Part I Overview Information


Department of Health and Human Services

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

Components of Participating Organizations
National Institute on Aging (NIA) (http://www.nia.nih.gov)
National Institute on Child Health and Human Development (NICHD) (http://www.nichd.nih.gov)
National Center for Complementary and Alternative Medicine (NCCAM)(http://nccam.nih.gov )
Office of Research on Women’s Health (ORWH) (http://orwh.od.nih.gov)

Title: New Interventions for Menopausal Symptoms (U01)

Announcement Type
New

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

Request For Applications (RFA) Number:  RFA-AG-08-004

Catalog of Federal Domestic Assistance Number(s)
93.866, 93.865, 93.213

Key Dates
Release Date:  July 18, 2007
Letters of Intent Receipt Date(s): October 26, 2007
Application Receipt Date(s): November 23, 2007
Peer Review Date(s): January/February 2008
Council Review Date(s): May 2008 
Earliest Anticipated Start Date(s): July 1, 2008
Additional Information To Be Available Date (Url Activation Date): Not applicable
Expiration Date: November 24, 2007

Due Dates for E.O. 12372

Not Applicable

Additional Overview Content

Executive Summary

Women going through the menopause transition may experience a variety of symptoms, ranging from vasomotor symptoms (hot flashes and night sweats) to sleep disturbance, mood disorders, loss of sexual desire, and vaginal dryness. As many as two-thirds of all women report vasomotor symptoms, and over 85% report at least one menopausal symptom as they transition through menopause.  For the 25% of women whose symptoms are severe, the resulting discomfort greatly diminishes their quality of life.  For many decades, menopausal hormone therapy (MHT) using estrogen (or, in a woman with a uterus, a combination of estrogen and a progestin) has been the therapy of choice for relieving menopause-related symptoms.  But recently, several large clinical trials, and in particular, the Women’s Health Initiative, have found an increased risk of serious health problems, such as blood clots, stroke, heart disease, breast cancer and cognitive impairment, in women using estrogen-progestin regimens.  Not surprisingly, women are reluctant to use MHT for menopausal symptoms and in search of alternative strategies to improve their quality of life.

The purpose of this FOA issued by the NIA, NICHD, NCCAM and ORWH is to establish a Menopausal Symptoms Clinical Research Network to facilitate clinical intervention studies targeting bothersome vasomotor symptoms and related sleep disturbance, mood disorders and vaginal dryness in a collaborative, multidisciplinary, multicenter setting.

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 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

Part II - Full Text of Announcement


Section I. Funding Opportunity Description


1. Research Objectives

The purpose of this Request for Applications (RFA) is to establish a Menopausal Symptoms Clinical Research Network that will accelerate the development and testing of promising therapies to provide new options to alleviate the most common, bothersome symptoms of the menopause transition.   The National Institute on Aging (NIA), the National Institute of Child Health and Human Development (NICHD), the National Center for Complementary and Alternative Medicine (NCCAM) and the NIH Office of Research on Women’s Health (ORWH) invite sets of linked applications for a Network comprised of a data coordinating center and 4-5 clinical field sites that would propose and test therapies targeting vasomotor symptoms (i.e., hot flashes and night sweats) in a collaborative, multidisciplinary, multicenter setting.  Proposed clinical intervention studies should focus on primary outcomes relating to vasomotor symptoms.  Where appropriate, secondary outcomes of these intervention studies should evaluate the potential effects of a given intervention (as well as those mediated by changes in VMS) on menopause-related sleep disturbance, mood disorders and vaginal dryness.  The network may test the efficacy of various hormonal and non-hormonal agents including botanicals and supplements, as well as behavioral strategies.  The network will provide the necessary infrastructure to develop, coordinate, and conduct multiple collaborative clinical protocols to facilitate application of existing therapies and emerging basic and clinical science discoveries into clinical investigations. The network will design and conduct multiple concurrent clinical intervention studies accommodating a wide scope of populations and intervention strategies.   Applicants may propose limited 1) observational and/or mechanistically-focused pilot studies to increase relevant knowledge of the pathophysiology of VMS and/or 2) secondary data analyses of existing data bases (of natural history studies of menopause) to facilitate the development of improved methodology to better assess menopausal symptoms and related outcomes.

Pertinent background:

Women going through the menopause transition may experience a variety of symptoms, ranging from vasomotor symptoms (hot flashes and night sweats) to sleep disturbance, mood disorders, loss of sexual desire, and vaginal dryness.  As many as two-thirds of all women report vasomotor symptoms, and over 85% report at least one menopausal symptom as they transition through menopause.  For the 25% of women whose symptoms are severe, the resulting discomfort greatly diminishes their quality of life. 

For many decades, menopausal hormone therapy (MHT) using estrogen (or, commonly, in a woman with a uterus, a combination of estrogen and a progestin) has been the therapy of choice for relieving menopause-related symptoms.  But recently, several large clinical trials, and in particular, the Women’s Health Initiative, have found an increased risk of serious health problems, such as blood clots, stroke, heart disease, breast cancer and cognitive impairment, in women using estrogen-progestin regimens.  Not surprisingly, women are reluctant to use MHT for menopausal symptoms and in search of alternative strategies to improve their quality of life.

To address the need to understand and/or develop better options for symptom management, the NIA along with the NIH Office of Medical Applications of Research (OMAR), the National Center for Complementary and Alternative Medicine (NCCAM), the NIH Office of Research on Women’s Health (ORWH), the National Institute of Mental Health, and other NIH institutes and centers convened an NIH State-of-the-Science (SoS) Conference on Management of Menopause-Related Symptoms March 21-23, 2005. The panel statement was published shortly thereafter [National Institutes of Health State-of-the-Science Conference Statement: Management of menopause-related symptoms. Ann Intern Med 2005;142:12( Part 1): 1003.]

As a follow-up to the NIH SoS conference, NIA staff in collaboration with NCCAM, NICHD, NIMH, NINR, NCI, ORWH and ODS, established the New Interventions for Menopausal Symptoms Action Panel.  This advisory panel was composed of prominent investigators with expertise in reproductive endocrinology, epidemiology, psychiatry, hot flash physiology, psychometrics, quality of life issues, complementary and alternative medicine, and clinical trials design and methodology.  Representatives from the FDA also participated in both meetings (July 11-12 and November 20-21, 2006) of the Action Panel. The charge to this panel of experts was to consider the intervention-related research recommendations from the 2005 NIH SoS conference and to prioritize promising new strategies aimed at reducing the burden of menopausal symptoms.

