Expansion of the Pool of Researchers in Developmental Pharmacology

As nationally recognized consortia of excellence in pediatric therapeutics, the PPTRC Nodal Centers are expected to train new researchers in pediatric and developmental pharmacology and therapeutics. This program will emphasize multidisciplinary cross training.  This is an important feature that differs from those of other programs in pediatric pharmacology and therapeutics.

Each PPTRC Nodal Center should develop a training plan in its specific therapeutic area. The proposed plan must not exceed five pages. This plan would be integrated with those of the other PPTRC Nodal Centers to provide a training environment for post-doctoral investigations in the different therapeutic areas. Utilization and adaptation of existing training programs in pediatric pharmacology are encouraged. In addition to a fellowship in pediatric clinical pharmacology, PPTRC Nodal Centers should offer rotations for fellows in other pediatric specialties and in adult training programs in clinical pharmacology.

Investigators heading the Translational Cores of all PPTR Consortia, in cooperation with the NICHD Program Scientist of the PPTRC, will actively promote the expansion of research in developmental pharmacology with emphasis on multidisciplinary collaboration.  A website for education and research in developmental pharmacology will be developed by the Coordinating Center in cooperation with consortium investigators and the staff of the OPPB branch of the NICHD. The target audience, in addition to pediatric pharmacologists, will include investigators with expertise in developmental biology, systems biology, pediatric pharmaco-epidemiology, metabolomics, transcriptomics, pediatric genetics and bioinformatics as well as obstetric and pediatrics clinical pharmacology.

In addition, a bi-monthly Web-cast will be organized with participation of both consortium and outside investigators. The investigators with active grants in developmental pharmacology who are not members of the PPTRC will be invited to join this group.   Semi-annual Web casts with participation of developmental pharmacology investigators from the EU, Canada, Japan and other countries will be jointly planned.

Plan to Monitor Center Progress

The PPTRC must develop a clear and concise plan for how progress will be monitored in meeting its goals. A section must be included that describes the qualitative and quantitative criteria that will be used to help monitor the PPTRC progress. These criteria must incorporate how the PPTRC will provide “added value” compared to other research mechanisms. Measurable criteria for helping to assess the progress of every component of the PPTRC toward its goals for the entire funding period must be provided.   

Statistics and Data Management and Coordinating Center (SDMCCC)

The SDMCC will be the subject of a separate solicitation. This central, completely independent coordinating center will provide data management and statistical services for all inter-Consortia clinical protocols in development and for active protocols. In addition, the SDMCC will be responsible for all statistical and data management services for all intra-Consortia clinical research projects within the PPTRC program. The SDMCC will coordinate and organize the clinical collaboration between the Nodal Centers and their subordinate clinical sites, and will serve as the primary unit to collect, manage, analyze, and store clinical data obtained from the individual Nodal Centers. This will require the full range of coordinating center activities including: organization of program communications through websites, e-mail listservs, conference calls and the like; study design and protocol development; preparation of forms and a Manual of Procedures for collaborative clinical trials; training center staff in data collection procedures; maintaining the study database; monitoring clinical center performance; providing patient accrual reports; performing appropriate  analyses of study data; and participating in the preparation of study publications. The SDMCC will continue to maintain, expand, and improve the existing Data Repository initiated in the prior PPRU Network (2003-2008) funding cycle. The registry contains de-identified, protected clinical, demographic, pharmacometric and pharmacogenetic data collected from patients in the consortium and individual centers studies. The follow-on registry will be used as a tool for the Steering Committee to plan collaborative clinical studies during the funding cycle, to develop a prior knowledge library and to plan studies relating within and across therapeutic groups and conditions.  The PPTRC Collaborative Data Registry and Repository will be accessible to any interested investigator outside the PPTRC program who proposes a legitimate research use. A separate database may also be developed for some collaborative (inter-Center) clinical studies carried out within the program, depending on the nature of the study, at the discretion of the Steering Committee.

The SDMCC will have the following additional responsibilities:

Public briefing

An informational session for investigators representing groups considering submission of applications in response to this FOA will be held. Details will be announced in the Guide to Grants and Contracts (http://grants.nih.gov/grants/guide/index.html) Representatives from the NICHD Obstetric and Pediatric Pharmacology Branch, Grants Management Branch and Division of Scientific Review will provide information and answer questions pertinent to preparing applications in response to this FOA.

Section II. Award Information


1. Mechanism of Support

This funding opportunity will use the U54 Cooperative agreement award mechanism(s).
The Project Director/Principal Investigator (PD/PI) will be solely responsible for planning, directing, and executing the proposed project.  

This FOA uses “Just-in-Time” information concepts. It also uses non-modular budget formats described in the PHS 398 application instructions (see http://grants.nih.gov/grants/funding/phs398/phs398.html). 

This funding opportunity will use a cooperative agreement award mechanism. In the cooperative agreement mechanism, the Project Director/Principal Investigator (PD/PI) retains the primary responsibility and dominant role for planning, directing, and executing the proposed project, with NIH staff being substantially involved as a partner with the Principal Investigator, as described under the Section VI. 2. Administrative Requirements, "Cooperative Agreement Terms and Conditions of Award.

2. Funds Available

The estimated amount of funds available for support of 7 PPTRC Nodal Centers awarded as a result of this announcement is 9.5 million dollars of total cost for fiscal year 2010. Future year amounts will depend on annual appropriations. The anticipated start date of the awards is January 2, 2010.

Although the financial plans of the NICHD provide support for this program, awards pursuant to this funding opportunity are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications.

Facilities and administrative costs requested by consortium participants are not included in the direct cost limitation. See NOT-OD-05-004.

NIH grants policies as described in the NIH Grants Policy     Statement.

3. Other-Special Eligibility Criteria

Applicants are not permitted to submit a resubmission application in response to this FOA. 

Renewal applications are not permitted in response to this FOA

Applicants may submit more than one application, provided each application is scientifically distinct.

Section IV. Application and Submission Information


1. Address to Request Application Information

The PHS 398 application instructions are available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. Applicants must use the currently approved version of the PHS 398. For further assistance contact GrantsInfo, Telephone (301) 435-0714, Email: GrantsInfo@nih.gov.

