CHEMICAL SCREENS FOR NEW INDUCERS OF FETAL HEMOGLOBIN (SBIR/STTR) RELEASE DATE: December 30, 2002 PA NUMBER: PA-03-049 EXPIRATION DATE: December 1, 2005, unless reissued APPLICATION RECEIPT DATES: Applications submitted in response to this PA will be accepted on the standard SBIR/STTR application deadlines (April 1, August 1, and December 1). National Heart, Lung, and Blood Institute (NHLBI) (http://www.nhlbi.nih.gov) National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (http://www.niddk.nih.gov) THIS PA CONTAINS THE FOLLOWING INFORMATION o Purpose of the PA o Research Objectives o Mechanism(s) of Support o Eligible Institutions o Individuals Eligible to Become Principal Investigators o Where to Send Inquiries o Submitting an Application o Peer Review Process o Review Criteria o Award Criteria o Required Federal Citations PURPOSE OF THIS PA The National Heart, Lung, and Blood Institute (NHLBI) and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) invite grant applications for Small Business Innovation Research (SBIR) and Small Business Technology Transfer (STTR) awards to support research and development of new drugs to increase fetal hemoglobin levels for the treatment of beta-chain hemoglobinopathies such as sickle cell disease (SCD) and Cooley's anemia (CA; beta-thalassemia). The goal of this Program Announcement (PA)is to encourage the use of SBIR and STTR mechanisms to support new chemical activity screens and drug design efforts for new pharmacologic inducers of fetal hemoglobin. The ultimate long-term objective will be to bring new fetal hemoglobin inducers to clinical practice to improve upon drugs such as hydroxyurea, the only FDA-approved drug for treatment of sickle cell disease. Hydroxyurea is thought to work in part through fetal hemoglobin induction, but does not benefit all patients. It is well established that SCD and CA can be cured with adequate reactivation of endogenous fetal hemoglobin genes silenced during development. Initial drug activity screens that are high-throughput in nature are encouraged. These screens should include but not be limited to compounds in the short chain fatty acid and carbonic acid classes, which have shown great promise in this area. As commercial activity in this area has decreased significantly in the last decade, it is hoped that this PA will stimulate and renew interest within the small business community to develop new pharmacologic and/or combined pharmacologic-genetic approaches to fetal hemoglobin induction, to cure SCD and CA. RESEARCH OBJECTIVES Background Since the late 1970s, strong epidemiologic evidence has been gathered that shows high levels of fetal hemoglobin are curative for SCD and CA. Over the last two decades, this knowledge has provided a strong rationale to search for drugs that modify expression of fetal hemoglobin. Historically, pharmacologic induction of fetal hemoglobin has been attempted with two approaches. One is the use of cytotoxic drugs. This method is based on the observation that production of fetal hemoglobin can be stimulated by rapid regeneration of erythropoiesis. Cytotoxic drugs produce rapid erythroid regeneration following the killing of cycling hematopoietic cells. The induction of fetal hemoglobin by hydroxyurea, currently approved for treatment of SCD patients in acute vaso-occlusive crisis, is based on that principle (though it has still not been conclusively proven that the therapeutic effect of hydroxyurea is mediated through fetal hemoglobin induction). Significant variation in the level of induction of fetal hemoglobin synthesis is characteristic of treatment with hydroxyurea, and in about one-third of patients this treatment is ineffective. Furthermore, hydroxyurea (and other cytotoxic drugs) are ineffective in severe homozygous CA and they are only slightly effective in intermediate severity CA. The second approach is the induction of fetal hemoglobin by compounds that most likely act at the level of chromatin. Two types of compounds fall in this category: 5-azacytidine, and short chain fatty acids. 5-azacytidine stimulates fetal hemoglobin synthesis by affecting the level of DNA methylation and indirectly increasing fetal hemoglobin gene transcription by modulating DNA/protein interactions and chromatin remodeling. Short chain fatty acids probably act by increasing the level of chromatin acetylation because of inhibition of the activity of histone deacetylase. 