Department of Health and Human Services

Participating Organizations
National Institutes of Health (NIH), (http://www.nih.gov/)

Components of Participating Organizations
National Institute of Dental and Craniofacial Research (NIDCR), (http://www.nidcr.nih.gov/)

Title: Development And Validation of Technologies for Saliva-Based Diagnostics

Announcement Type
This is a reissuance with modifications of RFA-DE-02-002, which was released January 2, 2002.

Request For Applications (RFA) Number: RFA-DE-06-003

Catalog of Federal Domestic Assistance Number(s)
93.121

Key Dates Release Date: June 28, 2005
Letters-Of-Intent Receipt Date: October 17, 2005
Application Receipt Date: November 14, 2005
Peer Review Date: January, 2006
Council Review Date: May, 2006
Earliest Anticipated Start Date: August, 2006
Additional Information To Be Available Date (URL Activation Date): Not Applicable
Expiration Date: Release Date: November 15, 2005

Due Dates for E.O. 12372
Not Applicable

Additional Overview Content

Executive Summary

The National Institute of Dental and Craniofacial Research (NIDCR) invites Cooperative Agreement Applications (U01) to support the technological advances needed for rapid, reliable, non-invasive identification of biomarker signature patterns in saliva indicative of local and systemic health status, particularly in regards to early diagnosis of diseases. The focus of such diagnostic technologies must be in disease areas in which saliva based diagnostics can have a major impact. The specific goals of the initiative are to: i) support the development of functional, miniature, portable, self-contained, easy-to-use diagnostic prototype devices for simultaneous multi-analyte detection; and ii) accelerate commercialization of such systems. To facilitate the development of a functional prototype that will attract commercial development, the NIDCR requires additional information, including:

• Description of the diagnostic area (autoimmune disease, periodontal disease, oral cancers etc.), for which such a diagnostic system will be developed;
• A product development plan through clinical evaluation;
• Plans for obtaining FDA approval and;
• Intellectual property management plan.

An individual can be the PI on only one proposal submitted under this announcement. However, an individual may be listed as a participant in another U01 applications provided that his/her research project activities within that U01 are entirely distinct. An individual may not propose overlapping research projects on multiple applications.

• The NIDCR intends to commit approximately $7.0 million in total costs in FY06
• The NIDCR anticipates 2 to 3 awards.
• This RFA will use the NIH cooperative agreement funding mechanism (U01) for new and competing awards.
• Eligible organizations include for-profit or non-profit organizations, public or private institutions, such as universities, colleges, hospitals, and laboratories, units of State and local governments, eligible agencies of the Federal government, domestic institutions/organizations. Foreign institutions are not eligible to apply; foreign Institutions may participate only as collaborating Institutions.
• Eligible principal investigators include any individual with the skills, knowledge, and resources necessary to carry out the proposed research. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH programs.
• Applicants may submit only one application. See Section IV.1 for application materials.
• Telecommunications for the hearing impaired is available at: TTY 301-451-5936

Part I Overview Information

Part II Full Text of Announcement

 Section I. Funding Opportunity Description
   1. Research Objectives

 Section II. Award Information
   1. Mechanism(s) of Support
   2. Funds Available

 Section III. Eligibility Information
   1. Eligible Applicants
     A. Eligible Institutions
     B. Eligible Individuals
   2.Cost Sharing or Matching
   3. Other - Special Eligibility Criteria

 Section IV. Application and Submission Information
   1. Address to Request Application Information
   2. Content and Form of Application Submission
   3. Submission Dates and Times
     A. Receipt and Review and Anticipated Start Dates
       1. Letter of Intent
     B. Sending an Application to the NIH
     C. Application Processing
   4. Intergovernmental Review
   5. Funding Restrictions
   6. Other Submission Requirements

 Section V. Application Review Information
   1. Criteria
   2. Review and Selection Process
     A. Additional Review Criteria
     B. Additional Review Considerations
     C. Sharing Research Data
     D. Sharing Research Resources
   3. Anticipated Announcement and Award Dates

 Section VI. Award Administration Information
   1. Award Notices
   2. Administrative and National Policy Requirements
     A. Cooperative Agreement Terms and Conditions of Award
       1. Principal Investigator Rights and Responsibilities
       2. NIH Responsibilities
       3. Collaborative Responsibilities
       4. Arbitration Process
   3. Reporting

 Section VII. Agency Contact(s)
   1. Scientific/Research Contact(s)
   2. Peer Review Contact(s)
   3. Financial/ Grants Management Contact(s)

 Section VIII. Other Information - Required Federal Citations

1. Research Objectives

Purpose

The NIDCR wishes to continue the support of the technological advances needed for rapid, reliable, non-invasive identification of biomarker signature patterns in saliva indicative of local and systemic health status, particularly in regards to early diagnosis of diseases.

The purpose of this RFA is to encourage outstanding multidisciplinary research to: i) support the development of functional, miniature, portable, self-contained, easy-to-use diagnostic prototype devices for simultaneous multi-analyte detection; and ii) accelerate commercialization of such systems.

Applicants are expected to: i) present evidence of an integrated system that can measure at least one analyte in saliva; ii) provide a description of the status of the device, and additional design aspects that will be completed during the first 2 years prior to the validation stage of the device; iii) include the product development plan, with a timetable and milestones, for accomplishing and coordinating fabrication, testing, achieving robust operation and high quality data; and iv) anticipate barriers and outline approaches for overcoming them.

It is envisioned that this initiative will catalyze targeted development efforts that offer the greatest opportunity for advances in the near and medium terms and will lower the barriers for these advances in order to facilitate the translation of these advances to the private sector for commercial development. In this regard, the NIDCR recognizes that significant issues exist concerning intellectual property rights with respect to patentable inventions developed within the awards made under this RFA program. This subject is discussed more fully below. Within this context, however, it is the NIDCR's intent that inventors will exercise any intellectual property rights retained on inventions developed as part of these awards in a way that will promote wide accessibility to and further development of the resources that are generated.

Background

Whole saliva, a complex mixture composed mainly of salivary gland secretions and gingival fluid, has been used for the diagnosis of systemic disease for many years. Because gingival fluid is a transudate reflecting the composition of serum, it mirrors serum changes caused by systemic diseases. Saliva offers a sample matrix that could enable the rapid assessment and monitoring of health and disease states, exposure to environmental and occupational toxins, or drugs of abuse, as well as exposure to infectious agents including those associated with bioterrorism. Saliva-based diagnostics may prove to be more accessible, accurate, less expensive, and present less risk than current methodology.

A growing number of proofs-of-principle have been established for using saliva to monitor several systemic diseases and conditions, as well as substance abuse. The barriers to widespread implementation of saliva diagnostics derive from technological problems such as sensitivity, miniaturization, high throughput, automation, portability, low cost, high functionality, and speed to enable detection and measurements of multiple disease markers in saliva. There is now renewed hope for overcoming these barriers because remarkable technological advances are promising to revolutionize the field of diagnostics, as we now know it. Techniques that are emerging from a combination of miniaturization technologies and discoveries in many different fields of biology, chemistry, physics and engineering are leading to high throughput, automated, portable, low cost, more efficient, and rapid biochemical analyses. Miniaturized diagnostic technologies will be able, with minuscule amounts of body fluids, to yield critical patient information reflecting health and disease status. Scientists predict that pocket-sized analyzers ( lab-on-a-chip ) that can perform multiple operations in parallel in non-laboratory settings such as the field, factory, hospital clinic or home will be developed. Current technologies provide a path toward these kinds of tests/devices. It is envisioned that such technologies will allow the simultaneous assessment of multiple conditions of health and disease and will provide clinicians with new prevention and therapeutic strategies to meet patient needs.