Telecommunications for the hearing impaired: TTY 301-451-5936.

2. Content and Form of Application Submission

Applications must be prepared using the most current PHS 398 research grant application instructions and forms. Applications must have a D&B Data Universal Numbering System (DUNS) number as the universal identifier when applying for Federal grants or cooperative agreements. The D&B number can be obtained by calling (866) 705-5711 or through the web site at http://www.dnb.com/us/. The D&B number should be entered on line 11 of the face page of the PHS 398 form.

The title and number of this funding opportunity must be typed in item (box) 2 only of the face page of the application form and the YES box must be checked.

Additional information is available in the PHS 398 grant application instructions.

Special requirements

Strategic Planning for this FOA

Applicants who expect to be competitive for this FOA will find it necessary to conduct collaborative strategic planning activities to develop a conceptual framework for the specific therapeutic areas of research proposed in their application. Such a process is key to identifying the most important research gaps and opportunities, identifying the expertise needed to address these gaps, developing a plan of action, adhering to policies and procedures, identifying outcome measures and plans for monitoring progress, developing an administrative structure for efficient management and research implementation, developing specific research projects, and maximizing synergy among PPTRC Nodal Centers partners, the investigators, and the research projects.  This planning is a critical first step in developing essential communication and collaborations among researchers from different disciplines.  The planning activities should also include developing training and career development plans for future investigators; disseminating research findings; and developing management strategies for implementation of research that will ultimately result in improved pediatric therapeutics.  The resulting strategic plan should include short and long term goals that can be used to help monitor progress. The ways in which input is to be obtained for strategic planning purposes must be documented in the application.

Applications failing to comply with this requirement will be considered non-responsive to the FOA.

Applicants are encouraged to consider the following elements of a strategic planning process as they prepare to respond to this FOA.

Identification and prioritization of research gaps and opportunities:

This includes a collaborative process to identify and prioritize research gaps in order to have an impact on clinical practice and a better assessment of efficacy and safety of drugs given to children.

The type and extent of knowledge gaps will vary between therapeutic areas. For example, issues of study design, feasibility and selection of clinical endpoints and measures of efficacy will be prominent in Newborn Therapeutics, while development and testing of models and biomarkers of disease progression would be a priority in Chronic Disease Therapeutics. The Strategic Plan should include a likely change in emphasis during the funding cycle as gaps in knowledge are filled with a shift toward novel approaches leading to personalized pediatric therapeutics.

Conceptual framework development:

This involves development and adoption of an overall conceptual framework, for addressing the selected therapeutic area and disease(s) in the specific pediatric populations under study.

Strengths of the proposed PPTRC Nodal Center:

This involves identification of strengths in terms of the experience, expertise and resources of the proposed consortium of institutions, organizations, agencies, researchers.  A realistic assessment should be made of the available experience and appropriate facilities for PPTRC Nodal Center research. 

Opportunities:

This involves identification of opportunities to conduct innovative studies and opportunities for the training and career development of researchers new to pediatric therapeutics.  Applicants should explore potential collaborations with a variety of organizations, such as federal agencies, private sector organizations, foundations, and other consortia.

Overarching PPTRC Nodal Center research theme:

A focused research theme for the PPTRC Nodal Center is identified to assure that the proposed studies produce synergy and maximize the body of evidence needed to influence clinical practice, and evolution toward personalized pediatric therapeutics.  The PPTRC program must not be a collection of independent, unrelated research projects. Rather, the PPTRC Nodal Center application must clearly delineate how the research projects, consortium, and investigators will collaborate synergistically to address the research theme that is identified in the strategic planning process.

Evidence of previous collaboration:

It is expected that the key members of each PPTRC Nodal Center team (e.g. PD, PI of Clinical Core, PI for pharmacometrics, and developmental pharmacologist)  have a long history of previous collaboration evidenced by joint publications, NIH grants, and participation in joint studies.

The strategic plan must not exceed 15 pages.

PPTRC research theme (programmatic pathways) in specific therapeutic areas

While each PPTRC Nodal Center is expected to bring together experts from multiple disciplines to form interdisciplinary collaborations and is expected to undertake a wide range of intervention research, it is not expected to address the entire spectrum of research in a particular therapeutic area.  The theme and range of research, training, and career development, must emerge from the strategic planning process.  This theme (programmatic pathways) should be used by the PPTR Center to focus its activities throughout the funding period.

The formation within PPRTC applications of consortium arrangements between institutions separated by any geographic distance (“virtual centers”) is strongly encouraged, so as to facilitate the assembly of the highest quality pediatric therapeutic research.

Consortium arrangements can also be included in the clinical cores to expand patient access. While consortium arrangements are encouraged, it is incumbent upon the applicants to present evidence that the proposed consortium is feasible, and that it can function well as a productive team. At a minimum, a Center’s administrative core should reside at the parent institution. The clinical core can either be located at the parent institution, or at a subcontract site, or both. The assembly of teams with prior collaborative experience is strongly encouraged but not required. Submission of a schedule of planned meetings, and/or a plan to develop web- or e-mail-based electronic communications infrastructure is encouraged.

The administrative core of the application must include the following:

 The administrative core of the application must describe in detail, and by diagram if appropriate, the chain of responsibility for decision-making and administration. Include to whom the PPRC PD reports and the administrative structure as it relates to the investigators responsible for the clinical and translational research.

The scientific component of the application must include the following:

Applicants must submit two proposals to provide reviewers with an idea of the capabilities of the proposed PPTRC Nodal Center:

1)  A demonstration research project geared to fill high priority gaps in knowledge that may be responsible for failed pediatric drug trials or that may prevent the design of academic or labeling studies.

Examples include:

The proposed project should be aimed to remove a major obstacle for the study of different drugs for a given indication. This research could include the development of a research strategy that would allow the performance of research studies currently considered infeasible. The proposal cannot exceed 10 pages.

2)   An R01-level multi-investigator demonstration proposal should be structured to show interactions between disciplines, investigators and synergy between the different cores (e.g. pharmacometrics, pharmacogenetics, clinical design, and related translational and basic research needs).

