MECHANISMS OF ADVERSE DRUG REACTIONS IN CHILDREN
RELEASE DATE: April 1, 2002
RFA: HD-02-001
National Institute of Child Health and Human Development (NICHD)
(http://www.nichd.nih.gov)
LETTER OF INTENT RECEIPT DATE: June 26,2002
APPLICATION RECEIPT DATE: July 26,2002
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) invites
applications to stimulate research on the mechanisms of adverse drug reactions
(ADRs) in children. The primary objective of this Request for Applications
(RFA) is to encourage and support the study of the molecular and cellular
mechanisms involved in the production of ADRs in children. This objective
includes research on the role of ontogeny and the characterization of
pharmacogenetic and developmental variations of drug metabolizing enzymes
(DMEs), transporters, ion channels, and receptors that are responsible for
drug toxicity in the pediatric population. Research on the role of ontogeny
in the production of, and immune responses to, reactive metabolites and
research on the efficiency of detoxification mechanisms are particularly
emphasized. The development of adequate animal models to spur discovery of
the mechanisms of hypersensitivity reactions in children and the
identification of toxicity biomarkers are an important part of this
initiative. The purpose of this research is to support studies that are
synergistic and complementary within the overall goal of RFA HD-02-001.
RESEARCH OBJECTIVES
Background
Adverse drug reactions (ADRs) are an important clinical problem and represent
a major contributor to mortality and morbidity in adults. Although most
research to date has largely been confined to adults, the significance of ADRs
in children has been increasingly recognized. ADRs in children differ from
those manifested in adults in frequency, nature and severity.
Upon exposure to some drugs, infants and young children are at a greater risk
than adults for developing ADRs (e.g., acute central nervous system and
hyperpyretic reactions to anticholinergic drugs such as atropine and
scopolamine, and life-threatening adverse reactions to valproic acid.
Conversely, children may also be less susceptible than adults to toxic
reactions from other drugs. For example, infants are less likely to develop
ototoxicity or nephrotoxicity from aminoglycosides, and the hepatocellular
damage resulting from an acute acetaminophen overdose is considerably milder
in young children than in adults.
Mechanistically ADRs encompass a diverse group of reactions:
o Dose-dependent, commonly known as Type A reactions.
o Dose-independent, commonly referred to as Type B reactions.
o End-of treatment reactions (i.e., withdrawal reactions).
o Long-term effects such as teratogenesis or carcinogenesis. These two
reactions fall outside the scope of this RFA.
Type A reactions are dose-related and can be predicted from the known
pharmacology of the drug. For example infants, especially preterm infants,
are at risk for this type of ADR because of immaturity of their drug
metabolizing enzymes (DMEs). The developmental patterns of many
biotransformation enzymes (both Phase I and Phase II) have not been
sufficiently characterized in children. There is evidence, however, that
CYP3A4 activity increases in early childhood and surpasses the enzyme activity
in adults. This knowledge raises the possibility that increased activity of
some P450 isoforms may be a pathogenic mechanism in the generation of reactive
metabolites involved in idiosyncratic reactions. Under normal circumstances
reactive metabolites are inactivated by detoxification mechanisms. The
glutathione pathway is important in the detoxification of exogenous and
endogenous compounds and in the cellular defense against oxidative stress.
The ontogeny of the enzymes involved in glutathione conjugation reactions
(e.g. glutathione-S-transferase and glutathione peroxidase) and the factors
that determine the size of the glutathione pool have not been sufficiently
characterized in children.
Genetic polymorphisms of DMEs, drug transporters, and drug targets may cause
Type A reactions. In slow metabolizers, the reduced enzymatic activity of
DMEs may result in severe toxicity when individuals receive standard doses of
drugs. Genetic polymorphisms in drug transporters (e.g., MDR1-Type P-
glycoprotein) may play an important role in drug accumulation and
hypersensitivity reactions. Polymorphisms of drug targets (receptors or ion
channels) may lead to toxicity. Drug-drug interactions may also produce ADRs
in connection with genetic polymorphisms.
Regardless of genotype, newborns have depressed activities of most DMEs,
consequently, the phenotypic manifestations of polymorphisms (e.g., fast
metabolizers) may not be apparent until later in the developmental continuum.
Thus, phenotypic expression of dose-dependent ADRs depends on both ontogenic
development and genetic polymorphisms.
Type B ADRs are unpredictable and dose-independent. This group includes
allergic, autoimmune, and hypersensitivity or idiosyncratic reactions.