The Action Panel identified a number of potential new interventions warranting further development which were based on their review of the NIH SoS panel statement (which itself was buttressed by an evidence based report contracted by AHRQ), as well as on findings from new published observational, pilot and small scale intervention studies.  These intervention strategies included: lower dose systemic or vaginal estrogens, vaginal lubricants, compounded (also known as “bioidentical”) hormones, selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs), Gabapentin, new selective estrogen receptor modulators (SERMs), hypnotics, biobehavioral therapies (e.g., paced respiration, cognitive behavioral therapy, exercise), phytoestrogens and other botanicals and Traditional Chinese Medicine (TCM).  The panel emphasized the need to test interventions in symptomatic women who have been systematically understudied including those 1) still menstruating in the menopause transition prior to their final menstrual period (FMP), 2) with premature ovarian failure, 3) with a hysterectomy and/or bilateral oophorectomy, 4) with menopause induced by radiation, chemotherapy or chemoprevention agents (e.g., aromatase inhibitors, SERMs), 5) who are amenorrheic due to the use GnRH (gonadotropin releasing hormone) agonists (e.g. leuprolide) as well as those 6) with prolonged symptoms (lasting more than 5 years after their final menstrual period).

There was consensus amongst the members of the action panel that the development of new therapies for menopausal symptoms would be best facilitated through a clinical research network infrastructure in order to provide the necessary interdisciplinary scientific input (in reproductive endocrinology, gynecology, oncology, behavioral medicine, psychiatry, sleep, physiology, biostatistics, psychometrics, pharmacology, complementary and alternative medicine (CAM) and clinical trials methodology).  As a collaborative partnership, a network arrangement would also be most conducive to facilitating the rapid identification/development of standard definitions and terminology, new methodologies, measures and data collection instruments. A network comprised of multiple clinical field sites would also increase the ease of recruitment by providing access to a broad base of populations of interest.  It was recommended that proposed research to be conducted within the network include 1) pilot and full-scale clinical intervention studies, 2) clinical and mechanistically-focused studies to increase understanding of the natural history and pathophysiology of menopausal symptoms and 3) development and validation of improved methodology to assess menopausal symptoms and related outcomes.

Scope:

The NIA, NICHD, NCCAM and ORWH seek to establish a Menopausal Symptoms Clinical Research Network consisting of a data coordinating center (DCC) and four to five clinical centers. The primary goal of the Network is to conduct multiple collaborative clinical protocols to evaluate a variety of strategies (e.g., pharmacological, botanical, behavioral, etc.) to alleviate vasomotor symptoms (VMS) and to assess the role of these strategies and changes in the burden of VMS on menopause-related sleep disturbance, mood disorders and vaginal dryness.  Secondary objectives of the Network are to:

Types of Research and Experimental Approaches

This FOA seeks a set of linked applications for a DCC and 4-5 Sites with appropriate multidisciplinary expertise and previous collaborative success to establish a Network which would expedite the fielding of intervention studies testing some of the most promising current strategies for relief of vasomotor symptoms.  Proposed research to be conducted within the network should focus on randomized, placebo controlled, masked (to the extent possible) clinical intervention studies to alleviate VMS in racially/ethnic diverse populations and populations with menopause occurring naturally or induced by a variety of agents or circumstances.   Applicants may propose limited 1) focus group studies and observational and/or mechanistically-focused pilot studies and/or 2) secondary data analyses (of natural history of menopause studies) to obtain particularly needed information bearing on the pathophysiology of VMS and/or to inform the development of improved methodology to assess menopausal symptoms and related outcomes in diverse populations .

Proposed research should focus on primary outcomes relating to vasomotor symptoms.  Where appropriate, secondary outcomes of clinical intervention studies should evaluate the potential effects of a given intervention (as well as those mediated by changes in VMS) on menopause-related sleep disturbance, mood disorders and vaginal dryness.  The network may test the efficacy of various hormonal and non-hormonal agents including botanicals and supplements, as well as behavioral strategies.  Intervention strategies of interest include but are not limited to:

Populations of special interest for proposed studies include (but are not limited to) women with bothersome vasomotor symptoms

The lists of potential intervention strategies and populations above are examples only.  Applicants should not feel limited to the topics mentioned above and are encouraged to propose other intervention strategies and populations pertaining to the objectives of this FOA.

Each applicant for a Site (within a proposed Network) should propose a research plan that includes one randomized, placebo-controlled, masked (to the extent possible) intervention protocol as a model that could potentially be used in the Network environment.  The inclusion by a Site applicant of a behavior modification strategy as one proposed intervention (within the Network) is especially encouraged because adverse effects are rare.   The protocols should demonstrate knowledge of current issues in the management of menopause-related symptoms. Applicants must provide the relevant outcome(s), and number and type of participants required for each proposed study based on sample size calculations. The applicant must indicate for each protocol how many participants are available in the applicant's Site and how many will be required from the entire Network. In the discussion of outcome measures, it will be important to describe appropriate objective measures of primary and secondary outcomes.  Applicants are encouraged to explore, within the context of their proposed protocols and the cost limitations outlined elsewhere in this FOA, new approaches and technologies to subjectively and objectively monitor symptom outcomes and/or improved response to therapy. The relevant technology should be available for each protocol proposed. It is also important to include strategies to assure adherence to therapy as a part of a protocol.

It is not the intent of the Network to provide support for one or two large protocols that run the entire five years. It is expected that several intervention studies, with two or more arms will be conducted over the five-year project period and that studies with different protocols will run concurrently at a given clinical site.  It is anticipated that the network will initiate new common protocols in the first year. Applicants should expect to propose and participate in multiple common protocols that should be conducted in all or most network sites. Applicants must be willing to work collaboratively in the development and implementation of protocols, as needed. The topics of these protocols will be decided and prioritized cooperatively by the Network Steering Committee and implemented after review and approval by the Data and Safety Monitoring Board (DSMB). It is anticipated that in the first year, studies will be selected from those proposed by the successful network of clinical field sites (Sites) and data coordinating center (DCC) applicants. However, a decision to fund a particular Network will not commit the Network to develop and implement a clinical protocol initially proposed in an awardee’s application.  

