OBSTETRIC-FETAL PHARMACOLOGY RESEARCH UNITS

RELEASE DATE:  July 29, 2003

RFA:  HD-03-017

Update: The following update relating to this announcement has been issued:

December 16, 2008 - This RFA has been reissued as (RFA-HD-09-002).

National Institute of Child Health and Human Development (NICHD) 
 (http://www.nichd.nih.gov/)

CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER(S):  93.865

LETTER OF INTENT RECEIPT DATE: October 24, 2003

APPLICATION RECEIPT DATE: November 24, 2003

THIS RFA CONTAINS THE FOLLOWING INFORMATION

o Purpose of this RFA
o Research Objectives
o Mechanism of Support
o Funds Available
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Special Requirements
o Where to Send Inquiries
o Letter of Intent
o Submitting an Application
o Peer Review Process
o Review Criteria
o Receipt and Review Schedule
o Award Criteria
o Required Federal Citations

PURPOSE OF THIS RFA

The National Institute of Child Health and Human Development (NICHD) invites 
cooperative agreement applications for the development of an Obstetric-Fetal 
Pharmacology Research Units (OPRU) Network to:  (1) serve as a resource for 
pharmacologic studies of drug disposition and effect during normal and 
abnormal pregnancies; (2) conduct single-site and multi-site cooperative 
clinical trials; (3) conduct pharmacogenetic studies on the effect of 
pregnancy on drug metabolizing enzymes, transporters and effectors; (4) 
perform studies of placental transfer of drugs; (5) conduct studies of fetal 
and maternal pharmacology; (6) facilitate the utilization of clinical 
materials for basic research studies; and (7) enhance the exchange of 
information between basic scientists and obstetricians and among various 
specialists involved in treating pregnant women.  The OPRUs will also serve 
as a resource for the training of health professionals in obstetric-fetal 
pharmacology and drug trials in pregnant women.

RESEARCH OBJECTIVES

Background

The study of drugs used during pregnancy is one of the most neglected areas 
in the field of clinical pharmacology and drug research.  The data available 
on drug biodisposition and effect are scarce, fragmentary and frequently 
contradictory.  The lack of Food and Drug Administration obstetric labeling 
and the universal off-label use of drugs are the direct result of the lack of 
research and clinical trials of drugs in this special population. 

Epidemiological surveys have determined that nearly two thirds of all 
pregnant women take at least four or five drugs during pregnancy and labor. 
These data demonstrate that drug use during pregnancy is of public concern 
because it is primarily based on an empiric approach rather than a scientific 
basis and does not take into account the profound physiologic changes 
characteristic of pregnancy.  These changes involve the mother, placenta and 
the fetus and may lead to variations in the absorption, distribution and 
elimination of drugs. 

A number of factors influence the pharmacokinetics (Pk) of drugs in 
pregnancy.  For example, both the gastric emptying time and intestinal 
transit time are increased during pregnancy and could affect the 
gastrointestinal absorption of drugs.  There is a dearth of bioavailability 
studies in pregnancy.  

The increase in cardiac output, plasma volume and extracellular water may 
profoundly affect the distribution of many drugs during pregnancy. 
Hypoalbuminemia, especially in the third trimester, is associated with a 
decrease in drug-binding capacity.  The total (bound and free) drug 
concentration for a number of drugs is decreased (e.g., phenytoin) compared 
to the non-pregnant state.

Drug elimination, by either metabolic inactivation or excretion, may also be 
altered by the pregnant state.  Pregnancy has a dramatic effect on the plasma 
concentrations of sex hormones that are known to alter drug-metabolizing 
enzymes.  These effects of the pregnant state on the biodisposition of drugs 
are superimposed on the changes associated with the female gender. 

Renal function is significantly altered by pregnancy.  The glomerular 
filtration rate and renal plasma flow increase from the sixth week of 
pregnancy.  As a consequence of these physiologic changes, there is an 
increase in the renal excretion of some drugs such as beta-lactam antibiotics 
and lithium.

The increase in glomerular filtration observed during pregnancy is 
counterbalanced to a significant degree by modifications in tubular 
reabsorptive capacity.  The effect of diurnal variations in renal function 
and their effect in drug elimination have not been sufficiently 
characterized.

The physiologic changes during normal gestation can be substantially modified 
by the pathophysiologic processes associated with various conditions and 
disease states.  Therefore, information accrued on the disposition and 
effects of drugs in normal pregnancy cannot be extrapolated to abnormal 
pregnancies.  There is a dearth of information on the effects of the 
pathologic abnormalities associated with the disposition and action of drugs 
in abnormal pregnancies. 

Research Objectives and Scope

A major goal of this program is to identify, characterize and study those 
drugs that are of therapeutic value during pregnancy and whose clinical  
pharmacology (both pharmacokinetics and pharmacodynamics) is altered by the 
pregnant state in normal or abnormal pregnancies.

The development of studies of drugs in pregnancy is expected to follow 
sequential phases:

Phase I:  Population pharmacokinetic studies will be used as a screening tool 
to determine candidate drugs requiring intensive pharmacokinetic (Pk) 
studies. 

