Research on the Health of Transgender and Gender Non-Conforming Populations

Research on the Health of Transgender and Gender Non-Conforming Populations is sponsored by National Institutes of Health (NIH). Supports research on the health of transgender and gender non-conforming populations, including mental health aspects.

Expired PA-18-729: Research on the Health of Transgender and Gender Nonconforming Populations (R01 Clinical Trial Optional) This notice has expired. Check the NIH Guide for active opportunities and notices. Department of Health and Human Services Part 1.

Overview Information Participating Organization(s) National Institutes of Health ( NIH ) of Participating Organizations Kennedy Shriver National Institute of Child Health and Human National Cancer Institute ( NCI ) National Human Genome Research Institute ( NHGRI ) National Institute on Aging ( NIA ) National Institute on Alcohol Abuse and Alcoholism ( NIAAA ) National Institute of Allergy and Infectious Diseases ( NIAID ) National Institute on Deafness and Other Communication National Institute of Environmental Health Sciences ( NIEHS ) National Institute on Minority Health and Health National Institute of Mental Health ( NIMH ) National Institute of Nursing Research ( NINR ) Division of Program Coordination, Planning and Strategic Initiatives: Sexual & Gender Minority Research Office ( SGMRO ) Office of AIDS Research ( OAR ) Office of Research on Women’s Health ( ORWH ) Funding Opportunity Title Research on the Health of Transgender and Gender Nonconforming Populations (R01 Clinical Trial Optional) R01 Research Project Grant May 19, 2020 - Notice of Special Interest (NOSI): Development and Preliminary Testing of Health-related Behavioral Interventions.

See Notice NOT-OD-20-106 . March 10, 2020 - Reminder: FORMS-F Grant Application Forms & Instructions Must be Used for Due Dates On or After May 25, 2020- New Grant Application Instructions Now Available. See Notice NOT-OD-20-077 .

Clarifying Competing Application Instructions and Notice of Publication of Frequently Asked Questions (FAQs) Regarding Proposed Human Fetal Tissue Research. See Notice Changes to NIH Requirements Regarding Proposed Human Fetal Tissue Research. See Notice NOT-OD-19-128 .

November 26, 2018 - NIH & AHRQ Announce Upcoming Updates to Application Instructions and Review Criteria for Research Grant Applications. See Notice NOT-OD-18-228 . Funding Opportunity Announcement (FOA) Number Companion Funding Opportunity PA-18-728 , R21 Exploratory/Developmental Grant Additional Information on Eligibility .

Catalog of Federal Domestic Assistance (CFDA) Number(s) 93. 865; 93. 399, 93.

396, 93. 395, 93. 394, 93.

393; 93. 172; 93. 866; 93.

273; 93. 855; 93. 173; 93.

113; 93. 307; 93. 313; 93.

242; 93. 361 Funding Opportunity Purpose This funding opportunity announcement (FOA) calls for research on the health of transgender and gender nonconforming people of all ages, including both youth and adults who are questioning their gender identity and those individuals who are making or who have made a transition from being identified as one gender to the other.

This group encompasses individuals whose gender identity differs from the sex on their original birth certificate or whose gender expression varies significantly from what is traditionally associated with or typical for that sex. Open Date (Earliest Submission Date) Letter of Intent Due Date(s) dates apply, by 5:00 PM local time of applicant organization.

All types of non-AIDS applications allowed for this funding opportunity announcement are due on these dates. Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date. AIDS Application Due Date(s) dates apply, by 5:00 PM local time of applicant organization.

All types of AIDS and AIDS-related applications allowed for this funding opportunity announcement are due on these dates. Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.

It is critical that applicants follow the Research (R) Instructions (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 I.

Funding Opportunity Description Section II. Award Information Section III. Eligibility Information Section IV.

Application and Submission Section V. Application Review Information Section VI. Award Administration Information Section VII.