The NIDCR has initiated a concerted research effort in the area of saliva diagnostics and progress is being made toward technologically viable systems moving toward commercial reality. Specifically, in fiscal year 2002, NIDCR funded a series of grants to develop strategies to measure and analyze multiple substances in saliva quickly and simultaneously. Seven projects were funded and represent diverse approaches to use oral fluids for the diagnosis of both oral and systemic disease. The teams include multiple expertises ranging from engineers to basic scientists and clinicians. The technologies under development through these projects include microelectromechanical systems (referred to as MEMS) and microfluidics. MEMS differ in that they are integrating systems consisting of mechanical elements, sensors, actuators, and electronics on a common silicon substrate developed through microfabrication technology. These systems use small sample and reagent volumes coupled with integrated detection methods to perform analysis. Because MEMS devices are manufactured using batch fabrication techniques similar to those used for integrated circuits, unprecedented levels of functionality, reliability, and sophistication can be placed on a small silicon chip at a relatively low cost. MEMS can be miniature, self-contained diagnostic systems.

The seven U01 awards currently supported by the NIDCR are focusing on the development of microfluidic and MEMS technologies. Specifically, both systems are in early development and testing stages for measuring DNA, gene transcripts (mRNA), proteins (cardiac and periodontal disease markers), electrolytes and small molecules in saliva as well as overall profile (e.g. cholesterol, C-reactive protein) correlates of a particular disease state such as cardiovascular disease. However, none of these new technologies will become a practical reality without strong partnerships with industry early in the development stage because of the many challenges such technologies present to reach the stage of fabrication, integration of individual components, validation, regulatory approval and finally commercialization.

Objectives and Scope:

This RFA encourages applications for outstanding multidisciplinary research for development and validation of technologies for saliva-based diagnostics. The specific goals of the initiative are to: i) support the development of functional, miniature, handheld, self-contained, easy-to-use diagnostic prototype devices for simultaneous multi-analyte detection; and ii) accelerate commercialization of such systems.

To be eligible for support under this program, applicants must present evidence of a handheld, miniature integrated system that can measure at least one analyte in saliva and that integrates:

• sample introduction and preprocessing (e.g. cell lysis, dilution, debris removal);
• analyzer platforms with various capture chemistries that provide surfaces able to select and bind different molecules of interest such as proteins or nucleic acids;
• detection systems that include appropriate light sources, sensors, detectors (e.g., fluorimetric dyes) and integrated electronic components;
• automated operation and data analysis; and
• wireless communication systems for data transfer.
• provide a description of the status of the device, and additional design aspects that will be completed during the first 2 years of the 5 year funding period);
• include a Product Development Plan that outlines validation and regulatory strategies through clinical evaluation to be achieved in the award years.

Product Development Plan

In preparing the Product Development Plan, the following components should be addressed:

1. Device fabrication materials and analytical reagent specifications

The plan should identify the materials selected for manufacture of the prototype device and describe the rationale for selection. Describe the reagents used for performing the in vitro testing and the methodology on which the analysis is based. A description of any potential risk with the use of the device must be stated.

2. Analyte Selection

The development plan should summarize the criteria for developing and selecting the analyte(s) for analysis and whether a current assay exists for detection and quantitation of these analytes in serum. An established assay for the serum biomarker can provide a gold standard for the validation of the prototype assay. Because saliva generally reflects serum composition, applicants should outline whether they plan to assess the correlation between biomarkers in serum and saliva in matched patient samples.

3. Sample Handling

The product development plan should address the details of sample collection, processing, and potential storage conditions. These details may include, e.g., the interval between collection of saliva and application to the device, use of any other equipment for sample collection or processing, potential archiving of saliva samples for future assay with this or other instrumentation, appropriately designed stability studies for the proposed handling of saliva samples, including any proposed studies testing the effect of diluents and short term temperature stability, and, if frozen storage is planned, freeze and thaw stability studies to assess effects on biomarkers and spiked standards.

4. Assay Validation

Validation of an analytical method identifies the sources of potential error and quantifies the performance characteristics of an assay. Validation of the analytical method will ensure that it provides reliable information for the intended diagnostic application, and therefore it is a key component of the development and approval process.

The validation process should address, at a minimum, the following key parameters, and may include any additional parameters proposed by the applicant:

• Standards: Describe the proposed source and storage of calibration (reference) standards and spiking strategies to validate the assay and provide a positive control in routine analysis. Discuss any standards planned for documenting variations in saliva conditions (e.g. viscosity, protein content/unit volume, concentration of specific enzymes).
• Accuracy: Describe any existing analytical procedures that can independently measure the biomarker and confirm the values reported by the prototype.
• Precision: Describe the procedures to determine the degree of agreement among individual test results (e.g., repeated sampling of a defined, homogenous sample), expressed as the variance, standard deviation, or coefficient of variation. Describe the following elements of precision testing, and necessary sample numbers and range to measure:

  1. Repeatability- intra-assay variability under the same operating conditions (same operator and day).
  2. Intermediate Precision- intra-assay variability by different analysts and assays on different days.
  3. Reproducibility- the variability of assays performed in different laboratories.

• Specificity: Describe procedures for determining the specificity of the analytic method(s). These methods should include, e.g., the effect of variations in saliva on assay performance using spiking standards into multiple saliva samples within a single patient under controlled conditions (e.g. after overnight fasting), and under variable conditions (e.g. time of day), or from multiple healthy donor and target patient populations. Proposed tests should be able to determine interference of analyte measurement by saliva components and conditions, including: saliva physicochemical properties (e.g. saliva viscosity, pH); oral conditions; and interfering drug substances (e.g. aspirin, antibiotics, prescription medications associated with the patient population tested)
• Detection Limit: Outline proposed tests to determine the limit of detection (LOD) of the analytes(s).
• Quantification Limit: Outline proposed tests to determine the lower limit of quantitation (LLOQ) and upper limit of quantitation (ULOQ) of the analytes(s) that can be measured with an acceptable level of accuracy and precision, and define the acceptable signal-to-noise ratio.
• Linearity and Range: Outline proposed tests to determine the range in which the assay result is proportional to the analyte concentration.
• Robustness: Outline proposed tests to determine the effect of environmental variations (e.g. temperature, humidity, electrical surge, concussion) on the quality of assay results. Include in this discussion deliberate variations (e.g. incubation times, longevity of reagents, variability within or between patients) that will be introduced into the method parameters that will define the limits on reliability in normal usage.

The product development plan should specify the acceptance criteria for each parameter, and discuss how these acceptance criteria will be established prospectively and be compared to appropriate standard assay parameters for in vitro diagnostics.

5. Data Analysis

Provide information on the format of data produced by the device and how the data will be processed and stored. Applicants should discuss the criteria for defining a positive response. This discussion should include details on the statistical methods for data analysis, including the number of data points required. Applicants should also define how the development process will determine the rate of false positives and false negatives, and the criteria for repeat testing.