Phase II:  Intensive pharmacokinetic, pharmacodynamic (Pd) and Pk-Pd 
correlations, as well as bioavailability studies, will be performed for drugs 
selected in Phase I.  Drugs that are chronically administered during 
pregnancy will be studied serially during the second and third trimester and 
puerperium.  Bioavailability studies will be performed as part of the overall 
pharmacologic evaluation.

Phase III:  For those drugs that exhibit clinically significant changes in 
pharmacokinetics during pregnancy, a determination will be made as to the 
need to make dose adjustments and to test modified dosing regimens in 
subsequent clinical trials.

Alterations in drug sensitivity during pregnancy, demonstrated by Pk-Pd 
correlation studies, may be elucidated by mechanistic studies of 
transporters, receptors or signaling pathways performed within the basic 
component of the OPRUs.

In addition to the above studies specific areas of interest include:

o Influence of the pregnancy on the expression and function of drug 
metabolizing enzymes, transport systems, receptors and signaling pathways.

o Use of in vitro and animal models to study placental drug transfer and 
fetal disposition of maternally administered drugs.

o Use of physiologic-based pharmacokinetic models and simulation technology 
for drug studies during pregnancy.

o Identification and development of biomarkers of efficacy and/or toxicity 
applicable during pregnancy.

o Performance of phenotypic-genotypic correlation studies to characterize and 
determine the clinical significance of changes in activity of DMEs and 
effectors during pregnancy and/or their polymorphic expression.

o Studies of the relationship between the natural history of chronic diseases 
during pregnancy and drug efficacy and safety.

o Studies of the influence of diseases or conditions complicating pregnancy 
(e.g., toxemia of pregnancy, cholestasis, gestational diabetes, hypertension, 
etc.) on the biodisposition and efficacy of drugs.

o Studies of the effect of intrauterine exposure to drugs on fetal organ 
development and function.

o Studies of genome and proteome changes associated with pregnancy and of 
pharmacogenomics and pharmacoproteomics during pregnancy.

Collaboration of OPRUs with industry in the performance of pharmacologic 
studies, clinical trials and adjunct basic mechanistic studies is encouraged. 
Also strongly encouraged is collaboration of OPRUs with other NIH and non-NIH 
Networks (e.g., NICHD's Maternal Fetal Medicine, Neonatal, and Pediatric 
Pharmacology Research Unit networks; other NIH disease-specific networks; and 
the DHHS Centers of Excellence in Women's Health pharmacokinetic units).  It 
is expected that the pharmacologic data gathered by the OPRUs will form the 
basis for the design of drug efficacy trials to be performed at the OPRUs, in 
cooperation with other Networks or exclusively in other Networks.  To 
accelerate the acquisition of knowledge, interaction and collaboration with 
other investigators involved in ongoing basic and translational research, 
studies that complement or expand knowledge in specific areas of obstetric-
fetal pharmacology are strongly encouraged.  

Each OPRU will include:  

(1) A pharmacologic component to conduct pharmacokinetic (Pk), 
pharmacodynamic (Pd) and Pk-Pd correlations to identify differences in drug 
biodisposition, effect and/or toxicity profiles of specific drug groups given 
during pregnancy compared to the non-pregnant state.  The pharmacologic 
component will also be involved in Phase I and Phase II studies of new 
molecular entities (NMEs) specifically designed to treat pregnancy conditions 
or diseases. 

(2) A clinical trials component to test the efficacy of drugs whose 
pharmacologic profile was found to differ during pregnancy.  Efficacy of new 
NMEs will also be studied by this component. 

(3) A multidisciplinary, interactive basic and/or pre-clinical research 
component to elucidate basic mechanisms for differences in biodisposition of 
drug response during normal and abnormal pregnancies. 

MECHANISM OF SUPPORT

This RFA will use the NIH Cooperative Clinical Research (U10) award 
mechanism.  As an applicant you will be solely responsible for planning, 
directing, and executing the proposed project.  The anticipated award date is 
July 01, 2004.  

The NIH U10 is a cooperative agreement award mechanism in which the Principal 
Investigator retains the primary responsibility and dominant role for 
planning, directing, and executing the proposed project, with NIH staff being 
substantially involved as a partner with the Principal Investigator, as 
described under the section "Cooperative Agreement Terms and Conditions of 
Award."  

FUNDS AVAILABLE

The NICHD intends to commit approximately $2.5 million in total costs [Direct 
plus Facilities and Administrative (F & A) costs] in FY 2004 to support two 
to four new and/or competing continuation 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 $500,000 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. The Office of 
Research on Women's Health (ORWH)(http://www4.od.nih.gov/orwh/)  has 
expressed interest in the potential co-funding of applications that focus on 
the improvement of the health of women through biomedical and behavioral 
research. 

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 Domestic  

Foreign institutions are not eligible to apply.

INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS

Any individual with the skills, knowledge, and resources necessary to carry 
out the proposed research is invited to work with his/her institution to 
develop an application for support.  Individuals from underrepresented racial 
and ethnic groups as well as individuals with disabilities are always 
encouraged to apply for NIH programs.   

