PEDIATRIC PHARMACOLOGY RESEARCH UNIT NETWORK 

RELEASE DATE:  November 18, 2002 
 
RFA: HD-03-001 

National Institute of Child Health and Human Development (NICHD)  
 (http://www.nichd.nih.gov)

LETTER OF INTENT RECEIPT DATE:  February 17, 2003

APPLICATION RECEIPT DATE:  March 17, 2003

THIS RFA CONTAINS THE FOLLOWING INFORMATION

o Purpose of this RFA
o Research Objectives
o Mechanism of Support 
o Funds Available
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Special Requirements 
o Where to Send Inquiries
o Letter of Intent
o Submitting an Application
o Peer Review Process
o Review Criteria
o Receipt and Review Schedule
o Award Criteria
o Required Federal Citations

PURPOSE OF THIS RFA 

The National Institute of Child Health and Human Development (NICHD) plans to 
continue to support an ongoing cooperative Network of Pediatric Pharmacology 
Research Units (PPRU) that serves as a resource for studies of drug action 
and disposition in infants, children, and adolescents.  Such studies will be 
conducted by pediatric clinical pharmacologists, clinical trialists, and 
experts in pediatric diseases cooperatively with investigators at other Units 
in the Network, or collaboratively with pharmaceutical companies, or 
independently with other support.  The goals of the Network are:  1) to 
provide the clinical data on new drugs and drugs already on the market that 
are necessary for U.S. Food and Drug Administration (FDA) approval for use in 
children; 2) to investigate the pharmacology of new molecular entities and 
biopharmaceuticals for use in children; 3) to provide the scientific 
foundation for drug studies in children; and 4) to collaborate with basic 
and/or translational research scientists in multidisciplinary interactive 
teams that seek to elucidate differences in biodisposition and response to 
drugs in children at different developmental stages and between children and 
adults. 

RESEARCH OBJECTIVES

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 use in 
them.
 
Over the years, 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 consent and 
children's assent; and the lack of a suitable infrastructure for the conduct 
of pediatric pharmacology research.  In response to the need for appropriate 
drug therapy studies in pediatric patients, the NICHD established the 
Pediatric Pharmacology Research Unit Network in 1994.

In 1994, the FDA implemented a regulation (Pediatric Rule of 1994) that 
allows 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 are 
similar in children and adults.  This regulation was designed to encourage 
pediatric labeling.  The FDA issued new regulations in August 1997 (Final 
Rule of 1997), requiring pediatric studies of certain new drugs.  Also, in 
1997 the Food and Drug Administration Modernization Act (FDAMA) was enacted 
into law.  This legislation contained a provision (Section 111) that provided 
exclusivity incentives for the pharmaceutical industry (six months of 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 until December of 2007.  The BPCA also provides a mechanism for 
the study of off-patent drugs and identifies the need to conduct studies in 
the newborn population.

Since the implementation of the pediatric provisions of FDAMA in 1997, a 
number of drugs have received FDA approval for use in pediatric subjects. 
Despite significant progress, a large number of drugs lacking FDA approval 
continue to be used in infants and children.  Because of this widespread use 
of unapproved drugs, studies leading to pediatric labeling remain a priority 
for the next funding cycle of this Network. 

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 the tools to decipher the mechanisms 
responsible for changes in drug biodisposition during development and the 
effects of ontogeny on both drug disposition and effects.

Objectives and Scope
 
The purpose of this RFA is to continue the ongoing multi-center program of 
the Pediatric Pharmacology Research Units (PPRU) for another award period of 
five years.

Each PPRU will have the following aims:
 
(1) To provide a locus for the conduct of studies in bioavailability,
formulations, drug metabolism, pharmacokinetics, pharmacodynamics, safety, 
and effectiveness of new drugs and drugs already the market.  These studies 
may be investigator-initiated or they may originate with pharmaceutical 
companies, Contract Research Organizations (CROs) or the National Institutes 
of Health.
 
(2) To gather or promote the accrual of the necessary clinical data for 
pediatric age-specific labeling of drugs.  Studies of off-patent drugs and 
drugs used in the newborn population are highly encouraged. 

(3) To carry out research on novel approaches and innovation in pediatric 
pharmacology.  Specific areas of interest include, but are not limited to:

o  Identification, development, validation, and/or extrapolation from adult 
studies of biomarkers of diagnosis, prognosis, efficacy, toxicity, and of 
disease activity.

o  Development and validation of non-invasive pharmacodynamic measurements.

o  Development and/or adaptation of novel pharmacokinetics-pharmacodynamics 
modeling technology in pediatrics (e.g., partial physiologic-based 
pharmacokinetics).

o  Development of new study designs in pediatrics.

o  Use of new molecular approaches.

o  Application of new drug delivery systems to pediatric subjects. 

(4) To implement studies on the developmental characteristics and genetic 
polymorphisms of drug metabolizing enzymes (DMEs), transporters, and 
receptors.  Phenotypic-genotypic correlations.

(5) To apply pharmacogenomic and proteomic tools in clinical studies.

6) To provide training in clinical and developmental pharmacology.

