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 Center for Complementary and Alternative Medicine (NCCAM), (http://nccam.nih.gov)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), (http://www.niddk.nih.gov)

Title: Phase I/II Trials of Silymarin for Chronic Liver Diseases

Announcement Type
New

Request For Applications (RFA) Number: RFA-AT-05-006

Catalog of Federal Domestic Assistance Number(s)
93.213, 93.848

Key Dates
Release Date: June 7, 2005
Letters of Intent Receipt Date(s): August 15, 2005
Application Receipt Dates(s): September 12, 2005
Peer Review Date(s): October/November, 2005
Council Review Date(s): February 3, 2006
Earliest Anticipated Start Date: April 1, 2006
Additional Information To Be Available Date (Url Activation Date): Not applicatble
Expiration Date: September 13, 2005

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, 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 Center for Complementary and Alternative Medicine (NCCAM), in collaboration with the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health, of the U.S Department of Health and Human Services is seeking applications to perform Phase I/II clinical trials with silymarin for chronic liver diseases. The purpose of the activities under this program is for the public purpose of supporting research in the area of chronic liver diseases and ultimately for the improvement of the national health. The purpose of the activities is not the acquisition of property or services for the direct benefit or use of the Federal Government. As a group of experts in this scientific field, the awardees will maintain the dominant role and prime responsibility for the planned activities, although specific tasks and activities in carrying out the activity will be shared among the awardees and the NCCAM and NIDDK Project Scientists. In a separate administrative action, NCCAM and NIDDK have solicited for a supplier of silymarin. Applicants of clinical trials under this RFA should assume that silymarin and matching placebo will be available. NCCAM will file an IND application with the FDA for the clinical studies resulting from this RFA.

The NCCAM and NIDDK estimate that a network of 4 Clinical Sites and a central Data Coordinating Center will be needed to enter patients and analyze results from a total of approximately 3 Phase I/II clinical trials. Each applicant for a Clinical Site will be asked to propose one Phase I/II clinical trial of silymarin in untreated chronic hepatitis C, previously treated chronic hepatitis C or nonalcoholic steatohepatitis. However, the protocols that will ultimately be implemented will be established by the Steering Committee. It is anticipated that each successful site will enroll approximately 25% of the patients in each of the final Phase I/II protocols that will be performed by the multi-site study. The Phase I/II protocols of the study will be coordinated by a Data Coordinating Center which will be responsible for the data acquisition and analysis and will participate actively in the design of the trials, the development of final protocols, manuals of operation, data collection forms, and ensuring the integrity of the data collection.

Thus, this RFA requests two separate types of applications: 4 Clinical Sites and a single Data Coordinating Center.

Applications to study basic mechanisms of silymarin action in vitro and in animal models are encouraged and will be funded via preexisting R21/R01 grant mechanisms as stated in an NCCAM Program Announcement at http://grants.nih.gov/grants/guide/pa-files/PA-02-124.html.

Background information:

Silymarin is a traditional medicine that has been used for millennia to treat liver diseases. Silymarin is presently available and regulated as a dietary supplement in the United States. “Silymarin” refers to extracts of the seeds of the milk thistle plant (Silybum marianum). Approximately 60% of the traditional extract is a mixture of 4 flavolignan isomers: silibinin (generally 50-60% of silymarin), isosilibin, silicristin, and silidianin. However, as for all dietary supplements, exact composition of the traditional product may vary with the manufacturer. The silymarin formulation chosen by NCCAM/NIDDK for the present clinical studies may differ in exact composition from the above figures.

1) Possible clinical indications for silymarin therapy:

2) Need for clinical research on silymarin for these indications:

Each of these indications (chronic hepatitis C and NASH) constitutes a major clinical problem not well addressed by conventional therapy, for which there is a potential role of silymarin. Hepatitis C is an attractive indication because of the limited response rate of conventional therapy in persons with genotype 1 infection and because of unpleasant side effects of conventional therapy. NASH is an attractive indication for treatment with silymarin because of its roots in obesity, the lack of standard therapy, and the possible role of oxidative stress in its pathogenesis. Importantly, the development of more effective and better-tolerated therapies for chronic hepatitis C and NASH were areas of research listed as priorities in the recently developed “Trans-NIH Action Plan for Liver Disease Research” (http://liverplan.niddk.nih.gov). The evaluation of silymarin as a potential therapy of NASH by Phase I and II trials was mentioned as a specific research goal in the Action Plan.

