Department of Health and Human Services

Part 1. Overview Information
Participating Organization(s)

National Institutes of Health (NIH)

Components of Participating Organizations

National Human Genome Research Institute (NHGRI)

Funding Opportunity Title

Clinical Sequencing Exploratory Research (U01)

Activity Code

U01 Research Project Cooperative Agreements

Announcement Type

New

Related Notices

  • April 20, 2012 - This RFA has been reissued as RFA-HG-12-009.
  • January 20, 2011 - See Notice NOT-HG-11-011 The purpose of this Notice is to correct the fiscal year in Part 2: Section II—Award Information.
  • January 6, 2011 - See Notice NOT-HG-11-008 Notice of Correction to Eligible Organizations.
  • December 21, 2010 - See Notice NOT-HG-11-007 Information Teleconference and Webinar for Applications to NHGRI Sequencing and Ethical, Legal, and Social Implications (ELSI) FOAs.

Funding Opportunity Announcement (FOA) Number

RFA-HG-10-017

Companion FOA

RFA-HG-11-003, R01
RFA-HG-11-004, R21

Number of Applications

Section III. 3. Additional Information on Eligibility

Catalog of Federal Domestics Assistance (CFDA) Number(s)

 93.172    

FOA Purpose

The NHGRI seeks grant applications to explore, within an active clinical setting, the application of genomic sequence data to the care of patients.  Our understanding of human genetic variation and its association with disease risk and with individual response to treatment continues to expand rapidly.  Simultaneously, a revolution has occurred in genomic sequencing technologies, making it technically and economically feasible to consider the application and utilization of genomic sequence data in clinical care.  Applications submitted in response to this FOA will address critical questions about the application of genomic sequencing to clinical care of individual patients, from generation of genomic sequence data, to interpretation and translation of the data for the physician, to communication to the patient, including an examination of the ethical and psychosocial implications of bringing broad genomic data into the clinic.

Key Dates
Posted Date
Open Date (Earliest Submission Date)

February 3, 2011

Letter of Intent Due Date

February 3, 2011

Application Due Date(s)

March 3, 2011

AIDS Application Due Date(s)

Not applicable

Scientific Merit Review

July, 2011

Advisory Council Review

 October, 2011

Earliest Start Date(s)

  December 1, 2011

Expiration Date

March 4, 2011

Due Dates for E.O. 12372

Not Applicable

Required Application Instructions

It is critical that applicants follow the instructions in the PHS398 Application Guide except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. While some links are provided, applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.

Table of Contents

Part 1. Overview Information
Part 2. Full Text of Announcement
Section I. Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

Part 2. Full Text of Announcement

Section I. Funding Opportunity Description

 A new generation of DNA sequencing instruments has made it feasible to determine the complete sequence of a human genome for costs of tens of thousands of dollars rather than the millions of only a few years ago.  The cost of determining the protein-coding sequences in the genome (i.e., the exome) is lower yet by a factor of five to ten.  The time is rapidly approaching when health care providers will be able to obtain the complete genomic sequence of their patients, and we can already anticipate many questions about how this information will be used to inform medical and preventive care decisions.  Already today, a small number of well-studied alleles may be examined and results applied to clinical decisions.  Currently, individual genetic test results for a few specific conditions, such as adverse drug reactions, HLA type, and hemoglobinopathies, are available in most clinical centers, and the potential for applying data from dense SNP arrays to clinical decisions is being explored in a few.  However, we do not yet understand the full potential for the application of genomic sequencing to routinely assess individual variation of medical relevance.  For example, it is unclear what diseases or individual susceptibilities will be usefully addressed by a genomic sequencing approach, or what the potential range of clinical applications will be.  Furthermore, incorporating comprehensive genomic sequence data in clinical care will require the development of institutional policies, standardization of procedures (including simplified analysis and interpretive tools), and development of the capacity to integrate sequence information into the clinical workflow.  Much exploratory research is required to understand the current potential for the use of sequence information in personalized genomic medicine and to identify the areas of opportunity for innovation. 