Guidance and Management Structures 

The management of the PPRU Network includes three committees: (1) The Network 
Steering Committee, comprising all Network Principal Investigators, the NICHD 
Program Coordinator, and a non-voting FDA representative, 2) an Advisory 
Board, and (3) a Data Safety and Monitoring Committee.  The roles of these 
committees are defined below in the section "Cooperative Agreement Terms and 
Conditions of Award."  

MECHANISM OF SUPPORT

This RFA will use the National Institutes of Health (NIH) Cooperative 
Clinical Research (U10) award mechanism.  As an applicant you will be solely 
responsible for planning, directing, and executing the proposed project.  The 
anticipated award date is January 1, 2004.

The NIH U10 is a cooperative agreement award mechanism in which the Principal 
Investigator 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 "Cooperative Agreement Terms and Conditions of 
Award."  

FUNDS AVAILABLE

The NICHD intends to commit approximately $4.8 million in FY 2004 to fund up 
to 13 new and/or competing continuation grants in response to this RFA.  An 
applicant may request a project period of five years and a budget for total  
costs of up to $375,000.  Because the nature and scope of the proposed 
research will vary from application to application, it is anticipated that 
the size and duration of each award will also vary.  Although the financial 
plans of NICHD provide support for this program, awards pursuant to this RFA 
are contingent upon the availability of funds and the receipt of a sufficient 
number of meritorious applications. 

ELIGIBLE INSTITUTIONS
 
You may submit an application if your institution has any of the following 
characteristics: 

o For-profit or non-profit organizations 
o Public or private institutions, such as universities, colleges, hospitals, 
and laboratories 
o Units of State and local governments
o Eligible agencies of the Federal government
o Domestic or foreign

Institutions that operate as or are associated with a for-profit contract 
research organization performing pediatric drug trials are not eligible.

INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS   

Any individual with the skills, knowledge, and resources necessary to carry 
out the proposed research is invited to work with his or her institution to 
develop an application for support.  Individuals from underrepresented racial 
and ethnic groups as well as individuals with disabilities are always 
encouraged to apply for NIH programs.   

The Principal Investigator (PI) should be a pediatrician with extensive 
training in pediatric clinical pharmacology or a clinical pharmacologist with 
extensive experience in clinical drug trials in pediatrics.  In applications 
naming a non-physician as PI, a board-certified pediatrician must be 
identified separately. 

For the purpose of this RFA, NICHD will allow the designation of a pediatric 
subspecialist with extensive experience in clinical trials as the PI of the 
PPRU and a physician, Pharm.D. or Ph.D as an Associate Clinical 
Pharmacologist responsible for the design of pharmacology studies.  It is 
expected that the investigator in charge of the pharmacologic component will 
have expertise in population pharmacokinetic modeling using sparse sampling 
and optimal sampling strategy and Bayesian forecasting.  It is highly 
desirable that this investigator will use pk-pd modeling that relates 
mechanisms of drug action to physiologic processes.

Evidence must be provided of the PI's and associate clinical pharmacologist's 
combined expertise in pharmacokinetics, pharmacodynamics, drug 
bioavailability and drug metabolism studies, pharmacogenetics, and study 
design of pediatric drug trials.

SPECIAL REQUIREMENTS 

Components of a PPRU
 
A.  Principal Investigator (PI)

The PI must be an established pediatric clinical pharmacologist or a clinical 
pharmacologist with extensive experience in clinical drug trials in 
pediatrics.  In case of a non-physician PI or a non-pediatric PI, a board- 
certified pediatrician must be identified separately in the application (see 
INDIVIDUALS ELIGIBLE TO BECOME PRINICIPAL INVESTIGATORS, above).  Those 
functions, whether PI alone or PI and pediatrician or PI and Associate 
Clinical Pharmacologist, may be supported up to 25 percent time and effort.   

B.  Clinical Facility
 
A designated physical site where the clinical research will be performed is 
required.  To allow optimal opportunities for collaboration among PPRUs in 
the network, it is desirable that each PPRU have both inpatient and 
outpatient capability.  These could be provided by a pediatric metabolic ward 
and an outpatient clinic, a General Clinical Research Center (GCRC) funded by 
the NIH National Center for Research Resources and suitable for admitting 
children and caring for them as outpatients, or some other unit similarly 
equipped for conducting pediatric clinical research.  Applicant institutions 
that wish to identify the GCRC as a site for conducting PPRU research should 
include with the application a letter of agreement from the GCRC Program 
Coordinator or PI.
 
C. Core Laboratory
 
A funded PPRU may include a core laboratory dedicated to performing 
specialized analyses and/or data management functions for studies conducted 
in the PPRU.  This should not include procedures routinely performed for a 
fee in institutional laboratories or available in the laboratories of the 
investigators utilizing the unit. 
 
The core laboratory may be staffed by a PPRU-supported doctoral-level core 
laboratory director (maximum 25 percent time and effort) and a core 
laboratory technician (maximum 50 percent time and effort), if the science 
proposed warrants.
 
The core laboratory director, who reports to the PI, should have 
responsibility for quality control in that laboratory.  The time and effort 
of the laboratory director may also be devoted to developing new methods for 
protocols being conducted with PPRU support and to standardizing procedures 
to be carried out for PPRU network collaborative protocols.  In addition, the 
core laboratory director is responsible for the care and maintenance of the 
laboratory equipment, and will cooperate with the PI in assisting other 
investigators in their use of the Unit.
 