Allergic drug reactions have been characterized often on the basis of
immunological reactions demonstrated in affected individuals. Unfortunately,
the mechanisms involved are usually unknown. In penicillin-induced
anaphylaxis, drug-specific IgE antibodies produce systemic mast cell release.
The IgE antibodies are directed against penicillin covalently bound to
proteins. Drug-specific antibodies, however, are often not demonstrated
(e.g.,drug fever).
Hypersensitivity reactions are unpredictable and rare. Drug reactions similar
to those seen in humans are difficult to produce in animal models.
Hypersensitivity reactions have been linked to the formation of reactive
metabolites that can cause cellular injury. Although Phase I enzymes play a
pivotal role in the bioactivation process, occasionally reactive metabolites
may be generated by Phase II enzymes. Variations in activity due to
polymorphisms may be an important pathogenic factor.
It is widely believed that after the initial activation process, the
subsequent step in the pathogenesis of hypersensitivity reactions is the
formation of adducts (drug-protein conjugates). Recent evidence indicates that
covalent binding to plasma or cellular proteins is not a prerequisite and that
unmodified drugs may elicit an immune response. The cascade of events
initiated by a reactive metabolite that produces the immune response
characteristic of drug hypersensitivity remains uncertain.
The development of immune reactions requires T helper cell (Th cell)
activation. It has been postulated that a balance between T helper cells
subtypes (Th1 and Th2) determines the type of immune response.
Drug hypersensitivity reactions in children occur at a time of significant
changes in the development of the immune system. Not known is whether these
ontogenic changes influence the expression and/or severity of pediatric
hypersensitivity reactions.
At birth, children have a predominance of Th2 immunity that wanes in the first
few years of life. Maturation of the immune response may be delayed by
environmental or viral infections. There are phenotypic and functional
differences in T lymphocytes that may lead to delayed or weaker antigen-
specific response in young children.
The apparent variability in the susceptibility to ADRs in children compared to
adults appears to be multifactorial. It is known that viral infections, which
are common in early childhood, are associated with an increased risk of ADRs,
but the mechanism is unknown. In addition to inadequate identification and
recognition systems, ontogenic variations in drug metabolism and immune
reactivity together with genetic, environmental, and nutritional factors may
all play significant roles in the observed differences in ADRs between
children and adults.
Research Objectives and Scope
The objective of RFA HD-02-001 is to encourage and support mechanistically
based research in pediatric ADRs, focusing specifically on the role of
ontogeny in the production of dose-dependent and dose-independent reactions.
To accomplish this goal the ontogeny of the immune system in children needs to
be taken into account.
Emphasis should be placed on differences in the pathogenesis of ADRs between
children and adults. Although the study population may range between newborns
and adolescents, the determination of windows of vulnerability (i.e., age
periods when ADRs are likely to occur or to have long-lasting consequences) is
important for the purpose of this RFA. This initiative encourages
significant, innovative, and hypothesis-driven research rather than
descriptive studies. The development of innovative molecular, genetic,
proteomic, and immunologic methods, techniques, and strategies is encouraged
to characterize the mechanisms responsible for dose-related ADRs and
hypersensitivity reactions in children.
Investigators are also encouraged to develop interdisciplinary approaches
involving clinical pharmacologists, geneticists, toxicologists, immunologists
and molecular and developmental biologists.
The identification and testing of age-related phenotyping probes and
biomarkers of bioactivation are important components in achieving the overall
goal of RFA HD-02-001 and should be integrated into the proposed research
program.
Matching phenotypes with DNA sequencing data will be needed to establish
functional significance of genetic polymorphisms of DMEs and effectors of drug
action. Applications focusing on the ontogeny of DMEs, receptors,
transporters, and ion channels must establish a mechanistic link to the
pathogenesis of ADRs.
Non-invasive techniques (e.g., use of urinary cells or blood cells) or use of
in vitro systems with human tissues will be needed for the identification of
receptor, ion channel or transporter polymorphisms. However the relevance of
cell culture studies needs to be established.
Research issues and topics that would be responsive to RFA HD-02-001 include,
but are not limited to, the following examples. Applicants are encouraged to
propose other topics that address the overall goals of this initiative.
