Required Application Instructions

It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.

Part 1. Overview Information
Part 2. Full Text of the Announcement

Section I. Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

Purpose

The purpose of this initiative is to assess the maximum health benefits that may result from reduced household air pollution through clean cooking intervention and, when applicable, intervention to reduce second hand cigarette smoke exposure to yield evidence against which other cooking interventions may be evaluated. This Funding Opportunity Announcement (FOA) represents a public/private partnership and unites a variety of partners including the NIH, the Gates Foundation, the Global Alliance for Clean Cookstoves (GACC), and the Global Alliance for Chronic Diseases (GACD).

Background

According to the Global Burden of Disease 2010 data, household air pollution and tobacco smoking are the third and second leading risk factors, respectively, after high blood pressure, for Global Mortality and Disability-Adjusted Life Years (DALYs) lost. These exposures disproportionately affect LMICs, particularly women and children.

Nearly 3 billion people still cook, heat, and light their homes using open fires and traditional stoves burning solid fuels (i.e., wood, crop wastes, charcoal, coal, and dung). Such inefficient cooking fuels and technologies produce high levels of household air pollution with a range of harmful pollutants, including fine particulate matter that penetrates deeply into the lungs. In poorly ventilated dwellings, household air concentrations of small particles (PM2.5) can reach concentrations 100 times higher than acceptable levels. According to WHO estimates, Household Air Pollution (HAP) from solid fuels is responsible for approximately 4.3 million early deaths per year, primarily in LMICs. Approximately 17% of annual lung cancer deaths in adults around the world are attributable to exposure to carcinogens from HAP. Additionally, research has shown that exposure to HAP is associated with low birth weight and higher infant mortality, increased respiratory infections in children, and increased rates of stroke, cardiovascular disease, lung cancer, and cataracts. HAP exposures disproportionately affect women and children, as they spend more time inside the home environment, and HAP exposures are responsible for a substantial portion of the increasing burden of chronic non-communicable diseases in men, women, and children. Cooking with solid fuels is also associated with increased burns and other injuries in both children and adults.

The need to address this problem has been underscored by world-wide initiatives led by the GACC, as well as several international development agencies, aimed at replacing open fires with cleaner cooking technology. The GACC has established a goal of 100 million additional homes adopting clean and efficient cooking by the year 2020. Many diverse stove and fuel distribution efforts are already underway around the world.

However, there is still insufficient evidence that the introduction of cleaner cooking technology, at a population scale, leads to significant positive health benefits. Studies have shown that continued use of traditional open fires occurs alongside cleaner stoves, commonly referred to as stacking. Similarly, polluted ambient air from multiple sources, including the chimneys from other homes, burning of fields, industrial, or other sources enters the home and confounds the results. Although progress is tangible and several field trials have demonstrated significant reductions in environmental emissions with improved cookstoves, proof of a concomitant effect on health outcomes lacks evidence. This may be because of a lack of a clear understanding of exposure-response relationships, together with a paucity of reliable direct personal exposure data; a lack of understanding of which combinations of interventions (targeting fuel, stove design, house architecture, behavior, regulation and/or financing) are likely to have the biggest impact in a given setting; the health markers currently employed are insensitive to the short term changes in air quality produced by the interventions; and/or the fact that an unmeasured health benefit requires longer follow-up.

There is a need for proof of principle data to guide ongoing and future large scale investments in stove and fuel development and rollout programs, prompting for carefully controlled interventional research projects that focus rigorous attention to adoption and use of the cleanest possible fuels and cooking technologies. It is not known how clean the household needs to be to achieve significant reductions, for example, in childhood pneumonia and other respiratory diseases. Moreover, there is a need to frame the research question within the complexities of the cultural and social barriers to cookstove adoption, the socioeconomic determinants of access to cleaner stoves and fuels, and the critical household behaviors behind successful adoption of new technologies. Interventions need to be designed to optimize the socio-economic and behavioral context to achieve greatest possible displacement of polluting forms of cooking and overall levels of air quality that approach or meet WHO's new Household Air Quality Guidelines (http://www.who.int/indoorair/guidelines/hhfc/en/). Recent experience indicates that this is unlikely to be possible without principal reliance on clean fuels, and the intervention may require additional technological and behavioral components.

While cookstoves are a major source of HAP, burning solid fuels for heating and lighting, and use of tobacco products, substantially contribute to the multiple exposures inside the home environment.

Secondhand cigarette smoke exposure is estimated to cause over 600,000 deaths worldwide each year, with a disproportionately high impact on non-smoking women and children. The largest disease burdens associated with secondhand smoke worldwide are from lower respiratory infections in children younger than 5 years, ischemic heart disease in adults, and asthma in adults and children. However, untangling the effects of multiple sources of indoor air pollution can be complex. For example, in China lung cancer incidence is very high in men and women, yet only 2.4% of women smoke, compared with 53% of men. Multiple factors may contribute to lung cancer among non-smoking women, including exposure to secondhand smoke and exposure to solid fuel smoke from cooking and heating, as well as ambient air pollution. However, while several studies have looked at lung cancer among women, the relative contributions of these factors are poorly understood. Thus, it is important in many environments to evaluate interventions that combine introduction of improved cookstoves with smoke-free home interventions designed to reduce all particulate matter exposures in the home.

An underlying premise of this initiative is that improvement of household air quality will result in the reduction of exposure as measured by environmental sampling (reduced exposure to air pollution) and through bio-monitoring of known and new analytes (reduction in body burden), resultant changes in biological responses, and ultimately improved health. There are validated analytical methods to quantitate biomarkers for some of the principal pollutants such as polycyclic aromatic hydrocarbons, specifically benzo[a]pyrene. Additionally, validated tobacco-specific biomarkers (including cotinine for nicotine exposure and metabolites of the tobacco-specific nitrosamines) exist for assessing tobacco exposure apart from other agents. However, there is a need to develop new methods to measure other indoor air pollutants of concern as well as to distinguish exposure from multiple sources (outdoor air pollution, indoor air pollution, and environmental cigarette smoke). This deficit poses a major challenge to interpret the relationship of exposure (or reduced exposures) to most health outcomes.