6. Regulatory Strategy

Applicants should outline a strategy for interacting with the FDA Center for Devices and Radiological Health (CDRH) (http://www.fda.gov/cdrh/devadvice/overview.html), which regulates the manufacture, application, and marketing of medical devices in the United States (e.g. user manual, device labels). An overview of the IVD regulation by the Office of In Vitro Diagnostic Device Evaluation and Safety (OIVD), a division of the CDRH, is available on the internet (http://www.fda.gov/cdrh/oivd/regulatory-overview.html#2). However, the regulatory landscape in the area of research and development is evolving rapidly, and applicants are advised to update their review of FDA regulations frequently. For the purposes of this announcement, applicants should outline a strategy for identifying and interacting with the appropriate FDA center, as well as rationalizing the level of review (e.g. BLA, PMA, 510K, etc.).

See Section VIII, Other Information - Required Federal Citations, for policies related to this announcement.

Organizational Structure of the Project

Each application must address the following critical components explicitly (provide examples and plans), and all components must be addressed for an application to be eligible for peer review:

• Description of the diagnostic area (autoimmune disease, periodontal disease, oral cancers etc.), for which such a diagnostic system will be developed;
• Proof-of-principle of the existing technology (status of the system prior to funding);
• A Product Development Plan, including a description of the design aspects/plans that will be completed during the period of the award;
• Description of how the technologies to be developed will contribute to automated, low cost, more efficient, and rapid simultaneous biochemical analysis for multi-analyte detection;
• Milestones (see below);
• Anticipated barriers and approaches for overcoming them;
• Explicit affiliation(s) with academic or research centers of engineering or physical sciences (e.g., mathematics, chemistry, physics, computational and/or materials science) that are directly involved with and actively contribute to the project (such a relationship is required for each proposed project but does not need to be unique for each);
• Fabrication/synthesis facilities and/or collaborative capabilities;
• Biocomputing capabilities to support proposed projects
• Existing private/not-for-profit technology development partnerships that are specific to the technologies proposed;
• Existing or planned relationships with industrial partners for down-stream development and commercialization activities;
• Mechanisms to share reagents and information among the participating projects awarded under RFA-DE-06-003; and
• A framework to disseminate information.

The NIDCR does not specify how these components are to be organized. However, the applicant must clearly address how the proposed organization of the project will ensure that each of these components is effectively accommodated. Because of the complexity of each project, NIDCR program staff expects to visit each project periodically to conduct an administrative site visit. Awardees must be prepared for annual site visits and must budget appropriately (including travel for collaborators to participate on site and other necessary costs).

Applicants are strongly encouraged to take advantage of the existing opportunities in salivary research supported by the NIDCR, particularly the salivary proteome project and the International Sjögren's syndrome registry contract.

In addition to the functions described above, there are a number of other issues important to the successful operation of the research projects that should be addressed separately in the application.

• Details of the governance structure for the project, which includes an Internal Advisory Committee, a Steering Committee and an NIDCR Scientific Advisory Panel to oversee all the awards under this RFA, are provided in Section VI.2.A., Cooperative Agreement Terms and Conditions of Award. To assist with these activities, the NIDCR will designate a program staff scientist who will have substantial scientific involvement during the conduct of this activity above and beyond normal program stewardship for grants.

• Applicants will be required to submit an intellectual property management plan, and a plan to disseminate research results as a condition of award (just-in-time requirements). Details of these requirements are found in Section IV.6, Other Submission Requirements.

Milestones

All applications must include a specific section labeled Milestones for each year. Milestones should be annual, well-described, quantitative, and scientifically justified and not simply a restatement of the specific aims. Rather, the milestones should offer a timeline and a pathway for the development of the proposed technology. These milestones will be used to judge the success of the proposed research on an individual-project basis. It is expected that the milestones will be adjusted annually at the award anniversary dates to incorporate the group's scientific accomplishments and progress and to reflect any recommendations of the Steering and Advisory Committees.

Internal Advisory Committee

Programs will be expected to have their own Internal Advisory Committee that includes experts outside the project. While a description of the Committee's activities should be included in the application, potential experts outside the project who would serve on the Internal Advisory Committee should not be named, contacted, or selected until an award has been made. Costs for activities of the Steering Committee should be included in the budget.

Progress Reviews, Milestones and Evaluations

The annual progress report will have two components. The first will be the standard NIH progress report (Form 2590). The second will be a more specialized report that will be developed by Steering Committee and Scientific Advisory Panel and NIDCR program staff. This specialized report should be included as an attachment to the standard progress report and will go to the NIDCR Program Director.

The NIDCR Program Director and Project Scientist will review the progress of the award annually to assure that satisfactory progress is being made in achieving the project objectives. During the first year of funding, and during subsequent years if deemed necessary by the Program Officer(s), reviews may be more frequent. The adherence of the awardee to the approved data sharing plan, product development and intellectual property plans, which will be part of the Terms and Conditions of award (see Section VI.3. Reporting), will also be reviewed annually. Should problems arise in the conduct of the study, the NIDCR Program Director may require that the awardee submit quarterly reports on technical progress and fiscal matters.

An evaluation component and evaluation criteria will be developed in partnership between the Steering Committee and Scientific Advisory Panel and NIDCR program staff. The purpose of the evaluation is to monitor and assess the performance of the projects awarded in achieving the goals of this RFA.

1. Mechanism(s) of Support

This funding opportunity will use the NIH U01 award mechanism. As an applicant, you will be solely responsible for planning, directing, and executing the proposed project.

This funding opportunity uses the just-in-time budget concepts. It also uses the non-modular budget format described in the PHS 398 application instructions (see http://grants.nih.gov/grants/funding/phs398/phs398.html). A detailed categorical budget for the "Initial Budget Period" and the "Entire Proposed Period of Support" is to be submitted with the application. A categorical budget for each project, along with a summary budget, is required.

The NIH U01 is a cooperative agreement award mechanism to continue the cooperative agreement project(s) beyond the initially awarded period of performance. In the cooperative agreement mechanism, the Principal Investigator retains the primary responsibility and dominant role for planning, directing, and executing the proposed project, with NIH staff being substantially involved as a partner with the Principal Investigator, as described under the Section VI. 2. Administrative Requirements, "Cooperative Agreement Terms and Conditions of Award".

2. Funds Available

The NIDCR intends to commit approximately $7.0 M in FY 2006 to fund up to 3 awards. An applicant should request a project period of 5 years. The budget may not exceed $2.5 million in total costs per year. Costs for equipment may be included in year 1, up to $500,000. Applicants should include travel funds in the budget for the annual site visit and annual awardee meetings.

This RFA is a one-time solicitation, and plans for this initiative beyond the current funding opportunity are indefinite.

Although the financial plans of the NIDCR provide support for this program, awards pursuant to this funding opportunity are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications.

Facilities and administrative costs requested by consortium participants are not included in the direct cost limitation, see NOT-OD-05-004.

1. Eligible Applicants

1.A. Eligible Institutions

You may submit (an) application(s) if your organization has any of the following characteristics:

• For-profit organizations
• Non-profit organizations
• Public or private institutions, such as universities, colleges, hospitals, and laboratories
• Units of State government
• Units of local government
• Eligible agencies of the Federal government
• Domestic Institutions only

Foreign institutions may participate only as subcontractors within the project.