Sample research topics:
o Role of the ontogeny of DMEs, transporters and ion channels in the
production of idiosyncratic and dose-related ADRs in children.
o Mechanisms by which an immune effect initiated by reactive metabolites
results in hypersensitivity.
o Mechanisms by which viral and other infections facilitate the development of
hypersensitivity reactions.
o Role of gender and age in the development of ADRs in children.
o Ontogeny of detoxification pathways particularly glutathione-S-transferase.
o Role of ontogeny of the immune system in the production of ADRs in children.
o Study of the immune recognition processes that result from the binding of
drugs to cellular macromolecules.
o Use of proteomic technology in the discovery and identification of toxicity
biomarkers.
o Development of animal models in species that develop idiosyncratic reactions
similar to humans.
o Use of animal models for expression genomic studies that may distinguish
those animals which develop idiosyncratic reactions and those which do not.
o Study of the role of reactive metabolites produced in extrahepatic tissues
in the production of toxic and/or hypersensitivity reactions.
o Efficiency of macromolecular adducts repair mechanisms in children compared
to adults.
o Determination of the cellular and molecular effects of botanicals in
interactive paradigms with proprietary drugs, or studies which may help to
predict the toxic effects of botanicals in children.
o Role of immunologic tolerance to macromolecular adducts in the pathogenesis
of pediatric ADRs.
o Use of genomics to define patterns of genes associated with pediatric ADRs.
o Role of imbalance between the activities of Phase I and Phase II enzymes in
the production of pediatric ADRs.
o Determination of the role of the developmental profile of Phase I DMEs
involved in the biotransformation of a drug in the pathogenesis of ADRs.
Other Considerations
Clinical material for phenotyping poor or extensive metabolizers and for
studying transporters, receptors, or ion channels may be obtained from
patients participating in ongoing pediatric clinical drug trials. Applicants
responding to this RFA may or may not be investigators of the parent clinical
trial(s) whose data and/or materials and/or subjects they propose to use. It
is expected that applicant Principal Investigators who are not parent study
investigators will work together with the parent study investigators in
developing their applications, documentation of access to participants in a
study whose PI is not the applicant investigator must be included with the
application. Collaboration with the NICHD Pediatric Pharmacology Research
Network is strongly encouraged.
For studies of dose-dependent ADRs, the subset of patients more sensitive to a
study drug should be selected for further study.
Ethical considerations may preclude the use of inaccessible human tissues, and
the type of research proposed may require the use of animal models. An
overriding consideration in the proposed research must be the appropriateness
of testing models and extrapolation to humans of animal data.
MECHANISM OF SUPPORT
This RFA will use NIH cooperative research project grant (UO1) award
mechanism. As an applicant you will be solely responsible for planning,
directing, and executing the proposed project. RFA HD-02-001 is a one-time
solicitation. The anticipated award date is April, 2003.
This RFA uses just-in-time concepts. The NIH UO1 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 $1,500,000 in total costs [Direct
plus Facilities and Administrative (F & A) costs] in FY 2003 to fund four to
six new grants in response to this RFA. An applicant may request a project
period of up to five years and a budget for direct costs of up to $250,000 per
year. 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 the 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
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 their 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.
SPECIAL REQUIREMENTS
Responsiveness
Applications that propose descriptive studies and which do not contain
hypothesis-driven studies directed at understanding the mechanisms of adverse
drug reactions in children will not be considered responsive to RFA HD-02-001.
Development of methodologies to enhance the study of the research areas
covered in this RFA is strongly encouraged.
Access to Research Subjects
Applicants must provide documentation of access to participants if they are to
be obtained from among subjects participating in another study.
Minimum Requirements
The minimum requirements for applicants are as follows (see also REVIEW
CONSIDERATIONS below):
o A competent, experienced Principal Investigator who is committed to
investigate mechanisms of ADRs in children and is willing to cooperate with
other Principal Investigators and the NICHD Project Coordinator.
o To provide peer reviewers and the NICHD an idea of the capabilities of the
investigators, applicants must submit one example of a research protocol on
specific aspects of ADRs that participating investigators intend to pursue if
funded (see Supplemental Instructions, below).
Meetings
PIs are expected to participate in two SC meeting annually. The purpose of
these meetings is to assess scientific progress, identify new research
opportunities, establish priorities, and discuss strategy. Budget requests
should include travel funds for the PI and critical staff to attend those
meetings in the Bethesda, MD area.
Milestones and Evaluations
Applications should define yearly milestones, which may be modified at the
time of the award. The awardee"s milestones will be provided to the SC. It
is expected that the milestones should be adjusted annually at the award
anniversary date, both to incorporate the group"s scientific accomplishments
and progress in the field in general, as well as to reflect the
recommendations of the SC and the Developmental and Clinical Pharmacology
Advisory Panel (DCPAP). In accordance with the procedure described under
Terms and Conditions of Award, below, NICHD program staff may recommend
reducing or withholding funds if a project substantially fails to meet its
milestones or fails to remain state-of-the-art.
