TECHNOLOGIES FOR COMPREHENSIVE, SENSITIVE, AND QUANTITATIVE PROTEIN ANALYSIS IN HUMAN TUMORS: PHASED INNOVATION Release Date: August 30, 2000 RFA: CA-01-011 National Cancer Institute National Human Genome Research Institute Letter of Intent Date: December 11, 2000 Application Receipt Date: January 18, 2001 PURPOSE The Technology Development Branch of the Cancer Diagnosis Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute (NCI), and the Functional Analysis of the Genome Program, Division of Extramural Research, National Human Genome Research Institute (NHGRI), invite grant applications proposing the development of innovative technologies for the sensitive quantitation of the comprehensive spectrum of proteins present in human tissues. In combination with protein identification strategies, sensitive, efficient, and reproducible protein quantitation technologies are needed to more accurately and rapidly determine altered levels of the spectrum of proteins in human tumor specimens. The approaches proposed should take into account the need to identify and quantitate a broad range of proteins including proteins present in low abundance and proteins that are membrane- associated or not readily soluble. Approaches should be sensitive enough to detect modest changes in the concentration of individual proteins since these changes may have significant biological consequences. This solicitation will utilize the newly created Phased Innovation Award Mechanism (R21/R33). Specific Features of this mechanism will include: o Support for either R21 or R33 or combined R21/R33 applications. o Single submission and evaluation of both the R21 and R33 as one application. o Expedited transition from feasibility phase to development phase. o Flexible budgets. o Flexible staging of feasibility and development phases. RESEARCH OBJECTIVES Background Profiling of gene expression in tumors promises to improve the clinical management of cancer patients. Technologies for the comprehensive evaluation of DNA and RNA alterations in tumors are rapidly being developed, but development of comparable technologies for the evaluation of protein expression in human tumor specimens has been slower due to the inherent difficulties of analyzing complex mixtures of proteins. Protein profiling technologies currently in use or under development are based on identification of proteins and/or analysis of the properties and characteristics of proteins. The research community has highlighted the importance of developing sensitive, quantitative protein analysis technologies to complement these approaches. No current technology allows both comprehensive identification and sensitive quantitation of proteins in human tissues. Investigators are forced to choose between technologies that provide a non-quantitative, comprehensive profile of proteins and technologies that provide a quantitative measurement of a limited subset of proteins in a specimen. Protein profiling will require knowledge of both the identity and relative abundance of all or a significant subset of proteins in tumors. This knowledge will greatly enhance our understanding of molecular pathways involved in cancer development. Measuring changes in the abundance of membrane-bound receptor proteins in human tumors is important since these proteins are involved in signaling cascades during cancer initiation or progression. Detecting subtle changes in the abundance of proteins in tumors is also important because these changes may be key to biological processes in cancer development. However, major technical challenges remain. These include the quantitation of hydrophobic, membrane-bound proteins and the improvement in detection sensitivity for measurement of very low-abundance proteins. Overcoming these technical challenges will allow the generation of informative protein profiles that have the potential to improve clinical decisions regarding diagnosis, prognosis, and selection of therapy for individual cancer patients. Post-translational modifications of proteins are critical to their function. Certain key information about the functional status of these proteins can be obtained only from the identification and quantitation of biologically active, properly modified proteins following the processing of inactive or unmodified translation products. Quantitative information about differentially phosphorylated proteins, differentially glycosylated membrane-bound proteins, and processing of precursor proteins into functional proteases, cytokines, and growth factors will allow investigators to gain increased understanding of the altered biological processes associated with the various stages of cancer development. Research Goals and Scope This Request for Applications (RFA) is intended to stimulate the initiation and/or continued development of high-risk/high-impact technologies that target the sensitive quantitation of the wide spectrum of proteins in human tissues. Investigators are invited to propose the development of technologies for both comprehensive identification and sensitive quantitation of proteins translated and modified in human tumor specimens. They are challenged to develop sensitive, efficient, and reproducible technologies that reliably measure altered concentrations of individual proteins. The proposed approaches should address