The research projects solicited by this FOA are expected to begin to generate a foundation on which to build the infrastructure and methods necessary to routinely interrogate a patient’s unique genetic code and to apply this fundamental knowledge to her/his medical care.  This objective requires that a large fraction of each patient’s genomic sequence be obtained and analyzed.  Research approaches can include high-coverage sequencing of large targeted regions of the genome, targeted whole exome sequencing, or even whole genome sequencing, pertaining to any disease where obtaining sequence information from individuals is likely to have a clinical impact.  However, whole exome sequencing approaches are particularly encouraged.

Genomic sequencing at the breadth of coverage required as a condition of this FOA will reveal thousands of rare or individually unique variants, most of which will not have been previously identified.  To begin to integrate this genetic knowledge into clinical care, many steps are necessary.  Annotation of variants with respect to function (e.g., those that disrupt protein structure), unambiguous association with disease susceptibility (e.g., CFH variants and macular degeneration), and clinical utility (e.g., a favorable balance of benefits to risks in terms of implications for health outcomes and personal impact to the patient) must be addressed.  The subset of variants that are determined to be useful for clinical consideration must be identified and presented to the clinician in an intuitive, user-friendly summary report.  Approaches to clinical translation are likely to evolve during the next decade in response to changes in healthcare, developments in sequencing and informatics, a greater understanding of disease biology, and a more mature understanding of ethical, legal, and social issues (ELSI).  The collaborative and cooperative nature of this program is designed facilitate the development and standardization of best practices and common approaches to clinical translation.

Applications submitted in response to this FOA should also include an empirical (behavioral or social science) research component designed to investigate the experiences of patients and clinicians with respect to the return of individual research results.  While issues related to the return of results are neither new nor unique to the context of genomics research, several unique characteristics of genomic sequencing make their resolution in this particular context especially daunting. First, these projects—unlike more traditional genetics research projects that involve the interrogation of more discrete parts of the genome—will involve the generation of information which will, by definition, be voluminous in quantity and comprehensive in scope.  While applicants to this FOA may or may not uncover the particular variant or variants they were originally looking for (related to the disease or trait of initial interest), they will inevitably uncover a large number of incidental findings—findings that are apparently unrelated to the original research questions.  Such incidental findings will include variants of both known and unknown significance, information about carrier status, and information about risk for late-onset disorders.  Considerable controversy exists about the precise threshold of utility that should be required before a result can or should be returned to a research subject or a patient.  Deciding what to do with these findings will present researchers with significant medical and ethical challenges. 

For the remainder of this FOA, the term “patients”, rather than “participants”, will be used to describe the individuals whose genomic information will be stored, analyzed, interpreted, and (potentially) communicated in this research, because such information will ultimately be used in the clinical setting.  Notwithstanding this terminology, applicants should remain alert at all times to the fundamental distinction between research and clinical care and to the different ethical obligations and implications for human subjects research that apply in each context.  

As the objective of this FOA is to support fundamental research on the clinical application of genome-scale sequence data, applications proposing to sequence only one or a few loci will not be responsive. Applicants must address how procedures and tools will be developed or standardized to begin to integrate sequence information into clinical care. Although research funded through this FOA may uncover novel alleles during the course of the work, proposals that focus primarily on discovery rather than clinical application will not be considered to be responsive.

Section II. Award Information
Funding Instrument

Cooperative Agreement: A support mechanism used when there will be substantial Federal scientific or programmatic involvement. Substantial involvement means that, after award, scientific or program staff will assist, guide, coordinate, or participate in project activities.

Application Types Allowed

New

The OER Glossary and the PHS398 Application Guide provide details on these application types.

Funds Available and Anticipated Number of Awards

NHGRI intends to commit $5.5 M/year for 3 to 6 awards anticipated in FY 2011.

Award Budget

Individual application budgets should not exceed $1,500,000 per year, direct costs and must reflect actual needs of proposed project.

Award Project Period

 The total award period requested for this RFA may not exceed four years

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.

Section III. Eligibility Information

1. Eligible Applicants
 
Eligible Organizations

Higher Education Institutions:

The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:

Nonprofits Other Than Institutions of Higher Education

For profit Organizations

Governments

Other

Foreign (non-U.S.) components of U.S. Organizations are  allowed.

Required Registrations

Applicant organizations must complete the following registrations as described in the PHS398 Application Guide to be eligible to apply for or receive an award. Applicants must have a valid Dun and Bradstreet Universal Numbering System (DUNS) number in order to begin each of the following registrations.

