REDUCING PRETERM & LOW BIRTH WEIGHT IN MINORITY FAMILIES

RELEASE DATE:  December 1, 2003

PA NUMBER:  PA-04-027

March 2, 2006 (NOT-OD-06-046) – Effective with the June 1, 2006 submission date, 
all R03, R21, R33 and R34 applications must be submitted through Grants.gov using 
the electronic SF424 (R&R) application. This announcement will stay active for 
only the May 1, 2006 AIDS and AIDS-related application submission date for these 
mechanisms. The non-AIDS portion of this funding opportunity for these mechanisms 
expires on the date indicated below. Other mechanisms relating to this announcement 
will continue to be accepted using paper PHS 398 applications until the stated 
expiration date below, or transition to electronic application submission. Parent 
R03 (PA-06-180) and R21 (PA-06-181) funding opportunity announcements have been 
issued for the submission date of June 1, 2006 and submission dates for AIDS and 
non-AIDS applications thereafter. Applications relating to R33 and R34 activities 
must be in response to NIH Institute/Center (IC)-specific announcements.

EXPIRATION DATE for R21 Non-AIDS Applications: March 2, 2006
EXPIRATION DATE for R21 AIDS and AIDS-Related Applications: May 2, 2006 
EXPIRATION DATE for All R01 Applications: December 5, 2006, unless reissued.

Department of Health and Human Services (DHHS)

PARTICIPATING ORGANIZATION:  
National Institutes of Health (NIH) 
 (http://www.nih.gov)

COMPONENTS OF PARTICIPATING ORGANIZATION:
National Institute of Nursing Research (NINR) 
 (http://www.ninr.nih.gov)
National Institute of Child Health and Human Development (NICHD) 
 (http://www.nichd.nih.gov)
National Institute of Dental and Craniofacial Research (NIDCR) 
 (http://www.nidcr.nih.gov)

CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER(S):

No. 93.361, Nursing Research
No. 93.865, Center for Research for Mothers and Children
No. 93.121, Oral Diseases and Disorders Research

THIS PA CONTAINS THE FOLLOWING INFORMATION

o Purpose of the PA
o Research Objectives
o Mechanism(s) of Support 
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Where to Send Inquiries
o Submitting an Application
o Supplementary Instructions
o Peer Review Process
o Review Criteria
o Award Criteria
o Required Federal Citations

PURPOSE OF THIS PA  

The National Institute of Nursing Research (NINR), National Institute of Child 
Health and Human Development (NICHD), and the National Institute of Dental and 
Craniofacial Research (NIDCR) invite applications to encourage collaborative 
multidisciplinary biobehavioral research that can elucidate the mechanisms 
underlying disparities in pregnancy outcomes as well as interventions to 
reduce such disparities. The disparity in pregnancy outcomes among minorities 
is largely due to preterm delivery (PTD) and low birth weight (LBW), which 
disproportionately affect these populations. While these problems occur across 
populations, and there are most likely commonalities among all groups, their 
greater incidence among minorities makes research with these groups 
particularly important. This program announcement solicits research to expand 
our understanding of the underlying mechanisms that contribute to the racial 
and ethnic variations in PTD and LBW and strategies for prevention. The goals 
of this program announcement are: (1) to develop innovative strategies to 
prevent PTD and LBW in minority populations; and, (2) to expand our 
understanding of how psychosocial and environmental factors affect or interact 
with the biologic mechanisms that influence pregnancy outcomes. This 
solicitation strongly encourages multidisciplinary biobehavioral approaches, 
defined as studies proposed by teams of scientists with the requisite 
expertise from diverse disciplines (e.g., nursing, medicine, social, 
behavioral, biological, health sciences, epidemiology) that reflect an 
integrated framework of social and biologic phenomena.  

