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 of Diabetes and Digestive and Kidney Diseases (NIDDK), ( http://www2.niddk.nih.gov/)

Title: Hepatitis B Clinical Research Network (U01)

Announcement Type
New



Request For Applications (RFA) Number: RFA-DK-07-011

Catalog of Federal Domestic Assistance Number(s)
93.848

Key Dates
Release Date:  October 11, 2007
Letters of Intent Receipt Date: January 30, 2008
Application Receipt Date: February 27, 2008
Peer Review Date(s): June-July 2008
Council Review Date:October 2008
Earliest Anticipated Start Date: November 1, 2008
Additional Information To Be Available Date (Url Activation Date):
Expiration Date: February 28, 2008

Due Dates for E.O. 12372

Not Applicable

Additional Overview Content

Executive Summary

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

Nature of the research opportunity:  The National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health of the U.S. Department of Health and Human Services is seeking applications to establish a Hepatitis B Clinical Research Network of investigators for the purposes of promoting translational research on hepatitis B focusing upon elucidating the pathogenesis and natural history and developing means of treatment and control.  The Network would be composed of up to 10 clinical centers with expertise in diagnosis and management of hepatitis B, a Virology Center with laboratory expertise in the molecular virology of HBV, an Immunology Center with expertise in the immunologic assays of cellular, humoral and cytokine activities in relation to chronic hepatitis B, and a Data Coordinating Center with expertise in the management of multicenter studies, clinical and translational datasets.  

This RFA requests four separate types of applications: up to 10 Clinical Centers, a single Data Coordinating Center, a single Virology Center and a single Immunology Center.

Background information: Chronic hepatitis B affects approximately 350 million persons throughout the world, a significant proportion of which are at risk for developing cirrhosis, liver failure, and liver cancer.  In the United States, approximately 1.5 million Americans, or ~ 0.5% of the population have acquired the disease.  Chronic hepatitis B is uncommon in the “general” population, but affects certain groups at a much higher rate.  Thus, the prevalence of chronic hepatitis B is estimated to be 3 to 5% among men who have sex with men, injection drug users, renal dialysis patients and persons with hemophilia.  Importantly, chronic hepatitis B in the United States affects 10 to 15% of foreign born and first generation Asian Americans and is also common among recent immigrants from the Middle East, Africa and Eastern Europe.  Approximately 5% of children adopted from Asia, Russia and Eastern Europe have chronic hepatitis B. 

Therapy has recently advanced considerably with the availability of 6 different agents to treat chronic hepatitis B (interferon alpha, peginterferon, lamivudine, adefovir dipivoxil, telbuvidine and entecavir) and several more likely to be approved in the near future (tenofovir and emtricitabine).  Each of these agents is effective; however, they do not cure hepatitis B but rather lead to potent suppression of viral replication.  The majority of patients respond to treatment with improvements in liver histology and serum aminotransferase levels, but almost all patients relapse when therapy is stopped.  Importantly, there are no reliable guidelines for how these agents should be used: which agent?  in which patient?  alone or in combination?  for a defined period (1 yr, 2 yr) or indefinitely?  using what markers to measure success or failure?   Many patients are placed on an oral anti-HBV agent indefinitely, although the long-term efficacy and safety of most of these agents is unproven. 

A major shortcoming of current therapies is the development of antiviral resistance. Antiviral resistance develops in ~ 20% of persons treated with lamivudine and approximately 3% of those treated with adefovir each year.  The rate with entecavir is lower but long-term studies have not been done.  Ultimately a large proportion of patients develop resistance, at which point the antiviral agent has little or no effect. At present there is no standardization of definitions for resistance or resistance testing.  In addition, the long-term clinical significance of the development of resistance is unclear.  These are important issues that are not likely to be addressed by phase III trials demonstrating efficacy of each drug separately and with little or no follow up (success being defined as improvements in viral levels, aminotransferase levels and histology at one year while on therapy with no or incomplete information on what occurs once therapy is stopped or with long-term treatment). 

Scientific knowledge to be achieved: Several research challenges remain regarding chronic hepatitis B despite the more than 40 years of investigation.  Basic questions regarding the immunologic factors that interplay between the host and the hepatitis B virus in the progression of acute to chronic hepatitis B or in the evasion of immune clearance; the components of the host and virologic interactions that influence hepatocellular injury; the determinants of liver disease progression versus quiescence; determining which patients should be treated with which agent(s) for how long and when to stop therapy on the basis of which criteria.  These issues in addition to several others were discussed during an NIH conference on the Management of Chronic HBV: 2006 that was summarized in Hepatology 2007 Apr;45(4):1056-75.  Other research priorities pertaining to viral hepatitis B can be found in the previously published Trans-NIH Action Plan for Liver Disease Research in the chapter on viral hepatitis (http://liverplan.niddk.nih.gov).

The Network would be charged with developing a large database of patients with chronic hepatitis B and with the design of a treatment protocol that would permit the development of testable hypotheses that will address the most important clinical research challenges that should be resolved in the next 5 to 10 years as delineated in the Management of Chronic HBV: 2006 summary. 

Objective of this research program: To promote translational research on chronic hepatitis B focusing upon elucidating the pathogenesis and natural history and developing means of treatment and control, the NIDDK proposes to establish a Hepatitis B Clinical Research Network.  The Network would accelerate clinical research and progress in understanding the immunopathogenesis of chronic hepatitis B and treatment strategies with the currently available therapeutic agents.