1.B. Eligible Individuals

Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with their institution to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH programs.

2. Cost Sharing or Matching

This program does not require cost sharing as defined in the current NIH Grants Policy Statement at http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_part2.htm.

3. Other-Special Eligibility Criteria

Applications that are focusing on the initial development of individual parts of microelectromechanical systems (MEMS) or solely on the development of a microfluidic platform are not responsive to this RFA.

Applications must meet the eligibility criteria described in Section I. Research Objectives, above:

To be eligible for support under this program, applicants must present evidence of a handheld, miniature integrated system that can measure at least one analyte in saliva and that integrates:

• sample introduction and preprocessing (e.g. cell lysis, dilution, debris removal);
• analyzer platforms with various capture chemistries that provide surfaces able to select and bind different molecules of interest such as proteins or nucleic acids;
• detection systems that include appropriate light sources, sensors, detectors (e.g., fluorimetric dyes) and integrated electronic components;
• automated operation and data analysis; and
• wireless communication systems for data transfer;
• provide a description of the status of the device, and additional design aspects that will be completed during the first 2 years of the 5 year funding period);
• include a Product Development Plan that outlines validation and regulatory strategies through clinical evaluation to be achieved in the award years.

1. Address to Request Application Information

The PHS 398 application instructions are available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. Applicants must use the currently approved version of the PHS 398. For further assistance contact GrantsInfo, Telephone (301) 710-0267, Email: [email protected].

Telecommunications for the hearing impaired: TTY 301-451-5936.

2. Content and Form of Application Submission

Applications must be prepared using the most current PHS 398 research grant application instructions and forms. Applications must have a D&B Data Universal Numbering System (DUNS) number as the universal identifier when applying for Federal grants or cooperative agreements. The D&B number can be obtained by calling (866) 705-5711 or through the web site at http://www.dnb.com/us/. The D&B number should be entered on line 11 of the face page of the PHS 398 form.

The title and number of this funding opportunity must be typed on line 2 of the face page of the application form and the YES box must be checked.

Given the multidisciplinary nature of this RFA, the page limit for the Research Plan is raised to 35.

3. Submission Dates and Times
Applications must be received on or before the receipt date described below (Section IV.3.A). Submission times N/A.

3.A. Receipt, Review and Anticipated Start Dates

Letters-Of-Intent Receipt Date: November 14, 2005
Application Receipt Date: October 17, 2005
Peer Review Date: January, 2006
Council Review Date: May, 2006
Earliest Anticipated Start Date: August, 2006

3.A.1. Letter of Intent

Prospective applicants are asked to submit a letter of intent that includes the following information:

• Descriptive title of proposed research
• Name, address, and telephone number of the Principal Investigator
• Names of other key personnel
• Participating institutions
• Number and title of this funding opportunity

Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review.

The letter of intent is to be sent by the date listed at the beginning of this document.

The letter of intent should be sent to:

H. George Hausch, Ph.D.
Division of Extramural Activities
National Institute of Dental and Craniofacial Research
National Institutes of Health
Natcher Bldg. 45, Room 4AN-44F
Bethesda, MD 20892-6402
Telephone: (301) 594-2904
FAX: (301) 480-8303
Email: [email protected]

3.B. Sending an Application to the NIH

Applications must be prepared using the research grant applications found in the PHS 398 instructions for preparing a research grant application. Submit a signed, typewritten original of the application, including the checklist, and three signed photocopies in one package to:

Center for Scientific Review
National Institutes of Health
6701 Rockledge Drive, Room 1040, MSC 7710
Bethesda, MD 20892-7710 (U.S. Postal Service Express or regular mail)
Bethesda, MD 20817 (for express/courier service; non-USPS service)

Personal deliveries of applications are no longer permitted (see http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-040.html).

At the time of submission, two additional copies of the application and all copies of the appendix material must be sent to:

H. George Hausch, Ph.D.
Division of Extramural Activities
National Institute of Dental and Craniofacial Research
National Institutes of Health
Natcher Bldg. 45, Room 4AN-44F
Bethesda, MD 20892-6402
Telephone: (301) 594-2904
FAX: (301) 480-8303
Email: [email protected]

Using the RFA Label: The RFA label available in the PHS 398 application instructions must be affixed to the bottom of the face page of the application. Type the RFA number on the label. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. The RFA label is also available at: http://grants.nih.gov/grants/funding/phs398/labels.pdf.

3.C. Application Processing

Applications must be received on or before the application receipt date(s) described above (Section IV.3.A.). If an application is received after that date, it will be returned to the applicant without review. Upon receipt, applications will be evaluated for completeness by the CSR and responsiveness by the NIDCR. Incomplete and non-responsive applications will not be reviewed.

The NIH will not accept any application in response to this funding opportunity that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. However, when a previously unfunded application, originally submitted as an investigator-initiated application, is to be submitted in response to a funding opportunity, it is to be prepared as a NEW application. That is, the application for the funding opportunity must not include an Introduction describing the changes and improvements made, and the text must not be marked to indicate the changes from the previous unfunded version of the application.

Although there is no immediate acknowledgement of the receipt of an application, applicants are generally notified of the review and funding assignment within eight (8) weeks.

4. Intergovernmental Review
This initiative is not subject to intergovernmental review.

5. Funding Restrictions

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm.

Pre-Award Costs are allowable. A grantee may, at its own risk and without NIH prior approval, incur obligations and expenditures to cover costs up to 90 days before the beginning date of the initial budget period of a new or competing continuation award if such costs: are necessary to conduct the project, and would be allowable under the grant, if awarded, without NIH prior approval. If specific expenditures would otherwise require prior approval, the grantee must obtain NIH approval before incurring the cost. NIH prior approval is required for any costs to be incurred more than 90 days before the beginning date of the initial budget period of a new or competing continuation award.

The incurrence of pre-award costs in anticipation of a competing or non-competing award imposes no obligation on NIH either to make the award or to increase the amount of the approved budget if an award is made for less than the amount anticipated and is inadequate to cover the pre-award costs incurred. NIH expects the grantee to be fully aware that pre-award costs result in borrowing against future support and that such borrowing must not impair the grantee's ability to accomplish the project objectives in the approved time frame or in any way adversely affect the conduct of the project. See NIH Grants Policy Statement http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part6.htm.

6. Other Submission Requirements

It is recognized that the applications in response to this RFA will be longer and more complex than those of many other NIH applications. To ensure effective review, the application should be well organized as described in Section IV.2. In particular, each of the required components identified earlier in the RFA (Section I.1. Research Objectives must be clearly addressed.

For cooperative agreements, awardees must agree to the "Cooperative Agreement Terms and Conditions of Award" in Section VI.3 Reporting. Other submission requirements are described in detail below.

Plan for Sharing Research Data

The precise content of the data-sharing plan will vary, depending on the data being collected and how the investigator is planning to share the data. Applicants who are planning to share data may wish to describe briefly the expected schedule for data sharing, the format of the final dataset, the documentation to be provided, whether or not any analytic tools also will be provided, whether or not a data-sharing agreement will be required and, if so, a brief description of such an agreement (including the criteria for deciding who can receive the data and whether or not any conditions will be placed on their use), and the mode of data sharing (e.g., under their own auspices by mailing a disk or posting data on their institutional or personal web site, through a data archive). Investigators choosing to share under their own auspices may wish to enter into a data-sharing agreement. References to data sharing may also be appropriate in other sections of the application.