D.  Other Investigators
 
Any person with pediatric privileges at the grantee institution is eligible 
to utilize the PPRU resources for studies of drug efficacy or metabolism, 
supported by independent research funds, if the protocols have been approved 
and prioritized by the Network Steering Committee.  These individual 
investigator protocols must not delay or interfere with pursuit of the 
collaborative studies that are the PPRU's primary responsibility.  For 
investigators inexperienced in clinical pharmacology, the PI is expected to 
provide advice and guidance. 

Clinical pharmacists are encouraged to participate in PPRU research in
collaboration with physicians who bear the responsibility for patient care. 
No funds for Other Investigators are authorized.
 
E.  Nurse Coordinator and Research Nurse
 
A qualified nurse coordinator is one of the most important assets of a PPRU.  
The nurse coordinator reports to and takes direction from the PI, whether or 
not he or she is a member of the institution's nursing service.  The nurse 
coordinator, in cooperation with the Associate Clinical Pharmacologist, 
carries out as many parts of the research protocols as possible, dovetailing 
schedules for maximum efficiency and instructing and supervising the other 
nursing staff in those operations or procedures for which he or she is 
unavailable.  He or she is responsible for data collection and organization, 
unless the latter responsibility is assigned to a data coordinator (see 
below).  The nurse coordinator is a full-time position supported by the 
grant.
 
If the need arises, an additional research nurse will assist the nurse 
coordinator in all the facets of clinical trials.  One or more individuals 
may be supported in the research nurse position, at a total of one full-time 
equivalent (100 percent time and effort).
 
F.  Patient Recruiter
 
A patient recruiter may be justified to insure the efficient recruitment of 
patients required in Network protocols.  This individual maintains a registry 
of potential study candidates, gathers recruitment information from different 
areas of the hospital, clinics and private offices to match potential study 
patients with specific protocols (up to 50 percent time and effort).
 
G.  Adjunct Clinical Pharmacologist
 
An applicant may request support for salaries and fringe benefits for this 
position (maximum 50 percent time and effort).  The Adjunct Clinical 
Pharmacologist may be a physician who is fully trained in pediatrics, has 
completed subspecialty training, and wishes to gain experience in the conduct 
of pediatric pharmacology research under the guidance and supervision of the 
PI or some other appropriate person.  Alternatively, the adjunct clinical 
pharmacologist may be a non-physician holding the Pharm.D. degree or a Ph.D. 
in Pharmacology who has had special training in pediatric pharmacology and 
wishes to obtain additional supervised clinical experience.  Support for the 
associate clinical pharmacologist from the PPRU is for research time and 
effort only, unless this person is a licensed physician who assists the PI in 
supervising patient care in the Unit.  A qualified individual may be 
supported for up to two years as an associate clinical pharmacologist at a 
PPRU.
 
H.  Data Coordinator
 
Each PPRU application should include information about the data management 
system to be used in the Unit for collaborative studies being performed by 
the Network.  If justified by the expected volume of work, a data coordinator 
may be supported (up to 25 percent time and effort) by a PPRU grant.  This 
person will organize the data in preparation for transmission to the PPRU 
Data Coordinating Center, NICHD and to other PPRUs when appropriate.  These 
functions are critical to the success of the Network.
 
I.  Pharmacy
 
The availability of a pharmacy capable of supporting clinical research 
activities and experienced in the preparation of materials for randomized 
clinical trials should be documented.
 
Budget Preparation
 
Allowable costs in NIH cooperative agreements are governed by rules set forth 
in the NIH Grants Policy Statement and as stated in the Notice of Grant 
Award.  Under these rules, the PI may exercise flexibility to meet unexpected 
requirements by rebudgeting or requesting approval to rebudget among 
categories within the total direct cost budget of the PPRU (as shown on the 
Notice of Grant Award), within the ceilings set in these guidelines.
 
PPRU grants are for five years, at a maximum level of $375,000 in total costs 
for the first year.  Competing continuation applications from existing PPRUs 
may request an initial year increase of three percent above the level of the 
direct costs for the final year of the last funding cycle.
 
Items supportable through a PPRU cooperative agreement award may include:
 
1) Administration  

o  Personnel:  Principal Investigator (maximum 25 percent time and effort); 
secretary (maximum 25 percent time and effort). 

o  Administrative Support Services:  supplies, duplication costs, telephone. 

o  Travel:  PI, Associate PIs, and Nurse Coordinator to all meetings of the 
NSC.  
 
2) Core Laboratory

o  Personnel:  Core laboratory director (maximum 25 percent time and effort); 
core laboratory technician (maximum 50 percent time and effort).  

o  Equipment:  The equipment used in the core laboratory should be primarily 
that available to the investigators or obtainable from institutional 
resources.  New equipment, to up to a maximum of $50,000 total cost 
distributed over the first four years of the award, may be requested in a 
PPRU application, with appropriate justification.  

o  Supplies:  Appropriate for PPRU participation in collaborative protocols 
and for support of specialized analyses for investigator-initiated studies 
within the PPRU.

o  Other:  Maintenance costs of equipment purchased with the award or 
otherwise dedicated to PPRU use.  The maximum allowable total annual amount 
for Supplies plus Other in the core laboratory is $20,000.
 
