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

Component of Participating Organization
National Institute on Aging (NIA/NIH), (http://www.nia.nih.gov)

Announcement Type
New

Update: The following update relating to this announcement has been issued:

• November 3, 2004 (NOT-AG-05-001) - NIA is requesting additional information regarding program RFA-AG-05-005.

Key Dates
Release Date: October 12, 2004
Letters Of Intent Receipt Date(s): December 10, 2004
Application Receipt Dates(s): January 11, 2005
Peer Review Date(s): March, 2005
Council Review Date(s): May, 2005
Earliest Anticipated Start Date: June, 2005
Additional Information To Be Available Date (Url Activation Date): Not Applicable
Expiration Date: January 12, 2005

Due Dates for E.O. 12372
Not Applicable

Executive Summary

• The National Institute on Aging (NIA) invites applications for planning and protocol development of a coordinated set of clinical trials of efficacy and safety of testosterone treatment in older men for specific symptomatic conditions that may be related to low testosterone levels, and of effects of testosterone treatment in middle-aged men on outcomes and risk factors possibly related to low testosterone levels.
• The NIA intends to commit up to $700,000 in total costs in FY 2005 to fund one award in response to this RFA. The award will support planning activities, biostatistical and other data analyses needed for trials design, and protocol development.
• This RFA will use the National Institute of Health (NIH) cooperative agreement (U01) award mechanism.
• 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, NIH Intramural laboratories may participate as collaborators.
• Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with his/her 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.
• Each applicant may submit one application.
• Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). The PHS 398 document is available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format.

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

Table of Contents

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
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
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
3. Merit Review Criteria
A. Additional Review Criteria
B. Additional Review Considerations
C. Sharing Research Data
D. Sharing Research Resources

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

The National Institute on Aging (NIA) invites applications for planning and protocol development for a coordinated set of clinical trials of the efficacy and safety of testosterone treatment in older men for specific symptomatic conditions that may be related to low testosterone levels, and of effects of testosterone treatment in middle-aged men on outcomes and risk factors possibly related to low testosterone levels. The award will support planning activities, biostatistical and other data analyses needed for trials design, and protocol development.

Background

Many older men have circulating levels of testosterone well below the usual range in healthy young men. Many older men also have conditions that might be related to low testosterone levels: e.g., muscle weakness, sexual dysfunction, and cognitive dysfunction. Though epidemiologic data and some small intervention studies indicate that testosterone treatment for older men with low testosterone levels might alleviate some of these conditions, there are no conclusive clinical trials data on this issue, nor are the adverse effects of this therapy in these populations completely understood.

Some data from epidemiologic studies and small intervention studies also indicate that testosterone treatment for older and middle-aged men with low testosterone levels may also have favorable effects on risk for cardiovascular disease, fractures, and other age-related conditions, but conclusive evidence from clinical trials is lacking regarding these possible preventive effects, and potential adverse effects on risk for these and other age-related outcomes.

Many clinical, methodological, ethical, and practical issues relate to the challenge of resolving the above uncertainties through clinical trials. Recently, in response to a request by the National Institute on Aging and the National Cancer Institute, the Institute of Medicine (IOM) of the National Academy of Sciences completed a study on these issues. The report of this study, Testosterone and Aging: Clinical Research Directions, is available from the Institute of Medicine (http://www.nap.edu/catalog/10852.html).

The report recommended that clinical trials be conducted in men 65 years of age and over with testosterone levels below the physiologic levels of young adult men, and with one or more symptoms that might be related to low testosterone. The report recommended that primary outcomes for such trials be clinical endpoints for conditions for which there have been suggestions of efficacy of testosterone, particularly where there are not clearly effective and safe alternative pharmacologic therapies. The report specifically identified four such conditions: weakness/frailty/disability, sexual dysfunction, cognitive dysfunction, and impaired vitality/well-being/quality of life.

The report also noted that the growing population of middle-aged men (age 45 to 65 years) using testosterone raises important public health concerns about the benefits and risks in this age group, and that relatively small clinical trials of the benefits of testosterone therapy in middle-aged men could readily be fielded as additional arms of the initial efficacy trials in older men.

The report made recommendations for addressing specific safety concerns regarding participants in such trials.

The report also recommended that such trials should be coordinated under a cooperative agreement or similar mechanism to produce a common core data set that would maximize the information obtained from different trials.

Objectives and Scope

This RFA seeks applications to plan and develop a protocol for a coordinated set of clinical trials of effects of testosterone treatment, consistent with the recommendations in the IOM report referred to above, in symptomatic older men to determine treatment efficacy for the four conditions identified in the report, and in middle-aged men having at least one of the four conditions. The plan to be developed should also include procedures for maximizing participants' safety, taking into consideration the issues discussed in the report.

