Part I Overview Information

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Department of Health and Human Services

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

Components of Participating Organizations
National Center for Research Resources (NCRR) (http://www.ncrr.nih.gov/)

Title: National Gene Vector Biorepository and Coordinating Center (P40)

Announcement Type
New

Request For Applications (RFA) Number: RFA-RR-07-002

Catalog of Federal Domestic Assistance Number(s)
39.389

Key Dates
Release Date:  March 6, 2007
Letters of Intent Receipt Date(s): June 11, 2007
Application Receipt Date(s): July 10, 2007
Peer Review Date(s): September – December 2007
Council Review Date(s): January 2008
Earliest Anticipated Start Date(s): March 1, 2008
Additional Information To Be Available Date (Url Activation Date): Not Applicable
Expiration Date: July 11, 2007

Due Dates for E.O. 12372

Not Applicable

Additional Overview Content

Executive Summary

• This funding opportunity announcement (FOA) solicits Specialized Centers (P40) grant applications from applicant institutions with the following goals:
• The provision of a biologic storage facility for gene vector materials.  
• The establishment of an archive for storing materials from human subjects exposed to gene therapy.   
• The creation of a pharmacology- toxicology database for gene vector-related study results.  
• The support of pharmacology-toxicology research related to gene therapy.  
• The development of a coordinating center to facilitate access to materials and information in the field of gene therapy. 
• NCRR will provide up to $660,000 per year in direct costs for a single biorepository. The award issued is contingent upon the submission of a meritorious application. 
• This Funding Opportunity Announcement (FOA) will utilize the P40 grant mechanism.
• Public/State Controlled Institution of Higher Education; Private Institution of Higher Education; Nonprofit with 501(c)(3) IRS Status (Other than Institution of Higher Education); Nonprofit without 501(c)(3) IRS Status (Other than Institution of Higher Education); Small Business; For-Profit Organization (Other than Small Business); State Government; U.S. Territory or Possession; Indian/Native American Tribal Government (Federally Recognized); Indian/Native American Tribal Government (Other than Federally Recognized); Indian/Native American Tribally Designated Organization; Hispanic-serving Institution; Historically Black Colleges and Universities (HBCUs); Tribally Controlled Colleges and Universities (TCCUs); Alaska Native and Native Hawaiian Serving Institutions; Regional Organization and Eligible agencies of the Federal government.
• Eligibility is limited to investigators with experience in data management and the handling and storage of gene therapy vectors, master cell banks, and related products. The investigator should be responsible for the operations of an established gene vector biorepository having the characteristics described elsewhere in this RFA. 
• See Section IV.1 for application materials.
• Telecommunications for the hearing impaired is available at: TTY 301-451-5936

Table of Contents

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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
  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

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Section I. Funding Opportunity Description

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1. Research Objectives

• The goals of the National Gene Vector Biorepository and Coordinating Center are
• To create a biologic storage facility for master cell banks, plasmids, and related gene vector materials and to support access to these materials by investigators funded by NIH grants.  The facility would provide investigators with a means to store, access, and share master cell banks, plasmids, and other gene vector related products for pre-clinical investigation. 
• To establish an archive for storing cellular, tissue, and other biological materials donated by study subjects who had been exposed to gene therapy.  The stored materials could be used to support investigations of delayed adverse events following exposure to gene therapy products.  The archive could provide a back up storage facility for specimens in the event that a clinical investigator of gene therapy or an institution was unable to continue to store the biological materials.  
• To create a database for gene vector-related pharmacology- toxicology study results in order to provide centralized, generally accessible storage of vector related information, to obviate duplication of costly pre-clinical studies, and to help predict the risks associated with human exposures to specific vectors.  The data storage facility would provide investigators in the field of gene therapy with access to information relevant to the use of vectors and/or genetic material in pre-clinical settings.  Because acute toxicities associated with gene therapy often relate to vector exposure, the investigators would benefit from the shared information.
• To conduct independent research regarding the pharmacology and toxicology of gene therapy.  The research could include pre-clinical studies and/or studies of delayed adverse events following gene therapy. It could be related to studies in the pharmacology-toxicology database or to the development of a reliable and generally acceptable method for assessing the risk of gene-therapy related toxicities such as insertional mutagenesis.
• To facilitate access to materials and information in the field of gene therapy.  The coordinating center should encourage investigators to use the facility as a storage site, to regard it as a source of gene vectors for research, and to refer to the database for preclinical information related to the use of gene vectors.
• Support for Gene Therapy Research
• The NIH supports a broad array of investigations that make use of vectors as transport vehicles for genetic material with defined functions.  Among the gene functions, the following are included:
• The potential to generate a specific product such as a cytokine, a hormone, an antigen, or an enzyme
• The potential to function inside a target cell as a replacement for a defective or inactive gene, a suppressor of an abnormally active host gene, or an activator of an abnormally silent host gene.
• The potential to transform a cell in order to induce a property in a normal cell that will result in a beneficial biologic effect or to induce a property in a malignant cell that will result in the inactivation or death of the cell.