Organization of the Hepatitis B Clinical Research Network: The Hepatitis B Clinical Research Network will be a cooperative network of up to 10 Clinical Centers (CC), one Data Coordinating Center (DCC), one Virology Center, and one Immunology Center.  Clinical Centers will be responsible for proposing protocols, participating in their overall development, conducting the research, and disseminating research findings. All individual CCs, the Virology Center, and Immunology Center will be required to participate in a cooperative and interactive manner with one another and with the DCC in all aspects of the Hepatitis B Clinical Research Network.  The Virology Center will be responsible for developing and testing hypotheses regarding the role of viral factors in the pathogenesis, course, and outcome of hepatitis B by utilization of the patients enrolled in protocols.  The Immunology Center will be responsible for developing and testing hypotheses regarding the role of the immune system in the course and outcome of chronic hepatitis B and in developing and performing state-of-the-art immunological assays on patients enrolled in protocols. The DCC will support protocol development, provide sample size calculations, statistical advice, questionnaires, and data analysis; support manuscript preparation; organize committee meetings; and provide overall study coordination and quality assurance, including coordination of the logistical activities of the Data and Safety Monitoring Board, the Steering Committee and other standing committees. Applicants for the DCC should also propose central laboratory and virologic testing of clinical specimens.

Governance: A Steering Committee will be the main governing body of the Hepatitis B Clinical Research Network. At a minimum, the Steering Committee will be composed of the principal investigators (or the corresponding principal investigator of a multiple PI application) of each Clinical Center in the Network, the principal investigator of the DCC, the Virology and Immunology Centers and the NIDDK Project Scientist.  The first meeting of the Steering Committee will be convened by the NIDDK Project Scientist in conjunction with the principal investigator of the DCC.  By the end of the first or second meeting of the Committee, the NIDDK will name a study Chairperson from one of the Clinical Centers to oversee and guide Steering Committee activities.  The Steering Committee will meet as often as three to six times during the first 12 months of the study, and two to four times per year thereafter.  All major scientific decisions will be determined by a majority vote of the Steering Committee.  Major decisions that have financial implications, such as the final protocol, or safety implications, such as the choice of study drugs will be made by the steering committee with final approval by the NIDDK.  Each Clinical Center, the Virology Center, the Immunology Center, the DCC, and the NIDDK Project Scientist will have one vote.  The Steering Committee will have primary responsibility for the general organization of Hepatitis B Clinical Research Network, finalizing common clinical protocols, facilitating the development of a standardized nomenclature, diagnostic criteria, histological definitions, and necessary components to the common database on patients.  The Steering Committee will be responsible for the conduct and monitoring of studies and reporting study results.  Topics for investigational and treatment protocols will be proposed and prioritized by the Steering Committee. 

For each investigational or therapeutic protocol, one Clinical Center will take the lead responsibility for drafting the protocol, although the Steering Committee will provide input and will be responsible for assuring development of a common protocol to be implemented by all of the CCs.  All clinical center principal investigators will be strongly encouraged to fully commit their center resources and efforts to the Network protocols.

A Pathology Committee will supplement the activities of the Steering Committee and will ensure a consistency of processing and interpretation of liver biopsies.  This committee will be composed of the hepatic pathologist from each Clinical Center as well as a lead hepatic pathologist who will be appointed by the NIDDK.  The lead hepatic pathologist will be either one of the hepatic pathologists from the Clinical Centers or the DCC, or an outside pathologist chosen specifically for this task. 

Other subcommittees of the Steering Committee will be established as necessary.  For example, a Publications Committee would be helpful to facilitate the process for authorship selection and to supervise preparation of manuscripts.

An independent Data and Safety Monitoring Board will be established by the NIDDK to review protocols and monitor patient safety and performance of each study.  As a part of its responsibilities, the Data and Safety Monitoring Board will submit recommendations to the NIDDK regarding the continuation of each study.

Each investigational or therapeutic protocol will be implemented in a minimum of two and optimally in all of the Clinical Centers, depending on the number of patients and investigational expertise needed for the study.  As specific protocols are developed, support will depend on the availability of funds and will be provided on a per patient basis.  All the Clinical Centers must be willing to pursue this funding arrangement for each new protocol conducted.

Clinical protocols must be approved by local institutional review boards and the Hepatitis B Clinical Research Network Data and Safety Monitoring Board before initiation.  The exact number of protocols supported in the program will depend on the nature and extent of the investigations proposed by the Steering Committee.  Databases may be developed; epidemiological studies and other clinical studies may be performed.  Planning may be done for large clinical trials that would be submitted as separate R01s if further funding is necessary.  The Hepatitis B Clinical Research Network investigators are also encouraged to seek out separate funding for special projects and to develop collaboration with laboratory and basic research investigators to draw upon the resources (clinical data, serum, tissue, DNA) made available by the Hepatitis B Clinical Research Network Database.  Any specific collaboration involving the resources of the Hepatitis B Clinical Research Network will require approval by the Steering Committee.

Research Scope: The objective of this RFA is to establish a Hepatitis B Clinical Research Network that will accelerate advances in the understanding and clinical management of this liver disease. 