RESEARCH OBJECTIVES

Background

Preterm delivery or short gestation (birth occurring before 37 weeks of 
pregnancy), low birth weight (less than 2,500 grams) and very low birth weight 
(VLBW; less than 1,500 grams), consequences of which can be profound, continue 
to be major public health concerns. Despite tremendous advances in medicine 
and a growing body of research on explanatory risk factors for adverse 
pregnancy outcomes, the gap between whites and nonwhites in pregnancy outcomes 
has widened. Black infants are more than twice as likely to die as White 
infants. For example, low birth weight and very low birth weight percent of 
live births are 13.1 and 3.1 percent, respectively, for Blacks or African 
Americans, compared to 6.5 and 1.1 percent, respectively, for Whites (Healthly 
People, 2010). Similarly, rates for American Indians and Alaska natives are 
approximately 50% higher than rates for White women. Rates for Hispanic women 
approximate or are slightly higher than rates for White women except for 
Puerto Ricans whose rates are 50% higher than Whites (Healthy People, 2010).  

Similarly, with respect to maternal mortality, Black mothers are three times 
more likely to die than White mothers. In a recent study on pregnancy related 
mortality from pre-eclampsia and eclampsia, it was reported that Black women 
were 3.1 times more likely to die from pre-eclampsia or eclampsia than White 
women. Women who had received no prenatal care had a higher risk of death from 
pre-eclampsia or eclampsia than women who had received any level of prenatal 
care. The overall pre-eclampsia/eclampsia case-fatality rate was 6.4 per 
10,000 cases at delivery, and the rate was twice as high for Black women as 
for White women.

It is well known that much of the disparity of preterm delivery and low birth 
weight is associated with racial and ethnic groups living under the burden of 
sub-optimal social, economic and health conditions. However, poverty, race 
and ethnicity are not the only contributing factors and, in and of 
themselves, do not explain the disparities in pregnancy outcomes between 
Whites and non-Whites. Hypotheses centering on prenatal care, health 
behaviors, teen births, poverty, education and genetics have not sufficiently 
explained the causes of PTD and LBW, nor the disparities in outcomes. The 
complexity of the issue is evidenced by the known variation within racial and 
ethnic groups. There may be a simple difference in "dose" of the experience 
or exposure to certain risk factors that leads to the poor outcome or it may 
be that a combination of common and uncommon experiences in one individual 
culminates in a poor outcome. There may also be an intergenerational effect 
of these experiences and associated risks factors and fetal exposures to 
these factors may trigger this risk in the next generation. There is most 
probably a convergence of factors but these hypotheses need to be tested.

Increasingly, social stress has become the focus of much research and, at the 
same time, it has become apparent that it is important to understand the 
context, especially the neighborhood context, in which women at risk for poor 
pregnancy outcomes live their lives. Maternal psychosocial stress, including 
the stress of infection, and racially based discrimination, can be linked to 
biological mechanisms that are associated with PTD. Maternal stress may 
affect PTD via neuroendocrine, immune/inflammatory and vascular pathways. 
Stress appears to decrease immunity thereby leaving the host susceptible to 
infection. Stress-induced changes may be caused, at least in part, via 
physiological mechanisms involving the autonomic nervous system and the 
hypothalamic-pituitary-adrenal (HPA) axis. If the stress activation is 
chronic it can then result in allostatic load or the inability to achieve 
stability in the face of stress. Elements of “weathering” such as poverty, 
racism and family functioning can lead to vulnerability prior to conception 
via alterations in HPA reactivity and degradation of the immune response and 
to risk factors for PTD such as elevations in corticotrophin-releasing 
hormone (CRH), hypertension, pre-eclampsia, and inflammatory responses that 
are associated with PTD/LBW.  Clearly more research is needed on PTD and LBW 
as the outcomes of chronic exposure to stressors prior to pregnancy. Stresses 
in the environment vary by ethnic background and the degree of acculturation. 
Potential buffers like hardiness, resilience and social support systems may 
mitigate some of the effects of stress. In order to develop effective 
interventions the mutability of risk factors needs to be understood. 
Interventions such as increased social support and other means of increasing 
the resistance of the host to the insult are important and may require 
collaboration with basic scientists to understand what is immutable. 
Additionally, when measuring stress, it is necessary to differentiate between 
stressors and stress responses.