The proposal should contain three separate but interrelated studies in the Nodal Center therapeutic area:

The proposed studies may address any of the translational areas of research interest and types of pharmacometrics and clinical types of studies listed under PPTRC Nodal Center research activities.

The studies within the proposal need to be connected and must complement each other within a programmatic pathway. The research demonstration project  proposals should be drafts (up to  twenty pages in length) for consideration by other participants  in the program, and should include enough detail (hypothesis, design, rationale, significance, procedures, resources required, end points, power calculations, and discussion of feasibility) to permit evaluation of the proposals for scientific merit.

SUPPLEMENTAL INSTRUCTIONS

These instructions refer to the Nodal Center and all of its cores institutions, and investigators.

The application requirements for all applicants are as follows:

1) Participants must be based in a Children's Hospital(s) with access to a sufficient number of eligible research subjects in the pediatric age groups:  newborn infants (including prematurely born infants), children, preadolescents and adolescents.  This is an essential component of the application and must be detailed in the application.  Statistical information should contain data for both inpatient and outpatient facilities, including clinics and access to pediatric practices that may contribute research subjects.

2) Departmental and Institutional commitments to collaborative research must be documented by letters to the applicant and by evidence of past support and history of clinical research productivity.

3) Evidence of access to pediatric patients with a wide variety of medical conditions who are available for drug studies must be provided.  Letters of commitment by pediatric subspecialists and evidence of previous collaborations must be provided.

4) Evidence of access to pediatric patients in the therapeutic area chosen by the applicant.

5) Evidence of the ability to recruit patients for pediatric drug studies must be provided.  A list of clinical trials performed during the last four years should be provided with the following information: a) investigator-initiated or pharmaceutical company sponsored; b) single center or multicenter study; c) number of centers involved and total number of patients studied; d) type of study (pharmacokinetics, pharmacodynamics, drug metabolism, bioavailability, efficacy or safety); e) number of patients studied; f) gender and racial/ethnic composition of the study subjects; g) whether the study was completed; and h) major findings of the study.

6) Qualifications of the PD of the PPTRC Nodal Center and his or her academic productivity must be documented, including history of NIH grants.

7) The PD/PIs of the Clinical and Pharmacometric Cores must hold an independent peer-reviewed grant(s) or contract(s), must be actively publishing, and must be familiar with academic and proprietary research in pediatric pharmacology.  Evidence must be provided of the PD’s and PI's combined expertise in pharmacokinetics, pharmacodynamics, drug bioavailability and drug metabolism studies, pharmacogenetics, and design of pediatric drug trials.  In addition, evidence should be provided of the applicant's research in previous or ongoing clinical trials, especially of a multicenter nature.  Contributions in key areas such as protocol design, data analysis, and interpretation, disease diagnosis, pathophysiology and biomarker development are important.

8) A description of current and past research collaborations of the key investigators with members of other pediatric clinical trials networks and other researchers involved in basic and translational research in pediatric pharmacology and therapeutics.

9) A detailed description of the clinical and research capabilities of the PPTRC Nodal Center should be provided, including a description of pharmacokinetics and pharmacodynamic capabilities, access to a pharmacogenetics and other “omics” technology (e.g. proteomics, metabolomics), and other strengths in pediatric pharmacology and therapeutics, both in basic and clinical research.

10) If applicant institution(s) received a CTSA award, detail its role in the activities and support of the PPTRC Nodal Center. 

Budget

Each application must allocate a significant effort to support pilot/demonstration projects for short term translational research that take maximum advantage of new or ongoing funding opportunities in pediatric and developmental pharmacology. Funding of pilot projects is intended to generate feasibility data and to have the most promising research potential for realizing the objectives of the different programmatic pathways. Pilot projects may not exceed $50,000. The developmental funds are intended to provide interim support for project development until research grants (e.g. RO1, R21, and R03) are awarded or funding from other sources (e.g. SBIR, private-private partnerships, consortiums) is obtained.

Developmental projects may be collaborative among scientists with one or more PPTRC or with scientists outside the PPTRC environment. Project/program developmental funds will not exceed $ 200,000 per year and must be approved by the External Advisory Committee and NICHD. Developmental funding is intended to remain flexible and to support studies of limited duration (two years or less). 

It is the intent of this FOA to provide minimal infrastructure funding support. The use of the resources available at institutions with a Clinical and Translational Science Award (CTSA) or General Clinical Research Center (GCRC) should be available to each PPTRC Nodal Center.

Direct costs to cover tasks assigned to administrative and research cores as needed for each Nodal Center must not exceed the following allocation:

PD maximum 20 % time and effort; Pediatric pharmacometrics PI 15% time and effort, pediatric subspecialist 10% time and effort; administrative assistant support maximum 20% time and effort.

A number of administrative activities (e.g., monitoring, allocation of research funds, webpage support etc) are assigned to the SDMCC. No funds for the SDMCC activities (see SDMCC Section I) can be included in the PPTRC Nodal Center budget.

No funds for training support must be included in the budget. NICHD intends to develop a MSCIDA to fund training after a PPTRC Nodal Center specific curriculum is jointly developed by the NICHD and the PPTRC investigators. In addition institutional and outside support for this program are encouraged.

The Consortium Steering Committee will meet at least three times per year in the Washington DC area.  Applicants should include costs for travel to these meetings in their budget request.

3. Submission Dates and Times

Applications must be received on or before the receipt date described below (Section IV.3.A). Submission times N/A.

3.A. Receipt, Review and Anticipated Start Dates
Letters of Intent Receipt Date: February 28, 2009
Application Receipt Date: March 31, 2009
Peer Review Date(s):  June/July 2009
Council Review Date:  October 2009
Earliest Anticipated Start Date: December 1, 2009

3. A.1. Letter of Intent

Prospective applicants are asked to submit a letter of intent that includes the following information:

Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review.

The letter of intent is to be sent by the date listed in Section IV.3.A.