All Program Directors/Principal Investigators (PD/PIs) must also work with their institutional officials to register with the eRA Commons or ensure their existing eRA Commons account is affiliated with the eRA Commons account of the applicant organization.

All registrations must be completed by the application due date. Applicant organizations are strongly encouraged to start the registration process at least four (4) weeks prior to the application due date.

Eligible Individuals (Project Director/Principal Investigator)

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Project Director/Principal Investigator (PD/PI) is invited to work with his/her organization to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support.

For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the PHS398 Application Guide.

Expertise is essential in all areas addressed by the FOA:  clinical medicine, genomic analysis, bioinformatics, bioethics, and social or behavioral sciences.  One Principal Investigator (PI) should be designated as the clinical lead.  Designation of additional PIs, with the appropriate experience and expertise to lead components 2 or 3, is encouraged, as suitable for the specific Research Plan. 

The Principal Investigator(s) must devote at least 1.2 person months effort to this Cooperative Agreement  

2. Cost Sharing

This FOA does not require cost sharing as defined in the NIH Grants Policy Statement.

3. Additional Information on Eligibility

Number of Applications

Applicant organizations may submit more than one application, provided that each application is scientifically distinct.

NIH will not accept any application in response to this FOA that is essentially the same as one currently pending initial peer review unless the applicant withdraws the pending application. NIH will not accept any application that is essentially the same as one already reviewed.

Section IV. Application and Submission Information

1. Address to Request Application Package

Applicants are required to prepare applications according to the current PHS 398 application forms in accordance with the PHS 398 Application Guide.

2. Content and Form of Application Submission

It is critical that applicants follow the instructions in the PHS398 Application Guide, except where instructed in this funding opportunity announcement to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

Letter of Intent

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.

By the date listed in Part 1. Overview Information, 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 PD(s)/PI(s)
Names of other key personnel
Participating institutions
Number and title of this funding opportunity

The letter of intent should be sent to:

Bradley A. Ozenberger, Ph.D.
Program Director
National Human Genome Research Institute
5635 Fishers Lane
Suite 4076, MSC 9305
Bethesda, MD 20892
Telephone: 301-496-7531
Email: bozenberger@mail.nih.gov

Application Submission

Applications must be prepared using the PHS 398 research grant application forms and 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)

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

Rudy Pozzatti, Ph.D.
Office of Scientific Review
National Human Genome Research Institute
5635 Fishers Lane
Suite 4076, MSC 9305
Bethesda, MD 20892
Telephone: (301) 496-7531
Email: pozzatr@mail.nih.gov

Page Limitations

All page limitations described in the PHS398 Application Guide must be followed, with the following exceptions or additional requirements:

Research Plan

All instructions in the PHS398 Application Guide must be followed, with the following additional instructions:

Applications to this FOA will be organized in three separate, but highly integrated projects: 1)  Clinical Genomics Study; 2) Sequencing, Analysis and Interpretation of Sequencing Data, and 3) Ethical and Psychosocial Implications Research, plus a Management Core describing the study management plan.  

Project 1.  Clinical Genomic Study.  The Research Strategy should emphasize one or more areas of medical investigation (i.e., disease or therapeutic approach) or a specific approach to the use of genotype-phenotype data within a clinical context (e.g., risk prediction modeling or cancer mutation profiling).  Efforts to discover new disease alleles may be included in a Research Plan but are not necessary or encouraged.  Applicants should justify the features of the disease or approach that make incorporation of clinical genomic sequence data particularly compelling.  Power calculations may be used to justify study design; however, given the exploratory nature of this FOA, other metrics may be acceptable.  Phenotypic data elements should be described fully, including methods for ascertainment, standardization and validation as relevant. Additionally, applicants should provide a detailed description of any ongoing study/cohort recruitment, including plans to reconsent patients for the return of results, or of readiness to enroll new appropriately consented patients in the study.  The informed consent must describe the potential benefits and risks of genomic sequencing and how individual research findings are expected to be offered back to patients and incorporated into the patient’s clinical care.  Given the significant ethical complexities involved in acquiring large amounts of genomic sequence data relating to identified patients, in deciding which individual findings to offer to return to patients, and in deciding when and how to communicate such findings, it is likely that all patients recruited for these studies—even those who have previously provided consent to participate in genomic research--will need to provide informed consent appropriate for participation in the study. 

