It is critical that applicants follow the Research (R) 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

The goal of this Funding Opportunity Announcement (FOA) is to improve cigarette smoking cessation treatment among people living with HIV (PLWH) in the United States (U.S.), with an emphasis on methodologically rigorous studies that propose to systematically test existing evidence-based smoking cessation interventions (e.g., combination of behavioral and pharmacological) and/or to develop and test adaptations of evidence-based smoking cessation interventions for application to this target population. The long-term goal is to reduce cigarette smoking rates among PLWH, and thus tobacco-related health disparities in this population. Responsive applications should address the highest HIV/AIDS research priorities as identified by NIH (see NOT-OD-15-137) which include research to reduce health disparities in the treatment outcomes of those living with HIV/AIDS.

This FOA will utilize the NIH Exploratory/Developmental Research Grant (R21) mechanism, and is suitable for early phase, pilot, or exploratory/developmental projects. For such projects, preliminary data are not required; however, they may be included if available.

Investigators who are interested in proposing larger scale, later phase projects based upon strong preliminary data should submit applications in response to the partner FOA of identical scientific scope, RFA-CA-18-027, which uses the Research Project Grant (R01) mechanism.

There are an estimated 1 million PLWH in the U.S. Of these, an estimated 40% smoke cigarettes, more than twice the prevalence observed in the U.S. adult population. Consequently, PLWH experience substantial tobacco-related morbidity and mortality, including from tobacco-related cancers. Thus, addressing tobacco cessation as early in life as possible among PLWH is extremely important. For PLWH who smoke, after achieving and maintaining a suppressed viral load, smoking cessation is the next most important intervention that will maximize both quality of life and life expectancy.

HIV/AIDS and Cancer

Antiretroviral therapy (ART) has prolonged the life expectancy among PLWH in the U.S., such that HIV infection is now considered a chronic health condition. With early diagnosis and access to treatment, the life expectancy of PLWH is very similar to that of people without HIV, and death from AIDS-related causes is decreasing. However, the incidence of both AIDS-defining (i.e., non-Hodgkin lymphoma, Kaposi sarcoma, and cervical cancer) and non-AIDS-defining (i.e., anal, colorectal, Hodgkin lymphoma, liver, lung, oropharyngeal, melanoma) cancers are higher among PLWH compared to the general population. Indeed, non-AIDS-defining cancers are now the leading non-AIDS cause of death among PLWH. Impaired immune function, chronic inflammation, and a higher prevalence of risk factors, such as cigarette smoking and viral co-infections, contribute to this substantial cancer burden. The mortality rate from cancer among PLWH has been estimated to be more than three times higher than that of uninfected persons.

Lung cancer is the leading cause of cancer death among PLWH on ART and is one of the leading causes of death overall in this population. The incidence of lung cancer in PLWH appears to be higher than can be explained by smoking alone. Lung infections, chronic inflammation, and other immune stressors may act in synergy with tobacco use to promote lung cancer development among PLWH. Generally, lung cancer is diagnosed a decade or more earlier among PLWH than those without, and it is estimated that 94% of lung cancer diagnoses among PLWH could potentially be prevented by eliminating cigarette smoking in this population.

Cigarette Smoking among PLWH

As noted above, the prevalence of cigarette smoking among PLWH is more than twice that of the general adult U.S. population. It is estimated that life expectancy among HIV-positive smokers is reduced by at least 16 years compared with HIV-positive nonsmokers. Further, cigarette smoking is associated with lower adherence to ART and can influence HIV pathogenesis. It is important to note that PLWH are not a homogeneous group. The Centers for Disease Control and Prevention reports that gay and bisexual men are the most affected by HIV, with 70% of new infections in 2014 occurring within this group; however, they note differences in infection trends by age and race/ethnicity. Sexual and gender minorities (e.g., lesbian, gay, bisexual) also have a higher prevalence of cigarette smoking than the general population. Sociodemographic characteristics associated with current smoking among PLWH center on socioeconomic status, such as lower educational level, poverty, homelessness, and incarceration. Age and race have also been shown to affect adherence to tobacco dependence treatment among PLWH.