Background:  In 1995, the NIH through the NCRR established the National Gene Vector Laboratories (NGVLs) as a resource for researchers to obtain adequate quantities of clinical-grade vectors for human gene transfer protocols.  The NIH created the NGVLs in response to concerns that access to clinical-grade vectors had been hindered by a lack of clinical grade facilities and high costs. 

The principal function of the NGVL is to produce clinical grade vectors for pharmacology-toxicology testing and for clinical trials.  By the end of 2006, the NGVLs had produced 36 clinical vectors for use in human studies.  Using vectors produced by the NGVLs, clinical investigators had conducted gene therapy studies in 310 individuals in 18 academic centers.  In addition, the NGVL provides services to all investigators who are recipients of NIH support.  The services include access to the archiving and repository program, NGVL clonality testing services, pharmacology-toxicology testing, and a pharmacology-toxicology database.  Data collected by the NGVL are currently available for vectors developed for human use by the NGVL at the NGVL Coordinating Center (http://www.ngvl.org/pharmtox/).

Sponsors of gene therapy products hold approximately 250 active Investigational New Drug applications (INDs) with the US Food and Drug Administration (FDA).  The Genetic Modification Clinical Research Information System (GeMCRIS, http://www.gemcris.od.nih.gov/) recently listed 538 open trials involving gene transfer by means of 474 different viral vector or plasmid products.

Distribution of Vectors in Products Used in Clinical Trials Listed in GeMCRIS:  156 use plasmids, 9 use retroviruses,     6 use lentiviruses, 193 use adenoviruses, 31 use adeno-associated viruses, 13 use herpes viruses, and 66 use pox viruses.

Disorders for which studies involving gene therapy are in progress include both malignant and non- malignant states.  The malignancies include glioma, squamous cell carcinoma of the head and neck, prostate cancer, breast cancer, colon cancer, lung cancer, lymphoma, melanoma, myeloma, ovarian cancer, and leukemia.  The non-malignant states include inherited disorders such as cystic fibrosis, severe combined immune deficiency, hemoglobinopathy, hemophilia, hyperlipidemia, and limb-girdle musculodystrophy, cardiovascular disorders such as  peripheral vascular disease and coronary disease, multifactorial disorders such as rheumatoid and osteo- arthritis, inflammatory joint syndromes, chronic pain syndrome, and erectile dysfunction, and infectious diseases such as acquired immunodeficiency syndrome (AIDS).

Gene transfer technology creates unique technical requirements for the storage of biologic materials.  In addition, gene therapy has a potential for adverse events that may be delayed in their clinical appearance for months or years.  Examples of this uncommon phenomenon have been reported in four of the many hundreds of individuals who received gene therapy.