The Research Strategy for Project 1 should address:

A) Medical Objectives and Rationale

Project 2. Sequencing, Analysis, and Interpretation of Sequencing Data.  Most clinicians will have neither the expertise nor the time during the normal clinical workflow to analyze extensive genomic sequencing datasets and extract from these voluminous data the subset of information that is of medical relevance and clinically actionable.  This FOA therefore anticipates not only the need to generate individual sequence data in the course of clinical care, but the need to categorize sequence variants efficiently and identify those that are potentially clinically actionable, and to provide this information to the practicing clinician in a user-friendly format with rapid turnaround time.  Investigations of more facile methods for sequencing data interpretation and timeliness of delivery of findings, from sequence generation to clinical summary, are important objectives of this FOA.  Applications should thus include as part of the Research Plan the development of methods to analyze genomic sequence data for clinically actionable variants, parse the data into manageable components (to be defined by the applicant), and translate findings into a format to ease interpretation by the clinician.  Subsequently, the transmission of this information to the patient requires a high level of comprehension by the physician or other healthcare provider (such as a genetic counselor or nurse).  This component also contains the genomic sequencing data generation description.

The Research Strategy for Project 2 should address:

A) Genomic Sequencing Plan

B) Genomic Sequence Analysis

C) Clinical Interpretation and Transmission

D) Costs

Project 3. Ethical and Psychosocial Implications Research.  Most ethicists agree that individual sequence variation results should be offered only in circumstances where they have actual utility.  However, considerable controversy exists about the precise threshold of utility that that is required before a result can or should be returned.  Some take the position that proven clinical utility is necessary (i.e., that some recognized preventive or therapeutic intervention must exist), while others believe that personal utility (e.g., the possibility that the information could be used for reproductive decision-making or general life planning) or even the mere recognition that the information may be useful in and of itself (e.g., by enhancing one’s sense of personal identity) may be sufficient. 

Given the lack of consensus in this area, a pressing need exists to develop rational and workable criteria to help guide decision-making about what types of information can, should, or should not be offered to patients.  Such criteria must, however, be informed by solid empirical data. This FOA thus  seeks proposals for studies that will investigate how patients understand, react to, and use individual genomic results when they are offered and returned.  Studies that examine the actual psychosocial and behavioral impact of receiving (or not receiving) such results are especially invited.  The generation of such data about patient responses will be important in the development of guidelines and policy.

This FOA also invites studies that investigate the experiences of clinicians regarding the return of results.  For example, to what extent are clinicians’ decisions motivated by a normative sense of duty, versus concerns about the potential for legal liability (e.g., for failing to disclose a clinically actionable result for a serious disorder for which a preventive or therapeutic intervention exists, or for disclosing information that turns out to be unwanted, causing the patient undue psychological distress)?  What are the advantages and disadvantages of various institutional processes or shared decision-making processes for deciding which results can, should, or should not be returned?  What are the implications of attempts to “mine” the data for potentially relevant information, versus limiting the focus to potentially relevant information merely “stumbled upon”?  What practical, logistical, and budgetary considerations enter into the calculus?  What are the implications of CLIA?  What practical difficulties do clinicians encounter when attempting to discern patients’ wishes and expectations regarding the return of results during the informed consent process?  What practical and regulatory challenges do they encounter when considering whether or how to incorporate such information into participants' medical records?  Are there intellectual property impediments to returning certain types of results?

The Research Strategy for Project 3 should include:

A.         A clear statement of the specific empirical research questions related to the return of results to patients that will be studied,

B.         A detailed description of the methodologies that will be used to study those questions,

C.         A concise description of how this component of the research will be integrated into the development and implementation of the overall study design, including the informed consent process.

Applicants may choose to include in their applications a component aimed at the analysis of normative

or legal issues related to the return of results, but are not required to do so.  Applicants proposing studies with a primary normative or legal focus should consider applying instead under RFA-HG-11-004 (R21).  Applicants proposing studies with a primarily research (non-clinical) focus should consider applying under RFA-HG-11-003 (R01).