3) Silymarin has been used for these liver diseases with efficacy as summarized in review articles by Flora et al [Am J Gastroenterol 1998;93:139] and Saller et al [Drugs 2001; 61:2035]. These reviews indicate that silymarin may have clinical efficacy for each of these indications. However, the wide variety of products, doses, indications, stages of disease, and disease endpoints used in the previous literature makes a consolidated judgment on silymarin efficacy difficult. The NCCAM/NIDDK Silymarin PDP is intended to evaluate a leading silymarin formulation, suitable for regulatory filing in the United States, for one or both of these indications. It is intended that this PDP will lead to a definitive statement as to whether or not silymarin has a favorable therapeutic index for one or more of these indications. General information on silymarin and discussion of issues surrounding its evaluation for liver disease can be found in the summary of an NIDDK and NCCAM-sponsored meeting entitled “Silymarin as Therapy for Liver Disease” on the NIDDK website: http://www.niddk.nih.gov/federal/ddicc/meetings.htm.

Applicants for a Data Coordinating Center should demonstrate expertise in the following areas and provide appropriate action plans as necessary: coordination of multisite studies on liver diseases; processing samples in multisite studies; data acquisition and management; monitoring GCP studies under IND; statistical issues in clinical trials; privacy policies; and preparing study reports for supplier of Drug Product and for filing with FDA.

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 Cooperative Agreement (U01) 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 anticipated award date is April 1, 2006. The NCCAM and NIDDK expect to commit a total of approximately $300,000 to $600,000 for the first year and a total of approximately $5,000,000 to $6,000,000 over the lifetime of the RFA. This total will be used to fund up to a total of 5 awards in response to this RFA. It is anticipated that the awards for EACH of the 4 Clinical Sites will average $700,000 in total direct costs. These funds will permit study of approximately ¼ of the patients needed for each of the 3 final protocols, i.e., a total of approximately 120 patients per site. The award for the Data Coordinating Center is anticipated to be a total direct cost of about $1,000,000. These funds will permit coordination of the data for all of the 3 protocols, i.e., the data from a total of approximately 480 patients. Approximately 5-10% of the costs is expected to be allocated to the first (planning) year, about 35-40% of the costs for years 2 and 3 during which the bulk of the patient care will be done, and about 10-15% of costs for year 4.

The participating IC(s), NCCAM and NIDDK, intend to commit approximately 6,000,000 dollars in FY 06-09 to fund 4 Clinical Sites and 1 Data Coordinating Center new and/or competing continuation grants in response to this RFA. An applicant may request a project period of up to 4 years and a budget for direct costs up to 500,000 dollars 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:

1.B. Eligible Individuals

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

2. Cost Sharing or Matching

Cost sharing is not required.

The most current Grants Policy Statement can be found at: http://grants.nih.gov/grants/policy/nihgps_2003/nihgps_Part2.htm#matching_or_cost_sharing.

3. Other-Special Eligibility Criteria

An applicant may submit only one application. Applications for a Clinical Site and the Data Coordinating Center may come from a single Institution, but the Principal Investigators on the two applications must be different persons. This restriction is meant to ensure the objectivity of the Data Coordinating Center in coordinating and overseeing the studies.

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.

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

Letter of Intent Receipt Date: August 15, 2005
Application Receipt Date(s): September 12, 2005
Peer Review Date: October/November 2005
Council Review Date: February 3, 2006
Earliest Anticipated Start Date: April 1, 2006

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:

Qi-Ying Liu, M.D., M.Sci.
Program Officer
Division of Extramural Research and Training
National Center for Complementary and Alternative Medicine
National Institutes of Health
6707 Democracy Boulevard, Suite 401
Bethesda, MD 20892-5475 (for express/courier service use 20817)
Phone: (301) 402-5867
Fax: (301) 480-3621
Email: liuqiy@mail.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:

Martin Goldrosen, Ph.D.
Director, Office of Scientific Review
National Center for Complementary and Alternative Medicine
6707 Democracy Blvd., Suite 401, MSC 5475
Bethesda, MD 20892-5475 (for express/courier service use 20817)
Telephone: (301) 594-2014
FAX: (301) 480-2419
Email: goldrosm@mail.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 NCCAM . Incomplete and non-responsive applications will not be reviewed.

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

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

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

5. Funding Restrictions

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm. Although the financial plans of the NCCAM and NIDDK provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications.

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

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

6. Other Submission Requirements

Women and minorities are expected to be enrolled in these Phase I/II clinical trials and documentation of previous experience in enrolling women and minorities into multicenter clinical trials is important to include in applications.

