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

The previously conducted exploratory in vitro studies showed the importance of assessing in vivo dissolution characteristics of poorly soluble drugs in dissolution media containing milk and baby formula. These studies support that solubility and potentially, the bioavailability of poorly soluble drugs such as furosemide (model drug) may be highly enhanced in the presence of milk or baby formula.

This project is for exploring in vivo performance of a drug product in adult healthy volunteers under conditions similar to that seen in pediatric patients. If the results of this study support that the bioavailability of a poorly soluble drug (furosemide is the model drug) may be highly enhanced in the presence of milk or baby formula, these results could lead to reassessment of furosemide dosing in neonates and infants, and adults, and possibly to additional studies and a change in the current dosing practice.

This project conducted in healthy adults will allow collecting in vivo data when furosemide (the model drug) will be given with milk, baby formula and Ensure Plus and also allow assessment of the impact of study designs and their information value. Data generated from this study is going to be combined with in vitro data generated outside this proposal.

Data and results obtained from this project will be publicly disseminated.

Exploring in vivo delivery (bioavailability) of furosemide from furosemide tablets when given with water, milk, baby formula and Ensure Plus under fasted conditions to healthy adult volunteers (in a four-way cross-over study).

Because the in vivo exploratory pharmacokinetic studies cannot be conducted in pediatric patients, the proposed in vivo study is in healthy adult volunteers. Furosemide dosing will be under conditions that may be similar to those in younger (two years old or less) pediatric patients.

A. Data generation

The in vivo assessment of the effect of milk and other media on furosemide bioavailability

The in vivo study will be conducted in healthy adult volunteers (n=6). To mimic conditions similar to the feeding conditions in pediatric patients, the furosemide dosing will be after an overnight fast, first a 6 oz. of water, or milk or baby formula or Ensure Plus given alone and 10 min later, followed with the furosemide dose (20-mg tablet) given with 6 oz. of water, or milk or baby formula or Ensure Plus according to a 4-way cross-over design. On each occasion, according to a randomized cross-over design, each subject will consume 6 oz. of either water or milk or baby formula or Ensure Plus before the furosemide dosing and again, 6 oz. of the same vehicle with the furosemide dose.

B. Sample and data analyses

Established methods will be used for quantitation of furosemide in the plasma samples.

Similarly, established PK and statistical methods will be utilized for data analyses.

The impact of the critical factors and their interactions on in vitro dissolution results as well as in vivo PK parameters (such as partial Area Under Curve (AUC)) will be determined using ANOVA.

Other statistical methods for correlations and trends will be explored as deemed appropriate for the collected data.

1. Clinical furosemide study (dosing healthy subjects (n=6), taking blood samples and shipping plasma samples to the analytical site).

2. Development and validation of furosemide assay in plasma and analysis of 240 plasma samples for furosemide concentration.

3. For comparing study findings, the awardee should conduct a literature review of relevant furosemide in vitro and in vivo studies and correlations, as applicable, and provide a review and comparison of their findings against the literature publications.

4. For further data analysis, modeling and data interpretation, the applicant should have access to data analysis and modeling tools and be capable to integrate the generated in vivo and in vitro furosemide dissolution and solubility data (from verified sources) for exploring and developing a physiologically based pharmacokinetic (PBPK) modeling for furosemide.

The parameters and the structure of the developed model should allow incorporation of drug substance characteristics, and relevant patient information and in vivo conditions.

FDA 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.
• An application that has substantial overlap with another application pending appeal of initial peer review (see NOT-OD-11-101).

In addition, the FDA will not accept a resubmission (A1) application that is submitted later than 12 months after submission of the new (A0) application that it follows. The FDA will accept 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.

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.

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.

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 FDA/CDER staff to estimate the potential review workload and plan the review.

By the date listed in Part 1. Overview Information, prospective applicants are asked to submit a letter of intent that includes the following information:

• Descriptive title of proposed activity
• Name(s), address(es), and telephone number(s) of the PD(s)/PI(s)
• Names of other key personnel
• Participating institution(s)
• Number and title of this funding opportunity

The letter of intent should be sent via electronic mail as a Word or PDF file to Lisa Ko at [email protected] with RFA-FD-14-081 CDER Letter of Intent and the Institution's Name in the message subject heading.

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 10 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:

• 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'.
• 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.

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 (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 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.

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, 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. 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.

No awardee or performance site institution may spend funds on human subject research or enroll subjects until documentation of IRB approval for the IRB of record is on file with the FDA grants management office.

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.

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 by the Grants Office and responsiveness by components of participating organizations, FDA. Applications that are incomplete 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, and give a separate score for each.

1. The scientific expertise for developing and conducting the listed studies for achieving the project goals within the estimated project duration. (40 points)

2. Demonstration of past experience and effectiveness in completing projects similar to those described in this project. (30 points)

3. Demonstration of effectiveness in working with regulatory research partners and other appropriate organizations to implement the goals of the project. (20 points)

4. Demonstration of adequate program resources (including staff) and infrastructure, or the ability to obtain the resources necessary, to complete the project needs. (10 points)

As applicable for the project proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall composite 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 the Guidelines for the Review of Human Subjects.