the current needs of identifying and quantitating proteins that are difficult to analyze, including low-abundance proteins and membrane-bound or hydrophobic proteins. Comprehensive protein analysis is defined, for purposes of this RFA, as analysis of a large subset of proteins. It is not necessary for applicants to propose strategies to analyze all proteins in a cell or tissue. Investigators may choose to identify and quantitate the proteins present in subcellular compartments of human tissues. For example, proteins associated with membranes, nuclei, mitochondria, microsomes, or cytoplasm could be analyzed separately. Technical approaches to quantitating subsets of proteins that are grouped on the basis of their chemical properties may also be proposed. Quantitative protein analysis technologies are intended to enable the measurement of relative differences in the abundance of individual proteins present in human tumors at various stages of cancer development. This is intended to include proteins in all ranges of concentrations within a tissue. Accurate information about relative quantitation of these proteins will allow the evaluation of the biological consequences of changes in protein expression. The proposed quantitation technologies should also be able to determine relative concentrations of differentially modified or processed proteins. Sensitive protein analysis technologies are intended to enhance the detection of very low-abundance proteins and the detection of changes in concentrations of these proteins. Subtle changes in the abundance of these proteins may have profound biological consequences and may play a major role in tumor initiation and progression. It is anticipated that investigators will develop general technologies that are applicable to quantitating proteins in the majority of human tissues. However, in all cases, applicants will have to carefully consider the sample preparation methods that will be used. It may be necessary to integrate tissue-specific sample preparation methodologies with the protein analysis technologies depending upon the tissues that are selected for analysis. Investigators may design novel adaptation or modification schemes that are compatible with available technologies as an alternative to proposing new approaches to the comprehensive, sensitive profiling of proteins in human tissues. For example, investigators who are currently developing approaches to comprehensive quantitation of proteins in model systems, such as yeast and cell lines, may propose adaptation strategies for applying their technology to profiling the broad spectrum of proteins present in human tissues. Investigators may also propose to explore modifying comprehensive, but non- quantitative proteomics technologies to add quantitation procedures to the analysis. If necessary, a single application could propose two or more complementary approaches to efficiently analyze the spectrum of proteins selected for study. While the purpose of this initiative is the development of sensitive, quantitative technologies for analysis of a wide spectrum of proteins in human tissues, identification of each protein is also important. Investigators should address the methodologies for linking data generated from the developing protein analysis technologies to existing databases, including peptide mapping databases, messenger RNA (mRNA) expression databases, three- dimensional protein structure databases, and/or protein function databases. Proteins that can not be clearly identified from available databases will need to be further characterized, but these studies are beyond the scope of this RFA. The intent of this initiative is to provide the proteomics research community with the opportunity to test and develop innovative strategies for comprehensive, sensitive, and quantitative protein profiling, not to support modest incremental advances in current technologies. Submissions proposing the application of existing protein analysis technologies to address biological questions will not be supported under this RFA. The R21/R33, exploratory/developmental Phased Innovation Award mechanism, will be used to support meritorious applications that are responsive to this RFA. The R21 phase will be used to demonstrate the feasibility of novel or improved technologies in comprehensive, sensitive, and quantitative analysis of proteins present in human tumor specimens. The R33 phase will be used for further development of the proposed approaches into comprehensive, sensitive, efficient, and reproducible quantitation technologies that work in conjunction with protein identification strategies. Summary This RFA is to encourage and stimulate the development of substantially improved or new technologies that can achieve both a comprehensive identification and a sensitive, quantitative analysis of an extensive range of proteins in human tumor specimens. This initiative is intended to take advantage of the increasing interest in the development of proteomics technologies, and specifically to meet the need identified by the research community for the ability to carry out sensitive and quantitative protein analysis. Investigators in both academic and commercial institutions are invited to propose projects in response to this RFA. Comprehensive, quantitative protein profiles of tumors