DEVELOPMENT OF ASSAY METHODS FOR CREUTZFELDT-JAKOB DISEASE (CJD) Release Date: December 15, 1998 RFA: HL-99-003 P.T. National Heart, Lung, and Blood Institute Letter of Intent Receipt Date: January 11, 1999 Application Receipt Date: February 12, 1999 THIS RFA USES "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. IT INCLUDES DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS RFA. PURPOSE The Division of Blood Diseases and Resources invites grant applications for research on the development of assay methods for the detection of CJD. The study of CJD and other Transmissible Spongiform Encephalopathies (TSE) has been hampered seriously by the lack of a satisfactory assay system. The ultimate goal of this program is the development of an assay to screen donated blood and donors of organs or tissues, although other uses of the technique are probable. Approaches that might be considered for mass screening for the hallmark abnormal isoform (PRP-res) or other potential markers for CJD are serologic, virologic, physical or physico-chemical. HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of Healthy People 2000, a PHS-led national activity for setting priority areas. This Request for Applications (RFA), Development of Assay Methods for CJD, is related to the priority area of immunization and infectious diseases. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0 or Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202-512-1800) or at http://www.crisny.org/health/us/health7.html). ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign for-profit and non-profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State or 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. All current policies and requirements that govern the research grant programs of the National Institutes of Health (NIH) will apply to grants awarded under this RFA. MECHANISM OF SUPPORT This RFA will use the NIH individual research project grant (R01) mechanism of support. However, specific application instructions have been modified to reflect "MODULAR GRANT" and "JUST-IN-TIME" streamlining efforts being examined by the NIH. The modular grant concept establishes specific modules in which direct costs may be requested as well as a maximum level for requested budgets. Only limited budgetary information is required under this approach. The just-in-time concept allows applicants to submit certain information only when there is a possibility for an award. It is anticipated that these changes will reduce the administrative burden for the applicants, reviewers and Institute staff. For this RFA, funds must be requested in $25,000 direct cost modules and a maximum of eight modules, $200,000 direct costs per year may be requested. For subcontracts, the $200,000 includes the direct costs and facilities and administrative costs. A feature of the modular grant concept is that no escalation is provided for future years, and all anticipated expenses for all years of the project must be included within the number of modules being requested. Only limited budget information will be required and any budget adjustments made by the Initial Review Group will be in modules of $25,000. Instructions for completing the Biographical Sketch have also been modified. In addition, Other Support information and the application Checklist page are not required as part of the initial application. If there is a possibility for an award, necessary budget, Other Support and Checklist information will be requested by NHLBI staff following the initial review. The APPLICATION PROCEDURES section of this RFA provides specific details of modifications to standard PHS 398 application kit instructions. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. It is anticipated that support for this program will begin in September 1999. Administrative adjustments in the project period and/or amounts may be required at the time of the award. This RFA is a one-time solicitation. Future unsolicited competing continuation applications will compete with all investigator-initiated applications and be reviewed according to the customary peer review procedures. FUNDS AVAILABLE It is anticipated that for fiscal year 1999, approximately $1.2 million total costs will be available for the first year of support for this initiative. The award of grants pursuant to this RFA is contingent upon receipt of such funds for this purpose. It is anticipated that approximately four to six new grants will be awarded under this program for up to four years of support. The specific number to be funded will, however, depend on the merit and scope of the applications received and on the availability of funds. Direct costs will be awarded in modules of $25,000, less any overlap or other necessary administrative adjustments. Facilities and Administrative costs will be awarded based on the negotiated rates. RESEARCH OBJECTIVES BACKGROUND CJD is a slow degenerative disease of the central nervous system characterized by motor dysfunction, progressive dementia, and vacuolar degeneration of the brain. A protease-resistant protein (PRP-res) or prion is the hallmark of the transmissible spongiform encephalopathies (TSE) to which CJD belongs. This protein is an isoform of a normal membrane protein (PRP-sen) that has undergone a marked conformational change. PRP-res appears able to recruit normal molecules to the abnormal shape. Some believe that PRP-res is the cause of TSE, others maintain that it is a result of infection by the true agent(s), despite repeated failure to detect nucleic acid-containing material. At the very least, it appears that this