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

Project Organization

The Menopausal Symptoms Clinical Research Network will be funded as a cooperative agreement consisting of a Data and Coordinating Center (DCC) and 4-5 Clinical field sites (Sites), and the NIH (NIA along with other co-sponsoring NIH ICs and offices). The responsibilities of each component of the Network are described below

I. NIH (NIA and participating NIH ICs and offices):

The NIA ,with participating NIH ICs and offices, will oversee the organization of the Network and thus will be substantially involved with the awardees in a partnership. The NIA Project Scientist will have significant scientific involvement with the awardees.  The NIA Program Official will have administrative duties, monitor patient recruitment and study progress, ensure disclosure of conflicts of interest, and ensure adherence to NIA policies. The plan will have an early collaboration with the Food and Drug Administration (FDA) in developing protocols. NIA will appoint the Study Chair (who may be from one of the applicant organizations or external to the Network) and all members of the data and safety monitoring board (DSMB). The NIH and Study Chair will be responsible for ensuring that there are well-documented policies, procedures, and bylaws to guide all aspects of Network activities and operations.

II. Clinical Field Sites (Sites):

Sites will propose and participate in the overall development and implementation of protocols, recruit participants, monitor participant safety, collect and transfer study data to the DCC and disseminate research findings. All individual Sites will be required to participate in a cooperative and interactive manner with one another and with the DCC in all aspects of the Network.  The Site should demonstrate both clinical science excellence and expertise in the assessment and/or management of menopausal symptoms, a strong background in menopause-related research, and a proven ability to recruit middle-aged women including participants from various racial/ethnic groups. It is expected that that individual Sites (within the proposed Network) will have access to different participant populations in order to enhance participant diversity (with respect to race/ethnicity and type of menopause) within the Network .  

The Principal Investigator (PI) at each Site will be responsible for proposing and estimating the costs of protocols, and participating in their overall development, conducting the research, assuring quality of participant management and protocol adherence, assuring the accurate and timely transmission of data collected to the DCC, and disseminating research findings.

III. Data and Coordinating Center (DCC):

The DCC will coordinate, administer, and support all Network clinical research activities. These activities include, but are not limited to, administrative support for the Network Study Chair, scientific leadership and committees, organization of investigator meetings, acquisition and distribution to the Sites of drugs or other agents for testing, providing funds for implementing the protocols and for participant accrual.  The DCC will assist in protocol development, provide statistical expertise and leadership, and prepare operational timetables. The DCC will develop a data collection system and manuals of operations, determine sampling and randomization schemes, and assist in defining primary and secondary outcomes and approaches for  protocol data analyses. The DCC will coordinate the conduct of laboratory assays with external laboratories as needed, coordinate with suppliers of drugs, and arrange for the preparation and packaging of medications. The DCC will manage and distribute all protocol funds, including funding of centralized core laboratory(ies), if such activity will be deemed necessary for conducting the proposed research.

The DCC will develop procedures for quality control and training and certification for data collection and management.  It will monitor the quality and quantity of data received from the Sites, provide relevant reports to the NIA, Study Chair, Sites, and Steering Committee (SC), and serve as a central repository for study data. The DCC is responsible for any site visits necessary for training, quality control, data management and at a minimum will visit each site at least three times in the course of the study period. The DCC will prepare protocols for submission to the DSMB, and to the FDA, or other government agencies as required, and prepare confidential data analyses and reports for the DSMB. There will be early collaboration with FDA in developing protocols. The DCC will support manuscript preparation through data analysis, statistical consultation, editorial support, and meeting coordination.  It will schedule and make arrangements for all meetings/conference calls of established committees and boards. The DCC will be subject to annual administrative review.  

III. Steering Committee (SC):

The SC will be the main governing body of the Network. Voting members of the SC include, at a minimum, the Study Chair, the PIs of the Sites and of the DCC (or their designated alternate), and the NIA Project Scientist. The Study Chair will be appointed by NIA. The Study Chair will plan network activities, oversee its functions, conduct SC meetings, and cast tie-breaking votes in that committee. The SC will develop and ensure compliance with Network policies and procedures, identify and prioritize strategies for investigation, evaluate protocols proposed by the Sites, and develop common protocols for submission to the DSMB for approval. The SC will ensure that studies are properly conducted and monitored, that data are appropriately analyzed and interpreted, and that study results are reported in the scientific literature in a timely manner. The SC may meet in-person as often as three to four times in the first 12 months of the study, and two to three times per year thereafter. All major scientific decisions will be determined by majority vote of the SC.

Subcommittees of the SC will be established as necessary, and will include, at a minimum, a Publications and Presentations Subcommittee, a Research Subcommittee, a Safety Committee and a Quality Control Subcommittee. The Publications and Presentations Subcommittee will facilitate and supervise preparation of manuscripts and their evaluation prior to submission for publication. The Research Subcommittee will recommend research ideas and develop network research protocols. The Safety Committee is responsible for ongoing safety surveillance during the trial(s) and usually meets monthly to review any emerging safety issues. The Quality Control Subcommittee will be responsible developing standards for designing, deploying and evaluating specific instruments, questionnaires, laboratory tests and other measures to be used in the Network protocols and for periodic review of quality control/quality assurance of study measures and data.  

IV. Data and Safety Monitoring Board (DSMB):

NIA will establish a DSMB in accordance with NIH policies to ensure data quality and participant safety and to provide independent advice to the NIA regarding progress and the appropriateness of continuing each study.  The DSMB members will be selected by NIA and the Board will report to the Director, NIA.   

The DSMB (with additional ad hoc scientific and/or clinical experts as needed) will also evaluate protocols proposed by the SC.  The recommendation of the DSMB will be based on the importance of the question to be addressed, scientific merit of the experimental design and approach, feasibility, appropriateness for the Network and consistency with NIA missions and policies. The DSMB will provide a written report of each proposal and a final recommendation to the NIA.  APPLICANTS SHOULD NOT NOMINATE PROSPECTIVE DSMB MEMBERS IN THEIR APPLICATIONS.