at various stages of cancer development could ultimately permit the identification of multiple tumor-specific markers that will aid in identification of cancer therapeutic targets and of new approaches to cancer diagnostics. Comprehensive information about the identification and quantitation of proteins will allow investigators to correlate expression levels of mRNAs and biologically active proteins in human tumors. This information will augment our knowledge of molecular pathways underlying the development of cancer, and ultimately improve clinical decisions regarding early detection, diagnosis, prognosis, and treatment of cancer. MECHANISM OF SUPPORT Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. Except as otherwise stated in this solicitation, awards will be administered under NIH grants policy as stated in the NIH Grants Policy Statement, NIH Publication No 99-8, October 1998. Support for this program will be through the National Institutes of Health (NIH) Exploratory/Developmental Research Grant (R21) and the Exploratory/Developmental Research Grant Phase 2 (R33). The R33 is a newly established NIH grant mechanism to provide a second phase for the support of innovative exploratory and developmental research initiated under the R21 mechanism. Transition of the R21 to the R33 phase will be expedited and is dependent on completion of negotiated milestones. Under this RFA, applicants can choose one of three options in submitting applications, as described in the APPLICATION PROCEDURES section of this solicitation: an R21 application alone, a combined R21/R33 application (Phased Innovation Award application), or an R33 application alone if feasibility of the project can be documented. Applicants requesting the support of an R21 phase alone under this initiative will be allowed up to two years to explore the feasibility of their high-risk, challenging applications. The total project period for a combined R21/R33 applications may not exceed 4 years, i.e., applicants can propose either two years of R21 and two years of R33 or one year of R21 and three years of R33 funding. Applicants who request the support of an R33 phase alone will be allowed up to three years for the completion of their studies. For combined R21/R33 applications, the R21 phase may not exceed $100,000 direct costs per year. R21 budgets can exceed this cap to accommodate Facility and Administrative (F&A) costs to subcontracts to the project. Although the R33 application has no official budgetary limit, applications requesting in excess of $500,000 dollars direct costs in any single year of the grant period require prior approval before submission. It is strongly recommended that applicants contact program staff at an early stage of application development to convey critical information, such as potentially large budget requests or to discuss programmatic adherence to the guidelines of the proposed project. Early contact with program staff is particularly critical relative to this RFA because it uses a new grant mechanism R33 as well as an expedited review procedure between a successful R21 and the R33 phases. Refer to the INQUIRIES sections of this solicitation for program staff contacts. The combined R21/R33 application offers two advantages over the regular application process: 1. Single submission and evaluation of both the R21 and the R33 as one application. 2. Minimal or no funding gap between R21 and R33. The award of R33 funds will be based on successful completion of negotiated scientific milestones as determined by the Institutes in the context of peer review recommendations, on program priorities, and on the availability of funds. To be eligible for the Phased Innovation Award, the R21 phase must include well defined quantifiable milestones that will be used to judge the success of the proposed research, as well as a credible plan for the development of technology for the R33 phase. The Phased Innovation Award must have a section labeled Milestones at the end of the Research Plan of the R21 application. This section must include well-defined quantifiable milestones for completion of the R21 part of the application, a discussion of the suitability of the proposed milestones for assessing the success in the R21 phase, and a discussion of the implications of successful completion of these milestones for the proposed R33 study. FUNDS AVAILABLE The NIH intends to commit approximately $1,750,000 in FY 2001 to fund 4 to 6 new grants in response to this RFA. Because the nature and scope of the research proposed may vary, it is anticipated that the size of each award will also vary. Although the financial plan of the NCI and NHGRI provides support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications. At this time, it is not known if competing renewal applications will be accepted and/or if this RFA will be reissued. ELIGIBILITY REQUIREMENTS Applications may be submitted by foreign and domestic, for-profit and non-profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal government. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as principal investigators INQUIRIES Inquiries are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Min H. Song, Ph.D. Division of Cancer Treatment and Diagnosis National Cancer Institute Executive Plaza North, Room 6035 Bethesda, MD 20892 Telephone: (301) 402-4185 FAX: (301) 402-7819 E-mail: ms425z@nih.gov Elise A. Feingold, Ph.D. Division of Extramural Research National Human Genome Research Institute Building 31, Room B2B07 Bethesda, MD 20892-2033 Telephone: (301) 496-7531 FAX: (301) 480-2770 E-mail: ef5j@nih.gov Direct inquiries regarding fiscal matters to: Ms. Kathleen Shino Grants Administration Branch National Cancer Institute Executive Plaza South, Room 243 Bethesda, MD 20892-7150 Telephone: (301) 496-8635 FAX: (301) 496-8601 E-mail: shinok@gab.nci.nih.gov Jean Cahill Grants Administration Branch National Human Genome Research Institute Building 31, Room B2B34 Bethesda, MD 20892-2031 Telephone: (301) 435-7858 FAX: (301) 402-1951 E-mail: jc166o@nih.gov Direct inquiries regarding review matters to: Ms. Toby Friedberg Referral Officer National Cancer Institute 6116 Executive Boulevard, Room 8109, MSC 8329 Bethesda, MD 20892-8329 Rockville, MD 20852 (for overnight/courier service) Telephone: (301) 496-3428 FAX: (301) 402-0275 LETTER OF INTENT Prospective applicants are asked to submit, by the date listed on the first page of this RFA, a letter of intent that includes a descriptive title of the proposed research, the name, address, and telephone number of the Principal Investigator, the identities of other key personnel and participating institutions, and the number and title of the RFA in response to which the application is being submitted. 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 NCI staff to estimate the potential review workload and plan the review. The letter of intent is to be sent to Dr. Min H. Song listed under INQUIRIES by the letter of intent receipt date listed in the heading of this RFA. SCHEDULE Letter of Intent Receipt: December 11, 2000 Application Receipt Date: January 18, 2001 Peer Review Date: April/May 2001 Review by Institutes Advisory Board/Council: August/September 2001 Earliest Anticipated Start Date: September 1, 2001 APPLICATION PROCEDURES SPECIFIC INSTRUCTIONS FOR PREPARING THE COMBINED R21/R33 PHASED INNOVATION AWARD APPLICATION Applications for R21/R33 grants are to be submitted on the grant application form PHS 398 (rev. 4/98) and prepared according to the instructions provided unless specified otherwise within this section. Application kits are available at most institutional offices of sponsored research and may be obtained from the Division of Extramural Outreach and Information Resources, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/710-0267, email: grantsinfo@nih.gov. For those applicants with internet access, the 398 kit may be found at: http://grants.nih.gov/grants/forms.htm. The R21/R33 application must include the specific aims for each phase and the feasibility milestones that would justify transition to the R33 phase. Applications must include a specific section labeled Milestones following the Research Plan of the R21 phase. Milestones should be well described, quantifiable and scientifically justified. A discussion of the milestones relative to the progress of the R21 phase, as well as, the implications of successful completion of the milestones for the R33 phase should be included. This section should be indicated in the Table of Contents. Applications lacking this information as determined by the program staff, will be returned to the applicant without review. For funded applications, completion of the R21 milestones will elicit an expedited review by the Institutes that will determine whether or not the R33 should be awarded. The release of R33 funds will be based on successful completion of negotiated scientific milestones, program priorities, and on the availability of funds. The expedited review may result in additional negotiations of award. The R21/R33 Phased Innovation Award application must be submitted as a single application, with one face page. Although it is submitted as a single application, it should be clearly organized into two phases. To accomplish a clear distinction between the two phases, applicants are directed to complete Sections a-d of the Research Plan twice: one write-up of Sections a-d and milestones for the R21 phase and sections a-d again for the R33 phase. The Form 398 Table of Contents should be modified to show sections a-d for each phase as well as the milestones. There is a page limit of 25 pages for the composite a-d text (i.e., section a-d and milestones for the R21 and sections a-d for the R33 phase must be contained within the 25 page limit.) In preparing the R21/R33 application, investigators should consider the fact that applications will be assigned a single priority score. In addition, as discussed in the REVIEW CONSIDERATIONS section, the initial review panel has the option of recommending only the R21 phase for support. However, a Phased Innovation Award Application with an R33 Phase that is so deficient in merit that it is not recommended for support will reflect upon the judgement of the applicant. For these reasons, the clarity and completeness of the R21/R33 application with regard to specific goals and feasibility milestones for the R21 phase are critical. The presentation of milestones that are not sufficiently scientifically rigorous to be valid for assessing progress in the R21 phase will reflect upon the scientific judgement of the applicant in the application. 