This report provides a framework for comparing the harms and benefits of delivery options for women with prior cesarean delivery (CD). The information is designed to help consumers, providers, payers, and policymakers in decisionmaking about repeat cesarean or trial of labor (TOL).

Reporting the Evidence

The strength and suitability of the evidence regarding the risks of major maternal and infant morbidity and mortality associated with TOL or elective repeat cesarean delivery (ERCD) in women with prior low transverse or unknown scar. The scope of the review was to examine events that were specifically related to having had a prior CD. Comparisons purely about vaginal versus cesarean delivery such as incontinence, pelvic support disorders, and respiratory consequences but not specifically about VBAC or repeat cesarean, were not considered, though these topics are important to consider when deciding upon route of delivery. In judging the suitability of evidence, we took the perspective that the first thing a decision-maker would want to know is whether the risk of these complications is higher for a trial of labor, versus an elective cesarean delivery, under optimal conditions of care. That is, the most relevant evidence would compare the outcomes and risks of a properly managed trial of labor to that of a properly conducted elective cesarean delivery. Some components of obstetric care, as well as some aspects of the setting of this care, might increase the risks of TOL or ERCD. For example, it has been hypothesized that the use (or misuse) of drugs for induction and augmentation might increase the risk of uterine rupture in patients who have had a prior cesarean delivery. We examined the strength of evidence that these factors influence these outcomes and adverse effects and to what extent these factors can explain the results of observational studies of VBAC complications.

Methodology

Key Questions

Two types of key questions were addressed. The first group (Questions 1- 7) compares the outcomes of a TOL and an ERCD:

1. What is the frequency of vaginal delivery in women who undergo a TOL (spontaneous onset, induced, and augmented) after prior low transverse cesarean or unknown scar?
2. How accurate are risk assessment tools for identifying patients who will have a vaginal delivery after a TOL?
3. What are the relative harms associated with a TOL (spontaneous onset, induced, and augmented) and repeat cesarean?
4. What is the incidence of uterine rupture, and are there methods for preventing major morbidity and mortality due to uterine rupture?
5. What are the health status and health-related quality of life for VBAC and repeat cesarean patients?
6. Regarding VBAC and repeat cesarean, what factors influence patient satisfaction/dissatisfaction with their childbirth experience?
7. How are economic outcomes related to VBAC, repeat CD, and their respective complications?

The second group (Questions 8-10) address factors influencing the decision to have a TOL:

1. What individual factors influence route of delivery?
2. What factors influence a patient’s decisionmaking regarding VBAC or ERCD?
3. How do legislation, policy, guidelines, provider characteristics, insurance type, and access to care affect health outcomes for VBAC candidates?

Relevant studies were identified from multiple searches of MEDLINE® (1966 to 2002) and HealthSTAR (1975 to 2002), from the reference lists of systematic reviews and from local and national experts. The online Cochrane systematic reviews and controlled trials registries, DARE, National Centre for Reviews and Dissemination, and EMBASE databases were searched for relevant literature on specific topics as well. For topics related to patient preferences and satisfaction, PsycINFO and CINAHL® databases were searched. Databases were searched twice during the course of the project, with the final search in March 2002. For all VBAC topics combined, 14,449 citations were retrieved, including 4,867 about spontaneous labor and uterine rupture, 2,528 about ERCD, 2,416 about induction of labor, 2,945 citations about predictors, 1,257 about patient satisfaction, preference and health status, and 436 about cost and access.

All searches were limited to English-language articles published since 1980 (the date of the NIH Consensus Conference on VBAC) in developed countries. The report focused on studies that identified a group of patients with prior cesarean. For patient preferences and satisfaction, studies of the general birthing population, were considered if there were no studies that identified patients with prior cesarean. Studies were excluded if they focused on patients with particular conditions such as gestational diabetes, HIV, preeclampsia, and so on. Exclusions were also made for studies that focused primarily on the following: nulliparous women, vertical, lower vertical, “classical” or “classic” cesarean, vaginal breech delivery, preterm delivery, multiple gestation, or low birth weight.

Two investigators reviewed a random set of titles and abstracts for each topic to select articles for full-text review. When an appropriate level of reliability was reached for inclusion and exclusion of studies, the primary investigator reviewed the remaining titles and abstracts on the topic. Investigators read the full-text version of the retrieved papers and reapplied the initial eligibility criteria. Data from 224 studies were abstracted and included in the evidence tables described in the results section of this report.

Data Abstraction

Included study designs were determined by topic area. Study designs of included articles consisted of randomized controlled trials, cohort studies, case-control studies, cross-sectional studies, large case series (more than 10 subjects), and economic or decision models. All data were abstracted by the lead investigator for the topic. If the lead investigator encountered difficulty in finding or interpreting information in the published report, a second investigator reviewed the article and a consensus was reached.

Assessment of Study Quality

To assess the internal validity of individual studies, we applied a set of design-specific criteria developed by the current U.S. Preventive Services Task Force and additional criteria developed by the NHS Centre for Reviews and Dissemination, based at the University of York in England. In general, studies were rated good if they met all criteria, fair if they addressed some but not all criteria, and poor if they had a “fatal flaw.” Investigators were asked to use the study quality ratings as previously described to determine for their topic which quality components were most important in assessing internal validity. This process allowed for some individual topic fit for fatal flaws, etc. A second investigator independently rated all included articles, and disagreements were resolved by consensus.

Data Synthesis

Where appropriate, meta-analysis was performed using WinBugs® or StatsDirect® software. To reduce potential bias, only studies of fair or good quality were included in the analyses.

Findings

Question 1. Likelihood of Vaginal Delivery

• Rates of vaginal delivery when attempting TOL ranged from 60 to 82 percent. The largest population-based study reported a rate of 60.4 percent. The combined vaginal delivery rate for all prospective cohort studies, largely conducted in tertiary care centers and university settings, was 75.9 percent.
• There are limited data on the effect of medical induction and augmentation of labor.
• There was a 10-percent reduction in the likelihood of vaginal delivery when oxytocin was used for ether induction or augmentation. There was a similar trend in reduced likelihood of vaginal delivery with prostaglandins.

Question 2. Predictive Tools

• Two validated scoring systems categorized women into groups with likelihoods of vaginal delivery ranging from roughly 45 to 95 percent.
• One tool was able to stratify more of the population (up to 50 percent of women choosing TOL) into high and low probability subgroups, with a relatively low false-positive rate.
• By using a prospective cohort design and the largest study population, the best scoring system created a 10-point score based on the presence or absence of five variables commonly available for most patient admissions.
• An RCT clearly demonstrated the inability of X-ray pelvimetry (XRP) to predict route of delivery reliably.
• Imaging studies that combined the measurements of the pelvis and fetus showed promising results, but were limited by their lack of control for confounding and biases.

Question 3. Maternal and Infant Outcomes

General

• In the absence of RCTs of TOL versus repeat cesarean, evidence that is most generalizable comes from large country, State, or regional population-based studies (referred to as population-based studies) followed by large multicenter cohort studies, large single-institution or single-practice cohort studies, then smaller cohort studies, respectively.
• There is no direct evidence regarding the benefits and harms of TOL relative to ERCD in women who are similar in every respect except choice of delivery route.
• Several fair and good quality studies provide indirect evidence about relative benefits and harms of each route.

