Department of Health and Human Services

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

Components of Participating Organizations
National Human Genome Research Institute (NHGRI), (http://www.nhgri.nih.gov)

Title: Near-Term Technology Development for Genome Sequencing STTR (R41/R42)

Announcement Type
New

Updates: The following updates relating to this announcement have been issued:

• September 29, 2006 (RFA-HG-06-019) - This RFA has been reissued as RFA-HG-06-019.

NOTICE: Applications submitted in response to this Funding Opportunity Announcement (FOA) for Federal assistance must be submitted electronically through Grants.gov (http://www.grants.gov) using the SF424 Research and Related (R&R) forms and the SF 424 (R&R) SBIR/STTR Application Guide. APPLICATIONS MAY NOT BE SUBMITTED IN PAPER FORMAT.

This FOA must be read in conjunction with the application guidelines included with this announcement in Grants.gov/Apply for Grants (hereafter called Grants.gov/Apply).

A registration process is necessary before submission and should be started at least two weeks in advance of the planned submission. See Section IV.

Two steps are required for on time submission:

1) The application must be submitted to Grants.gov by 8:00 p.m. Eastern Time on the submission date (see Key Dates below).

2) Applicants must complete a verification step in the eRA Commons within two business days of notification from NIH. Note: Since email can be unreliable, it is the responsibility of the applicant to periodically check on their application status in the Commons.

Request For Applications (RFA) Number: RFA-HG-06-003

Catalog of Federal Domestic Assistance Number(s)
93.172

Key Dates
Release/Posted Date: December 15, 2005
Opening Date: December 17, 2005 (Earliest date an application may be submitted to Grants.gov)
Letters of Intent Receipt Date(s): January 17, 2006
Application Submission Dates(s): February 17, 2006
Peer Review Date(s): June-July 2006
Council Review Date(s): September 12, 2006
Earliest Anticipated Start Date: September 29, 2006
Additional Information To Be Available Date (Url Activation Date): Not applicable
Expiration Date: February 18, 2006

Due Dates for E.O. 12372
Not Applicable

Additional Overview Content

Executive Summary

This Funding Opportunity Announcement (FOA) solicits Small Business Technology Transfer (STTR) grant applications from small business concerns (SBCs) to develop novel technologies that will substantially reduce the cost of genomic DNA sequencing. Current technologies are able to produce the sequence of a mammalian-sized genome of the desired data quality for $10 to $50 million; the goal of this initiative is to reduce costs by at least two orders of magnitude. It is anticipated that emerging technologies are sufficiently advanced that, with additional investment, it may be possible to achieve proof of principle or even early stage commercialization of multiple different approaches for genome-scale sequencing within five years.

• This FOA (RFA-HG-06-003) will utilize the STTR (R41/R42) grant mechanisms for Phase I, Phase II, and Fast-Track applications and runs in parallel with FOAs of identical scientific scope that solicit applications under the Small Business Innovation Research (SBIR [R43/44]) grant mechanisms (RFA-HG-06-002) and Research Project (R01), Exploratory/Developmental Grants (R21), and Exploratory/Developmental/Phase II Exploratory/Developmental Grants (R21/R33) grant mechanisms (RFA-HG-05-003).
• Contingent upon the availability of funds and the submission of a sufficient number of meritorious applications, the National Human Genome Research Institute (NHGRI) may make 1-6 awards and may award $1.5 million for STTR grants responding to this and a related STTR FOA, RFA-HG-06-005.
• Budgets up to $250,000 total costs per year and time periods up to 2 years may be requested for Phase I grants; budgets up to $1.5 million total costs per year and time periods up to 3 years may be requested for Phase II grants; and the total duration of support for Fast-Track applications cannot exceed 3 years.
• The following related FOAs solicit grant applications to support technology development to reduce genomic DNA sequencing costs by four orders of magnitude: RFA-HG-05-004; RFA-HG-06-004; and RFA-HG-06-005.
• Eligible organizations: Only United States SBCs are eligible to submit STTR applications. A SBC is one that, on the date of award for both Phase I and Phase II funding agreements, meets ALL of the criteria as described in Section III.
• Eligible individuals: Any individual with the skills, knowledge, and resources necessary to carry out the proposed research 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 programs. On an STTR application, the Project Director/Principal Investigator (PD/PI) may be employed with the SBC or the participating non-profit research institution as long as he/she has a formal appointment with or commitment to the applicant SBC, which is characterized by an official relationship between the small business concern and that individual.
• Applicant SBCs may submit more than one application, provided each application is scientifically distinct.
• See Section IV.1 for application materials. The application instructions for this Funding Opportunity Announcement (FOA) are located at the following links:
  • http://grants.nih.gov/grants/funding/424/SF424_RR_Guide_SBIR_STTR.doc (MS Word)
  • http://grants.nih.gov/grants/funding/424/SF424_RR_Guide_SBIR_STTR.pdf (PDF)
• For general information on SF424 (R&R) Application and Electronic Submission, see the following Web sites:
• SF424 (R&R) Application and Electronic Submission Information: http://grants.nih.gov/grants/funding/424/index.htm
• General information on Electronic Submission of Grant Applications: http://era.nih.gov/ElectronicReceipt/
• Telecommunications for the hearing impaired is available at: TTY 301-451-5936.
• Special receipt/submission dates are listed under Key Dates.
• Initial merit review convened by the Division of Extramural Activities, NHGRI.

Part I Overview Information

Part II Full Text of Announcement

Section I. Funding Opportunity Description
1. Research Objectives

Section II. Award Information
1. Mechanism 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. Request Application Information
2. Content and Form of Application Submission
3. Submission Dates and Times
A. Submission, 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

1. Research Objectives

PURPOSE

The purpose of this Funding Opportunity Announcement (FOA) issued by the National Human Genome Research Institute (NHGRI) is to solicit Small Business Technology Transfer (STTR) grant applications from small business concerns (SBCs) to develop novel technologies that will substantially reduce the cost of genomic DNA sequencing. Current technologies are able to produce the sequence of a mammalian-sized genome of the desired data quality for $10 to $50 million; the goal of this initiative is to reduce costs by at least two orders of magnitude. It is anticipated that emerging technologies are sufficiently advanced that, with additional investment, it may be possible to achieve proof of principle or even early stage commercialization of multiple different approaches for genome-scale sequencing within five years.

BACKGROUND

The ability to sequence complete genomes and the free dissemination of the sequence data have dramatically changed the nature of biological and biomedical research. Sequence and other genomic data have the potential to lead to remarkable improvement in many facets of human life and society, including the understanding, diagnosis, treatment and prevention of disease; advances in agriculture, environmental science and remediation; and the understanding of evolution and ecological systems.

The ability to sequence many genomes completely has been made possible by the enormous reduction of the cost of sequencing in the past two decades, from tens of dollars per base in the 1980s to a few cents per base today. However, even at current prices, the cost of sequencing a mammalian-sized genome is tens of millions of dollars and, accordingly, we must still be very selective when choosing new genomes to sequence. In particular, we remain very far away from being able to afford to use comprehensive genomic sequence information in individual health care. For this, and many other reasons, the rationale for achieving the ability to sequence entire genomes very inexpensively is very strong.

There are many areas of high priority research to which genomic sequencing at dramatically reduced cost would make vital contributions.