Agency Contacts Section VIII. Other Information Full Text of Announcement Section I. Funding Opportunity Description This funding opportunity announcement (FOA) calls for research on the health of transgender and gender nonconforming people.

Transgender and gender nonconforming people encompass individuals whose gender identity differs from the sex on their original birth certificate, including individuals who are making or who have made a transition from being identified as one gender to the other, as well as individuals who are questioning their gender identity, who identify with more than one gender, or whose gender expression varies significantly from what is traditionally associated with or typical for that sex.

While there are a number of terms for this group of individuals, for the sake of consistency this document will refer to the group as transgender and gender nonconforming people. This FOA calls for research addressing the medical, sociological, psychological and structural causes and consequences of transgender and gender nonconforming identities.

Investigations of the social determinants of health in these populations are needed, including understanding the impact of stigma, the high impact of HIV, minority stress, education, employment, violence, homelessness, and incarceration. More information is needed on relationships with partners and family, as well as on sexual and reproductive health.

Successful aging, including the impact of life events, experiences, and interventions such as hormone therapy and surgery are other important topics to investigate. It will also be important to learn more about brain development, resilience, and end-of-life issues. Collaborative, cross disciplinary work will be essential.

Areas of research sought include but are Methodology and Measurement Development and validation of methods responsive to the heterogeneity of transgender and gender nonconforming populations (gender identity and fluidity, sexual orientation, developmental stages, hormonal regimens, surgical procedures, SES, racial/ethnic differences).

Development and testing of new and/or current measures of identifying transgender and gender nonconforming people in research studies. Development and testing of new methods to improve estimates of the size and demographic characteristics of the transgender and gender nonconforming populations in the United States.

Development of methods to better understand item non-response and non-participation among transgender and gender nonconforming persons in scientific surveys and other studies. Approaches to improve the representativeness of existing and emerging data, including the use of electronic health records. Longitudinal/life-course approaches.

Methods to obtain larger sample sizes of transgender and gender nonconforming populations and sub-groups that would allow for well-powered Improvement in standardizing terminology for reporting phenotypes, surgical procedures, hormone regimens, clinical records, data collection, management, and analysis across a variety of clinical and Consideration of improvement in legal and ethical issues in research on transgender and gender nonconforming populations, such as personal and/or community consent for study participation.

of Transgender and Gender Nonconforming Identities Examination of the biological underpinnings of gender and gender identity, and the health implications of identification with the range of identities and with the chosen rather than the sex on their original birth Research producing data on the incidence and prevalence of childhood gender-variant or transgender and gender nonconforming identities and the factors associated with continuing this identity into adolescence and adulthood, and implications for health.

Research on gender identity development and change, including diversity in gender identity and expression, particularly for non-binary transgender identities and within diverse racial and ethnic groups and Research on how family and social support during gender identity development impact children’s health outcomes.

Research on how age of development of transgender and gender nonconforming identities affect mental and physical health. in Diagnosis and Clinical Management of Gender Dysphoria Evaluation of how the timing of interventions, including hormonal and surgical interventions, affect development and physical and mental health.

Studies of the outcomes, physical and psychological, of pubertal suppression [blocking] and cross-sex hormones, considering the age of initiation of such treatment. Research on the impact of brain development of hormonal therapy and surgical interventions such as removal of testes and ovaries.

Studies of the impact of standardized treatment plans and prescription guidelines, addressing clinician gatekeeping as a factor in Research evaluating the health outcomes of contemporary approaches to treatment whereby hormone therapy is not necessarily followed by surgery, and gender identity and expression do not conform to binary conceptualizations of sex and gender.

Rigorous empirical evaluation of the criteria in the Standards of Care to assess and treat gender dysphoria. These could include whether and when diagnosis of gender dysphoria is stigmatizing, whether psychotherapy should be required before hormone therapy or surgery, whether a period of real life experience before hormone therapy is helpful or potentially harmful, and the value and length of the real-life experience before surgery.

