Required Application Instructions

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

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

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

Background

Treatment of asthma often involves the use of metered dose inhalers (MDIs) or dry powder inhalers (DPIs) to deliver locally acting drug products such as short- or long-acting adrenergic 2-agonists to reduce airway hyper-responsiveness and/or corticosteroids to reduce inflammation. A short-acting adrenergic 2-agonist such as albuterol sulfate (AS) is most effectively delivered to the smooth muscles of the conducting airways, where the majority of the muscle mass is located in the larger airways [1]. However, though asthma was once thought of as a disease of the large airways, there is significant evidence that shows small airway involvement for some cases [2]. Therefore, complete understanding of the treatment effect for a given oral inhalation drug product (OIDP) requires knowledge regarding its regional deposition to both the large and small airways. Of note, the critical airway diameter to distinguish small from large airways is conventionally set to 2 mm [3].

Depositional data from MDIs and DPIs in the small airways of healthy or diseased subjects are difficult to obtain. Rapid prototyping may be used to create rigid tracheobronchial models based on CT scan data, but limitations in both CT scan and rapid prototyping resolution prohibit the creation of models that include the small airways [4-5]. An estimate of small airway deposition may be procured in vivo from gamma scintigraphy, PET, or SPECT studies, but accuracy of the borderline between regions is difficult to obtain due to patient variability and the inability of these methods to identify individual airway dimensions at the relevant scale [6]. However, a recent study demonstrated in vivo data on a bifurcation-level basis using a SPECT/CT method, which is expected to greatly improve the accuracy of regional in vivo data [7]. The primary limitations of the new in vivo method are the cost and ethical concerns associated with it. Computational modeling is desirable as a substitute for the in vivo method because it avoids those limitations and is capable of producing depositional estimates on a bifurcation-level basis throughout the entire lung.

Lung deposition of inhaled pharmaceutical aerosols may vary considerably across individuals due to differences in subject lung morphology or inhalation pattern [8]. In vitro methods have been used to characterize the variability of regional drug deposition evident in various sources of in vivo data [8-9]. A common approach to address intersubject variability with computational models is to consider a lung geometry with dimensions that are considered average [10], though there has been some exploration into the range of possible values for total lung deposition in asthmatic subjects [11]. Complicating the issue further is that airway constriction from an asthmatic episode is known to be heterogeneous [12]. Age-related differences are significant as well [13], though for the scope of this study only adults are considered. Regarding this project, a set of computational models are desired that are capable of capturing effects of intersubject variability and characterizing their relationship to small airway deposition. Specifically, the effects of differences in lung morphology, inhalation pattern, and airway constriction are sought. Additionally, if dissolution modeling is featured in the application, then differences in physiology parameters such as mucus thickness should be addressed. Such data will allow for a population estimate of the small airway targeting mechanism for a given drug product.

Objectives

The objective is to characterize drug delivery to the small airways in adult asthmatic patients using a computational modeling approach. The approach should consider the effects of intersubject variability, especially as it relates to differences in lung morphology, inhalation pattern, and airway constriction. The desired outcome is a population estimate that may be used to categorize drug products based on whether or not a significant effect on small airway constriction may be expected.

Detailed Description

A computational modeling approach will be developed and utilized to predict small airway (<2 mm diameter) deposition of selected drug products in adult asthmatic patients. The approach should consider intersubject variability such that a reasonable population estimate may be obtained for each drug product. Changes in lung morphology, inhalation pattern, and airway constriction are the relevant variables of interest and should be accounted for in deposition predictions. Differences in lung morphology are ideally addressed with healthy subjects, while changes in inhalation pattern and airway constriction should be considered for asthmatic patients.

Physiological models should provide predictions from the mouth and throat to at least the terminal bronchioles, and inclusion of alveolar deposition is preferred. Validation of the computational approach should be performed with either in vivo or in vitro data, though in vivo data is preferable. The applicant may use publicly available in vitro or in vivo data. Device effects, which include spray characteristics, are expected to be considered. Transient, turbulent, heat transfer, and mass transfer effects should also be considered, unless any of these are shown to be irrelevant for a given drug product. The drug products to be studied will be selected based on consultation with the FDA. Albuterol sulfate and ciclesonide HFA are recommended because both have publicly available in vivo data from gamma scintigraphy studies. Ciclesonide HFA has a known treatment effect on small airway constriction and could serve as a control case.

The study will consist of four phases:

Phase 1: Selection, identification, and construction of physiological models and inhalation patterns that will best characterize intersubject variability.

Phase 2: Development and validation of computational fluid dynamics model.

Phase 3: Performance of simulations and post-processing of simulation data.

Phase 4: Development of population estimates of small airway deposition fraction for various drug products and assessment of significance.

References

[1] Ebina, M.; Yaegashi, H.; Chiba, R.; Takahashi, T.; Motomiya, M.; Tanemura, M., Hyperreactive site in the airway tree of asthmatic patients revealed by thickening of bronchial muscles. The American Review of Respiratory Disease, 1990. 141(5): 1327-1332.

[2] Hamid, Q., Pathogenesis of small airways in asthma. Respiration, 2012. 84(1): 4-11.

[3] van den Berge, M.; ten Hacken, N.H.; van der Wiel, E.; Postma, D.S., Treatment of the bronchial tree from beginning to end: targeting small airway inflammation in asthma. Allergy, 2013. 68(1): 16-26.

[4] de Rochefort, L.; Vial, L.; Fodil, R.; Ma tre, X.; Louis, B.; Isabey, D.; Caillibotte, G.; Thiriet, M.; Bittoun, J.; Durand, E.; Sbirlea-Apiou, G., In vitro validation of computational fluid dynamic simulation in human proximal airways with hyperpolarized 3He magnetic resonance phase-contrast velocimetry. Journal of Applied Physiology, 2007. 102(5): 2012-2023.