Reports of delayed toxicities attributed to gene therapy include the following:  One participant died of toxic shock after receiving the adenovirus vector carrying a transgene in a clinical trial intended to address ornithine transcarbamylase deficiency.  Three children developed leukemia after receiving vector-based gene therapy for X-linked severe combined immunodeficiency syndrome (X-linked SCID). 

As of December 2006, a single gene therapy product had been licensed for marketing in China, but none had been licensed in the United States.  As noted above, 474 are in clinical trials.  Some sponsors of gene therapy products are corporate entities; many are academic centers.  Academic centers have limited resources for storing gene-therapy related products to provide samples for study of delayed toxic effects.  The US FDA recommends that human subjects exposed to the risk of delayed toxic effects be observed for up to 15 years (for US FDA guidance see Gene Therapy Clinical Trials – Observing Subjects for Delayed Adverse Events, http://www.fda.gov/cber/gdlns/gtclin.htm).  Archived biologic material could prove to be a useful tool in the investigation of delayed toxic effects related to exposure to a gene therapy product.

Human studies that include exposure to new gene therapy products are contingent upon demonstration of safety in preclinical test models.  Acute toxicity associated with gene therapy is often attributable to the vector.  New gene therapy products often employ vectors that are the same or similar to vectors for which the NGVL currently has data from toxicology and biodistribution studies.  Making the data from these and other studies available on a searchable toxicology and biodistribution database could save time and resources. 

The intent of this FOA is to provide support for

• Access by NIH-supported sponsors of gene therapy investigations to repository resources that would allow for storage and re-accessioning of master cell banks, plasmids, or other vector-related products for potential laboratory investigation and/or product sharing.
• Access by NIH-supported sponsors of gene therapy clinical investigations to an archival storage system for retention of preserved biological materials from human subjects at risk of delayed adverse events associated with exposure to gene therapy products.
• Access by approved NIH-supported investigators to aliquots of stored products.
• Access by investigators to the pharmacology-toxicology database.
• Sharing of information regarding emerging knowledge of the pharmacology and toxicology of gene vectors and the assessment of delayed adverse events following exposure to gene therapy.

2. Key Functions of a Biorepository and Coordinating Center  

Structure of the National Gene Vector Biorepository and Coordinating Center (NGVBCC)

• The NGVBCC will
• Store master cell banks, plasmids, and related gene vector materials with indexing for secure identification and retrieval of products.
• Store cellular, tissue, and other biological materials from human subjects who have been exposed to gene therapy in an appropriate archive with indexing for secure identification and retrieval of products.
• Provide a reasonable estimate of (1) the number and volume of the samples NIH-supported investigators would seek to have stored and (2) the storage space that would be required to respond to their requests.
• Develop, operate, and maintain a pharmacology-toxicology database.  Entries should be searchable by key words such as vector system, animal species, vector grade, clinical indication, route of administration, and toxicity.
• Support pharmacology-toxicology research to improve evaluation of the delayed serious adverse events following gene therapy in order to provide investigators with a reliable, evidence-supported method for assessing the risk of insertional mutagenesis or other gene-therapy related toxicities.  The budget requested to support the research project(s) should not exceed 15% of the application.
• Facilitate information exchange regarding the toxicology and pharmacology of gene therapy to insure that investigators will avail themselves of the opportunity to deposit and retrieve materials and/or information from the biorepository, biomaterials archive, and pharmacology-toxicology database and to support the dissemination of information stored within the facility to investigators in the field of gene therapy.
• The application must have each of the following:
• A section labeled System Specifications.  Please specify the following:
• The system must employ a secure, verifiable, bar-code-based, inventory control system to allow for sample tracking, distribution, back-up, auditing, sample access, and retention in a sample-related, information database.
• The facility must have adequate alarms, back-up, and protection of the products against foreseeable risks.
• The facility must have a review policy and procedure for sample and data deposit and access.  The procedure should provide allowance for arbitration or decision appeal.
• The system must have a web-based catalog and information system of the gene vector biorepository and biological materials archive that is accessible to NIH-supported investigators who wish to use the facility for storage or a resource.
• The system must provide redundant sample storage and back-up capability.
• The system must be able to track and report any breaches of security, storage conditions, or maintenance issues.
• The system must have an information and inventory control system that will track accession to data and materials stored in the biorepository and archive.  It will monitor and report all tracked information.
• A section labeled “Quality Control and Quality Assurance” that describes a plan for a quality control and quality assurance program.
• A section labeled “Repository Manager” that provides a detailed job description for a Repository Manager who will coordinate all access to, deposits into, and distributions from the repository.