Systematic evaluation on the feasibility, acceptability, and effectiveness of the informed consent model and other treatment approaches that do not adhere to the Standards of Care. Research on whether adherence to the eligibility criteria of the Standards of Care predicted post-operative development and physical and mental health.

Studies of the prevalence and predictors of the persistence of gender dysphoria and the impact of interventions (psychological, hormonal, and surgical) on persisting dysphoria.

Outcomes of Long-term Hormone Use and Surgical Treatment Research on the factors associated with outcomes of gender Research on how socioeconomic status, race, ethnicity, and age among transgender and gender nonconforming persons affect treatment choices and Investigations of the safety of treatment with Gonadotropin-releasing [GnRH] analogues and hormones at various ages.

Research on the effects of hormone administration and/or how the blocking of puberty with GnRH analogs affect overall physical health and well-being, including sex-specific brain development.

Research that examines the differential impact of diseases and conditions in transgender and gender nonconforming individuals as a result of treatment options and interactions with hormone therapies, such as osteoporosis or hematologic issues, thrombosis related to estrogen and polycythemia related Examinations of differential mortality from diseases and conditions such as Type 2 diabetes mellitus, lipids disorders, cardiovascular disease (CVD), venous thromboembolism, and cancer as a result of long-term Research on the effects of hormone therapy on the fertility of transgender and gender nonconforming individuals and its implications for Studies of HIV drug treatment and prophylaxis interactions with hormonal and surgical treatments.

Research on how irregular use of hormonal treatment affects physical and emotional health. Studies on how estrogen hormone treatments affect the male reproductive tissues of individuals transitioning from male to female, and how androgen hormone treatments affect the female reproductive tissues of individuals transitioning from female to male.

Studies that examine the extent and consequences of the use of body fillers such as silicones on health outcomes. of Life and Mental Health Studies of interpersonal relationships and sexual and reproductive health, including studies on fertility, in men and women. Research on aging, including end-of-life care in transgender and gender nonconforming individuals.

Research on the impact of complementary health approaches and their integration into conventional health to facilitate successful aging, including end-of-life care. Research on the determinants and consequences of psychiatric conditions, pre- and post-transition. Research on substance use (alcohol, drugs, tobacco) and its treatment among transgender and gender nonconforming people.

Improved understanding of multivariate risk for, and protection against, the onset of mental disorders and suicidal behavior (including studies that look at multiple RDoC domains; https://www. nimh. nih.

gov/research-priorities/rdoc/index. shtml); with consideration for transition periods that may heighten risk. In particular, studies that utilize RDoC-consistent measures could inform the etiological factors for both transgender, gender nonconforming, and other individuals.

Given the high rates of suicide ideation and attempts, and frequent experiences of harassment, discrimination, violence and rejection among transgender and gender nonconforming individuals, research into what factors protect against suicide ideation in this population and how these factors can inform preventative interventions.

Strategies to improve mental health outcomes among transgender and gender nonconforming individuals, the effectiveness of strategies for referral and engagement in mental health treatment and services with providers and in settings that are informed about transgender-related care issues. VIII. Other Information for award authorities and regulations.

Grant: A support mechanism providing money, property, or both to an eligible entity to carry out an approved project or activity. Application Types Allowed Glossary and the SF424 (R&R) Application Guide provide details on Optional: Accepting applications that either propose or do not propose clinical trial(s) help determining whether you are doing a clinical trial?

Funds Available and Anticipated Number of Awards The number of awards is contingent upon NIH appropriations and the submission of a sufficient number of meritorious applications. Application budgets are not limited but need to reflect the actual needs of the proposed project. The scope of the proposed project should determine the project period.

