Key Dates

Related Announcements

PA-18-592 - Research Supplements to Promote Re-Entry into Biomedical and Behavioral Research Careers (Admin Supp - Clinical Trial Not Allowed)

PAR-20-052 - NCI Small Grants Program for Cancer Research for Years 2020, 2021, and 2022 (NCI Omnibus R03 Clinical Trial Optional)

PA-20-146 - NIDA Small Research Grant Program (R03 Clinical Trial Required)

PA-20-183 - Research Project Grant (Parent R01 Clinical Trial Required)

PA-20-184 - Research Project Grant (Parent R01 Basic Experimental Studies with Humans Required)

PA-20-185 - NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed)

PA-20-194 - NIH Exploratory/Developmental Research Grant Program (Parent R21 Clinical Trial Required)

PA-20-195 - NIH Exploratory/Developmental Research Grant Program (Parent R21 Clinical Trial Not Allowed)

PA-20-196 - NIH Exploratory/Developmental Research Grant Program (Parent R21 Basic Experimental Studies with Humans Required)

PA-20-200 - NIH Small Research Grant Program (Parent R03 Clinical Trial Not Allowed)

NOT-OD-21-113 - Notice of Intent to Reissue PAR-18-845 Electronic Nicotine Delivery Systems (ENDS): Basic Mechanisms of Health Effects (R01 - Clinical Trial Not Allowed) and PAR-18-846 (R21 - Clinical Trial Not Allowed) as a Notice of Special Interest (NOSI)

NOT-OD-22-024 - Notice of Early Expiration of NOT-OD-21-127

Issued by

Division of Program Coordination, Planning and Strategic Initiatives, Office of Disease Prevention (ODP)

National Institute of Dental and Craniofacial Research (NIDCR)

National Institute on Drug Abuse (NIDA)

National Institute of Environmental Health Sciences (NIEHS)

National Cancer Institute (NCI)

Purpose

The Office of Disease Prevention and participating ICOs are issuing this Notice to communicate our interest in research examining how electronic nicotine delivery systems (ENDS) affect normal and disease states relevant to human cells, tissues, organs, and behaviors. Research on alternative nicotine and tobacco delivery systems [e.g., heated tobacco products (also called heat-not-burn)] will also be considered. Studies exclusively examining smokeless tobacco or combustible tobacco products (e.g., cigarettes, cigars) will be considered non-responsive.

Background:

Electronic Nicotine Delivery Systems (ENDS) are designed to heat a liquid solution, typically containing nicotine, into an aerosol to be inhaled by a user. ENDS represent a diverse class of products that include e-cigarettes, vapes, vaporizers, vape pens, hookah pens, and pods. In recent years, heated tobacco products, which do not involve combustion and are sometimes called heat-not-burn", have become available in the United States. For the purposes of this Notice, research examining products within the entire class of ENDS and heated tobacco products is sought. Other emerging non-combustible products will be considered on a case-by-case basis.

Adult prevalence of ENDS in 2019 was 4.5%, with young adults having the highest prevalence among all age groups (2020 Morbidity and Mortality Weekly Report). Current electronic cigarette use among young adults aged 18-24 increased from 7.6% in 2018 to 9.3% in 2019 (2019 Morbidity and Mortality Weekly Report). Youth ENDS use is also a significant concern. According to the 2020 National Youth Tobacco Survey, 20% (3 million) of high school students and 4.7% (550,000) of middle school students reported current e-cigarette use.

The tobacco product landscape is continuously changing. Despite rapidly accumulating research, significant gaps remain in our understanding of the public health effects posed by ENDS and heated tobacco products. More information is needed to understand the risk profile of the various devices or products and the aerosols they generate. The constantly changing landscape presents additional challenges for understanding how variable patterns of use and exposure to ENDS aerosol affect biological, physiological, and behavioral health outcomes.

Research is needed to understand how ENDS product characteristics, product user characteristics, as well as the communication and policy environment interact to affect ENDS use patterns (e.g., exclusive use vs. dual use with combustible cigarettes). For example, although many adult smokers report using ENDS to help them quit smoking or to reduce their cigarette consumption, as noted in the 2020 Surgeon General’s Report on Smoking Cessation, there is presently inadequate evidence to conclude that e-cigarettes, in general, increase smoking cessation.