Children are not expected to be included as subjects in these Phase I/II clinical trials of silymarin in liver disease. These trials will be the first formal studies of higher-than-customary doses of silymarin and these safety studies should first be conducted in adults. Hepatitis C is rare in children and therapies with standard regimens of peginterferon and ribavirin are just now starting. Thus, it is unlikely that there will be adequate numbers of children with chronic hepatitis C who have failed current therapies or who are ineligible to receive interferon to be enrolled in a Phase I/II trial. Nonalcoholic steatohepatitis is more common in adults than children, but has been found to be increasing in incidence in pediatric populations in the United States. At present, however, the dose of silymarin that is appropriate for patients with liver disease has not been shown and trials of silymarin in children should await the demonstration of at least some evidence of benefit in adult populations. It is expected that if this multi-site silymarin clinical study establishes evidence of safety and efficacy of silymarin in hepatitis C and/or NASH, that studies of silymarin may be extended to the pediatric population.

The final Phase I/II trial designs will be developed collaboratively by the Steering Committee for the trial. However, applicants should demonstrate that they recognize the significance of the issues involved and possesses the knowledge necessary to contribute meaningfully to the final design, including understanding of the scientific, ethical, and practical issues underlying the proposed study. In regard to applications for a Clinical Site, the principal investigator needs to offer thoughtful ideas on means to achieve the goals of the Phase I/II trials in their design and clinical components; the principal investigator needs to demonstrate the understanding of the specific issues surrounding complementary and alternative medications such as silymarin and the challenges to demonstration of efficacy and safety; the application should address problems that may arise during the study and provide thoughtful solutions to the problems. In regard to applications for a Data Coordinating Center, the application needs to address problems that may arise during the study and provide thoughtful solutions to such problems.

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.

Applicants requesting more than $500,000 in direct costs in any year of the proposed research must include a plan for sharing research data in their application. The funding organization will be responsible for monitoring the data sharing policy (http://grants.nih.gov/grants/policy/data_sharing).

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 requires that grant awardee 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/grants/policy/nihgps_2003/index.htm and http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part7.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

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 NCCAM 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?

In regard to applications for Clinical Sites, has the applicant proposed an appropriate Phase I/II trial that will provide meaningful information for or against the safety and efficacy of silymarin and that would allow a decision to be made whether a more definitive Phase III trial is appropriate? Has the Principal Investigator proposed an appropriate Phase I/II trial that will provide information on safety and the appropriate dosage of silymarin? Has the applicant provided adequate documentation for sample size calculations that are appropriate for the end-points and Phase I/II studies? Have the endpoints of therapy been well defined and are they appropriate for the disease under investigation? Has the applicant provided an adequate and practical plan to recruit, evaluate, enroll and monitor patients? Does the application provide evidence of successful experience in recruitment and retention of patients with chronic hepatitis C and nonalcoholic steatohepatitis? Does the applicant provide documentation of access to an adequate patient population from which to recruit the proposed numbers of patients over a one- to two- year period?

In regard to applications for the Data Coordinating Center, does the proposed approach in managing the data coordination and conduct of the studies have scientific and technical merit? Are the proposed plans and experience relating to data collection, management, editing, processing, analysis, and reporting adequate?

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)?

In regard to applications for a Clinical Site, does the Principal Investigator have demonstrated knowledge of clinical and epidemiological aspects of hepatitis C and nonalcoholic steatohepatitis? Does the investigator have documented expertise in management and monitoring of therapy of patients with liver disease? Is there evidence of experience in and willingness to participate appropriately in a collaborative study as described in this RFA? Do the Principal Investigator and other professional, technical and administrative staff have specific competence and previous experience in multi site collaborative clinical research and ability to work with others in formulating and conducting clinical trials?

In regard applications for a Data Coordinating Center, does the Principal Investigator have demonstrated knowledge of data management, biostatistics, clinical trial design, and ethical issues in clinical research? Does the Principal Investigator have prior experience in collecting data from multiple clinical sites, monitoring of data quality and developing and utilizing statistical methods for analysis of data? Is there evidence of experience in and willingness to participate appropriately in a collaborative study as described in this RFA? Are there adequate assurances that Data Center personnel have experience in utilizing procedures that insure the safety and confidentiality of medical records and patient privacy?

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?

In regard to applications for a Clinical Site, has the Principal Investigator provided evidence for the adequacy of the proposed facility, space, and resources for the work proposed? Is there evidence of an appropriate organizational structure and institutional support for the Clinical Site? Is there evidence of successful collaborative interactions with other investigators under a common protocol in a multi site clinical trial?