The Network would be charged with developing a large database of all patients with hepatitis B followed at their centers with special focus on newly diagnosed cases. The Network would also be charged with developing standard nomenclature, diagnostic criteria and staging and grading systems. The Network would be responsible for designing a prospective trial of long-term therapy of hepatitis B and developing testable hypotheses regarding pathogenesis in collaboration with primarily the Virology and Immunology Center Principal Investigators or with outside research investigators.  The Network will be charged with developing a policy for ancillary studies that complement the clinical characterization of patients, which might include studies of immunologic responses, viral mutations and variants, and genetics.  The RFA would specify that Centers would be chosen in part on the basis of numbers of patients with hepatitis B being seen and followed at their site, as well as the racial/ethnic diversity of their population. The Virology Center will be charged with developing testable hypotheses from the main treatment protocol and database such as viral mechanisms of pathogenesis, viral genotype-phenotype comparisons, and HBV DNA mutation-resistance associations.  The Immunology Center will be charged with testing immunopathogenesis hypotheses generated from the main treatment protocol and database.  Serum, DNA and tissue samples would be stored in a central repository.  Once established, funding of ancillary studies would be offered through program announcements. 

A central challenge to the Hepatitis B Clinical Research Network will be to establish a randomized, controlled trial of long-term mono- versus combination therapy for chronic hepatitis B.  The Network steering committee will formulate and design this trial which will be aimed at assessing the long-term (4-5 year) efficacy of monotherapy versus combination therapy of chronic hepatitis B.  The Network will solicit industry partners to help support this trial. Possible agents to be studied would include (but not be limited to):              

1.        Entecavir vs tenofovir vs. the combination of both

2.        Tenofovir & emtricitabine vs. tenofovir alone vs emtricitabine alone

3.        Peginterferon vs entecavir vs. the combination of both

4.        Peginterferon & tenofovir vs. tenofovir alone vs. tenofovir & emtricitabine.

All projects must be completed within the 7-year duration of this research program.

These are examples only.  Applicants should not feel limited to the subjects mentioned above and are encouraged to submit other topics pertinent to the objective of the RFA.  It is not the intent of the Network to provide support for only one or two protocols that run for the entire seven years. Multiple trials or clinical and epidemiological investigations will be conducted, possibly two to four a year, some large and some small.  It is anticipated that in the initial one or two years, trials and investigations will be selected from the studies proposed by the successful Clinical Centers in their applications.

Each Clinical Center within the Network should propose a research plan that includes the structure of a large database as well as a clinical trial research protocol as a model that could be used in the Network environment.  The protocols should demonstrate knowledge of the disease and its pathogenesis.  Each protocol should require sufficient subjects to necessitate the use of a Network with multicenter participation.  Applicants should indicate knowledge of the number of patients required for each study based on sample size calculations.  One protocol must be a long-term study (four to five years) and the other protocol should be centered upon the database to address a research challenge as delineated in the Management of Chronic HBV: 2006 meeting summary or from the Trans-NIH Action Plan for Liver Disease Research.  For the overall structure and factors that are included in the common database of patients include a justification for necessary information on patients to be included.  For each of the two protocols include a description in approximately two pages of the rationale, research aims, outcome measures, and study design.  In addition, provide a description of the proposed patient populations with an estimate of the expected distribution of male and female patients, ages, and assurances of the applicant's access to the patient populations.

The Clinical Center principal investigator should indicate for each protocol how many patients meeting proposed criteria are available in his/her Clinical Center and how many will be required from the entire Network (all of the Clinical Centers).  In the discussion of outcome measures, it will be important to indicate appropriate objective measures of primary and secondary outcome.  The Clinical Center principal investigators are encouraged to explore, within the context of their proposed protocols, new technologies to monitor disease progression and response to therapy.  Funding for the relevant technology should be presently available for each protocol proposed.  It will also be important to include strategies to assure adherence to therapy as part of the protocol.

The Virology and Immunology Centers should put forth scientific proposals that are complementary and integrated with the patient database and that will be able to leverage the understanding of the pathophysiologic mechanisms from specimens collected from a proposed clinical research protocol.  As with the applications for Clinical Centers, applications for the Virology and Immunology Centers should include a research plan that would use samples and resources of the large patient database as well as prospective clinical research protocols involving a Network environment.  The Virology and Immunology Centers should propose hypotheses that could be tested with specialized virological or immunological testing on serum, tissue or peripheral blood mononuclear cells from patients in the database and clinical trials.  The research plan should discuss sample size calculations and be feasible within the 7 year time constraint.  The scientific proposal should demonstrate knowledge of the disease, its pathogenesis, and address an area of research challenge with significant clinical translational potential.  A detailed research plan should be proposed that will focus upon the viral and immunopathogenesis of chronic hepatitis B.  Proposals may address topics such as but not limited to: defining early events during HBV infection; identifying new targets in viral replication and the host for development of small molecule therapeutics; better characterization of the viral-host interactions, basis for the generation and stability of the cccDNA; and viral state of HBV in humans with different forms of chronic hepatitis B (such as the inactive carrier state, the immune tolerant phase of chronic hepatitis B, typical HBeAg-positive and HBeAg-negative chronic hepatitis B, HBV related cirrhosis), better characterize and delineate the viral and immunological changes that occur with antiviral therapy and that correlate with or determine outcome of treatment .   

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

Section II. Award Information


1. Mechanism(s) of Support

This funding opportunity will use the U01 cooperative agreement award mechanism(s).