The PI of the clinical component would ideally be an obstetrician with 
extensive training in clinical pharmacology and experience in clinical 
trials.  It is recognized that availability of individuals trained in both 
disciplines is limited.  To satisfy the requirements of this RFA, the NICHD 
will allow, if well justified, the designation of an obstetrician with 
experience in clinical trials as the PI of the OPRU and a physician, 
Pharm.D., or Ph.D. in pharmacology as the Co-Investigator responsible for the 
design, performance and analysis of the pharmacologic studies.  It is 
expected that the investigator in charge of the pharmacology component will 
use diverse Pk-Pd modeling that relates mechanisms of drug action to 
physiologic processes.  Evidence must be provided of the applicant's 
expertise in pharmacokinetics, pharmacodynamics, drug metabolism and drug 
bioavailability studies.

SPECIAL REQUIREMENTS

OPRU Network Organization

a. Network Steering Committee (NSC) 

The NSC will be the main governing committee and the committee through which 
the NIH interacts and collaborates with the project.  The NSC will consist of 
the Principal Investigators, the NICHD Program Scientists, a non-voting FDA 
representative and a non-voting independent chairperson appointed by the 
NICHD.  

b. Advisory Board

This board, appointed by NICHD, will consist of scientists who will advise 
the NSC.

c. Data, Safety and Quality Monitoring Board

The NICHD will appoint an independent Data, Safety and Quality Monitoring 
Board.

Meetings

The Network Steering Committee will meet at least four times a year in the 
Washington D.C. area.  In addition, PIs will communicate monthly by formal 
conference calls.  Travel funds for these meetings should be included in the 
budget of the individual Center applications.

Components of an OPRU 

A. Principal Investigator, basic/pre-clinical research co-investigator and 
other investigators

The Principal Investigator is the person responsible for the overall 
management of the clinical pharmacology component including coordination of 
the participating specialists whether within a single institution or a 
consortium of institutions; design and submission of proposed protocols for 
pharmacologic studies; and implementation, monitoring and data submission and 
analysis of the clinical studies. 

The application must identify a basic/pre-clinical research co-investigator 
as the person responsible for coordinating the OPRU basic pre-clinical 
research scientists, whether within a single institution or a consortium of 
institutions, in development of adjunct basic/pre-clinical studies in 
cooperation with clinicians, conduct of the basic studies in conjunction with 
ongoing clinical trials/studies, and collaboration and sharing of basic 
resources and reagents within an OPRU and with other OPRUs.  

The application must list scientists who will be involved in the OPRU studies 
including medical subspecialists, geneticists, experimental pharmacologists, 
molecular and developmental biologists, developmental toxicologists, and 
maternal-fetal medicine specialists.  The application must detail the role of 
all co-investigators.

The collaboration of clinicians and/or basic scientists from different OPRUs 
is encouraged, based on shared interests and complementary talents.

Other investigators with obstetric privileges at the awardee institution will 
be eligible to utilize the resources for studies of drug efficacy, metabolism 
and/or effects in pregnant patients, supported by independent research funds, 
if the protocols have been approved and prioritized by the NSC.  These 
individual investigator protocols must not delay or interfere with the 
pursuit of the collaborative studies that are the OPRUs' primary 
responsibility.  At each funded OPRU site, priority will be given to studies 
within the OPRU.

B. Facilities 

Each OPRU must include a clinical pharmacology research component that 
encompasses participation by the multiple clinical specialists who have 
access to high-risk and general obstetric population.  The clinical component 
may represent a single institution or a consortium of institutions within a 
close geographical region.  Diseases amenable to clinical pharmacology 
intervention include, but are not limited to, asthma, hypertensive disorders, 
psychiatric illness, seizure disorders, diabetes, renal disease, autoimmune 
disorders, clotting disorders and other chronic high risk obstetrical 
conditions.

Specialists who could participate in the clinical component include, but are 
not limited to, obstetricians, maternal-fetal medicine specialists, 
neurologists, endocrinologists, psychiatrics, anesthesiologists, 
hematologists, gastroenterologists, and infectious diseases specialists.  The 
obstetrical unit must have at least 2,700 births per year currently in the 
unit, with a minimum of 30 percent high-risk pregnancies.

Clinical Facility

A designated physical site where the clinical pharmacology/clinical trials 
will be performed is required.  It is desirable that each OPRU have both 
inpatient and outpatient capabilities.  These could be provided by a 
metabolic ward and an outpatient clinic or a General Clinical Research Center 
(GCRC) that is suitable for admitting pregnant women or a unit similarly 
equipped for conducting clinical research.  For extended Pk studies, visiting 
nurses may be used.  A labor and delivery suite may be used occasionally for 
drug studies during labor and delivery.

Other institutional components related to the OPRU must also be described.  
Established policies and procedures for conducting clinical research in these 
facilities, in both low-risk and complicated pregnancies, must be described.

C. Core Laboratory

A funded OPRU may include a core laboratory dedicated to perform specialized 
analysis (e.g., drug protein binding, radioreceptor assays, red cell drug 
partition studies, HPLS-MS drug assays).  This laboratory may also support 
basic and/or preclinical studies approved by the NSC. 

D. Basic and/or pre-clinical research capabilities  

The clinical component will be linked to an experimental pharmacology 
department or similar facility with a pharmacogenetic and pharmacogenomics 
laboratory and have easy access to animal facilities for experimental studies 
in obstetrics and fetal pharmacology.  The basic components of the 
application should identify the multi-disciplinary, interactive basic or 
preclinical team of researchers committed to perform studies on elucidation 
of different mechanisms of drug action during pregnancy compared to the non-
pregnant state, as well as studies of placental transport of xenobiotics and 
fetal pharmacology.  The team should be able to conduct fetal 
pharmacokinetics and toxicokinetics, and determination of fetal dose exposure 
and secondary pharmacologic and/or toxic drug effects on fetal organ 
development.