• Expanded comparative genomic analysis across species, which will yield great insights into the structure and function of the human genome and, consequently, the genetics of human health and disease. Studies to date that have compared small regions of several genomes, and draft versions of full genomes, have clearly demonstrated the need for much more complete data sets. While some of the needed data will be obtained over the next two or three years using existing DNA sequencing technology, and while costs will continue their gradual decline, the cost of current approaches to sequence acquisition will continue to limit the amount of much-needed data that can be produced.
  
  
• Studies of human genetic variation and the application of such information to individual health care, which will also require much cheaper sequencing technology. Today, genetic variation must be assessed by genotyping the relatively few known differences at a relatively small number of loci within the human population. A richer and better characterized catalog of such variable sites is being generated to support more detailed and powerful analyses. While these methods are, and will become even more, powerful and likely to provide a significant amount of important new information, they are nevertheless only a surrogate for determining the full, contiguous sequence of individual human genomes, and are not as informative as sequencing would be. For example, current genotyping methods are likely to miss rare differences between people at any particular location in the genome and have limited ability to determine long-range information (e.g., genomic rearrangements). Therefore, new methods based on complete genomic sequencing will be needed to use genomic information for individual health care in the most effective manner possible.
  
  
• Characterization of somatic changes of the genome that contribute to cancer. Currently, combinations of technologies can be applied in comparisons of tumor and normal tissue to obtain sequence data (on a very few genes) plus limited information on copy number changes, rearrangements, or loss of heterozygosity. However, such studies suffer from poor resolution and/or incomplete coverage of the genome. Furthermore, the cellular heterogeneity of tumor samples results in substantially reduced signal to noise differential in most genomic analyses of cancer. Low cost complete genome sequencing from exceedingly small samples, perhaps even single cells, would alter the battle against cancer in all aspects, from the research lab to the clinic.
  
  
• While the genomes of a few agriculturally important animals and plants have been sequenced, the most informative studies will require comparisons between different individuals, different domesticated breeds and several wild variants of each species.
  
  
• Sequence analysis of microbial communities, many members of which cannot be cultured, would provide a rich source of medically and environmentally useful information. And accurate, rapid sequencing may also be the best approach to microbial monitoring of food and the environment, including rapid detection and mitigation of bioterrorism threats.

Given the broad utility and high importance of dramatically reducing DNA sequencing costs, NHGRI is engaged in two parallel technology development programs. The first, described in this FOA and parallel FOAs for other grant mechanisms, has the objective of reducing the cost of producing a high quality sequence of a mammalian-sized genome by two orders of magnitude. The goal of the second program is the development of technology to sequence a genome for a cost that is reduced by four orders of magnitude. For both programs, the cost targets are defined in terms of a mammalian-sized genome, about 3 gigabases (Gb), with a target sequence quality equivalent to, or better than, that of the mouse assembly published in December 2002 (Nature 420:520, 2002).

The ultimate goal of these programs is to obtain technologies that can produce assembled sequence (i.e., de novo sequencing). However, an accompanying shorter-term goal is to obtain highly accurate sequence data at the single base level, i.e., without assembly information, that can be overlaid onto a reference sequence for the same organism (i.e., re-sequencing). This could be achieved, for example, with short reads that have no substantial information linking them to other reads. While the sequence product of this kind of technology would lack some important information, such as information about genomic rearrangements, it would nevertheless potentially be available more rapidly and produce data of great value for certain uses in studying disease etiology and in individualized medicine. Therefore, both programs objectives include a balanced portfolio of projects developing both de novo and re-sequencing technologies. As for de novo sequencing, the goal of technology development for re-sequencing is to reduce costs by two orders of magnitude, and ultimately four orders of magnitude, from the current cost of producing comparable data.

Sequencing strategy and quality

State-of-the-art technology, fluorescence detection of dideoxynucleotide-terminated DNA extension reactions resolved by capillary array electrophoresis (CAE), allows the determination of sequence read segments approximately 1000 nucleotides long. If all of the DNA in a 2-3 Gb genome were unique, it would be possible to determine the sequence of the entire genome by generating a sufficient number (10s of millions) of randomly-overlapping thousand-base reads and aligning their overlaps. However, the human and the majority of other interesting genomes contain a substantial amount of repetitive DNA (short [tens to thousands of nucleotides], nearly or completely identical sequences present in multiple [tens to thousands of] copies). To cope with the complexities of repetitive DNA elements and to assemble the thousand-base reads in the correct long-range order across the genome, current genomic sequencing methods involve a variety of additional strategies, such as the sequencing of both ends of cloned DNA fragments, use of libraries of cloned fragments of different lengths, incorporation of map information, achievement of substantial redundancy (multiple reads of each nucleotide from overlapping fragments) and application of sophisticated assembly algorithms to align and filter the reads.

The gold standard for genomic sequencing is 99.99% accuracy (not more than one error per 10,000 nucleotides) with essentially no gaps (http://www.genome.gov/10000923). At present, the final steps in achieving that very high sequence quality cannot be automated and require substantial hand-crafting. However, recent experience suggests that the majority of comparative sequence information can be obtained from automatically generated sequence assemblies that have been variously identified as high-quality draft or comparative grade. Therefore, while the ultimate goal is sequencing technology that produces perfect accuracy, the goal of the current de novo sequencing program is to develop technology for automatically generating sequence of at least the quality of the mouse draft genome sequence that was published in December 2002 (Nature 420:520, 2002).

For re-sequencing technologies, in which newly-determined sequence is overlaid on a scaffold of a known reference sequence from other individuals of the same organism, the challenges include the production of sequence of sufficiently high quality to distinguish between sequencing errors and real polymorphism. The presence of gene families with very similar sequence presents another complication, particularly when using technologies that produce short sequence reads. Additional challenges for short-read sequencing include the identification of genomic rearrangements, and the identification of haplotypes (i.e., linear juxtapositioning of particular single nucleotide polymorphism [SNP] alleles along a single chromosome) in diploid organisms. Thus, in proposing the development of re-sequencing technologies, it is essential to state the goals clearly in terms of the technical capability and costs associated with meeting these challenges.

Technology path

Most investigators interested in reducing DNA sequencing costs anticipate that a few additional two-fold decreases in cost can be achieved with the current CAE-based technology, with a realistic lower limit of perhaps $5 million per mammalian-sized genome. However, it is likely that this efficiency will only be achieved in a few very large, well-capitalized, experienced, automated laboratories. To achieve the broadest benefit from DNA sequencing technology for biology and medicine, systems are needed that are not only substantially more efficient but also are easier to use by the average research laboratory.

One set of current technology development efforts is aimed at increasing parallel sample processing while integrating the sample preparation and analysis steps on a single platform. Thus, in one approach, lithography is used to create a large number of microchannels on a single device and to integrate an efficient sample injector with each separation channel. Chambers for on-chip DNA amplification, cycle sequencing reactions and sample clean-up have been also developed, and experiments to integrate these steps, an approach that effectively places much of the sequencing process and process control onto the device, are being conducted in several laboratories. Improvements in separation polymers and fluorescent dyes will facilitate these developments. As these approaches are based largely on the experience of currently successful high-throughput CAE-based methods, they have potential to produce cost savings in the range of several factors of two beyond the CAE-based system itself. They also have the potential to widen the user base for the technology, as the infrastructure and knowledge needed to conduct relatively high-throughput sequencing, or clinical diagnostic sequencing, would be substantially reduced and simplified.