All applicants are expected to include a plan for sharing research data in their application. The data sharing policy is available at http://grants.nih.gov/grants/policy/data_sharing. All investigators responding to this funding opportunity should include a description of how final research data will be shared, or explain why data sharing is not possible.

The reasonableness of the data sharing plan or the rationale for not sharing research data will be assessed by the reviewers. Reviewers will factor the proposed data sharing plan into the determination of scientific merit or the priority score.

Sharing Research Resources

NIH policy requires that grant awardee recipients make unique research resources readily available for research purposes to qualified individuals within the scientific community after publication. See the NIH Grants Policy Statement at http://grants.nih.gov/grants/policy/nihgps_2003/index.htm and at http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part7.htm#_Toc54600131. Investigators responding to this funding opportunity are expected to include a plan for sharing research resources addressing how unique research resources will be shared or explain why sharing is not possible.

The adequacy of the resources sharing will be considered by Program staff of the NIDCR when making recommendations about funding applications. The effectiveness of the resource sharing will be evaluated as part of the administrative review of each non-competing Grant Progress Report (PHS 2590, http://grants.nih.gov/grants/funding/2590/2590.htm). See Section VI.3. Reporting

Dissemination of Research Results

This initiative encourages investigators to facilitate translating effective interventions and tools into practice. As part of the NIDCR's commitment to the rapid translation of research evidence into practice, applicants should include explicit plans to disseminate research results into practice.

Guidance for Preparation of an Intellectual Property Management Plan.

Intellectual property management plans are a just-in-time requirement; it is not necessary to include the final plan approved by all parties in the grant application, but final, approved plans will be expected before the application can be awarded. NIDCR program staff will consider the adequacy of the plans in determining whether to recommend an application for award. The approved plans would become a condition of the grant award and Progress Reports must contain information on activities for the sharing of research resources and intellectual property.

In the development of any research resource sharing and intellectual property management plans, applicants should confer with their institutions' office(s) responsible for handling technology transfer related matters and/or sponsored research. If applicants or their representatives require additional guidance in preparing such plans, they are encouraged to make further inquiries to the appropriate contacts listed above for such matters.

The intellectual property management plans are expected under this RFA. Such plans should address the following components:

1. Invention Disclosure and Patent Management

The Bayh-Dole Act and subsequent amendments addressing Rights to Inventions Made by Nonprofit Organizations and Small Business Firms , as codified in 37 CFR 401, confers rights and responsibilities for inventions arising from federally funded grants. As part of the Intellectual Property (IP) Management Plan, applicants should define procedures for documenting and patenting new inventions arising from the work funded by this RFA. These should include:

• Record Keeping- To document discoveries made in the course of device development, applicants should describe institution policies for maintaining proper records.
• Invention Disclosure- The IP Management Plan should identify the institutional mechanism for reporting inventions, specifying the responsible office and forms. This plan should include provisions to establish appropriate invention disclosures prior to publication or presentation of project data, novel biomarker identification, or prototype design and Confidentiality Agreements amongst collaborators.
• Patenting - The IP management plan should include the institutional process and timetable for deciding whether to retain title on inventions, filing U.S. and foreign patent applications, and notifying NIDCR. Recipients of federal funds must disclose each new invention to the funding agency within two months after disclosure in writing to the institution. Describe institutional policies for patent searches and basis for filing provisional patents.
• Patent Reporting- Summarize the institutional mechanism for providing patent and licensing information to the appropriate government agency, including:

  • Office of Policy for Extramural Research Administration (OPERA) notification of any invention developed under funding for this project and provision of a non-exclusive, nontransferable, irrevocable, paid-up license.
  • Annual Invention Utilization Report documenting the status of licensing and development, including date of first commercial sale or use and gross royalties received. Reporting requirements can be satisfied by electronic data entry into the Interagency Edison system.
  • Final Invention Statement (form HHS 568) should be sent to NIDCR prior to grant closeout.

2. Licensing and Commercialization

The IP management plan should identify the institutional office responsible for technology licensing and outline potential strategies for licensing the prototype device for commercialization. Provisions for dissemination and licensing may include:

• Material Transfer Agreement- To encourage further research and development by not-for-profit institutions, awardees should disseminate information and reagents developed in this grant consistent with the NIH Research Tools Policy (http://www.ott.nih.gov/policy/rt_guide_final.html), such as through the Simple Letter Agreement (SLA).
• Option- A limited time option may be granted to an existing or potential partner during the period of development, leading to negotiation of a subsequent license for commercial purposes to the extent consistent with NIH policies, e.g., see http://iedison.gov/Edison/sponsored.html.
• Non-exclusive License
• Exclusive License
• Company spin-outs
• Other novel commercialization strategies

3. Inter-Institutional Agreement

If investigators in the grant application are collaborators from multiple independent institutions, the IP Management Plan should include an inter-institutional agreement for coordinating patent prosecution, licensing, and for sharing royalties amongst institutions and investigators. This agreement should specify the lead office for patenting and licensing inventions that arise from the collaboration. A uniform policy on record keeping and reporting should also be presented.

This guidance is provided to assist applicants in preparing the intellectual property management plans to encourage partnerships with industry in order to meet certain programmatic objectives and goals of particular funding announcements. Applicants are encouraged to use their own discretion to independently develop and submit their own plans for consideration.

1. Criteria

In addition to the review criteria described below the following criteria will be considered in making funding decisions:

• Scientific merit of the proposed projects as determined by peer review
• Availability of funds
• Relevance of program priorities
• Programmatic balance--The purpose of the project award is to develop a functional saliva-based diagnostic prototype that will allow early disease detection. Therefore, decisions about awards will consider the stage of technology offered by the proposed project to achieve this goal; and
• Adequacy of proposed data and research resource sharing plans (required in application), product development plan and intellectual property management plan (just-in-time requirement).

Adequacy of proposed data and research resource sharing plans and intellectual property management plan. The goals of the RFA program are to: i) support the development of functional, miniature, portable, self-contained, easy-to-use diagnostic prototype devices for simultaneous multi-analyte detection; and ii) accelerate commercialization of such systems. The NIDCR will support the research and technology needed to accelerate the development and commercialization of saliva-based diagnostic technologies that will allow early disease diagnostics and thus prevention and control of diseases progression.

Applicants selected for funding in response to this RFA are expected to include a plan addressing how they will exercise their intellectual property rights, while making such research resources available to the broader scientific community for research purposes consistent with the goals of the NIDCR. A reasonable time frame for release of materials should be specified in the data sharing plan and will be considered by NIDCR Program staff. Furthermore, transfers of research resources must be made consistent with the NIH Research Tools Policy (http://www.ott.nih.gov/policy/rt_guide_final.html) and other NIH sharing policies. In the development of any sharing and intellectual property plans, applicants should confer with their own institution's office(s) responsible for handling technology transfer related matters and/or their sponsored research office. If applicants or their representatives require additional guidance in preparing these plans, they are encouraged to make further inquiries to the appropriate contacts listed below for such matters.