3) Research Services Core  

o  Personnel:  Nurse Coordinator and research nurse (maximum 100 percent time 
and effort each); Adjunct Clinical Pharmacologist (maximum 50 percent time 
and effort); Data Coordinator (maximum 25 percent time and effort).
 
Each proposed Network protocol should include an estimate of staff time and 
required hospital ancillary costs needed for the protocol.  (These costs 
should NOT be included in the overall requested PPRU budget, since they will 
be distributed over all the Network participants in that protocol.)  For 
studies performed in collaboration with pharmaceutical firms, those firms 
should pay the fees for research-related clinical determinations.  For 
investigator-initiated studies in which pharmaceutical firms do not 
participate, costs must be supported by sources other than PPRU funding.
 
Studies of drugs already on the market with no commercial sponsors may be 
funded through a capitation system.  Specific protocol-related costs will be 
capitated according to the anticipated number of patients to be enrolled at 
the applicant PPRU.  Level of funding will be based on actual recruitment.  
Allocations for this purpose will depend on the availability of funds.
 
For drug company-initiated protocols being pursued in the PPRUs, there must 
be appropriate reimbursements from non-PPRU sources for core laboratory 
equipment maintenance, supplies, and personnel time, as well as for data 
management costs.  These reimbursements must be used to offset PPRU costs and 
should be reported as grant-related income.
 
The following items are not fundable through a PPRU grant:

1) Costs of clinical care, such as patient bed costs, outpatient visit fees, 
and clinical laboratory determinations.  These costs must be paid by the 
pharmaceutical companies for protocols performed on their initiative or by 
third-party carriers or other sources for investigator-initiated protocols. 

2) Laboratory costs (outside the core laboratory) for projects being 
performed by non-PPRU investigators using the PPRU. 

3) Travel to scientific meetings or for any other purpose except for the PI, 
associate PI's, Nurse Coordinator, and budget personnel to attend meetings of 
the NSC.
 
Meetings

The Network Steering Committee will meet at least four times per year.  
Applicants should include costs for travel to these meetings in their budget 
request.

Collaboration

It is expected that most of the studies conducted in the PPRU Network will be 
clinical and/or translational for the pediatric age group.  In addition to 
studies leading to pediatric labeling, joint NICHD-industry sponsored 
research in the development and testing of new molecular entities for the 
treatment of pediatric conditions is strongly encouraged.

Clinical trials in conjunction with other NICHD networks (e.g., Neonatal 
Research and Maternal-Fetal Medicine Networks) or other NIH pediatric 
networks designed to provide definitive evidence of the efficacy or lack of 
efficacy of drugs for specific indications are highly encouraged.
Pre-clinical basic studies may be conducted (with other support) in a PPRU's 
core laboratory.

Since advances in pediatric pharmacology depend on studies involving basic, 
translational, and clinical drug research, it is highly desirable that the 
PPRU investigators interact and develop joint projects with investigators 
involved in basic research on the ontogeny of drug metabolizing enzymes, 
transporters, and receptors, and on mechanisms of pediatric adverse drug 
reactions.  It is expected that all Principal Investigators will cooperate 
with the NICHD PPRU Program Coordinator in identifying research areas of high 
priority and in the development of an overall research plan for 
implementation during the funding cycle.  It is expected that all 
participating PPRUs will be involved in collaborative clinical trials of 
drugs with other units in the Network through protocols determined by 
consensus and that individual PPRU will have different and complementary 
research strengths in pediatric clinical pharmacology.  A major consideration 
in the design of protocols is the thematic integration and synergistic 
interaction of PPRUs.  Local protocols will be permitted only if they fulfill 
objectives 3, 4 or 5 (above) or if the proposed local study would provide the 
basis for an anticipated Network protocol.  Local protocols must conform to 
the research priorities established by the Network Steering Committee (NSC) 
rather than being isolated and unrelated projects.  The NSC must approve all 
local protocols.  Pharmacokinetics studies requested by pharmaceutical 
companies for pediatric labeling purposes and assigned by the NSC to a single 
PPRU are not considered local protocols.  All investigator-initiated 
protocols must be approved by the NSC.

Data Safety and Monitoring

For proposals including human subjects, investigators must submit a 
description of a data safety and monitoring plan that meets the NIH Policy 
for Data Safety and Monitoring (NIH Guide for Grants and Contracts, June 12, 
1998: http://grants.nih.gov/grants/guide/notice-files/not98-084.html and NIH 
Guide for Grants and Contracts, June 5, 2000: 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-038.html).

Cooperative Agreement Terms and Conditions of Award

The following Terms and Conditions will be incorporated into the award 
statement.  They are to be followed 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, PHS, and NIH grant 
administration policies.

