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CIRCULATING CELLS IN CANCER DETECTION RELEASE DATE: December 12, 2003 PA NUMBER: PA-04-035 EXPIRATION DATE: February 17, 2006, unless reissued. Department of Health and Human Services (DHHS) PARTICIPATING ORGANIZATION: National Institutes of Health (NIH) (http://www.nih.gov) COMPONENT OF PARTICIPATING ORGANIZATION: National Cancer Institute (NCI/NIH) (http://www.nci.nih.gov) CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER(S): 93.393, 93.394 This Program Announcement (PA) replaces PA-02-086, which was published in the NIH Guide on March 21, 2002. THIS PA CONTAINS THE FOLLOWING INFORMATION o Purpose of the PA o Research Objectives o Mechanism of Support o Eligible Institutions o Individuals Eligible to Become Principal Investigators o Where to Send Inquiries o Letter of Intent o Submitting an Application o Peer Review Process o Review Criteria o Award Criteria o Receipt and Review Schedule o Required Federal Citations PURPOSE OF THIS PA The purpose of this PA is to develop novel technologies for capturing, enriching, and preserving exfoliated abnormal cells and macromolecules in body fluids or effusions and to develop methods for concentrating the enriched cells for biomarker studies. In the context of this PA, we have extended the definition of exfoliation to include not only the cellular materials, but also subcellular materials, such as DNA and proteins. In body fluids, such as sputum, the number of exfoliated tumor cells is often small compared to the number of non-neoplastic cells. Therefore, the detection of exfoliated abnormal cells by routine cytopathology is often limited because few atypical cells may be present in the specimen. There may be difficulty in separating dysplastic cells from non-specific reactive changes and degenerating cells or variation in diagnostic criteria. Furthermore, exfoliated cells are frequently contaminated with normal cells, bacteria, and other cellular debris, which makes molecular analysis difficult without physical separation of the neoplastic cells. Thus, the development of enrichment methods becomes prerequisite for the routine detection of small numbers of exfoliated cells and small amounts of subcellular materials in biological fluids for molecular analysis. Similarly, subcellular materials are in amounts that may not be detectable by available technologies and therefore the enrichment of such materials is of paramount importance. Enrichment will allow exfoliated cells and subcellular molecules, for example from urine, to be used for genomic, proteomic, and epigenomic analyses that may lead to improvements in the detection of bladder cancer through measurements of alterations in expressed genes, peptide profiles, and epigenetic markers. RESEARCH OBJECTIVES Background The most common human tumors arise from epithelial surfaces (e.g. colon, lung, prostate, oral cavity, esophagus, stomach, uterine cervix, bladder). Their development often becomes apparent when tumor cells exfoliate spontaneously into sputum, urine, or even into various effusions. The molecular and genetic abnormalities within these exfoliated cells could be used to detect and identify precancerous lesions or very early stage cancer if highly sensitive technologies were clinically available to identify the few abnormal cells among millions of normal cells. For example, detection of widespread microsatellite instability (MSI), as demonstrated by expansion or deletion of repeat elements of DNA, may be adapted for exfoliated cells in general. With the advent of PCR-based detection of DNA from rare neoplastic cells in body fluids, mutations have been detected in ras genes from the stools of patients with colorectal cancer, in p53 from the urine of patients with bladder cancer, and in p53 genes in the sputum of patients with lung cancer. As these assays are complex and technically challenging, they depend on the development of novel technologies for isolating and enriching cells or subcellular materials of interest. Abnormal exfoliated cells can be routinely identified by cytologic examination of brushings and fluids, for instance, from bronchi, pancreatic ducts, voided urine, and effusions. Currently, fluids are usually processed by centrifugation or membrane filtration. However, the detection of abnormal exfoliated cells, for instance, cancer cells by routine cytopathological examination may be limited because the number of abnormal cells may be very small compared to the number of normal cells, is difficult. Alternatively, the cellular and nuclear changes in abnormal cells may be minimal compared to normal cells. This is particularly true of cytological examinations of urine cytology, where many low-grade papillary lesions are often missed on. New PCR-based technologies may substantially enhance the sensitivity, but current technologies for isolating and analyzing exfoliated cells are too cumbersome to be of practical utility. The cellular and molecular changes that ensue during tumor progression do so over a number of years and in an apparently stochastic manner. This progressive accumulation of genetic and epigenetic changes in precancerous cell populations eventually confers the malignant phenotype on emerging clonal subpopulations. In human and animal clinical and experimental