Another area of maternal-fetal interaction receiving much attention is 
inflammation. One hypothesis is that immune hyper-responsiveness in pregnancy 
can lead to inflammation and contribute to adverse pregnancy outcomes. In the 
presence of a hyper-inflammatory response the mother may avoid death via 
sepsis by delivering the baby early. There may be a genetic susceptibility to 
maternal hyper-responsiveness carried by the mother. Additionally, women with 
Syndrome X (also termed "metabolic syndrome" and defined as a clustering of 
heart disease risk factors in some people including central obesity, glucose 
intolerance, hyperlipidemia and high blood pressure), molar pregnancy or HIV 
positive women not taking anti-viral medications may be more at risk for pre-
eclampsia. It is interesting to note that in perinatal and neonatal mortality 
cases there is a higher rate of infection seen among minority populations. 
Infection appears to trigger premature rupture of membrane and morbidity, 
however, PTD may occur at various levels of bacterial burden and may be 
influenced by cytokine polymorphisms. Infection is only part of the problem, 
however, and requires further study as evidenced by the finding that when 
placentas are examined post delivery, a relatively high proportion of the 
cases have pathologies that are vascular in origin, not the result of 
infections. 

PTD and LBW contribute substantially to both infant mortality and to childhood 
physical impairment.  Recent evidence suggests that these impairments persist 
well into adulthood.  Although infant mortality in the United States has 
declined steadily over the past several decades and is at a record low of 7.2 
per 1,000 live births, the United States still ranks 25th in infant mortality 
compared with other industrialized nations, largely due to its high PTD and 
LBW rates. The strong association between LBW and preterm delivery places LBW 
children at risk for neurosensory, developmental, physical, and psychological 
problems. Cerebral palsy is a major neurologic abnormality in LBW occurring 
much more commonly in LBW infants than their normal weight peers.  
Additionally, LBW children are at risk for lower scores on intelligence tests 
and developmental delay. As a group, LBW children experience more health 
problems, such as asthma, upper and lower respiratory infections and ear 
infections. A decade ago, the costs associated with LBW were estimated at more 
than $5.4 billion, with 75% of these costs due to infant care. Approximately 
10% of annual health care expenditures for children result from LBW-related 
problems.  As the rate of low birth weight rate increases among minority 
families, associated costs will increase as well. 

Although the exact causes of PTD and LBW are not known, associations with 
modifiable causes have been demonstrated in the literature but the underlying 
biologic mechanisms are poorly understood. These include genital tract and 
oral microbial infections and inflammation, poverty, social support, stress 
and its correlates, housing (i.e., physical environment such as lead paint, 
safety, crowding, pollution), community resources, toxic habits including 
smoking, alcohol use during pregnancy and risky behaviors and exposure to 
violence. To date, interventions directed toward these risk factors have not 
been effective in reducing disparities associated with PTD and LBW. More 
research is needed on health behaviors including smoking, nutrition, eating 
patterns and exercise. Some women report that smoking helps reduce stress but 
smoking exposes them to cadmium and benzopyrene, which can have toxic 
effects. Similarly, the effects of fasting on CRH levels are not known and 
further research is needed on the role of micronutrients and vitamins.  
Minority women are more likely to have high fat, low protein diets and little 
exercise. They may have less social support, including childcare, to enable 
them to take time from parenting to exercise. A group oriented, community 
supported form of exercise might be a solution. Women of color are more 
likely to experience unwanted pregnancies that lead to not taking proper care 
of their health. As such, there is still much to be gleaned from studies 
investigating the impact of behavioral influences on maternal health as it 
relates to disparities in pregnancy outcomes. 

Finally, the impact of cultural beliefs and practices on disparities in 
pregnancy outcome is poorly understood. Although information on the nature of 
these practices exists, knowledge of the mechanisms of action on pregnancy 
outcome is sparse.