1. Face Page of the application: Item 2. Check the box marked YES and type the number and title of this RFA. Also indicate that the application is an R21/R33. Item 7a, DIRECT COSTS REQUESTED FOR INITIAL PERIOD OF SUPPORT: For the R21 phase of the combined R21/R33 application, direct costs are limited to a maximum of $100,000 per year for a maximum of two years and the award may not be used to supplement an ongoing project. The requested budgets can exceed this cap to accommodate for F&A costs to subcontracts to the project. Insert the first year of R21 support in item 7a. Item 8a, DIRECT COSTS REQUESTED FOR PROPOSED PERIOD OF SUPPORT: For the R21 phase, direct costs requested for the proposed period may not exceed $200,000 for two years of support. The statement in item 7a above pertaining to subcontract costs also applies here. Insert sum of all years of requested support in item 8a. 2. Description: As part of the description, identify concisely the technology or methodology to be developed, its innovative nature, its relationship to presently available capabilities, and its expected impact on comprehensive, sensitive, and quantitative protein analysis in human tumors. 3. Budget: The application should provide a detailed budget for Initial Budget Period (form page 4), for each of the initial years of the R21 and R33 phases as well as a budget for the entire proposed period of support (form page 5). Form pages should indicate which years are R21 and R33. All budgets should include a written justification. Investigators funded through this program will be invited to an annual meeting of investigators funded by the Phased Innovation Award mechanism under NCI’s Program Announcements. The annual meeting will facilitate sharing of progress and research insights with other investigators. Applicants should request travel funds in their budgets for the principal investigator and one additional senior investigator to attend this annual meeting. 4. Research Plan: Item a., Specific Aims. The applicants must present specific aims that the applicant considers to be scientifically appropriate for the relevant phases of the project. The instructions in the PHS 398 booklet for this section of research grant applications suggest that the applicant state the hypotheses to be tested. Since the goal of this RFA is to develop innovative technologies, biological hypothesis testing per se may not be the driving force in developing such an application and, therefore, may not be applicable. Furthermore for R21 grant applications, preliminary data are not required, although they should be included when available. For both the R21 and R33 phase, research that develops new technologies is likely to require the application of principles of fields such as engineering, materials science, physics, mathematics, and computer science. Clear statements of these underlying principles within this section are essential. Item b: Background and Significance Elaborate on the innovative nature of the proposed research. Clarify how the technology development proposed in this project is a significant improvement over existing approaches. Explain the potential of the proposed technology for having a broad impact on cancer research. Clearly identify how the project, if successful, would result in new capabilities for research, the immediacy of the opportunity and how these proposed technologies would differ from existing technologies. Item c., Preliminary Studies/Progress Report While preliminary data are not required for submission of the R21 phase, this section should provide current thinking or evidence in the field to substantiate feasibility of the R21 phase. The R33 need not repeat information already provided in the R21. In the event that an applicant feels that technology is too proprietary to disclose, applicants at a minimum should provide a demonstration (results) of the capabilities of the proposed technology. Item d., Research Design and Methods Follow the instructions in the PHS 398 booklet. In addition, for the R21 phase only, the following information must be included as a final section of Item d: Applications must include a specific section labeled Milestones following the Research Design and Methods of the R21 phase. Milestones should be well described, quantifiable, and scientifically justified and not be simply a restatement of the specific aims. A discussion of the milestones relative to the success of the R21 phase, as well as the implications of successful completion of the milestones for the R33 phase, and the page number of the milestones section should be listed. This section should be indicated in the Table of Contents. Applications lacking this information, as determined by the program staff, will be returned to the applicant without review. For funded applications, completion of the R21 milestones will elicit an expedited review by the Institutes that will determine whether or not the R33 should be awarded. The release of R33 funds will be based on successful completion of milestones, program priorities and on the availability of funds. The expedited review may result in additional negotiations of award. SPECIFIC INSTRUCTIONS FOR PREPARATION OF THE R21 APPLICATION WHEN SUBMITTED WITHOUT THE R33 PHASE. Applications for R21 grants are to be submitted on the grant application form