E. Nurse Coordinator 

A qualified nurse coordinator is one of the most important assets of an OPRU.  
The nurse coordinator reports to and takes direction from the PI. The nurse 
coordinator, in cooperation with the Adjunct Clinical Pharmacologist (see 
below), carries out as many parts of the research protocols as possible, 
dovetailing schedules for maximum efficiency and instructing and supervising 
the other nursing staff in those operations or procedures for which he or she 
is unavailable.  The nurse coordinator is a full-time position supported by 
the grant.
 
F. Patient Recruiter

A patient recruiter may be justified to insure the efficient recruitment of 
patients required in Network protocols.  This individual maintains a registry 
of potential study candidates, gathers recruitment information from different 
areas of the hospital, clinics and private offices to match potential study 
patients with specific protocols (up to 50 percent time and effort).
 
G. Adjunct Clinical Pharmacologist

This position applies to those applications in which the PI of the OPRU is 
both an obstetrician and a clinical pharmacologist.  An applicant may request 
support for salaries and fringe benefits for this position (maximum 50 
percent time and effort).  The Adjunct Clinical Pharmacologist may be a 
physician who is fully trained in obstetrics, may have completed subspecialty 
training, and wishes to gain experience in the conduct of obstetric or fetal 
pharmacology research under the guidance and supervision of the PI or some 
other appropriate person.  Alternatively, the adjunct clinical pharmacologist 
may be a non-physician holding the Pharm.D. degree or a Ph.D. in Pharmacology 
who has had special training in clinical pharmacology and wishes to obtain 
additional supervised clinical experience.  Support for the associate 
clinical pharmacologist from the OPRU is for research time and effort only, 
unless this person is a licensed physician who assists the PI in supervising 
patient care in the Unit.  A qualified individual may be supported for up to 
two years as an associate clinical pharmacologist at an OPRU.
 
H. Data Coordinator

Each OPRU application should include information about the data management 
system to be used in the Unit for collaborative studies being performed by 
the Network.  If justified by the expected volume of work, a data coordinator 
may be supported (up to 20 percent time and effort) by an OPRU grant.  This 
person will organize the data in preparation for transmission to a future 
OPRU Data Coordinating Center, to the NICHD and to other OPRUs when 
appropriate.  These functions are critical to the success of the Network.
 
I. Pharmacy

The availability of a pharmacy capable of supporting clinical research 
activities and experienced in the preparation of materials for randomized 
clinical trials should be documented.

Minimum Application Requirements

o The academic productivity of the investigators who will be involved in the 
clinical core must be documented.  Evidence of the ability of the PI to 
recruit patients for clinical studies must be provided.

o Principal Investigators of the basic and/or pre-clinical research 
components must be established researchers, preferably holding peer-reviewed 
grant and/or contract support, and must provide evidence of academic 
productivity. 

o The application must list facilities available for fetal and placental 
research and indicate whether primate animal facilities will be available for 
obstetric-pharmacology research activities.

o Evidence of participation in multi-center trials and/or collaborative 
efforts.

o Evidence of an established computerized perinatal data system.

o Letters of support and history of clinical and basic research productivity 
must be provided to document departmental and institutional commitments to 
collaborative research.

o Evidence of access to obstetrical patients with a variety of medical 
conditions who are available for drug studies must be provided.  Letters of 
commitment by subspecialists and evidence of previous collaborations must be 
provided.

o Evidence should be provided of the proposed OPRU's adherence to the 
International Conference on Harmonization (ICH) Good Clinical Practice 
guidelines.  Applicants should describe how the unit complies or intends to 
comply with ICH Good Clinical Practice guidelines adopted by the Food and 
Drug Administration (FR 62:90, 1997).

o To provide peer reviewers and the NICHD with an idea of the capabilities of 
the investigators, applicants must submit one sample protocol that they would 
propose to the Network NSC.  This example should be a draft (up to six pages 
in length) of a sequential drug study design following the phases outlined 
under Research Objectives and Scope.  The draft research project should 
include a hypothesis, brief background information, and a narrative of the 
procedures to be employed.  Applicants should include details of statistical 
and pharmacokinetic and pharmacodynamic designs and methods of analysis, and 
enough additional specific material for a scientific review.

o To provide peer reviewers and the NICHD with an idea of the investigators 
capacity to interact with other researchers, applicants must submit two 
sample protocols of a basic and a translational or preclinical research 
project in obstetric and fetal pharmacology that the investigators would 
propose to the NSC for collaboration with other investigators.  The research 
projects proposed should provide evidence of synergy.  This sample protocol 
should be a draft for consideration by other participants in the program, and 
should include enough detail (hypothesis, design, rationale, significance, 
procedures, resources required, and discussion of feasibility) to permit 
evaluation of the proposal for scientific merit.  The research proposed 
should complement the specific research proposed in response to the previous 
paragraph.  These protocols should be presented in no more than six pages.

