DEVELOPMENTAL PHARMACOLOGY

Release Date:  January 5, 2000

RFA:  HD-00-001

National Institute of Child Health and Human Development
National Institute on Drug Abuse 
National Institute of Neurological Disorders and Stroke

Letter of Intent Receipt Date: March 7, 2000
Application Receipt Date: April 13, 2000

THIS RFA USES THE "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS.  IT INCLUDES 
DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED 
WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS RFA.

PURPOSE

The National Institute of Child Health and Human Development, the National 
Institute on Drug Abuse, and the National Institute of Neurological Disorders 
and Stroke invite research grant
applications to study the ontogeny of drug metabolizing enzymes, 
transporters, and receptors, and the corresponding ion channels and related 
proteins.  A major objective of this initiative is the characterization of 
the mechanisms involved in gene regulation and expression of these proteins 
during development, both prenatal and postnatal.

This initiative is aimed at unraveling the effects of development on 
mechanisms of drug action, pharmacodynamics, and drug biotransformation, 
prenatally and from birth through adolescence.  In addition, because drugs 
are now being developed to target specific receptors or modulators, it is 
imperative to determine their functional expression over time in the 
pediatric population. Applications should be designed around a central theme 
of ontogeny of processes that have pharmacologic relevance, with emphasis on 
the interaction and/or relationships between these processes (e.g., drug 
metabolism and drug transport, receptors and ion channels, or receptors and 
pharmacologic ligands).

HEALTHY PEOPLE 2000

The Public Health Service (PHS) is committed to achieving the health 
promotion and disease prevention objectives of "Healthy People 2000," a PHS-
led national activity for setting priority areas.  This Request for 
Applications (RFA) is related to one or more of the priority areas.  
Potential applicants may obtain "Healthy People 2000" at 
http://odphp.osophs.dhhs.gov/pubs/hp2000.

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic and foreign, for-profit and non-
profit organizations, public and private, such as universities, colleges, 
hospitals, laboratories, units of State or local governments, and eligible 
agencies of the Federal government.  Racial/ethnic minority individuals, 
women, and persons with disabilities are encouraged to apply as Principal 
Investigators.

MECHANISM OF SUPPORT

This RFA will use the National Institutes of Health (NIH) individual research 
project grant (R01) funding mechanism.  Responsibility for the planning, 
direction, and execution of the proposed project will be solely that of the 
applicant.  This RFA invites applicants to participate in a collaborative 
group of R01 grants.  Applicants may apply independently or as part of such a 
collaborative group.

The collaborative group approach encourages interaction and collaboration 
among independent scientists with common goals.  It is intended to bring 
together research projects from investigators who wish to collaborate, but 
who do not require extensive shared resources.  There should be constructive 
interchange of ideas, data, and/or materials (for example a shared pediatric 
human tissue bank).  To form such a group, at least two independent 
investigators are encouraged to submit concurrent, collaborative, cross-
referenced individual research project grant (R01) applications.  These 
applications must be freestanding and contain independent hypotheses and 
aims.  An application that provides only a service to other applicants is not 
acceptable.  Although these applications must describe the objectives and 
scientific importance of the collaboration, each project should be able to be 
accomplished independently.  The Principal Investigators may be from one or 
more institutions.  Each application will be reviewed independently for 
scientific merit, and those judged to have substantial merit will be 
considered for funding both as an independent award and as a component of the 
proposed collaborative R01 group.

Specific application instructions have been modified to reflect "MODULAR 
GRANT" and "JUST-IN-TIME" streamlining efforts being examined by the NIH.  
Complete and detailed instructions and information on Modular Grant 
applications can be found at 
http://grants.nih.gov/grants/funding/modular/modular.htm.

This RFA is a one-time solicitation.  Future unsolicited competing 
continuation applications will compete with all investigator-initiated 
applications and be reviewed according to the customary peer review 
procedures.  The anticipated award date is September 29, 2000.

FUNDS AVAILABLE

The NICHD intends to commit approximately $1 million, the NINDS $600,000, and 
NIDA $500,000 in total costs (direct plus Facilities and Administrative) in 
FY 2000 to fund new grants in response to this RFA.  It is anticipated that 
approximately three to five awards will be made by NICHD, two to three by 
NINDS, and one to three by NIDA.  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 research proposed may vary, it is 
anticipated that the size of awards also will vary.  Although this program is 
provided for in the financial plans of the NICHD, NINDS, and NIDA, awards 
pursuant to this RFA are contingent upon the availability of funds for this 
purpose and the receipt of a sufficient number of applications of the highest 
scientific and technical merit. 