Maternal

• Maternal death rates did not differ between TOL and ERCD.
• The best evidence suggests that hysterectomy rates do not differ between TOL and ERCD.
• No studies examined specifically the risks of incontinence or pelvic support disorders in women with prior cesarean.
• Rates of infection were increased in ERCD versus TOL overall. Studies that performed subgroup analyses for TOL with and without vaginal delivery consistently found increased rates of infection for women who attempted TOL but ultimately had a cesarean delivery.
• There is conflicting evidence regarding whether induction of labor affects infection rates.

Infant

• There is insufficient evidence regarding the effect of selected route of delivery and Apgar score or respiratory morbidity.
• No study measured infant death directly attributable to a mother’s choice of TOL or repeat CD.
• There is uncertainty about the magnitude of risk of perinatal death due to TOL. Results from two large studies differ in the magnitude of increased risk from TOL versus ERCD (90/1,000 TOL versus 50/1,000 ERCD compared with 12.9/1,000 TOL versus 1.1/1,000 ERCD). Neither study provides direct evidence of risk.

Question 4. Uterine Rupture

• The use of terms among studies is inconsistent.
• Definitions among studies for similar terms are ambiguous.
• There is no difference in asymptomatic uterine rupture rates in TOL versus ERCD.
• Symptomatic uterine rupture is significantly more common in TOL versus ERCD, with an increased risk of 2.7/1000.
• Based on the frequency and severity of symptomatic uterine rupture, the risk of perinatal death due to a rupture of a uterine scar is 1.5/10,000 and the risk of maternal hysterectomy is 4.8/10,000. These rates of serious complications such as perinatal death are probably more precise than overall risks from studies measuring death directly.
• The definition of uterine rupture as an outcome is confounded by a definition that includes the potential predictor of fetal heart rate (FHR) tracing abnormality.
• Measurement of frequency of occurrence, predictors for what population is at greatest risk, and predictors for poor outcomes are not possible, because of the lack of standard case definition.

Question 5. Health Status

• There were no studies of health status or health-related quality of life for VBAC or repeat CD patients.

Question 6. Patient Satisfaction

• Studies of patient satisfaction largely consisted of the patient’s own provider obtaining information about patient satisfaction, introducing the possibility of measurement bias.
• Only two cross-sectional studies used methods other than the patient’s own provider to obtain satisfaction information.
• No study measured satisfaction for the three types of delivery outcomes that could be experienced by women with prior CDs (VBAC, TOL followed by CD, or ERCD).

Question 7. Cost and Health Care Resources

• For a TOL success probability of 76 percent or greater, TOL is more cost-effective and provides higher quality of life.
• Further evaluation is needed of the sensitivity of the probability cut point of 76 percent to other potential predictor variables.

Question 8. Individual Factors

• The vast majority of studies looking at individual factors that influence the route of delivery were of poor quality due to the lack of control for confounding factors.
• The factors that were significantly associated with an increased likelihood of vaginal delivery (i.e., successful TOL) were maternal age less than 40 years, prior vaginal delivery (particularly vaginal delivery after cesarean), a nonrecurrent indication for the prior CD, and favorable cervical factors.
• The factors that were significantly associated with a decreased likelihood of vaginal delivery (i.e., failed TOL) were an increasing number of prior CD, gestational age greater than 40 weeks, birthweight greater than 4000 g, and augmentation of labor.

Question 9. Patient Preferences

• Patient preferences for birth choice are unclear because of the heterogeneity of the 11 included studies.
• Several factors appear related to choice for TOL (White race, prior vaginal delivery, lower levels of anxiety during the pregnancy).
• Lack of medical information along with cultural ideologies might account for minority women being less likely to attempt a TOL when compared with white women.
• A woman’s choice for delivery was often based on social motives (e.g., easier recovery, so she can care for baby and children at home).
• Only four of 11 studies cited safety for mother or baby as important reasons for delivery choice.
• It remains unclear whether VBAC education increases the proportion of women who choose TOL.

Question 10. Legal, Provider, Hospital, Insurance Characteristics

General

• Studies of legislation, policy, guidelines, hospital characteristics, provider characteristics, insurance type, or access to care focus exclusively on VBAC rates rather than safety.

Legal

• No study provides direct evidence for the impact of malpractice issues on VBAC or ERCD.
• One study reported that VBAC rates increased when legislation was enacted that standardized VBAC guidelines had to be provided to obstetric providers.
• The best evidence suggests that use of opinion leaders provides a greater likelihood of changing practice compared with audit and feedback.

Provider

• Studies of provider characteristics failed to control for important variables such as patient selection bias.

Hospital

• VBAC rates were higher in teaching hospitals compared to private, community, regional, or non-teaching hospitals.
• Three studies conflicted over the effect of hospitals containing a neonatal intensive care unit (NICU).

Insurance

• There was conflicting evidence regarding whether insurance status predicts VBAC.

Summary of Evidence

The following summarizes the type of study design, the quality of the evidence from studies, and the suitability of the study design to answer the particular question for each key question.

¹ Study design categories—I: randomized, controlled trials; II-1: controlled trials without randomization; II-2: cohort or case-control; II-3: multiple time series; III: opinions, descriptive epidemiology. U.S. Preventive Services Task Force (1996).

² Suitability of study design categories—Greatest: For comparison studies: Concurrent comparison groups and prospective measurement of exposure and outcome; For rates: population-based or multicenter prospective cohort studies. Moderate: All retrospective designs or multiple pre or post measurements but no concurrent comparison group; Least: Single pre and post measurements and no concurrent comparison group or exposure and outcome measured in a single group at the same point in time. Community Preventive Services Task Force (2000).

Limitations

• Data are insufficient to allow conclusions about the most appropriate delivery choice for a given patient.
• Studies suffered from inconsistent and imprecise definitions for important outcomes.
• Studies frequently failed to ensure comparability between TOL and ERCD groups.
• No study or collection of studies, provide data about the impact of practice variation, provider characteristics, legal considerations such as the effect of rising malpractice rates on the safety of TOL or ERCD.
• The degree to which the association between fetal bradycardia and poor perinatal outcome from uterine rupture rather than confounding by factors detection bias is unclear.
• The degree to which the association between TOL and perinatal death reflects causation rather than confounding by factors such as misclassification of cases, lethal conditions of the fetus, or detection bias is unclear.

Evidence Report/Technology Assessment: Number 71

Under its Evidence-based Practice Program, the Agency for Healthcare Research and Quality (AHRQ) is developing scientific information for other agencies and organizations on which to base clinical guidelines, performance measures, and other quality improvement tools. Contractor institutions review all relevant scientific literature on assigned clinical care topics and produce evidence reports and technology assessments, conduct research on methodologies and the effectiveness of their implementation, and participate in technical assistance activities.

Future Research

Future research should focus on conducting methodologically rigorous studies to provide direct evidence regarding the relative benefits and harms of TOL and ERCD. If randomized trials are not done, good-quality studies of TOL versus ERCD must pay attention to the following:

Population. Studies should be conducted in populations of women who are similar in every respect except choice of delivery route (comparability of groups).

Specificity of intervention. Studies should pay close attention to and account for the importance of co-interventions such as use of oxytocin and other medical agents for augmentation or induction of labor.