Other approaches to improving sequencing technology involve methods that are independent of the Sanger dideoxynucleotide chain termination reaction and electrophoretic separation of the termination products. Two methods that were proposed in the early days of the Human Genome Project involve the use of mass spectrometry and sequencing by hybridization. Both methods have been pursued, with some limited success for sequencing, but substantial success for other types of DNA analysis. Both continue to hold additional potential utility for sequencing, although certain inherent limitations will need to be overcome.

More recently, additional methodologies have been investigated. These may be classified into two approaches. One is sequencing-by-extension, in which template DNA is elongated in stepwise fashion, and each sequential extension product is detected. Extension is generally achieved by the action of a polymerase that adds a deoxynucleotide, followed by detection of a fluorescent or chemiluminescent signal, and the cycle is then repeated. Variants of this approach rely on other enzymes and detection of hybridization of labeled oligonucleotides. To obtain sufficient throughput, the method is implemented at a high level of multiplexing, by arraying large numbers of sequencing extension reactions on a surface. Key factors in this general approach include the manner in which the fluorescent signal is generated and the system requirements thus imposed. Depending on the specific approach, challenges of template extension methods include the synthesis of appropriate labeled nucleotide analogues of high purity; identifying processive polymerases that incorporate nucleotide analogs with high fidelity; discriminating fluorescent nucleotides that have been incorporated into the growing chain from those present in the reaction mix (background); distinguishing subsequent nucleotide additions from previous ones; accurate enumeration of homopolymer runs (multiple sequential occurrence of the same nucleotide); maintaining synchrony among the multiple copies of DNA being extended to generate a detectable signal or achievement of sensitivity that detects extension of individual DNA molecules; and developing fluidics, surface chemistry, and automation to build and run the system. Current efforts to develop such methods have generally produced short sequence reads (less than or equal to 100 bases), so a continuing challenge is to extend read length and develop sequence assembly strategies. NHGRI anticipates that the state of the art for this approach is sufficiently advanced that, with additional investment, it should be possible to achieve proof of principle or even early commercialization of multiple different approaches for genome-scale sequencing within five years. It is anticipated that the cost of genome sequencing with this technology could be reduced by two orders of magnitude from today’s costs. It is important to note that sequencing by extension is one prototype for achieving these time and cost goals, but other technological approaches may also be viable. Achieving these goals is the subject of this FOA.

A second alternative to CAE sequencing seeks to read the linear sequence of nucleotides without copying the DNA and without incorporating labels, relying instead on extraction of signal from the native DNA nucleotides. One now-familiar model for this approach, but almost certainly not the only way to achieve 10,000-fold reduction in sequencing costs, is nanopore sequencing, first introduced in the mid-1990s. Generally, this approach requires a sensor, perhaps comparable in size to the DNA molecule itself, that interacts sequentially with individual nucleotides in a DNA chain and distinguishes between them on the basis of chemical, physical or electrical properties. Optimal implementation of such a method would analyze intact, native genomic DNA molecules isolated from biological, medical or environmental samples without amplification or modification, and would provide very long sequence reads (tens of thousands to millions of bases) rapidly and at sufficiently high redundancy to produce assembled sequence of high quality. NHGRI seeks to support high quality projects to pursue novel technologies for decreasing sequencing costs by four orders of magnitude. NHGRI anticipates that it may take ten years to conduct the substantial basic research and technology development that are needed to achieve such a dramatic reduction of sequencing costs. Achieving this goal is the subject of the parallel Request for Applications (RFA) funding opportunities.

RESEARCH SCOPE

The goal of research supported under this FOA is to develop new or improved technology to enable rapid, efficient genomic DNA sequencing. The specific goal is to reduce sequencing costs by at least two orders of magnitude -- $100,000 serves as a useful target cost for a mammalian-sized genome because the availability of complete genomic sequences at that cost would revolutionize biological research and medicine. While not in a cost range that would enable the use of sequencing in individualized medicine, such technology would permit the sequencing of many genomes for a small fraction of current costs. A 100-fold cost reduction would make possible extensive studies of human variation for disease gene studies, substantially expanded comparative genomics to understand the human genome, and many other studies relevant to NIH, other federal agencies and the private sector. Entirely new lines of investigation would be enabled by making large-scale sequencing accessible to the diverse interests of many research laboratories and companies.

Many projects aimed at next-generation DNA sequencing technologies require substantial advances in a combination of fields such as signal detection, enzymology, chemistry, engineering, bioinformatics, etc. It is therefore anticipated that proposals responding to this FOA will involve fundamental and engineering research conducted by multidisciplinary teams of investigators. The guidance for budget requests accommodates the formation of groups having investigators at several institutions, in cases where that is needed to assemble a team of the appropriate balance, breadth and experience.

The scientific and technical challenges inherent in achieving a 100-fold reduction in sequencing costs are considerable. Achieving this goal may require research projects that entail substantial risk. That risk should be balanced by an outstanding scientific and management plan designed to achieve the very high payoff goals of this solicitation. High risk, high payoff projects may fail for legitimate reasons; applicants proposing such projects should describe plans to terminate the project if key milestones cannot be achieved in a reasonable time.

Applicants may propose to develop full-scale sequencing systems, or to investigate key components of such systems. For the latter, applicants must describe how the knowledge gained as a result of their project would be incorporated into a full system that they might subsequently propose to develop, or that is being developed by other groups. Such independent proposals are an important path for pursuing novel, high risk/high pay-off ideas.

Research conducted under this FOA may include development of the computational tools associated with the technology, e.g., to extract sequence information, including image analysis and signal processing, and to evaluate sequence quality and assign confidence scores. It may also address strategies to assemble the sequence from the information being obtained from the technology or by merging the sequence data with information from parallel technology. However, this FOA will not support development of sequence assembly software independent of technology development to obtain the sequence.

The quality of sequence to be generated by the technology is of paramount importance for this solicitation. Two major factors contributing to genomic sequence quality are per-base accuracy and contiguity of the assembly. Much of the utility of comparative sequence information will derive from characterization of sequence variation between species, and between individuals of a species. Therefore, per-base accuracy must be high enough to distinguish polymorphism at the single-nucleotide level (substitutions, insertions, deletions). Experience and resulting policy have established a target accuracy of not more than one error per 10,000 bases. All applications in response to this FOA, whether to develop re-sequencing or de novo sequencing technologies, must propose achieving per-base quality at least to this standard.

Assembly information is needed for determining sequence of new genomes, and ultimately also for genomes for which a reference sequence exists, to detect rearrangements, insertions and deletions. Rearrangements are known to cause diseases, and knowledge of rearrangements can reveal new biological mechanisms. The phase of single nucleotide polymorphisms to define haplotypes is important in understanding and diagnosing disease. Achieving a high level of sequence contiguity may be essential to achieve the full benefit from the use of sequencing for individualized medicine, e.g., to evaluate genomic contributions to risk for specific diseases and syndromes, and drug responsiveness. Nevertheless, it is recognized that perfect sequence assembly from end to end of each chromosome is unlikely to be achievable with most technologies in a fully automated fashion and without adding considerable cost. Therefore, for the purpose of this solicitation, grant applications proposing technology development for de novo sequencing shall describe how they will achieve, for about $100,000, a draft-quality assembly that is at least comparable to that represented by the mouse draft sequence produced by December 2002: 7.7-fold coverage, 6.5-fold coverage in Q20 bases, assembled into 225,000 sequence contigs connected by at least two read-pair links into supercontigs [total of 7,418 supercontigs at least 2 kb long], with N50 length for contigs equal to 24.8 kb and for supercontigs equal to 16.9 Mb (Nature 420:520, 2002). Grant applications that propose technology development for re-sequencing should explain how they will achieve a two-order-of magnitude reduction in cost compared to technologies that can produce similar quality of data, today.