The administrative and funding instrument used for this program will be the 
U10, an "assistance" mechanism (rather than an "acquisition" mechanism), in 
which substantial NIH scientific and/or programmatic involvement with the PI 
is anticipated during performance of the activities.  Under the cooperative 
agreement, the NIH purpose is to support and/or stimulate the PI's activities 
by involvement in and otherwise working jointly with the PI in a partnership 
role; it is not to assume direction, prime responsibility, or a dominant role 
in the activities.  Consistent with this concept, the dominant role and prime 
responsibility resides with the PI for the project as a whole, although 
specific tasks and activities may be shared between the awardee and NIH 
program staff.  Facilities and Administrative cost (indirect cost) award 
procedures apply to cooperative agreements in the same manner as for grants.  
Business management aspects of these awards will be administered by the NICHD 
Grants Management Branch in accordance with HHS and NIH grant administration 
requirements.

(1)  Awardee Responsibilities 

The PI is responsible for developing and maintaining the PPRU as an 
institutional and national resource and for overseeing the work of the 
associate clinical pharmacologist and other members of the PPRU staff.  It is 
expected that the PI will be active in conducting research within the PPRU 
and in negotiating support from proprietary pharmaceutical organizations.  
The PI may be responsible for industry-sponsored Network protocols.  The PI 
will assist other investigators in conducting PPRU Network research 
protocols.  The PI will attend the meetings of the Network Steering Committee 
and participate in its deliberations.  Each PI will have primary 
responsibility to define objectives and approaches and to plan, analyze, and 
publish results, interpretations, and conclusions of his/her studies.  For 
Network collaborative protocols, this responsibility will be shared with 
other Network members and the NICHD PPRU Program Coordinator (see below).  

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.  Awardees will be 
required to accept and implement common protocols and procedures approved by 
the Network Steering Committee.

(2)  NICHD Responsibilities 

NICHD PPRU Program Coordinator:

The NICHD Program Coordinator is responsible for the overall scientific 
administration of the PPRU Network.  The role of the NICHD Program 
Coordinator will be to aid the awardees and the Network Steering Committee in 
the following ways:

o  Assist in the efficient conduct of studies, interventions and trials, 
including ongoing review of progress, possible redirection of activities to 
improve performance, and frequent communication with other members of the 
Network Steering Committee.

o  Assist in the development of study protocols.

o  Assist in the review and evaluation of the program and in the development 
of new research goals through the funding cycle in conjunction with the 
Steering Committee and the Advisory Board.

o  Assist in reporting results in the community of investigators and health 
care recipients.

o  Serve as liaison between the grantees and the other researchers involved in 
basic and translational research in developmental pharmacology to foster 
scientific collaboration and interaction.

o  Coordinate the PPRU Network activities with other NIH-funded pediatric 
clinical trials networks to facilitate development of joint projects, avoid 
duplication, and maximize efficiency.   

o  Participate in data analysis, interpretations and, where warranted, co-
author publications that report results of studies performed under RFA HD-03-
001.

o  Provide assistance to the Network Steering Committee in the development of 
procedures for monitoring the performance of the studies.  This includes 
participation in periodic on-site monitoring with respect to compliance with 
protocol specifications, quality control and accuracy of data recording, and 
accrual.

NICHD Project Officer:

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

o  Assure the scientific merit of studies, interventions, and trials done 
under this initiative, including the option to withhold support of a 
participating PPRU if technical performance requirements such as protocol 
compliance and enrollment targets are not met.

o  Initiate a decision to modify or terminate a study based on the advice of 
the Data Safety and Monitoring Committee and the Advisory Board after 
consultation with the Network Steering Committee.

o  Perform other duties required for normal program stewardship of grants.

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.

(3) Collaborative Responsibilities
 
The management of the PPRU Network includes three committees:
 
o  The Network Steering Committee (NSC) will be responsible for protocol 
development and review assisted by the Advisory Board and by a Data Safety 
and Monitoring Committee (see below).  The NSC will have responsibility for 
the conduct of protocols, preparation of publications, and update of Network 
Policies and Procedures. The Network Steering Committee will consist of the 
Principal Investigators, the NICHD Program Coordinator, and a non-voting FDA 
representative.  The NSC will be chaired by a non-voting outside chairperson 
selected by the NICHD.  The members of the NSC will meet at least quarterly 
and will communicate biweekly by formal conference calls.
 
o  An Advisory Board will advise the NSC on the identification and
prioritization of drugs for study and recommend research initiatives.
The Advisory Board (chosen by the NICHD with the advice of the Steering 
Committee) will be composed of individuals with expertise in clinical and 
developmental pharmacology and clinical trials and drug development in 
children.  Ad hoc members for evaluation of quality of science and of 
specific research initiatives will be appointed by the NICHD.  The research 
initiatives necessary to fulfill objectives (3) and (4) of this RFA will be 
approved by the Advisory Board.  The NICHD Program Coordinator will serve as 
Executive Secretary of the Advisory Board, reporting findings to the Steering 
Committee and protocol investigators.
 
o  A Data Safety and Monitoring Committee will monitor the safety of ongoing 
trials in investigator-initiated trials that do not have pharmaceutical 
company sponsorship.  The Committee will be established by the NICHD and will 
be composed of individuals with expertise in the design and conduct of 
clinical trials, ethics, and pharmacology.  The Data Safety and Monitoring 
Committee reports to both the NICHD and the NSC.
 