Changes in program activities and/or withholding of funds recommended by the
NICHD staff will be approved by the Director of NICHD.
The NICHD expects that biologic samples and associated clinical data will be
made available to the broader scientific community at an appropriate juncture
to support further studies related to mechanisms of ADRs. Reviewers will
assess the adequacy of the proposed data sharing plan. Protection of
confidentiality of research subjects must be assured.
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
U01, 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 NICHD
Project Coordinator. 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, PHS, and NIH grant
administrative requirements.
1. Awardee Rights and Responsibilities
The PI will coordinate project activities scientifically and administratively
at the awardee institution and at other sites that may be supported by
subcontracts to this award. The PI will have the primary responsibility for
defining the details of the project within the guidelines of RFA HD-02-001,
and for performing the scientific activities. The PI will agree to accept
close coordination, cooperation, and participation of the NICHD Project
Coordinator, the SC and the DCPAP in those aspects of scientific and technical
management of the project
Specifically, the PI will:
o Determine experimental approaches, design protocols, direct experiments,
and set project milestones, in consultation with NICHD Project Coordinator and
the SC,
o Implement approved plans for sharing research resources,
o Present results and plans at SC meetings,
o Accept and implement the common guidelines and procedures approved by the
SC and the DCPAP,
o Solicit the views of the broad biomedical research community for the
phenotypes and/or genotypes of interest,
o Release data and publish results.
Awardees will retain custody of and have primary rights to the data developed
under these awards, subject to Government rights of access consistent with
current HHS, PHS, and NIH policies.
2. NICHD Responsibilities
NICHD Project Coordinator:
The NICHD Project Coordinator will be staff member(s) of the Endocrinology,
Nutrition and Growth Branch. They will have substantial
scientific/programming involvement that includes facilitating the partnership
between NIH and the proposed research projects, helping to balance the
project?s activities with new and emerging research opportunities, and
ensuring that the project?s activities are consistent with the mission of
NICHD. They will help to maintain scientific balance between accomplishing
goals and addressing emerging research opportunities. The role of the NICHD
Project Coordinator will be to facilitate, but not to direct activities. It
is anticipated that decisions will be reached by consensus with the PI through
the SC. The Project Coordinator will participate as a member of the SC.
NICHD staff will have a total of one vote.
The NICHD Project Coordinator will:
o Provide relevant expertise and overall knowledge.
o Provide information about ongoing NIH-supported research and resource
collections.
o Attend SC meetings as one voting member participate with other SC members
in the group process of setting research priorities based on thematic
integration and synergy, and contribute to the adjustment of research
protocols or approaches as warranted. The Project Coordinator will assist and
facilitate the group process and not direct it. He will help develop
operating guidelines, quality control procedures, and consistent policies for
dealing with situations that require coordinated action. The Project
Coordinator must be included in all major interactions of SC members.
o Serve as liaison to the DCPAP, attend DCPAP meetings as a non-voting member
to help coordinate the activities of the projects with those of other NIH
pediatric or developmental pharmacology initiatives. The Project Coordinator
will also coordinate the activities of projects funded under RFA HD-02-001
with other US and international efforts.
o Serve as liaison between the grantees and the other NIH program staff.
o Coordinate the project"s activities with NIH-funded repositories and
databases to ensure the rapid and efficient distribution and long-term storage
of biomaterials and data.
o Participate in data analysis, interpretations and, where warranted, co-
author publications that report results of studies performed under RFA HD-02-
001.
o Provide assistance to the SC 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 Project Coordinator,
who will:
o Carry out continuous review of all activities to ensure that the objectives
are being met and that all regulatory, fiscal, and administrative matters are
handled according to NIH guidelines.
o Have the option to withhold support to a participating institution if
technical performance requirements are not met.
o Perform other duties required for normal program stewardship of grants.
3. Collaborative Responsibilities
Guidance and Management Structure
The overall guidance and management of the program will be provided by a
Steering Committee (SC). Additional advice will be provided by the DCPAP,
which helps integrate and coordinate the projects funded under RFA HD-02-001
with other related projects. It consists of scientists who are not affiliated
with any of the projects.
Steering Committee Functions:
The Steering Committee (SC) will be the main governing body of the projects to
be funded by RFA HD-02-001. It will oversee and coordinate interactions among
the projects, and will mediate interactions between the projects and the NIH.