As an applicant, you will be solely responsible for planning, directing, and executing the proposed project.

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

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".

2. Funds Available

The NIDDK intends to commit approximately three million dollars in FY 2008 to fund up to 13 new and/or competing continuation grants in response to this RFA. An applicant may request a project period of up to seven years.  During the first year of the Network, it is estimated that the award for the DCC will be approximately $600,000 in direct costs (no more than $1,020,000 in total costs).  The awards to each CC and to the virology and immunology centers will be approximately $110,000 in direct costs (no more than $165,000 in total costs).  In years 2-7 of the Network, the amount awarded to each CC per year will vary between $200,000 to $300,000 in direct costs (no more than $450,000 in total costs); to the Immunology and the Virology Centers between $250,000 to $330,000 in direct costs (no more than $500,000 in total costs); and to the DCC up to $1,000,000 in direct costs (no more than $1,500,000 total costs) per year.

Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary. Although the financial plans of the IC(s) 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:

*Foreign institutions must be located within North America (Mexico or Canada).

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.

More than one PD/PI, or multiple PDs/PIs, may be designated on the application for projects that require a “team science” approach that clearly does not fit the single-PD/PI model. Additional information on the implementation plans and policies and procedures to formally allow more than one PD/PI on individual research projects is available at http://grants.nih.gov/grants/multi_pi.

The PI of the Data Coordinating Center can be from the same institution as a Clinical Center or the Virology Center or Immunology Center but the PI of the Data Coordinating Center cannot serve as a PI of the Clinical Center or Virology Center or Immunology Center.   In contrast, a PI of a Clinical Center can serve as the PI of the Virology Center or Immunology Center.  The Virology Center and Immunology Center can be at the same institution but must have separate PI’s. 

Additionally, due to organizational logistic constraints, applications will be limited from institutions located with in the United States, Mexico and Canada.  The NIH wishes to recruit a diverse patient study population and will seek geographically diverse Clinical Centers for the Network.  Clinical Centers may bridge up to two hospitals or institutions in a defined geographic or metropolitan area through subcontracts or a multiple PI application.  Multiple PI applications spanning more than one institution must document evidence of close collaboration among the PI’s.  NOT-OD-07-017 delineates further details concerning multiple PI applications and can be found at: http://grants.nih.gov/grants/guide/notice-files/NOT-OD-07-017.html.

2. Cost Sharing or Matching

The most current Grants Policy Statement can be found at: http://grants.nih.gov/archive/grants/policy/nihgps_2003/index.htm#matching_or_cost_sharing

3. Other-Special Eligibility Criteria

Not applicable.

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 GrantsInfo, 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.

Foreign Organizations

Several special provisions apply to applications submitted by foreign organizations:

Proposed research should provide special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions in other countries that are not readily available in the United States or that augment existing U.S. resources.

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: January 30, 2008
Application Receipt Date: February 27, 2008
Peer Review Date(s): June-July 2008
Council Review Date: October 2008
Earliest Anticipated Start Date: November 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:

Francisco O. Calvo, Ph.D.
Chief, Review Branch
National Institute of Diabetes and
Digestive and Kidney Diseases
National Institutes of Health
6707 Democracy  Blvd, Room 752, MSC 5452
Bethesda, MD 20892-5452
Phone: 301-594-8897
Fax:     301-480-3505
Email: FC15Y@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 of the appendix material must be sent to:

Francisco O. Calvo, Ph.D.
Chief, Review Branch
National Institute of Diabetes and
Digestive and Kidney Diseases
National Institutes of Health
6707 Democracy  Blvd, Room 752, MSC 5452
Bethesda, MD 20892-5452
Phone: 301-594-8897
Fax:     301-480-3505
Email: FC15Y@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 National Institute of Diabetes and Digestive and Kidney Diseases. 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.

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

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

6. Other Submission Requirements

To promote development of a collaborative program, the issues discussed below need to be addressed in each application for a CC within the Network.   This material is in addition to the submission of a research plan, as described in the section entitled Research Scope.

o Qualifications and experience.  Applicants for CCs must demonstrate experience and expertise to conduct clinical studies in hepatitis B. This must include documentation of experience in the diagnosis and management of patients with hepatitis B. Inclusion of an expert hepatic pathologist as a collaborator in the CC application is favorable but not an absolute requirement.

o Study population.  CCs must discuss the number of patients with hepatitis B seen and followed at the center who might be eligible to enroll in protocols.  The applicant for a CC in the Network must include a description of the pool of potential study participants by sex, age categories, and ethnic/racial distribution, as well as recruitment source. Patient access may be developed by establishing links with other groups outside the CC's institution. If outside links are proposed, there must be a well described plan to link the individual CCs with community health care providers such as HMOs, clinics, or private practice physicians to ensure adequate numbers patients for clinical studies of therapeutic agents and management strategies.

Applicants for a CC from institutions that have a General Clinical Research Center (GCRC) funded by the NIH National Center for Research Resources are encouraged to identify the GCRC as a resource for conducting the proposed research.  If so, a letter of agreement from either the GCRC Project Coordinator or Principal Investigator should be included with the application.

o Willingness to participate in the Hepatitis B Clinical Research Network.  The principal investigator should state his/her general support of collaborative research and interaction with the NIDDK, the other CCs, Virology Center, Immunology Center, and the DCC through the Network concept.  Applicants should discuss their willingness, and that of the institutions involved, to pursue a per patient basis (capitation) of operational costs for each protocol. CCs must be able to interact with the DCC to transmit and edit data and should discuss their capability to participate in a distributed data entry system.

o Institutional resources for patient care and follow-up including personnel, space, and special laboratory facilities should be described.