The literature points to numerous risk factors associated with cigarette smoking among PLWH, including but not limited to substance use or co-dependence on other substances, alcohol use, marijuana use, mental illness, depression, lack of social support, not achieving HIV viral suppression, and other HIV-related symptoms. Some of these risk factors, particularly chronic stressors (e.g., poverty, racism/discrimination, stigmatization, lack of access to HIV treatment, emotional distress, pain, comorbid substance use), may serve as barriers to cessation. Additionally, given the increased number of tobacco products available to consumers, and the increasingly complex patterns of tobacco product use observed in the general population, it is likely that dual and poly tobacco product use has also increased among PLWH, which may pose another barrier to successful smoking cessation. The diversity of PLWH and risk factors posed by these sub-groups present unique challenges for smoking cessation. Understanding the complex interplay between sociodemographic and behavioral risk factors associated with cigarette smoking among PLWH will contribute to the development of effective smoking cessation interventions, as well as inform and guide the adaptation of existing evidence-based interventions for this population.

Smoking Cessation Interventions for PLWH

The high prevalence of cigarette smoking and the high incidence of tobacco-related cancer and other smoking-related diseases among PLWH call for swift action to intervene with this population to reduce tobacco use rates. However, evidence to guide the care of PLWH smokers is inadequate. PLWH who smoke have substantially lower quit rates compared with the general population. It is not clear how to best structure or deliver evidence-based tobacco cessation treatment that will address the complex and unique needs of PLWH (e.g., risk factors, treatment needs). Tailored cessation studies designed for eventual dissemination and implementation are likely necessary to focus efforts on diverse groups of PLWH who use tobacco. The 2008 U.S. Public Health Service Guideline for Treating Tobacco Use and Dependence reported that, "No long-term RCTs [randomized controlled trials] have examined the effectiveness of interventions in this [HIV-positive] population." (p. 144). In addition, the Guideline identified three topics requiring additional research: 1) effectiveness of medications and counseling/behavioral interventions, including tailored interventions; 2) effectiveness of motivational interviewing and educational approaches in increasing motivation to quit; and 3) effectiveness of community and social support networks in bolstering quitting motivation and improving treatment outcomes. Given the few randomized clinical trials examining smoking cessation treatment for PLWH conducted to date, and the major methodological limitations of many of these studies (e.g., lack of randomization, comparison conditions, treatment fidelity assessments, abstinence verification tests), there is a strong need for additional research in this area.

Key barriers to successful cessation among PLWH include patient-level, provider-level, and systems- or contextual-level factors. The complex interplay among these factors presents unique challenges.

Patient-Level. There is little evidence regarding the optimal smoking cessation treatment (e.g., combination of behavioral and pharmacological) for this population. Thus, it is not clear whether existing evidence-based smoking cessation interventions will be effective for PLWH or if modifications to standard treatments will enhance their effectiveness. PLWH are a diverse group of individuals, and certain subgroups of PLWH with higher tobacco use rates (e.g., sexual and gender minorities, individuals with mental and substance use disorders) may have unique treatment needs. For example, PLWH who have behavioral health conditions (e.g., mental and substance use disorders) have disproportionately high smoking rates and may have unique treatments needs; both from a medication standpoint (nicotine impacts the effectiveness of some psychotropic medications) and a counseling/behavioral standpoint (this subpopulation may need more intensive support). A better understanding of how tobacco cessation interventions can be adapted for different subgroups of PLWH is needed. Finally, few studies have examined relapse to smoking among PLWH. Among the general population, relapse is highest within the first few weeks after a quit attempt; this is also likely to be true among PLWH.

Provider-Level. The health care setting provides opportunities to identify tobacco users and offer evidence-based cessation treatments. However, few studies have focused on understanding barriers and facilitators of smoking cessation treatment delivery by HIV treatment providers (e.g., doctors, nurses, peer educators, social workers). Several studies suggest that these providers may not be adequately addressing tobacco use among their patients. Existing studies indicate that few PLWH are offered cessation treatment, often because it is not viewed as a high priority by patients and providers alike. This emphasizes the need for research to understand how to reduce barriers to delivering smoking cessation treatment among HIV treatment providers and increase motivation for smoking cessation among their patients.

Systems- or Contextual-Level. Although integrating evidence-based smoking cessation interventions into HIV clinical care settings has been shown to be feasible, treating tobacco dependence is not yet the standard of care in these settings. Barriers include lack of provider and patient time, competing demands, and lack of staff training. Integration of evidence-based smoking cessation interventions into the HIV clinical care setting may provide greater continuity of care and opportunities to intervene with this population. Research is also needed to understand how to implement evidence-based tobacco cessation interventions for PLWH in settings beyond the HIV clinical care setting (e.g., community settings, prisons, and other medical care settings).