[5] Phuong, N.L.; Ito, K., Investigation of flow pattern in upper human airway including oral and nasal inhalation by PIV and CFD. Building and Environment, 2015. (in press)

[6] Scheuch, G.; Bennett, W.; Borgstr?m, L.; Clark, A.; Dalby, R.; Dolovich, M.; Fleming, F.; Gehr, P.; Gonda, I.; O Callaghan, C.; Taylor, G., Newman, S., Deposition, imaging, and clearance: What remains to be done? Journal of Aerosol Medicine and Pulmonary Drug Delivery, 2010. 23(S2): S39-S57.

[7] Conway, J.; Fleming, J.; Majoral, C.; Katz, I.; Perchet, D.; Peebles, C.; Tossici-Bolt, L.; Collier, L.; Caillibotte, G.; Pichelin, M.; Sauret-Jackson, V.; Martonen, T.; Apiou-Sbirlea, G.; Muellinger, B.; Kroneberg, P.; Gleske, J.; Scheuch, G.; Texereau, J.; Martin, A.; Montesantos, S.; Bennett, M., Controlled parametric, individualized, 2-D and 3-D imaging measurements of aerosol deposition in the respiratory tract of healthy human subjects for model validation. Journal of Aerosol Science, 2012. 52: 1-17.

[8] Delvadia, R.R.; Longest, P.W., Byron, P.R., In vitro tests for aerosol deposition. I: Scaling a physical model of the upper airways to predict drug deposition variation in normal humans. Journal of Aerosol Medicine and Pulmonary Drug Delivery, 2012. 25(1): 32-40.

[9] Olsson, B.; Berg, E.; Svensson, M., Comparing aerosol size distributions that penetrate mouth-throat models under realistic inhalation conditions. Respiratory Drug Delivery, Orlando, FL, 2010. David Healthcare International Publishing, River Grove, IL. pp. 225-234.

[10] Matida, E.A.; Finlay, W.H.; Lange, C.F.; Grgic, B., Improved numerical simulation of aerosol deposition in an idealized mouth-throat. Journal of Aerosol Science, 2004. 35: 1-19.

[11] Vinchurkar, S.; de Backer, L.; Vos, W.; van Holsbeke, C.; de Backer, J.; de Backer, W., A case series on lung deposition analysis of inhaled medication using functional imaging based computational fluid dynamics in asthmatic patients: effect of upper airway morphology and comparison with in vivo data. Inhalation Toxicology, 2012. 24(2): 81-88.

[12] Inthavong, K.; Tu, J.; Ye, Y.; Ding, S.; Subic, A.; Thien, F., Effects of airway obstruction induced by asthma attack on particle deposition. Journal of Aerosol Science, 2010. 41(6): 587-601.

[13] Golshahi, L.; Vehring, R.; Noga, M.L.; Finlay, W.H., In vitro deposition of micrometer-sized particles in the extrathoracic airways of children during tidal oral breathing. Journal of Aerosol Science, 2013. 57: 14-21.

HHS grants policies as described in the HHS 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 FDA support as Public or Private Institutions of Higher Education:

• Hispanic-serving Institutions
• Historically Black Colleges and Universities (HBCUs)
• Tribally Controlled Colleges and Universities (TCCUs)
• Alaska Native and Native Hawaiian Serving Institutions
• Asian American Native American Pacific Islander Serving Institutions (AANAPISIs)

Nonprofits Other Than Institutions of Higher Education

• Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education)
• Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education)

For-Profit Organizations

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

Governments

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

Other

• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• Native American Tribal Organizations (other than Federally recognized tribal governments)
• Faith-based or Community-based Organizations
• Regional Organizations
• Non-domestic (non-U.S.) Entities (Foreign Institutions)

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 apply.
Foreign components, as defined in the HHS Grants Policy Statement, are allowed.

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. 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 FDA 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 HHS Grants Policy Statement.

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

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

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

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

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

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

• For this specific FOA, the Research Strategy section is limited to 30 pages.

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 with the following additional instructions:

• Applications requesting multiple years of support must complete and submit a separate detailed budget breakdown and narrative justification for each year of financial support requested.
• If an applicant is requesting indirect costs as part of their budget, a copy of the most recent Federal indirect cost rate or F&A agreement must be provided as part of the application submission. This agreement should be attached to the RESEARCH & RELATED Other Project Information Component as line #12 'Other Attachments'.
• If the applicant organization has never established an indirect cost rate and/or does not have a negotiated Federal indirect cost rate agreement, a de minimis indirect cost rate of 10 percent (10%) of modified total direct costs (MTDC) will be allowed. MTDC means all direct salaries and wages, applicable fringe benefits, materials and supplies, services, travel, and subaward and subcontracts up to the first $25,000 of each subaward or subcontract. MTDC excludes equipment, capital expenditures, charges for patient care, rental costs, tuition remission, scholarships and fellowships, participant support costs and the portion of each subaward and subcontract in excess of $25,000.

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.

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.

Appendix: If no modifications to Appendix instructions, delete editable text below ( with the following modifications ). For R03, add this text as a bullet: No publications or other printed material, with the exception of pre-printed questionnaires or surveys, may be included in the Appendix. For other activity codes, add bullets as appropriate. Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

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

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

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

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.

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, FDA's electronic system for grants administration. eRA Commons 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. Late applications will not be accepted for this FOA.

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 FDA awards are subject to the terms and conditions, cost principles, and other considerations described in the HHS Grants Policy Statement.