Furthermore, there is a need to identify and better understand markers of biological impact and response that may be related to disease processes which will manifest themselves at later stages in life. Recent epidemiological evidence indicates that the largest morbidity and mortality from HAP is due to slower developing conditions such as neurodevelopmental disorders, ischemic heart disease, chronic lung disease, lung cancer, hypertension, and stroke, for which the development of early indicators and biomarkers is still an enormous scientific challenge. Current investigations on early indicators for these major killers include a wide variety of measures, such as blood pressure, heart rate and lung function values, markers of inflammation like C reactive protein (CRP) and Interleukin-6 (IL-6), cytochrome P450s, and tumor associated antibodies. This HAP intervention trial offers an important platform to explore and expand the range of markers in varied exposure and genetic backgrounds.

Finally, in a large research project in LMICs, such as this one, it is both ethically required and practically necessary to develop local scientists and other participants to conduct such research. In particular, as this is a growing research area and a major global public health need, enabling local scientists and others to conduct related research is imperative.

In summary, the focus on clean cooking and smoke-free homes has particular relevance for non-communicable diseases worldwide and represents a common interest for multiple ICs of the NIH and other non-Government partners.

For example, with the burden of chronic non-communicable diseases rapidly increasing, the Global Alliance for Chronic Diseases (GACD) is launching coordinated calls for proposals with a focus on implementation research which examines interventions that aim to prevent and/or manage chronic lung diseases in low- and middle-income countries (LMICs as defined by The World Bank: http://data.worldbank.org/about/country-and-lending-groups). Implementation research examines what interventions work, for whom, under what contextual circumstances, and whether the intervention(s) are affordable, adaptable, and scalable in ways that are long-term, accessible, and equitable.

This FOA represents the NIH's contribution to the GACD coordinated call for research on prevention and management of chronic lung diseases for 2016.

Applicants may also want to review the activities of the Fogarty International Center-led Clean Cooking Implementation Science Network (ISN) as an example of investigators engaged in HAP-relevant research. This network aims to develop the science of clean cooking implementation and enhanced guidance to the research and development communities in relation to uptake and use of clean cooking technology.

The Bill & Melinda Gates Foundation (http://www.gatesfoundation.org/) is interested in quantifying exposure to PM2.5 in children under 5 years of age using newly developed personal monitors adapted to the pediatric population, improving our knowledge of exposure-response relationship between cooking smoke and pediatric pneumonia endpoints, and evaluating the potential for clean cooking interventions to achieve significant reductions in the incidence of childhood pneumonia and thereby enhance survival of children under 5 years of age.

The Global Alliance for Clean Cookstoves (GACC) is interested in enhancing the evidence base for the health benefits of clean cooking, including effects on child survival, and on chronic cardiopulmonary diseases.

NIH and the Bill & Melinda Gates Foundation combined funds will support the successful projects under this FOA. The GACC will negotiate and leverage additional support for the CICBC, in the form of an additional trial site and/or expanded support to enable assessment of additional outcomes, directly with the awardee upon final selection of the most meritorious application.

Program Structure

This FOA is intended to support an overall program consisting of a Clinical Intervention, Coordinating and Biomarker Center (CICBC) and a Steering Committee (SC).

The CICBC

It is anticipated that the CICBC will:

1) Implement and manage a clinical trial across three or more Low and Middle Income Country (LMIC) settings to improve household air quality by testing the impact of improved stove and fuel interventions and, when applicable intervention to reduce second-hand cigarette smoke on health outcomes in exposed populations, especially women and children under the age of 5 years; assess short-term (4-5 years) and long-term health outcomes of interventions studied with a particular focus on women and children under the age of 5 years; develop and implement an air pollution exposure monitoring strategy, including personal monitoring, for the selected stove/fuel used in the intervention trial.

2) Establish a biomarker center for the development and validation of clinical, physiological, chemical, biochemical and/or microbiological markers of exposure and pathophysiological responses to household air pollution.

The CICBC will assist in the development of study-specific documents and manuals of procedures, including standardized exposure assessment protocols, archive study documents, and distribute them through a secure website accessible to the Investigators, NHLBI and other NIH partners; organize meetings and teleconferences of HAP committees and boards; develop standard processes to expedite network operations, such as use of master trial agreements and a central IRB of record. The CICBC will coordinate protocol-specific training of staff at the LMIC Clinical Centers and sub-sites in the protection of human research subjects and their privacy and in study procedures, including completion of forms; administration of questionnaires; laboratory testing; bio-specimen procurement, processing, and shipping; data entry; quality control; and ascertainment and reporting of adverse events. The CICBC will develop standards for testing and certification of staff, obtain steering Committee (SC, see below) concurrence, and maintain related records.

The CICBC will create and operate a biospecimen repository for the biospecimen collection as necessary for the protocol, assuring linkage of biospecimens to clinical data in a manner that protects human subject privacy; the physical location of the biospecimens may vary according to the local situation, nevertheless the CICBC or its local representative will store and retrieve specimens under appropriate conditions and with provision for catastrophic events such as power failure. The biomarker development and validation element of the CICBC will perform protocol specific HAP biomarker analyses and -omics analyses (i.e., transcriptome and microbiome analyses, mRNA, miRNA, viro-, phylo-chip) of the samples obtained by the LMIC Clinical Centers, will analyze specific biomarkers and -omic data, testing for associations with the clinical phenotypes, and will prepare a limited dataset for deposit in the NHLBI BioLINCC repository and will be expected to coordinate with the NHLBI BioLINCC program to ensure that study procedures are compatible with that program's requirements for bio-specimen collection, labelling, and storage. Interventions must incorporate adequate and repeated measures of exposure in the household to HAP and, in any population where relevant, secondhand smoke using state of the art methods.

The CICBC will provide a secure web-based portal for distribution of study documents, communications among investigators, and outreach to the public. Access to materials in development and other confidential information will be limited by password protection to authorized members of the HAP network. The CICBC will maintain an operations calendar; records of HAP activities; and a file of all study documents, including protocols, manuals of Standard Operating Procedures (SOPs), minutes of meetings, summaries of study progress, a log of SC decisions, dates of protocol approvals and modifications, IRB approvals at all sites, and staff training certifications. The CICBC will implement procedures for backing up the program’s administrative data, including intermittent duplication of the database with storage at a remote facility. The CICBC will contribute summaries of study progress to reports prepared for submission to the Data and Safety Monitoring Board (DSMB, see below) and NHLBI.