All study protocols performed by the Network must be recommended by the DSMB and approved by the NIA before initiation. Each Site is expected to participate in at least two protocols per year after the first year. The exact number and duration of protocols supported in the five-year program will depend on the nature and extent of the investigations proposed by the SC.

Section II. Award Information


1. Mechanism(s) of Support

This funding opportunity will use the National Institutes of Health (NIH) U01 award mechanism(s).

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 Requirements, "Cooperative Agreement Terms and Conditions of Award".

This FOA is a one-time solicitation.  At this time, it is not known if this FOA will be reissued. Future unsolicited, competing-continuation applications based on this project will compete with all investigator-initiated applications and will be reviewed according to the customary peer review procedures. The anticipated award date is July 1, 2008

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.

2. Funds Available

Collectively, the NIA, NICHD, NCCAM and ORWH intend to commit approximately $4.35 million total costs (direct plus indirect) in FY2008, to support the Network and up comprised of a DCC and 4-5 Sites.    The total project period for the Network is five years.

Although the financial plans of NIA 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.

Section III. Eligibility Information


1. Eligible Applicants

1.A. Eligible Institutions

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

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 support.

2. Cost Sharing or Matching

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

3. Other-Special Eligibility Criteria

An applicant for a Site may submit an application in conjunction with more than one Network under this announcement.

Section IV. Application and Submission Information


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 Grants Info, Telephone (301) 435-0714, 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 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.

Supplementary Instructions

Expectation of Cooperation: To promote development of a collaborative program among the award recipients, the issues discussed below need to be addressed in each application for a Site. This material is in addition to the submission of a research plan as described in the section entitled, “Types of Research and Experimental Approaches.”

Applicants must indicate their willingness and ability to participate in all stated aspects of the Network.

Special Requirements

The Network will be a collaborative effort that will require the data coordinating center (DCC) and all individual clinical field sites (Sites) to participate in a cooperative and interactive manner with each other, and with the NIA and participating NIH ICs and offices.  Applicants should explicitly state their willingness to: participate in Steering Committee (SC) meetings, site visits, and regular telephone conference calls; serve as both members and chairpersons on subcommittees within the Network ; cooperate with other Network awardees in the development and design of research protocols; abide by study policies, and common definitions, protocols, procedures, and quality assurance measures as chosen by majority vote of the SC.  They should agree to actively implement each protocol approved by the Data and Safety Monitoring Board (DSMB) and the NIH; to oversight of the study by a DSMB; and to cooperate with other awardees in the publication of study results. They should explicitly state their acceptance of the Cooperative Agreement Terms and Conditions of Award which are found in Section VI, Award Administration Information

Clinical Field Sites (Sites):

Clinical Trial Agreement (CTA): When a pharmaceutical or device collaborator (third party) provides a study agent/device to the Network, a CTA will be negotiated describing respective responsibilities and rights. The agreement will include, but is not limited to, Investigational New Drug/Investigational Device Exemption (IND/IDE) sponsorship, safety and data monitoring, and access to data. Third party agreements must be developed and implemented by the DCC with approval from the NIA.

Budget Requirements for Site Applications: For each year, each Site should request non-protocol budget costs only. For the purpose of the RFA, the direct costs budget for the Site may not exceed $200,000 per year.

Site applicants should consider the following additional issues regarding budgets. The Site’s effort is essential to maintain the infrastructure required to perform multiple clinical trials. While it is expected that the type and complexity of each Site may vary, it is estimated that the individual Site will require a minimum level of effort to sustain the organizational aspects of the Network. 

The first year budget at the time of application will be limited to a BASE BUDGET of $200,000 (direct costs).  Allowances for the following required personnel and travel are:

It is anticipated that 6-8 months of the first year will be devoted to protocol development and staff training and, where necessary, focus group assessments and pilot testing, with patient recruitment commencing before the end of the first year. This should be considered in the proposed budget structure. Requests must be submitted with appropriate justification and description of the training, experience and involvement in clinical research by all proposed personnel.

In addition to their Site budget, each Site will be provided funds by the DCC for protocol implementation and participant enrollment and retention. This support will be provided for each protocol on a per-participant basis. The precise number of protocols conducted over the five years will be determined by the Network SC and will depend on a number of factors, including scientific priority, availability of funds, complexity and protocol requirements, length of the protocols, and ease of enrollment. It is anticipated that after the first year, at least two protocols would be active at each Site each year. Note that ongoing annual budgets for protocols will be based on the protocols approved by the Network SC and DSMB, and the NIA.  Continuation and level of funding for each Site will be based on actual recruitment and overall performance.

Each applicant for Site within the proposed Network should describe a distinct protocol for implementation at his/her site and at least one other site (in order to insure representativeness with respect to geographic location, racial/ethnic diversity and type/cause of menopause). Each Site applicant should prepare budgets (but SHOULD NOT INCLUDE these in their Site budget request) for implementing their proposed protocol considering costs for their own and the additional Site(s) to conduct the proposed protocols.  Thus, the protocol budget (to be indicated in a separate budget table) for implementation of an Site applicant’s proposed protocol by participating Sites should include: a) the number of participants available for the proposed protocol at each participating Site; and b) the costs at each participating Site for recruitment and retention of the specified number of participants, including a separate cost per participant and the cost of the proposed therapy/intervention.  All direct costs and the associated protocol facilities and administrative costs should be included. 

It should be noted that funds will not be provided for the purchase of expensive medical equipment.  If any of the protocols proposed by Site applicants include obtaining blood or tissue samples, the applicant should delineate how such specimens will be handled, analyzed and/or stored. In the event that a central laboratory is required to analyze specimens, the Sites will be responsible for obtaining the sample(s) and the cost of obtaining them will be part of the Sites per-participant expense. The cost of shipping, analyzing, and storage, as well as training of personnel and quality control will be the responsibility of the DCC.

Applicants should clearly identify the potential source(s) for all agents, drugs, substances or devices being considered for clinical protocols and indicate those which are currently unavailable commercially. If donations from a pharmaceutical company are anticipated, applicants should provide documents that indicate the commitment or willingness of the source to contribute to the study and should also describe contingency plans and anticipated extra costs should the arrangements not develop as expected.   