Precise and standard outcome measures. Variations in reporting of important clinical outcomes were striking. Studies should consider the following factors in developing outcome measures:

• Etiology. Outcomes such as hysterectomy, infection, maternal mortality, and perinatal mortality must pay specific attention to explicitly identifying the etiology. Lack of precision in this regard allows for both under and overreporting of cases due to misclassification. Examples include whether hysterectomy was performed due to maternal hemorrhage secondary to clinically significant uterine rupture versus hemorrhage due to abruption, uterine rupture through the uterine fundus in a woman with a low transverse incision either due to trauma or other non-incisional causes, and perinatal death due to lethal anomaly versus intolerance or management of labor.
• Standard terminology. In order to accurately measure outcomes, there must be a consistent terminology. Lack of this prevents accurate and meaningful comparisons of risks for each delivery choice. Outcomes such as infection, hemorrhage, and uterine rupture were not consistently defined.
• Separating prevention/prediction strategies from outcomes. As long as potentially important predictors of events such as prolonged fetal bradycardia as a predictor for clinically significant uterine rupture are included in the definition of uterine rupture, their true value as a predictor rather than a confounder will remain unknown.

Predictive Tools

Additional studies are needed to measure the accuracy and yields of existing predictive tools. Future studies of predictive tools should include measurements of the consequences of false-positive screens and false-negative screens to determine whether there are clinically important harms that result from screening.

Cost

The costs (rather than charges) of labor and delivery and of the surgical processes are poorly understood. Detailed time-in-motion studies would help to estimate these costs.

Availability of Full Report

The full evidence report from which this summary was taken was prepared for the Agency for Healthcare Research and Quality (AHRQ) by the Oregon Health & Science University Evidence-based Practice Center (EPC), Portland, OR, under Contract No. 290-97-0018. Printed copies may be obtained free of charge from the AHRQ Publications Clearinghouse by calling 1-800-358-9295. Requesters should ask for Evidence Report/Technology Assessment No. 71, Vaginal Birth After Cesarean (VBAC).

The Evidence Report is also online on the National Library of Medicine Bookshelf.

AHRQ Publication Number 03-E017

Current as of March 2003

Source: Agency for Healthcare Research and Quality – http://www.ahrq.gov/clinic/epcsums/vbacsum.htm

This FOA extends the current efforts of OPPB to provide training and research funding opportunities for basic and clinical scientists to conduct drug research and development focusing on pediatric and obstetric populations. The FOA also complements the ongoing efforts that are supported via the Best Pharmaceuticals for Children Act (BPCA) (http://bpca.nichd.nih.gov/index.cfm) as well as the Pediatric Pharmacology Research Units (PPRU) (http://www.nichd.nih.gov/research/supported/ppru1.cfm) and the Obstetric-Fetal Pharmacology Research Units (OPRU) (http://www.nichd.nih.gov/research/supported/opru_network.cfm) networks in the OPPB.

The OPPB encourages investigator-initiated basic, translational, and clinical studies to address the goals described in this FOA.

Background

Conventional drug development is generally conducted in the adult population and does not include children, women of reproductive age or pregnant women. The appropriate therapeutic use of drugs in pediatric and obstetric patients is a major concern for patients, family members and health care professionals. Although it has been increasingly recognized that one size does not fit all, information guiding drug treatment for pediatric and obstetric patients is still largely extrapolated from the adult and non- pregnant drug development studies or trials. Many obstacles have hindered tailored therapeutic approaches considering many differences among children at various developmental stages, between children and adults, and between pregnant and non-pregnant women, leading to unpredictable clinical consequences. Thus, there is an urgent need to study drug metabolism, disposition, toxicity and efficacy in pediatric and obstetric patients to understand the important differences of drug actions and responses in these special populations, and to develop effective and safe drugs for these special populations.

Research investigating drug metabolism, disposition, and responses, and new drug development in children, has been limited by many factors including scientific and technical difficulties, ethical constraints, legal risks and financial disincentives. In addition, biological differences and developmental changes, as well as inter-individual variability in drug metabolism and disposition, and responses due to genetic and environmental factors, have increased the difficulty and the complexity of pediatric drug research and development. As a result, nearly 80 percent of all drugs marketed today do not have U.S. Food and Drug Administration approved labeling for use in children. The lack of knowledge of appropriate drug dosage, efficacy, and safety for pediatric patients has caused some therapeutic disasters. For example, chloramphenicol administered to newborn babies with doses that were extrapolated from adult patients resulted in cardiovascular collapse and death.

Research, on the other hand, for drug usage and drug development for pregnant women has also been largely excluded due to many factors including teratogenic, psychological, social, technical, ethical, and legal concerns. Pharmacoepidemiological surveys indicate that nearly two thirds of all pregnant women take at least four drugs during pregnancy and labor. However, the current therapeutic practice does not take into account the profound physiologic changes during pregnancy. The use of drugs in pregnant women is largely based on an empiric understanding of dosage, safety and efficacy from non-pregnant women rather than scientific evidence. The lack of appropriate drug testing and research in pregnant women has raised significant public health concerns.

In recent years, with the increased participation of pediatric and obstetric patients in clinical studies/trials, progress has been made in drug research and development, which provides valuable therapeutic information for children and pregnant women. However, information guiding drug usage for the majority of drugs used in children and pregnant women is still scarce and incomplete.

With recent advances in genetics, pharmacogenomics and basic developmental biology, as well as the expansion of robust technologies (such as microarray and proteomic technologies) and bioinformatics tools, both basic and clinical scientists are now better equipped to conduct drug research and development in children and pregnant women. In addition, with the increased public understanding about the importance of tailored drug treatment for children and pregnant women, it creates an excellent research opportunity for both basic and clinical scientists to apply systems approaches to studying the pharmacokinetics and pharmacodynamics and the underlying drug metabolism, disposition, transporters and signaling pathways for improving the existing drug use, and accelerating future drug development in children and pregnant women.

Research Objectives and Scope

This FOA is intended to support basic, translational, and clinical studies to improve the safety and effectiveness of current drugs for pediatric and obstetric patients, and to enhance the development of new drugs to meet emerging clinical needs for these special populations. Studies from a variety of scientific fields that address the different metablism, gene-drug interactions, drug-drug interactions, drug toxicity, responses and actions in children at different developmental age groups, between childen and adults, and between pregnant and non-pregnant women are of particular interest. Studies using genomic, epigenomic, proteomic, and systems biology approaches to increase the knowledge for these differences and underlying mechanisms are highly encouraged.

Studies involving human subjects and animal models as well as in vitro and in silico models are appropriate under this FOA. Studies encompassing innovative approaches and multidisciplinary collaborations are also encouraged.