The CICBC will schedule, organize, and accommodate all HAP committees and boards meetings and teleconferences. Payment for meeting rooms and consultant costs of the DSMB members will be the responsibility of the CICBC.

The Biomarker Center

The second section of the program will include a biomarker center (this can be in the form of a subcontract) for the development and validation of clinical, physiological, chemical, biochemical and/or microbiological markers of: a) exposure and b) pathophysiological responses. The data accrued in this study will provide possible mechanistic understanding of the clinical questions. This t of the FOA will be awarded and managed in an integrated manner with the field trial to establish a conduit to test known and novel biomarkers and their feasibility in measuring exposure and potential health effects from use of improved cookstove fuels and technologies. The biomarker development and validation study must be led by a lead investigator other than the one for the clinical study. This individual must have demonstrated expertise in biomarker development and validation. It is envisioned that for various reasons in some circumstances the lead investigator(s) of the biomarker project may need to perform biomarker analyses within the LMIC where the samples have been collected. Exportability and adaptability to different local situations (i.e., cultural, legal, etc.) of the biomarkers analysis platforms should be addressed in the application, and it is highly recommended that the lead investigator(s) proposes solutions in the application to possible challenges that involve the specific LMIC research communities proposed. The biomarker development and validation study may be conducted by an investigator at a separate institution through a sub-contract or consortium agreement. The lead investigator(s) of both projects will collaborate closely to create a seamless research process and integrated data set that analyzes and connects the outcomes of the clinical trial with the biomarker data.

Steering Committee (SC)

The SC will have responsibility for developing the overall scientific direction of the study; assuring compliance with study policies and procedures; selecting topics for investigation; designing study protocols; implementing studies; ensuring data quality and completeness; participating in the analysis and interpretation of data; and reporting results in presentations and publications.

Supported Research Activities and Requirements

The FOA is intended to support trans-disciplinary teams of researchers that propose to work together within existing research infrastructures in low and middle income countries to develop and/or test improved stove and fuel interventions, along with interventions to reduce second-hand tobacco smoke exposure, where relevant, at the population scale. It is anticipated that studies will be tailored to the specific communities studied, and that the overall design and execution should result in highlighting principles applicable across diverse community and social and cultural settings. It is envisioned that cooking interventions will emphasize the cleanest possible fuels for cooking and other combustion activities in the home, recognizing that minimizing concurrent use of traditional open fires may require a multi-component intervention.

This initiative encourages leveraging existing infrastructure and building upon data and cohorts already developed through existing initiatives related to implementation of household air pollution and secondhand smoke interventions or other relevant projects. Field research projects should address short-term (4-5 years) health outcomes of interventions by evaluating parameters including, but not limited to, low birth weight and infant mortality, respiratory infections, incidence of symptom precursors of respiratory diseases like wheezing, neurocognitive development in children, and rates of respiratory, stroke, and cardiovascular diseases, and lung cancer in adults. Given the long latencies for these latter chronic conditions, early stage indicators and biomarkers, and possibly other approaches, including linked epidemiological studies, may be necessary.

Research that addresses: 1) structural, systems, and community level analysis of relevant environmental and behavioral patterns before and after an intervention; 2) community level influences that determine preferences for specific practices; 3) motivators and barriers to adoption; and 4) key behaviors associated with use of solid fuels and tobacco products inside the home, is strongly encouraged. Collaboration with the NIH Clean Cooking Implementation Science Network (see description below under Organization and Cooperation) could be helpful in this regard. It is anticipated that the research conducted should provide high quality data useful for evaluation of the intervention on exposure reductions, short-term and long-term health outcomes.

It is envisioned that the CICBC and the study PDs/PIs should be responsible for the timely analysis of data and publication of study results in an open access journal. All publications should be available immediately upon their publication, without any embargo period. Data underlying the published research results should also be immediately accessible and open.

It is anticipated that the CICBC application will propose and carry out many of the functions that are performed by a Data Coordinating Center of an international multi-center study, including all statistical, data management and data analysis responsibilities. Additionally the CICBC should implement across the LMICs a single protocol, albeit tailored to local social and cultural environments. The CICBC will receive individual level data for study participants.

Only studies assessing the use of demonstrably clean cooking technologies (i.e. those with the potential to achieve extremely low emissions and associated health benefits) will be considered. In order to maximize public health benefits, demonstrably clean is defined here as clean cookstoves at IWA tier 3 or higher for indoor air emissions, based on third-party verification, or clean fuels (LPG, electricity, ethanol, biogas).

Examples of Research Programs

Examples of (but not limited to) the types of clinical trials that could be proposed:

• Evaluate the cleanest possible technology and home environments and incorporate some features of efficacy trials including, but not limited to, the use of the cleanest available fuels and stoves, minimizing of fuel stacking , measurement and assurance of best possible adherence and adoption of use.
• Test interventional models that significantly reduce the health impacts of HAP on: pregnancy, pregnancy outcomes such as maternal hypertension, preeclampsia, pregnancy loss, birth outcomes such as as low birth weight, co-morbidities in infants and children less than 5 years of age such as acute respiratory illness, incidence of wheezing, growth and cognition.
• For health outcomes with long incubation periods, collect specific clinical indicators and biomarkers at intervals appropriate for the developmental susceptibility of the relevant tissues including in-utero and early-life germline, somatic, or tissue-specific epigenetic changes.
• Study design and proposed analyses accounting for the possibility that germline or tissue-specific epigenetic changes may be induced by HAP exposure and, therefore, heritable-risk may persist even after exposures are reduced or eliminated.

Examples (but not limited to) of the types of biomarker development and validation studies that could be proposed:

• Target biological matrix-derived exogenous (e.g., PAHs) or endogenous (e.g., inflammatory cytokines) biomarkers of exposure.
• Test clinical and/or biochemical markers predictive (e.g., oxidative stress, FEV1, autoantibodies to TAA) of long term diseases such as cardiovascular disease, cancers, Chronic Obstructive Pulmonary Disease.
• Use unbiased approaches to explore (i.e., agnostic) potential biomarkers of exposure and/or response to exposure (e.g., transcriptomics, metabolomics, epigenomics, microbiome).