Pre-award costs are allowable only as described in the HHS Grants Policy Statement.

Additional funding restrictions may be part of the Notice of Award.

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. 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 FDA. 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 assigned Grants Management Specialist and responsiveness by components of participating organizations in FDA. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.

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

Only the review criteria described below will be considered in the review process.

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

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?

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

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

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

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 FDA-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

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

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

Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: (1) Data Sharing Plan; (2) Sharing Model Organisms; and (3) Genomic 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 Objective Review Committee using the stated review criteria.

As part of the objective review, all applications:

• Will receive a written critique.

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

Applications will compete for available funds with all other recommended applications submitted in response to this FOA. The following will be considered in making funding decisions:

• Scientific and technical merit of the proposed project as determined by objective review.
• Availability of funds.
• Relevance of the proposed project to program priorities.

Successful applicants will be notified of additional information that may be required or other actions leading to an award. The decision not to award a grant, or to award a grant at a particular funding level, is discretionary and is not subject to appeal to any FDA or HHS official or board.

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 in the HHS Grants Policy Statement.

All FDA grant and cooperative agreement awards include the HHS Grants Policy Statement as part of the NoA.

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.

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.

Additional terms and conditions regarding FDA regulatory and CDER programmatic requirements may be part of the Notice of Award.

Cooperative Agreement Terms and Conditions of Award

The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (DHHS) grant administration regulations at 45 CFR Part 75, and other HHS, PHS, and FDA grant administration policies.

The administrative and funding mechanism used for this program is a cooperative agreement, an "assistance" mechanism in which substantial FDA programmatic involvement with the awardees is anticipated during the performance of the activities.

Under the cooperative agreement, FDA's purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the awardees for the project, although specific tasks and activities may be shared among the awardees and FDA as defined below:

a. All awardees are required to participate in a cooperative manner with FDA staff.

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

c. An agency program official/Project Officer (PO) or a Center program director will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice. FDA staffs have substantial programmatic involvement that is above and beyond the normal stewardship role in award as described below:

Cooperative Agreement - Principal Investigator(s) (PI)/Program Director (PD) responsibility:

The Principal Investigator (PI)/Program Director (PD) will have responsibility for the scientific, technical, and programmatic aspects of the grant, and for the day-to-day management of the project or program. The PD/PI(s) will maintain general oversight for ensuring compliance with the financial and administrative aspects of the award, and ensuring that all staff has sufficient clearance and/or background checks to work on this project or program. This individual will work closely with designated officials within the recipient organization to prepare justifications, appropriately acknowledge Federal support in publications, announcements, news programs, and other media; and ensure compliance with other Federal and organizational requirements.

The awardee is responsible for submitting interim progress reports (e.g. at specified intervals), when requested, to the Office of Generic Drug Project Officer (OGD PO) and the Grants Management Officer (GMO)/Specialist (GMS), listed as a contact on the Notice of Grant Award (NGA/NoA) including summary data on progress and expenses to date.

The awardee is encouraged to publish and publicly release and disseminate results, data and other products of the study, concordant with the study protocol and governance and the approved plan for making data and materials available to the scientific community, or as required by any federal regulation or statute. Awardee will work with the appropriate FDA staff to develop and implement an appropriate rapid data release OGD policy.

Manuscripts shall be submitted to OGD PO within two weeks of submission for publication. Publications or oral presentations of work performed under this Cooperative Agreement will require appropriate acknowledgement of FDA support. Timely publication of major findings is encouraged.

The awardee is responsible for obtaining prior approval for the development and design of FDA projects prior to execution. See additional prior approval requirements in the HHS Grants Policy Statement http://www.hhs.gov/asfr/ogapa/aboutog/hhsgps107.pdf

Cooperative Agreement - OGD Responsibility:

The PO will monitor grantees periodically. The monitoring may be in the form of telephone conversations, e-mails, or written correspondence between the PO/GMO/ GMS and the PI. Information including, but not limited to, study progress, enrollment, problems, adverse events, changes in protocol, and study monitoring activities will be requested. Periodic site visits with officials of the grantee organization may also occur. The scope of the recommendations will consider the following: (1) progress toward enrollment, based on specific circumstances of the study; (2) adequate supply of the product/device; and (3) compliance with applicable FDA and HHS regulatory requirements for the trial.

The PO must ensure that any grant or progress report forms required and submitted under the grant shall include a certification that the grantee has made all the required submissions to ClinicalTrials.gov. The GMO/GMS must also verify that clinical trial information has been submitted to ClincialTrials.gov before releasing any remaining funding for a grant.

An OGD PO with scientific/technical expertise and other members of the FDA staff will have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below:

The responsibilities of the OGD PO include involvement during conduct of the activity, through technical assistance, advice, coordination, and/or other assistance activities.

As appropriate, the OGD PO will participate in the definition of objectives and approaches, and in planning, conducting, analyzing, and publishing results, interpretations, and conclusions of their studies. However, the dominant role and prime responsibility for the activity reside with the awardees(s) for the project.

The OGD PO will be responsible for the administration and general scientific and programmatic stewardship of the award and have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below.

The FDA, through the OGD PO, will have access to data generated under this Cooperative Agreement and may periodically review the data and progress reports. The OGD PO may use information obtained from the data for the preparation of internal reports on the activities of the study. However, awardees will retain custody of and have primary rights to all data developed under these awards or as stated in the terms and conditions of award.

Retain the right to have prior approval on the appointment of all key personnel substantially supported by the grant.

Be directly involved in the guidance and development of the program and the collaborative structure of for the program.

Participate with the grantee in determining and carrying out the methodological approaches to be used. Collaboration will also include data analysis, interpretation of findings and where appropriate, co-authorship of publications.