Applications for a Virology Center and Immunology Center:

Principal Investigators of the Virology Center and Immunology Center should state his/her general support of collaborative research and to communicate with the DCC and the NIDDK Project Scientist on a regular basis.   All Principal Investigators must agree to implement the protocol and manual of operations that will be developed cooperatively and agree to transmit all study data to the DCC for combination and analysis.  These studies will address virological, immunological, pharmacological and host factors that might explain the nature of viral and immunopathogenesis of chronic hepatitis B.  The PIs of the Virology Center and Immunology Center will participate in the protocol design and set up the important collaborations and arrangements with the CCs that will be needed to carry out the analyses of viral and host factors that correlate with chronic hepatitis B immunologic and viral status.

Principal Investigators of the Virology Center and Immunology Center will be expected to perform hypothesis-driven laboratory research on serum and/or tissue samples from patients participating in the Network.  The PIs will direct all technical help and participate in the completion of planned experiments.  The PIs will be expected to report results regularly and provide results to the DCC for analysis with respect to the clinical and other virological and immunological features of individual patients.

The Principal Investigators of the Virology Center and Immunology Center are expected to complete the planned experiments in a timely fashion and help analyze and prepare the findings for publication. 

Applications for a DCC:

o Qualifications and experience.  The applicant for a DCC must demonstrate experience in the area of coordinating multi-center clinical trials and epidemiological studies in all phases: protocol and manual of operations development, staff training in study procedures, research instrument development, data collection and management, quality assurance, data analysis, distributed data entry, electronic communications, administrative management and coordination. Specific experience in coordinating or monitoring studies of liver disease is not required, but the applicant may wish to include a hepatologist or hepatic pathologist in the application as a key collaborator and advisor.

o Study design and management. DCC proposals should discuss the applicant's familiarity and experience with various aspects of study design that would be important in developing clinical protocols, for example: eligibility criteria; baseline and outcome measures; methods of randomization; important considerations for making sample size and power calculations; methods and frequency of data collection and entry; monitoring accuracy of data collection; quality control procedures including training and certification for multiple protocols, some of which may occur simultaneously; managing labeling and handling of serum and tissue samples (see below); and plans for statistical analysis. The DCC proposal should also describe their familiarity with model plans for managing the Data and Safety Monitoring Board. Approximately $70,000 for the whole 7 years should be budgeted for managing the Data and Safety Monitoring Board.

o The applicant for the DCC should delineate how laboratory specimens will be handled.  NIDDK anticipates that some clinical outcome measures may be centrally assessed.  Laboratories responsible to the DCC will manage specimens and laboratory studies as required by the Steering Committee.  The costs of performing specific laboratory tests will be budgeted as a part of the per patient costs of each CC. The costs of specimen shipment as well as laboratory data acquisition and management will be a part of the budget of the DCC. The DCC does not need to prepare two protocols.  Estimated shipping and handling costs for specimens should be included in the budget of DCC.

BUDGET AND RELATED ISSUES

Applicants should complete the budget information as directed in the PHS 398 application form.

Applications for CCs

Applicants for the CC should prepare budgets for seven 12-month periods.  CCs should consider the following additional issues regarding budgets.  The underlying concept of theHepatitis B Clinical Research Network is that a core effort is essential to maintain the infrastructure required to perform multiple clinical trials or clinical studies.  Based on this approach, it is estimated that the individual CCs will require a minimum level of effort to sustain the organizational aspects of the Network.  Therefore, individual CCs should submit requests that will cover a minimum of ten percent effort for the principal investigator, and a small percent effort for other key personnel (nurse, technician, clinic coordinator, secretary), and travel costs for two people to attend up to six Hepatitis B Clinical Research Network meetings during the first year and two to four times a year thereafter in Bethesda, MD.  These costs should be justified appropriately in budgets and may be distributed into subcontracts. 

In addition to the core budget, each CC will be provided funds for implementation of protocols.  The precise number of protocols conducted will be determined by the Hepatitis B Clinical Research Network Steering Committee and will depend on availability of funds.  It is anticipated that after the first year, two to four protocols may be active each year.  CCs may request PATIENT CARE costs.  This amount should be placed in the patient care category.  Allowable total costs for each CC (core costs, costs per patient to conduct the protocols, and indirect costs) will vary. 

The CCs are requested to present the following information:

The budget for each clinical protocol should be developed on a cost per patient basis and include all direct and any applicable facilities and administrative costs. Costs of laboratory tests should be part of the per patient cost of conducting a protocol.  The clinical protocol should identify the potential source(s) for any drugs or substances that are being considered for clinical protocols that are currently unavailable commercially.  Investigators should only prepare budgets for their own CC to conduct the proposed study or trial, and not for the entire Hepatitis B Clinical Research Network.  The CC should state the total number of patients required by the entire Network to complete each proposed study or trial.  The yearly budget for each CC should include the number of patients available for the proposed protocol at that CC. A budget based on the costs per patient for recruiting and maintaining the specified number of subjects at the applicant's center should be included for each protocol.