The grant applications will be evaluated, and funding decisions made, in such a way as to develop a balanced portfolio that has strong potential to develop both robust re-sequencing and de novo sequencing technologies. If the estimate is correct, that achieving the goal of a 100-fold cost reduction for de novo genome sequencing will require about 5 years, then low-cost re-sequencing technologies might be expected to be demonstrated in a shorter time. Grant applications that present a plan to achieve high quality re-sequencing while on the path to high quality de novo sequencing will receive high priority.

The major focus of this FOA is on the development of new technologies for detection of nucleotide sequence. Any new technology will eventually have to be incorporated effectively into the entire sequencing workflow, starting with a biological sample and ending with sequence data of the desired quality, and this issue should be addressed. Sample preparation requirements are a function of the detection method and the sample detection method affects the way in which output data are handled. Therefore, these aspects of the problem are clearly relevant and should be addressed in an appropriate timeframe in the research plan. However, applicants should address the most critical and highest-risk aspects of the project, on which the rest of the project is dependent, as early as possible in the research plan.

Practical implementation issues related to workflow and process control for efficient, high quality, high-throughput DNA sequencing should be considered early in system design. Some technology development groups lack practical experience in high throughput sequencing, and in testing of methods and instruments for robust, routine operation. Applicants may therefore wish to include such expertise as they develop their suite of collaborations and capabilities.

The goal of this research is to develop technology to produce sequence from entire genomes. It is conceivable that sequence from selected important regions (e.g., all of the genes) could be determined in the near future. Grant applications that propose to meet the cost targets by sequencing only selected regions of a genome will be considered unresponsive. However, applications that propose novel ways to sequence selected genomic regions, cost-effectively, while on a path to whole-genome sequencing, will be considered.

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

1. Mechanism(s) of Support

This FOA (RFA-HG-06-003) will utilize the STTR (R41/R42) grant mechanisms for Phase I, Phase II, and Fast-Track applications and runs in parallel with FOAs of identical scientific scope that solicit applications under the Small Business Innovation Research (SBIR [R43/44]) grant mechanisms (RFA-HG-06-002) and Research Project (R01), Exploratory/Developmental Grants (R21), and Exploratory/Developmental/Phase II Exploratory/Developmental Grants (R21/R33) grant mechanisms (RFA-HG-05-003). Related FOAs (RFA-HG-05-004, RFA-HG-06-004, RFA-HG-06-005) solicit grant applications from SBCs and others to develop technologies to meet the more challenging goal of achieving cost reduction by four orders of magnitude in about ten years.

Applicants may not simultaneously submit identical/essentially identical applications under both this funding opportunity and any other HHS FOA, including the SBIR or STTR Parent FOAs (see Small Business Funding Opportunities web page).

Phase II applications in response to this funding opportunity will only be accepted as competing renewals (formerly competing continuations ) of previously funded Phase I STTR awards. The Phase II must be a logical extension of the Phase I research but not necessarily as a Phase I project supported in response to this funding opportunity.

The applicant SBC will be solely responsible for planning, directing, and executing the proposed project. Future unsolicited, competing renewal applications based on this project will compete with all STTR and other applications, as appropriate, and will be reviewed according to the customary peer review procedures. Applications that are not funded in the competition described in this FOA may be submitted as NEW applications through Grants.gov/Apply using the standard NIH STTR submission dates of April 1, August 1, and December 1 (or January 2, May 1, and September 1 for NIH AIDS and AIDS-related STTR applications).

This funding opportunity uses just-in-time concepts. The modular budget format is no longer accepted for STTR grant applications. Applicants must complete and submit budget requests using the SF424 Research and Related (R&R) Budget component found in the application package attached to this FOA in Grants.gov/Apply.

2. Funds Available

The SF424 (R&R) SBIR/STTR Application Guide indicates the statutory guidelines of funding support and project duration periods for Phase I and Phase II STTR awards. Because the length of time and cost of research in this area often exceed those normally awarded, NHGRI will entertain well-justified applications for this funding opportunity, as follows. Budgets up to $250,000 total costs per year and time periods up to 2 years for Phase I may be requested. Budgets up to $1.5 million total costs per year and up to 3 years may be requested for Phase II. Total costs include direct costs, Facilities & Administrative (F&A)/indirect costs, and fee. Fast-Track applications may not exceed a total duration period of 3 years.

The NHGRI intends to commit approximately $1.5 million dollars in FY 2006 to fund 1-6 Phase I and/or Phase II applications under the STTR set-aside funding mechanism for this FOA and a related STTR FOA, RFA-HG-06-005. Although the NHGRI’s financial plans provide support for this program, awards pursuant to this FOA are contingent upon the availability of funds and the submission of a sufficient number of meritorious applications. At this time, it is not known if competing renewal applications will be accepted and/or if this FOA will be reissued.

1. Eligible Applicants

1.A. Eligible Institutions

Only United States small business concerns (SBCs) are eligible to submit STTR applications. A small business concern is one that, at the time of the award for both Phase I and Phase II STTR awards, meets all of the following criteria:

1. Is independently owned and operated, is not dominant in the field of operation in which it is proposing, has a place of business in the United States and operates primarily within the United States or makes a significant contribution to the US economy, and is organized for profit.

2. Is (a) at least 51% owned and controlled by one or more individuals who are citizens of, or permanent resident aliens in, the United States.

3. Has, including its affiliates, an average number of employees for the preceding 12 months not exceeding 500, and meets the other regulatory requirements found in 13 C.F.R. Part 121. Business concerns are generally considered to be affiliates of one another when either directly or indirectly, (a) one concern controls or has the power to control the other; or (b) a third-party/parties controls or has the power to control both.

Control can be exercised through common ownership, common management, and contractual relationships. The term "affiliates" is defined in greater detail in 13 C.F.R. 121.103. The term "number of employees" is defined in 13 C.F.R. 121.106.

A business concern may be in the form of an individual proprietorship, partnership, limited liability company, corporation, joint venture, association, trust, or cooperative. Further information may be obtained at http://sba.gov/size, or by contacting the Small Business Administration's Government Contracting Area Office or Office of Size Standards.

One of the circumstances that would lead to a finding that an organization is controlling or has the power to control another organization involves sharing common office space and/or employees and/or other facilities (e.g., laboratory space). Access to special facilities or equipment in another organization is permitted (as in cases where the awardee organization has entered into a subcontractual agreement with another organization for a specific, limited portion of the research project). However, research space occupied by an STTR awardee organization must be space that is available to and under the control of the STTR awardee for the conduct of its portion of the proposed project.