NIDCR program staff, in determining whether the application shall be awarded, will consider the adequacy of the proposed plans. The plans as approved after negotiation with the applicant when necessary will be part of the terms and conditions of the award. Evaluation of progress reports (PHS 2590) will include assessment of the awardee's adherence to the proposed plans, and will be a criterion for continued funding of the award.

Applicants also are reminded that the grantee institution is required to disclose each subject invention to NIDCR within 2 months after the inventor discloses it in writing to grantee institutional personnel responsible for patent matters. The NIDCR reserves the right to monitor awardee activity in this area to ascertain if patents or patent applications are adversely affecting the goals of this RFA.

Public Domain of Data

All awards made under this RFA are subject to the Final NIH Statement on Sharing Research Data (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-032.html) and the Principles and Guidelines for Recipients of NIH Research Grants and Contracts on Obtaining and Disseminating Biomedical Research Resources (http://www.ott.nih.gov/policy/rt_guide_final.html). This document also defines terms, parties, responsibilities, prescribes the order of disposition of rights, prescribes a chronology of reporting requirements, and delineates the basis for and extent of government actions to retain rights. Patent rights clauses may be found at 37 CFR Part 401.14 and are accessible from the Interagency Edison web page, http://www.iedison.gov. It is expected that research resources generated through the award will be shared by awardees according to these guidelines. The plans for the development of resources for use by the biomedical community will have the appropriate timelines and milestones. NIDCR program staff will evaluate the compliance with the sharing plan and scientific progress in the non-competing progress report (Form 2590); such compliance will be a criterion for continued funding of the award.

Awardees should address how, they will exercise their intellectual property rights, should any intellectual property be generated under the award, while making such research resources available to the broader scientific community consistent with the goals of the NIDCR.

2. Review and Selection Process

Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the NIDCR in accordance with the review criteria stated below.

As part of the initial merit review, all applications will:

• Undergo a selection process in which only those applications deemed to have the highest scientific merit, generally the top half of applications under review, will be discussed and assigned a priority score.
• Receive a written critique.
• Receive a second level of review by the National Dental and Craniofacial Research Council

The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. In the written comments, reviewers will be asked to discuss the following aspects of the application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. The scientific review group will address and consider each of these criteria in assigning the application's overall score, weighting them as appropriate for each application.

• Significance
• Approach
• Innovation
• Investigator
• Environment
• Additional Review Criteria

The application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward.

The scientific review group will address and consider each of the above criteria with respect to the proposed project in assigning the application's overall score, weighting them as appropriate for each application.

Significance: Does the project focus on a disease or general health stage where the development of saliva-based diagnostic systems will contribute to the early disease diagnosis? If the milestones of the project are achieved, how will scientific knowledge be advanced?

Approach: Are the conceptual framework, design, methods, and capabilities adequately defined and developed, well integrated, and appropriate to the aims of the overall application, within the limits inherent in an emerging, complex approach to saliva-based diagnostic technologies? Does the applicant acknowledge potential problem areas and consider alternative tactics? Is the governance plan appropriate? Are the individual expertise adequate to carry on the proposed studies? Are the proposed collaborative capabilities with other Institutions and Industry adequate to achieve the proposed goals of the project? Is there evidence of strong interaction and feedback among the collaborating academic or research centers in bioengineering or the physical sciences? Is there an adequate plan to disseminate the products that will be produced by the project?

Innovation: Does the proposed project employ novel concepts, approaches or methods? Does the proposed research challenge existing collaborative paradigms and effectively integrates across scientific and clinical disciplines? Does the project demonstrate an adequate plan to identify and attack impediments for development of saliva-based diagnostic technologies?

Investigators: Is the Principal Investigator appropriately trained and well-suited to lead and coordinate a research program of this size and complexity? Does the overall research team have sufficient expertise in all the critical aspects of this undertaking?

Environment: Does the scientific environment of the proposed project contribute to the probability of success? Is there strong evidence of institutional support and interdisciplinary interactions? Is the project that is being developed recognized as a major element within the organizational structure of the institution?

2.A. Additional Review Criteria:

In addition to the above criteria, the following items will continue to be considered in the determination of scientific merit and the priority score:

Protection of Human Subjects from Research Risk: The involvement of human subjects and protections from research risk relating to their participation in the proposed research will be assessed (see the Research Plan, Section E on Human Subjects in the PHS Form 398).

Inclusion of Women, Minorities and Children in Research: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research will be assessed. Plans for the recruitment and retention of subjects will also be evaluated (see the Research Plan, Section E on Human Subjects in the PHS Form 398).

Care and Use of Vertebrate Animals in Research: If vertebrate animals are to be used in the project, the five items described under Section F of the PHS Form 398 research grant application instructions will be assessed.

Biohazards: If materials or procedures are proposed that are potentially hazardous to research personnel and/or the environment, determine if the proposed protection is adequate.

2.B. Additional Review Considerations

Budget: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. The priority score should not be affected by the evaluation of the budget.

2.C. Sharing Research Data

Data Sharing Plan: The reasonableness of the data sharing plan or the rationale for not sharing research data will be assessed by the reviewers. However, reviewers will not factor the proposed data sharing plan into the determination of scientific merit or the priority score. The presence of a data sharing plan will be part of the terms and conditions of the award. The funding organization will be responsible for monitoring the data sharing policy.

2.D. Sharing Research Resources

NIH policy requires that grant awardee recipients make unique research resources readily available for research purposes to qualified individuals within the scientific community after publication (See the NIH Grants Policy Statement http://grants.nih.gov/grants/policy/nihgps/part_ii_5.htm#availofrr and http://www.ott.nih.gov/policy/rt_guide_final.html). Investigators responding to this funding opportunity should include a sharing research resources plan addressing how unique research resources will be shared or explain why sharing is not possible.

The adequacy of the both the data and resources sharing plans will be considered by Program staff of the funding organization when making recommendations about funding applications. Program staff may negotiate modifications of the data and resource sharing plans with the awardee before recommending funding of an application. The final version of the data and resource sharing plans negotiated by both will become a condition of the award of the grant. The effectiveness of the resource sharing will be evaluated as part of the administrative review of each non-competing Grant Progress Report. (PHS 2590). See Section VI.3. Reporting.

3. Anticipated Announcement and Award Dates
Not applicable

1. Award Notices

After the peer review of the application is completed, the Principal Investigator will also receive a written critique called a Summary Statement.

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant. For details, applicants may refer to the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General (http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_part4.htm).

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization. The NoA signed by the grants management officer is the authorizing document. Once all administrative and programmatic issues have been resolved, the NoA will be generated via email notification from the awarding component to the grantee business official (designated in item 14 on the Application Face Page). If a grantee is not email enabled, a hard copy of the NoA will be mailed to the business official.

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. See Also Section IV.5. Funding Restrictions.

2. Administrative and National Policy Requirements

All NIH Grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the notice of grant award. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General at http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part4.htm and Part II Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities at http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_part9.htm.

The following Terms and Conditions will be incorporated into the award statement and will be provided to the Principal Investigator, as well as to the appropriate institutional official, at the time of award.