In regard to applications for a Data Coordinating Center, has the application documented the adequacy of the proposed facility, technical hardware and software, and space for the Data Coordinating Center? Is there an appropriate organizational and administrative structure to the Center? Is there evidence of Institutional support and commitment for the proposed program?

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
Not applicable

2.D. Sharing Research Resources

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

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
Not applicable

Section VI. Award Administration Information

1. Award Notices

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

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

A formal notification in the form of a Notice of Grant Award (NGA) will be provided to the applicant organization. The NGA signed by the grants management officer is the authorizing document. Once all administrative and programmatic issues have been resolved, the Notice of Grant Award will be generated via email notification from the awarding component to the grantee business official (designated in item 14 on the Application Face Page). If a grantee is not email enabled, a hard copy of the Notice of Grant Award 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 NGA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs. See Also Section IV.5. Funding Restrictions.

2. Administrative and National Policy Requirements

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

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 above.

2.A.1. Principal Investigator Rights and Responsibilities

The Principal Investigator will have the primary responsibility for: in a manner consistent with the collaborative responsibilities listed in Section 2.A.3: defining the research objectives, approaches and details of the projects within the guidelines of the RFA and for performing the scientific activity. Specifically, the Principal Investigators of Clinical Sites will: (1) be responsible for the overall conduct of the clinical trial and for providing scientific, technical, and administrative leadership to the study; (2) determine and coordinate the project activities scientifically and administratively in his/her site; (3) be responsible for ensuring that his/her clinic personnel are trained and certified to carry out study procedures; (4) have the primary responsibility of identifying and recruiting of eligible patients and the follow up of each patient enrolled in his/her site, as specified in the study protocol; (5) accept and implement the approved protocols and common guidelines; (6) submit data to the DCC in accordance with policies agreed upon and established by the Steering Committee and the NIH data sharing policy available at: http://grants.nih.gov/grants/policy/data_sharing/; (7) serve as voting members of the Steering Committee and be responsible for establishing and following the policies of the committee; (8) be responsible for implementing the approved research resource sharing plan and intellectual property plan.

The Data Coordinating Center will, in a manner consistent with the collaborative responsibilities in Section 2.A.3: (1) establish and maintain a centralized information management system to help the clinical investigators, the Steering Committee, and the NIH to edit, store, analyze, publish, and disseminate results from the research; (2) support the activities of the Steering Committee, and the Data and Safety Monitoring Board (DSMB) through provision of materials and documentation, meeting planning and logistics, and conference call coordination; (3) assist the NIH Staff and the Steering Committee in monitoring research progress; (4) ensure data integrity, accuracy, security, and accessibility; (5) provide support, in concert with the NCCAM Program Officer and Scientific Coordinator, as necessary, to ensure that all clinical study sites and investigators fully comply with NIH regulatory requirements, including Human Subject Protections, informed consent, reporting of adverse events, and human and animal subject safety and welfare protections; (6) compile for the Steering Committee, the DSMB, the NCCAM Program Officer site visit reports, monthly and quarterly reports of research activities (including, but not limited to, subject enrollment), meeting summaries, quarterly research site performance reports from each Clinical Site, and other reports as needed; (7) prepare, design, and disseminate operations manuals, data collection forms, databases, and results reporting summaries; (8) may also be involved in performing specified support functions such as training and certification of clinical site staff, and designing and maintaining quality assurance programs.

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

NCCAM and NIDDK Program Officials will be responsible for the normal program stewardship including monitoring program progress. Their responsibilities also include releasing yearly funding increments based on a review of progress towards achieving the previously agreed upon milestones and for the DCC, based on achieving effective support of clinical trials and the DSMB; having access to data generated under this Cooperative Agreement and periodically review the data and progress reports; approving any changes in the proposed research objectives and redirection of research projects.

The NCCAM or NIDDK reserve 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 the NIDDK and the NCCAM cannot concur, (d) reaching a major study endpoint substantially before schedule with persuasive statistical significance, or (e) human subject safety and ethical issues that may dictate a premature termination.