RESEARCH OBJECTIVES  

Background

In the last two years, major drug legislative and regulatory events have 
occurred that will profoundly affect pediatric drug development in the 
future:  1) the enactment of the pediatric provisions of the Food and Drug 
Administration Modernization Act of 1997, and 2) the adoption by the Food and 
Drug Administration (FDA) of the Final Rule of 1998.  The former provides for 
a six-month exclusivity for marketed drugs with remaining patent or any kind 
of exclusivity.  The Final Rule of 1998 became effective on April 1999 and 
mandates pediatric studies on new drugs that can benefit children.  An 
unprecedented surge in the number of pediatric drug trials has occurred as a 
result of these regulatory changes.  The performance of drug trials in young 
children uncovered the need to expand the current knowledge of pediatric 
pharmacology.  Similarly, given concerns about drug abuse and exposure in 
children and adolescents, expanding our understanding of pediatric 
pharmacology will greatly improve efforts to prevent and treat addiction in 
the pediatric population.

Recent developments in the biological sciences now offer the opportunity to 
address problems fundamental to the understanding of drug action and 
disposition in children in a manner that was not possible a few years ago.  
Application of molecular biological techniques in pediatrics has permitted 
insights into a number of physiologic or pathophysiologic mechanisms (e.g., 
role of D1 and D2 receptors in brain development and of an immature Th2-
predominance in the pathophysiology of asthma).  Knowledge of the expression 
and function of genes is being accrued at a fast pace. 

Application of molecular biological techniques to drug biotransformation, 
drug transport proteins, and interaction with receptors, however, has been 
more limited.  The ontogeny of drug metabolizing enzymes (DMEs) is only 
partially known.  Although significant advances have been made in the 
elucidation of the expression patterns of individual CYP isoforms, the 
mechanisms determining both constitutive and induced expression of these 
enzymes remain largely unexplored.  The mechanisms responsible for the 
developmental patterns of tissue-specific expression of CYP genes remain 
unknown.  The marked species differences in the ontogeny of drug metabolizing 
enzymes limit the applicability to humans of animal data.

Members of the cytochrome P450 family, such as CYP2D6 and CYP2A6, play 
important roles in the metabolism of exogenous drugs.  CYP2D6 metabolizes 
drugs of abuse, including opiates, while CYP2A6 is the major nicotine C-
oxidase.  Like many other members of the cytochrome P450 family, CYP2D6and 
CYP2A6 are genetically polymorphic, and genetic variability may contribute to 
vulnerability to addiction.  The developmental patterns of CYP2C19, CYP9 and 
CYP2D6 expression are not well characterized.  As a group, Phase II enzymes 
such as CYP enzymes have not been well studied.  Limited information suggests 
variable developmental patterns.  The impact of dietary changes and 
nutritional status on CYP450 expression during development has not been 
characterized.

An understanding of the role of drug transporters is fundamental for the 
characterization of drug disposition in children.  The P-glycoprotein, a 
transmembrane ATP-dependent efflux pump, has been demonstrated in adult 
tissues including proximal renal tubule cells, blood-brain barrier interface, 
adrenal glands, intestine, interstitium, CD4 cells, and macrophages. There is 
evidence of drug transporters not only across cells, but also within cells.  
Anticancer drugs, calcium channel blockers, steroid hormones, certain 
antibiotics, and antiarrhythmic drugs are transported by P-glycoprotein.  In 
the gastrointestinal tract, P-glycoprotein promotes the excretion of drugs in 
the lumen.  In the brain, the P-glycoprotein efflux transport system can be a 
major impediment for the treatment of CNS disorders. P-glycoprotein and other 
newly described transport proteins are responsible for drug resistance to 
some chemotherapeutic agents and protease inhibitors.
There is scant information on the ontogeny of P-glycoprotein in children.  