Title 13 C.F.R. 121.3 also states that control or the power to control exists when key employees of one concern organize a new concern ... and serve as its officers, directors, principal stockholders, and/or key employees, and one concern is furnishing or will furnish the other concern with subcontracts, financial or technical assistance, and/or other facilities, whether for a fee or otherwise. Where there is indication of sharing of common employees, a determination will be made on a case-by-case basis of whether such sharing constitutes control or the power to control.

For purposes of the STTR program, personnel obtained through a Professional Employer Organization or other similar personnel leasing company may be considered employees of the awardee. This is consistent with SBA’s size regulations, 13 C.F.R. 121.106 Small Business Size Regulations.

All STTR grant applications will be examined with the above eligibility considerations in mind. If it appears that an applicant organization does not meet the eligibility requirements, NIH will request a size determination by the SBA. If eligibility is unclear, NIH will not make an STTR award until the SBA provides a determination..

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 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 programs.

For a STTR application, the Project Director/Principal Investigator (PD/PI) may be employed with the SBC or the participating non-profit research institution as long as s/he has a formal appointment with or commitment to the applicant SBC, which is characterized by an official relationship between the SBC and that individual.

As defined in 42 CFR 52, the PD/PI is the single individual designated by the grantee in the grant application who is responsible for the scientific and technical direction of the project. When the proposed PD/PI clearly does not have sufficient qualifications to assume this role, the application is not likely to receive a favorable evaluation.

The PD/PI must commit a minimum of 10% effort to the project and the PD/PI must have a formal appointment with or commitment to the applicant small business concern, which is characterized by an official relationship between the small business concern and that individual. Such a relationship does not necessarily involve a salary or other form of remuneration. In all cases, however, the PD/PI’s official relationship with the grantee must entail sufficient opportunity for the PD/PI to carry out his or her responsibilities for the overall scientific and technical direction of the project. Documentation (e.g., consultant, consortium and contractual arrangements) describing the official relationship of the PD/PI with the applicant small business concern should NOT be submitted with the grant application, but a copy must be furnished upon the request of the NIH awarding component.

The following are examples of situations describing the official relationship of the PD/PI with the applicant small business organization:

• PD/PI with a full-time, university appointment may also have appointments with other organizations (with or without salary) and still appropriately consider his or her commitment to the university to be full-time, consistent with the personnel policies and procedures of the university applied on a routine basis. The PD/PI’s commitment to the university and other organizations (including the applicant small business concern) cannot exceed 100% of his or her total professional effort.
  
  
• PD/PI with a full-time, 12-month appointment with a small business concern would be considered to have a commitment to the applicant organization of 100% of his or her total professional effort.
  
  
• PD/PI who has a part-time appointment with a small business concern and has concurrent commitments or appointments with organizations in addition to the small business concern would deem each commitment as a portion of 100% of his or her total professional effort.

2. Cost Sharing or Matching
This program does not require cost sharing as defined in the current NIH Grants Policy Statement.

3. Other-Special Eligibility Criteria

In STTR Phase I and Phase II, at least 40% of the work must be performed by the small business concern and at least 30% of the work must be performed by the single, partnering research institution. The basis for determining the percentage of work to be performed by each of the cooperative parties will be the total of direct and F&A/indirect costs attributable to each party, unless otherwise described and justified in Item 12, Consortium/Contractual Arrangements, of the PHS398 Research Plan component of the SF424 (R&R) application forms.

The NIH will accept as many "different" applications as the applicant organization chooses. However, the NIH will not accept similar grant applications with essentially the same research focus from the same applicant organization. This includes derivative or multiple applications that propose to develop a single product, process, or service that, with non-substantive modifications, can be applied to a variety of purposes. Applicants may not simultaneously submit identical/essentially identical applications under both this funding opportunity and another HHS FOA, including the SBIR or STTR Parent FOAs (see Small Business Funding Opportunities web page).

To download a SF424 (R&R) Application Package and SF424 (R&R) SBIR/STTR Application Guide for completing the SF424 (R&R) forms for this FOA, link to http://www.grants.gov/Apply/ and follow the directions provided on that Web site.

A one-time registration is required for institutions/organizations at both:

• Grants.gov (http://www.grants.gov/GetStarted) and
• eRA Commons (http://era.nih.gov/ElectronicReceipt/preparing.htm)

PD/PIs should work with their institutions/organizations to make sure they are registered in the NIH Commons.

Several additional separate actions are required before an applicant SBC can submit an application through Grants.gov. See "Preparing for Electronic Submission" at http://era.nih.gov/ElectronicReceipt/preparing.htm.

Several of the steps of the registration process could take up to two weeks. Therefore, applicants should immediately check with their business official to determine whether their small business is already registered in both Grants.gov and the Commons.

Note: The STTR applicant organization must officially affiliate the PD/PI with the small business concern in the Commons if the PD/PI is not an employee of the small business concern.

Following are the steps to affiliate a PD/PI to the applicant organization/institution:

1. PD/PI gives Commons user ID and email address to the administrator of the applicant institution. (The email address must be the one that is contained in the Personal Profile for the PD/PI.)

2. Administrator logs into the Commons. (The administrator can be the Signing Official, Administrative Official, or the Accounts Administrator.)

3. Administrator selects "Administration" tab and then "Accounts" tab.

4. Administrator selects "Create Affiliation" tab.

5. Administrator enters the Commons User ID and Email address into the appropriate fields and clicks "Submit."

Note: The account cannot have any other roles attached to it other than the PD/PI.

1. Request Application Information

Applicants must download the SF424 (R&R) application forms and SF424 (R&R) Application Guide for this FOA through Grants.gov/Apply.

Note: Only the forms package directly attached to a specific FOA can be used. You will not be able to use any other SF424 (R&R) forms (e.g., sample forms, forms from another FOA), although some of the "Attachment" files may be useable for more than one FOA.

For further assistance contact GrantsInfo: Telephone (301) 710-0267, Email: [email protected].

Telecommunications for the hearing impaired: TTY (301) 451-5936.

2. Content and Form of Application Submission

Prepare all STTR applications using the SF424 (R&R) application forms and SF424 (R&R) SBIR/STTR Application Guide (MS Word) or PDF) instructions.

The SF424 (R&R) application is comprised of data arranged in separate components. Some components are required, others are optional. The forms package associated with this announcement in Grants.gov/ APPLY will include all applicable components, required and optional. A completed application in response to this announcement will include the following components:

Required Components:

SF424 (R&R) (Cover component)
Research & Related Project/Performance Site Locations
Research & Related Other Project Information
Research & Related Senior/Key Person
Research & Related Budget
Research & Related Subaward Budget Form

PHS398 Cover Page Supplement
PHS398 Research Plan
PHS398 Checklist
SBIR/STTR Information

Optional Components:

PHS398 Cover Letter File

3. Submission Dates and Times
See Section IV.3.A. for details.

3.A. Submission, Review and Anticipated Start Dates

Opening Date: December 17, 2005 (Earliest date an application may be submitted to Grants.gov)
Letters of Intent Receipt Date: January 17, 2006
Application Submission Dates: February 17, 2006
Peer Review Date: June-July 2006
Council Review Date: September 12, 2006
Earliest Anticipated Start Date: September 29, 2006

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 PD/PI
• 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 NHGRI staff to estimate the potential review workload and plan the review.

The letter of intent is to be sent by the date listed in Section IV.3.A.