5-azacytidine induces fetal hemoglobin in patients with SCD and CA, but its clinical use is very limited because this compound is considered to be carcinogenic. Butyrate induces fetal hemoglobin in patients with SCD and CA, but the therapeutic usefulness of this treatment is limited by the need of administration of this drug through intravenous infusions that last for several hours. A significant development of the last ten years has been the realization that the potential of induction of fetal hemoglobin synthesis is shared by a large number of compounds. Thus, all short chain fatty acids with 2-9 carbon atoms, as well as short chain fatty acid derivatives and analogues have been shown to act as fetal hemoglobin inducers. Other categories of organic chemicals have shown to have this property in vitro or in vivo. These findings permit the prediction that potent inducers of fetal hemoglobin synthesis can be discovered through empirical screening of chemicals. Thus, there is solid clinical, cell biological and biochemical evidence that the induction of fetal hemoglobin can cure SCD and CA, and there is proof of principle that fetal hemoglobin can be induced with pharmacological means, but there are severe limitations to the effectiveness of the currently used fetal hemoglobin inducers. It is therefore necessary to launch a focused research effort to discover new approaches for therapeutic induction of fetal hemoglobin synthesis. Compounds that can be taken orally and are effective in both SCD and CA are required. This PA encourages the use of the National Institutes of Health (NIH) SBIR and STTR grant mechanisms to explore various approaches to high-throughput screening of synthetic chemical or natural product libraries, to identify new drugs with fetal hemoglobin induction activity and develop them for clinical application (e.g. file an Investigational New Drug application with the FDA, and carry out Phase I-III clinical trials). The NHLBI has supported through a cooperative agreement since 1997 a Reference Laboratory to Evaluate New Therapies for Sickle Cell Disease, that is located at the Children's Hospital of Philadelphia and that carries out small-scale drug screening for fetal hemoglobin inducers. Applicants planning to respond to this PA are encouraged to consult with this Reference Laboratory before preparing an application (contact NHLBI Program representative listed below). In addition, the NHLBI and NIDDK are co-sponsoring an active Request for Applications(RFA) on transactivation of fetal hemoglobin genes, and the NHLBI is soon to sponsor a second RFA on fetal hemoglobin gene silencing. Grantees funded in response to this PA are encouraged to attend the joint RFA investigator meetings to be held for these two RFAs in the Fall (contact NHLBI Program representative listed below for details). It is expected that the high-throughput initial screening portion of this research will be carried out primarily, but not exclusively using in vitro cell culture systems. Toxicology studies, pharmacokinetic, and late stage efficacy studies may be carried out in rodent models engineered to contain a human fetal hemoglobin gene, and/or in large animal models (e.g. non-human primates). Research Goals and Topics The following research areas are examples of appropriate topics for applications in response to this PA. This list is meant to be representative and not all-inclusive: o Develop new automated, high-throughput assays or chemical activity screens for classical drug discovery efforts based on fetal hemoglobin induction activity. Assay methods that employ robotics, and that are physiologically relevant are needed. o Screen synthetic or natural product chemical libraries of high complexity for fetal hemoglobin induction activity using new or existing rapid assays. The application of new assay methods to existing chemical libraries published in the scientific literature is encouraged. New chemical libraries with well- documented diversity and complexity may also be useful. o Screen synthetic or natural product chemical libraries of low complexity and limited to compounds in the short chain fatty acid and carbonic acid classes (many examples of which are known to possess fetal hemoglobin induction activity). o Using rational drug design, study, refine, and optimize the structure- activity relationships of candidate fetal hemoglobin-inducing drugs identified in initial screens. o Develop genetic approaches to drug discovery focused on fetal hemoglobin induction. Methods that might be employed include the construction and screening of artificial transcription factors that activate gamma-globin, interfering RNAs (RNAi), or catalytic RNAs, all coupled with gene transfer methods. o Pursue signal transduction pathway-based drug discovery for fetal hemoglobin inducers by screening for drugs that modify or modulate the activity of specific regulatory proteins known to participate in the activation of fetal hemoglobin expression. o Advance to large animal studies candidate inducers of fetal hemoglobin that have shown promise in vitro, and/or in small animal studies. o Advance to clinical studies in hemoglobinopathy subjects inducers that have shown promise in large animal studies or prior pilot clinical studies. o Develop genetic or pharmacologic means to specifically inhibit the gamma- globin gene silencing that occurs in the neonatal period of human development. Therapeutic agents developed from such approaches could potentially be used for treatment of newborns diagnosed with homozygous sickle