(4) Arbitration Process

Any disagreements that may arise in scientific or programmatic matters within 
the scope of the award between grantees and the NIH may be brought to 
arbitration.  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 regulation 
at 45 CFR Part 16.  An Arbitration Panel will help resolve both scientific 
and programmatic issues that develop during the course of work that restrict 
progress.  The Arbitration Panel will be composed of three members:  a 
designee of the NSC chosen without the NIH staff voting, one NIH designee, 
and a third designee with expertise in the relevant area who is chosen by the 
other two members.

WHERE TO SEND INQUIRIES

We encourage inquiries concerning this RFA 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:

o Direct your questions about scientific/research issues to:

George P Giacoia, M.D.
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 4B11B, MSC 7510
Bethesda, MD  20892-7510
Telephone:  (301) 496-5589
FAX: (301) 480-9791
Email:  gg65m@nih.gov 
 
o Direct your questions about peer review issues to:

Robert Stretch, Ph.D.
Director, Division of Scientific Review
National Institute of Child Health and Human Development
6100 Executive boulevard, Room 5B01, MSC 7510
Bethesda, MD  20892-7510
Telephone:  (301)496-9254 
Email:  stretchr@mail.nih.gov 

o Direct your questions about financial or grants management matters to:

Dianna N. Bailey
Grants Management Specialist
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 8A07E, MSC 7510
Bethesda, MD  20892-7510
Telephone:  (301) 435-6978
FAX:  (301) 402-0915
Email:  Baileydi@mail.nih.gov  
 
LETTER OF INTENT
 
Prospective applicants are asked to submit a letter of intent that includes 
the following information:

o Descriptive title of the proposed research
o Name, address, and telephone number of the Principal Investigator
o Names of other key personnel 
o Participating institutions
o Number and title of this RFA 

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 the institute staff to estimate the potential review workload 
and plan the review.
 
The letter of intent is to be sent by the date listed at the beginning of 
this document.  The letter of intent should be sent to:

George P. Giacoia, M.D.
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 4B11B, MSC 7510
Bethesda, MD  20892-7510
Telephone:  (301) 496-5589
FAX:  (301) 480-9791
Email:  gg65m@nih.gov 

SUBMITTING AN APPLICATION

Applications must be prepared using the PHS 398 research grant application 
instructions and forms (rev. 5/2001).  The PHS 398 is available at 
http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive 
format.  For further assistance contact Grants Info, Telephone (301) 435-
0714, Email: GrantsInfo@nih.gov.
 
SUPPLEMENTAL INSTRUCTIONS: 

The application requirements for all applicants are as follows:
 
1) Participants must be based in a Children's Hospital or its equivalent 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.  The pediatric subspecialties for which no 
collaboration is anticipated should be listed.
 
4) 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 in the PPRU; f) gender and racial/ethnic composition of the study 
subjects; g) whether the study was completed; and h) major findings of the 
study.
 
5) Qualifications of Principal Investigator and his or her academic 
productivity must be documented.  The PI and/or associate clinical 
pharmacologist must hold an independent peer-reviewed grant(s) or contract(s) 
support, must be actively publishing, and must be familiar with academic and 
proprietary research in pediatric pharmacology.  Evidence must be provided of 
the PI's and associate clinical pharmacologist'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 are 
important.

Applicants who are current PPRU Principal Investigators should describe their 
participation in PPRU Network research during the current award period, 
including responsiveness to Terms and Conditions of Award.

New applicants should describe their research achievements and their
participation in randomized trials.
 
6) Evidence should be presented of the PPRU's adherence to the International 
Conference on Harmonization (ICH) Good Clinical Practice guidelines adopted 
by the FDA on May 9, 1997.  Applicants should describe how the PPRU complies 
or intends to comply with ICH Good Clinical Practice (FR 62:90, 1997).  

7) A description of the equipment available and pharmacological studies 
performed in the PPRU's laboratory should be provided.  It should be stated 
whether the laboratory is certified for Good Laboratory Practice by the FDA.
 
8) A description of the data management system used in clinical trials should 
be provided. 
 
9) A description of the standard operating procedures adopted in the PPRU to 
guide the activities needed to plan, conduct and manage single or multi-
center clinical trials should be provided.

10) Information about the data management system to be used in the Unit for 
collaborative studies being performed by the Network should be provided.  
 
11) The availability of a pharmacy capable of supporting clinical research 
activities and experienced in the preparation of materials for randomized 
clinical trials should be documented.

12) A detailed description of the clinical and research capabilities of the 
PPRU should be provided, including a description of pharmacokinetics and 
pharmacodynamic capabilities, access to a pharmacogenetics laboratory and 
other strengths in pediatric pharmacology, both in basic and clinical 
research.

13) To provide peer reviewers and the NICHD with an idea of the capabilities 
of the Unit's investigators, new applicants must submit one or two examples 
of drug evaluation studies that they would propose as Network protocols to 
the Network Steering Committee (Objectives 1 and 2).  These examples should 
be drafts (up to six 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.
 