The goal of this FOA is to provide support for studies that employ rigorous designs that seek to systematically test existing evidence-based tobacco cessation interventions (e.g., combination of behavioral and pharmacological) and/or to develop and test adaptations of evidence-based tobacco cessation interventions for PLWH in the U.S. The principal focus of this initiative is on cigarette smoking cessation. Studies that address dual/poly tobacco use cessation as part of a cigarette smoking cessation intervention will be acceptable. Proposed projects must include prospective, comparative evaluation of the intervention(s) in terms of the rates of cigarette smoking cessation, including sustained abstinence, among current cigarette smokers.

All projects must include the following:

• Research strategies need to be consistent with the highest HIV/AIDS research priorities as identified by NIH (see NOT-OD-15-137). It is desirable to address health consequences of smoking that may be prevalent among PLWH.
• Research designed to estimate the effect of an intervention on cigarette smoking cessation outcomes with at least one control or comparison group.
• A detailed assessment of cigarette smoking and cigarette smoking history among study participants. Use of other tobacco products, including electronic cigarettes, should also be assessed.
• The following cessation endpoints/characteristics are required for all studies: rates of cessation, including quit attempts, and sustained abstinence among current smokers. Biological verification of tobacco abstinence is strongly encouraged.
• Markers of HIV/AIDS immune status (e.g., CD4 cell count) must be assessed. If feasible, examination of HIV/AIDS related co-infections (e.g., hepatitis B or C, Kaposi's sarcoma associated herpes virus, human papilloma virus) and/or co-morbidities (e.g., non-AIDS-defining cancer such as lung, anal, or Hodgkin lymphoma) should be assessed.
• Studies should be designed for dissemination (e.g., feasibility/acceptability of the intervention for PLWH and providers) and suitable for the intended context. Applicants are encouraged to use an evaluation framework (e.g., RE-AIM) to assess the potential of the intervention to be scaled up.
• Applications that include secondary assignment to NIDA should include data regarding concurrent use of licit or illicit substances of abuse and, where applicable, participation in medication-assisted or other forms of drug treatment.

Primary research questions that fall within the scope of this FOA include, but are not limited to the following:

• What evidence-based smoking cessation interventions are most effective in helping PLWH to achieve long-term tobacco abstinence?
• How can evidence-based smoking cessation interventions be adapted to improve smoking cessation outcomes among PLWH?
• Considering the diverse and unique needs of PLWH, including culture, country of origin, English language proficiency, socioeconomic status, and race/ethnicity, how can existing evidence-based smoking cessation interventions be adapted to best reach and be effective in specific groups?
• What smoking cessation interventions are most effective among subgroups of PLWH with disproportionately high smoking rates? These include African American men, American Indian/Alaska Natives, rural residents, sexual and gender minorities, individuals with mental illness, persons with other substance use disorders, those of low socioeconomic status (SES), and medically underserved or uninsured.

Additional topics (e.g., secondary research questions) that fall within the scope of this FOA include but are not limited to the following:

• What barriers are identified when integrating evidence-based tobacco dependence treatment interventions into the existing HIV prevention and treatment context?
• How does the social and behavioral context of tobacco use among PLWH, including the use of alcohol and other drugs, influence tobacco use behaviors and cessation outcomes within the context of smoking cessation interventions?
• How is smoking cessation related to the concurrent use of alcohol and drug use, particularly classes of alcohol and drug use associated with increased behavioral risk for HIV transmission?
• How can relapse prevention strategies best be incorporated into existing evidence-based tobacco cessation interventions for PLWH?
• How does HIV treatment adherence play a role in the effects of smoking cessation interventions?
• How do smoking cessation and/or smoking cessation interventions influence HIV treatment adherence?
• How can evidence-based smoking cessation interventions be adapted and implemented in the context of diverse HIV care settings?
• What smoking cessation services, such as phone-based, web-based, text-based, and app-based interventions, influence tobacco use behaviors and cessation outcomes?
• What educational and training strategies are most effective within health care delivery systems to inform HIV treatment providers and PLWH about the health risks associated with cigarette smoking?
• What strategies are effective in increasing motivation for smoking cessation among PLWH?
• What strategies are effective to decrease barriers to provision of evidence-based smoking cessation interventions for PLWH, including increasing motivation of providers?
• What healthcare systems-based approaches can facilitate the delivery of evidence-based smoking cessation interventions for PLWH?