2.A. Cooperative Agreement Terms and Conditions of Award

The following special terms of award are in addition to, and not in lieu of, otherwise applicable OMB administrative guidelines, DHHS grant administration regulations at 45 CFR Parts 74 and 92 (Part 92 is applicable when State and local Governments are eligible to apply), and other DHHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program will be the cooperative agreement (NIH U01), an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the awardees is anticipated during the performance of the activities. Under the cooperative agreement, the NIH 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 reside with the awardees for the project as a whole, although specific tasks and activities may be shared among the awardees and the NIH as defined below.

2.A.1. Principal Investigator Rights and Responsibilities

The PI will coordinate project activities scientifically and administratively at the awardee institution, including research design and protocol development, data collection, quality control, interim data and safety monitoring, final data analysis and interpretation, and preparation of publications.

• Determine experimental approaches, design protocols, set project milestones, and conduct experiments
• Propose protocol modifications as required
• Analyze and interpret research data
• Provide goals for assay optimization, screening throughput, quality, and cost to the NIDCR Program Director as requested, usually at the outset of the award and in annual progress reports, but also at other times if requested
• Release data according to the approved plans for timely sharing of research resources and data generated through the award, and publish results, as agreed upon by the Steering Committee
• Establish an Internal Advisory Committee to provide scientific and administrative oversight. The Internal Advisory Committee will be composed of the lead institute personnel, external scientific advisors and other technical or research personnel. The committee is expected to meet at least twice a year. Minutes of these meetings will be made available to NIDCR staff upon request
• Serve on the Steering Committee or appoint an appropriate designee to do so
• Provide information to the NIDCR Program Director and Project Scientist concerning progress by submitting periodic progress reports in a standard format, as agreed upon by the Steering Committee and Scientific Advisory Panel
• Accept and implement all scientific, practical, and policy decisions, common guidelines and procedures approved by the Steering Committee and Scientific Advisory Panel
•  Share facilities, research resources, tools, and data of interest to those facilities with other awardees, as directed by the Steering and Advisory Committees; • Share standardized information on new developments and/or methods for solving obstacles with the investigators funded through this initiative and with the NIDCR staff
• Prepare for annual administrative site visits by NIDCR staff
• Upon completion of the project put all study design materials and procedure manuals into the public domain and/or make them available to other investigators, according to the approved plan for making data and materials available to the scientific community and the NIDCR, for the conduct of research at no charge other than the costs of reproduction and distribution.
• The PI will be responsible for collaborations between his/her project and NIDCR Proteomics and Sjögren '’s syndrome supported initiatives as appropriate.

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 NIH policies.

2.A.2. NIH Responsibilities

• Assist in avoiding duplication of effort across awardee projects
• Help coordinate collaborative research efforts that involve multiple awardees
• Review and comment on critical stages in the research program before subsequent stages are implemented
• Assist in the interaction between the awardee and investigators at other institutions
• Be a voting member of the Steering Committee and its subcommittees
• Help the Steering Committee develop and draft operating policies and policies addressing recurring situations that require coordinated action
• Review the scientific progress of the individual awards for compliance with operating policies developed by the Steering Committee, and may recommend to the NIDCR to withhold support, suspend, or terminate an award for lack of scientific progress or failure to adhere to policies established by the Steering Committee.
• May consult with other NIDCR and NIH staff as well as non-NIH experts in the field in order to carry out these responsibilities.

In addition, the NIDCR will designate a Program Director and a Grants Management Specialist to provide administrative oversight of the cooperative agreement.

The NIDCR Program Director will:

• be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice as the NIH program official.
• Carry out continuous review of all activities to ensure objectives are being met
• Have the option to recommend, with the advice of the Steering Committee and Scientific Advisory Panel, the withholding, reduction or termination of support for any awardee that substantially fails to achieve its goals according to the milestones agreed to at the time of the award, fails to maintain state-of-the-art capabilities, or fails to comply with the Terms and Conditions of the award
• Retain the option to recommend additional research endeavors within the constraints of the approved research and negotiated budget and the scope of RFA-DE-06-003.
• The NIDCR Program Director may also serve as a NIDCR Project Scientist.

2.A.3. Collaborative Responsibilities

Steering Committee The NIDCR Program Scientist and PIs of the projects funded under this RFA will be responsible for forming a Steering Committee as defined below. The Steering Committee will act as the main governing board that will review the progress of the research activities, develop collaborative protocols, identify technological impediments to the progress, select strategies to surmount them, and identify opportunities for sharing techniques and tools developed within each individual project. The Steering Committee will:

• Advise NIDCR Program Staff of scientific developments and opportunities that may enhance the goals of the program.
• Help to develop uniform procedures and policies, for the governance of the awards under RFA-DE-06-003.
• Serve as a venue for coordination on improving the state of the art, for example by reporting progress, disseminating best practices and collectively evaluating new procedures, resources, and technologies.

The Steering committee will be composed of the PI from each project funded through RFA-DE-06-003, and the NIDCR Program Scientist. The PI from each project will have one vote and the NIDCR Program Scientist will have one vote. The Steering Committee may, as it deems necessary, invite additional, non-voting scientific advisors to meetings at which research priorities and opportunities are discussed.

There will be two meetings of the Steering Committee in the first year and one meeting per year in the following years. The first meeting of the PIs funded under this RFA will be a Planning Meeting in the Bethesda, MD area soon after awards are issued. At the planning Meeting the Steering Committee will be formed and select a chairperson who is not the NIDCR Program Scientist. At the first Steering Committee meeting the members may: (a) draft a charter to detail policies and procedures and develop a process for monitoring compliance with the policies and procedures and for recommending that the NIDCR Program Director act on evidence of non-compliance with Steering Committee policies; (b) agree upon the terms of the charter; and (c) discuss the approaches that were proposed in the project applications and any relevant new information, and set initial priorities for the projects to be pursued.

Scientific Advisory Panel

The Scientific Advisory Panel (SAP) will be responsible for reviewing and evaluating the progress of the awardees toward meeting their individual and collective goals. The SAP will provide recommendations to the Director, NIDCR, about continued support of the individual projects and the group of projects awarded under RFA-DE-06-003. The Advisory Panel will be composed of four senior scientists with relevant expertise who are not PIs of a cooperative agreement involved in the saliva-based diagnostic technologies. The membership of the Scientific Advisory Panel may be enlarged permanently, or on an ad hoc basis, as needed. The Scientific Advisory Panel will meet at least once a year. During part of this meeting, there will be a joint meeting with the Steering Committee to allow the Scientific Advisory Panel members to interact directly with the awardees. Annually, the Scientific Advisory Panel will make recommendations regarding progress of the individual and collective group of projects and present advice about changes, if any, to the Director, NIDCR.

2.A.4. Arbitration Process

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to arbitration. An Arbitration Panel composed of three members will be convened. It will have three members: a designee of the Steering Committee chosen without NIH staff voting, one NIH 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 arbitration procedure in no way affects the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulations 42 CFR Part 50, Subpart D and HHS regulations 45 CFR Part 16.

3. Reporting

Awardees will be required to submit the PHS Non-Competing Grant Progress Report, Form 2590 annually (http://grants.nih.gov/grants/funding/2590/2590.htm) and financial statements as required in the NIH Grants Policy Statement. The annual progress report for the U01 award will use the standard 2590 form as well as supplementary information that will be more extensive. Additional information in the progress report will include both the progress made in the project as well as the relationship between the awardee and collaborators. Details of the progress report are spelled out in the notice of grant award and in the Terms and Conditions section of this RFA.