PHS 398 (rev. 4/98) and prepared according to the instructions provided for R21 applications in the previous section except that Milestones and discussion of the implication of the milestones to the R33 phase are not required. Application kits are available at most institutional offices of sponsored research and may be obtained from the Division of Extramural Outreach and Information Resources, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892- 7910, telephone 301/710-0267, email: grantsinfo@nih.gov. For those applicants with internet access, the 398 kit may be found at: http://grants.nih.gov/grants/forms.htm. 1. Face Page of the application: Item 2. Check the box marked YES and type the number and title of this RFA. Also indicate that the application is an R21. SPECIFIC INSTRUCTIONS FOR PREPARATION OF THE R33 APPLICATION WHEN SUBMITTED WITHOUT THE R21 PHASE. Applications for R33 grants are to be submitted on the grant application form PHS 398 (rev. 4/98) and prepared according to the instructions provided unless specified otherwise within items 1-5 below. Application kits are available at most institutional offices of sponsored research and may be obtained from the Division of Extramural Outreach and Information Resources, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/710-0267, email: grantsinfo@nih.gov. 1. Face Page of the application: Item 2. Check the box marked YES and type the number and title of this RFA. Also indicate that the application is an R33. 2. Description: As part of the description, identify concisely the technology or methodology to be developed, its innovative nature, its relationship to presently available capabilities and its expected impact on comprehensive, sensitive, and quantitative protein analysis in human tumors. 3. Research Plan: Item a., Specific Aims. The instructions in the PHS 398 booklet for this section of research grant applications suggest that the applicant state the hypotheses to be tested. Because the goal of this RFA is to develop innovative technologies, biological hypothesis testing per se may not be the driving force in developing such a proposal and, therefore, may not be applicable. Item b: Background and Significance Elaborate on the innovative nature of the proposed research. Clarify how the technology development proposed in this project is a significant improvement over existing approaches. Explain the potential of the proposed technology for having a broad impact on cancer research. Clearly identify how the project, if successful, would result in new capabilities for research, the immediacy of the opportunity, and how these proposed technologies would differ from existing technologies. Item c: Preliminary Studies/Progress report This section must document that feasibility studies have been completed, and progress achieved, equivalent to that expected through the support of an R21 project. The application must clearly describe how the exploratory/developmental study is ready to scale up to an expanded development stage. In the event that an applicant feels that the technology is too proprietary to disclose, applicants at a minimum should provide a demonstration (results) of the capabilities of the proposed technology. FOR ALL APPLICATIONS Appendix: All instructions in the Form 398 application kit apply. Submit a signed, typewritten original of the application, including the checklist, and three signed, exact, single-sided photocopies, in one package to: Center for Scientific Review National Institutes of Health 6701 Rockledge Drive, Room 1040 - MSC 7710 BETHESDA, MD 20892-7710 BETHESDA, MD 20817 (for express/courier service) To expedite the review process, at the time of submission, send two additional copies of the application to: Ms. Toby Friedberg Referral Officer National Cancer Institute 6116 Executive Boulevard, Room 8109, MSC 8329 Bethesda, MD 20892-8329 Rockville, MD 20852 (for overnight/courier service) Telephone: (301) 496-3428 FAX: (301) 402-0275 Applications must be received by the receipt date listed at the beginning of this RFA. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by CSR and responsiveness by the program staff. Incomplete and/or non-responsive applications will be returned to the applicant without further consideration. Applications that are complete and responsive to this RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the Division of Extramural Activities, NCI, in accordance with the review criteria stated below. As part of the initial merit review, all applicants will receive a written critique and may undergo a process in which only those applications deemed to have the highest scientific merit generally the top half of the applications will be discussed, assigned a priority score, and receive a second level review by the National Cancer Advisory Board and/or the National Advisory Council for Human Genome Research. Review Criteria The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. The reviewers will comment on the following aspects of the application in their written critiques in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered by the reviewers in assigning the overall score weighting them as appropriate for each application. Note that the application does not need to be strong in all categories to be judged likely to have a major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a technology forward. 