The letter of intent should be sent to:

George P. Giacoia, MD
Program Scientist
Obstetric and Pediatric Pharmacology Branch
Eunice Kennedy Shriver  National Institute of Child Health and Human Development
6100 Executive Boulevard, 4B11B, MSC 7510
Rockville, MD 20892-7510
Rockville, MD 20852 (for express/courier service)
Telephone: (301) 496-5593
FAX: (301) 480-9791
Email: giacoiag@mail.nih.gov 

3.B. Sending an Application to the NIH

Applications must be prepared using the forms found in the PHS 398 instructions for preparing a research grant application. 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 (U.S. Postal Service Express or regular mail)
Bethesda, MD 20817 (for express/courier service; non-USPS service)

Personal deliveries of applications are no longer permitted (see http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-040.html).

At the time of submission, two additional copies of the application and all copies of the appendix material must be sent to:

Robert Stretch, Ph.D.
Director, Division of Scientific Review
Eunice Kennedy Shriver National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 5B01, MSC 7510
Bethesda, MD  20892-7510
Telephone:  (301)496-1485
Email:  stretchr@mail.nih.gov

3.C. Application Processing

Applications must be received on or before the application receipt date) described above (Section IV.3.A.). If an application is received after that date, the application may be delayed in the review process or not reviewed.  Upon receipt, applications will be evaluated for completeness by the CSR and for responsiveness by the reviewing Institute Incomplete and/or non-responsive applications will not be reviewed.

The NIH will not accept any application in response to this funding opportunity that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. However, when a previously unfunded application, originally submitted as an investigator-initiated application, is to be submitted in response to a funding opportunity, it is to be prepared as a NEW application. That is, the application for the funding opportunity must not include an Introduction describing the changes and improvements made, and the text must not be marked to indicate the changes from the previous unfunded version of the application.

Information on the status of an application should be checked by the Principal Investigator in the eRA Commons at: https://commons.era.nih.gov/commons/.

4. Intergovernmental Review

This initiative is not subject to intergovernmental review.

5. Funding Restrictions

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The Grants Policy Statement can be found at NIH Grants Policy Statement.

Pre-award costs are allowable. A grantee may, at its own risk and without NIH prior approval, incur obligations and expenditures to cover costs up to 90 days before the beginning date of the initial budget period of a new award if such costs: 1) are necessary to conduct the project, and 2) would be allowable under the grant, if awarded, without NIH prior approval. If specific expenditures would otherwise require prior approval, the grantee must obtain NIH approval before incurring the cost. NIH prior approval is required for any costs to be incurred more than 90 days before the beginning date of the initial budget period of a new award.

The incurrence of pre-award costs in anticipation of a competing award imposes no obligation on NIH either to make the award or to increase the amount of the approved budget if an award is made for less than the amount anticipated and is inadequate to cover the pre-award costs incurred. NIH expects the grantee to be fully aware that pre-award costs result in borrowing against future support and that such borrowing must not impair the grantee's ability to accomplish the project objectives in the approved time frame or in any way adversely affect the conduct of the project (see NIH Grants Policy Statement http://grants.nih.gov/archive/grants/policy/nihgps_2003/index.htm.)

6. Other Submission Requirements and Information

Awardees must agree to the "Cooperative Agreement Terms and Conditions of Award" in Section VI.2.A "Award Administration Information".

Research Plan Page Limitations

The overall research plan including the strategic plan must not exceed 15 pages

The demonstration research project addressing the need to fill gaps in knowledge must not exceed 10 pages. The RO1-level demonstration proposal must not exceed 20 pages.

Appendix Materials

All paper PHS 398 applications submitted must provide appendix material on CDs only. Include five identical CDs in the same package with the application.  See http://grants.nih.gov/grants/guide/notice-files/NOT-OD-08-031.html.

Do not use the Appendix to circumvent the page limitations of the Research Plan component. An application that does not observe the required page limitations may be delayed in the review

Section V. Application Review Information


1. Criteria

Only the review criteria described below will be considered in the review process.

2. Review and Selection Process

Applications that are complete and responsive to the FOA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the Eunice Kennedy Shriver NICHD and in accordance with NIH peer review procedures (http://grants1.nih.gov/grants/peer/), using the review criteria stated below.

As part of the scientific peer review, all applications will:

The following will be considered in making funding decisions:

NIH considers the following in evaluating Center grant applications:

PPRT Nodal Center Applications

Each PPTRC Nodal Center application will receive an overall priority score. Reviewers will assign overall priority scores to PPTRC Nodal Center based on the strategic plan, project scores, the PPTRC specific review criteria listed below, and the reviewer assessment of the quality of the core components of the PPRTC Nodal Center.

The administrative unit , the qualifications of the core components (pharmacometrics, translational and clinical), the training plan within a  PPRTC Nodal Center, the overall clinical research program organization, and capability institutional commitment components of the  application will not receive priority scores, but will either be recommended, or not recommended by the review committee.

Review Criteria

Overall Scientific Merit: What is the composite scientific merit of the overall application, including the scored research projects and PPTRC Nodal Center components based on the detailed review criteria listed below? What is the potential for synergy within the proposed collaborative research program?

Review Criteria of research applications:

Personalized pediatric therapeutics

The three studies addressing translational, pharmacometrics, and clinical research, respectively, will be reviewed separately and then as an integrated proposal.

The goals of NIH supported research are to advance our understanding of biological systems, to improve control of disease, and enhance health. In their written critiques, reviewers will be asked to comment on each of the following criteria 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 and weighted as appropriate for each application. Note that an 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.

Significance:

Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge or clinical practice be advanced? What will be the effect of these studies on the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?    What is the potential of the proposed study? Does this study address an important aim?  What is the likelihood that this study will lead to other synergetic and complementary projects that will close knowledge gaps, remove obstacles and/or move toward personalized pediatric therapy?

In order to better understand the use of drugs in children and the important clinical problems that derive from patient- oriented therapeutics, a more focused use of genomics, proteomics, biomarkers, functional imaging, pharmacogenetics and bench to bedside/bedside-to- bench will be required.  