Disentangling the underlying psychosocial and biologic mechanisms responsible 
for racial and ethnic variations in LBW and preterm delivery and eliminating 
or significantly reducing this variation is an ongoing challenge to research 
in this area. While race and ethnicity are clearly implicated, caution has 
been urged in defining and using race as a variable, rather than as a 
process. There may be a case for a relationship between health outcomes and 
genes with no strong evidence to link the outcome to race. A unifying 
paradigm to study minority women at risk of PTD or LBW takes into account the 
environment, socio-cultural experiences or exposures, lifestyle, maternal-
fetal interactions, physiologic responses and “weathering.”

Research Scope

The National Institute of Nursing Research (NINR), National Institutes of 
Health (NIH), convened the workgroup “Optimizing Pregnancy Outcomes in 
Minority Populations” on March 3-4, 2003 in Bethesda, Maryland. This 
workgroup brought together researchers in the fields of nursing, 
epidemiology, psychology, and clinical and basic sciences in a collaborative, 
multi-disciplinary approach to address this issue and formulate future 
research strategies. In addition, each of 
the sponsors of this PA has a strategic plan, which addresses research 
related to minority health and health disparities. This is located on their 
websites. For purposes of this initiative, the definitions of health 
disparities and minority populations are those outlined in the NINR’s 
Strategic Plan on Reducing Health Disparities located at 
http://www.ninr.nih.gov. Health disparities are defined as differences in the 
incidence, prevalence, mortality, and burden of diseases and other adverse 
health conditions that exist among specific population groups in the US. 
Specific population groups are identified as African American, Asian and 
Asian Pacific Islander, Hispanic and Latino, American Indian and Alaska 
Native. These groups are the target populations for this announcement.

Clinical and basic research applications that address questions pertaining to 
the goals of this PA are appropriate. The following are offered as 
illustrations of topics that would be appropriate for this PA. Applications 
need not, however, be limited to these specific topics: 

o   Interventions targeting underlying health problems among minorities, e.g., 
anemia, hypertension, diabetes, infections and their relationship to 
disparities in birth outcomes.

o   Investigations to further identify specific stressors and associated 
mechanisms related to the “weathering” hypothesis (e.g., poverty, racism, 
family functioning), including quantifying “weathering” and its link to 
pregnancy outcomes.

o   Interventions targeting specific physiologic pathways and biochemical 
markers known to be associated with poor pregnancy outcomes, including serial 
measurements to ascertain critical time periods. 

o   Studies focused on the relationship of stressors and stress response, pre-
eclampsia, CRH, and cytokine polymorphisms in PTD and LBW.

o   Investigations representing collaborations among diverse disciplines (e.g., 
basic, clinical and social scientists) focused on delineating risk and 
protective factors and biological pathways utilizing interdisciplinary 
theoretical and methodological approaches (e.g., What risk factors for poor 
pregnancy outcomes are mutable? How are biologic phenomena impacted? What are 
the biologic markers of risk?)

o   Studies focused on acute and chronic stress, with special attention to 
measures of stressors and stress responses including the role of antecedent 
and concurrent environmental exposures as risk factors for pregnancy outcomes 
(e.g., Are there familial patterns or patterns of acquired risk? Are all 
stressors associated with some biologic phenomena? How are additive and 
interactive effects linked with PTD and LBW?)

o   Investigations to explore the relationship between metabolic syndrome and 
allostatic load, in response to the stress of internalized racism, and its 
impact on PTD and LBW.

o   Studies to identify biomarkers in the fetus, mother, cord, and placenta 
associated with disparities in pregnancy outcomes. 

o   Studies focused on gene/environment interactions (e.g., studies to isolate 
the genetic components of hardiness/resilience in subgroups within specific 
ethnic groups). 

o   Investigations to examine the role of nutrition and its impact on 
disparities in pregnancy outcomes (e.g., fasting and its impact on CRH levels; 
the role of micronutrients; the effects of culture on diet patterns and 
physical activity.)

o   Development and testing of interventions, including the effectiveness of 
social supports, home visitation, and other approaches that mediate adverse 
psychological, social, and environmental effects, and improve or prevent 
microbial infections and inflammation.

o   Interventions to test the impact of culturally competent preconception and 
prenatal care, access to care and linkages with public health and social 
services, on pregnancy outcomes. 