cell disease or Cooley's anemia, in order to inhibit the gamma- to beta-globin gene switch and thus continue synthesis of fetal hemoglobin into infancy. Either genetic or non-genetic approaches may be feasible. o Develop pharmacologic or genetic means to inhibit the gamma-globin gene silencing that takes place during the process of maturation of adult erythroid progenitors. o Use combined pharmacologic-genetic approaches to fetal hemoglobin induction. MECHANISM OF SUPPORT SBIR AND STTR This PA will use the NIH Small Business Innovation Research (SBIR) and Small Business Technology Transfer (STTR) award mechanisms. As an applicant, you will be solely responsible for planning, directing, and executing the proposed project. Except as otherwise stated in this PA, awards will be administered under NIH grants policy as stated in the NIH Grants Policy Statement, March 2001, available at http://grants.nih.gov/grants/policy/nihgps_2001. Applications can be submitted for support as Phase I STTR (R41) or Phase I SBIR (R43) grants; or under the SBIR/STTR FAST-TRACK option as described in the SBIR/STTR Omnibus Solicitation. Phase II applications in response to this PA will only be accepted as competing continuations of previously funded NIH Phase I SBIR/STTR awards. The Phase II proposal must be a logical extension of the Phase I research. ELIGIBLE INSTITUTIONS Eligibility requirements are described in the SBIR/STTR Omnibus Solicitation. Small business concerns are eligible to submit applications. A small business concern is one that, on the date of award for both Phase I and Phase II agreements, meets all of the following criteria: o is organized for profit, with a place of business located in the United States, which operates primarily within the United States or which makes a significant contribution to the United States economy through payment of taxes or use of American products, materials, or labor; o is in the legal form of an individual proprietorship, partnership, limited liability company, corporation, joint venture, association, trust or cooperative, except that where the form is a joint venture (as defined in this section) there can be no more than 49 percent participation by foreign business entities in the joint venture; o is at least 51 percent owned and controlled by one or more individuals who are citizens of, or permanent resident aliens in, the United States; has, including its affiliates, not more than 500 employees, and meets the other regulatory requirements found in 13 CFR Part 121. Business concerns, other than investment companies licensed, or state development companies qualifying under the Small Business Investment Act of 1958, 15 U.S.C. 661, et seq., are affiliates of one another when either directly or indirectly, (a) one concern controls or has the power to control the other; or (b) a third party/parties controls or has the power to control both. Control can be exercised through common ownership, common management, and contractual relationships. The term "affiliates" is defined in greater detail in 13 CFR 121.3-2(a). The term "number of employees" is defined in 13 CFR 121.3-2(t). Business concerns include, but are not limited to, any individual (sole proprietorship), partnership, corporation, joint venture, association, or cooperative. Further information may be obtained by contacting the Small Business Administration Size District Office at http://www.sba.gov/size/. For both Phase I and Phase II, the R&D must be performed in its entirety in the United States. For both Phase I and Phase II, the proposed work must be performed in its entirety in the United States. 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: Pankaj Qasba, Ph.D. Blood Diseases Program National Heart Lung and Blood Institute 6701 Rockledge Dr, MSC 7950 Bethesda MD 20892-7950 Telephone: 301-435-0050 Fax: 301-480-0868 Email: qasbap@nhlbi.nih.gov David G. Badman, Ph.D. Hematology Program Director Deputy Director for Basic Program Administration DKUHD, NIDDK, NIH 2 Democracy Plaza, Room 621 MSC 5458 6707 Democracy Blvd. Bethesda, MD 20892-5458 Telephone: 301-594-7717 Fax: 301-480-3510 Email: db70f@nih.gov o Direct your questions about financial or grants management matters to: Shelia Ortiz Division of Extramural Affairs National Heart, Lung, and Blood Institute 6701 Rockledge Dr, MSC 7926 Bethesda MD 20892-7926 Telephone: 301-435-0166 Fax: 301-480-3310 Email: ortizs@nhlbi.nih.gov SUBMITTING AN APPLICATION The PHS 398 research grant application (rev. 5/2001) must be used for all Phase I, Phase II and Fast-Track applications (new and revised.) Instructions and forms are available at http://grants.nih.gov/grants/funding/phs398/phs398.html. Prepare your application in accordance with the SBIR/STTR Omnibus Solicitation and Chapter VI of the PHS 398. The NIH will return applications that are not submitted on the 5/2001 version of the PHS 398. For further assistance contact GrantsInfo, Telephone: (301) 710-0267, Email:GrantsInfo@nih.gov. SPECIFIC