4. Management Core.  Research projects proposed in response to this FOA will require close and consistent interaction among the Research Projects to ensure successful integration of all elements.  This section will contain:

A.         A detailed description of the integration of and interdependent associations between Projectss 1, 2, and 3,

B.         A description of management structure, leadership roles, and mechanisms of communication; note that the senior investigator for each project is required to devote at least 1.2 person months of effort to this project,

C.         A description of institutional human subjects protections oversight, and

D.         Specific Aims for the overall project and each research component.

Program Formation and Governance / Cooperative Agreement

Awards funded under this FOA will be cooperative agreements (see Section VI.2., Cooperative Agreement Terms and Conditions of Award).   Close interaction among awardees and the NIH will be required to develop appropriate strategies and tools to carry out this program.  Furthermore, a consortium will be organized with all of the principal investigators and key personnel funded under this FOA; the consortium may include other investigators who are working on the same or similar research issues, as well as investigators to be funded under two related FOAs relating to the ethical, legal, and psychosocial implications of returning results, referenced above, that are being issued concurrently. 

The Principal Investigator(s) from each investigative group and the NIH Project Scientist(s) will meet as a Steering Committee at least annually, and by conference call on an ongoing basis, to identify and address common sequencing, analytic and translational issues, review preliminary results, explore opportunities for synergy among studies, develop best practices, and explore the crucial psychosocial and ethical issues and findings.  Subcommittees and working groups may be established to facilitate collaborative work and standardize approaches. Working groups may propose new research collaborations with non-network investigators and organizations, as long as the activities are conducted in accordance with the policies and practices of the consortium.  Key co-investigators, and pre- and postdoctoral trainees, in addition to the PIs, will be eligible to attend Steering Committee meetings.  The costs of 5-6 persons to attend these meetings, as well as the costs associated with monthly conference calls, should be included in the proposed research budget.

Resource Sharing Plan

Individuals are required to comply with the instructions for the Resource Sharing Plans (Data Sharing Plan, Sharing Model Organisms, and Genome Wide Association Studies (GWAS) as provided in the PHS398 Application Guide.

Appendix

Do not use the appendix to circumvent page limits. Follow all instructions for the Appendix (please note all format requirements) as described in the PHS398 Application Guide,    

Other information about application content and form

In addition to the instructions above regarding the Research Plan sections, the application should include the following:

Data Sharing Plans.

The NHGRI large-scale sequencing program has long championed the concept of rapid pre-publication data release.  However, privacy issues associated with clinical research, such as in the program described in this FOA, can provide a rationale for exception to those long-held precepts.  Some genomic sequencing and variation data sets generated as a result of this research may become a part of an individual patient’s medical record.  However, sequence and phenotype data resulting from this research may have value beyond that intended by the submitting investigators.  Therefore, submission of data sets to the database of Genotype and Phenotype (dbGaP), while not required before publication, is encouraged, and should be released at the time of publication, within the rules and regulations of the controlling IRB and local jurisdiction and with informed consent to permit broad data release via an NIH database.  Applications to this FOA must include a discussion of whether or not release to dbGaP will be authorized in the informed consent for the study.  Any restrictions on data use (such as limitations to a specific disease or condition) should be described. Although this information must be included in the application, the plans for data sharing will not be a review criterion.

The general NIH data sharing policy is available at http://grants.nih.gov/grants/policy/data_sharing. All investigators responding to this funding opportunity and requesting $500,000 or more per year direct costs are expected to include a description of how research data will be shared.

3. Submission Dates and Times

Part I. Overview Information contains information about Key Dates. 

Information on the process of receipt and determining if your application is considered “on-time” is described in detail in the PHS398 Application Guide.

Applicants may track the status of the application in the eRA Commons, NIH’s electronic system for grants administration.

4. Intergovernmental Review (E.O. 12372)

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.

Pre-award costs are allowable only as described in the NIH Grants Policy Statement.

6. Other Submission Requirements and Information

Applications must be received on or before the due dates in Part I. Overview Information. 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 Center for Scientific Review and responsiveness by components of participating organizations, NIH. Applications that are incomplete and/or nonresponsive will not be reviewed.

Post Submission Materials

Applicants are required to follow the instructions for post-submission materials, as described in NOT-OD-10-115

Section V. Application Review Information

1. Criteria

Only the review criteria described below will be considered in the review process. As part of the NIH mission, all applications submitted to the NIH in support of biomedical and behavioral research are evaluated for scientific and technical merit through the NIH peer review system.