Note that ongoing annual budgets for protocols will be based on the protocols approved by the Hepatitis B Clinical Research Network Steering Committee and will be funded through a per patient basis (capitation) funding mechanism.  The individual CCs will be expected to project patient enrollment for a specific protocol during a specified time frame; continuation and level of funding for each CC will be based on actual recruitment and overall performance.

The Hepatitis B Clinical Research Network awards will be subject to administrative review annually.

Virology Center and Immunology Center Budget:

Applicants for either the Virology Center or Immunology Center should prepare budgets for seven 12-month periods that correspond with the scientific endeavors proposed and within the budgetary guidelines outlined in other sections of this RFA.  PIs for the Virology Center and Immunology Center are essential to Hepatitis B Clinical Research Network and a core level of effort commensurate to the scientific proposals and activities of the consortium will maintain the Network environment.  Travel costs should be requested in the application for two people to attend up to six Hepatitis B Clinical Research Network steering committee meetings during the first year and two to four times a year thereafter in Bethesda, MD. 

The Immunology Center and Virology Center will be subject to administrative review annually.

DCC Budget:

Applicants for the DCC should prepare budgets for seven 12-month periods that roughly correspond with the standard coordinating center responsibilities outlined in other sections of this RFA.  In the first year, DCC applicants should include all costs associated with the organization of all administrative aspects of the Hepatitis B Clinical Research Network to be developed and with the initiation of one protocol to be developed and started.  For subsequent years, applicants may assume that two to four protocols a year will be active, i.e. either in the protocol development, implementation, or analysis and writing phase. DCC should include costs for managing the Data and Safety Monitoring Board including the cost of meeting three times/year in Bethesda.

The DCC will be subject to administrative review annually. It is expected that all protocols will be performed in a manner consistent with United States Food and Drug Administration guidelines.

Plan for Sharing Research Data

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 (NIH Grants Policy Statement http://grants.nih.gov/archive/archive/grants/policy/nihgps_2003/index.htm and http://grants.nih.gov/archive/grants/policy/nihgps_2003/index.htm#_Toc54600131). Investigators responding to this funding opportunity should include a plan for sharing research resources addressing how unique research resources will be shared or explain why sharing is not possible.

The adequacy of the resources sharing 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, http://grants.nih.gov/grants/funding/2590/2590.htm). 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 RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the NIDDK 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?

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?

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 (if applicable)? For applications designating multiple PDs/PIs, does the Leadership Plan ensure that there will be sufficient coordination and communication among the PDs/PIs?  Are the administrative plans for the management of the research project appropriate, including plans for resolving conflicts? 

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?

2.A. Additional Review Criteria:

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

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

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

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

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

2.B. Additional Review Considerations

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

2.C. Sharing Research Data

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

2.D. Sharing Research Resources

NIH policy 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/part_ii_5.htm#availofrr and http://www.ott.nih.gov/policy/rt_guide_final.html). Investigators responding to this funding opportunity should include a sharing research resources plan addressing how unique research resources will be shared or explain why sharing is not possible.

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

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

3. Anticipated Announcement and Award Dates

N/A.

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 Notice of Award. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General (http://grants.nih.gov/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 primary responsibility for:

The awardee(s) will have lead responsibilities in all aspects of their protocols, 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.   Awardees will be required to accept and implement the common protocol(s) and procedures approved by the Steering Committee.  Modifications and ancillary protocols will be approved by the Steering Committee and the Data and Safety Monitoring Board.

Awardees will retain custody of and have primary rights to their data 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 DCC for a collaborative database; the submission of copies of the collaborative data sets to each principal investigator upon completion of the study; procedures for data analysis, reporting and publication; and procedures to protect and ensure the privacy of medical and genetic data (if any) and records of individuals.  The NIDDK Project Scientist, on behalf of the NIDDK, will have the same access, privileges and responsibilities regarding the collaborative data as the other members of the Steering Committee.

Designating Protocol Chairs. The Principal Investigators (for studies involving multiple coordinated awards) shall designate a single Protocol Chairperson (if the Principal Investigator does not assume this role) for each protocol within the described research plan. The Protocol Chairperson shall function as the scientific coordinator for the protocol and shall assume responsibility for obtaining approval to implement the protocol from the Steering Committee and for developing and monitoring the protocol. Any significant modifications to approved protocols must be submitted to the Steering Committee by the Protocol Chairperson.

Implementing the core data collection method and strategy collectively decided upon by the Steering Committee. For a study involving multiple institutions, it is the responsibility of each awardee/site to ensure that data will be submitted in a timely way to the central Data Coordinating Center. Additionally, individual investigators/sites must demonstrate the ability to implement the strategy specifically designed for their individual study population.

Implementing the core data collection method and strategy collectively decided upon by the Steering Committee. For a study involving multiple institutions, it is the responsibility of each awardee/site to ensure that data will be submitted in a timely way to the central Data Coordinating Center. Additionally, individual investigators/sites must demonstrate the ability to implement the strategy specifically designed for their individual study population.

Establishing mechanisms for quality control and monitoring. Awardees are responsible for ensuring accurate and timely assessment of the progress of each study, including development of procedures to ensure that data collection and management are: (1) adequate for quality control and analysis; (2) for clinical trials, as simple as appropriate in order to encourage maximum participation of physicians and patients and to avoid unnecessary expense; and (3) sufficiently staffed across the participating institutions. For research involving multiple awards, strategies for the analyses of pooled data will be developed by the Steering Committee.