Research that is NOT responsive to this FOA:

This FOA is intended to stimulate a novel approach to clinical research in LMIC settings and, for the research to be efficient it needs to take advantage of existing research infrastructures and local research collaborations, and potentially existing or planned clean fuel distribution programs.

Applications that do not have such a pre-existing research infrastructure will be considered not responsive. Applications that propose Phase I or II clinical studies will be considered not responsive. The following studies will also be considered not responsive:

• Etiological, mechanistic, or epidemiological research that is not part of a wider study to develop a health outcomes trial.
• Replication of effectiveness studies and clinical trials testing the efficacy or effectiveness of new or established pharmacological agents (or combination of agents).
• Clinical trials of new diagnostic tools, devices or pharmacological agents. Studies can, however, include research on diagnostic tools, devices in order to increase the validity of the health outcomes sought by the applicant's proposed trial.
• Create new infrastructure to conduct the research proposed.

Non-responsive applications will not be reviewed.

Organization and Cooperation, and Investigators Meetings

Oversight and governance of the initiative will be provided by a Steering Committee (SC) composed of one NIH project officer from each participating Institute/Center, two BMGF representatives, two CICBC PD(s)/PI(s) (one for the trial, the other for the biomarker element), and the PD(s)/PI(s) of each of the LMIC clinical research projects, including representation from both U.S. and foreign institutions. A SC Chair will be appointed by NHLBI. The SC will identify emerging scientific opportunities or impediments to progress for the network, promote collaboration and communication across study teams, work with other partners, and hold annual meetings of the participating researchers and partners. The NHLBI will assemble a Data and Safety Monitoring Board (DSMB) to monitor the trial and the biomarker research, and make recommendations to NHLBI. The budget for the clinical trial should include costs associated with preparation and logistics for DSMB meetings. An additional board of External Scientific Advisors will be assembled by NHLBI after award and will be charged to evaluate the program as a whole and during the course of the years of award (not supported by this FOA).

NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made in response to this FOA.

Higher Education Institutions

• Public/State Controlled Institutions of Higher Education
• Private Institutions of Higher Education

The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or 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
• Asian American Native American Pacific Islander Serving Institutions (AANAPISIs)

Nonprofits Other Than Institutions of Higher Education

• 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)

For-Profit Organizations

• Small Businesses
• For-Profit Organizations (Other than Small Businesses)

Governments

• State Governments
• County Governments
• City or Township Governments
• Special District Governments
• Indian/Native American Tribal Governments (Federally Recognized)
• Indian/Native American Tribal Governments (Other than Federally Recognized)
• Eligible Agencies of the Federal Government
• U.S. Territory or Possession

Other

• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• Native American Tribal Organizations (other than Federally recognized tribal governments)
• Faith-based or Community-based Organizations
• Regional Organizations

Non-domestic (non-U.S.) Entities (Foreign Institutions) are not eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are eligible to apply.
Foreign components, as defined in the NIH Grants Policy Statement, are allowed.

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.

• Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. After obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.
• System for Award Management (SAM) (formerly CCR) Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
  • NATO Commercial and Government Entity (NCAGE) Code Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
• eRA Commons - Applicants must have an active DUNS number and SAM registration in order to complete the eRA Commons registration. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
• Grants.gov Applicants must have an active DUNS number and SAM registration in order to complete the Grants.gov registration.

Program Directors/Principal Investigators (PD(s)/PI(s))

All PD(s)/PI(s) must have an eRA Commons account. PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons. If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) 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.

For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF424 (R&R) Application Guide.

The PD(s)/PI(s) of the application should be the leader of the clinical trial. This individual should have demonstrated experience in design and recruiting into clinical studies or trials conducted in LMIC setting. The PD(s)/PI(s) must not lead the biomarker study.

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

Applicant organizations may submit more than one application, provided that each application is scientifically distinct.

The NIH will not accept duplicate or highly overlapping applications under review at the same time. This means that the NIH will not accept:

• A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.
• A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.
• An application that has substantial overlap with another application pending appeal of initial peer review (see NOT-OD-11-101).

Applicants must download the SF424 (R&R) application package associated with this funding opportunity using the Apply for Grant Electronically button in this FOA or following the directions provided at Grants.gov.

It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, including Supplemental Grant Application Instructions except where instructed in this funding opportunity announcement to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

For information on Application Submission and Receipt, visit Frequently Asked Questions Application Guide, Electronic Submission of Grant Applications.

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.

By the date listed in Part 1. Overview Information, prospective applicants are asked to submit a letter of intent that includes the following information:

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

The letter of intent should be sent to:

Director, Office of Scientific Review
Division of Extramural Research Activities
National Heart, Lung, and Blood Institute
National Institutes of Health
6701 Rockledge Drive, Room 7214
Bethesda, MD 20892-7924 (Express Mail Zip: 20817)
Telephone: 301-435-0270
Fax: 301-480-0730
Email: nhlbichiefreviewbranch@nhlbi.nih.gov

All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed, with the following exceptions or additional requirements:

1. Overview - 6 pages.
2. Clinical Trial - 12 pages
3. Biomarker Study - 6 pages

Applications received that exceed these page limitations will not be reviewed.

The following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing an application to this FOA.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed. Describe pre-existing research infrastructure that is amenable to the proposed research.

All instructions in the SF424 (R&R) Application Guide must be followed.

Other Attachments

Provide the following information as .pdf files:

• Full trial protocol (file name "(PD/PI name) Trial Protocol")
• Sample consent form (file name "(PD/PI name) Sample Consent Form")
• Biomarkers collection and analyses plan, inclusive of the potential involvement of local facilities and researchers (file name "(PD/PI name) Biomarkers Study Plan)"

All instructions in the SF424 (R&R) Application Guide must be followed.