There is also a dearth of data on the ontogeny of receptors involved in 
pharmacologic activity.  Most research has focused on the physiologic role of 
receptors.  Age differences in alpha-adrenergic receptor expression have been 
demonstrated in a variety of animal species.  Alpha-adrenergic receptor 
density decreases with development.  Limited information is available on the 
regulation of receptor expression, although hormonal influences have been 
demonstrated for some receptors.  Gastrointestinal motility is regulated by 
transmitters and a variety of receptors:  cholinergic, adrenergic, dopamine, 
histamine, 5-hydroxytryptamine (5-HT), gamma aminobutyric (GABA), prostanoid, 
and dihydropyridine.  Current knowledge of the ontogeny of this complex 
system is fragmentary and incomplete.

The ontogenetic expression of dopamine receptors in the brain has been 
studied primarily in relation to their role in brain development.  There is 
little knowledge, however, on the pharmacologic significance of various brain 
receptor assemblies during development.  The increased use of psychotropic 
medications in children raises concerns about their short-term and long-term 
effects in brain development.  The effects of antipsychotic drugs on receptor 
expression and function during development remain unknown.

Similar types of receptors may have different developmental patterns.  For 
example cardiac beta-receptors and their linkage to adenylcyclase are present 
early in development and increase with age.  Conversely, in the liver there 
is a developmental decrease in beta-receptors with consequent decrease in 
adenylcyclase activity. 

 There is evidence that a decrease in beta-adrenergic receptor function may 
contribute to the severity of asthma.  There is a dearth of information on 
the ontogeny of airway beta-adrenergic receptors.

There is increasing evidence that the effects of dopamine are attenuated in 
younger animals. Studies are needed to determine the ontogeny of differences 
in vascular and tubular dopamine receptors and their coupling mechanisms.

The ontogeny of ion channels is another area of research need.  As with DMEs, 
animal studies have documented marked species-dependent developmental 
changes.  The characterization of multiple channel subtypes in the adult 
myocardium has led to significant advances in the treatment of arrhythmias.  
Developmental changes in ion channels expression and function are likely to 
markedly influence response to therapy in pediatric arrhythmias.

The pathophysiology of convulsions and response to therapy is different in 
children, especially newborns, compared to adults.  The mechanisms of action 
of anticonvulsants are characterized by sodium channel blockage, increase in 
GABA inhibition, and calcium channel blockage.  The GABA(A) receptor is the 
site of action of phenobarbital and benzodiazepines.  Phenytoin, 
carbamazepine, and lamotrigine appear to bind to sodium ion channel 
receptors.  The mechanisms regulating the developmental expression and 
function of these receptors and channels remain obscure.

Goals and Objectives

The long-term goal of this RFA is to provide the scientific basis for the 
rational use of drugs in children of all ages, and to characterize the 
metabolism of drugs of abuse in children and adolescents.  The objective is 
to encourage pre-clinical research on the ontogeny of those processes that 
are involved in the biotransformation, transport of drugs, drug and receptor 
interactions, and/or mechanisms of drug action in children.

It is known that ontogeny is organ specific.  Insights gleaned from 
developmental biology studies need to be applied to understanding the 
pharmacology of drugs used in children in an integrated manner.  Development 
and organ maturation involve the completion of a series of complex and 
interlocking events that proceed as a continuum.  Drugs are juxtaposed at 
different stages of the developmental continuum.  The functional readiness of 
the processes of drug disposition and pharmacological effector mechanisms 
varies according to the age of the child.  Clearly, chronologic age per se is 
a poor indicator of the stage of development because of large biologic 
variability.  For the rational use of drugs in children and for an 
understanding of the metabolism of illicit substances in children, a 
functional map needs to be constructed based on the developmental stage of 
the processes involved in drug disposition and action.  These developmental 
guideposts then can replace the current system of allocating children in drug 
trials and of grouping children in clinical studies of substance abuse solely 
on the basis of chronological age.

This initiative seeks to stimulate cooperation and interaction among 
scientists working in different but complementary areas of research.  For 
example, pathways of drug metabolism may require the sequential involvement 
of enzymes with different patterns of developmental expression.  Also, a drug 
may be metabolized by more than one type of isoenzyme.  The contribution of 
individual isoenzymes to the overall metabolism of a drug may vary according 
to the stage of development of the child and may be quite different from the 
adult pattern.  In this context, drug-drug interactions also need to be 
considered, including the effect of interactions between illicit and 
therapeutic drugs, both in neonates exposed to drugs in utero and in children 
using illicit substances.