Funds for implementing a protocol are not to be included in the budget requests for the operation of the Sites.  They are to be identified as proposed costs in a separate table. Therefore, the total costs on the application face page should reflect the Site’s non-protocol costs.  Distribution of protocol funds will be based on the approved protocols actually carried out by the network and may be more or less than the budget identified in the application.  Protocol funds will be distributed by the DCC once the per participant costs have been established for approved protocols.

Data and Coordinating Center (DCC): The applicant should have significant prior experience as a coordinating center in multicenter clinical intervention studies and demonstrated ability and expertise to provide quality logistical and information support to the Network.   The PI and research staff should have appropriate biostatistician, data management, and study management/coordination expertise.  The proposed DCC should have demonstrated ability to assist in designing and implementing protocols; developing the data collection system, including secure data transmission via the Internet and collecting high quality, standardized data.

Budget Requirements for DCC Applications: Applicants for the DCC should prepare budgets for five one-year periods with maximum allowable direct costs for the DCC limited to $1,000,000 per year for five years. Additionally, DCC applicants will receive a budget of $1,200,000 direct costs per year to fund protocols conducted by the Sites for the five year study period. The protocol funds will be issued by the DCC to the Sites for the costs of recruitment, participant retention, devices, agents and/or drugs used in the protocols.  The DCC will also cover costs associated with central laboratory assessments (if required). It is expected that participant care costs will be greatest in years two through five.

The DCC should request not more than $1,200,000 in direct costs per year for 5 years in the participant care category for the distribution of approved protocols. These funds will be managed by the DCC and distributed to each participating Site as a fee for service arrangement after a protocol has been approved and the NIH has released the funds for distribution.

 A 30% to 50% position should be budgeted to cover costs associated with the management and distribution of approved protocol dollars to the Sites. The budget justification for each year should include a table that apportions the Total Direct Cost request among the following categories: 1) DCC costs, 2) costs of protocol initiation (per protocol), and 3) costs of protocol support (per protocol).  DCC costs should include support for essential personnel and facilities.  Costs of protocol initiation should include the costs of preparing the manual of procedures and of developing questionnaires, forms, and database structures. Protocol support costs should include the costs of pharmaceutical handling, data entry and analysis, quality control, and manuscript preparation. The DCC budget must include support for the Study Chair over the 5 years (20% effort needed and travel expenses), and also for at least three site visits made to all the clinical field sites during the 5 year interval.

For budget purposes, DCC applicants should assume that in the first year all administrative aspects of the Network will be organized and at least one protocol will be developed and enrollment started.  For subsequent years, DCC applicants may assume that additional protocols will be initiated and at least 3 different protocols a year will be active (either in the protocol development, implementation, or analysis and writing phase). The funds released for DCC operations in each year will be based in part on the number of protocols actually carried out by the Network and may be more or less than the budget requested in the application.

DCC applicants must include costs for coordinating the DSMB, and the SC, including the cost of DSMB conference calls and meetings (DSMB in-person meetings of 7-9 members will be held twice annually in the Bethesda, Maryland/Metropolitan Washington DC area) and honoraria, and the administrative expenses of bi-weekly SC conference calls and up to four SC meetings in Bethesda, Maryland, in year one and three meetings per year thereafter.   Costs allowed for the participation of the Study Chair include salary support (up to 20% of the NIH cap), travel expenses, and administrative support.  The DCC also needs to include costs for at least three site visits of each of the Sites over the five-year study period, and a three-member site visit team for purposes of budget preparation.  Costs for financial administration to prepare protocol budgets and to distribute and monitor funds should also be addressed. 

DCC applications will describe methods to coordinate study planning and implementation. The DCC must include a budget and justification for any additional costs of this collaborative effort.

The awards will be subject to annual administrative review. It is expected that all protocols will be performed in a manner consistent with United States FDA regulations and other requirements as appropriate.

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(s): October 26, 2007
Application Receipt Date(s): November 23, 2007
Peer Review Date(s): January/February 2008
Council Review Date(s): May 2008 
Earliest Anticipated Start Date(s): July 1, 2008

3.A.1. Letter of Intent

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

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:

Sherry Sherman, Ph.D.
Geriatrics and Clinical Gerontology Program
National Institute on Aging, NIH
Gateway Building, Suite 3C-307
7201 Wisconsin Ave.
Bethesda, MD 20892-9205
(Courier/Express Mail ZIP 20814)
Phone:   301-496-6942
Fax:         301-402-1784
Email:   shermans@nia.nih.gov

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 (preferably on CD) of the appendix material must be sent to:

Mary Nekola, Ph.D., Chief
Scientific Review Office
National Institute on Aging, NIH
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/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 NIA. 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.

Information on the status of an application should be checked by the Principal Investigator in the eRA Commons at: https://commons.era.nih.gov/commons/.

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.

6. Other Submission Requirements


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 website, through a data archive or enclave). 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 must 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. However, reviewers will not factor the proposed data sharing plan into the determination of scientific merit or the priority score.

Sharing Research Resources

NIH policy expects that grant 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/archive/grants/policy/nihgps_2003/index.htm#_Toc54600131). 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 resources sharing plan and any related data sharing plans will be considered by Program staff of the funding organization 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). See Section VI.3., “Reporting.

Section V. Application Review Information


1. Criteria

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

The following will be considered in making funding decisions:

2. Review and Selection Process

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

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

The goals of NIH supported research are to advance our understanding of biological systems, to improve the control of disease, and to enhance health. In their written critiques, reviewers will be asked to comment on each of the following criteria in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered in assigning the overall score, weighting them as appropriate for each application. Note that an 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 or clinical practice be advanced? What will be the effect of these studies on the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field? How compelling is the evidence that the proposed intervention strategy will successfully reduce the burden of hot flashes?  Does the constellation of candidate therapeutic interventions proposed by the individual applicant Sites within the Network provide sufficient breadth and opportunity for finding a safe, efficacious and broadly acceptable strategy for managing VMS? for reducing the burden of  other vasomotor and menopause-related symptoms?

