Participating Organization(s)	U.S. Food and Drug Administration (FDA) The FDA does not follow the NIH Page Limitation Guidelines or the Enhanced Peer Review Scoring Criteria. Applicants are encouraged to consult with FDA Agency Contacts for additional information regarding page limits and the FDA Ad Hoc Review Process.
Components of Participating Organizations	Center for Drug Evaluation Research - Office of Generic Drugs
Funding Opportunity Title	Pharmacokinetic and Pharmacodynamic (PK-PD) Studies of Cardiovascular Drugs (U01)
Activity Code	U01 Research Project Cooperative Agreements
Announcement Type	New
Related Notices	May 16, 2014 - See Notice NOT-FD-14-008. Notice of Change to Patient Population Requirements.
Funding Opportunity Announcement (FOA) Number	RFA-FD-14-024
Companion Funding Opportunity	None
Number of Applications	See Section III. 3. Additional Information on Eligibility.
Catalog of Federal Domestic Assistance (CFDA) Number(s)	93.103
Funding Opportunity Purpose	The purpose of this project is to conduct a prospective PK/PD study to identify the key product attributes and patient factors that may impact the PK/PD and therapeutic equivalence of metoprolol products. The findings from the PK/PD study will help establish scientific and regulatory standards for assuring therapeutic equivalence of generic metoprolol products.

Posted Date	April 16, 2014
Open Date (Earliest Submission Date)	April 18, 2014
Letter of Intent Due Date(s)	Not Applicable
Application Due Date(s)	June 1, 2014, by 5:00 PM local time of applicant organization. Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.
AIDS Application Due Date(s)	Not Applicable
Scientific Merit Review	June, 2014
Advisory Council Review	September, 2014
Earliest Start Date	September, 2014
Expiration Date	June 2, 2014
Due Dates for E.O. 12372	Not Applicable

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

Metoprolol is a selective 1 receptor blocker used in treatment of several cardiovascular diseases, especially hypertension. Metoprolol is metabolized primarily by the cytochrome P450 isoform CYP2D6, which is subject to a genetic polymorphism. It has been formulated in different salt forms including tartrate, fumarate, and succinate salts, as well as different dosage forms such as immediate release and, extended release products. Different metoprolol drug products showed different pH-dependent drug release characteristics which seem to be consistent with the observed PK profile differences.

The US FDA currently recommends single dose bioequivalence studies in healthy subjects to establish the bioequivalence of generic metoprolol products with their corresponding reference listed drug (RLD) based on 90% confidence interval of Cmax and AUC within 80.00-125.00%. The same bioequivalence criteria apply to any post approval changes of brand products which require in-vivo bioequivalence studies. Therapeutic inefficacy and adverse events have been reported by physicians and patients switching from brand to generic metoprolol extended release products. The FDA continues to monitor the FDA Adverse Event Reporting System (FAERS) for reports relating to currently marketed metoprolol products. However, based on current data available to the agency, it is difficult to draw definitive conclusions about the cause of the concern. Therefore, PK/PD studies in patient population are needed to help address the potential bioequivalence and therapeutic equivalence issues with metoprolol products.

The objectives of this project are to conduct a prospective PK/PD study in hypertensive patients to link the PK profiles to the time-course of PD activity of metoprolol, therefore, to identify the key product attributes and patient factors that may impact the therapeutic equivalence of metoprolol products. The specific objectives of the study were to:

1) Evaluate the PK-PD relationship;

2) Evaluate the effect of treatment (before and after switching metoprolol products) on the PK-PD relationship;

3) Evaluate the effect of pH variation in the population and rate of delivery on the PK-PD relationship;

4) Evaluate the effect of CYP2D6 phenotype on the PK-PD relationship;

Additional details regarding the study objectives are listed below:

• A prospective, randomized crossover trial design is suggested, i.e., switching over to a different metoprolol product at the same dose level as the prior one. The study should use a combination of products having different shapes of PK profiles. Simultaneous collections of PK and PD samples (before and after switch) at steady state are recommended to link PK profiles to PD effect. The selection of appropriate PD endpoint(s) has to be well justified.
• The study should enroll CYP2D6 extensive and poor metabolizers to assess the CYP2D6 phenotype impact on the PK profiles and PD activity of metoprolol extended release tablets.
• The study should evaluate the pH variations of the population and its impact on the PK profiles and PD effect of metoprolol extended release tablets.