Budget Preparation
 
Allowable costs in NIH cooperative agreements are governed by rules set forth 
in the NIH Grants Policy Statement and as stated in the Notice of Grant 
Award.  Under these rules, the PI may exercise flexibility to meet unexpected 
requirements by rebudgeting or requesting approval to rebudget among 
categories within the total direct cost budget of the OPRU (as shown on the 
Notice of Grant Award), within the ceilings set in these guidelines.
 
OPRU grants are for five years, at a maximum level of $500,000 in direct 
costs for the first year.  The maximum level may be exceeded by the amount of 
F&A costs for subcontracts.  Items supportable through an OPRU cooperative 
agreement award may include:
 
(1) Administration  

o Personnel: 

Principal Investigator (maximum of 15 percent time and effort); Principal 
Investigator and Co-Investigator (maximum 20 percent time and effort for 
both); Co-Investigator for basic/translational research (maximum 10 percent 
time and effort).

o Administrative Support Services:  supplies, duplication costs, telephone 
(not to exceed $4,500).

o Travel:  PI, Associate PIs, and Nurse Coordinator to all meetings of the 
NSC (a total of 12 trips a year).

o Other costs (itemized and individually justified) not to exceed $2,500.
  
(2) Core Laboratory

o Personnel:  Core laboratory director (maximum 25 percent time and effort); 
core laboratory technician (maximum 50 percent time and effort).  

o Equipment:  The equipment used in the core laboratory should be primarily 
that available to the investigators or obtainable from institutional 
resources.  New equipment, up to a maximum of $50,000 total cost distributed 
over the first four years of the award, may be requested in an OPRU 
application, with appropriate justification.  

o Supplies:  Appropriate for OPRU participation in collaborative protocols 
and for support of specialized analyses for investigator-initiated studies 
within the OPRU.

o Other:  Maintenance costs of equipment purchased with the award or 
otherwise dedicated to OPRU use.  The maximum allowable total annual amount 
for Supplies plus Other in the core laboratory is $20,000.
 
(3) Protocol Implementation Support 

o Personnel:  Nurse Coordinator (maximum 100 percent time and effort each); 
Adjunct Clinical Pharmacologist (maximum 50 percent time and effort); Data 
Coordinator (maximum 20 percent time and effort).
 
For studies performed in collaboration with pharmaceutical firms, those firms 
should pay the fees for research-related clinical determinations.  For 
investigator-initiated studies in which pharmaceutical firms do not 
participate, costs must be supported by sources other than OPRU funding.
 
Studies of drugs with no commercial sponsors may be funded through a 
capitation system.  Specific protocol-related costs will be capitated 
according to the anticipated number of patients to be enrolled at the 
applicant OPRU.  Level of funding will be based on actual recruitment.  
Allocations for this purpose will depend on the availability of funds.
 
For drug company-initiated protocols being performed in the OPRUs, there must 
be appropriate reimbursements from non-OPRU sources for core laboratory 
equipment maintenance, supplies, and personnel time, as well as for data 
management costs.  These reimbursements must be used to offset OPRU costs and 
should be reported as grant-related income.
 
The following items are not fundable through an OPRU grant:

(1) Costs of clinical care, such as patient bed costs, outpatient visit fees, 
and clinical laboratory determinations.  These costs must be paid by the 
pharmaceutical companies for protocols performed on their initiative or by 
third-party carriers or other sources for investigator-initiated protocols. 

(2) Laboratory costs (outside the core laboratory) for projects being 
performed by non-OPRU investigators using the OPRU. 

(3) Travel to scientific meetings or for any other purpose except to attend 
meetings of the NSC.

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 and NIH grant 
administration policies.

The administrative and funding instrument used for this program will be the 
U10, an "assistance" mechanism (rather than an "acquisition" mechanism), in 
which substantial NIH scientific and/or programmatic involvement with the PI 
is anticipated during performance of the activities. Under the cooperative 
agreement, the NIH purpose is to support and/or stimulate the PI's activities 
by involvement in and otherwise working jointly with the PI in a partnership 
role; it is not to assume direction, prime responsibility, or a dominant role 
in the activities.  Consistent with this concept, the dominant role and prime 
responsibility resides with the PI for the project as a whole, although 
specific tasks and activities may be shared between the awardee and NICHD 
Program Scientists.  Facilities and Administrative cost (indirect cost) award 
procedures apply to cooperative agreements in the same manner as for grants.  
Business management aspects of these awards will be administered by the NICHD 
Grants Management Branch in accordance with HHS and NIH grant administrative 
requirements.

1.  Awardee Rights and Responsibilities

The awardee will have the primary responsibility for defining the details of 
the project within the guidelines of RFA-HD-03-017 and for performing the 
scientific activities.  