Arrange to have professional scientific and administrative/clerical personnel working in collaboration with the grantee as required.

The FDA agency program official will have primary responsibility for finalizing standard procedures, and measures common to all funded projects.

Cooperative Agreement - Collaborative Responsibilities:

The grantee organization must comply with all special terms and conditions of the grant, including those which state that future funding of the study will depend on recommendations from the OGD PO.

As relevant, the PD/PI s, in collaboration with OGD PO, will work collaboratively in evaluating the most appropriate research methods, data quality control strategies, safety issues, study design and implementation, data analysis and interpretation, publication and dissemination of study results. Projects require FDA approval prior to implementation/initiation.

During performance of the award, the OGD PO, with assistance from other scientific program staff, designated based on their relevant expertise, may provide appropriate assistance, advice and guidance. The role of the OGD PO will be to facilitate and not to direct the activities. It is anticipated that decisions in all activities will be reached by consensus between the PD/PI and the OGD PO, and that the FDA programmatic staff will be given the opportunity to offer input into this process. The OGD PO will facilitate liaison activity for partnerships, and provide assistance with access to FDA supported resources and services.

The FDA will work collaboratively to identify and coordinate training, professional development and training-related scientific exchange opportunities.

Cooperative Agreement - Steering Committee (Optional)

If a Steering Committee is determined to be necessary, it must be comprised of the PD(s)/PI(s) of the cooperative agreement, the PI’s of additional performance sites, and the OGD PO. The steering committee will meet every three to six months, or as dictated by the needs of the project. Each full member of the Steering Committee will have one vote, and all major decisions will be determined by majority vote of the Steering Committee. Awardees will be required to accept and implement OGD policies and procedures as approved by the Steering Committee.

The primary governing body of the study will be the Steering Committee, which will have responsibility for the final details of project activity, and OGD policy decisions and will define the rules regarding access to data and/or product outputs or samples, etc.

Cooperative Agreement - Dispute Resolution Process

Any disagreements that may arise in technical or programmatic matters (within the scope of the award) between award recipients and the FDA may be brought to Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened and comprised of (1) a designee of the Steering Committee (if a Steering Committee is not active, a designee of the recipient organization) chosen without FDA staff voting, one FDA designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual awardee. This special dispute resolution procedure does not alter the awardees right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and DHHS regulation 45 CFR Part 16.

Cooperative Agreement Third Party Collaboration

It is expected that grantees be transparent with the FDA about who they are planning to collaborate or already collaborating with for the FDA funded research project. Grantees must not give any preferential access to study results to any party, unless their collaborating party is a substantive participant of the research project of interest, i.e., doing part of the study. In addition third parties providing study drugs to the grantee should not gain early access to study results in exchange. If grantees plan to collaborate with third parties not proposed in the original application (i.e., a company or database holder), grantees must notify FDA before they start such a collaboration.

Cooperative Agreement - Reporting Requirements:

Periodic program monitoring will be conducted by FDA on an ongoing basis which may include telephone conversations between the Principal Investigator and the Project Officer/Grants Management Officer/Grants Management Specialist, site visits and the review of written reports.

1. Mid-year and Annual progress reports will be required. A Mid-year Progress Report will be due 14 days following the close of the 6 month from date of award. The Annual Progress Report will be due as part of the Research Performance Progress Report (RPPR).

2. Grants with Multiple Years: When multiple years are involved, awardees will be required to submit the Research Performance Progress Report (RPPR).

3. Financial Reporting:

A. Cash Transaction Reports

The Federal Financial Report (FFR) has a dedicated section to report Federal cash receipts and disbursements. For recipients this information must be submitted quarterly directly to the Payment Management System (PMS) using the web-based tool. Quarterly reports are due 30 days following the end of each calendar quarter. The reporting period for this report continues to be based on the calendar quarter. Questions concerning the requirements for this quarterly financial report should be directed to the PMS.

B. Financial Expenditure Reports

A required Federal Financial Report (FFR) must be submitted annually.

FDA now requires all financial expenditure reports to be submitted electronically using the Federal Financial Report (FFR) system located in the eRA Commons. This includes all initial FFRs being prepared for submission and any revised FSR/FFRs being submitted or re-submitted to FDA. Paper expenditure/FFR reports will not accepted.

Annual FFRs must be submitted for each budget period no later than 90 days after the end of the calendar quarter in which the budget period ended. The reporting period for an annual FFR will be that of the budget period for the particular grant; however, the actual submission date is based on the calendar quarter. Failure to submit timely reports may affect future funding.

4. Closeout Requirements (when applicable): A Final Program Progress Activity Report, Final Federal Financial Report SF-425, Final Invention Statement HHS-568 (if applicable), Tangible Personal Property Report SF-428, and Statement of Disposition of Equipment (if applicable) must be submitted within 90 days after the expiration date of the project period. All forms can be found at: http://grants.nih.gov/grants/forms.htm.

5. The recipient will conduct, when appropriate, an annual Single Audit as required by OMB Circular A-133. This audit must be submitted to the Federal Audit Clearinghouse at the Bureau of the Census within 9 months of the close of their fiscal year. If you need information on your organization’s obligations under the Single Audit Act, please visit the following website: http://harvester.census.gov/sac/. Valuable information is included under the Frequently Asked Questions section of that website.