Approach: Are the conceptual or clinical framework, design, methods, and analyses adequately developed, well integrated, well reasoned, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? Does the patient-oriented therapeutics research include the focused use of newer technology (e.g., genomics, proteomics, and pharmacogenetics)?

Innovation: Is the project original and innovative? For example: Does the project challenge existing paradigms or clinical practice; address an innovative hypothesis or critical barrier to progress in the field? Does the project develop or employ novel concepts, approaches, methodologies, tools, or technologies for this area?  Does it take advantage of historical research strengths at the center? Does the project develop or employ novel approaches, drugs, or devices?

Investigators: Are the investigators 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? Does the PD/PI(s) and investigative team bring complementary and integrated expertise to the project (if applicable)? 

Environment: Does the clinical research infrastructure in which the work will be done contribute to the probability of success? Do the proposed studies benefit from unique features of the scientific environment, or subject populations, or employ useful collaborative arrangements? Is there evidence of institutional support? Are adequate numbers of patients available to answer the questions asked?

2) Gaps in knowledge research application

In their written critiques, reviewers will be asked to comment on each of the following criteria in order to judge the likelihood that the proposed research will have a substantial impact  in preventing failures of efficacy drug trials in pediatrics. These criteria will be addressed and considered in assigning the overall score, and weighted as appropriate for each application. Note that an application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a meritorious 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.

Significance: Does the application addresse an important pharmacologic and/or therapeutic knowledge deficiency that prevents or significantly contributes to failure of efficacy drug trials in pediatrics? Are the results likely to positively impact pediatric drug development?

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

Innovation: Is the project original and innovative? For example does the project propose an innovative biomarker or pharmacodynamic measurement allowing pk-pd correlations and modeling? Does the project develop or employ novel approaches or study designs?

Investigators: Are the investigators 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?

Environment: Does the clinical research infrastructure in which the work will be done contribute to the probability of success? Are adequate numbers of patients available at this center to make a significant contribution toward completion of the proposed trial? Do the proposed studies benefit from unique features of the scientific environment, or subject populations, or employ useful collaborative arrangements? Is there evidence of institutional support?

PPTRC Nodal Center Administration unit

Are the plans for overall administration of the Nodal Center, coordination of clinical, translational and collaborations presented and sufficient for the requirements of the proposed PPTRC Nodal Center? Is the plan for communication of all personnel within the consortium well described?

Core Components

Are the investigators in each core trained and well suited to carry out the work required by this FOA? Does the investigative team in each core bring complementary and integrated expertise to conduct the type of studies specified in this FOA? Are the investigators committed to the collaborative and nature of this program? Is the investigative team committed to collaborate in projects that involve all three cores and inter-Center studies?  Are the plans for integrating the activities of the PPRT Nodal Center’s clinical, pharmacometrics and/or translational research cores well develop? Are the plans to integrate disease and pharmacologic research with existing institutional resources (e.g., laboratory support including pharmacometrics/pharmacogenomics, and other “omics’ technologies) effective?

Training Component

Is the plan for training new investigators adequate and appropriate?  Does the proposed plan for the training describe how promising candidates for clinical and translational research in pediatric therapeutics will be selected? Are environments within PPTRC Nodal Center appropriate for supporting the training of new investigators? Does the proposed plan address how the investigators will seek out and include qualified women and minorities for participation in the training component of the program

Overall Clinical Research Program Organization and Capability

Leadership:

Are the scientific qualifications and involvement of the Principal Investigator (PPTRN Nodal Center Director) as well as his/her scientific and administrative leadership capabilities and commitment presented and sufficient for the requirements of the proposed PPTRC?

Are the qualifications, experience, and commitment of the key investigators (pediatric subspecialist, pharmacometrics and developmental pharmacologist) commensurate with the goals of this FOA?

Pediatric population availability:  

Is the access to   patients in the chosen therapeutic areas and other populations for conducting current and projected clinical/translational research adequate to ensure likely success of the goals of the program?

Institutional Commitment:

Is there institutional commitment to establishing the PPTRC Nodal Center as an integral part of its overall clinical research environment? Will the institution align or adjust incentives and rewards to promote the academic mission of collaborative pediatric pharmacology research? Is there commitment from the institutional leadership to protect the time of the investigators to pursue clinical research and mitigate the demands of providing patient care? Will clinical researchers/trainees training be supported? Is the institutional leadership committed to this program and its goals in terms of providing specific assets specifically for the program, such as faculty support, specific equipment, dedicated space, or financial support as a few examples? If a pediatric CTSA resides in the institution(s) is there evidence of support supporting the goals of the PPTRC?

Performance in Collaborative Clinical Trials:

Does the applicant center have a track record of success enrolling patients in prior multicenter  

collaborative clinical trials?

Participation and Collaboration: How many collaborative clinical trials has the applicant center participated in during the last ten years? Is the applicant center likely to be a strong team player in the PPRTC clinical or translational research component? Does the present overall application reflect a willingness to collaborate on the part of the applicant center working with other institutions and relying on multidisciplinary teams?

Collaboration: Do the investigators state their willingness to participate in joint meetings, share methods and data resources, and embark on collaborative efforts to decide overall research direction? Is the research plan flexible enough to accommodate further refinement and integration with other efforts? While it will be a group decision to actually engage in any particular proposed collaborative activities, do the applicants show an understanding of how joint collaborative activities can be conducted in a consortium of this type?

2. A. Additional Review Criteria:

In addition to the above criteria, the following items will continue to be considered in the determination of scientific merit and the rating:

Protection of Human Subjects from Research Risk: The involvement of human subjects and protections from research risk relating to their participation in the proposed research will be assessed (see the Research Plan section on Human Subjects in the PHS 398 instructions).

Inclusion of Women, Minorities and Children in Research: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research will be assessed. Plans for the recruitment and retention of subjects will also be evaluated (see the Research Plan section on Human Subjects in the PHS 398 instructions).

Care and Use of Vertebrate Animals in Research: If vertebrate animals are to be used in the project, the five points described in the Vertebrate Animals section of the Research Plan will be assessed.

Biohazards: If materials or procedures are proposed that are potentially hazardous to research personnel and/or the environment, determine if the proposed protection is adequate.