14) Competing continuation applications, as well as new applications, should 
include one or two examples of research protocols on specific aspects of 
pediatric pharmacology that participating investigators intend to pursue if 
the PPRU is funded (see Objectives 3 and 4 and 5).  These protocols should be 
presented in no more than six pages.  Each should include a clearly 
identified hypothesis, brief background information, and a narrative of the 
procedures to be employed.  They should include details of statistical design 
and enough additional specific material for a scientific review.  In 
addition, each protocol should provide a brief justification of its need for 
PPRU resources.
 
15) An explicit statement of the applicant's preparedness to participate in 
PPRU Network clinical trials according to the terms of the RFA should be in 
the application, and evidence of a long-term institutional commitment to the 
needs of the PPRU is required.  This may take various forms, including (but 
not limited to) the waiver of facility fees or bed costs for use of an 
outpatient clinic or research ward for patients on protocol; equipment and 
space for a core laboratory; released time for faculty to perform clinical 
pharmacology research in children; and/or funding for support personnel.
 
16) A description of the proposed training program in pediatric clinical 
pharmacology and in the conduct of pediatric drug trials should be included. 
The training program should include a clinical and research component.  The 
training of nurses, pharmacists, and other health professionals in the 
conduct of pediatric drug trials should be detailed.  The objectives, design, 
and the direction of the research training program of the Adjunct Clinical 
Pharmacologist should be described. 

Page Limitations

Because applicants will be proposing at least two research plans, an 
individual and a collaborative, the page limit for the Research Plan sections 
of the application is 25 pages plus six pages for each proposed protocol.  
For questions related to application format, applicants may contact one of 
the individuals listed under WHERE TO SEND INQUIRIES, above.

USING THE RFA LABEL:  The RFA label available in the PHS 398 (rev. 5/2001) 
application form must be affixed to the bottom of the face page of the 
application.  Type the RFA number on the label.  Failure to use this label 
could result in delayed processing of the application such that it may not 
reach the review committee in time for review.  In addition, the RFA title 
and number must be typed on line 2 of the face page of the application form, 
and the YES box must be marked. The RFA label is also available at: 
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf.
 
SENDING AN APPLICATION TO THE NIH:  Submit a signed, typewritten original of 
the application, including the Checklist, and three signed, photocopies, in 
one package to:
 
Center for Scientific Review
National Institutes of Health
6701 Rockledge Drive, Room 1040, MSC 7710
Bethesda, MD  20892-7710
Bethesda, MD  20817 (for express/courier service)
 
At the time of submission, two additional copies of the application must be 
sent to:

Robert Stretch, Ph.D.
Director, Division of Scientific Review
National Institute of Child Health and Human Development
6100 Executive boulevard, Room 5B01, MSC 7510
Bethesda, MD  20892-7510
Rockville, MD 20852 (for express/couriers service) 
 
APPLICATION PROCESSING:  Applications must be received by the application 
receipt date listed in the heading of this RFA.  If an application is 
received after that date, it will be returned to the applicant without 
review.
 
The Center for Scientific Review (CSR) will not accept any application in 
response to this RFA that is essentially the same as one currently pending 
initial review, unless the applicant withdraws the pending application.  The 
CSR will not accept any application that is essentially the same as one 
already reviewed. This does not preclude the submission of substantial 
revisions of applications already reviewed, but such applications must 
include an Introduction addressing the previous critique.

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

Applications that are complete and responsive to the RFA will be evaluated 
for scientific and technical merit by an appropriate peer review group 
convened by the NICHD in accordance with the review criteria stated below.  
As part of the initial merit review, all applications will:

o Receive a written critique
o Undergo a process in which only those applications deemed to have the 
highest scientific merit, generally the top half of the applications under 
review, will be discussed and assigned a priority score
o Receive a second level review by the National Advisory of Child Health and 
Human Development Council.
 
REVIEW CRITERIA

1) Criteria for Evaluation of Concept Protocol(s)

The goals of NIH-supported research are to advance our understanding of 
biological systems, improve the control of disease, and enhance health.  In 
the written comments, reviewers will be asked to discuss the following 
aspects of your application in order to judge the likelihood that the 
proposed research will have a substantial impact on the pursuit of these 
goals: 

o Significance 
o Approach 
o Innovation
o Investigator
o Environment
  
The scientific review group will address and consider each of these criteria 
in assigning your applications overall score, weighting them as appropriate 
for each application.  Your application does not need to be strong in all 
categories to be judged likely to have major scientific impact and thus 
deserve a high priority score.  For example, you 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 protocol(s) address an important problem in pediatric 
pharmacology? 

APPROACH:  Are the conceptual framework, design, methods, and analyses 
adequately developed, well integrated, and appropriate to the aims of this 
RFA? 

INNOVATION:  Does the project employ novel concepts, approaches or methods? 

INVESTIGATOR:  Is the investigator appropriately trained and well suited to 
carry out this work?  Is the work proposed appropriate to the experience 
level of the Principal Investigator and to that of other researchers (if 
any)?

ENVIRONMENT:  Does the scientific environment in which the work will be done 
contribute to the probability of success?  Does the project(s) proposed take 
advantage of unique features of the scientific environment or employ useful 
collaborative arrangements?  Is there evidence of institutional support?