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

Sites

How appropriate are the design and protocol(s) of the proposed intervention strategy for each Site?  Is there adequate rationale/justification for the proposed end points and sample size(s)?  Are power calculations included? Has the applicant provided sufficient information about the available participant population (with respect to race/ethnicity and type/cause of menopause) in their geographic area and convincingly described strategies likely to be successful in recruitment and retention for the proposed intervention protocol(s).  How adequate are plans across the various Sites proposed for the Network to ensure appropriate representation by ethnic group, age and type/cause of menopause?    

Do the applicants show an understanding of how joint collaborative activities can be conducted in a Network of this type and that it will be a group decision of the Steering Committee to actually engage in any particular proposed collaborative activities.  Is the research plan of the Site applicant flexible enough to accommodate further refinement and integration with other efforts?

DCC

Is there demonstrated evidence of an ability to address the complex scientific, statistical, logistical, and technical needs and issues underlying multi-center clinical intervention studies?  What is the evidence that the investigators will be successful in addressing emerging issues relating to assessment of outcomes when deploying potentially novel treatments using pharmacological, behavioral and complementary and alternative medicine approaches?   What is the potential for effective leadership in study design and statistics, data acquisition and management, data quality control, data analysis, handling and quality control of laboratory specimens, and Network coordination? 

How will the plan for study management (the administrative, supervisory, and collaborative arrangements for achieving the goals of the program, including management and distribution of funds to the Sites for the implementation and conduct of protocols, ability to assist Sites confronting problems recruiting participants and managing data collection, etc.) and cooperation with the participating Sites and the NIA enhance the likelihood of successfully completed clinical intervention studies?  

Innovation: Is the project original and innovative? For example: Does the project challenge existing paradigms or clinical practice; address an innovative hypothesis or critical barrier to progress in the field? Does the project develop or employ novel concepts, approaches, methodologies, tools, or technologies for this area?

Investigators: Are the investigators 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? Does the investigative team bring complementary and integrated expertise to the project?  Does the aggregate expertise across the proposed Network provide the comprehensive knowledge and capability needed for appropriately conceptualizing and addressing the substantive and methodological issues underlying potential interventions for bothersome menopause-related symptoms in women of diverse race/ethnicity and type/cause of menopause? How might the various disciplinary and methodological perspectives of the applicants contribute to such a cooperative research effort?

What is the expertise, training, and experience of the investigators in planning and conducting randomized controlled clinical trials?  What is their experience in coordinating or participating in multisite collaborative intervention studies? Do the Principal Investigators (PI) have adequate administrative capabilities?  Is the time the PI and co-PI plan to devote to the program for the effective conduct of clinical interventions or coordination of the Network adequate?

What is the investigator’s level of commitment to participating in a Network program? Do the investigators state their willingness to participate in joint meetings and chair subcommittees; share methods and data resources; and embark on collaborative efforts to decide the overall research directions? What is the investigator’s stated willingness and ability to work with other Network components (Sites, the DCC and the NIA [(and participating NIH ICs and offices)]? 

Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed studies benefit from unique features of the scientific environment, or subject populations, or employ useful collaborative arrangements? Is there evidence of institutional support? Does the applicant institution have a history of, and current commitment to, collaborative research?   How adequate are the institutional assurances to provide resources and/or support related to fiscal administration, personnel management and equipment?  What kind of dedicated space will be provided?

DCC:  How adequate are the facilities, equipment, and organizational structure to effectively support the coordination of Network activities and provide assistance to Sites in developing and implementing Network protocols, and collecting and managing high-quality data? Does this environment facilitate the development of collaborations with laboratories, repositories, and other entities for the storage of specimens, the conduct of lab tests and the procurement of study drugs, investigational agents or products?

Sites:  Does the environment provide good access to potential study populations of women 1) with burdensome vasomotor symptoms, 2) with different causes of menopause (e.g, spontaneous or induced by surgery, medical agents, etc), and 3) of diverse race/ethnicity?

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 and Minorities in Research: The adequacy of plans to include subjects from both genders and all racial and ethnic groups (and subgroups), 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:  Applicants requesting more than $500,000 in direct costs in any year of the proposed research must include a data sharing plan in their application.  The reasonableness of the data sharing plan or the rationale for not sharing research data may 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 funding organization will be responsible for monitoring the data sharing policy. http://grants.nih.gov/grants/policy/data_sharing.

2.D. Sharing Research Resources

NIH policy expects that grant 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/archive/grants/policy/nihgps_2003/index.htm#_Toc54600131). 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.

Program staff will be responsible for the administrative review of the plan for sharing research resources.

The adequacy of the resources sharing plan and any related data sharing plans will be considered by Program staff of the funding organization 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), See Section VI.3., “Reporting.”

3. Anticipated Announcement and Award Dates

The anticipated award date is July 1, 2008.

Section VI. Award Administration Information


1. Award Notices

After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons.

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/archive/grants/policy/nihgps_2003/index.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 12 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 NoA. 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/archive/grants/policy/nihgps_2003/index.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/archive/grants/policy/nihgps_2003/index.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, 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 (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 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 following rights and responsibilities:  

1.       AWARDEES: The awardee will have the primary responsibility for identifying priority areas for research with input from the Steering Committee, the DSMB and NIA (with participating NIH ICs and offices) and developing and implementing protocols.   The awardee(s) will have lead responsibilities in all aspects of the study, including any modification of study design, conduct of the study, quality control, data analysis and interpretation, preparation of publications, and collaboration with other investigators, unless otherwise provided for in these terms or by action of the Steering Committee.  Principal Investigators are expected to:  participate in Steering Committee (SC) meetings, site visits, and regular telephone conference calls; serve as both members and chairpersons on subcommittees within the Network ; cooperate with other Network awardees in the design and development of research protocols; abide by common definitions, common methods for participant selection and enrollment, and common protocols, procedures, tests, and reporting forms as chosen by majority vote of the SC.  Awardees will actively implement each protocol approved by the Data and Safety Monitoring Board (DSMB) and the NIH; comply with study policies and quality assurance measures approved by the SC; agree to oversight of studies by the DSMB;  and report all adverse events in accordance with procedures and policies established by the SC, the DSMB and the NIH/NIA.