o   Investigation of the role of environmental and occupational factors (i.e., 
exposure to chemicals in the home and work environment, indoor and outdoor air 
pollution, contaminants in the food supply) on disparities in pregnancy 
outcomes.

o   Investigation into the diagnosis, mechanisms and treatment of intrauterine 
growth restriction.

o   Studies focused on new or novel methodologies, conceptual models, data 
analytic approaches, or the development and testing of culturally sensitive 
instruments to capture psychosocial and biologic influences resulting in 
disparities in PTD and LBW (e.g., lifestyle exposure, sociocultural factors, 
risk factors associated with “weathering,” data mining techniques). 

MECHANISMS OF SUPPORT 

This PA will use the NIH R01 and R21 award mechanisms.  As an applicant, you 
will be solely responsible for planning, directing, and executing the 
proposed project.  The objective of the R01 mechanism is to support a 
discrete, specified circumscribed project.  Investigators are encouraged to 
explore the feasibility of an innovative research question or approach that 
will provide a basis for future research projects. Exploratory/developmental 
grants (R21) are limited to 2 years of support with a combined budget for 
direct costs of up $275,000 for the two-year period.  For example, the 
applicant may request $100,000 in the first year and $175,000 in the second 
year.  The request should be tailored to the needs of the project. Normally, 
no more than $200,000 may be requested in any single year.  Please see the 
NIH-wide R21 program announcement (PA-03-107) (see 
http://grants.nih.gov/grants/guide/pa-files/PA-03-107.html). Please see the 
"Submitting an Application" section for more details. 

This PA uses just-in-time concepts.  It also uses the modular budgeting as 
well as the non-modular budgeting formats (see 
http://grants.nih.gov/grants/funding/modular/modular.htm).  Specifically, if 
you are submitting an application with direct costs in each year of $250,000 
or less, use the modular budget format.  Otherwise follow the instructions 
for non-modular budget research grant applications.  This program does not 
require cost sharing as defined in the current NIH Grants Policy Statement at 
http://grants.nih.gov/grants/policy/nihgps_2001/part_i_1.htm.    

ELIGIBLE INSTITUTIONS 

You may submit (an) application(s) if your institution has any of the 
following characteristics: 
   
o For-profit or non-profit organizations 
o Public or private institutions, such as universities, colleges, hospitals, 
and laboratories 
o Units of State and local governments
o Eligible agencies of the Federal government  
o Domestic or foreign institutions/organizations
o Faith-based or community-based organizations 

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 

Data and safety monitoring is required for all types of clinical trials. The 
establishment of data and safety monitoring boards (DSMBs) is required for 
clinical trials involving interventions that entail potential risk to the 
participants.
    
Starting with the October 1, 2003 receipt date, investigators submitting an 
NIH application seeking $500,000 or more in direct costs in any single year 
are expected to include a plan for data sharing or state why this is not 
possible. 

WHERE TO SEND INQUIRIES

We encourage your inquiries concerning this PA and welcome the opportunity to 
answer questions from potential applicants.  Inquiries may fall into two 
areas:  scientific/research and financial or grants management issues:

o Direct your questions about scientific/research issues to:

Yvonne Bryan, PhD
Program Director
National Institutes of Health   
Office of Extramural Programs
National Institute of Nursing Research
6701 Democracy Blvd, Room 710, MSC 4870
Bethesda, MD  20892-4870
Telephone:  (301) 594-6908
Fax:  (301) 480-8260
Email:  bryany@mail.nih.gov   

John V. Ilekis, PhD
Health Scientist Administrator
National Institutes of Health
National Institute of Child Health and Human Development
Center for Developmental Biology and Perinatal Medicine
Pregnancy and Perinatology Branch
6100 Executive Blvd, Room 4B03C, MCS 7510
Bethesda, MD 20892-7510 
Telephone:  301-435-6895
Fax:      301-496-3790
Email:   ilekisj@mail.nih.gov