The PI is the person responsible for the overall management of the clinical 
pharmacology component.  A basic/pre-clinical research co-investigator is 
responsible for coordinating the OPRU basic pre-clinical research scientists. 
The PI agrees to accept close coordination, cooperation, and participation of 
the NICHD Program Scientists, the Network Steering Committee (NSC) and the 
Advisory Board in those aspects of scientific and technical management of the 
project described below. Specifically, the awardees will:

o Identify priority issues for research;

o Maintain a clinical pharmacology research component, a designated physical 
site where the clinical pharmacology/clinical trials will be performed, and a 
core laboratory; the obstetrical unit must have at least 2,700 births per 
year currently in the unit, with a minimum of 30 percent high-risk 
pregnancies.

o Develop and implement protocols;

o Collect and transmit data in an accurate manner;

o Execute and supervise the design of pharmacologic studies and clinical 
trials;

o Determine experimental approaches, design protocols, direct experiments, 
and set project milestones, in consultation with the NSC;

o Implement approved plans for sharing research resources;

o Submit periodic progress reports in a standard format, as agreed upon by 
the Network Steering Committee;

o Present results and plans at NSC meetings;

o Accept and implement the common guidelines and procedures approved by the 
NSC;

o Release data and publish results, as agreed upon by the NSC; and

o Implement Data Safety Monitoring plans following NIH guidelines.

The OPRU PI may be responsible for industry-sponsored studies leading to 
labeling of drugs in obstetrics.

Other investigators with obstetric privileges at the grantee institution are 
eligible to utilize the resources for studies of drug efficacy, metabolism 
and/or effects in pregnant patients, supported by independent research funds, 
if the protocols have been approved and prioritized by the NSC.  These 
individual investigator protocols must not delay or interfere with the 
pursuit of the collaborative studies that are the OPRUs' primary 
responsibility.  At each funded OPRU site, priority is given to studies 
within the OPRU.

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. NIH Responsibilities

NICHD Program Scientists:

Two NICHD Program Scientists will have substantial involvement above and 
beyond the normal stewardship of the award.  The two NICHD Program Scientists 
will be staff from the Endocrinology, Nutrition and Growth Branch  
(Pharmacologist) and the Pregnancy and Perinatology Branch (Obstetrician).  
The role of the NICHD Program Scientists will be to aid the awardees and the 
NSC in the following ways:

o Provide relevant expertise and overall knowledge;

o Provide information about ongoing NIH-supported research and resource 
collections;

o Communicate with members of professional organizations of obstetricians and 
pharmacologists to determine their preference in prescribing drugs for 
pregnant women and, as part of the NSC, prioritize those drugs in need of 
study by the OPRU Network;

o Attend NSC meetings as one voting member and participate with other NSC 
members in the group process of setting research priorities, deciding optimal 
research approaches and protocol designs, and contributing to the adjustment 
of research protocols or approaches as warranted.  The Program Scientists 
will assist and facilitate the group process and not direct it.  They will 
help develop operating guidelines, quality control procedures, and consistent 
policies for dealing with situations that require coordinated action.  The 
Project Scientist must be informed of all major interactions of NSC members;

o Serve as liaison to the Advisory Board; attend Advisory Board meetings as a 
non-voting member to help coordinate the activities of the projects with 
those of other NIH pharmacology initiatives.  The NICHD Program Scientists 
will also coordinate the activities of projects funded under this RFA with 
other U.S. 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 this RFA;

o Provide assistance to the NSC 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.

The NICHD plans to establish a separate Data center to provide statistical 
consultation, data management, and data analysis, in addition to various 
logistical services required for Phase III drug trials.

NICHD Project Officer:

The NICHD will appoint a Project Officer, apart from the Program Scientists, 
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

o The Network Steering Committee (NSC) 

The NSC will be the overall main governing and management committee and the 
committee through which the NIH interacts and collaborates with the project. 
The Network Steering Committee will meet at least four times a year in the 
Washington D.C. area.  In addition< PIs will communicate monthly by formal 
conference calls.

The NSC will consist of the Principal Investigators, the NICHD Program 
Scientists, a non-voting FDA representative and a non-voting independent 
chairperson appointed by the NICHD.  Each PI will have one vote and the NIH 
Program Scientists will have a total of one vote.  The NSC will establish the 
Policies and Procedures that govern the Networks' operations, including 
publications.  These documents will undergo periodic review.  

The NSC will determine all major scientific decisions.  The NSC will be 
responsible for protocol development and review, assisted by a Data Safety, 
Quality and Monitoring Committee and an Advisory Board.  The NSC will also be 
responsible for facilitating the conduct of translational and basic research 
related to OPRUs trials/studies, promoting trans-OPRUs collaboration among 
and between clinical and basic components, analyzing and interpreting OPRU-
wide study data, and establishing procedures for reporting results of OPRU 
trials/studies. 

Proposed protocols for clinical trials/studies to be performed by a single 
OPRU or group of OPRUs will be submitted to the NSC for review and 
evaluation.  The three phases of development for the study of drugs in 
pregnancy will be addressed by the OPRU Network that emerges from this RFA. 
Protocols to be implemented will be selected by the Network Steering 
Committee in accordance with criteria and procedures established by the NSC; 
criteria will include thematic integration and evidence of integrated synergy 
of proposed research projects.  After approval, those clinical investigators 
participating in the trial/study, in collaboration with investigators from 
the basic components who will be performing adjunct basic mechanistic 
studies, will develop detailed protocols.  

As needed, the NSC may establish subcommittees for special purposes.  It is 
expected that most of the work of the NSC will be performed in these 
subcommittees.  Clinical trials/studies will proceed into the implementation 
stage only with the concurrence of the NSC and the NICHD.  The NSC will 
appoint a Research Committee to evaluate basic and translational research 
proposals responsive to the objectives of RFA-HD-03-017.  The membership will 
include the PIs of the basic/preclinical research components of the OPRUs and 
ad hoc members.  The NSC and the NICHD will jointly appoint ad hoc members 
for the evaluation of quality of science of specific research initiatives. 