We encourage your inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into three areas: scientific/research, peer review, and financial or grants management issues:

1. Scientific/Research Contacts:

Eleni Kousvelari, DDS, D.Sc.
Acting Director,
Center for Biotechnology and Innovation
National Institute of Dental and Craniofacial Research
Natcher Building, Room 4N 24F
Bethesda, MD 20892-6402
Telephone: (301) 594-2427
FAX: (301) 480-8318
Email: [email protected]

2. Peer Review Contacts:

H. George Hausch, Ph.D.
Division of Extramural Activities
National Institute of Dental and Craniofacial Research
Building 45, Room 4AN-44F
Bethesda, MD 20892-6402
Telephone: (301) 594-2904
Fax: (301) 480-8303
Email: [email protected]

3. Financial or Grants Management Contacts:

Mary Daley
Chief Grants Management Officer
National Institute of Dental and Craniofacial Research
Building 45, Room 4AN-44B
Bethesda, MD 20892-6402
Phone: (301) 594-4808
Fax: (301) 480-3562
Email: [email protected]

Required Federal Citations

Use of Animals in Research:
Recipients of PHS support for activities involving live, vertebrate animals must comply with PHS Policy on Humane Care and Use of Laboratory Animals (http://grants.nih.gov/grants/olaw/references/PHSPolicyLabAnimals.pdf) as mandated by the Health Research Extension Act of 1985 (http://grants.nih.gov/grants/olaw/references/hrea1985.htm), and the USDA Animal Welfare Regulations (http://www.nal.usda.gov/awic/legislat/usdaleg1.htm) as applicable.

Human Subjects Protection:
Federal regulations (45CFR46) require that applications and proposals involving human subjects must be evaluated with reference to the risks to the subjects, the adequacy of protection against these risks, the potential benefits of the research to the subjects and others, and the importance of the knowledge gained or to be gained (http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm).

Data and Safety Monitoring Plan:
Data and safety monitoring is required for all types of clinical trials, including physiologic toxicity and dose-finding studies (phase I); efficacy studies (Phase II); efficacy, effectiveness and comparative trials (Phase III). Monitoring should be commensurate with risk. The establishment of data and safety monitoring boards (DSMBs) is required for multi-site clinical trials involving interventions that entail potential risks to the participants (NIH Policy for Data and Safety Monitoring, NIH Guide for Grants and Contracts, http://grants.nih.gov/grants/guide/notice-files/not98-084.html).

Sharing Research Data:
Investigators submitting an NIH application seeking $500,000 or more in direct costs in any single year are expected to include a plan for data sharing or state why this is not possible (http://grants.nih.gov/grants/policy/data_sharing).

Investigators should seek guidance from their institutions, on issues related to institutional policies and local IRB rules, as well as local, State and Federal laws and regulations, including the Privacy Rule. Reviewers will consider the data sharing plan but will not factor the plan into the determination of the scientific merit or the priority score.

Sharing of Model Organisms:
NIH is committed to support efforts that encourage sharing of important research resources including the sharing of model organisms for biomedical research (see http://grants.nih.gov/grants/policy/model_organism/index.htm). At the same time the NIH recognizes the rights of grantees and contractors to elect and retain title to subject inventions developed with Federal funding pursuant to the Bayh Dole Act (see the NIH Grants Policy Statement http://grants.nih.gov/grants/policy/nihgps_2003/index.htm). All investigators submitting an NIH application or contract proposal, beginning with the October 1, 2004 receipt date, are expected to include in the application/proposal a description of a specific plan for sharing and distributing unique model organism research resources generated using NIH funding or state why such sharing is restricted or not possible. This will permit other researchers to benefit from the resources developed with public funding. The inclusion of a model organism sharing plan is not subject to a cost threshold in any year and is expected to be included in all applications where the development of model organisms is anticipated.

Inclusion of Women And Minorities in Clinical Research:
It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported clinical research projects unless a clear and compelling justification is provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing clinical research should read the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines is available at http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm. The amended policy incorporates: the use of an NIH definition of clinical research; updated racial and ethnic categories in compliance with the new OMB standards; clarification of language governing NIH-defined Phase III clinical trials consistent with the new PHS Form 398; and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH-defined Phase III clinical trials that: a) all applications or proposals and/or protocols must provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable; and b) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences.

Inclusion of Children as Participants in Clinical Research:
The NIH maintains a policy that children (i.e., individuals under the age of 21) must be included in all clinical research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them.

All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines" on the inclusion of children as participants in research involving human subjects (http://grants.nih.gov/grants/funding/children/children.htm).

Required Education on the Protection of Human Subject Participants:
NIH policy requires education on the protection of human subject participants for all investigators submitting NIH applications for research involving human subjects and individuals designated as key personnel. The policy is available at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

Human Embryonic Stem Cells (hESC):
Criteria for federal funding of research on hESCs can be found at http://stemcells.nih.gov/index.asp and at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html. Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (http://escr.nih.gov). It is the responsibility of the applicant to provide in the project description and elsewhere in the application as appropriate, the official NIH identifier(s) for the hESC line(s)to be used in the proposed research. Applications that do not provide this information will be returned without review.

Access to Research Data through the Freedom of Information Act:
The Office of Management and Budget (OMB) Circular A-110 has been revised to provide access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this funding opportunity in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award.

Standards for Privacy of Individually Identifiable Health Information:
The Department of Health and Human Services (DHHS) issued final modification to the "Standards for Privacy of Individually Identifiable Health Information", the "Privacy Rule", on August 14, 2002. The Privacy Rule is a federal regulation under the Health Insurance Portability and Accountability Act (HIPAA) of 1996 that governs the protection of individually identifiable health information, and is administered and enforced by the DHHS Office for Civil Rights (OCR).

Decisions about applicability and implementation of the Privacy Rule reside with the researcher and his/her institution. The OCR website (http://www.hhs.gov/ocr/) provides information on the Privacy Rule, including a complete Regulation Text and a set of decision tools on "Am I a covered entity?" Information on the impact of the HIPAA Privacy Rule on NIH processes involving the review, funding, and progress monitoring of grants, cooperative agreements, and research contracts can be found at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html.

URLs in NIH Grant Applications or Appendices:
All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site.

Healthy People 2010:
The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This PA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople.

Authority and Regulations:
This program is described in the Catalog of Federal Domestic Assistance at http://www.cfda.gov/ and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The NIH Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm.

The PHS strongly encourages all grant recipients to provide a smoke-free workplace and discourage the use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.

Loan Repayment Programs:
NIH encourages applications for educational loan repayment from qualified health professionals who have made a commitment to pursue a research career involving clinical, pediatric, contraception, infertility, and health disparities related areas. The LRP is an important component of NIH's efforts to recruit and retain the next generation of researchers by providing the means for developing a research career unfettered by the burden of student loan debt. Note that an NIH grant is not required for eligibility and concurrent career award and LRP applications are encouraged. The periods of career award and LRP award may overlap providing the LRP recipient with the required commitment of time and effort, as LRP awardees must commit at least 50% of their time (at least 20 hours per week based on a 40 hour week) for two years to the research. For further information, please see: http://www.lrp.nih.gov.

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NIH Funding Opportunities and Notices

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