Richard L. Mowery, Ph.D. 
Chief, Clinical, Epidemiology and Behavioral Research Branch 
Division of Population and Health Promotion Sciences 
National Institute of Dental and Craniofacial Research 
Building 45, Room 4AS-43F 
45 Center Drive, MSC 6401 
Bethesda, MD 20892-6401 
Telephone: (301) 594-4848 
Fax: (301) 480-8322 
Email: Richard.Mowery@nih.gov 

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

Lawrence Haller
Office of Grants and Contracts Management
NIH, National Institute of Nursing Research
6701 Democracy Blvd, Room 710, MSC 4870
Bethesda, MD  20892-4870
Telephone:  (301) 402-1878
FAX:  (301) 451-5652
Email:  HALLERL@mail.nih.gov

SUBMITTING AN APPLICATION

Applications must be prepared using the PHS 398 research grant application 
instructions and forms (rev. 5/2001). Applications must have a Dun and 
Bradstreet (D&B) Data Universal Numbering System (DUNS) number as the 
Universal Identifier when applying for Federal grants or cooperative 
agreements. The DUNS number can be obtained by calling (866) 705-5711 or 
through the web site at http://www.dunandbradstreet.com/  The DUNS number 
should be entered on line 11 of the face page of the PHS 398 form. The PHS 
398 is available at http://grants.nih.gov/grants/funding/phs398/phs398.html 
in an interactive format.  For further assistance contact Grants Info, 
Telephone (301) 435-0714, Email: GrantsInfo@nih.gov.

The title and number of this PA must be typed on line 2 of the application 
form and the YES box must be checked.

SUPPLEMENTARY INSTRUCTIONS 

When submitting an R21 application, all instructions for the PHS 398 (rev. 
5/2001) must be followed, with these exceptions:

o Research Plan

Items a - d of the Research Plan (Specific Aims, Background and Significance, 
Preliminary Studies, and Research Design and Methods) may not exceed a total 
of 15 pages.  No preliminary data is required but may be included if it is 
available.  Please note that a Progress Report is not needed; competing 
continuation applications for an exploratory/developmental grant will not be 
accepted.  

Appendix. Use the instructions for the appendix detailed in the PHS 398 
except that no more than 5 manuscripts, previously accepted for publication, 
may be included.

APPLICATION RECEIPT DATES: Applications submitted in response to this program 
announcement will be accepted at the standard application deadlines, which 
are available at http://grants.nih.gov/grants/dates.htm.  Application 
deadlines are also indicated in the PHS 398 application kit.

SPECIFIC INSTRUCTIONS FOR MODULAR BUDGET GRANT APPLICATIONS:  Applications 
requesting up to $250,000 per year in direct costs must be submitted in a 
modular budget grant format.  The modular budget grant format simplifies the 
preparation of the budget in these applications by limiting the level of 
budgetary detail.  Applicants request direct costs in $25,000 modules.  
Section C of the research grant application instructions for the PHS 398 
(rev. 5/2001) at http://grants.nih.gov/grants/funding/phs398/phs398.html 
includes step-by-step guidance for preparing modular grants.  Additional 
information on modular grants is available at 
http://grants.nih.gov/grants/funding/modular/modular.htm.

SPECIFIC INSTRUCTIONS FOR APPLICATIONS REQUESTING $500,000 OR MORE PER YEAR: 
Applications requesting $500,000 or more in direct costs for any year must 
include a cover letter identifying the NIH staff member within one of NIH 
institutes or centers who has agreed to accept assignment of the application.   

Applicants requesting more than $500,000 must carry out the following steps:
1) Contact the IC program staff at least 6 weeks before submitting the 
application, i.e., as you are developing plans for the study; 

2) Obtain agreement from the IC staff that the IC will accept your         
application for consideration for award; and,
  
3) Identify, in a cover letter sent with the application, the staff member       
and IC who agreed to accept assignment of the application.  

This policy applies to all investigator-initiated new (type 1), competing 
continuation (type 2), competing supplement, or any amended or revised 
version of these grant application types. Additional information on this 
policy is available in the NIH Guide for Grants and Contracts, October 19, 
2001 at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-004.html. 

SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of 
the application, including the checklist, and five 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)

APPLICATION PROCESSING: Applications must be mailed on or before the receipt 
dates described at 
http://grants.nih.gov/grants/funding/submissionschedule.htm.  The CSR will 
not accept any application in response to this PA 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 a substantial revision of an unfunded version of an application 
already reviewed, but such application must include an Introduction 
addressing the previous critique.  

Although there is no immediate acknowledgement of the receipt of an 
application, applicants are generally notified of the review and funding 
assignment within 8 weeks.

PEER REVIEW PROCESS

Applications submitted for this PA will be assigned on the basis of 
established PHS referral guidelines.   Appropriate scientific review groups 
convened in accordance with the standard NIH peer review procedures 
(http://www.csr.nih.gov/refrev.htm) will evaluate applications for scientific 
and technical merit.  

As part of the initial merit review, all applications will:

o Undergo a selection process in which only those applications deemed to have 
the highest scientific merit, generally the top half of applications under 
review, will be discussed and assigned a priority score
o Receive a written critique
o Receive a second level review by the appropriate national advisory council 
or board  

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 evaluate application in 
order to judge the likelihood that the proposed research will have a 
substantial impact on the pursuit of these goals.  The scientific review 
group will address and consider each of the following criteria in assigning 
the application’s overall score, weighting them as appropriate for each 
application.

o Significance 
o Approach 
o Innovation
o Investigator
o Environment
  
The 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, an investigator may propose to carry out important work 
that by its nature is not innovative but is essential to move a field 
forward.

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?

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?

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?

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)?

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?  

ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, the following 
items will be considered in the determination of scientific merit and the 
priority score:

The NIH R21 exploratory/developmental grant is a mechanism for supporting 
novel scientific ideas or new model systems, tools or technologies that have 
the potential to significantly advance our knowledge or the status of health- 
related research.  Because the research plan is limited to 15 pages, an 
exploratory/developmental grant application need not have extensive 
background material or preliminary information as one might normally expect 
in an R01 application.  Accordingly, reviewers will focus their evaluation on 
the conceptual framework, the level of innovation, and the potential to 
significantly advance our knowledge or understanding.  Reviewers will place 
less emphasis on methodological details and certain indicators traditionally 
used in evaluating the scientific merit of R01 applications including 
supportive preliminary data. Appropriate justification for the proposed work 
can be provided through literature citations, data from other sources, or, 
when available, from investigator-generated data.  Preliminary data are not 
required for R21 applications.    

PROTECTION OF HUMAN SUBJECTS FROM RESEARCH RISK: The involvement of human 
subjects and protections from research risk relating to their participation 
in the proposed research will be assessed. (See criteria included in the 
section on Federal Citations, below).
http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm

INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH: 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 will be assessed.  Plans for the recruitment and retention of 
subjects will also be evaluated. (See Inclusion Criteria in the sections on 
Federal Citations, below).

CARE AND USE OF VERTEBRATE ANIMALS IN RESEARCH: If vertebrate animals are to 
be used in the project, the five items described under Section f of the PHS 
398 research grant application instructions (rev. 5/2001) will be assessed.  

ADDITIONAL REVIEW CONSIDERATIONS 

Sharing Research Data 

Applicants requesting $500,000 or more in direct costs in any year of the 
proposed research are expected to include a data-sharing plan in their 
application. The reasonableness of the data-sharing plan or the rationale for 
not sharing research data will be assessed by the reviewers. However, 
reviewers will not factor the proposed data-sharing plan into the 
determination of scientific merit or priority score. The Final NIH Statement 
on Sharing Research data is found at 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-032.html
 
BUDGET:  The reasonableness of the proposed budget and the requested period 
of support in relation to the proposed research.