The mechanisms regulating the developmental expression of pharmacological 
receptors constitute another fertile area of research to be supported by this 
initiative.  Sometimes the low levels of receptors require modifications of 
the conventional techniques used for their detection. New techniques may be 
needed, in some instances, to study the tissue distribution of these 
proteins.  Factors that modulate the ontogeny of transporters, DMEs, 
receptors, and ion channels are largely unknown.  Research on the regulation 
of the ontogenetic expression of these proteins as well as the role of 
ethnicity and gender are within the scope of this RFA.

Research Scope

Research issues and topics that would be responsive to this RFA include, but 
are not limited to, the following examples.  Applicants are encouraged to 
propose other topics that address the overall goals of this initiative.

o  Regulation and ontogenetic expression of DMEs, transporters, receptors, 
and related proteins including mechanisms involved, impact of disease 
processes, and roles of endogenous and exogenous modulators;

o  Characterization of the developmental patterns of the different isoforms 
of P450 and Type II enzymes;

o  Elaboration of the different factors that regulate the expression of P450 
genes during different developmental stages;

o  Characterization of the ontogeny of extrahepatic DMEs;

o  Determination of the correlation between the developmental patterns of 
expression of Phase I and Phase II DMEs;

o  Developmental variations in P-glycoproteins and other related 
transporters;

o  The role of intestinal P-glycoprotein in drug bioavailability in children 
and its correlation with the activity of CYP3A4;

o  Environmental influences (e.g., nutrition, diet, chemicals, drugs of 
abuse) and modulating influences (hormones and other ligands) on DMEs and 
transporters during development;

o  Inducibility and imprinting of protein expression;

o  Characterizing the effect of interactions between illicit and therapeutic 
drugs on the ontogeny of DMEs, transporters, and ion channels;

o  Imprinting of DME expression due to environmental chemical exposure in 
early development;

o  Identification of the mechanisms responsible for activity levels in 
children of some DMEs (e.g., CYP3A4, CYP1A2) surpassing the activity levels 
found in adults;

o  Regulation of constitutive expression of DMEs, transporters, 
pharmacological receptors, and ion channels during development; 

o  Interrelationship of DMEs and transporters.  Is co-expression 
developmentally regulated?

o  Developmental regulation of brain GABA(A) receptor expression, the role of 
GABA(A) receptors in epileptogenesis, and their modulation by neurosteroids, 
therapeutic drugs, and substances of abuse;

o  Ontogeny of airway and lung adrenergic receptors;

o  Ontogeny of ion channels.  Characterization of how the pharmacology of 
these ion channels changes during development;

o  Ontogeny  of polymorphic expression of DMEs and transporters exhibiting 
genetic polymorphisms;

o  Mechanisms of action of antiarrhythmic drugs in the immature heart; 
effects of these drugs on ion channels;

o  Role of ethnicity in the ontogeny of DMEs, transporters, and receptors;

o  Ontogeny of 5 HT, dopamine, GABA , and other receptors, and their 
pharmacological significance in different tissues;

o  Ontogeny of opioid receptors and their pharmacological significance;

o  Ontogeny of brain NMDA receptors/ion channel complex and pharmacological 
prevention of hypoxic damage;

o  Pharmacokinetic-pharmacodynamic models assessing the sensitivity of the 
CNS, and other organs, to therapeutic drugs and drugs of abuse;

o  Effects of hypoxia-ischemia, cold exposure, seizures, and other transient 
pathophysiologic stresses on the developmental ontogeny of receptors, 
transporters, and signal transduction systems in specific brain regions 
during infancy and childhood;

o  Defining the critical period of neuromodulation by endogenous hormonal 
influences such as CRF, FSH, and LH on the excitability of neural systems of 
the neonatal brain. 

The use of appropriate and newer techniques for the study of ontogeny from a 
pharmacological perspective is encouraged (e.g., knockout animals and drug 
applications in vivo, gene expression over time in living animals).  An 
overriding consideration in the proposed research must be the appropriateness 
of testing models and extrapolation to humans of animal data.