• The NGVBCC should exist within an institution that provides broad support for the development, operation, and maintenance of the NGVBCC’s facilities.  The proposed award could support some new equipment purchases.  However, the NIH expects that the applicant will currently have well-developed facilities with the necessary equipment and information systems to provide a substantial portion of the expected services described in this RFA.

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

Section II. Award Information

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1. Mechanism(s) of Support

This funding opportunity will use the P40 award mechanism.

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

This funding opportunity uses the just-in-time budget concepts. It also uses the non-modular budget format described in the PHS 398 application instructions (see https://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 P40 is a resource grant mechanism. Under the P40 mechanism, the Project Director/Principal Investigator (PD/PI) is responsible for maintaining a resource center with the following basic characteristics: 

• The resource must be able to store master cell banks, plasmids, and other gene vector related products
• The resource must be prepared to archive biological materials from subjects who may be at risk from exposure to gene therapy
• The resource must provide a reasonable estimate of the demand for suitable storage space and include a plan to make an adequate amount of space available to meet the demand.
• The resource must maintain a web-based catalogue of stored materials
• The resource must develop and maintain a generally accessible and  searchable pharmacology-toxicology database
• The resource must have a research component to advance understanding and evaluation of toxicities related to gene therapy
• The resource must serve the needs of and be available to all NIH-supported investigators whose work is in the field of gene therapy

Contingent upon demonstrated use of the facility, NCRR may fund the NGVBCC beyond the three years of this award.  At this time, however, the NCRR does not know whether it will use the same funding mechanism and accept competing renewal (formerly “competing continuation”) applications, whether if it will reissue this FOA, or whether it will employ a different funding mechanism.

2. Funds Available

• Although the financial plans of the NCRR provides support for this program, awards pursuant to this funding opportunity are contingent upon the availability of funds and the submission of a sufficient number of meritorious applications.
• The total project period for an application submitted in response to this funding opportunity may not exceed 3 years. NCRR intends to commit approximately $660,000 dollars in direct costs in FY2008 to fund a single application.
• NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made in response to this FOA.
• Facilities and Administrative (F&A) costs requested by consortium participants are not included in the direct cost limitation. See NOT-OD-05-004, November 2, 2004.
• The anticipated start date for the 3-year award is March 1, 2008.
  

Section III. Eligibility Information

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1. Eligible Applicants

1.A. Eligible Institutions

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

• Public/State Controlled Institution of Higher Education
• Private Institution of Higher Education
• Not-for-profit with 501(c)(3) IRS Status (Other than Institution of Higher Education)
• Not-for-profit without 501(c)(3) IRS Status (Other than Institution of Higher Education)
• Small Business
• For-Profit Organization (Other than Small Business)
• State Government
• U.S. Territory or Possession
• Indian/Native American Tribal Government (Federally Recognized)
• Indian/Native American Tribal Government (Other than Federally Recognized)
• Indian/Native American Tribally Designated Organization
• Hispanic-serving Institution
• Historically Black Colleges and Universities (HBCUs)
• Tribally Controlled Colleges and Universities (TCCUs)
• Alaska Native and Native Hawaiian Serving Institutions
• Regional Organization

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 suuport.

Eligibility is limited to established investigators with experience in the handling of gene therapy vectors, master cell banks, and gene-vector related products. 