The letter of intent should be sent to:

Jeffery A. Schloss, Ph.D.
Division of Extramural Research
National Human Genome Research Institute, NIH
5635 Fishers Lane, Suite 4076
Bethesda, MD 20892-9305
Telephone: (301) 496-7531
Email: [email protected]

3.B. Sending an Application to the NIH

Applications in response to this FOA may only be submitted to Grants.gov through Grants.gov/Apply.
PAPER APPLICATIONS WILL NOT BE ACCEPTED.

3.C. Application Processing

Applications may be submitted to Grants.gov on or after (i.e., the Opening Date on Grants.gov) and must be submitted no later than 8:00 p.m. Eastern Time on the application submission dates identified in Section IV.3.A.. If an application is not submitted by that date, the application may be delayed in the review process or not reviewed.

Upon receipt, applications will be transferred from Grants.gov to the NIH Electronic Research Administration process for validation. Both the PD/PI and the Signing Official for the organization must verify the submission via Commons within 2 business days of notification of the NIH validation.

Upon receipt, applications will be evaluated for completeness by the Center for Scientific Review (CSR), NIH, and for responsiveness by the NHGRI. 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.

There will be an acknowledgement of receipt of applications from Grants.gov and the Commons. Information related to the assignment of an application to a Scientific Review Group is also in the 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.

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 renewal 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 renewal 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.

6. Other Submission Requirements

The NHGRI anticipates that research to meet the goals of this program will require about five years. Therefore, a timeline for up to a 5 year project should be presented, culminating in the demonstration of sequencing a substantial amount of DNA (e.g., at least 0.5-1 gigabase) at the target cost and quality; other measures may be proposed by the applicant. A detailed research plan must be presented for the 1-3 years of requested support. The application should include a description of the level of risk of key technical challenges, alternative approaches, go/no-go decision points, etc. It should also include a detailed timeline accompanied by quantitative milestones (see below) that address the key scientific and technical challenges central to the approach. The timeline and milestones will be essential for use by both the grantee and NHGRI for planning the research projects and assessment of progress toward goals, and by the reviewers for evaluating the proposal.

Timelines and quantitative milestones are essential for development of a realistic research plan; they provide a basis for project leaders to make decisions, assess their own progress, set priorities, and redistribute resources when needed. It will be particularly important to establish quantitative milestones in cases where subsequent steps in technology development depend upon threshold performance characteristics of earlier developments. Elaboration of timelines and milestones is primarily the responsibility of the applicant, and the quality and utility of the proposed timelines and milestones will be a review criterion, because they reflect the insights and judgment of the applicant concerning key challenges and how best to conduct the research. The NHGRI appreciates that these projects will require research, not just engineering; progress toward milestones will be evaluated accordingly. If the proposed timeline and milestones are not adequate in the case of an otherwise meritorious proposal, reviewers of the application may make recommendations to NHGRI regarding improved timelines and milestones.

To accelerate progress in the field of advanced DNA sequencing technology development, grantees will be required to participate actively and openly in at least one grantee meeting per year. Substantial information sharing will be required and is a condition of the award; failure to openly share information will be grounds for discontinuation of funding. It is understood that some information developed under the grants will be proprietary and cannot be shared immediately without damaging the commercialization potential of the technology. Applicants should describe their plans for participating in the grantee meetings and for managing the intellectual property concerns in the context of those meetings and other opportunities for information sharing. Other investigators in the field (i.e., not supported under this program) may be invited to participate in these workshops; their agreement to share information substantially will be a prerequisite to participation. Applicants should request travel funds in their budgets for the PD/PI and two additional lead investigators to attend the annual meetings.

Applicants may include funds for an internally appointed advisory board. However, they should not contact potential advisors, nor should potential advisors be named in the grant application, to avoid conflicts of interest in the review process.

All applicants must describe their plan for providing access to the technology developed under this grant support. For example, the technology might be made available as a fee-for-service, through sale of instruments and/or reagents, through collaboration, through publication and posting of results, plans and methods, or by other means.

In summary, applicants must incorporate into application section Research Design and Methods :

• A 5-year timeline that broadly describes the path to achieving long term goals;
• A detailed timeline for the period of requested funding;
• Quantitative milestones against which progress toward the timeline will be measured;

In addition to the research plan, applicants must include, after Research Design and Methods and before Literature Cited, a management plan (not to exceed 4 pages) incorporating:

• Plans to manage collaborations, including e.g., multidisciplinary interactions, geographic separation;
• Plans to manage key project decision points, e.g., use of milestones for determining resource re-allocation, project re-direction, etc.;
• A plan for sharing data at grantee meetings, consistent with the goals described above;
• Plans for data and technology dissemination (see below, Plan for Sharing Research Data);
• Institutional commitment, if any (see Section III, 2, Cost Sharing or Matching); and
• Plans for an internal advisory board, if desired.

Page limits for the management plan are in addition to the page limits for the STTR Research Plan.

All application instructions outlined in the SF424 (R&R) SBIR/STTR Application Guide (MS Word or PDF) are to be followed, with the following requirements.

Note: While each section of the Research Plan needs to eventually be uploaded separately as a PDF attachment, applicants are encouraged to construct the Research Plan as a single document, separating sections into distinct PDF attachments just before uploading the files. This approach will enable applicants to better monitor formatting requirements such as page limits.

STTR Phase I applications:

• Although preliminary data are not required, they may be included.
• Items 2-5 of the Research Plan component may not exceed 15 pages, including tables, graphs, figures, diagrams, and charts.
• Introduction (required for a resubmission application) is limited to one (1) page.
• The Biographical Sketch is limited to a maximum of 4 pages for each senior/key person. (This includes the table at the top of the first page.)
• There is no further limitation on the total number of pages for the entire Phase I application; however, applicants are encouraged to be succinct.

STTR Phase II applications:

• Items 2-5 of the Research Plan component may not exceed 25 pages, including tables, graphs, figures, diagrams, and charts.
• Introduction (required for a resubmission application) is limited to three (3) pages.
• The Biographical Sketch is limited to a maximum of four (4) pages for each senior/key person. (This includes the table at the top of the first page.)
• The Phase II application must present a Commercialization Plan (maximum 15 pages) that addresses specific points as described in the SF424 (R&R) SBIR/STTR Application Guide (MS Word or PDF) and the SBIR/STTR Information Component.
• There is no further limitation on the total number of pages for the entire Phase II application; however, applicants are encouraged to be succinct.

STTR Fast-Track applications:

• Unlike in the past where Fast-Track applicants were required to submit two separate applications (one for Phase I and one for Phase II), the NIH Fast-Track application is now a single application consisting of Phase I and Phase II activities. See the SF424 (R&R) SBIR/STTR Application Guide.
• The Phase I portion of a Fast-Track must specify clear, measurable goals (milestones) that should be achieved prior to initiating Phase II work.
• The Fast-Track application must present a Commercialization Plan (maximum 15 pages) that addresses specific points as described in the SF424 (R&R) SBIR/STTR Application Guide.
• Introduction (required for a resubmission application) is limited to three (3) pages.
• Items 2-5 of the Research Plan may not exceed 25 pages. That is, the combined Phase I and Phase II plans for Fast-Track applications (for Items 2-5) must be contained within the 25-page limitation.

Plan for Sharing Research Data

All applicants must describe their plans for disseminating information about, and providing access to the technology developed under this grant support. For example, the technology might be made available as a fee-for-service, through sale of instruments and/or reagents, through collaboration, through publication and posting of results, plans and methods, or by other means.