models, the progression of precancer to cancer is known to be lengthy. For example, it takes an average of estimated 15 to 20 years for a small adenomatous polyp to become malignant. Prior to the appearance of a morphologically identified precancerous lesion, numerous genetic and molecular alterations would have already occurred. During histological progression into a morphologically identifiable lesion, the stochastic process of molecular events in different cells confers genetic heterogeneity. Finding molecular and genetic biomarkers of malignancy is particularly important in detecting the emergence of precancerous cell populations and is what the NCI considers to be an “Extraordinary Opportunity.” In these earliest stages of neoplasia, lesions should be amenable to complete eradication. This principle has been well-demonstrated in cervical neoplasia, where screening for dysplastic exfoliated cells can result in a 70% or greater reduction in the cervical cancer mortality. During the early stages of cancer development, there is a window of opportunity to detect precancerous cells with genetic or molecular biomarkers that identify and characterize their progression towards cancer. Detection of genetic abnormalities in preneoplastic lesions poses challenges because of the small size of lesions, the heterogeneity of precancerous cells, and their dilution by normal cellular constituents. Therefore, assays should be tailored to detect a small number of abnormal cells or molecules among a large number of normal cells or molecules in biological fluids – such as, in colonic washes of the gastrointestinal tract, in sputa, and in bronchial biopsies. In order to detect and analyze precancerous and cancerous cells in biologic fluids, there are a variety of approaches. The most appropriate approach depends upon i) the type of biological fluid (sputum, bronchial washing, cervical brushing, voided urine, etc.), and ii) the form of analysis to be performed (e.g., cytopathological analysis, morphometric analysis, molecular biomarkers for specific receptors or genetic changes, FISH-or-PCR based analyses). All of these approaches require an enrichment of atypical epithelial cells through selective processing to concentrate the assay target of interest. The enrichment methods currently used can be grouped into the following two broad categories: i) mechanical (centrifugation, cytospin, sucrose gradients, etc.) and ii) antibody-based selection with mechanical separation (FACS - flow assisted cell sorting, MACS - magnetic assisted cell sorting, etc.). While one type of enrichment process can be sequentially added to another to improve the yield, all of these methods have good but not adequate sensitivity or specificity required for detecting precancerous cells in body fluids. Given that the concentration of these cells or molecules can be very low compared to other commonly present cell types or molecules, one needs enrichment factors of 1 to 10,000 or 1 to million. More than 80 percent of human tumors originate from epithelial cells, often at a mucosal surface, and are clonal in origin. Precancerous exfoliated cells can be routinely identified in pathology departments by cytologic examination of washings or brushings from bronchi, oral cavity, esophagus, stomach, bile and pancreatic ducts, sputum and urine; however, the detection of exfoliated cancer cells by routine cytopathological examination is limited because of the presence of few atypical cells in specimens, the difficulty of distinguishing low grade dysplasias from non-specific reactive or inflammatory changes, and the low sensitivity and specificity of the available diagnostic methodology. These limitations are particularly true of urine cytology, where most low-grade papillary lesions are missed on cytologic examination of urine. New PCR-based technologies may substantially enhance sensitivity, but current technologies for isolating exfoliated cells are too cumbersome to be of practical utility. For example, exfoliated cells are frequently contaminated with normal cells, bacteria, and other cellular debris, making molecular analysis difficult without further physical separation of neoplastic cells. Therefore, the development of novel, high- throughput, sensitive technologies for sample preparation is a prerequisite for the successful detection of small numbers of exfoliated cells or small amounts of subcellular materials, such as DNA and proteins, in biological. There are occasions in which the only biologic materials available from patients are stored plasma or serum samples. The amount of DNA in these samples are generally very low when they are obtained from normal(healthy) individuals, but increased amounts of circulating DNA have been found in cancer. The circulating DNA in plasma/serum of cancer patients has been shown to reflect the characteristics of the tumor DNA including molecular changes, such as methylation, point mutations, and microsatellite instability. Fragmented nucleosomal DNA in plasma resulting from apoptotic death of the tumor cells may also provide an indication for tumor DNA. There is a need to develop high-yield technologies to isolate circulating DNA that can be used for early detection of cancer and the follow-up of the disease. Goals and Scope The primary purpose of this initiative is