INSTRUCTIONS FOR PHASE I APPLICATIONS: Application forms, requirements, and procedures are the same as listed in the Omnibus Solicitation for Phase I SBIR/STTR Grant applications (http://grants.nih.gov/grants/funding/sbirsttr1/index.pdf), except for the following: o Type the title and number of this PA on line 2 on the face page of the application. o The Omnibus Solicitation states levels for Phase I and Phase II budgets that are guidelines, not ceilings. SBIR applications requesting up to $100,000 in total costs (direct costs, indirect costs, and fee) 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. Section VI of the research grant application instructions for the PHS 398 at http://grants.nih.gov/grants/funding/phs398/instructions2/p1_preparing _SBIR_STTR_app.htm includes step-by-step guidance for preparing modular grants. Additional information on SBIR modular grants is available at http://grants.nih.gov/grants/funding/phs398/instructions2/p1_SBIRSTTR _general_instructions.htm. Applications for over $100,000 total costs must include a detailed budget and budget justification (Form Pages 4 and 5). SPECIFIC INSTRUCTIONS FOR Phase II Applications: Phase II applications will be accepted only as competing continuations of previously funded NIH Phase I SBIR or STTR awards. The Phase II application must be for developmental work that is a logical extension of the feasibility research conducted during Phase I. When preparing an application for a Phase II award, you should follow the instructions for NIH Phase II SBIR or STTR applications. The instructions and forms for a Phase II SBIR and STTR award are available at http://grants.nih.gov/grants/funding/phs398/phs398.html. SPECIFIC INSTRUCTIONS FOR FAST TRACK APPLICATIONS: The NIH Fast-Track mechanism expedites the decision and award of SBIR and STTR Phase II funding for scientifically meritorious applications that have a high potential for commercialization. Fast Track incorporates a submission and review process, in which complete Phase I and Phase II grant applications are submitted simultaneously and reviewed together. The FAST-TRACK must have a section labeled Milestones at the end of the Phase I Research Plan. This section must include well-defined quantifiable milestones for completion of Phase I, a discussion of the suitability of the proposed milestones for assessing the success in Phase I, and a discussion of the implications of successful completion of these milestones on the proposed Phase II. Failure to provide such information in the Phase I application and/or sufficient detail in the Phase II application may be sufficient reason for the peer review committee to exclude the Phase II from consideration. If so, the applicant may apply later for Phase II support. Such applications will be reviewed by an appropriate scientific review group convened by the NIH. In addition, the Phase II portion of a Fast Track application must include a concise Commercialization Plan (Product Development Plan), which is limited to ten pages. Label this section clearly and include it in Section J of the Phase II Research Plan. More detailed instructions on the preparation of a Fast Track application are described in the PHS 398 at http://grants.nih.gov/grants/funding/sbirsttr1/index.pdf#page=21. 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) APPLICATIONS HAND-DELIVERED BY INDIVIDUALS TO THE CENTER FOR SCIENTIFIC REVIEW WILL NO LONGER BE ACCEPTED. This policy does not apply to courier deliveries (i.e. FEDEX, UPS, DHL, etc.) (http://grants.nih.gov/grants/guide/notice-files/NOT-CA-02-012.html) APPLICATION PROCESSING: Applications must be received by or mailed on or before the receipt dates described above. 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. This does not preclude the submission of a substantial revision of an application already reviewed, but such application must include an Introduction addressing the previous critique. 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 Receive a written critique 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 second level review by the National Heart, Lung and Blood Advisory Council and the National Diabetes and Digestive and Kidney Diseases Advisory Council. 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 discuss the following aspects of your application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals: o Significance o Approach o Innovation o Investigator o Milestones and Proof of Principle o Environment The scientific review group will address and consider each of these criteria in assigning your application's overall score, weighting them as appropriate for each application. Your 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, you may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. ALL SBIR/STTR APPLICATIONS 1. Significance: Does the proposed project have commercial potential to lead to a marketable product or process? Does this study address an important problem? What may be the anticipated commercial and societal benefits of the proposed activity? If the aims of the application are achieved, how will scientific knowledge be advanced? Does the proposal lead to enabling technologies (e.g., instrumentation, software) for further discoveries? Will the technology have a competitive advantage over existing/alternate technologies that can meet the market needs? 