Applicants should include a brief one paragraph description of how final research data will be shared, or explain why data-sharing is not possible. The specific nature of the data to be collected will determine whether or not the final dataset may be shared. If the final data are not amenable to sharing, for example, if they are proprietary, this must be explained in the application. The Small Business Act requires NIH to protect from disclosure and nongovernmental use all SBIR and STTR data developed from work performed under an SBIR and STTR funding agreement for a period of 4 years after the closeout of either a Phase I or Phase II grant unless NIH obtains permission from the awardee to disclose these data. The data rights protection period lapses only upon expiration of the protection period applicable to the SBIR and STTR award, or by agreement between the small business concern and NIH. Applicants are encouraged to discuss their data-sharing plan with NHGRI Program staff.

The reasonableness of the data sharing plan or the rationale for not sharing research data may be assessed by the reviewers. However, reviewers will not factor the proposed data sharing plan into the determination of scientific merit or the priority score. For more information on data sharing see http://grants.nih.gov/grants/policy/data_sharing/ and http://grants.nih.gov/grants/policy/data_sharing/data_sharing_faqs.htm. (See FAQ #13.)

Sharing Research Resources

NIH policy requires that grant awardee recipients make unique research resources readily available for research purposes to qualified individuals within the scientific community after publication (NIH Grants Policy Statement http://grants.nih.gov/grants/policy/nihgps_2003/index.htm and http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part7.htm#_Toc54600131). Investigators responding to this funding opportunity should include a plan for sharing research resources addressing how unique research resources will be shared or explain why sharing is not possible.

The adequacy of the resources sharing plan and any related data sharing plans will be considered by NHGRI Program staff when making recommendations about funding applications. The effectiveness of the resource sharing will be evaluated as part of the administrative review of each Non-Competing Grant Progress Report (PHS 2590). See Section VI.3. Reporting.

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

2. Review and Selection Process

Applications that are complete and responsive to the FOA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the NHGRI 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 the National Advisory Council for Human Genome Research.

Applications submitted in response to this funding opportunity will compete for available funds with all other recommended STTR applications. The following will be considered in making funding decisions:

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

The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. In the written comments, reviewers will be asked to discuss the following aspects of the application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. The scientific review group will address and consider each of these criteria in assigning the application's overall score, weighting them as appropriate for each application.

• Significance
• Approach
• Innovation
• Investigator
• Environment
• Additional Review Criteria

The 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.

All STTR Applications

Significance: Does the proposed project have commercial potential to lead to a marketable product, process or service? Does this study address an important problem? What may be the anticipated commercial and societal benefits that may be derived from the proposed research? 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 application lead to enabling technologies (e.g., instrumentation, software) for further discoveries? Will the technology have a competitive advantage over existing/alternate technologies that can meet the market needs? Does the study directly address the problem outlined in this FOA? Are the plans sufficiently bold to constitute a substantial advance, if they can be achieved, toward the demanding goals of the FOA?

Approach: Are the conceptual or clinical framework, design, methods, and analyses adequately developed, well-integrated, and appropriate to the aims of the project? Is the proposed plan a sound approach for establishing technical and commercial feasibility? Does the applicant acknowledge potential problem areas and consider alternative strategies? Are the milestones and evaluation procedures appropriate? Are key scientific and technological issues on which the rest of the approach depends, identified and addressed early in the project? Does the proposed technology address sequence quality and the sequencing of entire genomes? Does the application clearly state whether the goal is to develop re-sequencing, or de novo sequencing technology, and if the latter, is there an adequate plan for evaluating the achieved long-range contiguity? Is the analysis of sequencing costs well developed and well-informed? Are bold plans counterbalanced to manage the inherent risk, for example by firm theoretical basis, reasonable preliminary data (depending on the mechanism), the track record of the lead investigators, and an outstanding scientific and management plan? Are the timeline and milestones logical and realistic? Are key technical barriers and dependencies identified? Are milestones adequately developed and quantitative, to serve as effective guidance for assessment of progress by the investigators and the NHGRI? Are plans to participate actively and openly in grantee meetings sufficiently clear and forthcoming so as to contribute substantially to advancement of the field?

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

Investigator: Is the PD/PI appropriately trained and capable of coordinating and managing the proposed STTR? Are the investigators well suited to carry out this work? Does the investigative team bring complementary and integrated expertise to the project (if applicable)? Is the work proposed appropriate to the experience level of the PD/PI and other researchers, including consultants and subcontractors (if any)? Are the relationships of the key personnel to the small business and to other institutions appropriate for the work proposed? Do the PD/PI and other lead investigators have sufficient experience to manage a project of the proposed complexity? Are plans to integrate activities and set priorities across the multiple disciplines and investigators (and institutions, if appropriate), adequately developed and explained?

Environment: Is there sufficient access to resources (e.g., equipment, facilities)? Does the scientific and technological 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?

Phase II Applications
In addition to the above review criteria:

1. How well did the applicant demonstrate progress toward meeting the Phase I objectives, demonstrating feasibility, and providing a solid foundation for the proposed Phase II activity?

2. Did the applicant submit a concise Commercialization Plan that adequately addresses the specific areas described in the SF424 (R&R) SBIR/STTR Application Guide and the SBIR/STTR Information component?

3. Does the project carry a high degree of commercial potential, as described in the Commercialization Plan?

Resubmission Applications (formerly amended applications)

In addition to the above criteria, the following criteria will be applied to resubmission applications.

1. Are the responses to comments from the previous scientific review group adequate?

2. Are the improvements in the resubmission application appropriate?

Phase I/Phase II Fast-Track Application Review Criteria

For Phase I/Phase II Fast Track applications, the following criteria also will be applied:

1. Does the Phase I application specify clear, appropriate, measurable goals (milestones) that should be achieved prior to initiating Phase II?

2. Did the applicant submit a concise Commercialization Plan that adequately addresses the specific areas described in the SF424 (R&R) SBIR/STTR Application Guide and the SBIR/STTR Information component?

3. To what extent was the applicant able to obtain letters of interest, additional funding commitments, and/or resources from the private sector or non-SBIR/ STTR funding sources that would enhance the likelihood for commercialization?

4. Does the project carry a high degree of commercial potential, as described in the Commercialization Plan?

Phase I and Phase II Fast-Track applications that satisfy all of the review criteria will receive a single rating.

For Fast-Track applications, the Phase II portion may not be funded until a Phase I final report and other documents necessary for continuation have been received and assessed by program staff that the Phase I milestones have been successfully achieved. Items 2-5 of the Research Plan may not exceed 25 pages. That is, the combined Phase I and Phase II plans for a Fast-Track application (for Items 2-5) must be contained within the 25-page limitation.

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 item 6 of the Research Plan component of the SF424 (R&R).

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 item 7 of the Research Plan component of the SF424 (R&R).

Care and Use of Vertebrate Animals in Research: If vertebrate animals are to be used in the project, the five items described under item 11 of the Research Plan component of the SF424 (R&R) 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 may be assessed by the reviewers. Is the percent effort listed for the PD/PI appropriate for the work proposed? Is each budget category realistic and justified in terms of the aims and methods?

Period of Support: The appropriateness of the requested period of support in relation to the proposed research.