to encourage the development of high-throughput technologies to facilitate the isolation and enrichment of exfoliated cells and subcellular materials. In pursuit of these goals, the NCI invites applications that address the following areas: o Development of high-throughput technologies for identifying abnormal exfoliated cells and subcellular materials in body fluids; o Development of sampling technologies for capturing and preserving exfoliated tumor cells and subcellular materials in body fluids; o Development of enrichment methods for the isolation of tumor cells and subcellular materials; o Development of sensitive, high-throughput molecular, cytomorphometric, immunologic, and other relevant technologies to isolate tumor cells or subcellular materials in malignant effusions to help detect low tumor burden and distinguish reactive cells from tumor cells. The long-term goal, to which this initiative will eventually lead, is the development of panels of well-characterized biomarkers derived from exfoliated cells that can be sampled in the clinical setting. These methodologies will be tested and validated in future population-based clinical trials, and integrated into a comprehensive information system that will be developed under the Early Detection Research Network. MECHANISM OF SUPPORT This PA will use the NIH exploratory/developmental (R21) award mechanism. As an applicant, you will be solely responsible for planning, directing, and executing the proposed project. The applicant may request a project period of up to two years with a combined budget for direct costs of up $275,000 for the two year period. For example, the applicant may request $100,000 in the first year and $175,000 in the second year. The request should be tailored to the needs of the project. Normally, no more than $200,000 may be requested in any single year. These grants are non-renewable and continuation of projects developed under this PA will be through the traditional unsolicited investigator initiated grant program. This PA uses just-in-time concepts. It also uses the modular budgeting format. (see http://grants.nih.gov/grants/funding/modular/modular.htm). Specifically, if you are submitting an application with direct costs in each year of $250,000 or less, use the modular format. This program does not require cost sharing as defined in the current NIH Grants Policy Statement at http://grants.nih.gov/grants/policy/nihgps_2001/part_i_1.htm. ELIGIBLE INSTITUTIONS You may submit (an) application(s) if your institution has any of the following characteristics: o For-profit or non-profit organizations o Public or private institutions, such as universities, colleges, hospitals, and laboratories o Units of State and local governments o Eligible agencies of the Federal government o Domestic or foreign institutions/organizations INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with their institution to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH programs WHERE TO SEND INQUIRIES We encourage your inquiries concerning this PA and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into two areas: scientific/research and financial or grants management issues: o Direct your questions about scientific/research issues to: Mukesh Verma, Ph.D. Division of Cancer Prevention National Cancer Institute Executive Plaza North, EPN 3144 Bethesda, MD 20892 Rockville, MD 20852 (for express/courier service) Telephone: (301) 496-3893 FAX: (301) 402-8990 Email: mv66j@nih.gov Or Sudhir Srivastava, Ph.D., M.P.H. Division of Cancer Prevention National Cancer Institute Executive Plaza North, EPN 3142 Bethesda, MD 20892 Rockville, MD 20852 (for express/courier service) Telephone: (301) 496-3983 FAX: (301) 402-8990 Email: ss1a@nih.gov o Direct your questions about financial or grants management matters to: Ms. Karen Chuang Grants Management Specialist National Cancer Institute Executive Plaza South, Room 243 6120 Executive Blvd. MSC 7148 Bethesda, MD 20892-7150 Telephone: (301) 496-2784 FAX: (301) 496-8601 Email: chuangk@mail.nih.gov SUBMITTING AN APPLICATION Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). Applications must have a Dun and Bradstreet (D&B;) Data Universal Numbering System (DUNS) number as the Universal Identifier when applying for Federal grants or cooperative agreements. The DUNS number can be obtained by calling (866) 705-5711 or through the web site at http://www.dunandbradstreet.com/. The DUNS number should be entered on line 11 of the face page of the PHS 398 form. The PHS 398 document is available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 435-0714, Email: GrantsInfo@nih.gov. The title and number of the program announcement must be typed on line 2 of the face page of the application form and the YES box must be checked. SUPPLEMENTARY INSTRUCTIONS: All instructions for the PHS 398 (rev. 5/2001) must be followed, with these exceptions: o Research Plan Items a - d of the Research Plan (Specific Aims, Background and Significance, Preliminary Studies, and Research Design and Methods) may not exceed a total of 15 pages. No preliminary data is required but may be included if it is available. Please note that a Progress Report is not needed; competing continuation applications for an exploratory/developmental grant will not be accepted. Appendix. Use the