6. The grantee will be responsible for recording and disseminating all official meeting minutes under this project.

Cooperative Agreement - Prior Approval:

All requests that require prior approval must include the award number and bear the signature of an authorized official of the grantee business office as well as that of the PI/PD. Any requests involving budgetary issues must include a new proposed budget and a narrative justification of the requested changes. If there are any questions regarding the need or requirement for prior approval for any activity or cost, the grantee is to contact the assigned Grants Management Specialist prior to expenditure of funds. Below are activities that require prior approval from FDA/CDER:

CHANGE IN SCOPE OR OBJECTIVES

CHANGE IN KEY PERSONNEL

CHANGE IN GRANTEE ORGANIZATION

CHANGE IN KEY PARTNER ORGANIZATION(S)

ANY DEVIATION FROM TERMS AND CONDITIONS OF THE AWARD

CARRYOVER OF UNOBLIGATED BALANCES

NO COST EXTENSIONS

SIGNIFICANT REBUDGETING

Cooperative Agreement - PUBLICATIONS, EDUCATIONAL MATERIALS AND PRESS STATEMENTS

The grantee and its employees shall have the right, consistent with academic standards, to publish the results of research performed under this Agreement, provided such publication does not disclose proprietary trade secrets or confidential information of the FDA and does not reference, imply or infer any FDA endorsement of regulatory and/or policy changes related to the project.

The grantee agrees that, prior to submission of a manuscript with FDA co-author (s) describing the results for publication, the grantee shall forward to the FDA a copy of the manuscript to be submitted and shall allow the FDA 30 days to review for any potential language that might reference, imply or infer any FDA endorsement of regulatory and/or policy changes related to the project. For publications without a FDA co-author but using FDA/GDUFA funds to support the grant, a courtesy review of the publication is appreciated to ensure that any potential language that might reference, imply, or infer any FDA endorsement of regulatory and/or policy changes related to the project is not stated.

At this time the grantee shall be free to submit the manuscript and publish results in any manner consistent with academic standards. The FDA will have the right to request deletion of any trade secret, proprietary, or confidential information, and any inference to FDA endorsement of regulatory and/or policy changes related to the project.

Cooperative Agreement - CONFERENCES AND TRAVEL

Before a grantee expends any grant funds on newly proposed conference attendance and/or travel that was never previously proposed in the original application submission or subsequent progress reports, they must obtain prior approval from FDA/CDER. A prior approval request for conference attendance and/or travel must be submitted in writing to the Grants Management Specialist and must include the following information:

A. Title/Topic of Conference

B. Purpose of Conference

C. Explanation of how the Conference directly supports the CDER/OGD goals and objectives

D. Dates of Conference

E. Location of Conference

F. Detailed breakdown on costs associated with Conference attendance/travel

ALL THE ABOVE REQUIREMENTS MUST BE SENT VIA E-MAIL TO:

Eric Bozoian
Grants and Assistance Agreements Branch
U.S. Food and Drug Administration
5630 Fishers Ln, Rockville MD 20857
Phone: 240-402-7623
Email: [email protected]

Cooperative Agreement - Acknowledgement of Federal Support:

When issuing statements, press releases, publications and other documents describing projects or programs funded in whole or in part with Federal money, all awardees receiving Federal funds, including and not limited to state and local governments and recipients of Federal research grants, shall clearly indicate:

* Funding for this (insert appropriate venue, i.e.: conference, training, manuscript, etc.) was made possible, in part, by the Food and Drug Administration through grant (insert grant number), views expressed in written materials or publications and by speakers and moderators do not necessarily reflect the official policies of the Department of Health and Human Services; nor does any mention of trade names, commercial practices, or organization imply endorsement by the United States Government.*

Cooperative Agreement - Program Income:

1. The grantee is required to report any Program Income generated during the Project Period of this grant. Except for royalty income generated from patents and inventions, the amount and disposition of Program Income must be identified on lines 10 (l), (m), (n), and (o) of the grantee s Federal Financial Report (FFR) SF-425.

2. Examples of Program Income include (and not limited to): fees for services performed during the grant or sub-grant period, proceeds from sale of tangible personal or real property, usage or rental fees, patent or copyright royalties, and proceeds from the sale of products and technology developed under the grant.

3. Any Program Income generated during the Project Period of this grant by the grantee or sub-grantee is subject to the Addition Alternative for Program Income and, therefore, must only be used to further the goals of the project for which this grant was awarded.

Cooperative Agreement - Equipment and Products:

To the greatest extent practicable, all equipment and products purchased with FDA funds should be American-made.

Cooperative Agreement - Payment Management System (PMS):

The Payment Management System is administered by the Program Support Center (PSC), DHHS, and payments for FDA grant awards are made through the Division of Payment Management. Applicant organizations are assigned a 12-digit Entity Identification Number for payment and accounting purposes. That number is an expansion of the 9-digit Employer Identification Number assigned to an organization by the Internal Revenue Service.

Included are the following Links & Instructions for drawing down funds, reporting expenditures, required forms, and the help desk info:

Homepage: http://www.dpm.psc.gov/Default.aspx

Grant Recipient Information: http://www.dpm.psc.gov/grant_recipient/grant_recipient.aspx?explorer.event=true

Grant Recipient Forms: http://www.dpm.psc.gov/grant_recipient/grantee_forms.aspx?explorer.event=true

PMS Help Desk: http://www.dpm.psc.gov/help/help.aspx?explorer.event=true

The ONE-DHHS Help Desk for PMS Support is now available Monday Friday from 7 a.m. to 9 p.m. EST (except Federal Holidays). Phone (877) 614-5533; Email [email protected]

Clinical Trials - Human Subjects Protections:

The Grantee/Principal Investigator (PI) is required to have a current Federalwide Assurance (FWA) for the Protection of Human Subjects on file with the Office for Human Research Protections (OHRP), 1101 Wooton Parkway, Suite 200, Rockville, MD 20852, before conducting research that involves human subjects. Questions about FWAs should be directed to OHRP.