• The Principal Investigator (PI) should have the necessary expertise to direct, operate, and manage a biorepository, an archive of biological materials, and an informational database.  The description of the facility must reflect the investigator’s
  • Experience in the storage of gene-vector related products.
  • Procedures for the operation of a biorepository and an archive.
  • Anticipation of the demand for storage of the master cell banks, plasmids, and gene therapy-related products and ability to respond to the demand.
  • Anticipation of the demand for archival storage of biological material from human subjects in gene therapy studies. 
  • Familiarity with the design, development, operation, and maintenance of an information and inventory control system.

2. Cost Sharing or Matching

This program does not require cost sharing as defined in the current NIH Grants Policy Statement

The most current Grants Policy Statement can be found at: https://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

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1. Address to Request Application Information

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

Format of the Application

• The application should contain an appendix labeled “Procedures Related to Materials Obtained From Human Subjects”  To include a letter to document that:
  • The facility is in compliance with the Health Insurance Portability and Accountability Act (HIPAA) as described in the section below labeled “Standards for Privacy of Individually Identifiable Health Information.”
  • The biorepository will not accept materials for storage from any human subject unless that subject has given signed, explicit informed consent for his/her materials to be stored in the facility.
  • The biorepository will not distribute human materials to any scientific investigators unless the donor of those materials has given signed, explicit informed consent for this purpose. 

3. Submission Dates and Times

Applications must be received on or before the receipt date described below (Section IV.3.A). Submission times NOT APPLICABLE.

3.A. Receipt, Review and Anticipated Start Dates
Letters of Intent Receipt Date(s): June 11, 2007
Application Receipt Date(s): July 10, 2007
Peer Review Date(s): September – December, 2007
Council Review Date(s): January 2008
Earliest Anticipated Start Date(s): March 1, 2008

3.A.1. Letter of Intent

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

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

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

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

The letter of intent should be sent to:

Daniel Rosenblum, MD
Division of Clinical Research Resources
National Center for Research Resources
6701 Democracy Blvd
Room 910 
Bethesda, MD 20892
Telephone: (301) 435-4051
FAX: (301) 480-3661
e-mail: rosenblumd@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 https://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:

Bonnie Dunn, PhD
Office of Review
National Center for Research Resources  
6701 Democracy Blvd
Room Number 1074
Bethesda, MD 20817
Telephone: (301) 435-0824
FAX: (301) 480-3660
e-mail: dunnbo@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: https://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 NCRR. 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 https://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 https://grants.nih.gov/archive/grants/policy/nihgps_2003/index.htm.

6. Other Submission Requirements

Not Applicable

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 https://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 https://grants.nih.gov/archive/archive/grants/policy/nihgps_2003/index.htm and https://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, https://grants.nih.gov/grants/funding/2590/2590.htm). See Section VI.3. Reporting.

The applicant should provide a plan to make the gene therapy biorepository, human subject materials archive, and pharmacology-toxicology database available to all investigators who are the recipients of NIH peer-reviewed grant support without the application of utilization fees.  The applicant should also institute a plan for the dissemination of pharmacology-toxicology information and evaluation methodology relevant to exposure to gene therapy and the vectors associated with it by organizing and sponsoring a formal annual program directed at an audience of NIH-sponsored investigators engaged in studies of gene therapy. This requirement extends beyond NIH policy and will be considered a review criterion.   

Section V. Application Review Information

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1. Criteria

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

The following will be considered in making funding decisions:

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

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 NCRR in accordance with the review criteria stated below.

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

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

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? Does the range of proposed resources contribute to NIH’s gene therapy initiatives (please refer to Phase I, II, and III Study Protocols in GeMCRIS, http://www.gemcris.od.nih.gov/)? Is the pharmacology-toxicology research relevant and important to an improved understanding of the pharmacology and toxicity associated with gene therapy or the assessment of the causality of toxicity?

