Developmental Pharmacology and Toxicology: Role of Ontogeny (R01)

Developmental Pharmacology and Toxicology: Role of Ontogeny (R01) is sponsored by National Institutes of Health (NIH). Encourages grant applications from institutions or organizations that propose multidisciplinary, investigator-initiated basic and translational research in developmental pharmacology and toxicology, with emphasis on the role of ontogeny on drug metabolizing enzymes, transporters…

Expired PAR-13-306: Developmental Pharmacology and Toxicology: Role of Ontogeny (R01) This notice has expired. Check the NIH Guide for active opportunities and notices. of Health and Human Services Part 1.

Overview Information Participating Organization(s) National Institutes of Health ( NIH ) Components of Participating Eunice Kennedy Shriver National Institute of Child Health and Human Development ( NICHD ) National Institute of Environmental Health Sciences ( NIEHS ) National Institute of General Medical Sciences ( NIGMS ) Funding Opportunity Title Pharmacology and Toxicology: Role of Ontogeny (R01) R01 Research Project Grant NOT-OD-16-004 - NIH & AHRQ Announce Upcoming Changes to Policies, Instructions and Forms for 2016 Grant Applications (November 18, 2015) NOT-OD-16-006 - Simplification of the Vertebrate Animals Section of NIH Grant Applications and Contract Proposals NOT-OD-16-011 - Implementing Rigor and Transparency in NIH & AHRQ Research Grant Applications supersedes instructions in Section III.

3 regarding applications that are essentially the same. August 21, 2013: Removed reference to ASSIST in section IV. 3, since ASSIST is currently only available for multi-project applications.

Funding Opportunity Announcement (FOA) Number Companion Funding Opportunity PAR-13-307 , R03 Small Grant Program PAR-13-308 , R21 Exploratory/Developmental Grant Additional Information on Eligibility .

Catalog of Federal Domestic Assistance (CFDA) Number(s) Funding Opportunity Purpose This Funding Opportunity Announcement (FOA) encourages grant applications from institutions or organizations that propose multidisciplinary, investigator-initiated basic and translational research in developmental pharmacology and toxicology.

Particular emphasis should be placed on the role of ontogeny on drug metabolizing enzymes, transporters, receptors and signaling pathways across developmental periods from fetal life to adolescence affecting drug action and toxicity. Open Date (Earliest Submission Date) Letter of Intent Due Date(s) 30 days prior to the application due date dates apply, by 5:00 PM local time of applicant organization.

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) Required Application Instructions It is critical that applicants follow the instructions in (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 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 This Funding Opportunity Announcement (FOA) encourages multidisciplinary, investigator-initiated basic and translational research grant applications in developmental pharmacology and toxicology.

Particular emphasis should be placed on the role of ontogeny on drug metabolizing enzymes, transporters, receptors and signaling pathways activity across developmental periods from fetal life to adolescence affecting drug action and toxicity. This initiative is aimed at unraveling the effects of development on mechanisms of drug action/ pharmacodynamics and biotransformation, prenatally and from birth through adolescence.

In addition, because drugs are now being developed to target specific receptors or modulators, it is imperative to determine their functional expression over time in the pediatric population.

Applications should be designed around a central theme of ontogeny of processes that have pharmacologic relevance, with emphasis on the interaction and/or relationships between these processes (e.g., drug metabolism and drug transport, receptors and ion channels, or receptors and pharmacologic ligands).

Knowledge accrued in developmental biology studies need to be applied to the study of the pharmacology of drugs used in children in an It is known that developmental pharmacology is both organ-specific as well as biological process -specific.

In recent years the ontogeny of Phase I drug metabolizing enzymes (DMEs) has been characterized, but limited information is available on Phase II DMEs, ontogeny of drug metabolic pathways and functional interaction between transporters and DMEs during development. Insights gleaned from developmental biology need to be applied to understand the pharmacology of drugs used across the course of development in an integrated manner.

Development and organ maturation involve the completion of a series of complex and interlocking events that proceed as a continuum but at uneven rates. Drugs are juxtaposed at different stages of the developmental continuum. For the rational use of drugs across development, a systems biology framework needs to be established based on the developmental stage of the processes involved in drug disposition and action.

Progress in this area can only be realized by cross-disciplinary research that integrates related processes. Isolated studies of a particular DME can be misleading without consideration of the functional integrity of the whole pathway.

There is also a need to determine existence of developmental shifts in activity between different enzymes, transporters, and pharmacologic targets into predictive tools and targeted treatment strategies at different developmental periods. The PAR also seeks to stimulate research on the molecular and cellular mechanisms involved in the production of pediatric ADRs from a developmental context.

There is an urgent need to understand the mechanisms of ADRs in children in order to develop preventive strategies.

There is also a need to study the relationship between gene expression and conventional This announcement includes research on the role of ontogeny and the characterization of pharmacogenetic and developmental variations of DMEs, transporters, ion channels, receptors and signaling pathways that are responsible for drug toxicity in the pediatric population.