Research funded by this initiative must comply with federal regulations governing the protection of human subjects in research at 45 CFR Part 46 and may also be subject to FDA’s human subject protection regulations at 21 CFR Parts 50 & 56. These regulations require that research involving human subjects must be approved by an IRB that must assess the risks of the research to the subjects and whether any risks of the research are minimized, the anticipated benefits of the research to the subjects, and the importance of the knowledge that may be reasonably expected to result. (See 45 CFR Part 46, available at http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html.

The proposed research protocol should comply with ICHE6 Good Clinical Practice: Consolidated Guidance, available at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM073122.pdf. This guidance lays out an international ethical and scientific quality standard for designing, conducting, recording, and reporting trials that involve the participation of human subjects. Applicants are encouraged to review the regulations, guidance, and information sheets on human subject protection and good clinical practice available on FDA’s webpage on Clinical Trials and Human Subject Protection at http://www.fda.gov/oc/gcp/.

Clinical Trial - Human Subject Training for Key Personnel

The grantee/PI is responsible for ensuring that all key personnel receive appropriate training in their human subject protection responsibilities. Key personnel include all principal investigators, co-investigators, and performance site investigators responsible for the design and conduct of the study. HHS, FDA, and OGD PO do not require or endorse any specific education programs. Appropriate instruction might include, for example, the online tutorials offered by the NIH and OHRP, at http://grants.nih.gov/grants/policy/hs/training.htm and by OHRP at http://www.hhs.gov/ohrp/education/

Within 30 days of the award, the principal investigator must provide a letter that includes the names of the key personnel, the title of the human subjects protection education program completed by each of the key personnel, and a one-sentence description of the program. This letter should be signed by the PI and cosigned by the institutional signing official and sent to the FDA Project Officer, Grants Management Officer (GMO)/Specialist (GMS), and to CDER’s Extramural Studies Coordinator, whose names appear on the official Notice of Grant Award.

Clinical Trials - Protocol

The grant application must include a copy of the research/investigational plan or protocol in the grant application.

Clinical Trials - Informed Consent

Consent forms, assent forms, and any other information given to a subject should be included in the grant application, even if in draft form. All such documents should be attached in an appendix section. The applicant is referred to HHS and FDA regulations at 45 CFR 46.116 and 21 CFR 50.25 for details regarding the required elements of informed consent.

Clinical Trials - Monitoring

Data and safety monitoring of a clinical trial should be commensurate with the risks posed to study participants and with the size and complexity of the study. In addition, a Grantee, and any third party engaged in supporting the clinical research, is responsible for oversight of data and safety monitoring, ensuring that monitoring systems are in place, that the quality of the monitoring activity is appropriate, and that the OGD PO is informed of recommendations resulting from monitoring activities.

Each proposed research study must have data and safety monitoring procedures in place to safeguard the well-being of study participants and to ensure scientific integrity. Monitoring must be performed on a regular basis throughout subject accrual, while study procedures are being conducted, and during follow-up periods. Information regarding data and safety monitoring should be included in the grant application or protocol.

The specific approach to monitoring will depend on features of the research study to be conducted (e.g., several levels of monitoring), such as having a Data and Safety Monitoring Board (DSMB), Study Monitoring Committee (SMC), and/or Independent Medical Monitor (IMM). Monitoring activities should be appropriate to the study, study population, research environment, and degree of risk involved. Guidance is available at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm073122.pdf and http://www.fda.gov/RegulatoryInformation/Guidances/ucm127069.htm

Clinical Trial - Study Monitoring Plan

The study protocol must include a section describing the proposed plan for interim data monitoring. This section should explain who is to be responsible for interim monitoring (i.e., a Data Safety Monitoring Board (DSMB), a Safety Monitoring Committee ( SMC), or the study investigator), what data will be monitored (i.e., performance and safety data only vs. efficacy data as well), the timing of the first data review (e.g., "the first interim monitoring will occur when the initial 20 participants have completed the 6 month follow-up visit"), and the frequency of interim reviews (which will depend on such factors as the study design, interventions, and anticipated recruitment rate). The plan will specify "stopping guidelines" and other criteria, if appropriate, for the monitors to follow in their review of the interim data. Guidance on these topics is available at: http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM127073.pdf.

A preliminary monitoring plan must be submitted as part of the Research Plan section of the grant application for a clinical trial. The monitoring plan will be examined as part of the peer review process, and any comments and concerns will be provided to the applicant in a summary statement (a document which reflects Ad Hoc Reviewer comments on the application submitted for funding). OGD staff will work with the applicant to address concerns raised before the grant award is made.

Clinical Trials - Clinical Trials.gov

The Food and Drug Administration Amendments Act of 2007 (FDAAA) contains provisions that expanded the current database known as ClinicalTrials.gov to include additional requirements for individuals and entities, including grantees, who are involved in conducting certain clinical trials of drugs (including biological products) or devices. Such trials are referred to in the statute as applicable clinical trials . These additional requirements include mandatory registration of certain applicable clinical trials, as well as reporting of results for certain applicable clinical trials for inclusion in the ClinicalTrials.gov database. More detailed information on the definition of "applicable clinical trial" and the registry and results reporting requirements can be found at http://clinicaltrials.gov/ct2/manage-recs/fdaaa.

FDAAA also added new requirements concerning applicable clinical trials supported by grants from HHS, including FDA. Under these provisions, any grant or progress report forms required under a grant from any part of HHS, including FDA, must include a certification that the person responsible for entering information into ClinicalTrials.gov (the "responsible party") has submitted all required information to the database. There are also provisions regarding when agencies within HHS, including FDA, are required to verify compliance with the registration and results submission requirements of FDAAA before releasing funding to grantees. OGD program staff will be providing additional information on these requirements, including the appropriate means by which to certify that a grantee has complied with the database requirements.