Submitting interim progress reports, when requested, to the NIDDK Program Director including as a minimum, summary data on protocol performance. For coordinated multiple awards or a multi-site single award, the Steering Committee may require additional information from individual awardees/sites. Such reports are in addition to the annual awardee noncompeting continuation progress report

Establishing procedures, where applicable, for all participating institutions in coordinated awards to comply with FDA regulations for studies involving investigational agents or devices and to comply with the requirements of 45 CFR Part 46 for the protection of human subjects, and the NIH policy requirements for the inclusion of women, minorities and children.

The Data Coordinating Center will be involved in collaborations with the NIDDK, the Clinical Centers and the Immunology and Virology Centers during all phases of the trial and will maintain the Specimen Core facility.  Thus, the awardee is expected to work cooperatively with Clinical Centers and sponsoring organizations in a multicenter trial and oversee the implementation of and adherence to a common protocol, as well as assure quality control of the data collected and storage of collected tissue specimens.  In addition to organizing and attending regular meetings, the Data Coordinating Center will be expected to maintain close communications with the NIDDK Project Scientist and the Principal Investigators of the Clinical Centers.

Awardees are encouraged to publish and to publicly release and disseminate results, data and other products of the study, concordant with the study protocol and governance and the approved plan for making data and materials available to the scientific community and the NIDDK.  However, during or within three years beyond the end date of the project period of NIDDK support, unpublished data, unpublished results, data sets not previously released, or other study materials or products are to be made available to any third party only with the approval of the Steering Committee.

Support or other involvement of industry or any other third party in any study performed by the Network -- e.g., participation by the third party; involvement of project resources or citing the name of the project or the NIDDK support; or special access to project 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 to, and concurrence by, NIDDK.

Upon completion of the project, the DCC is expected to put all study 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 NIDDK, for the conduct of research at no charge other than the costs of reproduction and distribution.

The NIDDK has established Central Biosample, Genetic, and Data Repositories for the archival and storage of data and biosamples collected in large, multi-site studies funded by NIDDK. The Data Coordinating Center (DCC) will work with the NIDDK Biosample Repository to coordinate procedures for coding, shipping, processing, receipt, and storage of study samples that are to be maintained in the Repository. In addition, the DCC will coordinate with the NIDDK Data Repository to prepare the collected data for eventual archiving and distribution. All samples and data transferred to the Repositories will be under the custodianship of the NIDDK, although the study's Steering Committee will have proprietary control of and exclusive access to the samples and data for an agreed-upon period of time. Subsequently samples and data will be available to the wider scientific community in accordance with the NIH policy on Data Sharing ( http://grants.nih.gov/grants/policy/data_sharing/ and, http://grants.nih.gov/grants/policy/data_sharing/data_sharing_guidance.htm#goals, and http://grants.nih.gov/grants/policy/data_sharing/data_sharing_faqs.htm) through a process that will include prioritized distribution based on review of the scientific merit of the proposed use. Therefore, it is expected that samples and data collected will be available to the broader scientific community, after a proprietary period, at no charge other than the cost of reproduction and distribution.

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 NIH Project Scientist will have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below.
The NIDDK will name a Project Scientist from within the Division of Digestive

Diseases and Nutrition whose function will be to assist the Steering Committee in carrying out the study.  The Project Scientist will have one vote for all key study group subcommittees.  The Project Scientist will have substantial scientific-programmatic involvement in quality control, interim data analysis, safety monitoring, and final data analysis and interpretation, preparation of publications, and coordination and performance monitoring.  The dominant role and prime responsibility for these activities resides with the awardees for the project as a whole, although specific tasks and activities in carrying out the studies will be shared among the awardees and the NIDDK Project Scientist.

The NIDDK 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, quality control, or other major breach of the protocol, (c) substantive changes in the agreed-upon protocol with which NIDDK cannot concur, (d) reaching a major study endpoint substantially before schedule with persuasive statistical significance, or (e) human subject ethical issues that may dictate a premature termination.

Other NIDDK Project Scientist responsibilities and levels of involvement in the project, as described below.

  1. For multi-institutional protocols, convening the first meeting of and subsequent participation in the Steering Committee that oversees study conduct. The NIDDK Project Scientist or designee will be a full participant and voting member of the Steering Committee and, if applicable, subcommittees.
  2. Serving as a resource with respect to other ongoing NIDDK activities that may be relevant to the protocol to facilitate compatibility and avoid unnecessary duplication of effort.
  3. Substantial involvement assisting in the design and coordination of research activities for awardees as elaborated below:

Assisting by providing advice in the management and technical performance of the investigations, coordinating clearances for investigational agents held by NIDDK. The NIDDK may reserve the right to cross file or independently file an Investigational New Drug Application form with the FDA.

For multi-institutional protocols, through participation in the Steering Committee and with the agreement of the Principal Investigator(s) of any coordinating center and data management centers, the NDDK Project Scientist or designee may coordinate activities among awardees by assisting in the design, development, and coordination of a common research or clinical protocol and statistical evaluations of data; in the preparation of questionnaires and other data recording forms; and in the publication of results.

Reviewing and approving advice regarding the establishment of mechanisms for quality control and study monitoring.

An NIDDK Program Director identified in the Notice of Grant Award will be responsible for the normal stewardship and monitoring of the award. The Program Director may also serve as the Project Scientist.