Identify key personnel and their relevant qualifications for carrying out all functions of the Clinical Intervention, Coordinating and Biomarker Center (CICBC), especially with regard to international network management, clinical monitoring, and biomarker collection, storage, and analyses in the context of clinical phenotype and validation of biomarkers. The lead PD/PI of the biomarker element must be a different individual than the overall PD/PI. Describe any experience in collaboration with LMICs and collecting and analyzing biomarker samples collected from disparate geographical settings. Applicants are strongly encouraged to name an experienced research team in global health that will support the project management and implementation of the network trial and to list additional clinical research expertise they could draw upon on an as-needed basis, as well as any research resources they have established at their institution.

Describe the expertise and track record of the research staff, including a track record of achieving relatively short trial start-up times with regard to contract negotiations, IRB approval times, and study personnel training (provide examples and describe features of research team training they have conducted). Describe track record in areas that will be the subject of the HAP trial, namely low birth weight and infant mortality, infant respiratory infections, incidence of symptoms precursors of respiratory diseases, neurocognitive development in children and/or rates of respiratory, stroke, cardiovascular diseases, and/or lung cancer in adults. Describe experience in project management of recent trials and collaborative leadership structure used in recent multi-center trials. Describe any special expertise or unique strengths relevant to the collaborative effort (e.g., experience in international clinical trial management and collaborations with national and international industry partners or patient groups).

All instructions in the SF424 (R&R) Application Guide must be followed.

A detailed budget for the CICBC should be presented. The budget must reflect all activities delineated in the list of responsibilities included in this FOA.

• Activities related to coordinating multiple, simultaneous, clinical research centers in different LMICs should be budgeted, including: planning activities; start-up activities; implementation activities; close-out phase activities; participation in investigator meetings, SC and other leadership committee functions; site monitoring; communication, documentation and reporting; support of study drug management. Budgeting for the support of potential trial participant discovery and retention activities of LMIC Clinical Centers should be presented.
• The budget should also include costs for monthly HAP-wide teleconferences and travel costs for approximately one trip each year for two CCC team members and each of the PD(s)/PI(s) of the LMICs Clinical Centers to attend SC meetings in Bethesda, MD, and other travel related to network operations, DSMB meetings and reimbursements, including 2 Clinical Center site visits per year.
• Trial costs should be requested in Section F Other Direct Costs and not comingled with other line items. Funding for trial costs in the HAP will be distributed to the LMICs Clinical Centers from the CCC on a per-patient (household) basis (capitation) via master trial agreements. NHLBI expects to allocate sufficient funds for capitation costs for approximately 4,500 households in a minimum of three to five different LMICs.
• Core and recruitment system funds may be requested at up to $1,297,000 direct costs per year, if needed for trial completion.
• Protocol (capitation) funds may be requested at up to $3,000,000 per year.
• The biomarker development and validation study may not exceed $778,000 direct costs per year.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:

Specific Aims

Summarize how the CICBC in close collaboration with local researchers and communities will recruit, assess, certify, and maintain 3 to 5 LMIC Clinical Centers, which in turn will enroll participants, perform and/or follow interventions, retain and follow research subjects, and store and maintain samples for biomarker analyses; how the CICBC will conduct the protocol specific training of personnel at the Clinical Centers; how the CICBC will reimburse the Clinical Centers for protocol costs, using pre-established, capitated rates, specific for the protocol; coordinate Clinical Center activities for the conduct of the approved protocol; how the CICBC will certify staff, track regulatory approvals and Clinical Center performance, and propose and implement corrective actions if deficiencies at the Centers are identified.

Research Strategy

The Research Strategy must consist of the following clearly labeled sections uploaded as a single attachment.

Overview

A description of the proposed research with detailed explanation of the relationship between the clinical and biomarker studies, including how the biomarker study complements and integrates with the clinical study, should be included.

Clinical Trial

Clinical Trial Overview

CICBC applicants should propose a trial protocol (note the full protocol, the sample consent form, and the biomarkers collection and analyses plan, inclusive of the potential involvement of local facilities and researchers to conduct the analysis, should be included as separate files named as above in the Other Attachment section). Describe the significance and rationale of the proposed clinical intervention study.

Leadership and Operations Plan

Describe in detail plans for assembling and supervising a network of LMIC Clinical Centers capable of conducting one single clinical trial targeting short- and long-term health outcomes as a consequence of the HAP interventions studied. Parameters to be evaluated include but are not limited to, low birth weight and infant mortality, infant respiratory infections, incidence of symptoms precursors of respiratory diseases like wheezing, neurocognitive development in children and/or rates of respiratory, stroke, and cardiovascular diseases, lung cancer, and eye disorders, in adults.

The applicant should describe the following:

• Plans for the CICBC, in close collaboration with local researchers and communities, will recruit, assess, certify, and maintain 3 to 5 LMIC Clinical Centers.
• Appropriateness of the proposed intervention clinical centers for the trial and include their relation to other ongoing programs.
• How the interventions will be assessed, i.e. detail information on evaluated cooking technologies and practices.
• Expected impact of the intervention on air pollution exposure.
• Expected household and possibly community air pollution reductions in relationship to how the intervention is being rolled out.
• How the clinical project will benefit from unique features of the scientific environment, subject populations, or collaborative arrangements.
• Existing local research infrastructure that will be involved in the trial. Attach letters of agreement from local investigators or other appropriate authority in the other attachment section.
• How the LMIC Clinical Centers chosen will leverage their resources and how the results from the multi-site study will provide insights into intervention implementation in heterogeneous populations and contexts.
• How each of the LMIC Clinical Centers will recruit research participants (with focus on women and children and preferably as household units) for the trial, and establish a cohort of at least 800 households (i.e., 400 interventional and 400 controls).
• How the CICBC will procure, install and monitor the performance of the appropriate stove(s) and/or fuel(s) and monitor HAP reduction
• Quality of community engagement, enrollment and technology deployment plans.
• plans for exposure assessment, including how other sources of pollutants that may affect outcomes will be factored and addressed.
• Plans for recruiting additional Clinical Centers to the HAP network if additional funds should become available.
• Administration of network activities and the clinical trial, and the management of the biospecimen repository either centrally or locally supported.
• Current and planned standard operating procedures (SOPs) for delegation and supervision of tasks, direction of the management team and plans for communication among team members, the LMIC Clinical Centers, the NHLBI, and the steering committee (SC). The potential for substantially changing clinical management must be addressed.
• Planned support for all aspects of a complex multi-center trial in LMICs, oversight of the Clinical Centers, and the organization and functioning of the SC. Applicants must state their willingness to participate in a collaborative and interactive manner with the NHLBI, and potential additional partners (including academic, foundation, and industry partners) in all aspects of the network program.
• Plans to achieve successful collaboration among local and international investigators and administrators.
• Local and general ethical issues that may affect interventions, assessments, sample and data sharing.
• Engagement with relevant communities.
• How the chosen approach is expected to lead to improvements in health.
• Stakeholders such as decision-makers and service delivery partners and their roles in the research planning and conduct and provide evidence of their commitment to the project.
• Intended pathway to embedding the intervention into policy and practice and address how local and/or national policy makers will be engaged from the start and throughout the project as well as at the end.
• Future scaled-up implementations and how they will fit within the local health systems, socio-political, social, cultural, economic, policy and regulatory context of the LMIC target of the intervention and how these context factors will be analyzed.
• Plans for providing assistance in the development of study-specific documents and manuals of procedures, including standardized exposure assessment protocols, archive study documents, and how such will be distributed securely via a website accessible to the Investigators, NHLBI and other NIH partners.
• Statistical plan, including power analysis, interim reviews, and stopping rules. Elaborate on why the primary endpoints described were chosen. Include a description of data management plans and statistical evaluation, including the typing of clinical data to biomarkers/-omics evaluation.
• Plans for coordination and utilization of standardized network master trial agreements for per patient cost of clinical programs.
• Plans for distribution of capitated funds, including plans for master trial agreements and organization of centralized IRB services.
• Procedures for tracking the performance of Clinical Centers, and implementing orderly closure of Clinical Centers whose performance does not meet pre-specified standards.

Staff Education Plan

Describe plans for training of Clinical Center personnel as needed for implementation of the common HAP protocol and how these efforts will provide for increased capacity locally and internationally to conduct such research in the future.

Timeline for Management of the HAP Clinical Trial

Describe a schedule for completion of the target study within the 5-year project period, and methods for quickly establishing the procedures and tools necessary for launching the trial protocol, activating the LMIC Clinical Centers assembled, and ensuring study progress. Milestones for protocol initiation should be described.

As an illustration, the early goals listed below could be used for implementation of the first protocol within the first year of the project period.

a) Three months after award - Publish templates for master trial agreements. Have an operational 508-compliant website that lists the CCC and Clinical Centers operations, begin awarding start-up costs to LMIC Clinical Centers, describe the procedure for patient recruitment, and provide written operating procedures for the Clinical centers operations. Begin steps for the launching of the trial protocol.

b) Six months after award - Negotiate capitated costs of trials. Convene first meeting of the Steering Committee. Have completed negotiation with funding partners and revised budgets submitted to the NIH for steering committee review. Schedule first DSMB meeting and distribute materials. Finalize budget for protocol. Publish forms and procedures for the protocol to be launched.

c) Nine months after award - DSMB review and NHLBI approval of the protocol. Submit the protocol to IRBs.

d) Nine months after award - Have State Department clearances for each country involved.

e) Twelve months after award - Enrollment of first subjects.

Biomarker Center - Biomarker Study

Describe the proposed biomarker center (this can be in the form of a subcontract) for the development and validation of clinical, physiological, chemical, biochemical and/or microbiological markers of: a) exposure and b) pathophysiological responses.

The applicant should describe the following:

• The biomarkers platforms to be employed and how they will be adaptable to diverse research environments and amenable to use in LMIC settings.
• The biomarkers selected for analysis and their relevance to household air pollution.
• Plans to correlate the biomarkers to exposures and clinical data.
• Plans for data management and statistical evaluation, including the tying of clinical data to biomarkers/-omics evaluation.
• The contextual factors (e.g., health systems, local and national policy) which may affect the implementation of proposed interventions, indicating how those contextual factors and their impact will be analyzed and how those contextual factors might affect future implementation of the approach.
• Overall scalability and sustainability of the approach.
• How the intervention takes into account socio-economic determinants of health, equity gaps and gender issues.
• The strategy for and scope of the exploratory biomarkers part of the study.
• Describe how local stakeholders such as community groups and relevant government representatives are included in the biomarker study decision process.
• How the required number of participants will be achieved.
• How the biomarker analysis is related to existing infrastructures and has scientific ties with the LMICs proposed.
• How the biomarker project will benefit from unique features of the scientific environment, subject populations, or collaborative arrangements.
• How the biomarker analysis setting is adequate to deliver state of the art information.

Protection of Human Subjects:

This section should describe procedure and assurances as in place in the U.S. and in the LMICs subject of the research proposed. Applicants should demonstrate access to a sufficient number of patients to accomplish the protocol by providing specific, objective sources of data on the size of the available population. This can include documentation of participation in previous clinical trials of similar patients. If links with local research groups are anticipated, the application should include a plan with appropriate letters of support that describe (1) how the applicant will link to and operate with the local groups, and (2) how the PD(s)/PI(s) will monitor the quality of the local group’s performance (recruitment and data quality).

Letters of Support

Letters of Support as needed to document commitments of LMIC Institutions and other parties involved. Institutions should provide proof of commitment to the PD(s)/PI(s) such as departmental and/or institutional, State, or National government, support letters and any other relevant documents that demonstrate appropriate commitment such as protected time, departmental research leadership position, facilities, space, or resources for the PD(s)/PI(s). Applicants are encouraged to provide letters of support from potential LMIC Clinical Centers willing to participate in the HAP trial.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide, including a Data Sharing Plan, Sharing Model Organisms, and Genomic Data Sharing Plan as provided in the SF424 (R&R) Application Guide.

Appendix: Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

When conducting clinical research, follow all instructions for completing Planned Enrollment Reports as described in the SF424 (R&R) Application Guide.

When conducting clinical research, follow all instructions for completing Cumulative Inclusion Enrollment Report as described in the SF424 (R&R) Application Guide.