Clinical Trials - Data and Safety Monitoring Boards

The establishment of data and safety monitoring boards (DSMBs) may be appropriate for multi-site clinical trials depending on the risk to the study participants. See http://www.fda.gov/RegulatoryInformation/Guidances/ucm127069.htm and http://www.fda.gov/downloads/regulatoryinformation/guidances/ucm127073.pdf

The Grantee/PI must adhere to the following processes for Grants involving Human Subject research from the FDA.

1. The Grantee is required to have a current Federalwide Assurance for the Protection of Human Subjects for its institution on file with the Office for Human Research Protections (OHRP), 1101Wootton Parkway, Suite 200, Rockville, MD 20852, before conducting research that involves human subjects. Questions about FWAs should be directed to OHRP. A copy of the current FWA shall be included in the Grantee/PI's proposal.

2. Upon award, the OGD PO and Extramural Clinical Studies Coordinator will arrange a meeting via telephone conference with the Grantee/PI and Study Coordinator to discuss requirements of the Research Involving Human Subjects Committee (RIHSC), the FDA’s Institutional Review Board (IRB), including the roles and responsibilities of the OGD PO, OGD Sponsor (if different from OGD PO) and Extramural Clinical Studies Coordinator.

3. Following the meeting referenced above, the Grantee/Principal Investigator shall submit the proposed study documents including the research protocol, informed consent and recruitment advertisements to the OGD PO and Extramural Clinical Studies Coordinator for review. The Grantee/PI also shall submit the final research study documents to the OGD PO and the Extramural Clinical Studies Coordinator. The Extramural Clinical Studies Coordinator shall review the submitted study documents to ensure completeness of the submission package. Following the review and sign-off by the CDER RIHSC Liaison (signatory authority), the submission package shall be submitted electronically to the RIHSC and the OGD PO and Grantee/PI.

4. If the Grantee/PI has already received IRB approval or exemption for the final study documents prior to the submission to RIHSC, then a copy of the IRB certification letter must be included in the submission package sent to the OGD PO, Extramural Clinical Studies Coordinator, and the Grants Management Officer (GMO)/Specialist (GMS). The Grantee/PI may submit the final research study documents to their IRB at the same time as submission to RIHSC, and shall provide the IRB approval letter to the OGD PO and Extramural Clinical Studies Coordinator. This requirement would include proposed research that is exempt from IRB approval. Please note: Certification of IRB review, exemption or approval must include the following: the PHS/HHS application number, title of the project, and name of the program director/principal investigator, date of IRB approval or exemption, and appropriate signatures. The PI must ensure that any protocol(s) are consistent with the research plan in the corresponding application.

5. The RIHSC will review the research study documents, to assure that the rights and welfare of human subjects involved are adequately protected and for compliance with all relevant regulations. The RIHSC will also determine whether the proposed research is exempt under 45 CFR 46.101(b) and whether an investigational new drug application is required (see 21 CFR Part 312). Upon approval by the RIHSC, the Extramural Clinical Studies Coordinator will provide a copy of the RIHSC’s letter stating that it has reviewed and approved the proposed research study to the OGD PO, the Grants Management Specialist, and the Grantee/PI. If RIHSC renders a decision other than approval of the proposed research study documents (i.e. approvable with stipulations or disapproval), the Extramural Clinical Studies Coordinator and/or OGD PO will provide a copy of the RIHSC’s letter to the Grantee/PI and will assist the Grantee/PI in revising the research study documents for re-submission to RIHSC for review and approval.

6. The Grantee/Pl shall not advertise for, recruit, or enroll human subjects, or otherwise commence any research involving human subjects until the RIHSC has reviewed and approved the proposed research study, but may begin other limited aspects of grant performance prior to receiving RIHSC approval of the proposed research study (such as training, and development of protocol training documents, planning, communications, travel, etc.). Research involving human subjects may commence immediately upon the Grantee/PI receipt of the RIHSC’s approval documentation.

7. Failure to obtain RIHSC approval of the proposed research study will result in termination of the grant. However, failure to obtain RIHSC approval during RIHSC’s initial review will not automatically result in termination of the grant. Instead, the grantee may correct any deficiencies identified during the RIHSC review and resubmit the proposed research study to RIHSC for a second review. The Grantee/PI is encouraged to solicit the RIHSC’s input during the resubmission process via the Extramural Clinical Studies Coordinator and/or OGD PO as mentioned above.

8. The Grantee/PI shall seek RIHSC (through the Extramural Clinical Studies Coordinator and/or OGD PO) and IRB review and approval whenever modifications, amendments or other changes are made to the research study documents. Modifications and amendments include, but are not limited, to changes to the protocol, consent forms, recruitment materials, and the addition or deletion of investigators. Changes may be instituted immediately after the recipient has received both the IRB and RIHSC approval, unless the changes are necessary to eliminate apparent immediate hazards to the subject. The Extramural Clinical Studies Coordinator and/or OGD PO will provide a copy of RIHSC’s approval of the proposed changes to the Grantee/PI and the GMO/GMS within three days of receipt.

9. Quality Assurance monitoring will be performed (either remotely or via on-site visits) by the CDER Extramural Studies Coordinator to help ensure human subject protection throughout the conduct of the study and assess compliance with the regulations and the RIHSC requirements that govern the conduct of research involving human subjects.