instructions for the appendix detailed in the PHS 398 except that no more than 5 manuscripts, previously accepted for publication, may be included. SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: Applications requesting up to $250,000 per year in direct costs must be submitted in a modular grant format. The modular grant format simplifies the preparation of the budget in these applications by limiting the level of budgetary detail. Applicants request direct costs in $25,000 modules. Section C of the research grant application instructions for the PHS 398 (rev. 5/2001) at http://grants.nih.gov/grants/funding/phs398/phs398.html includes step-by-step guidance for preparing modular grants. Additional information on modular grants is available at http://grants.nih.gov/grants/funding/modular/modular.htm. For the NIH Exploratory/Developmental Grant (R21), applicants may request direct costs in $25,000 modules, up to a total direct cost of $275,000 for the combined two year award period. SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of the application, including the checklist, and five signed photocopies in one package to: Center for Scientific Review National Institutes of Health 6701 Rockledge Drive, Room 1040, MSC 7710 Bethesda, MD 20892-7710 Bethesda, MD 20817 (for express/courier service) APPLICATION PROCESSING: Applications must be received by or mailed on or before the receipt dates described at http://grants.nih.gov/grants/funding/submissionschedule.htm. The CSR will not accept any application in response to this PA that is essentially the same as one currently pending initial review unless the applicant withdraws the pending application. The CSR will not accept any application that is essentially the same as one already reviewed under this PA. This does not preclude the submission of a substantial revision of an unfunded version of an application already reviewed, but such application must include an introduction addressing the previous critique. Unfunded applications previously reviewed as investigator-initiated applications under a different research grant mechanism may be resubmitted as a new application under this PA (see http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-019.html ). Although there is no immediate acknowledgement of the receipt of an application, applicants are generally notified of the review and funding assignment within 8 weeks. PEER REVIEW PROCESS Applications submitted for this PA will be assigned on the basis of established PHS referral guidelines. An appropriate scientific review group, convened in accordance with the standard NIH peer review procedures (http://www.csr.nih.gov/refrev.htm), will evaluate applications for scientific and technical merit. As part of the initial merit review, all applications will: o 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 o Receive a written critique o Those that receive a priority score will receive a second level review by an appropriate national advisory council or board. REVIEW CRITERIA 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 evaluate 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. o Significance o Approach o Innovation o Investigator o Environment 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. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. SIGNIFICANCE: Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? 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? INNOVATION: Does the project employ novel concepts, approaches or methods? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? 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)? 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 REVIEW CRITERIA: In addition to the above criteria, the following items will 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 criteria included in the section on Federal Citations, below). 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 Inclusion Criteria in the sections on Federal Citations, below). CARE AND USE OF VERTEBRATE ANIMALS IN RESEARCH: If vertebrate animals are to be used in the project, the five items described under Section f of the PHS 398 research grant application instructions (rev. 5/2001) will be assessed. ADDITIONAL REVIEW CONSIDERATIONS Sharing Research Data Applicants requesting more than $500,000 in direct costs in any year of the proposed research must include a data sharing plan in their application. The reasonableness of the data sharing plan or the rationale for not sharing research data will be assessed by the reviewers. However, reviewers will not factor the proposed data sharing plan into the determination of scientific merit or priority score. (See url in Federal Citations, below.) BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. AWARD CRITERIA Applications submitted in response to a PA will compete for available funds with all other recommended applications. The following will be considered in making funding decisions: o Scientific merit of the proposed project as determined by peer review o Availability of funds o Relevance to program priorities REQUIRED FEDERAL CITATIONS 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). The establishment of data and safety monitoring boards (DSMBs) is required for multi-site clinical trials involving interventions that entail potential