SPECIAL REQUIREMENTS

Applications that propose descriptive studies and do not contain hypothesis-
driven studies directed at understanding the ontogeny of DMEs, transporters, 
and receptors of pharmacologic significance in pediatrics will not be 
considered responsive to the RFA.  The principal focus of applications should 
be pre-clinical studies of developmental pharmacology in the areas described 
above.  Multidisciplinary investigations bringing together investigators with 
expertise in pharmacology, developmental biology, and genetics are strongly 
encouraged.  Development of methodologies to enhance the study of the 
research areas covered by this RFA is strongly encouraged.  Clinical studies 
are not within the scope of this RFA.

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of the NIH that women and members of minority groups and 
their subpopulations must be included in all NIH-supported biomedical and 
behavioral research projects involving human subjects, unless a clear and 
compelling rationale and justification are provided 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 research involving human subjects should follow 
the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in 
Clinical Research," published in the Federal Register of March 28, 1994  (FR 
59 14508-14513) and in the NIH Guide for Grants and Contracts, Vol. 23, No. 
11, March 18, 1994, available on the web at:
http://grants.nih.gov/grants/guide/notice-files/not94-100.html.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of the NIH 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 was published in the NIH Guide for 
Grants and Contracts, March 6, 1998, and is available at:  
http://grants.nih.gov/grants/guide/notice-files/not98-024.html.

Investigators also may obtain copies of these policies from the program staff 
listed under INQUIRIES.  Program staff may also provide additional relevant 
information concerning the policy.

LETTER OF INTENT

Prospective applicants are asked to submit a letter of intent that includes a 
descriptive title of the proposed research, the name, address, and telephone 
number of the Principal Investigator, the identities of other key personnel 
and participating institutions, and the 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 subsequent applications, the information that it 
contains allows NICHD staff to estimate the potential review workload and to 
avoid conflict of interest in the review.

The letter of intent is to be sent to Dr. George P. Giacoia at the address 
listed under INQUIRIES by March 7, 2000.

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 4/98) is to be used in 
applying for these grants, with the modifications noted below.  These forms 
are available at most institutional offices of sponsored research and from 
the Division of Extramural Outreach and Information Resources, National 
Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-
7910, telephone 301-435-0714, E-mail: GrantsInfo@nih.gov, and on the Internet 
at http://grants.nih.gov/grants/funding/phs398/phs398.html.

Application Instructions:  Collaborative R01

Modular grant application procedures, described below, must be followed.  A 
separate application must be prepared by each participating 
institution/Principal Investigator.  It is crucial that all applications 
comprising the collaborative R01 group cite this RFA in section 2 on the 
application face page (see below).  Each participating application must be 
prepared with the same detail and thoroughness required of any R01 
application.  Each project must be capable of standing on its own 
scientifically and of being accomplished independently.

If there is a question about the appropriateness of a set of applications for 
a collaborative R01 group, applicants are encouraged to discuss the issues 
with one of the NIH staff contacts listed under INQUIRIES.

Application Instructions:  Modular Grants/Just-in-Time

The modular grant concept establishes specific modules in which direct costs 
may be requested as well as a maximum level for requested budgets.  Only 
limited budgetary information is required under this approach.  The 
just-in-time concept allows applicants to submit certain information only 
when there is a possibility for an award.  It is anticipated that these 
changes will reduce the administrative burden for the applicants, reviewers, 
and Institute staff.  The research grant application form PHS 398 (rev. 4/98) 
is to be used in applying for these grants, with the modifications noted 
below.

Modular grant applications will request direct costs in $25,000 modules, up 
to a total direct cost request of $250,000 per year.  The total direct costs 
must be requested in accordance with the program guidelines and the modifications 
made to the standard PHS 398 application instructions described below:

o  FACE PAGE:  Items 7a and 7b should be completed, indicating Direct Costs 
(in $25,000 increments up to a maximum of $250,000) and Total Costs [Modular 
Total Direct plus Facilities and Administrative  (F&A) costs] for the initial 
budget period.  Items 8a and 8b should be completed indicating the Direct and 
Total Costs for the entire proposed period of support.

o  DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD:  Do not complete Form Page 
4 of the PHS 398.  It is not required and will not be accepted with the 
application.

o  BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT:  Do not complete the 
categorical budget table on Form Page 5 of the PHS 398.  It is not required 
and will not be accepted with the application.

o  NARRATIVE BUDGET JUSTIFICATION:  Prepare a Modular Grant Budget Narrative 
page. (See http://grants.nih.gov/grants/funding/modular/modular.htm for 
sample pages.)  At the top of the page, enter the total direct costs 
requested for each year.  This is not a Form Page.