As recommended in the IOM report, applicants are requested to plan the development of a common core data set. To implement the recommendation for coordination, applicants are requested to consider options for establishment and operation of a coordinating center and central laboratory, as well as other procedures or structures for coordination they consider to be useful.

To accomplish these tasks, applicants for the planning/protocol development award may request support for activities such as meetings of the investigators, conference calls, data analyses, acquisition of expert advice from consultants, preliminary recruitment of clinical sites, and related support and logistical activities.

Applicants are encouraged to include in their planning group individuals with expertise in the wide range of scientific areas pertinent to this research, including biostatistics, clinical trials design and implementation, data management, central laboratory procedures, endocrinology (particularly with regard to androgen therapy), medicine (including geriatrics), evaluation of muscle and physical performance, sexual dysfunction, cognitive dysfunction, psychology, psychiatry, functional assessment methodology, and evaluation of prostate conditions and symptoms.

NIA expects that at the end of this one year planning/protocol development project, the awardee will submit a proposal to the Institute to support the coordinated set of trials. This proposal will be peer-reviewed by a NIA scientific review group, with secondary review by the National Advisory Council on Aging. Any resulting award will be a Cooperative Agreement with appropriate terms and conditions of award.

NIA has planned for the option of allocating up to $24 million (direct plus indirect costs) over up to five years of support for the set of coordinated trials that will be planned by the awardee. The set of coordinated trials should be planned assuming that the contribution from NIA is not more than $24 million. NIA funding of the planning/protocol development project will not obligate NIA to accept an application for the set of trials, nor will NIA acceptance of such a proposal imply that NIA will necessarily fund the set of trials. In the event that NIA agrees to accept such an application to support the coordinated set of trials , the final scope and budget range of the proposed set of clinical trials that NIA will accept will be determined by the NIA.

The NIH (U01) is a cooperative agreement award mechanism. 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 and National Policy Requirements, "Cooperative Agreement Terms and Conditions of Award".

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. http://grants.nih.gov/grants/funding/phs398/phs398.html

This RFA is a one-time solicitation. The total project period for applications submitted in response to this RFA may not exceed one year.

2. Funds Available

NIA intends to commit approximately 700,000 dollars in total costs in FY 2005 to fund one new grant in response to this RFA. An applicant may request a project period of up to one year. Applications requesting a larger amount will be returned to the applicant.

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

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 governments
• Eligible agencies of the Federal government
• Domestic or foreign institutions/organizations

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

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#matching_or_cost_sharing

3. Other-Special Eligibility Criteria
An applicant may submit one application under this announcement.

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. For further assistance contact GrantsInfo, Telephone (301) 710-0267, Email: GrantsInfo@nih.gov.

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

2. Content and Form of Application Submission

Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). 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/. The D&B number should be entered on line 11 of the face page of the PHS 398 form.

See Section VI.2 Administrative Requirements for additional information.

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.

3. Submission Dates

Applications must be received on or before the application receipt date listed below.

3.A. Receipt, Review and Anticipated Start Dates

Letter of Intent Receipt Date: December 10, 2004
Application Receipt Date: January 11, 2005
Peer Review Date: March, 2005
Council Review Date: May, 2005
Earliest Anticipated Start Date: June, 2005

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:

Sergei V. Romashkan, M.D., Ph.D.
Clinical Trials Branch
Geriatrics and Clinical Gerontology Program
National Institute on Aging
7201 Wisconsin Avenue
Suite 525A
Bethesda, MD 20892-9205
(Fed Ex Packages use ZIP 20814)
Telephone: 301-435-3047
Fax: 301-480-1066
Email: romashks@nia.nih.gov

3.B. Sending an Application to the NIH

Applications must be prepared using the PHS 398 research grant application instructions and forms as described above. 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)

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

Mary Nekola, Ph.D., Chief
Scientific Review Office
National Institute on Aging
7201 Wisconsin Avenue,
Suite 2C212
Bethesda, MD 20892-9205
Telephone: (301) 496-9666
FAX: (301) 402-0066
Email: NekolaM@nia.nih.gov

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/label-bk.pdf.

3.C. Application Processing

Applications must be received on or before the application receipt date listed in the heading of this funding opportunity. If an application is received after that date, it will be returned to the applicant without review. Applications will be evaluated for completeness by CSR and for responsiveness by the NIA. Incomplete and nonresponsive 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 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 (See also Section VI.3. Award Criteria)

6. Other Submission Requirements

All of the following instructions apply to the proposal for the planning/protocol development project.