risk to the participants. (NIH Policy for Data and Safety Monitoring, NIH Guide for Grants and Contracts, June 12, 1998: http://grants.nih.gov/grants/guide/notice-files/not98-084.html). Clinical trials supported or performed by NCI require special considerations. The method and degree of monitoring should be commensurate with the degree of risk involved in participation and the size and complexity of the clinical trial. Monitoring exists on a continuum from monitoring by the principal investigator/project manager or NCI program staff or a Data and Safety Monitoring Board (DSMB). These monitoring activities are distinct from the requirement for study review and approval by an Institutional review Board (IRB). For details about the Policy for the NCI for Data and Safety Monitoring of Clinical trials see: http://deainfo.nci.nih.gov/grantspolicies/datasafety.htm. For Phase I and II clinical trials, investigators must submit a general description of the data and safety monitoring plan as part of the research application. See NIH Guide Notice on “Further Guidance on a Data and Safety Monitoring for Phase I and II Trials” for additional information: http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-038.html. Information concerning essential elements of data safety monitoring plans for clinical trials funded by the NCI is available: http://www.cancer.gov/clinical_trials/ SHARING RESEARCH DATA: Starting with the October 1, 2003 receipt date, investigators submitting an NIH application seeking more than $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, local IRB rules, as well as local, state and Federal laws and regulations, including the Privacy Rule. Reviewers will consider the data sharing plan but will not factor the plan into the determination of the scientific merit or the priority score. 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 - Amended, October, 2001," published in the NIH Guide for Grants and Contracts on October 9, 2001 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines are available at http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm. The amended policy incorporates: the use of an NIH definition of clinical research; updated racial and ethnic categories in compliance with the new OMB standards; clarification of language governing NIH-defined Phase III clinical trials consistent with the new PHS Form 398; and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH-defined Phase III clinical trials that: a) all applications or proposals and/or protocols must provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable; and b) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS: The NIH maintains a policy 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 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 is available at 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 proposals for research involving human subjects. You will find this policy announcement in the NIH Guide for Grants and Contracts Announcement, dated June 5, 2000, at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html. A continuing education program in the protection of human participants in research is available online at: http://cme.nci.nih.gov/ PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this PA in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award. STANDARDS FOR PRIVACY OF INDIVIDUALLY IDENTIFIABLE HEALTH INFORMATION: The Department of Health and Human Services (DHHS) issued final modification to the “Standards for Privacy of Individually Identifiable Health Information”, the “Privacy Rule,” on August 14, 2002. The Privacy Rule is a federal regulation under the Health Insurance Portability and Accountability Act (HIPAA) of 1996 that governs the protection of individually identifiable health information, and is administered and enforced by the DHHS Office for Civil Rights (OCR). Those who must comply with the Privacy Rule (classified under the Rule as “covered entities”) must do so by April 14, 2003 (with the exception of small health plans which have an extra year to comply). Decisions about applicability and implementation of the Privacy Rule reside with the researcher and his/her institution. The OCR website (http://www.hhs.gov/ocr/) provides information on the Privacy Rule, including a complete Regulation Text and a set of decision tools on “Am I a covered entity?” Information on the impact of the HIPAA Privacy Rule on NIH processes involving the review, funding, and progress monitoring of grants, cooperative agreements, and research contracts can be found at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html. URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site. HEALTHY PEOPLE 2010: The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This PA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople. AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal Domestic Assistance at http://www.cfda.gov/ and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284)and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The NIH Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm The PHS strongly encourages all grant recipients to provide a smoke-free workplace and discourage the use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.
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