Under Personnel, list key project personnel, including their names, percent 
of effort, and roles on the project.  No individual salary information should 
be provided.  However, the applicant should use the NIH appropriation 
language salary cap and the NIH policy for graduate student compensation in 
developing the budget request.

For Consortium/Contractual costs, provide an estimate of total costs (direct 
plus Facilities and Administrative) for each year, each rounded to the 
nearest $1,000.  List the individuals/organizations with whom consortium or 
contractual arrangements have been made, the percent effort of key personnel, 
and the role on the project.  Indicate whether the collaborating institution 
is foreign or domestic. The total cost for a consortium/contractual 
arrangement is included in the overall requested modular direct cost amount.  
Include the Letter of Intent to establish a consortium.

Provide an additional narrative budget justification for any variation in the 
number of modules requested.

o  BIOGRAPHICAL SKETCH:  The Biographical Sketch provides information used by  
reviewers in the assessment of each individual's qualifications for a 
specific role in the proposed project, as well as to evaluate the overall 
qualifications of the research team.  A biographical sketch is required for 
all key personnel, following the instructions below.  No more than three 
pages may be used for each person.  A sample biographical sketch may be 
	viewed at:  http://grants.nih.gov/grants/funding/modular/modular.htm.

- Complete the educational block at the top of the form page;
- List position(s) and any honors;
- Provide information, including overall goals and responsibilities, on 
research projects ongoing or completed during the last three years.
- List selected peer-reviewed publications, with full citations.

o  CHECKLIST:  This page should be completed and submitted with the 
application.  If the F&A rate agreement has been established, indicate the 
type of agreement and the date.  All appropriate exclusions must be applied 
in the calculation of the F&A costs for the initial budget period and all 
future budget years.

o  The applicant should provide the name and telephone number of the 
individual to contact concerning fiscal and administrative issues if 
additional information is necessary following the initial review. 

The RFA label found in the PHS 398 (rev. 4/98) application form must be 
attached to the bottom of the face page of the application and must display 
the number of this RFA (HD-00-001).  A sample RFA label is available at 
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf.   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 (Developmental Pharmacology) and number (HD-00-001) must be typed on 
line 2 of the face page of the application form, and the YES box must be 
marked.

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 should be 
sent to:

Director
Division of Scientific Review
National Institute of Child Health and Human Development 
6100 Executive Blvd., Room 5E03, MSC 7510
Bethesda, MD  29892-7510
Rockville, MD  20852 (for express/courier service)

Applications must be received by April 13, 2000.  If the 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.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by CSR and 
responsiveness by NICHD, NIDA, and NINDS.  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, a process will be used by the initial 
review group in which applications receive a written critique and undergo a 
process in which only those applications deemed to have the highest 
scientific merit will be discussed, assigned a priority score, and receive a 
second level review by the National Advisory Council of NICHD, NIDA or NINDS.
 
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 the application in order to judge the likelihood that the proposed 
research will have a substantial impact on the pursuit of these goals.  Each 
of these criteria will be addressed and considered in assigning the overall 
score, weighting them as appropriate for each application.  Note that the 
application does not need to be strong in all categories to be judged to have 
major scientific impact and thus deserve a high priority score.  For example, 
an investigator may propose to carry out important work that by its nature is 
not innovative, but is essential to move a field forward.

(1) Significance:  Does this study address an important problem?  If the aims 
of the application are achieved, how will scientific knowledge be advanced?  
What will be the effect of these studies on the concepts or methods that 
drive this field?

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

(3) Innovation:  Does the project employ novel concepts, approaches or 
methods?  Are the aims original and innovative?  Does the project challenge 
existing paradigms or develop new methodologies or technologies?

(4) 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 other researchers (if any)?

(5) Environment:  Does the scientific environment in which the 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?

In addition to the above criteria, applied to the evaluation of all research 
projects, applications proposing participation in a collaborative R01 group 
also will be evaluated with respect to the intended group interactions.  In 
an administrative note, the reviewers will indicate the effectiveness and 
feasibility of the proposed collaborative R01 group interactions, whether or 
not they enhance the prospects for reaching the stated objectives of the 
group, and the extent of the synergy among the various projects.  