This knowledge may result in the development of predictive tools and targeted treatment strategies of adverse drug reactions at different developmental stages. The characterization of the disposition and effect of drugs across the course of development will ultimately allow the use of developmental guideposts to replace the current system of allocating children in drug trials and clinical studies on the basis of chronological age.

This initiative seeks to stimulate interdisciplinary collaboration of clinical, translational and basic researchers working in complementary areas of research in developmental therapeutics. Knowledge accrued in developmental biology studies needs to be applied to the study of the pharmacology of drugs used across the course of development in an integrated manner.

Incorporation of genomics, pharmacogenomics, proteomics, cell biology and metabolomics in developmental pharmacologic research is encouraged. The long term goal of this initiative is to provide the scientific basis for the rational use of drugs in children of all ages. Applications developed as a result of this initiative must be patient oriented and designed to answer research questions of clinical significance.

The following topics and study areas are not intended to be comprehensive or exhaustive. Synergistic studies that reach across two or more of these areas are welcomed and interdisciplinary and multidisciplinary research is especially encouraged.

Determination of the correlation between the developmental patterns of expression of DMEs and regulatory pathways; Use of sensitive, specific, rapid methods (e.g., microarrays, proteomics, metabolomics) to identify predictive biomarkers of drug response and toxicity; Inducibility and imprinting of genes involved in pharmacokinetics Short-term or long-term alterations of genes involved in pharmacokinetics or pharmacodynamics in response to drug and environmental chemical exposure in early development; Interrelationships of the expression and development of functional activity of DMEs and transporters that are clinically important in drug absorption and distribution; Ontogeny of both expression and functional characteristics of polymorphic expression of DMEs, receptors and transporters exhibiting genetic Role of disease, ethnicity and sex in the ontogeny of DMEs, transporters, and receptors; The role played by intestinal and liver transporters in drug Environmental influences (e.g., nutrition, diet, chemicals, drugs of abuse) and modulating influences (hormones and other ligands) on DMEs, transporters and receptors (efficacy and toxicity) during development; Systems models, including, but not limited to, pharmacokinetic-pharmacodynamic approaches to assess the sensitivity of the CNS, and other organs, to therapeutic drugs (e.g., anesthetics) and drugs of abuse across the course of development; Analysis and comparison of cell, tissue and organ-specific effects of drug responses across various developmental stages: e.g., changes in receptor coupling, second messengers, and signal transduction pathways; Application of in vitro systems (e.g., transporter knockout and humanized transporter animal models) for evaluating transporters interactions Identification of the effect of current drug therapies on critical developmental CNS processes such as synapse formation and remodeling, cell migration, cell replication and differentiation and cell survival; Role of the ontogeny of DMEs, transporters, and ion channels in the production of idiosyncratic and dose-related ADRs in children Use of sensitive, specific rapid methods (eg.

, microarrays, proteomics, metabolomics) to identify predictive biomarkers of drug response; Inducibility and imprinting of genes involved in pharmacokinetics Short-term or long-term alterations of genes involved in pharmacokinetics or pharmacodynamics in response to drug and environmental chemical exposure in early development; Ontogeny of both expression and functional characteristics of polymorphic expression of DMEs, receptors and transporters exhibiting genetic Role of disease, ethnicity and sex in the ontogeny of DMEs, transporters, and receptors; The role played by ontogeny of intestinal, kidney and liver transporters in drug distribution action and toxicity; Environmental influences (e.g., nutrition, diet, chemicals, drugs of abuse) and modulating influences (hormones and other ligands) on DMEs, transporters and receptors (efficacy and toxicity) during development; Analysis and comparison of cell, tissue and organ-specific effects of drug responses across various developmental stages, e.g., changes in receptor coupling, second messengers, and signal transduction pathways; Application of in vitro systems (e.g., transporter knockout and humanized transporter animal models) for evaluating transporters interactions Identification of the effect of current drug therapies on critical developmental CNS processes such as synapse formation and remodeling, cell migration, cell replication and differentiation and cell survival; Role of the ontogeny of DMEs, transporters, and ion channels in the production of idiosyncratic and dose-related ADRs in children; Ontogeny of detoxification pathways; Use of genomics, proteomics and transcriptomics technology in the discovery and identification of toxicity biomarkers during development; In vitro and in vivo models to predict toxicity in pediatric populations due to fetal drug exposure; Study of the role of reactive metabolites produced in extrahepatic tissues as a result of oxidative stress, in the pathogenesis of toxic and/or hypersensitivity reactions in children.

Statement of Interest: The NIGMS is interested in tools or data that will enhance the preclinical evaluation of drug candidates, especially for ADME-Tox information in children. Metabolic pathways and a systems biology approach to understanding drug actions need to be identified, such as modeling the interactions of Phase I, II and III enzymes.

NIGMS is also interested in the development of novel approaches to correlating pharmacokinetic and pharmacodynamic data in order to better understand the underlying biochemical and molecular processes.

