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: https://grants.nih.gov/grants/guide/notice-files/not98-084.html and NIH
Guide for Grants and Contracts, June 5, 2000:
https://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
https://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive
format. For further assistance contact Grants Info, Telephone (301) 710-0267, 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:
https://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: https://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
(https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html);
a complete copy of the updated Guidelines is available at
https://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
https://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
https://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
https://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
https://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.