Examples of research topics include but are not limited to:

• Identify, develop and validate biomarkers to monitor disease progression and treatment responses (efficacy and/or toxicity) in pediatric and obstetric patients

• Develop in vivo animal models for preclinical testing of new agents for the treatment of diseases in children or pregnant women

• Perform genome-wide gene expression (mRNA) analysis to identify biomarkers and new targets for pharmacologic intervention in children and pregnant women

• Study genetic variations through genome-wide association analysis to determine whether genetic variants affect drug metabolism and disposition, and alter the treatment responses in clinical trials for pediatric and obstetric patients

• Study microRNAs (miRNAs) that affect transcription and/or translation of the target transcripts for drug transporters, receptors, metabolizing signaling pathways during development in childhood and pregnancy

• Study genomic, proteomic and epigenomic changes that are associated with variability in pharmacokinetics and pharmacodynamics in different developmental stages spanning from neonates to adolescents

• Study genomic, proteomic and epigenomic changes that are associated with variability in pharmacokinetics and pharmacodynamics during pregnant state, comparing normal pregnancy with abnormal pregnancy

• Develop novel mathematical, statistical and computational methods to modeling and simulating PK/PD, and evaluate existing methods in children and pregnant women

• Use predictive modeling approach with ontogenetic data to study drug disposition in pediatric populations to improve clinical trial design, drug dosage regimen design and toxicological risk assessment

• Conduct longitudinal studies to determine changes in pregnancy that have an effect on drug metabolism and distribution at various gestational stages

• Conduct longitudinal studies to determine developmental changes that have an effect on drug metabolism and distribution at various developmental stages from neonates to adolescents

• Conduct pharmacoepidemiological studies to determine the frequency and pattern of medication use in children and pregnant women, and to develop novel methodologies for drug safety surveillance for these special populations

• Study placental drug transfer and fetal disposition of maternally administered drugs using in vitro and animal models

• Develop therapeutic agents that can be utilized for bio-defense purposes as well as for treatment of diseases in pediatric and obstetric populations

• Apply imaging tools such as magnetic resonance imaging (MRI), positron emission tomography (PET), single photon emission computed tomography (SPECT) to assess the drug effects and clinical outcomes of pediatric and obstetric patients

• Use / identify robust imaging markers for the development of new drugs for pediatric and obstetric patients

• Develop and validate novel drug delivery devices and non-invasive pharmacodynamic measurements in pediatrics

See Section VIII, Other Information – Required Federal Citations, for policies related to this announcement.

Section II. Award Information

This FOA will use the NIH Research Project Grant R01 award mechanism. The Project Director/Principal Investigator (PD/PI) will be solely responsible for planning, directing, and executing the proposed project.

This FOA uses Just-in-Time information concepts (see SF424 (R&R) Application Guide). It also uses the modular as well as the non-modular budget formats (seehttp://grants.nih.gov/grants/funding/modular/modular.htm). Specifically, a U.S. organization submitting an application with direct costs in each year of $250,000 or less (excluding consortium Facilities and Administrative [F&A] costs) should use the PHS398 Modular Budget component.

U.S. applicants requesting more than $250,000 in annual direct costs and all foreign applicants must complete and submit budget requests using the Research & Related Budget component.

2. Funds Available

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 IC(s) provide support for this program, awards pursuant to this funding opportunity are contingent upon the availability of funds.

Facilities and Administrative (F&A) costs requested by consortium participants are not included in the direct cost limitation see NOT-OD-05-004.

Section III. Eligibility Information

1.A. Eligible Institutions

The following organizations/institutions are eligible to apply:

• Public/State Controlled Institutions of Higher Education
• Private Institutions of Higher Education
• Hispanic-serving Institutions
• Historically Black Colleges and Universities (HBCUs)
• Tribally Controlled Colleges and Universities (TCCUs)
• Alaska Native and Native Hawaiian Serving Institutions
• Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education)
• Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education)
• Small Businesses
• For-Profit Organizations (Other than Small Businesses)
• State Governments
• Indian/Native American Tribal Governments (Federally Recognized)
• Indian/Native American Tribally Designated Organizations
• County Governments
• City or Township Governments
• Special District Governments
• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• U.S. Territory or Possession
• Indian/Native American Tribal Governments (Other than Federally Recognized)
• Regional Organizations
• Non-domestic (non-U.S.) Entities (Foreign Organizations)
• Eligible Agencies of the Federal Government
• Faith-based or Community-based Organizations.

1.B. Eligible Individuals

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the PD/PI is invited to work with his/her organization 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 support.

More than one PD/PI (i.e., multiple PDs/PIs), may be designated on the application for projects that require a team science approach and therefore clearly do not fit the single-PD/PI model.Additional information on the implementation plans and policies and procedures to formally allow more than one PD/PI on individual research projects is available athttp://grants.nih.gov/grants/multi_pi. All PDs/PIs must be registered in the NIH electronic Research Administration (eRA) Commons prior to the submission of the application (seehttp://era.nih.gov/ElectronicReceipt/preparing.htm for instructions).

The decision of whether to apply for a grant with a single PD/PI or multiple PDs/PIs grant is the responsibility of the investigators and applicant organizations and should be determined by the scientific goals of the project. Applications for grants with multiple PDs/PIs will require additional information, as outlined in the instructions below. When considering the multiple PD/PI option, please be aware that the structure and governance of the PD/PI leadership team as well as the knowledge, skills and experience of the individual PDs/PIs will be factored into the assessment of the overall scientific merit of the application. Multiple PDs/PIs on a project share the authority and responsibility for leading and directing the project, intellectually and logistically.Each PD/PI is responsible and accountable to the grantee organization, or, as appropriate, to a collaborating organization, for the proper conduct of the project or program, including the submission of required reports. For further information on multiple PDs/PIs, please see http://grants.nih.gov/grants/multi_pi.

2. Cost Sharing or Matching

This program does not require cost sharing as defined in the current NIH Grants Policy Statement.

3. Other-Special Eligibility Criteria

Number of Applications. Applicants may submit more than one application, provided that each application is scientifically distinct.

Resubmissions. Applicants may submit a resubmission application, but such application must include an Introduction Beginning with applications intended for the January 25, 2009 official submission due date, all original new applications (i.e., never submitted) and competing renewal applications will be permitted addressing the previous peer review critique (Summary Statement). only a single amendment (A1). See http://grants.nih.gov/grants/guide/notice-files/NOT-OD-09-003.html and NOT-OD-09-016. Original new and renewal applications that were submitted prior to January 25, 2009 will be permitted two amendments (A1 and A2). For these grandfathered applications, NIH expects that any A2 will be submitted no later than January 7, 2011, and NIH will not accept A2 applications after that date.

Renewals. Applicants may submit a renewal application.

Section IV. Application and Submission Information

A one-time registration is required for institutions/organizations at both:

• Grants.gov (http://www.grants.gov/applicants/get_registered.jsp) and
• eRA Commons (http://era.nih.gov/ElectronicReceipt/preparing.htm)

PDs/PIs should work with their institutions/organizations to make sure they are registered in the NIH eRA Commons.

Several additional separate actions are required before an applicant can submit an electronic application, as follows:

1) Organizational/Institutional Registration in Grants.gov/Get Registered

• Your organization will need to obtain a Data Universal Number System (DUNS) number and register with the Central Contractor Registration (CCR) as part of the Grants.gov registration process.
• If your organization does not have a Taxpayer Identification Number (TIN) or Employer Identification Number (EIN), allow for extra time. A valid TIN or EIN is necessary for CCR registration.
• The CCR also validates the EIN against Internal Revenue Service records, a step that will take an additional one to two business days.
• Direct questions regarding Grants.gov registration to:
  Grants.gov Customer Support
  Contact Center Phone: 800-518-4726
  Business Hours: M-F 7:00 a.m. – 9:00 p.m. Eastern Time
  Email support@grants.gov

2) Organizational/Institutional Registration in the eRA Commons

• To find out if an organization is already Commons-registered, see the “List of Grantee Organizations Registered in NIH eRA Commons.
• Direct questions regarding the Commons registration to:
  eRA Commons Help Desk
  Phone: 301-402-7469 or 866-504-9552 (Toll Free)
  TTY: 301-451-5939
  Business hours M-F 7:00 a.m. 8:00 p.m. Eastern Time
  Email commons@od.nih.gov

3) Project Director/Principal Investigator (PD/PI) Registration in the NIH eRA Commons: Refer to the NIH eRA Commons System (COM) Users Guide.