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? Does the biorepository have the capability of storing gene vector materials such as master cell banks, plasmids, and other gene vector products? Does the archive for materials from subjects in human trials have the capability of storing these materials?  Does the system have a web-based catalog and information system of the gene vector biorepository and biological materials archive that is accessible to NIH-supported investigators who wish to use the facility for storage or a resource?  Has the applicant developed a plan to enable NIH-supported investigators to access the facilities for storing gene vector products and human subject materials?  Does the system have a review policy and procedure for sample and data deposit and access?  Does the procedure provide allowance for arbitration or decision appeal? Is the pharmacology-toxicology database comprehensive, accessible, and searchable?  Does the pharmacology-toxicology research proposal appear feasible and well designed? Does the applicant have a “Quality Control and Quality Assurance” program?

Innovation: Will the resource and research project facilitate advancements in the study of toxicology associated with gene therapy? Does the proposed resource employ any novel concepts, approaches, methodologies, tools, or technologies for this area? Is the research component innovative?

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? Has the investigator provided sufficient evidence of the ability to operate and maintain a biorepository, biomaterials archive, and pharmacology-toxicology database? Has the investigator proposed to establish a robust, web-based catalog?  Has the investigator provided a plan for back-up protection of the resource in the event that s/he is unavailable to provide it her/him-self? Has the investigator identified a Repository Manager who will coordinate all access to, deposits into, and distributions from the repository?

Environment: Has the applicant provided a reasonable estimate of the demand for storage space in the biorepository and biomaterials archive and ability to respond to it? 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? Has the applicant adequately addressed environmental concerns, security, and safety? For example, does the system employ a secure, verifiable, bar-code-based, inventory control system to allow for sample tracking, distribution, back-up, auditing, sample access, and retention in a sample-related, information database?   Does the system have adequate alarms, back-up, and protection of the products against foreseeable risks? Does the system have redundant sample storage and back-up capability? 

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 https://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. 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

The Summary Statements will be posted in the NIH eRA Commons following peer review. Information regarding awards will be available following the National Advisory Research Resources Council meeting of January 30, 2008.

Section VI. Award Administration Information

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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 (https://grants.nih.gov/archive/grants/policy/nihgps_2003/index.htm).

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization. The NoA signed by the grants management officer is the authorizing document. Once all administrative and programmatic issues have been resolved, the NoA will be generated via email notification from the awarding component to the grantee business official (designated in item 12 on the Application Face Page). If a grantee is not email enabled, a hard copy of the NoA will be mailed to the business official.

Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs. See Also Section IV.5. Funding Restrictions.

2. Administrative and National Policy Requirements

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General (https://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 (https://grants.nih.gov/archive/grants/policy/nihgps_2003/index.htm).

3. Reporting

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

Section VII. Agency Contacts

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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:

Daniel Rosenblum, MD
Division for Clinical Research Resources, National Center for Research Resources
6701 Democracy Blvd, Room 910
Bethesda, MD 20892
Telephone: (301) 435-4051
Fax (301) 480-3661
e-mail: rosenblumd@mail.nih.gov

2. Peer Review Contacts:

Bonnie B Dunn, Ph.D.
Scientific Review Administrator
National Center for Research Resources
6701 Democracy Blvd, Rm 1074
Bethesda, MD 20892-4874
(Use zip code 20817 for courier services)
Telephone:  (301) 435 0824
Fax: (301) 480 3660
e-mail: dunnbo@mail.nih.gov

3. Financial or Grants Management Contacts:

Jean Richelsen
Office of Grants Management
National Center for Research Resources
6701 Democracy Blvd, Room 1052
Bethesda, MD 20892-4874
Telephone: (301) 453-0853
Fax: (301) 480-3777
e-mail: richelsj2@mail.nih.gov

Section VIII. Other Information

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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 (https://grants.nih.gov/grants/olaw/references/PHSPolicyLabAnimals.pdf) as mandated by the Health Research Extension Act of 1985 (https://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, https://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 (https://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 https://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 https://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 https://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 (https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines is available at https://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 (https://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 https://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 https://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 https://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 https://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.