The degree to which changes in the devices, products, or aerosols affect nicotine delivery is unknown. Furthermore, questions about their effect on human physiology and behavior still exist. For example, while many of the flavoring chemicals used in the liquids are approved for use in foods, there is incomplete information on their effects when inhaled. Such gaps in our understanding around ENDS and heated tobacco products indicate the need for further investigation at the molecular, cellular, physiological, and behavioral levels to increase our understanding of the risks and potential benefits. These and other research gaps introduce challenges for accurate and meaningful communication about ENDS and heated tobacco products impact on an individual’s health.

Research Objectives:

This NOSI encourages research on ENDS and heated tobacco products related to:

• evaluating the biological mechanisms whereby aerosols affect the normal and disease states relevant to human cells, tissues, or organs
• understanding the generation and characteristics of aerosols
• understanding how constituents alter molecular, cellular, and physiological pathways important in maintaining homeostatic functions or progression to disease states
• developing specific biomarkers that reflect short- and long-term exposure to aerosols and could provide information on the risks or benefits of exposure
• understanding the short- and long-term health effects across subject populations
• understanding the neurobiological and behavioral mechanisms associated with exposure to aerosols, and their long-term consequences
• determining whether and how exposure to aerosols specifically affects development during adolescence, given that this is a window of neural plasticity and dynamic hormonal changes; and
• Identifying potential sex differences in the effects of aerosol exposure

This NOSI encourages feasibility and pilot research, as well as efficacy and effectiveness research on new or adapted interventions. Investigators must carefully review the specific research interests of NIH Institutes, Centers, and Offices that are participating in this NOSI. Responsive studies should make use of human cells or specimens, and where appropriate, may utilize cell or animal models that are relevant to humans and well justified. Research with a focus on other non-combustible nicotine and tobacco products will be considered on a case-by-case basis. Specific Research areas of interest for participating NIH institutes are listed below.

Where appropriate, the standardized research e-cigarette (https://www.drugabuse.gov/funding/supplemental-information-nida-e-cig) should be considered for use in addressing specific research questions, or as a comparator for commercially available ENDS.

Investigators who conduct original and innovative basic biomedical, social, behavioral, clinical, or population-based research directed toward eliminating health disparities are invited to apply to this NOSI. Research shows that diverse teams working together outperform homogenous teams. Scientists and trainees from diverse backgrounds and with different life experiences bring different perspectives, creativity, and individual enterprise to address complex scientific problems. Diverse teams of scientists will lead the way to develop more innovative inclusive research that will more broadly enhance public health. Fostering diversity by addressing underrepresentation in the scientific research workforce is a key component of the NIH strategy to identify, develop, support, and maintain the quality of our scientific workforce. It is expected that research programs will include a diverse group of scientists, including individuals from underrepresented backgrounds as per NOT OD 20-031 (Notice of NIH's Interest in Diversity).

IC Specific Application and Submission Information:

Applicants must select the IC and associated FOA to use for submission of an application in response to this NOSI. The selection must align with the IC requirements listed in order to be considered responsive to that FOA. Non-responsive applications will be withdrawn from consideration for this initiative. In addition, applicants using NIH Parent Announcements (listed below) will be assigned to those ICs on this NOSI that have indicated those FOAs are acceptable and based on usual application-IC assignment practices.

• PA-18-592 - Research Supplements to Promote Re-Entry into Biomedical and Behavioral Research Careers (Admin Supp - Clinical Trial Not Allowed)
• PA-20-183 -NIH Research Project Grant (Parent R01 Clinical Trial Required)
• PA-20-184 - NIH Research Project Grant (Parent R01 Basic Experimental Studies with Humans Required)
• PA-20-185 - NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed)
• PA-20-194 - NIH Exploratory/Developmental Research Grant Program (Parent R21 Clinical Trial Required)
• PA-20-195 - NIH Exploratory/Developmental Research Grant Program (Parent R21 Clinical Trial Not Allowed)
• PA-20-196 - NIH Exploratory/Developmental Research Grant Program (Parent R21 Basic Experimental Studies with Humans Required)
• PA-20-200 - NIH Small Research Grant Program (Parent R03 Clinical Trial Not Allowed)

All instructions in the?SF424 (R&R) Application Guide?and the listed funding opportunity announcements must be followed, with the following additions:

• For funding consideration, applicants must include NOT-OD-21-127 in the Agency Routing Identifier field (box 4B) of the SF424 R&R form. Applications without this information in box 4B will not be considered for this initiative.