Foreign (non-U.S.) institutions must follow policies described in the NIH Grants Policy Statement, and procedures for foreign institutions described throughout the SF424 (R&R) Application Guide.

See Part I. Section III.1 for information regarding the requirements for obtaining a Dun and Bradstreet Universal Numbering System (DUNS) Number and for completing and maintaining an active System for Award Management (SAM) registration. Part I. Overview Information contains information about Key Dates. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission.

Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies). Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date. If a Changed/Corrected application is submitted after the deadline, the application will be considered late.

Applicants are responsible for viewing their application before the due date in the eRA Commons to ensure accurate and successful submission.

Information on the submission process and a definition of on-time submission are provided in the SF424 (R&R) Application Guide.

This initiative is not subject to intergovernmental review.

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 only as described in the NIH Grants Policy Statement.

Applications must be submitted electronically following the instructions described in the SF424 (R&R) Application Guide. Paper applications will not be accepted.

Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.

For assistance with your electronic application or for more information on the electronic submission process, visit Applying Electronically. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Guidelines for Applicants Experiencing System Issues.

Important reminders:

All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF424(R&R) Application Package. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this FOA for information on registration requirements.

The applicant organization must ensure that the DUNS number it provides on the application is the same number used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the SF424 (R&R) Application Guide.

See more tips for avoiding common errors.

Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review and responsiveness by components of participating organizations, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.

Applicants are required to follow the instructions for post-submission materials, as described in NOT-OD-13-030.

Only the review criteria described below will be considered in the review process. As part of the NIH mission, all applications submitted to the NIH in support of biomedical and behavioral research are evaluated for scientific and technical merit through the NIH peer review system.

For this particular announcement, note the following:

In addition to standard peer review criteria for NIH cooperative agreements, a series of project specific criteria are included in this FOA. While each application will be evaluated in its entirety based on one overall impact score per application, the clinical trial and the biomarker study within each application will also each receive a separate impact/priority score.

Reviewers will provide an overall impact 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 review criteria and additional review criteria (as applicable for the project proposed).

Reviewers will consider each of the review criteria below in the determination of scientific 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.

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?

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or New Investigators, or in the early stages of independent careers, 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?

For the clinical trial:

• Do the Investigators have experience in setting up clinical and biomarker analyses collaborations in LMIC?
• Have the Investigators demonstrated engagement of LMICs decision-makers?
• Have the Investigators identified stakeholders such as decision-makers and service delivery partners and included them on the research team?
• Is there in the application demonstrable engagement with relevant patient and community groups?

For the biomarker study:

• Is the Investigator of the biomarker element experienced in biomarker collection, analysis in the context of clinical phenotype, and the validation of biomarkers in general?
• Do the Investigators describe experience in setting up biomarker analyses collaborations in LMICs?
• Do the Investigators have experience in collecting and analyzing biomarker samples in disparate geographical settings?

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?

For the clinical trial:

• Does the application address how the chosen approach is expected to lead to improvements in health?
• Does the application address scalability and sustainability of the approach?
• Does the application describe a clear pathway to embedding the intervention into policy and practice, and address how local and/or national policy makers will be engaged from the start and throughout the project as well as at the end?
• Will project outcomes/evidence be utilized for the scaling up of the intervention on a local, national and international level?
• Will future scaled-up implementations fit within the local health systems, socio-political, social, cultural, economic, policy, and regulatory context?
• Are socio-economic determinants of health, equity gaps, and gender issues taken into account in adapting the intervention?

For the biomarker study:

• Does the application address scalability and sustainability of the approach?
• Is the biomarker proposal technologically advanced to correlate findings to clinical outcomes?
• Are the biomarkers platforms employed adaptable to diverse research environments and amenable to use in LMIC settings?
• Is the strategy for and extent of the exploratory biomarkers part of the study innovative?

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?

For the clinical trial:

• How appropriate are the proposed intervention sites for the trial and do they have a relationship with other ongoing programs?
• Are the household units considered for the intervention encompassing an adequate children population? Is there a realistic plan to recruit the required number of patients?
• What is the quality of the community engagement, enrollment, and technology deployment plans?
• Does the application demonstrate understanding of the contextual factors (e.g., health systems, local and national policy) which affect the implementation of proposed interventions, indicating how those contextual factors and their impact will be analyzed?
• How would those contextual factors affect future implementation of the approach and its scalability? Is there a clear justification for the sites chosen and how the results from the multi-site studies will provide insights into intervention implementation in heterogeneous populations and contexts?
• Are local stakeholders such as community groups, fuel and stove providers, and relevant government representatives included in the decision process?
• Is the statistical plan sound, including power analysis, interim reviews, and stopping rules? Is the primary endpoint meaningful?
• Is there a sufficient plan to educate local investigators and staff to significantly enhance research capacity?
• Have the local and general ethical issues been considered?
• What is the rigor of the exposure assessment plans?
• What is the quality of the plans for data management and statistical evaluation, including the tying of clinical data to biomarkers/-omics evaluation?

For the biomarker study:

• Does the study complement and integrate with the clinical study?
• Are local stakeholders such as community groups and relevant government representatives included in the biomarker study decision process?
• Is the statistical plan sound, including power analysis?
• Is there a sufficient plan to train local investigators and staff to significantly enhance research capacity?
• What is the quality of plans for data management and statistical evaluation, including the tying of clinical data to biomarkers/-omics evaluation?
• What is the relevance of the biomarkers that will be analyzed to household air pollution?
• Is the plan to correlate biomarkers to exposures and clinical data sound? Is the managing of the biospecimen repository, either centralized or locally supported, sufficiently described?

If the project involves human subjects and/or NIH-defined clinical research, are the plans to address 1) the protection of human subjects from research risks, and 2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of children, justified in terms of the scientific goals and research strategy proposed?

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?

For the clinical trial:

• Does the application demonstrate that the institution will be able to coordinate and utilize standardized network master trial agreements for per patient cost of clinical programs?
• Is the trial hinging upon existing infrastructures and clinical ties with the LMICs proposed?
• Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements?

For the biomarker study:

• Does the biomarker analysis hinge upon existing infrastructures and have scientific ties with the LMICs proposed?
• Will the biomarker project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements?

