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: 
http://grants.nih.gov/grants/guide/notice-files/not98-084.html and NIH Guide 
for Grants and Contracts, June 5, 2000: 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-038.html).

Cooperative Agreement Terms and Conditions of Award

The following Terms and Conditions will be incorporated into the award 
statement.  They are to be followed in addition to, and not in lieu of, 
otherwise applicable OMB administrative guidelines, HHS grant administration 
regulations at 45 CFR Parts 74 and 92, and other HHS, PHS, and NIH grant 
administration policies.

The administrative and funding instrument used for this program will be the 
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:  [email protected]

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:  [email protected]

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:  [email protected]
 
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: [email protected]

SUBMITTING AN APPLICATION

Applications must be prepared using the PHS 398 research grant application 
instructions and forms (rev. 5/2001).  The PHS 398 is available at 
http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive 
format.  For further assistance contact GrantsInfo, Telephone (301) 710-0267, 
Email:  [email protected].
 
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: 
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf.

SENDING AN APPLICATION TO THE NIH:  Submit a signed, typewritten original of 
the application, including the Checklist, and three signed, photocopies, in 
one package to:
 
Center For Scientific Review
National Institutes of Health
6701 Rockledge Drive, Room 1040, MSC 7710
Bethesda, MD  20892-7710
Bethesda, MD  20817 (for express/courier service)
 
At the time of submission, two additional copies of the application must be 
sent to:

Robert Stretch, Ph.D.
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: 
http://grants.nih.gov/grants/guide/notice-files/not98-084.html).  

INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH:  It is the policy of 
the NIH that women and members of minority groups and their sub-populations 
must be included in all NIH-supported clinical research projects unless a 
clear and compelling justification is provided indicating that inclusion is 
inappropriate with respect to the health of the subjects or the purpose of the 
research. This policy results from the NIH Revitalization Act of 1993 (Section 
492B of Public Law 103-43).

All investigators proposing clinical research should read the AMENDMENT "NIH 
Guidelines for Inclusion of Women and Minorities as Subjects in Clinical 
Research - Amended, October, 2001," published in the NIH Guide for Grants and 
Contracts on October 9, 2001 
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html)
, a complete copy of the updated Guidelines are available at 
http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm.
The amended policy incorporates: the use of an NIH definition of clinical 
research, updated racial and ethnic categories in compliance with the new OMB 
standards, clarification of language governing NIH-defined Phase III clinical 
trials consistent with the new PHS Form 398, and updated roles and 
responsibilities of NIH staff and the extramural community.  The policy 
continues to require for all NIH-defined Phase III clinical trials that: a) 
all applications or proposals and/or protocols must provide a description of 
plans to conduct analyses, as appropriate, to address differences by 
sex/gender and/or racial/ethnic groups, including subgroups if applicable, and 
b) investigators must report annual accrual and progress in conducting 
analyses, as appropriate, by sex/gender and/or racial/ethnic group 
differences.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS: 
The NIH maintains a policy that children (i.e., individuals under the age of 
21) must be included in all human subjects research, conducted or supported by 
the NIH, unless there are scientific and ethical reasons not to include them. 
This policy applies to all initial (Type 1) applications submitted for receipt 
dates after October 1, 1998.

All investigators proposing research involving human subjects should read the 
"NIH Policy and Guidelines" on the inclusion of children as participants in 
research involving human subjects that is available at  
http://grants.nih.gov/grants/funding/children/children.htm. 

REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS:  NIH 
policy requires education on the protection of human subject participants for 
all investigators submitting NIH proposals for research involving human 
subjects.  You will find this policy announcement in the NIH Guide for Grants 
and Contracts Announcement, dated June 5, 2000, at 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT:  The 
Office of Management and Budget (OMB) Circular A-110 has been revised to 
provide public access to research data through the Freedom of Information Act 
(FOIA) under some circumstances.  Data that are (1) first produced in a 
project that is supported in whole or in part with Federal funds and (2) cited 
publicly and officially by a Federal agency in support of an action that has 
the force and effect of law (i.e., a regulation) may be accessed through FOIA. 
 It is important for applicants to understand the basic scope of this 
Amendment. NIH has provided guidance at:
http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm.

Applicants may wish to place data collected under this RFA in a public 
archive, which can provide protections for the data and manage the 
distribution for an indefinite period of time.  If so, the application should 
include a description of the archiving plan in the study design and include 
information about this in the budget justification section of the application. 
In addition, applicants should think about how to structure informed consent 
statements and other human subjects procedures given the potential for wider 
use of data collected under this award.

URLs IN NIH GRANT APPLICATIONS OR APPENDICES:  All applications and proposals 
for NIH funding must be self-contained within specified page limitations. 
Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) 
should not be used to provide information necessary to the review because 
reviewers are under no obligation to view the Internet sites.   Furthermore, 
we caution reviewers that their anonymity may be compromised when they 
directly access an Internet site.

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

AUTHORITY AND REGULATIONS:  This program is described in the Catalog of 
Federal Domestic Assistance No. 93.865, and is not subject to the 
intergovernmental review requirements of Executive Order 12372 or Health 
Systems Agency review.  Awards are made under authorization of Sections 301 
and 405 of the Public Health Service Act as amended (42 USC 241 and 284 and 
administered under NIH grants policies described at 
http://grants.nih.gov/grants/policy/policy.htm and under Federal Regulations 
42 CFR 52 and 45 CFR Parts 74 and 92.  

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

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