Applications nonresponsive to terms of this NOSI will be withdrawn from consideration for this initiative.

National Cancer Institute (NCI)

The National Cancer Institute encourages submission of applications that investigate potential mechanisms of toxicity and carcinogenicity of ENDS and heated tobacco products. Examples of specific topics of interest to NCI include but are not limited to:

• Effects of aerosols on carcinogenesis and tumor progression
• Effects of exposure on the response or resistance to targeted therapies, radiation, or chemotherapies
• Consequences of aerosol exposure in relevant animal models of cancer
• Cellular and molecular mechanisms of carcinogenicity by exposure to aerosols; and
• Identification and validation of specific molecular markers of aerosol exposure or toxicity.

NCI’s FOAs for this NOSI include the following or their subsequent reissued equivalents:

National Institute of Dental and Craniofacial Research (NIDCR)

The NIDCR is interested in all applications that are relevant to the NIDCR mission and strategic plan. Applications that propose to prove causal pathways between ENDS (specifically e-cigarettes) and dental, oral, and/or craniofacial diseases and conditions are of higher priority. Those applications that demonstrate correlations are of lower priority. NIDCR supports research that examines the basic mechanisms of effects in pre-clinical investigations.

NIDCR is interested in investigations that include, but are not limited to:

• Determination of the synergistic biological effects of e-cigarette aerosol mixtures on cells, tissues and organs of the oral cavity using appropriate in vitro and in vivo model systems,
• Analysis of genotoxicity/DNA damage, cellular metabolism, mutagenicity, and/or transformation potential, effects on cell proliferation and cell death, of e-cigarette aerosol mixtures using appropriate in vitro and/or in vivo model systems with an emphasis on oral and periodontal epithelial cells,
• High throughput analysis (e.g. genomic, epigenomic and proteomic analyses) to understand the biological and physiological effects of e-cigarette aerosols on cells, tissues, and organs of the oral cavity,
• Examination and comparison of the effects on oral and/or periodontal epithelial cells in chronic users of e-cigarettes, smokers of combustible cigarettes and non-smokers,
• Assessment of effects of e-cigarettes on salivary gland function, saliva flow; and on dental/periodontal health using appropriate in vivo model systems.

Potential applicants are encouraged to speak with a NIDCR program official to discuss the relevance of proposed research topic(s). For additional information on the NIDCR mission and strategic plan please see the NIDCR website:http://www.nidcr.nih.gov.

National Institute on Drug Abuse (NIDA)

NIDA is interested in supporting pre-clinical and clinical research that examines the basic mechanisms of effects by ENDS, and alternative novel nicotine and tobacco delivery systems, such as heated tobacco products (also called heat-not-burn), as they relate to addiction. Investigations that explore the interaction with genetics or epigenetics are of interest. The Institute also encourages research on the effects of flavoring via in vitro or in vivo investigations.Further, NIDA is interested in investigations that explore neuronal mechanisms, such as function of neurons, astrocytes, microglia, or brain circuitry, associated with the use and exposure to the aerosol constituents. How sex differences might impact the effects of use are also of interest. Potential applicants are advised to speak with a NIDA program official to discuss the relevance and priority to NIDA of potential research topic(s).

NIDA is interested in studies that include, but are not limited to:

• Behavioral or cognitive processes (e.g., learning, memory, emotion), and their neurobiological mechanisms, as variables contributing to ENDS trajectories of use (e.g., initiation, escalation, maintenance, abstinence, and/or relapse).
• Understanding the effects of prenatal exposure to electronic cigarette aerosols on fetal and infant brain and cognitive development.
• Characterization of transition points and stages in the development of an ENDS substance use disorder, including the use of biomarkers or other neurobiological signatures that predict transition to more compulsive patterns of intake.
• Understanding the neurobiological mechanisms underlying the effect of different flavors beyond menthol on ENDS trajectories of use.
• Computational approaches to investigating ENDS use behaviors and underlying neural mechanisms.
• Bidirectional translational research, with an emphasis on investigating ENDS use through ecologically valid animal models.
• Understanding the role of environmental and individual sources of ENDS use vulnerability and resilience, including sex and/or gender differences.
• Understanding genetic and/or epigenetic factors associated with ENDS use and addiction.
• Assessments of transcriptomic-, proteomic-, or metabolomic profiles either in vitro or in vivo associated with ENDS exposure, including effects produced by flavorings or by non-combusted cigarettes (heat-not-burn products).
• How use of ENDS affects the trajectory of use of other addictive substances.