1. Significance. Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? To what degree does the technology support the needs of the targeted research community? For systems intended for clinical research the additional criteria will be considered: to what degree is the analysis system appropriate for clinical research and likely to have utility for the analysis of clinical specimens or patients? 2. Approach. Are the conceptual framework, design, methods, and analyses adequately developed, well-integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? What is the time frame for developing the proposed technologies and suitability of this time frame for meeting the scientific community’s needs? How easy will it be to use the proposed technology? Are the plans for proposed technology dissemination adequate? 3. Milestones. How appropriate are the proposed milestones against which to evaluate the demonstration of feasibility for transition to the R33 development phase? 4. Innovation. Does the project employ novel concepts, approaches or method? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? 5. Investigator. Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers (if any)? 6. Environment. Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? Additional Considerations For the R21/R33 Phased Innovation Award Application, the initial review group will evaluate the specific goals for each phase and the feasibility milestones that would justify expansion to the R33 phase. A single priority score will be assigned to each scored application. As with any grant application, the initial review group has the option of recommending support for a shorter duration than that requested by the applicant, and basing the final merit rating on the recommended portion of the application. For the R21/R33 application, this may result in a recommendation that only the R21 phase be supported, based on concerns related to the applicant’s specific goals and the feasibility milestones justifying expansion to the R33 phase. Deletion of the R33 phase by the review panel or inadequate milestones will affect the merit rating of the application. The initial review group will also examine: the appropriateness of the proposed project budget and duration, the adequacy of plans to include both genders and minorities and their subgroups, and children as appropriate for the scientific goals of the research and plans for the recruitment and retention of subjects, the provisions for the protection of human and animal subjects, and the safety of the research environment. AWARD CRITERIA Applications will compete for available funds with all other recommended applications received in response to this RFA. The following will be considered in making funding decisions: quality of the proposed project as determined by peer review, availability of funds, and program priority. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS 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 biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification are 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 research involving human subjects should read the UPDATED "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research," published in the NIH Guide for Grants and Contracts on August 2, 2000 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html), a complete copy of the updated Guidelines are available at http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm: The revisions relate to NIH defined Phase III clinical trials and require: a) all applications or proposals and/or protocols to 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) all investigators to report accrual, and to conduct and report analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS. It is the policy of NIH that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are clear and compelling scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. 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 that was published in the NIH Guide for Grants and Contracts, March 6, 1998, and is available at the following URL address: http://grants.nih.gov/grants/guide/notice-files/not98-024.html Investigators also may obtain copies of the policy from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. 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. Reviewers are cautioned that their anonymity may be compromised when they directly access an Internet site. HEALTHY PEOPLE 2010 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of Healthy People 2010, a PHS led national activity for setting priority areas. This RFA, Technologies for Comprehensive, Sensitive, and Quantitative Protein Analysis in Human Tumors, is related to the priority area of cancer. 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 No. 93.394 (Cancer Detection and Diagnosis Research) and No. 93.172 (Human Genome Research). Awards are made under authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and administered under NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The PHS strongly encourages all grant recipients to provide a smoke-free workplace and promote the non-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.

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