The maximum project period is 5 years. 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: 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 Nonprofits Other Than Institutions of Higher Education Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Nonprofits without 501(c)(3) IRS Status (Other than Institutions For-Profit Organizations (Other than Small Businesses) City or Township Governments Special District Governments Indian/Native American Tribal Governments (Federally Recognized) Indian/Native American Tribal Governments (Other than Federally Eligible Agencies of the Federal Government U.S. Territory or Possession 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 Non-domestic (non-U.S.) Entities (Foreign Institutions) Non-domestic (non-U.S.) Entities (Foreign Institutions) are eligible to apply.

Non-domestic (non-U.S.) components of U.S. Organizations are eligible Foreign components, as defined in the NIH Grants Policy Statement , are allowed. 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 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 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. 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.

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 must have an active DUNS number and SAM registration in order to complete the 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.

Eligible Individuals (Program Director/Principal 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 This FOA does not require cost sharing as defined in the NIH Grants Policy Statement . 3.

Additional Information on Eligibility 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 A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission 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 ). Section IV. Application and Submission Information 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. 2. Content and Form of Application Submission It is critical that applicants follow the Research (R) Instructions (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 For information on Application Submission and Receipt, visit Frequently Asked Questions Application Guide, Electronic Submission of Grant All page limitations described in the SF424 Application Page Limits must be followed.

Instructions for Application Submission The following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing an All instructions in the SF424 (R&R) Application Guide SF424(R&R) Project/Performance Site Locations All instructions in the SF424 (R&R) Application Guide SF424(R&R) Other Project Information All instructions in the SF424 (R&R) Application Guide SF424(R&R) Senior/Key Person Profile All instructions in the SF424 (R&R) Application Guide All instructions in the SF424 (R&R) Application Guide All instructions in the SF424 (R&R) Application Guide PHS 398 Cover Page Supplement All instructions in the SF424 (R&R) Application Guide All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions: 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 include a Data Sharing Plan.

The Data Sharing Plan will be considered during peer review and by program staff as award decisions are being made as appropriate and consistent with achieving the goals of the program. It is expected that the results of NICHD-funded research will be shared with the wider scientific community in a timely manner.

Awardees are strongly encouraged to deposit large-scale, human genetic data in the database for Genotype and Phenotype dbGaP ( https://www. ncbi. nlm.

nih. gov/gap ). For other data and biospecimens from human genetic or non-genetic studies, awardees are encouraged to use the NICHD Data and Specimen Hub DASH ( https://dash.

nichd. nih. gov/ ) or other equivalent broad-sharing data and/or biospecimen repositories.

The following resource describing Common Data Elements may be helpful during the planning phases of a project when considering ways to optimize data collection in order to facilitate broad data sharing: https://www. nlm. nih.

gov/cde/ . Only limited Appendix materials are allowed.

Follow all instructions for the Appendix as described in the SF424 (R&R) Application PHS Human Subjects and Clinical Trials Information 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 Record: PHS Human Subjects and Clinical Trials Information All instructions in the SF424 (R&R) Application Guide All instructions in the SF424 (R&R) Application Guide PHS Assignment Request Form All instructions in the SF424 (R&R) Application Guide Foreign (non-U.S.) institutions must follow policies Grants Policy Statement , and procedures for foreign institutions.

3. Unique Entity Identifier and System for Award Management (SAM) 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 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 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 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. 5.

Intergovernmental Review This initiative is not subject to intergovernmental 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 .

Requirements and Information 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 Electronically .

If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must for Applicants Experiencing System Issues . For assistance with application submission, contact the Application Submission Contacts in Section VII . 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, NIH.

Applications that are incomplete or non-compliant will Requests of $500,000 or more for direct costs in any year Applicants requesting $500,000 or more in direct costs in any year (excluding consortium F&A) must contact a Scientific/ Research Contact at least 6 weeks before submitting the application and follow the Policy on the Acceptance for Review of Unsolicited Applications that Request $500,000 or More in Direct Costs as described in the SF424 Post Submission Materials 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 Section V. Application Review Information 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 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 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?

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?

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?

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 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?

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?

addition, for applications involving clinical trials Does the application adequately address the following, if applicable? 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