The SC will discuss scientific goals and progress, and recommend further
research activities based on research findings of ongoing projects. It will
help to monitor the plans for sharing research resources. It will also
address the recommendations made by the DCPAP. The SC will consist of the PIs
of each of the projects, and the NICHD Project Coordinator. Each PI will have
one vote and the NIH staff will have a total of one vote.
DCPAP Functions:
The DCPAP evaluates and makes recommendations regarding appropriateness of
projects and of the coordination of activities funded by RFA HD-02-001. The
DCPAP also makes recommendations on the appropriateness of research
methodology used during the span of this cooperative agreement and on the
incorporation of new knowledge in the research area covered by RFA HD-02-001.
The DCPAP consists of scientists in clinical pharmacology, immunology,
genetics and molecular and developmental biology. The DCPAP is chosen by the
NICHD with the advice of the SC. Ad hoc members will be appointed by the
NICHD for evaluation of quality of science and of specific research
initiatives.
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 SC 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.
Endocrinology, Nutrition and Growth Branch
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.
Acting 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) 496-1485
Email: stretchr@mail.nih.gov
o Direct your questions about financial or grants management matters to:
Mary Daley
Grants Management Branch
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 8A07E, MSC 7510
Bethesda, MD 20892-7510
Telephone: (301) 496-1305
FAX: (301) 402-0915
Email: md74u@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 NICHD 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.
Endocrinology, Nutrition and Growth Branch
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 GrantsInfo, Telephone (301) 710-0267,
Email: GrantsInfo@nih.gov.
SUPPLEMENTAL INSTRUCTIONS: The proposed research project should include a
clearly identified hypothesis, brief background information, and a narrative
of the procedures to be employed. Applicants should include details of
statistical design and enough additional specific material for a scientific
review. In addition, the PI should provide a brief justification and details
about complementary types of research that could be undertaken by other SC
investigators.
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.
Acting 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 Child Health and
Human Development Council.
REVIEW CRITERIA
The goals of NIH-supported research are to advance our understanding of
biological systems, improve the control of disease, and enhance health. In
the written comments, reviewers will be asked to 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.
(1) SIGNIFICANCE: Does your study address an important problem? If the aims of
your application are achieved, how do they advance scientific knowledge? What
will be the effect of these studies on the concepts or methods that drive this
field? What will be the expected impact of the information produced by this
project on our understanding of the mechanisms responsible for ADRs in
children?
(2) APPROACH: Are the conceptual framework, design, methods, and analyses
adequately developed, well integrated, and appropriate to the aims of the
project? Do you acknowledge potential problem areas and consider alternative
tactics? If applicable, is the conceptual framework for studying the ontogeny
and conducting phenotyping and genotyping studies of transporters, receptors
or ion channels adequately developed and appropriate to the aims of this RFA?
(3) INNOVATION: Does your project employ novel concepts, approaches or
methods? Are the aims original and innovative? Does your project challenge
existing paradigms or develop new methodologies or technologies?
(4) INVESTIGATOR: Are you appropriately trained and well suited to carry out
this work? Is the work proposed appropriate to your experience level as the
principal investigator and to that of other researchers (if any)? Does the
project proposed challenge existing paradigms or develop new methodologies or
technologies?
(5) ENVIRONMENT: Does the scientific environment in which your work will be
done contribute to the probability of success? Do the proposed experiments
take advantage of unique features of the scientific environment or employ
useful collaborative arrangements? Is there evidence of institutional
support?
ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, your
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 included 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.
OTHER REVIEW CRITERIA:
o Willingness to share patient data, as needed, and specimens derived from
collaborative studies.
o Adequacy of plans to ensure accurate collection, confidentiality, and
timely transmission of study data.
o Documentation of the expertise of the investigators relevant to the goals
of this RFA as evidenced by past accomplishments and by the proposed
protocol(s).
RECEIPT AND REVIEW SCHEDULE
Letter of Intent Receipt Date: June 26,2002
Application Receipt Date: July 26,2002
Peer Review Date: October/November 2002
Council Review: January 2003
Earliest Anticipated Start Date: April 2003
AWARD CRITERIA
Award criteria that will be used to make award decisions include:
o Scientific merit (as determined by peer review)
o Availability of funds
o Programmatic priorities.
o Synergy with other research proposals: In addition to the application?s
overall score, selection for funding will also take into account thematic
integration and evidence of synergy with other research proposals responding
to this RFA.
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 are 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.