Non-Responsive Projects

The following types of projects are not responsive to this FOA (applications proposing non-responsive projects will not be reviewed):

• Applications or research projects focused on biological mechanisms or disease processes.
• Studies that do not test an intervention that is intended to reduce cigarette smoking among PLWH.
• Observational studies.
• Studies that lack a control or comparison group.
• Studies that employ non-evidence-based tobacco cessation interventions.

Annual grantee meetings: Awardees will be expected to participate in an annual investigators' meeting that may be hosted at NCI and/or on a rotating basis at the participating Principal Investigators' institutions. The meetings will provide a forum for presenting scientific findings from each of the funded studies and will facilitate interactions among the community of funded scientists. Applicants should budget for the Principal Investigator and one additional project personnel to attend the planned annual grantee meeting. Investigators will be expected to participate in conference calls for planning purposes biannually or at other appropriate intervals; they may also be asked to participate in committees that meet periodically by conference call.

Standardization and coordination: Funded investigators will, to the extent possible, be expected to collaborate and report key common variables in a standardized manner. Investigators may also be asked to collaborate in the development of formative tools, approaches to dissemination, and other areas of shared investigator interest.

See Section VIII. Other Information for award authorities and regulations.

NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made from 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:

o Hispanic-serving Institutions

o Historically Black Colleges and Universities (HBCUs)

o Tribally Controlled Colleges and Universities (TCCUs)

o Alaska Native and Native Hawaiian Serving Institutions

o 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 not eligible to apply.
Foreign components, as defined in the NIH Grants Policy Statement, are not 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.

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).

Buttons to access the online ASSIST system or to download application forms are available in Part 1 of this FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

It is critical that applicants follow the Research (R) Instructions in the SF424 (R&R) Application Guide, 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:

Annette Kaufman, PhD, MPH
National Cancer Institute (NCI)
Telephone: 240-276-6706
Email: [email protected]

All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed.

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.

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.

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:

Research Strategy: The entire Research Strategy must adhere to the general requirements listed in Section I of this FOA. The subsections indicated below should address the following specific aspects.

Significance:

• Explain how the successful completion of the proposed research will facilitate the rapid development and implementation of effective cessation services for PLWH.

Preliminary Data:

• If available, provide preliminary data regarding the efficacy of the smoking cessation intervention(s) to be developed and other relevant documentation in support of the proposed project.

Approach:

The description in this sub-section must address and provide the necessary supporting details explaining how the proposed project will meet the following key requirements:

• Research strategies need to be consistent with the highest HIV/AIDS research priorities as identified by NIH (see NOT-OD-15-137).
• The design of clinical trials: Research designed to estimate the effect of an intervention on cigarette smoking cessation outcomes with at least one control or comparison group.
• Tobacco use history: All projects must include a detailed assessment of cigarette smoking and cigarette smoking history. Other tobacco product use history, including electronic cigarettes, should also be assessed.
• Cessation endpoints: The interventions must be rigorously evaluated in terms of the rates of cessation, including quit attempts, and sustained abstinence among current smokers. Biochemical verification of abstinence is strongly encouraged.
• HIV/AIDS immune status: All projects must assess markers of HIV/AIDS immune status (e.g., CD4 cell count). If feasible, examination of HIV/AIDS related co-infections (e.g., hepatitis B or C, Kaposi's sarcoma associated herpes virus, human papilloma virus) and/or co-morbidities (e.g., non-AIDS-defining cancer such as lung, anal, or Hodgkin lymphoma) should be assessed.
• Intervention delivery: Studies should be designed for dissemination (e.g., feasibility/acceptability of the intervention for PLWH and providers) and suitable for the intended context. Applicants are encouraged to use an evaluation framework (e.g., RE-AIM) to assess the potential of the intervention to be scaled up.
• Examples of other considerations applicable to all project types: Applicants should consider a variety of options regarding the people and resources engaged in delivering the cessation intervention. These options may include the involvement of primary care physicians or others who provide care for PLWH, and telephone quit lines or Web-based cessation resources.

Investigators are strongly encouraged to use standard data collection measures to the extent possible given the scientific areas covered in the project. The Institute of Medicine reports entitled "Capturing Social and Behavioral Domains in Electronic Health Records," the PhenX Toolkit, and other consensus documents and resources should be reviewed for relevant measures. Applicants must also anticipate that funded investigators will be encouraged to use measures that are common across the funded projects, to the extent feasible given the scientific areas covered in the projects.