abnormal protein is a marker of TSE. The recent demonstration of an association between an abnormal spinal fluid protein, 14-3-3, and clinically manifested TSE shows that other markers may exist. A spinal fluid test is not practicable as a test for pre-symptomatic individuals or for screening large number of individuals (e.g., blood donors), but its discovery suggests that a search for other markers could be fruitful. PRP-res has been found in several tissues in man and animals with TSE (e.g., CJD, scrapie in sheep and goats, bovine spongiform encephalopathy, also referred to as "mad cow disease"), most notably in brain, lymph nodes, spleen and circulating platelets. Peripheral blood lymphocytes are in continuous circulation through lymphatics, lymph nodes, and peripheral blood. Hence, it is a tenable hypothesis that small amounts of PRP-res are also present in circulating lymphocytes. Cases of CJD occur worldwide at a rate of one to two cases per million population per year. From 1979 through 1994, CJD was recorded as a cause in 3,642 deaths in the United States, with a stable incidence. The disease is rare, but invariably fatal, and has been proven to be associated with a transmissible agent. Cases arise spontaneously at low frequency for unknown reasons (sporadic CJD), perhaps acquired by external exposure to the etiologic agent, or may arise spontaneously at higher frequency in persons with certain genetic mutations (familial CJD). The disease can also be iatrogenic, i.e., transmitted between humans by transplanted corneas and cadaver dura mater grafts from affected individuals, by use of contaminated EEG electrodes, by certain neurological procedures, and by injections of human growth hormone (HGH). The incubation period between inoculation and disease is long (for US HGH cases, the median incubation period was 14 years, in Europe it was 18-20 years), making it difficult to detect new sources of infection. Some animal TSEs appear to be transmitted through the food chain. For example, the epidemic of bovine spongiform encephalopathy (BSE) in the United Kingdom (UK) appears to have been caused by the practice of grinding together material left over after slaughtering and butchering beef and using that material as a high protein feedstock. Banning that practice may have begun to control the epidemic in livestock. A new variant of CJD (nv-CJD) has been described in more than 25 patients in the UK and is apparently related to the BSE epidemic. Whether or not this came from humans eating infected beef is not yet clear. Nv-CJD may represent a jump across the species barrier, which is generally uncommon for TSE. The discovery of nv-CJD has heightened the concern about transmissibility by blood because the BSE agent(s) appears to be in higher concentrations in lymph tissues than classical CJD. Recent reports of 37 US donors who had made a number of blood donations between 1983 and 1997 before they were diagnosed with CJD stimulated concern about possible transmission by blood components or plasma protein derivatives. These reports led to precautionary product quarantines, withdrawals and recalls, and the adoption an FDA suggestion for CJD-related donor deferral criteria for both the plasma industry and whole blood sector. This loss of usable product is partially responsible for severe shortages of protein derivatives, most notably immune globulins and -1 protease inhibitor. An April 1998 poll conducted by the Immune Deficiency Foundation revealed that 87 percent of the physicians surveyed reported serious problems in the previous six months obtaining immune globulin for their patients. Experimental animal data suggest that blood may be infectious. Blood from mice ill with a mouse-adapted human CJD agent was separated into components, the plasma fractionated and blood and protein derivatives injected intracerebrally into other mice. All components and most protein fractions transmitted the disease, it seemed that cryoprecipitate was more infectious and albumin less infectious than other components and derivatives, which were not detectably different. Hamster studies with plasma "spiked" with infectious brain tissue and fractionated showed some transmission with fraction V, but at a low level. In a single experiment, blood from hamsters infected with hamster-adapted scrapie transmitted disease to one of 22 recipients. Full units of human blood from patients with CJD have failed to transmit the infection to chimpanzees, although these animals are still being observed years after inoculation. Studies with animal agents suggest that infectivity established by the intravenous route is logs lower than by the intracerebral route. Current assay procedures employing experimental animals which require months to years to obtain end points may not be sensitive enough to detect low levels of infectivity. Nevertheless, intravenous infectivity is probably much lower than via the intracerebral route, perhaps unmeasurable, but not zero. The discovery of nv-CJD in UK and the apparent greater presence of PRP-res in lymph nodes of patients with nv-CJD has raised the possibility that this type of CJD may be more likely transmissible by blood components or protein derivatives. Studies with animal models are incomplete as yet. Conversely, epidemiological data do not support transmission of CJD via blood transfusion in humans, either in the US and Germany with classical CJD or in the UK with nv-CJD. Furthermore, there have been no verified cases of CJD in patients with hemophilia, even among those treated for nearly 20 years exclusively with cryoprecipitate from a donor