2) Criteria for Evaluation of Overall Application

Qualifications, Experience, and Commitment of Key Personnel:

o  Scientific, clinical, and administrative abilities and academic 
productivity of the Principal Investigator, Associate Clinical 
Pharmacologist, and other team members.

o  Knowledge of the conduct of collaborative clinical research, especially 
pediatric drug trials (Phases I, II and III).  This should include specific 
experience in pharmacokinetic and pharmacodynamic analysis and study design 
and analysis of randomized clinical trials.

Protocols and Procedures:

o  Quality of the PPRU's participation in either (a) (current Network 
members) Network protocols, especially investigator-initiated protocols; or 
b) (new applicants) Phase I, II and III pediatric drug clinical trials in the 
recent past;

o  Willingness to work and cooperate with other PPRUs and the NICHD in the 
manner summarized in this RFA.

o  Adequacy of administrative, clinical, laboratory, and data organizational 
management facilities as described under Special Requirements.

o  Institutional assurance to provide support to the study in such areas as 
fiscal administration, personnel management, space allocation, procurement, 
planning, equipment, and budget.

o  Suitability of the proposed clinical locus for the Unit in the applicant
institution or its affiliated hospital, such as a pediatric metabolic ward and
outpatient clinic, a GCRC with staff accustomed to conducting studies in
children, or some unit similarly staffed and equipped.

o  Availability of and access to suitable populations to participate as 
research subjects in PPRU studies.

o  Demonstrated ability of the PPRU to recruit patients for pediatric drug
studies.

o  Evidence of previous successful research collaborations with industry or of
efforts to arrange future collaborations.

o  Evidence of compliance with the Good Clinical Practice and Good Laboratory
Practice guidelines that apply to investigators and/or institutions.

o  Training environment including the institutional commitment, the quality of
the facilities, and the availability of research support. 

o  Objectives, design, and direction of the training program in clinical 
pediatric pharmacology and pediatric drug trials.

ADDITIONAL REVIEW CRITERIA:  In addition to the above criteria, the 
application will also be reviewed with respect to the following:

o  PROTECTIONS:  The adequacy of the proposed protection for humans, animals, 
or the environment, to the extent they may be adversely affected by the 
project proposed in the application.

o  INCLUSION:  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.  Plans for the recruitment and 
retention of subjects will also be evaluated. (See Inclusion Criteria in the 
section on Federal Citations, below.)

o  DATA SHARING:  The adequacy of the proposed plan to share data.
 
o  BUDGET:  The reasonableness of the proposed budget and the requested 
period of support in relation to the proposed research.

RECEIPT AND REVIEW SCHEDULE

Letter of Intent Receipt Date:  February 17 2003
Application Receipt Date:  March 17 2003
Peer Review Date:  July 2003
Council Review:  September 2003
Earliest Anticipated Start Date:  January 1, 2004

AWARD CRITERIA

Criteria that will be used to make award decisions include:

o Scientific merit (as determined by peer review)
o Availability of funds
o Programmatic priorities.
 
REQUIRED FEDERAL CITATIONS 

MONITORING PLAN AND DATA SAFETY AND MONITORING BOARD:  Research components 
involving Phase I and II clinical trials must include provisions for 
assessment of patient eligibility and status, rigorous data management, 
quality assurance, and auditing procedures.  In addition, it is NIH policy 
that all clinical trials require data and safety monitoring, with the method 
and degree of monitoring being commensurate with the risks (NIH Policy for 
Data Safety and Monitoring, NIH Guide for Grants and Contracts, June 12, 
1998: http://grants.nih.gov/grants/guide/notice-files/not98-084.html).  

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 AMENDMENT "NIH 
Guidelines for Inclusion of Women and Minorities as Subjects in Clinical 
Research - Amended, October, 2001," published in the NIH Guide for Grants and 
Contracts on October 9, 2001 
(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 RESEARCH INVOLVING HUMAN SUBJECTS: 
The NIH maintains a policy that children (i.e., individuals under the age of 
21) must be included in all human subjects research, conducted or supported 
by the NIH, unless there are scientific and ethical reasons not to include 
them. This policy applies to all initial (Type 1) applications submitted for 
receipt dates after October 1, 1998.

All investigators proposing research involving human subjects should read the 
"NIH Policy and Guidelines" on the inclusion of children as participants in 
research involving human subjects that is available at 
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 proposals for research involving human 
subjects.  You will find this policy announcement in the NIH Guide for Grants 
and Contracts Announcement, dated June 5, 2000, at 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

PUBLIC 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 public access to research data through the Freedom of Information Act 
(FOIA) 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 FOIA.  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 RFA 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.

URLs IN NIH GRANT APPLICATIONS OR APPENDICES:  All applications and proposals 
for NIH funding must be self-contained within specified page limitations. 
Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) 
should not be used to provide information necessary to the review because 
reviewers are under no obligation to view the Internet sites. 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 
RFA 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 No. 93.865 and is not subject to the 
intergovernmental review requirements of Executive Order 12372 or Health 
Systems Agency review.  Awards are made under authorization of Sections 301 
and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and 
administered under NIH grants policies described at 
http://grants.nih.gov/grants/policy/policy.htm and under Federal Regulations 
42 CFR 52 and 45 CFR Parts 74 and 92. 

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.

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