Inclusion of Women, Minorities, and Children

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.

Vertebrate Animals

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 refer to the Worksheet for Review of the Vertebrate Animal Section.

Biohazards

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.

Resubmissions

Not Applicable

Renewals

Not Applicable

Revisions

Not Applicable

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

Applications from Foreign Organizations

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.

Select Agent Research

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).

Resource Sharing Plans

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 the budget and the requested period of support are fully justified and reasonable in relation to the proposed research.

Applications determined to be complete and responsive will undergo an objective review process. An objective review panel will evaluate complete and responsive applications, 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.

Information regarding the disposition of applications is available in the HHS Grants Policy Statement.

If the application is under consideration for funding, FDA will request "just-in-time" information from the applicant as described in the HHS Grants Policy Statement.

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization for successful applications. The NoA signed by the grants management officer is the authorizing document and will be sent via email to the grantee’s business official.

Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.

Any application awarded in response to this FOA will be subject to terms and conditions found in the HHS Grants Policy Statement.

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

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

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 policies.

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 Project Officer (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 CDER policy.

Manuscripts shall be submitted to PO within six 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 - FDA 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.

A FDA/CDER 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 FDA/CDER PO include involvement during conduct of the activity, through technical assistance, advice, coordination, and/or other assistance activities.
• As appropriate, the FDA/CDER 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 FDA/CDER 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 PO, will have access to data generated under this Cooperative Agreement and may periodically review the data and progress reports. The FDA/CDER 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 FDA/CDER PO.

As relevant, the PD/PI s, in collaboration with FDA/CDER 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 FDA/CDER 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 FDA/CDER 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 FDA/CDER PO, and that the FDA programmatic staff will be given the opportunity to offer input into this process. The FDA/CDER 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 FDA/CDEr 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 FDA/CDER 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 FDA/CDER 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 (Disallowance of Cost).

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 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 FDA/CDER 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). FDA/CDER 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. FDA/CDER 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 FDA/CDER 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 FDA/CDER PO, CDER Sponsor (if different from 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 FDA/CDER PO and Extramural Clinical Studies Coordinator for review. The Grantee/PI also shall submit the final research study documents to the FDA/CDER 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 FDA/CDER 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 FDA/CDER 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 FDA/CDER 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 FDA/CDER 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 FDA/CDER 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 FDA/CDER PO as mentioned above.

8. The Grantee/PI shall seek RIHSC (through the Extramural Clinical Studies Coordinator and/or FDA/CDER 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 FDA/CDER 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 FDA/CDER PO, within two weeks of receipt. If a Steering Committee or Monitoring Board is established by the Grantee/recipient, in collaboration with the FDA/CDER 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 FDA/CDER 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 FDA/CDER 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 FDA/CDER 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 CDER 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 FDA/CDER 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].

Funding Authorities (General) for Grants and Cooperative Agreements

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 Parts 74 and 92.

FDA will support the clinical studies covered by this notice under the authority of section 301 of the PHS Act as amended (42 U.S.C. 241) and under applicable regulations at 42 CFR Part 52 and 45 CFR Parts 74 and 92.

Funding Authorities (Specific) Grants and Cooperative Agreements involving human subjects

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, or 360e) or section 351 of the Public Health Service Act (the PHS Act) (42 U.S.C. 262), section 351 of the PHS Act, 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.

When multiple years are involved, awardees will be required to submit the annual Non-Competing Progress Report (PHS 2590 or RPPR) and financial statements as required in the HHS Grants Policy Statement.

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. See the HHS Grants Policy Statement for additional information on this reporting requirement.

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

eRA Commons Help Desk (Questions regarding eRA Commons registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, post submission issues)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)
Finding Help Online: http://grants.nih.gov/support/index.html
Email: [email protected]

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]

Arzu Selen, Ph.D.
FDA/CDER/OPS/Office of New Dug Quality Assessment (ONDQA)
Telephone: 301-796 1603
Email: [email protected]

David Morley
FDA/CDER/OPS/Office of New Dug Quality Assessment (ONDQA)
Telephone: 301-796-1719
Email: [email protected]

Lisa Ko
Food and Drug Administration (FDA)
Office of Acquisition & Grants Services (OAGS)
Telephone: 240-402-7592
Email: [email protected]

Lisa Ko
Food and Drug Administration (FDA)
Office of Acquisition & Grants Services (OAGS)
Telephone: 240-402-7592
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 Section 301 of the Public Health Service Act as amended (42 USC 241) and under Federal Regulations 42 CFR Part 52 and 45 CFR Parts 74 and 92.

Consistent with the property management requirements of 45 CFR Sections 74.36 and 92.34, FDA/CDER reserves a royalty-free, nonexclusive, and irrevocable right to reproduce, publish, or otherwise use work that was developed for Federal purposes, and to authorize others to do so.