2. B. Additional Review Considerations

Budget: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. The priority score should not be affected by the evaluation of the budget.

2. C. Resource Sharing Plan(s)   

When relevant, reviewers will be instructed to comment on the reasonableness of the following Resource Sharing Plans, or the rationale for not sharing the following types of resources. However, reviewers will not factor the proposed resource sharing plan(s) into the determination of scientific merit or priority score, unless noted otherwise in the FOA. Program staff within the IC will be responsible for monitoring the resource sharing.

3. Anticipated Announcement and Award Dates

Not applicable

Section VI. Award Administration Information


1. Award Notices

After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons.

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant. For details, applicants may refer to the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General.

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization. The NoA signed by the grants management officer is the authorizing document. Once all administrative and programmatic issues have been resolved, the NoA will be generated via email notification from the awarding component to the grantee business official (designated in item 12 on the Application Face Page). If a grantee is not email enabled, a hard copy of the Notice of Award will be mailed to the business official.

Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs. See Also Section IV.5. Funding Restrictions.

2. Administrative and National Policy Requirements

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General (http://grants.nih.gov/archive/grants/policy/nihgps_2003/index.htm) and Part II Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities (http://grants.nih.gov/archive/grants/policy/nihgps_2003/index.htm).

The following Terms and Conditions will be incorporated into the award statement and will be provided to the Principal Investigator as well as to the appropriate institutional official, at the time of award.

2. A. Cooperative Agreement Terms and Conditions of Award

Cooperative Agreement Mechanism

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 Parts 74 and 92, and other HHS, and NIH Grant Administration policy statements. [Part 92 applies when state and local governments are eligible to apply as a "domestic organization."]

The administrative and funding instrument used for this program is a cooperative agreement [U54), an "assistance" mechanism (rather than an "acquisition" mechanism) in which substantial NIH scientific and/or programmatic involvement with the awardee is anticipated during performance of the activity. Under the cooperative agreement, the NIH purpose is to support and/or stimulate the recipient's activity by involvement in and otherwise working jointly with the award recipient in a partner role, but it is not to assume direction, prime responsibility, or a dominant role in the activity. Consistent with this concept, the dominant role and prime responsibility for the activity resides with the awardee(s) for the project as a whole, although specific tasks and activities in carrying out the studies will be shared among the awardees and the [IC] Project Scientist/Coordinator/Collaborator as described below.

2. A.1. Principal Investigator Rights and Responsibilities

The PPRTC program will include non-collaborative, intra Center functions, as well as collaborative, inter-Nodal Center functions involving interactions between individual Nodal Centers.

The Principal Investigators (PIs) will be responsible for managing the PPRC Nodal Centers. This will include ensuring that all components for individual Nodal Centers are in place and functioning and all subprojects and cores are making satisfactory progress.

Each PI will have primary responsibility to define objectives and approaches and to plan, analyze, and publish results, interpretations, and conclusions of studies. The NICHD Program scientist will periodically review the progress of each Nodal Center but will not participate in the design of non-collaborative research.

The DSMB will be involved in approval and oversight of clinical protocols within no-collaborative intra Center clinical research projects. The External Advisory committee will review non-collaborative research for quality of science and compliance with the PPTRC goals and objectives. The reviews will be performed every 6 months for the first two years of the funding cycle and yearly thereafter. The SDMCC will play an assistive, optional role in the design of non-collaborative Nodal Centers research, but will be responsible for assisting with the preparation and presentation of all intra Center clinical research protocols before the DSMB.

The awardee(s) will have lead responsibilities in all aspects of research design, including any modification of study design; quality control; data interpretation; preparation of publications and collaboration with other investigators, unless otherwise provided for in these terms or by action of the Steering Committee.

Colaborative research protocols will be review by a protocol review Committee appointed by the Steering Committee. Awardee(s) agree to the governance of all collaborative studies. The awardees retain custody of and primary rights to the data developed under those awards, subject to government rights of access, consistent with current HHS and NIH policies.  Awardees must be willing to participate and collaborate with other awardees and with NICHD staff.

Awardee(s) are expected to contribute data to the PeDaR Awardee(s) are also expected to contribute DNA and plasma samples for all consenting patients specimens to the appropriate repository for studies requiring phenotypic-genotypic correlations or GWN studies.

2. A.2. NIH Responsibilities

NICHD PPTRC Program Scientist

The NICHD Program Scientist is responsible for the overall scientific administration of the PPTRC .The NIH Program Scientist will be a member of the PPRTC Steering Committee.

The role of the NICHD Program Scientist will be to aid the awardees and the consortium Steering Committee in the following ways:

NICHD Project Officer

The NICHD will appoint a Project Officer, apart from the Program Scientist, who will:

The NICHD reserves the right to terminate or curtail a study (or an individual award) in the event of substantial shortfall in participant recruitment, follow-up, data reporting, quality control or other major breach of a protocol; if a study reaches a major study endpoint substantially before schedule with persuasive statistical significance; if qualified scientific investigators are not available to participate in the study; if an awardee fails to participate in the committee/group activities; or if there are human subject ethical issues that may dictate a premature termination.

2. A.3. Collaborative Responsibilities

The PPTRC will be managed by a Steering Committee, an External Scientific Advisory Committee (ESAC) and designated NICHD staff.

The NICHD will be substantially involved as a partner in providing overall scientific guidance and support consistent with the U54 cooperative agreement mechanism a designated NICHD staff person will monitor study progress and serve in the Steering Committee, and External Scientific Advisory Committee.

 The Steering Committee will be composed of the PIs of each PPTRC Node Center. The Chairperson of the Steering Committee will be selected by NICHD. All major decisions will be made by the Steering Committee. As needed the Steering Committee may establish subcommittees for special purposes.

Each full member will have one vote. Awardee members of the Steering Committee will be required to accept and implement policies approved by the Steering Committee.

The role of the Steering Committee will be to review, approve, oversee and promote inter nodal centers’ projects and activities and harmonize research across the different therapeutic areas.