• The individual(s) designated as PDs/PIs on the application must be registered also in the NIH eRA Commons.In the case of multiple PDs/PIs, all PDs/PIs must be registeredand be assigned the PI role in the eRA Commons prior to the submission of the application.
• Each PD/PI must hold a PD/PI account in the Commons. Applicants should not share a Commons account for both an Authorized Organization Representative/Signing Official (AOR/SO) role and a PD/PI role; however, if they have both a PD/PI role and an Internet Assisted Review (IAR) role, both roles should exist under one Commons account.
• When multiple PDs/PIs are proposed, all PDs/PIs at the applicant organization must be affiliated with that organization.PDs/PIs located at another institution need not be affiliated with the applicant organization, but must be affiliated with their own organization to be able to access the Commons.
• This registration/affiliation must be done by the AOR/SO or his/her designee who is already registered in the Commons.

Both the PD(s)/PI(s) and AOR/SO need separate accounts in the NIH eRA Commons since both are authorized to view the application image.

Several of the steps of the registration process could take four weeks or more. Therefore, applicants should immediately check with their business official to determine whether their organization/institution is already registered in both Grants.gov and the Commons. The NIH will accept electronic applications only from organizations that have completed all necessary registrations.

1. Request Application Information

Applicants must download the SF424 (R&R) application forms and the SF424 (R&R) Application Guide for this FOA through Grants.gov/Apply.

Note: Only the forms package directly attached to a specific FOA can be used. You will not be able to use any other SF424 (R&R) forms (e.g., sample forms, forms from another FOA), although some of the “Attachment” files may be useable for more than one FOA.

For further assistance, contact GrantsInfo — Telephone 301-435-0714, Email: GrantsInfo@nih.gov.

Telecommunications for the hearing impaired: TTY: (301) 451-5936

2. Content and Form of Application Submission

Prepare all applications using the SF424 (R&R) application forms and in accordance with the SF424 (R&R) Application Guide for this FOA through Grants.gov/Apply.

The SF424 (R&R) Application Guide is critical to submitting a complete and accurate application to NIH. Some fields within the SF424 (R&R) application components, although not marked as mandatory, are required by NIH (e.g., the Credential log-in field of the Research & Related Senior/Key Person Profile component must contain the PD/PIs assigned eRA Commons User ID). Agency-specific instructions for such fields are clearly identified in the Application Guide. For additional information, see Frequently Asked Questions Application Guide, Electronic Submission of Grant Applications.

The SF424 (R&R) application has several components. Some components are required, others are optional. The forms package associated with this FOA in Grants.gov/APPLYincludes all applicable components, required and optional. A completed application in response to this FOA includes the data in the following components:

Required Components:
SF424 (R&R) (Cover component)
Research & Related Project/Performance Site Locations
Research & Related Other Project Information
Research & Related Senior/Key Person
PHS398 Cover Page Supplement
PHS398 Research Plan
PHS398 Checklist
PHS398 Modular Budget or Research & Related Budget, as appropriate (See Section IV.6., Special Instructions, regarding appropriate required budget component.)

Optional Components:
PHS398 Cover Letter File
Research & Related Subaward Budget Attachment(s) Form

Foreign Organizations (Non-domestic [non-U.S.] Entities)

NIH policies concerning grants to foreign (non-U.S.) organizations can be found in the NIH Grants Policy Statement at:http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part12.htm#_Toc54600260.

Applications from Foreign organizations must:

• Request budgets in U.S. dollars;
• Prepare detailed budgets for all applications (that is, complete the Research & Related Budget component of the SF424 (R&R) application forms not the PHS398 Modular Budget component)(see NOT-OD-06-096);
• Not include any charge-back of customs and import fees;
• Comply with the format specifications, which are based upon a standard U.S. paper size of 8.5 x 11 within each PDF;
• If appropriate, request funds for up to 8% Facilities and Administrative (F&A) costs (excluding equipment) ( see NOT-OD-01-028, March 29, 2001);
• Comply with Federal/NIH policies on human subjects, animals, and biohazards; and
• Comply with Federal/NIH biosafety and biosecurity regulations (see Section VI.2., Administrative and National Policy Requirements)

Proposed research should provide special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions in other countries that are not readily available in the United States (U.S.) or that augment existing U.S. resources.

SPECIAL INSTRUCTIONS

Applications with Multiple PDs/PIs

When multiple PDs/PIs are proposed, NIH requires one PD/PI to be designated as the “Contact PI, who will be responsible for all communication between the PDs/PIs and the NIH, for assembling the application materials outlined below, and for coordinating progress reports for the project. The contact PD/PI must meet all eligibility requirements for PD/PI status in the same way as other PDs/PIs, but has no other special roles or responsibilities within the project team beyond those mentioned above.

Information for the Contact PD/PI should be entered in Item 13 of the SF424 (R&R) Cover component.All other PDs/PIs should be listed in the Research & Related Senior/Key Person component and assigned the project role of PD/PI.Please remember that all PDs/PIs must be registered in the eRA Commons prior to application submission.The Commons ID of each PD/PI must be included in the Credential field of the Research & Related Senior/Key Person component.Failure to include this data field will cause the application to be rejected.

All projects proposing Multiple PDs/PIs will be required to include a new section describing the leadership plan approach for the proposed project.

Multiple PD/PI Leadership Plan: For applications designating multiple PDs/PIs, a new section of the research plan, entitled Multiple PD/PI Leadership Plan, must be included. A rationale for choosing a multiple PD/PI approach should be described. The governance and organizational structure of the leadership team and the research project should be described, and should include communication plans, process for making decisions on scientific direction, and procedures for resolving conflicts.The roles and administrative, technical, and scientific responsibilities for the project or program should be delineated for the PDs/PIs and other collaborators.

If budget allocation is planned, the distribution of resources to specific components of the project or the individual PDs/PIs should be delineated in the Leadership Plan. In the event of an award, the requested allocations may be reflected in a footnote on the Notice of Award (NoA).

Applications Involving a Single Institution

When all PDs/PIs are within a single institution, follow the instructions contained in the SF424 (R&R) Application Guide.

Applications Involving Multiple Institutions

When multiple institutions are involved, one institution must be designated as the prime institution and funding for the other institution(s) must be requested via a subcontract to be administered by the prime institution. When submitting a detailed budget, the prime institution should submit its budget using the Research & Related Budget component.All other institutions should have their individual budgets attached separately to the Research & Related Subaward Budget Attachment(s) Form.See Section 4.8 of the SF424 (R&R) Application Guide for further instruction regarding the use of the subaward budget form.

When submitting a modular budget, the prime institution completes the PHS398 Modular Budget component only.Information concerning the consortium/subcontract budget is provided in the budget justification. Separate budgets for each consortium/subcontract grantee are not required when using the Modular budget format. See Section 3.4 of the Application Guide for further instruction regarding the use of the PHS398 Modular Budget component.

3. Submission Dates and Times

See Section IV.3.A. for details.