2.C. Sharing Research Data

The reasonableness of the data sharing plan or the rationale for not sharing research data may be assessed by the reviewers. However, reviewers will not factor the proposed data sharing plan into the determination of scientific merit or the priority score. The funding organization will be responsible for monitoring the data sharing policy. http://grants.nih.gov/grants/policy/data_sharing and http://grants.nih.gov/grants/policy/data_sharing/data_sharing_faqs.htm. (See FAQ #13.)

2.D. Sharing Research Resources

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

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

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

3. Anticipated Announcement and Award Dates
Not applicable

1. Award Notices

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.

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.

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

Prior to funding an application, the NHGRI will negotiate the milestones with the applicant, beginning with the applicant’s stated milestones and incorporating recommendations from the review panel, the National Advisory Council for Human Genome Research, and staff. The negotiated milestones will become a condition of the award, including appropriate language to recognize that the project includes research whose outcomes are unpredictable. In the case of research programs projected to require longer than the initial grant period, the decision to fund beyond the initial period will be based on a competitive renewal process that will take into account overall progress in the field as well as progress on the individual research effort, as compared to the negotiated milestones.

For Fast-Track awards, the transition from the R41 to the R42 will depend upon completion of negotiated R41 milestones. Once these milestones have been achieved, the PD/PI will submit a progress report to NHGRI. Receipt of this report will trigger administrative review to determine if the R42 should be awarded. Administrative review may engage the use of outside consultants. The decision to award the R42 will be based on successful completion of negotiated milestones, negotiation of revised milestones for the R42 phase, program priorities, and availability of funds.

To accelerate progress in the field of advanced DNA sequencing technology development, grantees will be expected to participate actively and openly in at least one grantee meeting per year. Substantial information sharing will be required and is a condition of the award; failure to openly share information will be grounds for discontinuation of funding. It is understood that some information developed under the grants will be proprietary and cannot be shared immediately without damaging the commercialization potential of the technology. Applicants should describe their plans for participating in the grantee meetings and for managing the intellectual property concerns in the context of those meetings and other opportunities for information sharing. Other investigators in the field (i.e., not supported under this program) may be invited to participate in these workshops; their agreement to share information substantially will be a prerequisite to their participation. The applicant’s participation plan, after negotiation with NHGRI staff, will become the minimum standard for continued funding.

Grantees will be asked to host the annual grantee meetings on a rotating basis. The NHGRI will negotiate a schedule for the grantee meetings and will adjust budgets to accommodate these meetings. Holding these meetings at grantee sites will facilitate information sharing and participation of a larger portion of the research staff than would otherwise occur.

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.

3. Reporting

When multiple years are involved, awardees will be required to submit the Non-Competing Grant Progress Report (PHS 2590) annually and financial statements as required in the NIH Grants Policy Statement. Applicants must plan to submit two progress reports per year one at the time of the non-competing continuation and one at a time to be determined by NHGRI staff. The latter may coincide with grantee meetings, meetings of advisors to NHGRI, or site visits. The NHGRI will use information from reports, meetings, site visits, etc. to evaluate each grantee’s progress and the success of the overall program; this information will be used to determine if funding levels should be increased or decreased for future years, for each grant, and for the program.

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:

Jeffery A. Schloss, Ph.D.
Division of Extramural Research
National Human Genome Research Institute, NIH
5635 Fishers Lane, Suite 4076
Bethesda, MD 20892-9305
Telephone: (301) 496-7531
Fax: (301) 480-2770
Email: [email protected]

2. Peer Review Contacts:

Ken Nakamura, Ph.D.
Scientific Review Branch
National Human Genome Research Institute, NIH
5635 Fishers Lane, Suite 4076
Bethesda, MD 20892-9306
Phone: (301) 402-0838
Fax: (301) 435-1580
Email: [email protected]

3. Financial or Grants Management Contacts:

Cheryl Chick
Grants Administration Branch
National Human Genome Research Institute, NIH
5635 Fishers Lane, Suite 4076
Bethesda, MD 20892-9306
Phone: (301) 435-7858
Fax: (301) 402-1951
E-mail: [email protected]

Required Federal Citations

Use of Animals in Research:
Recipients of PHS support for activities involving live, vertebrate animals must comply with PHS Policy on Humane Care and Use of Laboratory Animals (http://grants.nih.gov/grants/olaw/references/PHSPolicyLabAnimals.pdf) as mandated by the Health Research Extension Act of 1985 (http://grants.nih.gov/grants/olaw/references/hrea1985.htm), and the USDA Animal Welfare Regulations (http://www.nal.usda.gov/awic/legislat/usdaleg1.htm) as applicable.

Human Subjects Protection:
Federal regulations (45CFR46) require that applications and proposals involving human subjects must be evaluated with reference to the risks to the subjects, the adequacy of protection against these risks, the potential benefits of the research to the subjects and others, and the importance of the knowledge gained or to be gained (http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm).

Data and Safety Monitoring Plan:
Data and safety monitoring is required for all types of clinical trials, including physiologic toxicity and dose-finding studies (Phase I); efficacy studies (Phase II); efficacy, effectiveness and comparative trials (Phase III). Monitoring should be commensurate with risk. The establishment of data and safety monitoring boards (DSMBs) is required for multi-site clinical trials involving interventions that entail potential risks to the participants ( NIH Policy for Data and Safety Monitoring, NIH Guide for Grants and Contracts, http://grants.nih.gov/grants/guide/notice-files/not98-084.html).

Sharing Research Data:
Investigators submitting an NIH application seeking $500,000 or more in direct costs in any single year are expected to include a plan for data sharing or state why this is not possible (http://grants.nih.gov/grants/policy/data_sharing).

Investigators should seek guidance from their institutions on issues related to institutional policies and local IRB rules, as well as local, State and Federal laws and regulations, including the Privacy Rule. Reviewers will consider the data sharing plan but will not factor the plan into the determination of scientific merit or the priority score.

Access to Research Data through the Freedom of Information Act:
The 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 the FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this funding opportunity in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award.

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

Inclusion of Women And Minorities in Clinical Research:
It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported clinical research projects unless a clear and compelling justification is provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing clinical research should read the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines is available at http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm. The amended policy incorporates: the use of an NIH definition of clinical research; updated racial and ethnic categories in compliance with the new OMB standards; clarification of language governing NIH-defined Phase III clinical trials consistent with the SF424 (R&R); and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH-defined Phase III clinical trials that: a) all applications or proposals and/or protocols must provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable; and b) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences.

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

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

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

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

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

NIH is requesting that authors submit manuscripts resulting from 1) currently funded NIH research projects or 2) previously supported NIH research projects if they are accepted for publication on or after May 2, 2005. The NIH Public Access Policy applies to all research grant and career development award mechanisms, cooperative agreements, contracts, Institutional and Individual Ruth L. Kirschstein National Research Service Awards, as well as NIH intramural research studies. The Policy applies to peer-reviewed, original research publications that have been supported in whole or in part with direct costs from NIH, but it does not apply to book chapters, editorials, reviews, or conference proceedings. Publications resulting from non-NIH-supported research projects should not be submitted.

For more information about the Policy or the submission process please visit the NIH Public Access Policy Web site at http://PublicAccess.nih.gov/ and view the Policy or other Resources and Tools including the Authors' Manual.

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

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

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

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

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

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

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

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NIH Funding Opportunities and Notices

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