Overall Impact

Reviewers will provide an overall impact/priority score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the project proposed).

Scored Review Criteria

Reviewers will consider each of the review criteria below in the determination of scientific merit, and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.

Significance

Does the project address an important problem or a critical barrier to progress in the field? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?  Do the applicants generally highlight new opportunities or address gaps in the communities overall knowledge related to how to use large-scale sequencing to address important biological and biomedical questions?     Does the project make a direct and important contribution to the implementation of sequence information in a clinical setting and to understanding the ethical and psychosocial implications of returning sequence results? Does the project address and overcome barriers or challenges to implementation that extend beyond the applicant’s institution to the wider field?

Investigator(s)

Are the PD/PIs, collaborators, and other researchers well suited to the project? If Early Stage Investigators or New Investigators, or in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?  

Innovation

Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed?  Does the applicant propose development of any point-of-care tools or clinical decision-making resources that will facilitate routine incorporation of sequence information into clinical care? Is the proposed approach or methodology dynamic and responsive to evolving changes in clinical care?  Does the applicant propose the development of innovative approaches to the return of results to patients?          

Approach

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? 

If the project involves clinical research, are the plans for 1) protection of human subjects from research risks, and 2) inclusion of minorities and members of both sexes/genders, as well as the inclusion of children, justified in terms of the scientific goals and research strategy proposed?

Does the management plan ensure the integration of researchers from all three Research Projects into the development and implementation of the overall research plan?

Does the application provide a clear plan for timely, accurate and efficient dissemination of sequence information to the practicing clinician in a user-friendly way?

Does the research plan adequately address how any research findings to be returned to patients will be obtained or validated in a CLIA-certified laboratory?

Does the research plan include an adequate description of the proposed informed consent process and of how the IRB will be involved in any plans to return individual research findings?

Is the Psychosocial and Ethical Implications Research Project fully integrated with the other components of the researach plan?

Has the application described possible best practices or approaches for integrating genomic sequence data into clinical care, or an intent to develop such activities?

Environment

Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements?   

Additional Review Criteria

As applicable for the project proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact/priority score, but will not give separate scores for these items.

Protections for Human Subjects

For research that involves human subjects but does not involve one of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or more of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to the Human Subjects Protection and Inclusion Guidelines.

Informed consentGiven the significant ethical complexities involved in generating large amounts of genomic sequence data relating to identified patients, in deciding which individual findings to offer to communicate to patients, and in deciding when and how to communicate such findings, it is expected that all patients recruited for these studies—even those who have previously provided consent to participate in genomic research--will need to provide a new informed consent for participation.  Plans for consent or reconsent will be reviewed.

Inclusion of Women, Minorities, and Children 

When the proposed project involves clinical research, the committee will evaluate the proposed plans for inclusion of minorities and members of both genders, as well as the inclusion of children. For additional information on review of the Inclusion section, please refer to the Human Subjects Protection and Inclusion Guidelines.

Vertebrate Animals

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following five points: 1) proposed use of the animals, and species, strains, ages, sex, and numbers to be used; 2) justifications for the use of animals and for the appropriateness of the species and numbers proposed; 3) adequacy of veterinary care; 4) procedures for limiting discomfort, distress, pain and injury to that which is unavoidable in the conduct of scientifically sound research including the use of analgesic, anesthetic, and tranquilizing drugs and/or comfortable restraining devices; and 5) methods of euthanasia and reason for selection if not consistent with the AVMA Guidelines on Euthanasia. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

Biohazards

Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate protection is proposed.

Resubmissions

Not Applicable

Renewals

Not Applicable

Revisions

Not Applicable

Additional Review Considerations - Overall

As applicable for the project proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact/priority score.

Applications from Foreign Organizations

Reviewers will assess whether the project presents special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions that exist in other countries and either are not readily available in the United States or augment existing U.S. resources.

Select Agent Research

Reviewers will assess the information provided in this section of the application, including 1) the Select Agent(s) to be used in the proposed research, 2) the registration status of all entities where Select Agent(s) will be used, 3) the procedures that will be used to monitor possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).