3.A. Submission, Review, and Anticipated Start Dates
Opening Date:August 16, 2009 (Earliest date an application may be submitted to Grants.gov)
Letters of Intent Receipt Date(s): August 17, 2009
NOTE: On-time submission requires that applications be successfully submitted to Grants.gov no later than 5:00 p.m. local time (of the applicant institution/organization).
Application Due Date(s): September 16, 2009, January 19, 2010, May 19, 2010, September 16, 2010, January 19, 2011, May 19, 2011
AIDS Application Due Date(s): Not applicable
Peer Review Date(s): January/February 2010; May/June 2010; September/October 2010; January/February 2011; May/June 2011; September/October 2011
Council Review Date(s): May 2010, October 2010, January 2011, May 2011, October 2011, January 2012
Earliest Anticipated Start Date(s): July 2010, December 2010, April 2011, July 2011, December 2011, April 2012

3.A.1. Letter of Intent

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

• Descriptive title of proposed research.
• Name, address, and telephone number of the PD(s)/PI(s).
• Names of other key personnel.
• Participating institutions.
• Number and title of this funding opportunity.

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 in Section IV.3.A.

The letter of intent should be sent to:

Zhaoxia Ren, M.D., Ph.D.
Medical Officer
Obstetric and Pediatric Pharmacology Branch
Center for Research for Mothers and Children
Eunice Kennedy Shriver National Institute
of Child Health and Human Development, NIH
6100 Executive Blvd Room 4B15 MSC 7510
Bethesda, MD 20892-7510
Phone: 301-402-9340
Fax: 301-480-2897
Email: zren@mail.nih.gov

3.B. Submitting an Application Electronically to the NIH

To submit an application in response to this FOA, applicants should access this FOA via http://www.grants.gov/applicants/apply_for_grants.jsp and follow Steps 1-4. Note: Applications must only be submitted electronically. PAPER APPLICATIONS WILL NOT BE ACCEPTED.

3.C. Application Processing

Applications may be submitted on or after the opening date and must be successfully received by Grants.gov no later than 5:00 p.m. local time(ofthe applicant institution/organization)on the application due date(s). (See Section IV.3.A. for all dates.) If an application is not submitted by the due date(s) and time, the application may be delayed in the review process or not reviewed.

Once an application package has been successfully submitted through Grants.gov, any errors have been addressed, and the assembled application has been created in the eRA Commons, the PD/PI and the Authorized Organization Representative/Signing Official (AOR/SO) have two weekdays (Monday Friday, excluding Federal holidays) to view the application image to determine if any further action is necessary.

• If everything is acceptable, no further action is necessary. The application will automatically move forward to the Division of Receipt and Referral in the Center for Scientific Review for processing after two weekdays, excluding Federal holidays.
• Prior to the submission deadline, the AOR/SO can Reject the assembled application and submit a changed/corrected application within the two-day viewing window. This option should be used if it is determined that some part of the application was lost or did not transfer correctly during the submission process, the AOR/SO will have the option to Reject the application and submit a Changed/Corrected application. In these cases, please contact the eRA Help Desk to ensure that the issues are addressed and corrected. Once rejected, applicants should follow the instructions for correcting errors in Section 2.12, including the requirement for cover letters on late applications. The Reject feature should also be used if you determine that warnings are applicable to your application and need to be addressed now. Remember, warnings do not stop further application processing. If an application submission results in warnings (but no errors), it will automatically move forward after two weekdays if no action is taken. Some warnings may need to be addressed later in the process.
• If the two-day window falls after the submission deadline, the AOR/SO will have the option to Reject the application if, due to an eRA Commons or Grants.gov system issue, the application does not correctly reflect the submitted application package (e.g., some part of the application was lost or didnt transfer correctly during the submission process). The AOR/SO should first contact the eRA Commons Helpdesk to confirm the system error, document the issue, and determine the best course of action. NIH will not penalize the applicant for an eRA Commons or Grants.gov system issue.
• If the AOR/SO chooses to Reject the image after the submission deadline for a reason other than an eRA Commons or Grants.gov system failure, a changed/corrected application still can be submitted, but it will be subject to the NIH late policy guidelines and may not be accepted. The reason for this delay should be explained in the cover letter attachment.
• Both the AOR/SO and PD/PI will receive e-mail notifications when the application is rejected or the application automatically moves forward in the process after two days.

Upon receipt, applications will be evaluated for completeness by the Center for Scientific Review, NIH. Incomplete applications will not be reviewed. 

There will be an acknowledgement of receipt of applications from Grants.gov and the Commons. The submitting AOR/SO receives the Grants.gov acknowledgments. The AOR/SO and the PI receive Commons acknowledgments. Information related to the assignment of an application to a Scientific Review Group is also in the Commons.

Note: Since email can be unreliable, it is the responsibility of the applicant to check periodically on their application status in the Commons.

The NIH will not accept any application in response to this FOA that is essentially the same as one currently pending initial merit review unless the applicant withdraws the pending application. The NIH will not accept any application that is essentially the same as one already reviewed. However, the NIH will accept a resubmission application, but such application must include an Introduction addressing the critique from the previous review.

4. Intergovernmental Review

This initiative is not subject to intergovernmental review.

5. Funding Restrictions

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Pre-award costs are allowable. A grantee may, at its own risk and without NIH prior approval, incur obligations and expenditures to cover costs up to 90 days before the beginning date of the initial budget period of a new or renewal award if such costs: 1) are necessary to conduct the project, and 2) would be allowable under the grant, if awarded, without NIH prior approval. If specific expenditures would otherwise require prior approval, the grantee must obtain NIH approval before incurring the cost. NIH prior approval is required for any costs to be incurred more than 90 days before the beginning date of the initial budget period of a new or renewal award.

The incurrence of pre-award costs in anticipation of a competing or non-competing award imposes no obligation on NIH either to make the award or to increase the amount of the approved budget if an award is made for less than the amount anticipated and is inadequate to cover the pre-award costs incurred. NIH expects the grantee to be fully aware that pre-award costs result in borrowing against future support and that such borrowing must not impair the grantee’s ability to accomplish the project objectives in the approved time frame or in any way adversely affect the conduct of the project. See NIH Grants Policy Statement http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part6.htm.

6. Other Submission Requirements and Information

PD/PI Credential (e.g., Agency Login)

The NIH requires the PD(s)/PI(s) to fill in his/her Commons User ID in the PROFILE Project Director/Principal Investigator section, Credential log-in field of the Research & Related Senior/Key Person Profile component.

Organizational DUNS

The applicant organization must include its DUNS number in its Organization Profile in the eRA Commons. This DUNS number must match the DUNS number provided at CCR registration with Grants.gov. For additional information, see Frequently Asked Questions Application Guide, Electronic Submission of Grant Applications.

PHS398 Research Plan Component Sections

All application instructions outlined in the SF424 (R&R) Application Guide are to be followed, incorporating “Just-in-Time” information concepts, and with the following additional requirements:

Specific Instructions for Applications Requesting $500,000 (direct costs) or More per Year

Applicants requesting $500,000 or more in direct costs for any year (excluding consortium F&A costs) must carry out the following steps:

1) Contact the IC program staff at least 6 weeks before submitting the application, i.e., as plans are being developed for the study;

2) Obtain agreement from the IC staff that the IC will accept the application for consideration for award; and,

3) Include a cover letter with the application that identifies the staff member and IC who agreed to accept assignment of the application.

This policy applies to all new, renewal, revision, or resubmission applications. See NOT-OD-02-004, October 16, 2001.