A Consortium  translational science and a pharmacometrics working groups that include PIs in developmental pharmacology and pharmacometrics investigators from all Nodal Centers, will integrate results from different programmatic pathways, oversee inclusion in the PPTRC data repository, further development of pediatric prior knowledge base and determine opportunities for expanded research conducted in the Consortium, in collaboration with other networks or with project specific ad hoc groups of investigators.

The External Scientific Advisory Committee will be appointed by the NICHD and will be composed of experts in the various disciplines involved in the PPTRC projects.  The ESAC will conduct at a minimum an annual review of the: 1) interim progress of all research projects of individual Nodal Centers and 2) review of accomplishments and progress towards meeting the PPTRC goals for the Consortium as a whole; 3); adherence to the PPTRC conceptual framework and theme In addition the ESAC will advise the NICHD on scientific merit and synergistic value of requests for developmental funds.

The NICHD will appoint and independent Data and Safety Monitoring Board for clinical trials.

Communication within each PPRTC Nodal Center and between Consortia will be facilitated by using Share Point and Adobe Connect web casts. The Statistics and Data Management and Coordinating Center will set up and coordinate all meetings within the Consortium and with other consortiums, networks or organizations.

During the early program development phase (first year) of the new Consortium conference calls between components within each PPTRC Nodal Center will be held weekly and biweekly thereafter. NSC conference calls will be held monthly.

2. A.4. Arbitration Process

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to arbitration. An Arbitration Panel composed of three members will be convened. It will have three members: a designee of the Steering Committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual awardee. This special arbitration procedure in no way affects the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulations 42 CFR Part 50, Subpart D and HHS regulations 45 CFR Part 16.

3. Reporting

Awardees will be required to submit the Non-Competing Continuation Grant Progress Report (PHS 2590) annually and financial statements as required in the NIH Grants Policy Statement.

A final progress report, invention statement, and Financial Status Report are required when an award is relinquished when a recipient changes institutions or when an award is terminated.

Section VII. Agency Contacts


We encourage your inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into three areas: scientific/research, peer review, and financial or grants management issues:

1. Scientific/Research Contacts:

George P. Giacoia, MD
Program Scientist
Obstetric and Pediatric Pharmacology Branch
Eunice Kennedy Shiver National Institute of Child Health and Human Development
Center for Research for Mothers and Children

6100 Executive Boulevard, 4B11B, MSC 7510
Bethesda, MD 20892-7510
Rockville, MD 20852 (for express/courier service)
Telephone: (301) 496-5593
FAX: (301) 480-9791
Email: giacoiag@mail.nih.gov  

Perdita Taylor-Zapata, M.D.
Program Officer
Obstetric and Pediatric Pharmacology Branch
Center for Research for Mothers and Children
Eunice Kennedy Shriver National Institute of Child Health and Human Development
National Institutes of Health
6100 Executive Boulevard, Room 4A01
MSC 7510
Bethesda, MD 20892
Phone:  (301) 496-9584
Fax:      (301) 480-2897
E-Mail: taylorpe@mail.nih.gov

2. Peer Review Contact(s):

Robert Stretch, Ph.D.
Director, Division of Scientific Review
Eunice Kennedy Shriver National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 5B01, MSC 7510
Rockville, MD  20892-7510
Telephone:  (301)496-1485
Email:  stretchr@mail.nih.gov

3. Financial/Grants Management Contact(s):

Bryan S. Clark, M.B.A.
Chief Grants Management Officer
Eunice Kennedy Shriver National Institute of Child Health and Human Development
National Institutes of Health
6100 Executive Blvd., Room 8A01A, MSC 7510
Rockville, MD 20852 (for express/courier service)
Telephone: (301) 435-6975
FAX: (301) 451-5510


Section VIII. Other Information


Required Federal Citations

Use of Animals in Research:
Recipients of PHS support for activities involving live, vertebrate animals must comply with PHS Policy on Humane Care and Use of Laboratory Animals (http://grants.nih.gov/grants/olaw/references/PHSPolicyLabAnimals.pdf) as mandated by the Health Research Extension Act of 1985 (http://grants.nih.gov/grants/olaw/references/hrea1985.htm), and the USDA Animal Welfare Regulations (http://www.nal.usda.gov/awic/legislat/usdaleg1.htm) as applicable.

Human Subjects Protection:
Federal regulations (45CFR46) require that applications and proposals involving human subjects must be evaluated with reference to the risks to the subjects, the adequacy of protection against these risks, the potential benefits of the research to the subjects and others, and the importance of the knowledge gained or to be gained (http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm).

Data and Safety Monitoring Plan:
Data and safety monitoring is required for all types of clinical trials, including physiologic toxicity and dose-finding studies (phase I); efficacy studies (Phase II); efficacy, effectiveness and comparative trials (Phase III). Monitoring should be commensurate with risk. The establishment of data and safety monitoring boards (DSMBs) is required for multi-site clinical trials involving interventions that entail potential risks to the participants (NIH Policy for Data and Safety Monitoring, NIH Guide for Grants and Contracts, http://grants.nih.gov/grants/guide/notice-files/not98-084.html).

Sharing Research Data:
Investigators submitting an NIH application seeking $500,000 or more in direct costs in any single year are expected to include a plan for data sharing or state why this is not possible (http://grants.nih.gov/grants/policy/data_sharing).

Investigators should seek guidance from their institutions, on issues related to institutional policies and local IRB rules, as well as local, State and Federal laws and regulations, including the Privacy Rule. Reviewers will consider the data sharing plan but will not factor the plan into the determination of the scientific merit or the priority score.

Policy for Genome-Wide Association Studies (GWAS):
NIH is interested in advancing genome-wide association studies (GWAS) to identify common genetic factors that influence health and disease through a centralized GWAS data repository. For the purposes of this policy, a genome-wide association study is defined as any study of genetic variation across the entire human genome that is designed to identify genetic associations with observable traits (such as blood pressure or weight), or the presence or absence of a disease or condition. All applications, regardless of the amount requested, proposing a genome-wide association study are expected to provide a plan for submission of GWAS data to the NIH-designated GWAS data repository, or provide an appropriate explanation why submission to the repository is not possible. Data repository management (submission and access) is governed by the Policy for Sharing of Data Obtained in NIH Supported or Conducted Genome-Wide Association Studies, NIH Guide NOT-OD-07-088. For additional information, see http://grants.nih.gov/grants/gwas/

Access to Research Data through the Freedom of Information Act:
The Office of Management and Budget (OMB) Circular A-110 has been revised to provide access to research data through the Freedom of Information Act (FOA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this funding opportunity in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award.