10. The Extramural Clinical Studies Coordinator will provide the Grantee/PI, GMO/GMS, and CDER RIHSC Liaison with a report of all identified concerns related to human subject protections, along with suggested corrective actions. If concerns are identified, the Grantee/PI is responsible for providing responses to the corrective actions listed in the report to the CDER’s Extramural Studies Coordinator, GMO/GMS and OGD PO, within two weeks of receipt. If a Steering Committee or Monitoring Board is established by the Grantee/recipient, in collaboration with the OGD PO, responses to the report must be routed through the Steering Committee and the Monitoring Board as established. Non-compliance with federal regulations and RIHSC requirements may be reported to OHRP or CDER’s Office of Compliance. As warranted, the Extramural Clinical Studies Coordinator will notify OHRP or CDER’s Office of Compliance of any regulatory concerns. The Grantee/PI must provide documentation that the QA report and revised study documents (if appropriate) have been submitted to their IRB. The documentation should reflect that the IRB is aware and indicate whether any further action is required. Copies of this documentation must also be provided to the Steering Committee, Monitoring Board, and Extramural Clinical Studies Coordinator and to the OGD PO. This documentation will be forwarded to RIHSC for review and documentation by the Extramural Clinical Studies Coordinator.

11. The Grantee/PI will provide a letter (certification of IRB approval), at least annually, stating that the IRB has reviewed and approved the continuation of the research performed under this grant. This letter shall be submitted to CDER’s Extramural Studies Coordinator, the GMO/GMS, and the OGD PO. The Extramural Clinical Studies Coordinator will provide a letter, at least annually, stating that RIHSC has reviewed and approved the continuation of the research performed under this grant. This letter shall be submitted to the Grantee/PI, PO and GMO/GMS.

12. The Grantee/PI will submit all proposed modifications and amendments to any of the research study documents for research performed under this grant to the Extramural Clinical Studies Coordinator with a copy to the OGD PO, for submission to RIHSC for review and approval. Modifications and amendments include, but are not limited to, changes to the protocol, consent forms, recruitment materials, and the addition or deletion of investigators. Changes may be instituted immediately after the Grantee/PI has received both the IRB and RIHSC approval documentation, unless the changes are necessary to eliminate apparent immediate hazards to the subject.

13. The grantee/PI or awardee institution is responsible for ensuring that all key personnel receive appropriate training in their human subject protection responsibilities. Key personnel include all principal investigators, co-investigators, study coordinators and performance site investigators responsible for the design and conduct of the study (or as deemed Key Personnel by the PI). HHS, FDA, and OGD do not require or endorse any specific education programs. Appropriate instruction might include the online tutorials offered by the Office of Human Subjects Research, NIH at http://grants.nih.gov/grants/policy/hs/training.htm and by OHRP at http://www.hhs.gov/ohrp/education/.

14. Within 30 days of the award, the PI must provide a letter that includes the names of the key personnel, the title of the human subjects protection education program completed by each of the key personnel, and a one-sentence description of the program. This letter should be signed by the PI and cosigned by the institutional signing official and sent to OGD’s PO, GMO/GMS and CDER’s Extramural Studies Coordinator whose names appears on the official Notice of Grant Award (NGA).

15. If it is determined that the proposed research study is not subject to 45 CFR Part 46, then the grant and programmatic file will be documented accordingly.

Questions on FDA RIHSC can be directed to CDER’s Extramural Clinical Studies Coordinator at [email protected].

All grant awards are subject to applicable requirements for clinical investigations imposed by sections 505, 512, and 515 of the act (21 U.S.C. 355, 360B, and 360E) and section 351 of the Public Health Service Act (the PHS Act) (42 U.S.C. 262), including regulations issued under any of these sections.

All human subject research regulated by FDA is also subject to FDA's regulations regarding the protection of human subjects (21 CFR Parts 50 and 56). Applicants are encouraged to review the regulations, guidance, and information sheets on human subject protection and Good Clinical Practice available on the Internet at http://www.fda.gov/oc/gcp/.

The applicant is referred to HHS regulations at 45 CFR 46.116 and 21 CFR 50.25 for details regarding the required elements of informed consent.

FDA/CDER Contact Information:

For direct inquiries regarding scientific/programmatic issues or fiscal and/or administrative matters please refer to STAFF CONTACT below:

Grants Management Contact (financial and/or administrative concerns):
Eric Bozoian
Grants and Assistance Agreements Branch
U.S. Food and Drug Administration
5630 Fishers Ln, Rockville MD 20857 \
Phone: 240-402-7623
Email: [email protected]

Programmatic Contact (technical and/or scientific concerns):
Andrew Babiskin, Ph.D.
DQMM/ORS/OGD/CDER/FDA
10903 New Hampshire Ave., Bldg. 75, Room 4667
Silver Spring, MD 20993
Phone: 240-402-7974
Email: [email protected]

Failure to comply with the above stated Program Terms and Conditions could result in the suspension or termination of this grant project.

THE EXPANDED AUTHORITIES DO NOT APPLY TO THIS GRANT

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 Notice of Award.

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

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

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

Andrew Babiskin, Ph.D.
DQMM/ORS/OGD/CDER/FDA
10903 New Hampshire Ave., Bldg. 75, Room 4667
Silver Spring, MD 20993
Telephone: 240-402-7974
Email: [email protected]

Eric Bozoian
Grants and Assistance Agreements Branch
U.S. Food and Drug Administration (FDA)
5630 Fishers Ln, Rockville MD 20857
Telehone: 240-402-7623
Email: [email protected]

Eric Bozoian
Grants and Assistance Agreements Branch
U.S. Food and Drug Administration (FDA)
5630 Fishers Ln, Rockville MD 20857
Telephone: 240-402-7623
Email: [email protected]

All awards are subject to the terms and conditions, cost principles, and other considerations described in the HHS Grants Policy Statement.

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