Resource Sharing Plans

Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: 1) Data Sharing Plan; 2) Sharing Model Organisms; and 3) Genome Wide Association Studies (GWAS).

Budget and Period of Support

Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research.

2. Review and Selection Process

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by the National Human Genome Research Institute  (assignments will be shown in the eRA Commons), in accordance with NIH peer review policy and procedures, using the stated review criteria.

As part of the scientific peer review, all applications will:

Applications will compete for available funds with all other recommended applications submitted in response to this FOA . Following initial peer review, recommended applications will receive a second level of review by the National Advisory Council on Human Genome Research . The following will be considered in making funding decisions:

3. Anticipated Announcement and Award Dates

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

Information regarding the disposition of applications is available in the NIH Grants Policy Statement.

Section VI. Award Administration Information

1. Award Notices

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant as described in the NIH Grants Policy Statement.

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization for successful applications. The NoA signed by the grants management officer is the authorizing document and will be sent via email to the grantee business official.

Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. 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.      

Any application awarded in response to this FOA will be subject to the DUNS, CCR Registration, and Transparency Act requirements as noted on the Award Conditions and Information for NIH Grants website.

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  and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities. . More information is provided at Award Conditions and Information for NIH Grants.

Cooperative Agreement Terms and Conditions of Award

The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (DHHS) 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, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the awardees is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the awardees for the project as a whole, although specific tasks and activities may be shared among the awardees and the NIH as defined below.

The PD(s)/PI(s) will have the primary responsibility for:

NIH staff have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below:

The Project Scientist is a scientist of the NHGRI staff who will have substantial scientific and programmatic involvement during the conduct of this activity through technical assistance, advice, and coordination.  However, the role of NIH staff will be to facilitate and not to direct the activities.  It is anticipated that decisions in all activities will be reached by consensus of the program and that NIH staff will be given the opportunity to offer input to this process.  The Project Scientist will participate as a member of the Steering Committee and will have one vote. 

The Project Scientists will have the following substantial involvement:

The assigned program director may also serve as an NIH Project Scientist.

Other NHGRI staff may assist the awardees, as designated by the Program Official. 

Areas of Joint Responsibility include:

The Steering Committee:

Dispute Resolution

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 Dispute Resolution. A Dispute Resolution 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 dispute resolution procedure does not alter the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and DHHS regulation 45 CFR Part 16.

The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for awardees of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later.  All awardees of applicable NIH grants and cooperative agreements are required to report to the Federal Subaward Reporting System (FSRS) available at www.FSRS.gov on all subawards over $25,000.  See the NIH Grants Policy Statement for additional information on this reporting requirement.  

3. Reporting

When multiple years are involved, awardees will be required to submit the Non-Competing Continuation Grant Progress Report (PHS 2590) annually and financial statements as required in the NIH Grants Policy Statement.

A final progress report, invention statement, and Financial Status Report are required when an award is relinquished when a recipient changes institutions or when an award is terminated.

Section VII. Agency Contacts

We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants.

Application Submission Contacts

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Telephone 301-435-0714
TTY 301-451-5936
Email: GrantsInfo@nih.gov

eRA Commons Help Desk(Questions regarding eRA Commons registration, tracking application status, post submission issues)
Phone: 301-402-7469 or 866-504-9552 (Toll Free)
TTY: 301-451-5939
Email: commons@od.nih.gov

Scientific/Research Contact(s)

Bradley A. Ozenberger Ph.D.
National Human Genome Research Institute
Telephone: 301-496-7531
Email: bozenberger@mail.nih.gov

Peer Review Contact(s)

Rudy Pozzatti, Ph.D.
Office of Scientific Review
National Human Genome Research Institute
5635 Fisher Lane, Suite 4076
Bethesda, MD 20892
Telephone: (301) 496-7531
FAX: (301) 435-1580
Email: pozzattr@mail.nih.gov 

Financial/Grants Management Contact(s)

Cheryl Chick
Grants Management Branch()
Telephone: 301- 496-7531
Email: chickc@mail.nih.gov

Section VIII. Other Information

Recently issued trans-NIH policy notices may affect your application submission. A full list of policy notices published by NIH is provided in the NIH Guide for Grants and Contracts. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Authority and Regulations

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 Part 52 and 45 CFR Parts 74 and 92.


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