In children and adults, identification of relevant biomarkers to indicate toxic or therapeutic effects is of interest, including anesthetic agents that may exert unique effects on neuronal activities in children at different stages of brain development. Section II. Award Information Grant: A support mechanism providing money, property, or both to an eligible entity to carry out an approved project or activity.

Application Types Allowed The OER Glossary and the SF424 (R&R) Application Guide provide details on these application 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.

Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary. The scope of the proposed project should determine the project period. The maximum project period is five years.

Grants Policy Statement will apply to the applications submitted and awards made in response to this FOA.

Higher Education Institutions Public/State Controlled Institutions of Higher Education Private Institutions of Higher Education The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education: Black Colleges and Universities (HBCUs) Controlled Colleges and Universities (TCCUs) Native and Native Hawaiian Serving Institutions 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 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 to 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 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 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. 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 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 and should work with their organizational officials to either create a new account or to affiliate an existing account with the applicant organization’s eRA Commons account.

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 (R&R) Application Guide.

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.

NIH will not accept any application that is essentially the same as one already reviewed within the past thirty-seven months (as described Grants Policy Statement ), except for submission: To an RFA of an application that was submitted previously as an investigator-initiated application but not paid; Of an investigator-initiated application that was originally submitted to an RFA but not paid; or Of an application with a changed grant activity code.

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

2. Content and Form of Application Submission It is critical that applicants follow the instructions in (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 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 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: Obstetric and Pediatric Pharmacology and Therapeutics Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) 6100 Executive Boulevard, Room 4A01C, MSC 7510 Bethesda, Maryland 20892-7510 (Rockville, Maryland 20852 for non USPS/courier service) All page limitations described in the SF424 Application Page Limits must be followed.

Required and Optional Components The forms package associated with this FOA includes all applicable components, required and optional. Please note that some components marked optional in the application package are required for submission of applications for this FOA. Follow all instructions in the SF424 (R&R) Application Guide to ensure you complete all appropriate optional components.

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 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 (Data Sharing Plan, Sharing Model Organisms, and Genome Wide Association Studies (GWAS)) 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.

Appendix: Do not use the Appendix to circumvent page limits.

Follow all instructions for the Appendix as described in the SF424 (R&R) Application Planned Enrollment Report When conducting clinical research, follow all instructions for completing Planned Enrollment Reports as described in the SF424 (R&R) PHS 398 Cumulative Inclusion Enrollment Report When conducting clinical research, follow all instructions for completing Cumulative Inclusion Enrollment Report as described in the SF424 Foreign (non-U.S.) institutions must follow policies Grants Policy Statement , and procedures for foreign institutions described throughout the SF424 (R&R) Application Guide.

Part I. Overview Information contains information about Key Dates. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission.

Organizations must submit applications to Grants. gov , the online portal to find and apply for grants across all Federal agencies. Applicants must then complete the submission process by tracking the status of the application in the eRA Commons , NIH’s electronic system for grants administration.

NIH and Grants. gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.

gov on or before the application due date. If a Changed/Corrected application is submitted after the deadline, the application will be considered late. 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. 4. 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 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.

tips for avoiding common errors. Upon receipt, applications will be evaluated for completeness by the Center for Scientific Review, NIH. Applications that are incomplete will not be reviewed.

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 NIH program staff 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 (R&R) Application Guide.

Post Submission Materials Applicants are required to follow the instructions for post-submission materials, as described in NOT-OD-13-030 . Section V. Application Review Information NOT-OD-16-006 and NOT-OD-16-011 for updated review language for applications for due dates on or after January 25, 2016.

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 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?

If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field? Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project?

If Early Stage Investigators or New Investigators, or in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)?

If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project? 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? Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project?

Are potential problems, alternative strategies, and benchmarks for success presented?

If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be If the project involves clinical research, are the plans for 1) protection of human subjects from research risks, and 2) inclusion of minorities and members of both sexes/genders, as well as the inclusion of children, justified in terms of the scientific goals and research strategy proposed?

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 Additional Review Criteria 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.

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

For research that involves human subjects and meets the criteria for one or more of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to for the Review of Human Subjects .

Inclusion of Women, Minorities, and When the proposed project involves clinical research, the committee will evaluate the proposed plans for inclusion of minorities and members of both genders, as well as the inclusion of children. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research .

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

For additional information on review of the Vertebrate Animals section, please 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.

For Resubmissions, the committee will evaluate the application as now presented, taking into consideration the responses to comments from the previous scientific review group and changes made to the For Renewals, the committee will consider the progress made in the last funding period. For Revisions, the committee will consider the appropriateness of the proposed expansion of the scope of the project.

If the Revision application relates to a specific line of investigation presented in the original application that was not recommended for approval by the committee, then the committee will consider whether the responses to comments from the previous scientific review group are adequate and whether substantial changes Additional Review Considerations 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.

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

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

Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: 1) Data Sharing Plan ; 2) Sharing Model Organisms ; and 3) Genome Wide Association Studies (GWAS) . Budget and Period of Support Reviewers will consider whether