Appendix Materials

Applicants must follow the specific instructions on Appendix materials as described in the SF424 (R&R) Application Guide (See http://grants.nih.gov/grants/funding/424/index.htm).

Do not use the Appendix to circumvent the page limitations. An application that does not comply with the required page limitations may be delayed in the review process.

Resource Sharing Plan(s)

NIH considers the sharing of unique research resources developed through NIH-sponsored research an important means to enhance the value and further the advancement of the research. When resources have been developed with NIH funds and the associated research findings published or provided to NIH, it is important that they be made readily available for research purposes to qualified individuals within the scientific community. If the final data/resources are not amenable to sharing, this must be explained in the Resource Sharing section of the application (see http://grants.nih.gov/grants/policy/data_sharing/data_sharing_faqs.htm).

(a) Data Sharing Plan: Not Applicable

(b) Sharing Model Organisms: Regardless of the amount requested, all applications where the development of model organisms is anticipated are expected to include a description of a specific plan for sharing and distributing unique model organisms and related resources, or state appropriate reasons why such sharing is restricted or not possible. SeeSharing Model Organisms Policy, and NIH Guide NOT-OD-04-042.

(c) Genome-Wide Association Studies (GWAS): Regardless of the amount requested, applicants seeking funding for a genome-wide association study are expected to provide a plan for submission of GWAS data to the NIH-designated GWAS data repository, or provide an appropriate explanation why submission to the repository is not possible. A genome-wide association study is defined as any study of genetic variation across the entire genome that is designed to identify genetic associations with observable traits (e.g., blood pressure or weight) or the presence or absence of a disease or condition. For further information see Policy for Sharing of Data Obtained in NIH Supported or Conducted Genome-Wide Association Studies (go to NOT-OD-07-088, and http://grants.nih.gov/grants/gwas/.)

Foreign Applications (Non-domestic [non-U.S.] Entities)

Indicate how the proposed project has specific relevance to the mission and objectives of the NIH/IC and has the potential for significantly advancing the health sciences in the United States

Section V. Application Review Information

Only the review criteria described below will be considered in the review process.

2. Review and Selection Process

Applications that are complete will be evaluated for scientific and technical merit by the Center for Scientific Review in accordance with NIH peer review procedures (http://grants1.nih.gov/grants/peer/) using the review criteria stated below.

As part of the scientific peer review, all applications will:

• Undergo a selection process in which only those applications deemed to have the highest scientific and technical merit, generally the top half of applications under review, will be discussed and assigned an impact/priority score;
• Receive a written critique; and
• Receive a second level of review by the National Advisory Child Health and Human Development Council (NACHHD).

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

• Scientific and technical merit of the proposed project as determined by scientific peer review.
• Availability of funds.
• Relevance of the proposed project to program priorities.

The mission of the NIH is to support science in pursuit of knowledge about the biology and behavior of living systems and to apply that knowledge to extend healthy life and reduce the burdens of illness and disability. As part of this mission, applications submitted to the NIH for grants or cooperative agreements to support biomedical and behavioral research are evaluated for scientific and technical merit through the NIH peer review system.

Overall Impact. Reviewers will provide an overall impact/priority score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following five core review criteria, and additional review criteria (as applicable for the project proposed).

Core Review Criteria. Reviewers will consider each of the five review criteria below in the determination of scientific and technical merit, and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.

Significance. Does the project address an important problem or a critical barrier to progress in the field? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

Investigator(s). Are the PD/PIs, collaborators, and other researchers well suited to the project? If Early Stage Investigators or New Investigators, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?

Innovation. Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed?

Approach. Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed?

If the project involves clinical research, are the plans for 1) Protections for Human Subjects, and 2) inclusion of minorities and members of both sexes/genders, as well as the inclusion of children, justified in terms of the scientific goals and research strategy proposed?

Environment. Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements?

In addition to the above review criteria, the following criteria will be addressed and considered in the determination of scientific merit and the rating.

Additional Review Criteria

As applicable for the project proposed, reviewers will consider the following additional items in the determination of scientific and technical merit, but will not give separate scores for these items.

Protections for Human Subjects. For research that involves human subjects but does not involve one of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or more of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials.

Inclusion of Women, Minorities, and Children. When the proposed project involves clinical research, the committee will evaluate the proposed plans for inclusion of minorities and members of both genders, as well as the inclusion of children.

Vertebrate Animals. The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following five points: 1) proposed use of the animals, and species, strains, ages, sex, and numbers to be used; 2) justifications for the use of animals and for the appropriateness of the species and numbers proposed; 3) adequacy of veterinary care; 4) procedures for limiting discomfort, distress, pain and injury to that which is unavoidable in the conduct of scientifically sound research including the use of analgesic, anesthetic, and tranquilizing drugs and/or comfortable restraining devices; and 5) methods of euthanasia and reason for selection if not consistent with the AVMA Guidelines on Euthanasia.

Resubmission Applications. When reviewing a Resubmission application (formerly called an amended application), the committee will evaluate the application as now presented, taking into consideration the responses to comments from the previous scientific review group and changes made to the project.

Renewal Applications. When reviewing a Renewal application (formerly called a competing continuation application), the committee will consider the progress made in the last funding period.

Revision Applications. When reviewing a Revision application (formerly called a competing supplement application), the committee will consider the appropriateness of the proposed expansion of the scope of the project. If the Revision application relates to a specific line of investigation presented in the original application that was not recommended for approval by the committee, then the committee will consider whether the responses to comments from the previous scientific review group are adequate and whether substantial changes are clearly evident.

Biohazards. Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate protection is proposed.

.

Protections for Human Subjects. For research that involves human subjects but does not involve one of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or more of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials.

Inclusion of Women, Minorities, and Children. When the proposed project involves clinical research, the committee will evaluate the proposed plans for inclusion of minorities and members of both genders, as well as the inclusion of children.

Vertebrate Animals. The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following five points: 1) proposed use of the animals, and species, strains, ages, sex, and numbers to be used; 2) justifications for the use of animals and for the appropriateness of the species and numbers proposed; 3) adequacy of veterinary care; 4) procedures for limiting discomfort, distress, pain and injury to that which is unavoidable in the conduct of scientifically sound research including the use of analgesic, anesthetic, and tranquilizing drugs and/or comfortable restraining devices; and 5) methods of euthanasia and reason for selection if not consistent with the AVMA Guidelines on Euthanasia.

Resubmission Applications. When reviewing a Resubmission application (formerly called an amended application), the committee will evaluate the application as now presented, taking into consideration the responses to comments from the previous scientific review group and changes made to the project.

Renewal Applications. When reviewing a Renewal application (formerly called a competing continuation application), the committee will consider the progress made in the last funding period.

Biohazards. Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate protection is proposed.

Additional Review Considerations

As applicable for the project proposed, reviewers will address each of the following items, but will not give scores for these items and should not consider them in providing an overall impact/priority score.

Budget and Period Support. Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research.

Select Agents Research. Reviewers will assess the information provided in this section of the application, including 1) the Select Agent(s) to be used in the proposed research, 2) the registration status of all entities where Select Agent(s) will be used, 3) the procedures that will be used to monitor possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).

Applications from Foreign Organizations. Reviewers will assess whether the project presents special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions that exist in other countries and either are not readily available in the United States or augment existing U.S. resources.