Letters of Support: In addition to standard letters of support, include other letter(s) of support documenting that the performance site(s) will provide access to the research team for the delivery of smoking cessation interventions as proposed.

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, with the following modification:

• All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.

Resource Sharing Plans should describe the sharing of materials and tools (e.g. training protocols, data collection tools, technical assistance resources) at a level of detail that permit other providers to implement the tested cessation intervention(s).

Appendix:

Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

When involving NIH-defined human subjects research, clinical research, and/or clinical trials (and when applicable, clinical trials research experience) follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

If you answered "Yes" to the question "Are Human Subjects Involved?" on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or Delayed Onset Study record.

Study Record: PHS Human Subjects and Clinical Trials Information

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

Delayed Onset Study

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

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

See Part 1. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants.gov

Part I. Overview Information contains information about Key Dates and times. 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. When a submission date falls on a weekend or Federal holiday, the application deadline is automatically extended to the next business day.

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 and time. If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Policy on Late Application Submission.

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. For assistance with application submission, contact the Application Submission Contacts in Section VII.

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 the policy. Any instructions provided here are in addition to the instructions in the policy.

Important Update: See NOT-OD-18-228 for updated review language for due dates on or after January 25, 2019.

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:

The R21 exploratory/developmental grant supports investigation of novel scientific ideas or new model systems, tools, or technologies that have the potential for significant impact on biomedical or biobehavioral research. An R21 grant application need not have extensive background material or preliminary information. Accordingly, reviewers will emphasize the conceptual framework, the level of innovation, and the potential to significantly advance our knowledge or understanding. Appropriate justification for the proposed work can be provided through literature citations, data from other sources, or, when available, from investigator-generated data. Preliminary data are not required for R21 applications; however, they may be included if available.

In addition, for applications involving clinical trials:

A proposed Clinical Trial application may include study design, methods, and intervention that are not by themselves innovative but address important questions or unmet needs. Additionally, the results of the clinical trial may indicate that further clinical development of the intervention is unwarranted or lead to new avenues of scientific investigation.

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? Is there a strong scientific premise for the project? 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?

Specific for this FOA: Will this project, if successful, contribute to optimizing smoking cessation treatment among PLWH in the U.S.?

In addition, for applications involving clinical trials:

Are the scientific rationale and need for a clinical trial to test the proposed hypothesis or intervention well supported by preliminary data, clinical and/or preclinical studies, or information in the literature or knowledge of biological mechanisms? For trials focusing on clinical or public health endpoints, is this clinical trial necessary for testing the safety, efficacy or effectiveness of an intervention that could lead to a change in clinical practice, community behaviors or health care policy? For trials focusing on mechanistic, behavioral, physiological, biochemical, or other biomedical endpoints, is this trial needed to advance scientific understanding?

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or those 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?

In addition, for applications involving clinical trials:

With regard to the proposed leadership for the project, do the PD/PI(s) and key personnel have the expertise, experience, and ability to organize, manage and implement the proposed clinical trial and meet milestones and timelines? Do they have appropriate expertise in study coordination, data management and statistics? For a multicenter trial, is the organizational structure appropriate and does the application identify a core of potential center investigators and staffing for a coordinating center?

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?

In addition, for applications involving clinical trials:

Does the design/research plan include innovative elements, as appropriate, that enhance its sensitivity, potential for information or potential to advance scientific knowledge or clinical practice?

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? 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? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?

Specific for this FOA: Applications must address the following study design considerations.

• Does the project propose to estimate the effect of an intervention on cigarette smoking cessation outcomes with at least one control or comparison group?
• Does the project include a detailed assessment of cigarette smoking and cigarette smoking history?
• Does the project assess other tobacco product use, including electronic cigarettes?
• Are the cessation interventions evaluated in terms of the rates of cessation, including quit attempts, and sustained abstinence among current smokers?
• Does the project assess markers of HIV/AIDS immune status?
• Is the study designed for dissemination (e.g., feasibility/acceptability of the intervention for PLWH and providers) and suitable for the intended context?
• Are the proposed interventions sufficiently well supported by the existing evidence and, if available, preliminary data?

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?