Is the biomarker analysis setting adequate to deliver state of the art information?

As applicable for the project proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact score, but will not give separate scores for these items.

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. For additional information on review of the Human Subjects section, please refer to the Guidelines for the Review of Human Subjects.

When the proposed project involves human subjects and/or NIH-defined clinical research, the committee will evaluate the proposed plans for the inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion (or exclusion) of children to determine if it is justified in terms of the scientific goals and research strategy proposed. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.

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. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

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.

Not Applicable

Not Applicable

Not Applicable

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

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.

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).

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; 2) Sharing Model Organisms; and 3) Genomic Wide Association Studies (GWAS) /Genomic Data Sharing Plan.

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

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by NHLBI, in accordance with NIH peer review policy and procedures, using the stated review criteria. Assignment to a Scientific Review Group will be shown in the eRA Commons.

As part of the scientific peer review, all applications:

• May 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 overall impact score.
• Will receive a written critique.

Appeals of initial peer review will not be accepted for applications submitted in response to this FOA.

Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this FOA. Following initial peer review, recommended applications will receive a second level of review by the National Heart, Lung, and Blood Advisory Council. 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.
• Merit of the clinical study

While each application will be evaluated in its entirety based on one overall impact score per application, each section within an application will also be scored separately. If the biomarker center section does not receive a meritorious score it will not be funded, but the clinical trial may still be funded if it is among the most meritorious clinical projects proposed for this FOA. A biomarker center will not be funded if it is not paired with a meritorious clinical project (i.e., as a standalone meritorious biomarker project). If no meritorious clinical project application pairs with a meritorious biomarker center application, NIH may issue an additional separate request for a biomarker application at a later time point.

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 eRA Commons.

Information regarding the disposition of applications is available in the NIH Grants Policy Statement.

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant as described in the NIH Grants Policy Statement.

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization for successful applications. The NoA signed by the grants management officer is the authorizing document and will be sent via email to the grantee’s business official.

Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. 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.

Any application awarded in response to this FOA will be subject to terms and conditions found on the Award Conditions and Information for NIH Grants website. This includes any recent legislation and policy applicable to awards that is highlighted on this website.

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. More information is provided at Award Conditions and Information for NIH Grants.

Cooperative Agreement Terms and Conditions of Award

The following special terms of award are in addition to, and not in lieu of, otherwise applicable

U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of

Health and Human Services (DHHS) grant administration regulations at 45 CFR Parts 74 and 92

(Part 92 is applicable when State and local Governments are eligible to apply), and other HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program will be the cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the awardees is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients 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 awardees for the project as a whole, although specific tasks and activities may be shared among the awardees and the NIH as defined below.

The PD(s)/PI(s) will have the primary responsibility for:

All aspects of the clinical study and coordination with the biomarker study. For the clinical study, these responsibilities include recruiting study participants, conducting the research in an ethical and safe manner, assuring quality of study participant care and protocol adherence, assuring the accurate and timely transmission of data collected, supervision or preparation of adverse event reporting, supervision of preparation of confidential interim reports, analyzing and interpreting data, preparing publications, and dissemination of research findings. The principal investigator of the biomarker study will have specific expertise in the field and will be responsible for all aspects of the research proposed. A coordination plan between clinical and biomarker investigators must be presented.

Awardees will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current DHHS, PHS, and NIH policies.

NIH staff has substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below:

An NHLBI Project Scientist will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice. The assigned NHLBI Program Officer, who may be advised by an IC contributing partner representative, will not serve as the NIH Project Scientist.

Progress will be administratively reviewed prior to issuance of non-competing awards. NHLBI reserves the right to phase out or curtail an individual award in the event of: (1) a substantial shortfall in participant recruitment as compared to pre-award negotiated Milestone Accrual Plans, follow-up, data reporting, or quality control; (2) a major breach of a protocol or substantive changes in the agreed-upon protocol with which NHLBI cannot concur; (3) attainment of a major study endpoint before schedule with persuasive statistical significance; or (4) human subject ethical issues that may dictate a premature phase out.

Annual continuation and level of funding will be based on NHLBI review of actual recruitment and overall performance, determined as part of the NHLBI review of the annual non-competing continuation grant progress reports submitted by the awardees.

Areas of Joint Responsibility include:

Awardees agree to the governance of the study through a Steering Committee (SC). All PD(s)/PI(s) and a Chairperson, to be appointed by the NHLBI, will comprise the SC. All major scientific decisions will be determined by majority vote of the SC. The PD/PI will have one vote, the PIs of the LMIC subawarded Clinical Centers will have one vote per Center, the BMGF representative will have one vote, and the NHLBI or the IC contributing partner representative PO will have one vote; the Chair will have one vote in case of a tie. If a subawarded LMIC Clinical Center has two PIs, each Clinical Center still has one vote. Awardee members of the Steering Committee will be required to accept and implement policies approved by the Steering Committee.

Dispute Resolution:

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to Dispute Resolution. A Dispute

Resolution Panel composed of three members will be convened. It will have three members: a designee of the Steering Committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual awardee. This special dispute resolution procedure does not alter the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and DHHS regulation 45 CFR Part 16.

When multiple years are involved, awardees will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement.

A final progress report, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement.

The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for awardees of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later. All awardees of applicable NIH grants and cooperative agreements are required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000. See the NIH Grants Policy Statement for additional information on this reporting requirement.

We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants.

eRA Commons Help Desk (Questions regarding eRA Commons registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, post submission issues)
Finding Help Online: http://grants.nih.gov/support/ (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading forms and application packages)
Contact CenterTelephone: 800-518-4726
Web ticketing system: https://grants-portal.psc.gov/ContactUs.aspx
Email: support@grants.gov

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Email: GrantsInfo@nih.gov (preferred method of contact)
Telephone: 301-710-0267

Antonello Punturieri, M.D., Ph.D.
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-435-0230
Email: punturieria@mail.nih.gov

Director, Office of Scientific Review
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-435-0270
Email: nhlbichiefreviewbranch@nhlbi.nih.gov

Howard Moore
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-435-0166
Email: mooreh@nih.gov

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