pool that contained several individuals who later developed CJD themselves. "Look back" from more than 20 of the 37 US donors later known to have developed CJD detected no cases of the disease in blood recipients. Studies of CJD and other TSE"s have been seriously hampered by existing assay systems which are slow in yielding results (months or years), insensitive and require intracerebral injection of test material into experimental animals. The infectivity of brain and other tissues has been assessed by intracerebral injections using rodents (time from inoculation to end point determination - three months to a year), small primates (squirrel monkeys two years) or chimpanzees (three-five years). These cumbersome biological assay systems make studies slow, tedious and difficult to plan and design. It is very difficult to determine in a timely manner the "clearance" or "partitioning" of CJD agent(s) between fractions during plasma fractionation. Furthermore, the relative infectivity of material injected intracerebrally compared to intravenous injections is difficult to determine with any precision. A Special Emphasis Panel on CJD and Blood Transfusion, recently convened by the NHLBI, concluded that "an unqualified and irreducible risk of exposure to CJD through blood and blood products does exist." They also agreed that the lack of a rapid sensitive and specific test for TSE infectivity was holding back progress in the study and control of CJD. PROPOSED RESEARCH The purpose of this solicitation is to encourage established investigators with expertise in basic biochemistry, protein chemistry, physical chemistry, virology, immunology and molecular biology to develop serologic, virologic or physical methods to detect markers of TSE pre-clinical infection. The ultimate goal of this program is the development of an assay to screen blood and tissue donors for the presence of the CJD agent. One strategy might be the development of monoclonal antibodies (Mab) specific to the conformation of PRP-res. Such a Mab could be utilized in an enzyme-linked immunosorbant assay (ELISA or EIA) for the detection of PRP-res. Physical or physico-chemical techniques might also be developed that would detect the abnormal conformation of PRP-res with sufficient specificity and sensitivity to be useful. There is evidence that the infectious agent(s) for CJD are present in plasma and lymph nodes, that B lymphocytes may be important in enabling the agent(s) to reach the brain and that PRP-res is present in platelets. Accordingly, any one of these peripheral blood components could represent a source for the assay. Another strategy might focus on the identification of TSE-associated foreign molecules in white blood cells that could be of value in developing a test. If the etiologic agent of CJD is a slow virus, peripheral lymphocytes may carry other viral-specific molecule(s) amenable to detection, either directly with nucleic acid amplification methods, or through serologic assay with the proper monoclonal/polyclonal antibodies. Applications should provide sufficient preliminary information from the literature, personal research or other sources to support the procedure(s) proposed. These assays, if developed, could help determine if CJD is truly transmitted by blood and blood products. It could form the basis of a blood/tissue donor screening test, and additionally, it could provide a diagnostic test for neurologists, since there is no way of detecting disease in the preclinical state. These tests could also be useful for testing TSE in animals, especially in domestic animals used for human consumption. SPECIAL REQUIREMENTS Upon initiation of the program, the NHLBI will sponsor annual meetings to encourage the exchange of information among investigators who participate in this program. Travel funds for a one day meeting each year, most likely to be held in Bethesda, Maryland, should be included in the modules. Applicants should also include a statement in the application indicating their willingness to participate in such meetings. 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 subpopulations must be included in all NIH supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification is provided that inclusion is inappropriate with respect to the health of the subjects or the purpose of 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 "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research", which have been published in the Federal Register of March 28, 1994 (FR 59 14508-14513), and in the NIH GUIDE FOR GRANTS AND CONTRACTS, Volume 23, Number 11, March 18, 1994, available on the Web at: http://www.nih.gov/grants/guide/1994/94.03.18/notice-nih-guideline008.html. Investigators also may obtain copies from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. INCLUSION OF CHILDREN AS PARTICIPANTS IN THE RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the 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 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. LETTER OF INTENT Prospective applicants are asked to submit, by January 11, 1999, 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 may be submitted. Although the 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 the NHLBI staff to estimate the potential review workload and to avoid conflict of interest in the review. The letter of intent is to be mailed, or faxed to: Dr. C. James Scheirer Division of Extramural Affairs National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room 7220, MSC 7924 Bethesda, MD 20892-7924 Telephone: (301) 435-0266 FAX: (301) 480-3541 Email: js110j@nih.gov APPLICATION PROCEDURES The research grant applications form PHS 398 (rev. 4/98) is to be used in applying for these grants, with the modifications noted below. These forms are available at most institutional offices of sponsored research, from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone (301) 710-0267, e-mail: grantsinfo@nih.gov, and on the internet at http://grants.nih.gov/grants/funding/phs398/phs398.html. The RFA label found in the PHS 398 (rev. 4/98) application form must be affixed to the bottom of the face page of the application. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title (Development of Assay Methods for Creutzfeldt-Jakob Disease) and number (HL-99-003-B) must be typed on line 2 of the face page of the application form and the YES box must be marked. BUDGET INSTRUCTIONS Samples budgets and justifications will be provided upon request or following the submission of a letter of intent. The total direct costs must be requested in accordance with the program guidelines and the modifications made to the standard PHS 398 application instructions described below: FACE PAGE As a reminder, Items 7a and 8a should be completed to indicate Modular Direct Costs requested and Items 7b and 8b should reflect Total Costs (Modular Direct plus F&A costs). Item 7 should reflect costs for the Initial Budget Period and item 8 should reflect costs for the Total Budget Period. DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD Do not complete Form Page 4 of the PHS 398 (rev 4/98). It is not required nor will it be accepted at the time of application. BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT Do not complete the categorical budget tables on page 5 of the PHS 398 (rev. 4/98) Form. Only the requested total direct costs line for each year should be completed based on the number of $25,000 modules being requested. Applicants may not request a change in the amount of each module. A maximum of eight modules ($200,000 direct cost) per year may be requested for each R01 application. Applicants may request up to four years of support for this RFA. Direct cost budgets will remain constant throughout the life of the project (i.e., the same number of modules requested for all budget periods). Any necessary escalation should be considered when determining the number of modules to be requested. However, in the event that the number of modules requested must change in any future year due to the nature of the research proposed, appropriate justification must be provided. Total Direct Costs for the Entire Proposed Project Period should be shown in the box provided. BUDGET JUSTIFICATION o Budget justifications should be provided under "Justifications" on Form Page 5 of the PHS 398. o List the names, role on the project and proposed percent effort for all project personnel (salaried or unsalaried)and provide a narrative justification for each person based on his/her role on the project. o Identify all consultants by name and organizational affiliation and describe the services to be performed. Provide a general narrative justification for individual categories (equipment, supplies, etc.) required to complete the work proposed. More detailed justifications should be provided for high cost items. Any large one-time purchases, such as large equipment requests, must be accommodated within these limits. CONSORTIUM/CONTRACTUAL COSTS If collaborations or subcontracts are involved that require transfer of funds from the grantee to other institutions, it is necessary to establish formal subcontract agreements with each collaborating institution. A letter of intent from each collaborating institution should be submitted with the application. Only the percentage of the consortium/contractual TOTAL COSTS (direct and facilities and administrative costs) relative to the total DIRECT COSTS of the overall project needs to be stated at this time. The following example should be used to indicate the percentage cost of the consortium, "The consortium agreement represents 27% of overall direct costs requested in the first year." A budget justification for the consortium should be provided as described in the "Budget Justification" section above (no Form Page 5 required for the consortium). Please indicate whether the consortium will be in place for the entire project period and identify any future year changes in the percentage relative to the parent grant. If there is a possibility of an award, the applicant will be requested to identify actual direct and indirect costs for all years of the consortium. Please note that total subcontract costs need not be calculated in $25,000 modules. However, when subcontract funds are added to the parent grant budget, the total direct cost amount must be included in the number of $25,000 modules requested. BIOGRAPHICAL SKETCH A biographical sketch is required for all key personnel, following the modified instructions below. Do not exceed the two-page limit for each person. o Complete the educational block at the top of the form page, o List current position(s) and those previous positions directly relevant to the application, o List selected peer-reviewed publications directly relevant to the proposed project, with full citation, o The applicant has the option to provide information on research projects completed and/or research grants participated in during the last five years that are relevant to the proposed project. OTHER SUPPORT - Do not complete the "Other Support" pages (Form Page 7). Selected other support information relevant to the proposed research may be included in the Biographical Sketch as indicated