In addition, for applications involving clinical trials:

Study Design

Is the study design justified and appropriate to address primary and secondary outcome variable(s)/endpoints that will be clear, informative, and relevant to the hypothesis being tested? Is the scientific rationale/premise of the study based on previously well-designed preclinical and/or clinical research? Given the methods used to assign participants and deliver interventions, is the study design adequately powered to answer the research question(s), test the proposed hypothesis/hypotheses, and provide interpretable results? Is the trial appropriately designed to conduct the research efficiently? Are the study populations (size, gender, age, demographic group), proposed intervention arms/dose, and duration of the trial, appropriate and well justified?

Are potential ethical issues adequately addressed? Is the process for obtaining informed consent or assent appropriate? Is the eligible population available? Are the plans for recruitment outreach, enrollment, retention, handling dropouts, missed visits, and losses to follow-up appropriate to ensure robust data collection? Are the planned recruitment timelines feasible and is the plan to monitor accrual adequate? Has the need for randomization (or not), masking (if appropriate), controls, and inclusion/exclusion criteria been addressed? Are differences addressed, if applicable, in the intervention effect due to sex/gender and race/ethnicity?

Are the plans to standardize, assure quality of, and monitor adherence to, the trial protocol and data collection or distribution guidelines appropriate? Is there a plan to obtain required study agent(s)? Does the application propose to use existing available resources, as applicable?

Data Management and Statistical Analysis

Are planned analyses and statistical approach appropriate for the proposed study design and methods used to assign participants and deliver interventions? Are the procedures for data management and quality control of data adequate at clinical site(s) or at center laboratories, as applicable? Have the methods for standardization of procedures for data management to assess the effect of the intervention and quality control been addressed? Is there a plan to complete data analysis within the proposed period of the award?

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

In addition, for applications involving clinical trials:

If proposed, are the administrative, data coordinating, enrollment, and laboratory/testing centers, appropriate for the trial proposed?

Does the application adequately address the capability and ability to conduct the trial at the proposed site(s) or centers? Are the plans to add or drop enrollment centers, as needed, appropriate?

If international site(s) is/are proposed, does the application adequately address the complexity of executing the clinical trial?

If multi-sites/centers, is there evidence of the ability of the individual site or center to: (1) enroll the proposed numbers; (2) adhere to the protocol; (3) collect and transmit data in an accurate and timely fashion; and (4) operate within the proposed organizational structure?

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.

Specific to applications proposing clinical trials:

Is the study timeline described in detail, taking into account start-up activities, the anticipated rate of enrollment, and planned follow-up assessment? Is the projected timeline feasible and well justified? Does the project incorporate efficiencies and utilize existing resources (e.g., CTSAs, practice-based research networks, electronic medical records, administrative database, or patient registries) to increase the efficiency of participant enrollment and data collection, as appropriate?? Are potential challenges and corresponding solutions discussed (e.g., strategies that can be implemented in the event of enrollment shortfalls)?

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 criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals. Reviewers will assess the use of chimpanzees as they would any other application proposing the use of vertebrate animals. 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.

Not applicable

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 Data Sharing Plan (GDS).

For projects involving key biological and/or chemical resources, reviewers will comment on the brief plans proposed for identifying and ensuring the validity of those resources.

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 the National Cancer Institute, 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 appropriate national Advisory Council or Board. 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.

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. Refer to Part 1 for dates for peer review, advisory council review, and earliest start date.

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.

Individual awards are based on the application submitted to, and as approved by, the NIH and are subject to the IC-specific terms and conditions identified in the NoA.

ClinicalTrials.gov: If an award provides for one or more clinical trials. By law (Title VIII, Section 801 of Public Law 110-85), the "responsible party" must register and submit results information for certain "applicable clinical trials" on the ClinicalTrials.gov Protocol Registration and Results System Information Website (https://register.clinicaltrials.gov). NIH encourages registration of all trials

whether required under the law or not. For more information, see http://grants.nih.gov/ClinicalTrials_fdaaa/

Institutional Review Board or Independent Ethics Committee Approval: Grantee institutions must ensure that the application as well as all protocols are reviewed by their IRB or IEC. To help ensure the safety of participants enrolled in NIH-funded studies, the awardee must provide NIH copies of documents related to all major changes in the status of ongoing protocols.

Data and Safety Monitoring Requirements: The NIH policy for data and safety monitoring requires oversight and monitoring of all NIH-conducted or -supported human biomedical and behavioral intervention studies (clinical trials) to ensure the safety of participants and the validity and integrity of the data. Further information concerning these requirements is found at http://grants.nih.gov/grants/policy/hs/data_safety.htm and in the application instructions (SF424 (R&R) and PHS 398).