The NIDDK Program Director responsibilities include:

  1. Retaining overall programmatic responsibility for the award, and will clearly specify to the awardee the name(s) and role (s) of any additional individuals with substantial involvement in the project and the lines of reporting authority.
  2. Interacting with the principal investigator(s) on a regular basis to monitor study progress. Monitoring may include: regular communications with the principal investigator and staff, periodic site visits for discussions with awardee research teams, observation of field data collection and management techniques, quality control, fiscal review, and other relevant matters; as well as attendance at Steering Committee, data safety and monitoring board, and related meetings. The NIDDK retains, as an option, periodic external review of progress.
  3. Reviewing and approving protocols to insure they are within the scope of peer review and for safety considerations, as required by Federal regulations. The NIDDK Program Director will monitor protocol progress, and may request that a protocol study be closed to accrual for reasons including: (a) accrual rate insufficient to complete study in a timely fashion; (b) accrual goals met early; (c) poor protocol performance; (d) patient safety and regulatory concerns; (e) study results that are already conclusive; and (f) emergence of new information that diminishes the scientific importance of the study question. The NIDDK will not permit further expenditures of NIDDK funds for a study after requesting closure (except for patients already on-study).
  4. Making recommendations for continued funding based on: a) overall study progress, including sufficient patient and/or data accrual; b) cooperation in carrying out the research (e.g., attendance at Steering Committee meetings, implementation of group decisions, compliance with the terms of award and reporting requirements); and/or c) maintenance of a high quality of research, which will allow pooling of data and comparisons across multiple cooperative agreement awards for common data elements.

Additionally, an agency program official or IC program director will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice.

2.A.3. Collaborative Responsibilities

The Steering Committee, composed of each of the Principal Investigators (or the corresponding PI from a multiple PI application) of the DCC, the Virology Center, the Immunology Center, and the CCs, the NIDDK Project Scientist and others from the DCC, the clinical sites and the NIDDK as deemed necessary will be the main governing board of the studies. However, only the principal investigators (or the corresponding PI from a multiple PI application) and the NIDDK Project Scientist or designee will be voting members of the Steering Committee and all major scientific decisions will be determined by a majority vote.   This committee will have the primary responsibility for approval of the common protocols, facilitating the conduct of participant follow-up, monitoring completeness of data collection and timely transmission of data to the DCC, and reporting the study results.  It will also be responsible for establishing study policies in such areas as access to patient data, ancillary studies, publications and presentations, and performance standards.  A Chairperson will be chosen from among the Steering Committee members by the NIDDK program director from among the principal investigators (but not the NIDDK Project Scientist or Data Coordinating Center Principal Investigator).  The Chairperson is responsible for coordinating the Committee activities, for preparing meeting agendas, and for scheduling and chairing meetings. Subcommittees will be established on topics such as ancillary studies, publications and presentations, quality control, recruitment, protocol adherence, among others. 

Each Network Awardee and the DCC Awardee agree to the governance of the study through the Steering Committee.  Meetings of the Steering Committee will ordinarily be held by telephone conference calls or in the Washington DC Metropolitan Area.

An independent Data and Safety Monitoring Board will be established by the NIDDK. The Data and Safety Monitoring Board will review interim results periodically as established in the data and safety monitoring plan and report to the NIDDK program director. The NIDDK Program Director will report in writing to the Steering Committee on the recommendations of the DSMB and the NIDDK concurrence/non-concurrence of the DSMB recommendations. The principal investigators will assume responsibility for reporting of the DSMB and the NIDDK recommendations to their respective Institutional Review Boards.

The NIDDK Project Scientist (and the other cited NIDDK scientists) may work with awardees on issues coming before the Steering Committee and, as appropriate, other committees, e.g., issues of recruitment, intervention, follow-up, quality control, standards and methods, adherence to protocol, assessment of problems affecting the study and potential changes in the protocol, interim data and safety monitoring, final data analysis and interpretation, preparation of publications, and development of solutions to major problems such as insufficient participant enrollment.  Regardless of the number of NIH staff participating in technical advisory roles, the NIDDK will be limited to one vote on the Steering Committee.

Each full member will have one vote. Awardee members of the Steering Committee will be required to accept and implement policies approved by the Steering Committee.

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:

Edward Doo, M.D.
Division of Digestive Diseases and Nutrition
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Boulevard, Room 651
Bethesda, MD 20892-5450
Telephone: (301) 451-4524
Fax: (301) 480-8300
Email: ed56o@nih.gov

2. Peer Review Contacts:

Francisco O. Calvo, Ph.D.
Chief, Review Branch
National Institute of Diabetes and  Digestive and Kidney Diseases
National Institutes of Health
6707 Democracy  Boulevard, Room 752, MSC 5452
Bethesda, MD 20892-5452
Phone: 301-594-8897
Fax:     301-480-3505
Email: FC15Y@NIH.GOV

3. Financial or Grants Management Contacts:

Florence Danshes
Senior Grants Management Specialist
Grants Management Branch
National Institute of Diabetes and Digestive and Kidney Diseases

6707 Democracy Blvd, Room 734
Bethesda, MD 20892-5450
Telephone: (301) 594-8861
Fax: (301) 594-9523
Email: fd39j@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.

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

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

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

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

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 RFA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople.

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

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

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


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