The criteria for review of the shared resources requested for the 
collaborative R01 group, which are evaluated independently from the research 
project, are the following:

o  Qualifications of key personnel;

o  Adequacy of approaches, methods, and facilities;

o  Appropriateness for the collaborative group; 

o  Adequacy of procedures to ensure access to data, sharing of data and 
resources (both
within and outside a collaborative group), publication rights, and means of 
arbitrating and resolving publication disagreements among the participating 
investigators.

The reviewers also may make recommendations about the shared resource(s) and 
the reasonableness of the budget request.  These recommendations will be 
considered when funding decisions are made by the awarding institute.  The 
amount awarded for shared resources may depend on the number of component 
projects awarded.

In addition to the above criteria, in accordance with NIH policy, all 
applications also will be reviewed with respect to the following:

o  The adequacy of plans to include both genders, minorities and their 
subgroups, and children as appropriate for the scientific goals of the 
research.  Plans for the recruitment and retention of subjects also will be 
evaluated.

o  The reasonableness of the proposed budget and duration in relation to the 
proposed research.

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

Schedule

Letter of Intent Receipt Date:  March 7, 2000
Application Receipt Date:  April 13, 2000     
Date of Initial Review:  July 2000  
Review by Advisory Council:  September 2000
Earliest Anticipated Award Date:  September 2000 

AWARD CRITERIA
Award criteria that will be used to make award decisions include:
  
o  Scientific and technical merit (as determined by peer review)
o  Total costs of the proposed project and availability of funds
o  Program priorities and program balance
o  For collaborative R01 groups, the interactive nature of the program and 
component R01s.

INQUIRIES

Inquiries concerning this RFA are encouraged.  The opportunity to clarify any 
issues or questions from potential applicants is welcome.

Direct inquiries regarding programmatic 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
E-mail: gg65m@NIH.GOV

Rebekah Rasooly, Ph.D.
Division of Neurobiology and Behavioral Research
National Institute on Drug Abuse
6001 Executive Blvd., Room 4260, MSC 9555
Bethesda, MD 20892-9555
Telephone:  301-443-6300
E-mail:  RRASOOLY@ngmsmtp.nida.nih.gov

Philip H. Sheridan, M.D. 
Developmental Neurobiology
National Institute of Neurological Disorders and Stroke 
6001 Executive Boulevard, Room 2138, MSC 9527
Bethesda, Maryland 20892-9527
Telephone:  301-496-5821
Fax:  301-402-1501
E-mail:  ps59i@nih.gov

Direct inquiries regarding fiscal matters to:

Mary E. Daley
Grants Management Branch
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 5E03D, MSC 7510
Bethesda, MD  20892-7510
Telephone:  301-496-1305
Fax:  301-402-0915
E-mail:  md74u@nih.gov

Gary Fleming, J.D., M.A.
Grants Management Branch
National Institute on Drug Abuse
6001 Executive Boulevard
Rockville, MD 20892-9537
Telephone:  301-443-6710
Fax:  301-594-6847
E-mail:  gf6s@nih.gov

King P. Bond, Jr.
Grants Management Branch
National Institute of Neurological Disorders and Stroke
6001 Executive Boulevard, Room 3254, MSC 9537
Bethesda, MD 20892-9537
Telephone:  301-496-9231
Fax:  301-402-0219
E-mail:  kb33s@nih.gov

Although they are not participants in this RFA, the National Institute of 
Environmental Health Sciences (NIEHS) and the National Heart, Lung and Blood 
Institute (NHLBI) maintain an interest in this area of research and should be 
contacted directly for information about their programs.

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance, Nos. 
93.865 (NICHD), 93.853 (NINDS), and 93.279 (NIDA).  Awards are made under 
authorization of the Public Health Service Act, Title IV, Part A (Public Law 
78-410, as amended by Public Law 99-158, 42 USC 241 and 285) and administered 
under NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 
74 and 92.  This program is not subject to the intergovernmental review 
requirements of Executive Order 12372 or a Health Systems Agency Review.

The PHS strongly encourages all grant recipients to provide a smoke-free 
workplace and promote the non-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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