Sharing of Model Organisms:
NIH is committed to support efforts that encourage sharing of important research resources including the sharing of model organisms for biomedical research (see http://grants.nih.gov/grants/policy/model_organism/index.htm). At the same time the NIH recognizes the rights of grantees and contractors to elect and retain title to subject inventions developed with Federal funding pursuant to the Bayh Dole Act (see the NIH Grants Policy Statement http://grants.nih.gov/archive/archive/grants/policy/nihgps_2003/index.htm). All investigators submitting an NIH application or contract proposal, beginning with the October 1, 2004 receipt date, are expected to include in the application/proposal a description of a specific plan for sharing and distributing unique model organism research resources generated using NIH funding or state why such sharing is restricted or not possible. This will permit other researchers to benefit from the resources developed with public funding. The inclusion of a model organism sharing plan is not subject to a cost threshold in any year and is expected to be included in all applications where the development of model organisms is anticipated.

Inclusion of Women And Minorities in Clinical Research:
It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported clinical research projects unless a clear and compelling justification is provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing clinical research should read the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines is available at http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm. The amended policy incorporates: the use of an NIH definition of clinical research; updated racial and ethnic categories in compliance with the new OMB standards; clarification of language governing NIH-defined Phase III clinical trials consistent with the new PHS Form 398; and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH-defined Phase III clinical trials that: a) all applications or proposals and/or protocols must provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable; and b) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences.

Inclusion of Children as Participants in Clinical Research:
The NIH maintains a policy that children (i.e., individuals under the age of 21) must be included in all clinical research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them.

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 (http://grants.nih.gov/grants/funding/children/children.htm).

Required Education on the Protection of Human Subject Participants:
NIH policy requires education on the protection of human subject participants for all investigators submitting NIH applications for research involving human subjects and individuals designated as key personnel. The policy is available at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

Human Embryonic Stem Cells (hESC):
Criteria for federal funding of research on hESCs can be found at http://stemcells.nih.gov/index.asp and at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html. Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (http://escr.nih.gov). It is the responsibility of the applicant to provide in the project description and elsewhere in the application as appropriate, the official NIH identifier(s) for the hESC line(s) to be used in the proposed research. Applications that do not provide this information will be returned without review.

NIH Public Access Policy Requirement:
In accordance with the NIH Public Access Policy (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-08-033.html) investigators must submit or have submitted for them their final, peer-reviewed manuscripts that arise from NIH funds and are accepted for publication as of April 7, 2008 to PubMed Central (http://www.pubmedcentral.nih.gov/), to be made publicly available no later than 12 months after publication. As of May 27, 2008, investigators must include the PubMed Central reference number when citing an article in NIH applications, proposals, and progress reports that fall under the policy, and was authored or co-authored by the investigator or arose from the investigator’s NIH award.  For more information, see the Public Access webpage at http://publicaccess.nih.gov/.

Standards for Privacy of Individually Identifiable Health Information:
The Department of Health and Human Services (DHHS) issued final modification to the "Standards for Privacy of Individually Identifiable Health Information", the "Privacy Rule", on August 14, 2002. The Privacy Rule is a federal regulation under the Health Insurance Portability and Accountability Act (HIPAA) of 1996 that governs the protection of individually identifiable health information, and is administered and enforced by the DHHS Office for Civil Rights (OCR).

Decisions about applicability and implementation of the Privacy Rule reside with the researcher and his/her institution. The OCR website (http://www.hhs.gov/ocr/) provides information on the Privacy Rule, including a complete Regulation Text and a set of decision tools on "Am I a covered entity?" Information on the impact of the HIPAA Privacy Rule on NIH processes involving the review, funding, and progress monitoring of grants, cooperative agreements, and research contracts can be found at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html.

URLs in NIH Grant Applications or Appendices:
All applications and proposals for NIH funding must be self-contained within specified page limitations. For publications listed in the appendix and/or Progress report, internet addresses (URLs) must be used for publicly accessible on-line journal articles.  Unless otherwise specified in this solicitation, Internet addresses (URLs) should not be used to provide any other information necessary for the review because reviewers are under no obligation to view the Internet sites. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site.

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

Authority and Regulations
This program is described in the Catalog of Federal Domestic Assistance at http://www.cfda.gov/ and is not subject to the intergovernmental review requirements of Executive Order 12372. Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The NIH Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm.

The PHS strongly encourages all grant recipients to provide a smoke-free workplace and discourage the use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.

Loan Repayment Programs:
NIH encourages applications for educational loan repayment from qualified health professionals who have made a commitment to pursue a research career involving clinical, pediatric, contraception, infertility, and health disparities related areas. The LRP is an important component of NIH's efforts to recruit and retain the next generation of researchers by providing the means for developing a research career unfettered by the burden of student loan debt. Note that an NIH grant is not required for eligibility and concurrent career award and LRP applications are encouraged. The periods of career award and LRP award may overlap providing the LRP recipient with the required commitment of time and effort, as LRP awardees must commit at least 50% of their time (at least 20 hours per week based on a 40 hour week) for two years to the research. For further information, please see: http://www.lrp.nih.gov.


Weekly TOC for this Announcement
NIH Funding Opportunities and Notices


Office of Extramural Research (OER) - Home Page Office of Extramural
Research (OER)
  National Institutes of Health (NIH) - Home Page National Institutes of Health (NIH)
9000 Rockville Pike
Bethesda, Maryland 20892
  Department of Health and Human Services (HHS) - Home Page Department of Health
and Human Services (HHS)
  USA.gov - Government Made Easy


Note: For help accessing PDF, RTF, MS Word, Excel, PowerPoint, Audio or Video files, see Help Downloading Files.