The NICHD plans to establish a separate OPRU Data Center to provide 
statistical consultation, data management, and data analysis, in addition to 
various logistical services required for Phase III drug trials.  The PI of 
this Data Center will be a member of the NSC.

o Advisory Board  

An Advisory Board of scientists will advise the NSC on the identification and 
prioritization of drugs, evaluate and make recommendations regarding 
appropriateness and coordination of OPRU activities, and make recommendations 
for adequate communication and sharing of information with other related 
projects (e.g., NICHD's MFMU and PPRU Networks) to avoid redundant activities 
and maximize research output.

The Advisory Board, chosen by the NICHD with the advice of the NSC, will  
consist of scientists who are not affiliated with any of the projects and 
have expertise in clinical pharmacology, maternal-fetal medicine, obstetrics, 
genetics, pharmacogenomics, molecular and developmental biology, and 
developmental toxicology.  Ad-hoc members will be appointed by the NICHD for 
evaluation of quality of science and of specific research initiatives.

o Data, Safety and Quality Monitoring Board

The NICHD will appoint an independent Data, Safety and Quality Monitoring 
Board to review the endpoint and safety data for all trials/studies on an 
ongoing basis and report directly to the NICHD Program Scientists.  This 
Board will review protocols and data collection and quality assurance 
procedures in an advisory capacity.  This Board will be funded separately 
from the Centers.

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 member 
selected by the Steering Committee without NIH staff voting, a member 
selected by NICHD, and a member with expertise in the relevant area selected 
by the other two members.

WHERE TO SEND INQUIRIES

We encourage inquiries concerning this RFA and welcome the opportunity to 
answer questions from potential applicants.  Inquiries may fall into three 
areas:  scientific/research, peer review, and financial or grants management 
issues:  

o Direct your questions about scientific/research issues to:  

George P. Giacoia, M.D.
Endocrinology, Nutrition and Growth Branch
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 4B11B, MSC 7510
Bethesda, MD  20892-7510
Telephone:  (301) 496-5589
FAX:  (301) 480-9791 
Email:  gg65m@nih.gov 

Catherine Y. Spong, M.D.
Pregnancy and Perinatology Branch
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 4B03B, MSC 7510
Bethesda, MD  20892-7510
Telephone:  (301) 435-6894
FAX:  (301) 496-3790
E-mail:  spongc@exchange.nih.gov 

o Direct your questions about peer review issues to:  

Robert Stretch, Ph.D.
Director, Division of Scientific Review
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 5B01, MSC 7510
Bethesda, MD  20892-7510
Telephone:  (301) 496-1485
FAX:  (301) 402-4104
Email:  stretchr@mail.nih.gov 

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

Kathy Hancock
Grants Management Branch
National Institute of Child Health and Human Development
6100 Executive Boulevard, 8A17, MSC 7510
Bethesda, MD  20892-7510
Telephone: (301) 496-5482
FAX:  (301) 402-0915
Email:  kh246t@nih.gov 
 
LETTER OF INTENT

Prospective applicants are asked to submit a letter of intent that includes 
the following information:  

o Descriptive title of the proposed research 
o Name, address, and telephone number of the Principal Investigator 
o Names of other key personnel 
o Participating institutions 
o Number and title of this RFA 

Although a letter of intent is not required, is not binding, and does not 
enter into the review of a subsequent application, the information that it 
contains allows IC staff to estimate the potential review workload and plan 
the review.

The letter of intent is to be sent by the date listed at the beginning of 
this document.  The letter of intent should be sent to:  

George P. Giacoia, M.D.
Endocrinology, Nutrition and Growth Branch
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 4B11B, MSC 7510
Bethesda, MD  20892-7510
Telephone:  (301) 496-5589
FAX:  (301) 480-9791
Email:  gg65m@nih.gov 

SUBMITTING AN APPLICATION

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

SUPPLEMENTAL INSTRUCTIONS:  

Page Limitations

Because applicants will be proposing at least three research plans, a 
clinical, translational, and a basic proposal, the page limit for the 
Research Plan sections of the application is 25 pages plus six pages for each 
proposed protocol.

See the SPECIAL REQUIREMENTS section, above, for additional application 
instructions.

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 and all 
five sets of any appendix material must be sent to:  

Robert Stretch, Ph.D.
Director, Division of Scientific Review
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 5B01, MSC 7510
Bethesda, MD  20892-7510
Rockville, MD  20852 (for express/courier service)

APPLICATION PROCESSING:  Applications must be received on or before 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.

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

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.  
However, when a previously unfunded application, originally submitted as an 
investigator-initiated application, is to be submitted in response to an RFA, 
it is to be prepared as a NEW application.  That is, the application for the 
RFA must not include an Introduction describing the changes and improvements 
made, and the text must not be marked to indicate the changes.  While the 
investigator may still benefit from the previous review, the RFA application 
is not to state explicitly how.

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

CRITERIA FOR EVALUATION OF CONCEPT PROTOCOLS:
 
A) Sequential study design protocol

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: 

o Significance 
o Approach 
o Innovation
o Investigator
o Environment

SIGNIFICANCE:  Does the drug selected address an important therapeutic 
dilemma in obstetrics?  