NIDA’s FOAs for this NOSI include the following or their subsequent reissued equivalents:

National Institute on Environmental Health Sciences (NIEHS)

NIEHS is most interested in supporting research that examines basic mechanisms of effects related to substances used in ENDS.NIEHS seeks to support studies that examine potential relationships between ENDS flavorings and exposure to toxicants. The Institute is also interested in studies that examine the relationship between secondary and tertiary ENDS aerosol exposures and genetic and physiological outcomes.

NIEHS invites applications that include, but are not limited to:

• Identifying relationships between individual flavored/non-flavored constituents and specific measures of toxicity,
• Identifying the flavored /non-flavored constituents of second hand and tertiary e-cigarette aerosol linked to known toxic effects,
• Evaluating health effects associated with toxic second hand/tertiary e-cigarette aerosol,
• Evaluating the air quality in homes where e-cigarettes are used,
• Identifying or discover pediatric adverse health issues associated with toxic second hand/tertiary e-cigarette aerosol exposures,
• Identifying cardio-pulmonary dysfunction(s) associated with toxic second hand/tertiary e-cigarette aerosol exposures,
• In utero exposures and developmental consequences with regard to epigenomic landscape, disease susceptibility, respiratory, pulmonary, metabolic, cognitive phenotypes
• Any impacts of exposures to ENDS aerosols on epitranscriptomic landscapes
• Impacts of paternal exposures and intergenerational/transgenerational effects on F1 and F2 offspring
• Analyzing of epigenetic reprogramming as a consequence of toxic second hand/tertiary e-cigarette aerosol exposures, and
• Analyzing of gene expression profile associated with toxic second hand/tertiary e-cigarette aerosol exposures.

Application and Submission Information

This notice applies to due dates on or after August 26, 2021 and subsequent receipt dates through May 8, 2023.

All instructions in the SF424 (R&R) Application Guide and the funding opportunity announcement used for submission must be followed, with the following additions:

• For funding consideration, applicants must include NOT-OD-21-127 (without quotation marks) in the Agency Routing Identifier field (box 4B) of the SF424 R&R form. Applications without this information in box 4B will not be considered for this initiative.

Applications nonresponsive to terms of this NOSI will be withdrawn from consideration for this initiative.

Application and Submission Information

This notice applies to due dates on or after June 5, 2019 and subsequent receipt dates through September 8, 2022.

Submit applications for this initiative using one of the following funding opportunity announcements (FOAs) or any reissues of these announcement through the expiration date of this notice.

• PA-19-055 - NIH Research Project Grant (Parent R01 Clinical Trial Required)
• PA-19-056 - NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed)
• PA-19-091 NIH Research Project Grant (Parent R01 Basic Experimental Studies with Humans Required)

All instructions in the SF424 (R&R) Application Guide and the funding opportunity announcement used for submission must be followed, with the following additions:

• For funding consideration, applicants must include NOT-IC-19-XXX (without quotation marks) in the Agency Routing Identifier field (box 4B) of the SF424 R&R form. Applications without this information in box 4B will not be considered for this initiative.

Applications nonresponsive to terms of this NOSI will be withdrawn from consideration for this initiative.

Inquiries

Scientific Contacts:

Ron Johnson, Ph.D.
National Cancer Institute (NCI)
Telephone: 240-276-6250
Email:[email protected]

Zhong Chen, M.D., Ph.D.
National Institute of Dental and Craniofacial Research (NIDCR)
Telephone: 301-529-7083
Email:[email protected]

Mary Kautz, Ph.D.
National Institute on Drug Abuse (NIDA)
Telephone: 301-443-3206
Email:[email protected]

Frederick L. Tyson, Ph.D.
National Institute of Environmental Health Sciences (NIEHS)
Telephone: 919-541-0176
Email:[email protected]

Melissa C. Green Parker, Ph.D.
Office of Disease Prevention (ODP)
Telephone: Phone: 301-480-1161
Email:[email protected]