above. Complete Other Support information will be requested by NHLBI staff if there is a possibility for an award. CHECKLIST No "Checklist" page is required as part of the initial application. A completed Checklist will be requested by NHLBI staff if there is a possibility for an award. The applicant should provide the name and phone number of the individual to contact concerning fiscal and administrative issues if additional information is necessary following the initial review. Applications not conforming to these guidelines will be considered unresponsive to this RFA and will be returned without further review. Submit a signed, typewritten original of the application and three signed, photocopies, in one package to: CENTER FOR SCIENTIFIC REVIEW NATIONAL INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE, ROOM 1040, MSC 7710 BETHESDA, MD 20892-7710 BETHESDA, MD 20817 (for express/courier service) At the time of submission, two additional copies of the application must be sent to Dr. C. James Scheirer, at the address listed under LETTER OF INTENT. Applications must be received by February 12, 1999. If an application is received after that date, it will be returned to the applicant without review. The Center for Scientific Review (CSR) will not accept any application in response to this RFA 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. This does not preclude the submission of substantial revisions of applications already reviewed, but such applications must include an introduction addressing the previous critique. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by CSR and responsiveness by NHLBI. Incomplete and/or unresponsive applications will be returned to the applicant without further consideration. Remaining applications may be subjected to a streamlined review process by a Special Emphasis Panel convened by NHLBI Scientific Review Office to determine their scientific merit relative to other applications received in response to the RFA. The roster of reviewers for the RFA will be available on the NHLBI home page approximately four weeks prior to the scheduled review date. Applications determined to be meritorious will be evaluated for scientific and technical merit by the review committee, be discussed and receive a priority score. All other applications will neither be discussed nor scored. Secondary review of the applications will be conducted by the National Heart, Lung, and Blood Advisory Council (NHLBAC). 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 review, comments on the following aspects of the application will be made in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered in the assignment of the overall score. 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? 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? 3) 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? 4) 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)? 5) 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? As part of the scientific and technical merit evaluation of the research plan, reviewers will be instructed to address the adequacy of plans for including both genders, minorities and their subgroups, and children as appropriate for the scientific goals of the research, or justification for exclusion. The personnel category will be reviewed for appropriate staffing based on the requested percent effort. The direct costs budget request will be reviewed for consistency with the proposed methods and specific aims. Any budgetary adjustments recommended by the reviewers will be in $25,000 modules. The duration of support will be reviewed to determine if it is appropriate to ensure successful completion of the requested scope of the project. AWARD CRITERIA Applicants should be aware that, in addition to scientific merit, program priorities and program balance, the total costs of the proposed project and the availability of funds will be considered by NHLBI staff as well as National Heart, Lung, and Blood Advisory Council in making funding recommendations. In circumstances in which applications have similar scientific merit, but vary in cost competitiveness, NHLBI is likely to select the more cost competitive application for funding. SCHEDULE Letter of Intent Receipt Date: January 11, 1999 Application Receipt Date: February 12, 1999 Date of Initial Review: April 1999 Review by NHLBI Advisory Council: September 16, 1999 Anticipated Award Date: September 30, 1999 INQUIRIES Inquiries concerning this RFA are encouraged. Potential applicants may request sample budget pages. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues and requests for sample budget pages to: Luiz H. Barbosa, D.V.M. Division of Blood Diseases and Resources National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room 10146, MSC 7950 Bethesda, MD 20892-7950 Telephone: (301) 435-0075 FAX: (301) 480-0868 Email: lb30o@nih.gov Direct inquiries regarding fiscal matters to: Ms. Jane Davis Grants Operations Branch National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Suite 7174, MSC 7926 Bethesda, MD 20892-7926 Telephone: (301) 435-0166 FAX: (301) 480-3310 Email: DavisJ@gwgate.nhlbi.nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.839. Awards are made under authorization of the Public Health Service Act, Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC 241 and 285) and administered under PHS grants policies and Federal Regulations 42 CFR 52 and 45 CFR Part 74. 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 and contract 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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