APPROACH:  Are the conceptual framework, design, methods, and analyses 
adequately developed, well integrated, and appropriate to the aims of this 
RFA?  Are the sequential phases to study a drug as outlined under Research 
Objectives properly characterized?  Are the pharmacokinetic and 
pharmacodynamic models appropriate for the study drug and for use in pregnant 
women? 

INNOVATION:  Does the project employ novel concepts, approaches or methods or 
will the proposed study optimize the use of the study drug in pregnant women? 

INVESTIGATOR:  Is the investigator appropriately trained and well suited to 
carry out this work?  Is the work proposed appropriate to the experience 
level of the Principal Investigator and to that of other researchers (if 
any)? 
   
ENVIRONMENT:  Does the scientific environment in which the work will be done 
contribute to the probability of success?  Does the project(s) proposed take 
advantage of unique features of the scientific environment or employ useful 
collaborative arrangements?  Is there evidence of institutional support?

B) Translational or basic research protocol(s)

The goals of NIH-supported research are to advance our understanding of 
biological systems, improve the control of disease, and enhance health.  In 
the written comments, reviewers will be asked to discuss the following 
aspects of the 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
  
SIGNIFICANCE:  Does the 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?

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?  Is there evidence of integrated synergy with other 
proposed protocols?  Do these protocols complement the specific research 
proposed in the sequential study design protocol?

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 to that of other researchers (if 
any)? 

ENVIRONMENT:  Does the scientific environment in which the work will be done 
contribute to the probability of success?  Do the proposed experiments take 
advantage of unique features of the scientific environment or employ useful 
collaborative arrangements?  Is there evidence of institutional support?  

REVIEW CRITERIA FOR THE EVALUATION OF THE CORE LABORATORY (if any):

o Qualifications, experience, and commitment of the core laboratory director 
and other core personnel.

o The quality of services provided.

o The cost effectiveness and quality control of the core laboratory.

o The utility of the core laboratory to the overall program.

REVIEW CRITERIA FOR THE EVALUATION OF THE OVERALL PROGRAM APPLICATION: 

The overall program application is evaluated by considering the research 
projects, supporting cores, and the administrative structure, and how these 
multi-disciplinary components function together to achieve the goals of this 
RFA.

Overall Assessment:

o Scientific merit of the program as a whole, as well as of the individual 
parts.

o Significance of the overall program goals.  This includes the significance 
and importance of the research program to furthering knowledge in obstetric 
pharmacology.

Qualifications, Experience, and Commitment of Key Personnel:

o Past accomplishments of the research team (Principal Investigators, Co-
Investigator responsible for the pharmacology studies, and Core Leaders).    

o Evidence of knowledge of the conduct of collaborative clinical research, 
especially obstetric drug trials (Phases I, II and III).

o Evidence of knowledge and expertise in the design and analysis of 
randomized clinical trials. 

o Evidence of the applicant's expertise in pharmacokinetics, 
pharmacodynamics, drug metabolism and drug bioavailability studies. 
 
o Evidence of knowledge and expertise in the use of diverse Pk-Pd modeling 
that relates mechanisms of drug action to physiologic processes. 

o Quality of the OPRU's participation in either investigator-initiated 
protocols or Phase I, II and III obstetric drug clinical trials in the recent 
past.

o Evidence of previous successful research collaborations with industry or of 
efforts to arrange future collaborations.

o Willingness to work and cooperate with other OPRUs and the NICHD in the 
manner summarized in this RFA.

Facilities, Procedures and Support:

o Adequacy of administrative, clinical, laboratory, animal facilities and 
data organizational management facilities as described under Special 
Requirements.

o Institutional assurance to provide support to the study in such areas as 
fiscal administration, personnel management, space allocation, procurement, 
planning, equipment, and budget.

o Suitability of the proposed clinical locus for the Unit in the applicant 
institution or its affiliated hospital, such as a  metabolic ward and 
outpatient clinic, a GCRC with staff accustomed to conducting studies in 
obstetric patients, or some unit similarly staffed and equipped.

o Availability of and access to suitable populations to participate as 
research subjects in OPRU studies.

o Demonstrated ability of the OPRU to recruit patients for obstetric drug 
studies.

o Evidence of compliance with the Good Clinical Practice and Good Laboratory 
Practice guidelines that apply to investigators and/or institutions.

o Training environment including the institutional commitment, the quality of 
the facilities, and the availability of research support.

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:

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.)

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.)

ADDITIONAL CONSIDERATIONS 

DATA SHARING:  The adequacy of the proposed plan to share data. 

BUDGET:  The reasonableness of the proposed budget and the requested period 
of support in relation to the proposed research.

RECEIPT AND REVIEW SCHEDULE

Letter of Intent Receipt Date:  October 24, 2003
Application Receipt Date:  November 24, 2003
Peer Review Date:  March 2004
Council Review:  June 2004
Earliest Anticipated Start Date:  July 01, 2004

AWARD CRITERIA

Criteria that will be used to make award decisions include: 

o Scientific merit (as determined by peer review)
o Availability of funds
o Programmatic priorities

REQUIRED FEDERAL CITATIONS

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 

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 "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 is 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.

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.

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 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.


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NIH Funding Opportunities and Notices


H H S Department of Health
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