Resource Sharing Plans. Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: 1) Data Sharing Plan (Not Applicable); 2) Sharing Model Organisms (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-04-042.html); and 3) Genome Wide Association Studies (GWAS) (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-07-088.html).

3. Anticipated Announcement and Award Dates

Not Applicable

Section VI. Award Administration Information

After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the NIH eRA Commons.

If the application is under consideration for funding, NIH will request “just-in-time” information from the applicant. For details, applicants may refer to the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General.

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization. The NoA signed by the grants management officer is the authorizing document. Once all administrative and programmatic issues have been resolved, the NoA will be generated via email notification from the awarding component to the grantee business official.

Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient’s risk. These costs may be reimbursed only to the extent considered allowable pre-award costs. See Section IV.5., Funding Restrictions.

2. Administrative and National Policy Requirements

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities.

3. Reporting

Awardees are encouraged to report any scientific highlights, publications, patents, and products resulted from the awards directly to the scientific program staff of the funding agency.

When multiple years are involved, awardees will be required to submit the Non-Competing Continuation Grant Progress Report (PHS 2590) annually and financial statements as required in the NIH Grants Policy Statement.

A final progress report, invention statement, and Financial Status Report are required when an award is relinquished when a recipient changes institutions or when an award is terminated.

Section VII. Agency Contacts

1. Scientific/Research Contact(s):

Zhaoxia Ren, M.D., Ph.D.
Medical Officer
Obstetric and Pediatric Pharmacology Branch
Center for Research for Mothers and Children
Eunice Kennedy Shriver National Institute
of Child Health and Human Development, NIH
6100 Executive Blvd Room 4B15 MSC 7510
Bethesda, MD 20892-7510
Phone: 301-402-9340
Fax: 301-480-2897
Email: zren@mail.nih.gov

2. Peer Review Contact(s):

Not Applicable

3. Financial/Grants Management Contact(s):

Bryan Clark, MBA
Grants Management
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
6100 Executive Boulevard, Room 8A01, MSC 7510
Rockville, MD 20892-7510
Telephone: (301) 435-6975
Fax: 301-451-5510
Email Brian.Clark@nih.gov

Section VIII. Other Information

Vertebrate Animals:
Recipients of PHS support for activities involving live, vertebrate animals must comply with PHS Policy on Humane Care and Use of Laboratory Animals (http://grants.nih.gov/grants/olaw/references/PHSPolicyLabAnimals.pdf) as mandated by the Health Research Extension Act of 1985 (http://grants.nih.gov/grants/olaw/references/hrea1985.htm), and the USDA Animal Welfare Regulations (http://www.nal.usda.gov/awic/legislat/usdaleg1.htm) as applicable.

Human Subjects Protection:
Federal regulations (45 CFR 46) 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). Monitoring should be commensurate with risk. The establishment of data and safety monitoring boards (DSMBs) is required for multi-site clinical trials involving interventions that entail potential risks to the participants (NIH Policy for Data and Safety Monitoring, NIH Guide for Grants and Contracts,http://grants.nih.gov/grants/guide/notice-files/not98-084.html).

Sharing Research Data:
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 (http://grants.nih.gov/grants/policy/data_sharing). Investigators should seek guidance from their institutions, on issues related to institutional policies and local institutional review board (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 impact/priority score.

Policy for Genome-Wide Association Studies (GWAS):
NIH is interested in advancing genome-wide association studies (GWAS) to identify common genetic factors that influence health and disease through a centralized GWAS data repository. For the purposes of this policy, a genome-wide association study is defined as any study of genetic variation across the entire human genome that is designed to identify genetic associations with observable traits (such as blood pressure or weight), or the presence or absence of a disease or condition. All applications, regardless of the amount requested, proposing a genome-wide association study are expected to provide a plan for submission of GWAS data to the NIH-designated GWAS data repository, or provide an appropriate explanation why submission to the repository is not possible. Data repository management (submission and access) is governed by the Policy for Sharing of Data Obtained in NIH Supported or Conducted Genome-Wide Association Studies, NIH Guide NOT-OD-07-088. For additional information, see http://grants.nih.gov/grants/gwas/

Sharing of Model Organisms:
NIH is committed to support efforts that encourage sharing of important research resources including the sharing of model organisms for biomedical research (seehttp://grants.nih.gov/grants/policy/model_organism/index.htm). At the same time the NIH recognizes the rights of grantees and contractors to elect and retain title to subject inventions developed with Federal funding pursuant to the Bayh-Dole Act (see the NIH Grants Policy Statement. Beginning October 1, 2004, all investigators submitting an NIH application or contract proposal are expected to include in the application/proposal a description of a specific plan for sharing and distributing unique model organism research resources generated using NIH funding or state why such sharing is restricted or not possible. This will permit other researchers to benefit from the resources developed with public funding. The inclusion of a model organism sharing plan is not subject to a cost threshold in any year and is expected to be included in all applications where the development of model organisms is anticipated.

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 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 funding opportunity 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.

Inclusion of Women, Minorities, and Children:
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 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines is available athttp://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 SF424 (R&R) application; 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 Clinical Research:
The NIH maintains a policy that children (i.e., individuals under the age of 21) must be included in all clinical research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them.

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 (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 applications for research involving human subjects and individuals designated as key personnel. The policy is available 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-09-116.html. Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (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.

NIH Public Access Policy Requirement:
In accordance with the NIH Public Access Policy, investigators funded by the NIH must submit or have submitted for them to the National Library of Medicines PubMed Central (seehttp://www.pubmedcentral.nih.gov/), an electronic version of their final, peer-reviewed manuscripts upon acceptance for publication, to be made publicly available no later than 12 months after the official date of publication. The NIH Public Access Policy is available at (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-08-033.html). For more information, see the Public Access webpage at http://publicaccess.nih.gov/.

Standards for Privacy of Individually Identifiable Health Information:
The Department of Health and Human Services (HHS) 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 HHS Office for Civil Rights (OCR).

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 athttp://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. For publications listed in the appendix and/or Progress report, Internet addresses (URLs) or PubMed Central (PMC) submission identification numbers must be used for publicly accessible on-line journal articles.Publicly accessible on-line journal articles or PMC articles/manuscripts accepted for publication that are directly relevant to the project may be included only as URLs or PMC submission identification numbersaccompanying the full reference in either the Bibliography & References Cited section, the Progress Report Publication List section, or the Biographical Sketch section of the NIH grant application. A URL or PMC submission identification number citation may be repeated in each of these sections as appropriate. There is no limit to the number of URLs or PMC submission identification numbers that can be cited.

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 FOA 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. 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 Part 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 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.

Loan Repayment Programs:
NIH encourages applications for educational loan repayment from qualified health professionals who have made a commitment to pursue a research career involving clinical, pediatric, contraception, infertility, and health disparities related areas. The LRP is an important component of NIH’s efforts to recruit and retain the next generation of researchers by providing the means for developing a research career unfettered by the burden of student loan debt. Note that an NIH grant is not required for eligibility and concurrent career award and LRP applications are encouraged. The periods of career award and LRP award may overlap providing the LRP recipient with the required commitment of time and effort, as LRP awardees must commit at least 50% of their time (at least 20 hours per week based on a 40 hour week) for two years to the research. For further information, please see:http://www.lrp.nih.gov/.

Source: U.S. Department of Health & Human Services, Office of Extramural Research, National Institutes of Health – http://grants.nih.gov/grants/guide/rfa-files/RFA-HD-07-019.html