AWARD CRITERIA

Applications submitted in response to a PA will compete for available funds 
with all other recommended applications.  The following will be considered in 
making funding decisions:  

o Scientific merit of the proposed project as determined by peer review
o Availability of funds 
o Relevance to program priorities

REQUIRED FEDERAL CITATIONS 

HUMAN SUBJECTS PROTECTION:  Federal regulations (45CFR46) require that 
applications and proposals involving human subjects must be evaluated with 
reference to the risks to the subjects, the adequacy of protection against 
these risks, the potential benefits of the research to the subjects and 
others, and the importance of the knowledge gained or to be gained.
http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm 

DATA AND SAFETY MONITORING PLAN: Data and safety monitoring is required for 
all types of clinical trials, including physiologic, toxicity, and dose-
finding studies (phase I); efficacy studies (phase II), efficacy, 
effectiveness and comparative trials (phase III). The establishment of data 
and safety monitoring boards (DSMBs) is required for multi-site clinical 
trials involving interventions that entail potential risk to the 
participants.  (NIH Policy for Data and Safety Monitoring, NIH Guide for 
Grants and Contracts, June 12, 1998: 
http://grants.nih.gov/grants/guide/notice-files/not98-084.html).  

SHARING RESEARCH DATA:  Starting with the October 1, 2003 receipt date, 
investigators submitting an NIH application seeking more than $500,000 or 
more in direct costs in any single year are expected to include a plan for 
data sharing or state why this is not possible. 
http://grants.nih.gov/grants/policy/data_sharing 
Investigators should seek guidance from their institutions, on issues related 
to institutional policies, local IRB rules, as well as local, state and 
Federal laws and regulations, including the Privacy Rule. Reviewers will 
consider the data sharing plan but will not factor the plan into the 
determination of the scientific merit or the priority score.

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 "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.

HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research 
on hESCs can be found at http://stemcells.nih.gov/index.asp and at  
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html.  Only 
research using hESC lines that are registered in the NIH Human Embryonic Stem 
Cell Registry will be eligible for Federal funding (see http://escr.nih.gov).   
It is the responsibility of the applicant to provide, in the project 
description and elsewhere in the application as appropriate, the official NIH 
identifier(s)for the hESC line(s)to be used in the proposed research.  
Applications that do not provide this information will be returned without 
review. 

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 PA 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.

STANDARDS FOR PRIVACY OF INDIVIDUALLY IDENTIFIABLE HEALTH INFORMATION:  The 
Department of Health and Human Services (DHHS) issued final modification to 
the “Standards for Privacy of Individually Identifiable Health Information”, 
the “Privacy Rule,” on August 14, 2002.  The Privacy Rule is a federal 
regulation under the Health Insurance Portability and Accountability Act 
(HIPAA) of 1996 that governs the protection of individually identifiable 
health information, and is administered and enforced by the DHHS Office for 
Civil Rights (OCR). Those who must comply with the Privacy Rule (classified 
under the Rule as “covered entities”) must do so by April 14, 2003  (with the 
exception of small health plans which have an extra year to comply).  

Decisions about applicability and implementation of the Privacy Rule reside 
with the researcher and his/her institution. The OCR website 
(http://www.hhs.gov/ocr/) provides information on the Privacy Rule, including 
a complete Regulation Text and a set of decision tools on “Am I a covered 
entity?”  Information on the impact of the HIPAA Privacy Rule on NIH 
processes involving the review, funding, and progress monitoring of grants, 
cooperative agreements, and research contracts can be found at 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html.

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 PA 
is related to one or more of the priority areas. Potential applicants may 
obtain a copy of "Healthy People 2010" at http://www.healthypeople.gov/.

AUTHORITY AND REGULATIONS: This program is described in the Catalog of 
Federal Domestic Assistance at http://www.cfda.gov/ and is not subject to the 
intergovernmental review requirements of Executive Order 12372 or Health 
Systems Agency review.  Awards are made under the authorization of Sections 
301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) 
and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. All 
awards are subject to the terms and conditions, cost principles, and other 
considerations described in the NIH Grants Policy Statement.  The NIH Grants 
Policy Statement can be found at 
http://grants.nih.gov/grants/policy/policy.htm 

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.

Weekly TOC for this Announcement
NIH Funding Opportunities and Notices

	Office of Extramural Research (OER)			National Institutes of Health (NIH) 9000 Rockville Pike Bethesda, Maryland 20892			Department of Health and Human Services (HHS)
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