NCCAM and NIDDK Project Scientists, an NCCAM and an NIDDK Medical Officer will also have substantial scientific involvement during the conduct of this activity through technical assistance, advice, and coordination above and beyond normal program stewardship for grants. These include: a) providing guidance and support in the development, assembly, and submission of all required regulatory documents; b) as members of the Steering Committee, serving as a resource for protocol design and development, and providing scientific support during the accomplishment of the research by participating in the design of the activities, advising in the selection of sources or resources (e.g., determining where a particular reagent can be found), advising in management and technical performance, or participating in the preparation of publications; c) being voting members (with one vote each for NCCAM and NIDDK) of the Steering Committee and participate in all Steering Committee activities, including, but not limited to, conference calls, subcommittees and special committees; d) assisting in scheduling the meetings of the Steering Committee and actively assisting the Chair in developing the meeting agendas; e) ensuring coordination of the Steering Committee's activities and implementation of the group's recommendations. NCCAM's Office Clinical and Regulatory Affairs (OCRA) will be the IND sponsor to the FDA and review the protocol in this capacity. The NCCAM and NIDDK Program Officials may also serve as the Project Scientists.

2.A.3. Collaborative Responsibilities

The NCCAM and NIDDK will establish a Steering Committee to serve as the governing body of the multi-site study. At a minimum, the Steering Committee will be composed of an NCCAM Project Scientist, an NIDDK Project Scientist, an NCCAM Medical Officer, an NIDDK Medical Officer, and each U01 Principal Investigator and the DCC PI. NCCAM and NIDDK each has one vote and each PI has one vote. The NIH votes will be less than 30% of the total. The silymarin product supplier will be an ex-officio member. A Chairperson will be selected by the Steering Committee from among the non-federal Committee members. Each Steering Committee member will be expected to participate in all meetings and activities.

The 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 at locations selected by the Steering Committee in consultation with the NCCAM. Proposed budgets should include funds to cover travel costs for these meetings. Conference calls will be held between meetings whenever necessary. All major scientific decisions will be determined by a majority vote of the Steering Committee. The Steering Committee will (1) have primary responsibility of proposing and prioritizing investigational and treatment protocols, finalizing common clinical protocols, and facilitating the development of a standardized nomenclature, diagnostic criteria, histological definitions, and necessary components to the common database on patients (prior to submission to NCCAM and final NCCAM approval); (2) be responsible for the conduct and monitoring of studies and reporting study results; (3) establish a process for the selection of the laboratories to perform protocol-associated laboratory studies; (4) establish standards for data collection, analysis, and data management; (5) prepare annual reports.

For each investigational or therapeutic protocol, one CC Principal Investigator 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 the CCs. In addition, one CC Principal Investigator will take the lead in directing and overseeing the conduct of the clinical protocols.

The Steering Committee will establish subcommittees on specific issues as needed. 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 (DSMB) will be established by the NCCAM 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 NCCAM regarding the continuation of each study.

Each Phase I/II clinical trial will be implemented by all of the Clinical Sites. As specific protocols are developed, support will depend on the availability of funds and will be provided on a per patient basis. All the CCs 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 Data Monitoring Board before initiation. The exact number of protocols supported in the four-year program will depend on the nature and extent of the investigations proposed by the Steering Committee. The investigators are also encouraged to seek out separate funding for special projects and to develop collaborations with laboratory and basic research investigators to draw upon the resources (clinical data, serum, tissue, DNA) made available by the multi-site study database. Any specific collaboration involving the resources of this multi-site study will require approval by the Steering Committee.

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:

Qi-Ying Liu, M.D., M.Sci.
Division of Extramural Research and Training
National Center for Complementary and Alternative Medicine
6707 Democracy Boulevard, Suite 401, MSC 5475
Bethesda, MD 20892-5475 (for express/courier service use 20817)
Telephone: (301) 402-5867
FAX: (301) 480-3621
Email: liuqiy@mail.nih.gov

Edward Doo, M.D.
Liver Diseases Research
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Boulevard, Room 646
Bethesda, MD 20892 (for express/courier service use 20817)
Telephone: (301)-451-4524
Email: dooe@niddk.nih.gov

2. Peer Review Contacts:

Martin Goldrosen, Ph.D.
Director, Office of Scientific Review
National Center for Complementary and Alternative Medicine
6707 Democracy Boulevard, Suite 401, MSC 5475
Bethesda, MD 20892-5475 (for express/courier service use 20817)
Telephone: (301) 594-2014
FAX: (301) 480-2419
Email: goldrosm@mail.nih.gov

3. Financial or Grants Management Contacts:

Mr. George Tucker
Grants Management Branch
National Center for Complementary and Alternative Medicine
6707 Democracy Boulevard, Suite 401
Bethesda, MD 20892 (for express/courier service use 20817)
Telephone: (301) 594-9102
Fax: (301) 4801552
Email: tuckerg@nccam.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.

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

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

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

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

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

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

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

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

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

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

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

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

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

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


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