2. Approach: Are the conceptual framework, design, methods, and analyses adequately developed, well-integrated, and appropriate to the aims of the project? Is the proposed plan a sound approach for establishing technical and commercial feasibility? Does the applicant acknowledge potential problem areas and consider alternative strategies? Are the milestones and evaluation procedures appropriate? 3. Innovation: Does the project challenge existing paradigms or employ novel technologies, approaches or methodologies? Are the aims original and innovative? 4. Investigators: Is the Principal Investigator capable of coordinating and managing the proposed SBIR/STTR? Is the work proposed appropriate to the experience level of the Principal Investigator and other researchers, including consultants and subcontractors (if any)? Are the relationships of the key personnel to the small business and to other institutions appropriate for the work proposed? 5. Environment : Is there sufficient access to resources (e.g., equipment, facilities)? Does the scientific and technological environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? In accordance with NIH policy, the following criteria will be applied to ALL applications: Budget: For all applications, is the percent effort listed for the PI appropriate for the work proposed? On applications requesting up to $100,000 total costs, is the overall budget realistic and justified in terms of the aims and methods proposed? On applications requesting over $100,000 in total costs, is each budget category realistic and justified in terms of the aims and methods? Human Subjects: 1. Protection of Human Subjects from Research Risks - for all studies involving human subjects. See instructions and "Guidance for Preparing the Human Subjects Research Section." If an exemption is claimed, is it appropriate for the work proposed? If no exemption is claimed, are the applicant's responses to the six required points appropriate? Are human subjects placed at risk by the proposed study? If so, are the risks reasonable in relation to the anticipated benefits to the subjects and others? Are the risks reasonable in relation to the importance of the knowledge that reasonably may be expected to be gained? Are the plans proposed for the protection of human subjects adequate? 2. Inclusion of Women Plan - for clinical research only. Does the applicant propose a plan for the inclusion of both genders that will provide their appropriate representation? Does the applicant provide appropriate justification when representation is limited or absent? Does the applicant propose appropriate and acceptable plans for recruitment/outreach and retention of study participants? 3. Inclusion of Minorities Plan - for clinical research only . Does the applicant propose a plan for the inclusion of minorities that will provide their appropriate representation? Does the applicant provide appropriate justification when representation is limited or absent? Does the applicant propose appropriate and acceptable plans for recruitment/outreach and retention of study participants? 4. Inclusion of Children Plan- for all studies involving human subjects . Does the applicant describe an acceptable plan in which the representation of children of all ages (under the age of 21) is scientifically appropriate and recruitment/retention is addressed realistically? If not, does the applicant provide an appropriate justification for their exclusion? 5. Data and Safety Monitoring Plan for clinical trials only . Does the applicant describe a Data and Safety Monitoring Plan that defines the general structure of the monitoring entity and mechanisms for reporting Adverse Events to the NIH and the IRB? Animal Welfare: If vertebrate animals are involved, are adequate plans proposed for their care and use? Are the applicant's responses to the five required points appropriate? Will the procedures be limited to those that are unavoidable in the conduct of scientifically sound research? Biohazards: Is the use of materials or procedures that are potentially hazardous to research personnel and/or the environment proposed? Is the proposed protection adequate? Phase II Application Review Criteria: In addition to the above criteria: 1. How well did the applicant demonstrate progress toward meeting the Phase I objectives, demonstrating feasibility, and providing a solid foundation for the proposed Phase II activity? 