1. The proposed applicant team may include staff of one institution or a consortium of institutions.

2. Applicants should present a table of organization for the planning/protocol development grant and time line indicating the sequence and date by which steps in planning and protocol development will be accomplished.

3. Prior experience in clinical research, including, IRB submissions, DSMB participation, FDA submissions, subject recruitment, and human subject protection should be described. Applicants must give evidence of their ability to recruit and retain subjects in clinical trials. Documentation of institutional support for participating in multi-center clinical trials should be provided in the form of letters of support from the appropriate institution officials.

4. The application must reflect adequate time commitment of personnel. Time commitment for the PI should be no less than 20%.

5. In order to ensure that data analysis is done independently of data acquisition, the Coordinating Center cannot have the same Principal Investigator as any of the clinical centers. In addition, there should be no overlap in personnel between the Coordinating Center and Clinical Centers.

6. Budget Information: Applicants should request support for the PI and other personnel, as outlined above. In addition, the budget for costs such as travel to the meetings of investigators, scheduling and conducting conference calls, acquisition of expert advice from consultants, preliminary data analyses, and related support and logistical activities associated with the project should be included. Applicants should budget for face-to-face meetings of the major investigators and for costs associated with organizing these meetings.

Plan for Sharing Research Data
Not applicable.

Plan for Sharing Research Resources
Not applicable.

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

2. Review and Selection Process

• 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 Advisory Council on Aging

3. Merit Review Criteria

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.

Significance : Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field?

Approach: Are the conceptual framework, design, methods, and analyses adequately developed, well-integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics?

Reviewers will evaluate the processes, organization, staffing, and types of information or analyses that applicants propose to use in developing their plans for the trials. Examples include approaches to evaluate and select options for protocol design, organization, and conduct of the Study, and approaches to selecting essential study components (e.g., clinical centers, a Coordinating Center, etc.).

Innovation: Does the project employ novel concepts, approaches or methods? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies?

Investigators: Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers (if any)?

Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support?

3.A. Additional Review Criteria:
In addition to the above criteria, reviewers will also consider plans for the Study to address the items below:

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 also Section VIII - Other Information.

Inclusion of Minorities in Research: The adequacy of plans to include subjects from all racial and ethnic groups (and subgroups) as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. See also Section VIII-Other Information.

3.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.

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 will be provided to the applicant organization by email. The notice of award signed by the grants management officer is the authorizing document.

Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NGA (Notice of Grant Award) are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.

2. Administrative 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 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 http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_part9.htm.

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, HHS 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 HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program will be the cooperative agreement (U 01 ), 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 resides 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 Principal Investigator will have the primary responsibility for planning and protocol development for the Study within the guidelines of the RFA and for performing the scientific activity.

Awardees will retain custody of, and have primary rights to, the protocol(s) and other Study materials developed under this award, subject to Government rights of access consistent with current HHS, PHS, and NIH policies.

2.A.2. NIH Responsibilities

NIA staff assistance as NIA Collaborating Scientist will be provided by the representative of the Geriatrics and Clinical Gerontology Program, NIA. This NIA Collaborating Scientist will have substantial scientific/programmatic involvement during the conduct of this activity through technical assistance, advice and coordination above and beyond normal program stewardship for grants.

During performance of the award, the NIA Collaborating Scientist may provide appropriate assistance, advice, and guidance by: participating in the design of the activities; advising in the selection of sources or resources; and advising in management and technical performance.

Additionally, the NIA Program Official will be assigned to perform normal program stewardship responsibilities for this award and will be named in the award notice. The Government, via the NIA Program Official, will have access to data generated under this Cooperative Agreement and may periodically review the data and progress reports. The NIA Program Official may use information obtained from the data for the preparation of internal reports on the activities of the project. However, awardee will retain custody of, and have primary rights to, all data developed under this award. The NIA Program Official also may serve as an NIA Collaborating Scientist.

2.A.3. Collaborative Responsibilities

The planning/protocol development phase will be a collaborative effort that will require frequent interactions of awardees among themselves and with the NIA. Applicants must explicitly indicate their willingness to: participate in the study planning group meetings (expected to occur approximately four times during the planning/protocol development phase), and regular (bi-weekly) telephone conference calls . The NIA Collaborating Scientist will be a voting member of this planning group.

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. Award Criteria

The following will be considered in making funding decisions:

• Scientific merit of the proposed project as determined by peer review
• Availability of funds
• Relevance of program priorities

4. Reporting

Awardees will be required to submit a final PHS Non-Competing Grant Progress Report, Form 2590: http://grants.nih.gov/grants/funding/2590/2590.htm and financial statements as required in the NIH Grants Policy Statement.

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