Awardees will retain custody of, and have primary rights to, their data as developed under these awards, subject to Government rights of access consistent with current HHS, PHS, and NIH policies. The collaborative protocol and governance policies will call for the continued submission of data centrally to the coordinating center for a collaborative database; procedures for data analysis, reporting and publication; procedures to protect and ensure the privacy of medical and genetic data and records of individuals and the submittal of copies of the collaborative datasets to each principal investigator upon completion of the study.  The collaborative group will participate in studies of the cost effectiveness of therapeutic interventions should the NIA choose to implement such research within the Network.  The NIA Project Scientist, on behalf of the NIA, will have the same access, privileges and responsibilities regarding the collaborative data as the other members of the Steering Committee.

2.       Clinical Field Site awardees. The Principal Investigator (PI) at each Site will have the primary responsibility of proposing protocols, estimating the costs of protocols, participating in their overall development and implementation, conducting the protocols, recruiting and enrolling subjects into approved protocols, assuring quality of participant management and protocol adherence, collecting and transmitting data to the DCC in a timely manner, analyzing the data and publishing the findings of the Menopausal Symptoms Network (MSN).  All individual Sites agree to participate in a cooperative and interactive manner with one another, with the DCC and with the NIA (and participating NIH ICs and offices) in all aspects of the Network.  Site PIs will accept awards from the DCC for the support of SC and DSMB approved research protocols based on per-participant (capitated) rates and actual numbers of participants enrolled, followed, and completing the study.  Each Site will be subject to annual administrative review.

3.       DCC awardees. The DCC will coordinate, administer, and support all Network clinical research activities. These activities include, but are not limited to, administrative support for the Network Study Chair, scientific leadership and committees; accepting, managing and distributing funds to the Sites for patient accrual; and organization of all meetings of established committees and boards.  The DCC will provide statistical leadership for developing approved study designs and procedures for data analysis, reporting and publication.  It will assist in final protocol development, prepare operational timetables and provide procedures to protect and ensure the privacy of medical and genetic data and records of participants.

The DCC will develop a data collection system, manuals of operations and data management procedures; determine sampling and randomization schemes; and assist in defining primary and secondary outcomes and analytical approaches for the protocols. The DCC will also support central registration for all study subjects as required by study protocols; develop standardized criteria for clinical endpoint verification; design and implement systems for the efficient tracking and transfer of clinical and laboratory data to the central database.  The DCC will coordinate the conduct of assays with external laboratories as needed; coordinate with suppliers of drugs, and arrange for the preparation and packaging of medications.  The DCC will manage and distribute all protocol funds, including funding a centralized core laboratory(ies), if such activity will be deemed necessary for conducting research agenda.

The DCC will monitor the quality and quantity of data received from the Sites and provide relevant monitoring reports to the Sites, the SC, the DSMB and the NIA.   It will standardize and centralize Network data, put the data sets into a common format that will facilitate their use by members of the Network and provide a central repository to preserve the data for future secondary analyses and for access by the outside community. The DCC will develop procedures for quality control/quality assurance, training and certification of data collection and management personnel at the Sites and will be responsible for any site visits necessary for these training sessions. At a minimum, DCC staff will visit each site at least three times in the course of the study period.

The DCC will prepare protocols for submission to the DSMB, and to the FDA, or other government agencies as required.  There will be early collaboration with FDA in developing protocols.  The DCC will assure compliance with all regulatory requirements in conjunction with NIH.   The DCC will develop a plan for data and safety monitoring and adverse event reporting for each implemented protocol in coordination with NIA; perform confidential interim analyses of safety and efficacy (where appropriate) and produce reports for the Data and Safety Monitoring Board, the SC and NIH.  The DSMB, with DCC support, will develop stopping rules where appropriate.  

The DCC will initiate, monitor and close out clinical sites to assure Good Clinical/Laboratory Practice; audit clinical sites and provide reports to the NIA and the Steering Committee. 

The DCC will be subject to annual administrative review.

The DCC awardee agrees to accept the participatory and cooperative nature of the Network.  The Principal Investigator of the DCC will have one vote on the Steering Committee.  All activities of the DCC must be closely coordinated with the Steering Committee.

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 HHS, PHS, and NIH policies.

2.A.2. NIH Responsibilities

An NIA Project Scientist will have substantial programmatic involvement that is above and beyond the normal stewardship role in awards.  The NIA Project Scientist will provide technical assistance and participate as one voting member of the Steering Committee. Specifically, the NIA Project Scientist will:

The NIA will appoint a Program Officer, who apart from the Project Scientist, will be responsible for normal program stewardship of the award, monitoring of patient recruitment and study progress, and ensuring disclosure of conflicts of interest, and adherence to NIA policies.  Specifically the Program Officer will:

2.A.3. Collaborative Responsibilities 
 
The management of the Menopausal Symptoms Network includes committees with the following functions:

Steering Committee

Awardee(s) agree to the governance of the study through a Steering Committee.  The Steering Committee will consist of the Site Principal Investigators (one from each Site), the Principal Investigator of the DCC, and the NIA Project Scientist. The Steering Committee will be the main governing body of the Menopausal Symptoms Network and will have primary responsibility for developing research protocols by consensus, supervising the conduct of the studies, and reporting results.  The SC will ensure that studies are properly conducted and monitored, that data are appropriately analyzed and interpreted, and that study results are reported in the scientific literature in a timely manner. The SC will develop and ensure compliance with Network policies and procedures, identify and prioritize topics for investigation, evaluate protocols proposed by the Sites, and develop consensus protocols for submission to the DSMB for approval.  Each member of the Steering Committee will have one vote.  The SC may meet in person as often as three to four times in the first 12 months of the study, and two to three times per year thereafter.  All major scientific decisions will be determined by majority vote of the SC. Subcommittees of the SC will be established as necessary, and will include, at a minimum, a Publications and Presentations Subcommittee, a Research Subcommittee, a Safety Committee and a Quality Control Subcommittee.  In-person meetings of the Steering Committee will ordinarily be held in the Bethesda MD/ metropolitan Washington DC area.

An outside chairperson, who is not participating as an investigator, may be selected by the NIA to serve on the Steering Committee; alternatively, the chairperson position may be held by one of the Principal Investigators by consensus of the Steering Committee.  The Study Chair will be responsible for ensuring that there are well-documented policies, procedures, and bylaws to guide all aspects of Network activities and operations. The Study Chair will plan network activities, oversee network functions, conduct SC meetings, and cast tie-breaking votes in that committee.