The focus of the first year is to develop a study protocol for FDA Research in Human Subject Committee (RIHSC) and investigator Institution Research Board (IRB) approval, product blinding, quality testing, bioanalytical method validation, and patient enrollment.

Funding Instrument	Cooperative Agreement: A support mechanism used when there will be substantial Federal scientific or programmatic involvement. Substantial involvement means that, after award, FDA scientific or program staff will assist, guide, coordinate, or participate in project activities.
Application Types Allowed	New The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types.
Funds Available and Anticipated Number of Awards	The FDA and partner components intend to commit $1,000,000 total costs per award, per year. Awards are contingent upon the availability of funds, annual appropriations and performance. Only one grant will be awarded.
Award Budget	Application budgets are not limited but need to reflect the actual needs of the proposed project and should not exceed $1,000,000 in Total Costs.
Award Project Period	The scope of the proposed project should determine the project period. The maximum project period is 3 years.

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.

FDA will not accept any application that is essentially the same as one already reviewed within the past thirty-seven months (as described in the HHS Grants Policy Statement), except for submission:

• To an RFA of an application that was submitted previously as an investigator-initiated application but not paid;
• Of an investigator-initiated application that was originally submitted to an RFA but not paid; or
• Of an application with a changed grant activity code.

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

The following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing an application to this FOA.

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

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

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

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

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

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

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

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, an 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.

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.

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 assigned Grants Management Specialist 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. As part of the FDA Mission, all applications submitted to the FDA in support of biomedical and behavioral research are evaluated for scientific and technical merit through the FDA Ad Hoc Review process.

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the project proposed).

Reviewers will consider each of the review criteria below in the determination of scientific merit, and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.

Significance

Does the project address an important problem or a critical barrier to progress in the field? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice are improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

Investigator(s)

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?

Innovation

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?

Approach

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed?

If the project involves human subjects and/or 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?

Environment

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 while determining scientific and technical merit, and in providing an overall impact score, but will not give separate scores for these items.

Protections for Human Subjects

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

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

Inclusion of Women, Minorities, and Children

When the proposed project involves human subjects and/or 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.

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

Applications from Foreign 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.

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 will be evaluated for scientific and technical merit by (an) appropriate Ad Hoc Review Group(s) convened by Center for Drug Evaluation Research, in accordance with FDA Ad Hoc Review Process, using the stated review criteria. Assignment to an Ad Hoc Review Group will be shown in the eRA Commons.

As part of the scientific Ad Hoc Reviews, all applications:

• May undergo a selection process in which only those applications deemed to have the highest scientific and technical merit (generally the top half of applications under review) will be discussed and assigned overall impacts score.
• Will receive a written critique.

Appeals of initial Ad Hoc Review will not be accepted for applications submitted in response to this FOA.

Following initial Ad Hoc Review, recommended applications will receive a second level of review by the appropriate national Advisory Council or Board. The following will be considered in making funding decisions:

• Scientific and technical merit of the proposed project as determined by scientific Ad Hoc Review.
• Availability of funds.
• Relevance of the proposed project to program priorities.

After the Ad Hoc Review of the application is completed, the PD/PI will receive a copy of his or her Summary Statement (written critique) via e-mail.

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 the DUNS, SAM Registration, and Transparency Act requirements as noted on the Award Conditions and Information for NIH Grants website.

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

Cooperative Agreement Terms and Conditions 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 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 (Disallowance of Cost).

Clinical Trial Terms and Conditions of Award

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 Ad Hoc 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

Research Involving Human Subjects Committee (RIHSC) Terms and Conditions of Award

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 Jill.Coker@FDA.HHS.GOV.

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.

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Lanyan (Lucy) Fang
Food and Drug Administration (FDA)
Telephone: 301-796-5005
Email: lanyan.fang@fda.hhs.gov

Lanyan (Lucy) Fang
Food and Drug Administration (FDA)
Telephone: 301-796-5005
Email: lanyan.fang@fda.hhs.gov

Gladys Melendez (Bohler)
Food and Drug Administration (FDA)
Telephone: 301-515-0642
Email: gladys.bohler@fda.hhs.gov

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

All awards will be subject to all OGD policies and requirements that govern the research grant programs of the PHS as incorporated in the HHS Grants OGD policy Statement, dated January 1, 2007.

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.