Investigational New Drug or Investigational Device Exemption Requirements: Consistent with federal regulations, clinical research projects involving the use of investigational therapeutics, vaccines, or other medical interventions (including licensed products and devices for a purpose other than that for which they were licensed) in humans under a research protocol must be performed under a Food and Drug Administration (FDA) investigational new drug (IND) or investigational device exemption (IDE).

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.

Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights law. This means that recipients of HHS funds must ensure equal access to their programs without regard to a person's race, color, national origin, disability, age and, in some circumstances, sex and religion. This includes ensuring your programs are accessible to persons with limited English proficiency. HHS recognizes that research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator's scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research.

For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA. HHS provides general guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see http://www.hhs.gov/ocr/civilrights/resources/laws/revisedlep.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html; and http://www.hhs.gov/ocr/civilrights/understanding/index.html. Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see http://www.hhs.gov/ocr/civilrights/understanding/disability/index.html. Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at http://www.hhs.gov/ocr/office/about/rgn-hqaddresses.html or call 1-800-368-1019 or TDD 1-800-537-7697. Also note it is an HHS Departmental goal to ensure access to quality, culturally competent care, including long-term services and supports, for vulnerable populations. For further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at http://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.

In accordance with the statutory provisions contained in Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal Year 2009 (Public Law 110-417), NIH awards will be subject to the Federal Awardee Performance and Integrity Information System (FAPIIS) requirements. FAPIIS requires Federal award making officials to review and consider information about an applicant in the designated integrity and performance system (currently FAPIIS) prior to making an award. An applicant, at its option, may review information in the designated integrity and performance systems accessible through FAPIIS and comment on any information about itself that a Federal agency previously entered and is currently in FAPIIS. The Federal awarding agency will consider any comments by the applicant, in addition to other information in FAPIIS, in making a judgement about the applicant's integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 45 CFR Part 75.205 "Federal awarding agency review of risk posed by applicants." This provision will apply to all NIH grants and cooperative agreements except fellowships.

Cooperative Agreement Terms and Conditions of Award

Not Applicable

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 RPPR, 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.

In accordance with the regulatory requirements provided at 45 CFR 75.113 and Appendix XII to 45 CFR Part 75, recipients that have currently active Federal grants, cooperative agreements, and procurement contracts from all Federal awarding agencies with a cumulative total value greater than $10,000,000 for any period of time during the period of performance of a Federal award, must report and maintain the currency of information reported in the System for Award Management (SAM) about civil, criminal, and administrative proceedings in connection with the award or performance of a Federal award that reached final disposition within the most recent five-year period. The recipient must also make semiannual disclosures regarding such proceedings. Proceedings information will be made publicly available in the designated integrity and performance system (currently FAPIIS). This is a statutory requirement under section 872 of Public Law 110-417, as amended (41 U.S.C. 2313). As required by section 3010 of Public Law 111-212, all information posted in the designated integrity and performance system on or after April 15, 2011, except past performance reviews required for Federal procurement contracts, will be publicly available. Full reporting requirements and procedures are found in Appendix XII to 45 CFR Part 75 Award Term and Conditions for Recipient Integrity and Performance Matters.

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

eRA Service Desk (Questions regarding ASSIST, eRA Commons, application errors and warnings, documenting system problems that threaten on-time submission, and 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)

General Grants Information (Questions regarding application processes and NIH grant resources)
Email: [email protected] (preferred method of contact)
Telephone: 301-945-7573

Grants.gov Customer Support (Questions regarding Grants.gov registration and Workspace)
Contact Center Telephone: 800-518-4726
Email: [email protected]

Annette Kaufman, PhD, MPH
National Cancer Institute
Telephone: 240-276-6706
Email: [email protected]

Richard A. Jenkins, PhD
National Institute on Drug Abuse (NIDA)
Telephone: 301-443-1923
Email: [email protected]

Referral Officer
National Cancer Institute (NCI)
Telephone: 240-276-6390
Email: [email protected].

Carol Perry
National Cancer Institute (NCI)
Telephone 240-276-6282
Email: [email protected]

Edith Davis
National Institute on Drug Abuse (NIDA)
Telephone: 301-827-6697
Email: [email protected]

Recently issued trans-NIH policy notices may affect your application submission. A full list of policy notices published by NIH is provided in the NIH Guide for Grants and Contracts. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Part 75.