A member of the NIA Grants Management Branch and/or the NIA Program Officer advises the Steering Committee on funding matters. The Menopausal Symptoms Network will establish and implement policies and procedures that govern its operations, including publications. These policies and procedures can be amended by the Steering Committee and the NIA.  Awardees will be required to accept and implement the common protocols and procedures approved by the Steering Committee

Data and Safety Monitoring Board (DSMB)

A Data and Safety Monitoring Board (DSMB) will have responsibility for overall monitoring of the safety (including adverse events) of ongoing Network studies and will advise the NIA and the Steering Committee on their conduct.  The DSMB will develop stopping rules as necessary for each protocol.  When appropriate, the DSMB will review interim data analyses regarding the potential need to terminate studies, and make recommendations to the Director of the NIA and the Steering Committee.  In addition, the DSMB will evaluate planned Network protocols, with an emphasis on participant safety, and with additional ad hoc scientific and/or clinical experts as needed.   Members of the DSMB will be appointed by the Director, NIA who will be provided a list of nominees identified by the Steering Committee. Each member of the DSMB will have one vote. The Principal Investigator of the DCC and the NIA Project Scientist will attend open sessions of DSMB meetings as non-voting members.  Meetings of the DSMB will ordinarily be held in the Bethesda MD/ metropolitan Washington DC area.  Because the Board serves as an independent group advisory to the NIA, study investigators will not communicate with Board members regarding study issues.  All study protocols performed by the Network must be approved by the DSMB and approved by the NIA before initiation.

Additional Provisions

Support or other involvement of industry or any other third party in the study; involvement of study resources or citing the name of the study or NIH support; or special access to study results, data, findings or resources -- may be advantageous and appropriate. However, except for licensing of patents or copyrights, support or involvement of any third party will occur only following notification of and concurrence by NIA.

The NIA reserves the right to terminate or curtail the study (or an individual award) in the event of (a) failure to develop or implement a mutually agreeable collaborative protocol, (b) substantial shortfall in participant recruitment, follow-up, data reporting, or quality control, (c) major breach of the protocol or substantive changes in the agreed-upon protocol with which NIA cannot concur, (d) attainment of a major study endpoint before schedule with persuasive statistical significance, or (e) human subject ethical issues that may warrant a premature termination.

Upon completion of the project, awardees are expected to put their intervention 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 NIA, for the conduct of research at no charge other than the costs of reproduction and distribution.

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.

Section VII. Agency Contacts


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:

Sherry Sherman, Ph.D.
Geriatrics and Clinical Gerontology Program
National Institute on Aging, NIH
Gateway Building, Suite 3C-307
7201 Wisconsin Ave.
Bethesda, MD 20892-9205
(Courier/Express Mail ZIP 20814)
Phone: 301-496-6942
Fax:     301-402-1784
Email:   shermans@nia.nih.gov

Estella Parrott, M.D., M.P.H.
Program Director
Reproductive Medicine Gynecology Program
Reproductive Sciences Branch
Center for Population Research
National Institute of Child Health and Human Development, NIH
6100 Executive Boulevard, Room 8B-01, MSC 7510
Bethesda, MD 20892-7510
Tel: 301-496-6515
Fax: 301-496-0962
E-mail: ep61h@nih.gov

National Center for Complementary & Alternative Medicine

Catherine M. Stoney, Ph.D.
National Center for Complementary & Alternative Medicine
6707 Democracy Blvd., Suite 401, MSC 5475
Bethesda, MD 20892-5475 (for express mail, use 20817)
Phone: 301-402-1272
Fax: 301-480-3621
Email: stoneyc@mail.nih.gov

Office of Research on Women's Health

Lisa Begg, Dr.P.H., R.N.
Director of Research Programs
Office of Research on Women's Health
Office of the NIH Director
National Institutes of Health
6706 Democracy Blvd., Suite 400
Bethesda, MD. 20892-5484
Phone: 301-496-7853
Fax: 301-402-1798
E-mail: beggl@od.nih.gov

2. Peer Review Contacts:

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

3. Financial or Grants Management Contacts:

Linda Whipp
Grants and Contracts Management Office
National Institute on Aging
7201 Wisconsin Avenue
Suite 2N212
Bethesda, MD 20892-9205
Telephone: (301) 496-1472
Fax: (301) 402-3672
Email: WhippL@nia.nih.gov

Section VIII. Other Information


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.

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.

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/archive/archive/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.

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.

NIH Public Access Policy:
NIH-funded investigators are requested to submit to the NIH manuscript submission (NIHMS) system (http://www.nihms.nih.gov) at PubMed Central (PMC) an electronic version of the author's final manuscript upon acceptance for publication, resulting from research supported in whole or in part with direct costs from NIH. The author's final manuscript is defined as the final version accepted for journal publication, and includes all modifications from the publishing peer review process.

NIH is requesting that authors submit manuscripts resulting from 1) currently funded NIH research projects or 2) previously supported NIH research projects if they are accepted for publication on or after May 2, 2005. The NIH Public Access Policy applies to all research grant and career development award mechanisms, cooperative agreements, contracts, Institutional and Individual Ruth L. Kirschstein National Research Service Awards, as well as NIH intramural research studies. The Policy applies to peer-reviewed, original research publications that have been supported in whole or in part with direct costs from NIH, but it does not apply to book chapters, editorials, reviews, or conference proceedings. Publications resulting from non-NIH-supported research projects should not be submitted.
For more information about the Policy or the submission process please visit the NIH Public Access Policy Web site at http://publicaccess.nih.gov/ and view the Policy or other Resources and Tools including the Authors' Manual (http://publicaccess.nih.gov/publicaccess_Manual.htm).

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. For publications listed in the appendix and/or Progress report, internet addresses (URLs) must be used for publicly accessible on-line journal articles.  Unless otherwise specified in this solicitation, Internet addresses (URLs) should not be used to provide any other information necessary for 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 FOA 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.


Weekly TOC for this Announcement
NIH Funding Opportunities and Notices


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