2. Did the applicant submit a concise Commercialization Plan (Product Development Plan) that adequately addresses the areas described in the Research Plan item J? 3. Does the project carry a high degree of commercial potential, as described in the Commercialization Plan? Amended Applications In addition to the above criteria, the following criteria will be applied to revised applications. 1. Are the responses to comments from the previous SRG review adequate? 2. Are the improvements in the revised application appropriate? Phase I/Phase II Fast-Track Application Review Criteria For Phase I/Phase II Fast Track applications, the following criteria also will be applied: 1. Does the Phase I application specify clear, appropriate, measurable goals (milestones) that should be achieved prior to initiating Phase II? 2. Did the applicant submit a concise Commercialization Plan (Product Development Plan) that adequately addresses the areas described in the Research Plan, item J? 3. To what extent was the applicant able to obtain letters of interest, additional funding commitments, and/or resources from the private sector or non-SBIR/ STTR funding sources that would enhance the likelihood for commercialization? 4. Does the project carry a high degree of commercial potential, as described in the Commercialization Plan? Phase I and Phase II Fast-Track applications that satisfy all of the review criteria will receive a single rating. Failure to provide clear, measurable goals may be sufficient reason for the scientific review group to exclude the Phase II application from Fast-Track review. ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, your application will also be reviewed with respect to the following: PROTECTIONS: The adequacy of the proposed protection for humans, animals, or the environment, to the extent they may be adversely affected by the project proposed in the application. INCLUSION: 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. Plans for the recruitment and retention of subjects will also be evaluated. (See Inclusion Criteria included in the section on Federal Citations, below) BUDGET: The appropriateness of the proposed budget and duration in relation to the proposed research. The following evaluation criterion will be presented in an administrative note in the Summary Statement and will not factor into the numerical score: DATA SHARING: The adequacy of plans to make the methods and materials generated in the project widely available in a timely fashion to the scientific community, given the proposed plan to exercise (or not to exercise) intellectual property rights. AWARD CRITERIA Applications will compete for available funds with all other recommended SBIR and STTR applications. Funding decisions for Phase I or Phase II applications will be based on quality of the proposed project as determined by peer review, availability of funds, and relevance to program priorities. Phase II applications will be selected for funding based on the initial priority score, assessment of the Phase I progress and determination that Phase I goals were achieved, the project's potential for commercial success, and the availability of funds. FAST-TRACK Phase II applications may be funded following submission of the Phase I progress report and other documents necessary for continuation. REQUIRED FEDERAL CITATIONS MONITORING PLAN AND DATA SAFETY AND MONITORING BOARD: Research components involving Phase I and II clinical trials must include provisions for assessment of patient eligibility and status, rigorous data management, quality assurance, and auditing procedures. In addition, it is NIH policy that all clinical trials require data and safety monitoring, with the method and degree of monitoring being commensurate with the risks (NIH Policy for Data Safety and Monitoring, NIH Guide for Grants and Contracts, June 12, 1998: http://grants.nih.gov/grants/guide/notice-files/not98-084.html). 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 AMENDMENT "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. HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research on hESCs can be found at http://grants.nih.gov/grants/stem_cells.htm and at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html. Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (see http://escr.nih.gov). It is the responsibility of the applicant to provide the official NIH identifier(s)for the hESC line(s)to be used in the proposed research. Applications that do not provide this information will be returned without review. 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. 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 No. 93.839 (NHLBI, DBDR), and No. 93.848 (NIDDK, DKUHD) and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Awards are made under authorization of Sections 301 and 405 of the Public Health Service Act as amended (15 USC 638 and 42 USC 241 and 284) and administered under NIH grants policies described at http://grants.nih.gov/grants/policy/policy.htm and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74. 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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