RFA-AT-02-003: BOTANICAL/DRUG INTERACTIONS IN HIV

Department of Health
and Human Services (HHS)

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BOTANICAL/DRUG INTERACTIONS IN HIV Release Date: December 6, 2001 RFA: RFA-AT-02-003 National Center for Complementary and Alternative Medicine (http://nccam.nih.gov) Letter of Intent Receipt Date: February 28, 2002 Application Receipt Date: March 28, 2002 THIS RFA USES "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. MODULAR INSTRUCTIONS MUST BE USED FOR RESEARCH GRANT APPLICATIONS REQUESTING LESS THAN $250,000 PER YEAR IN ALL YEARS. MODULAR BUDGET INSTRUCTIONS ARE PROVIDED IN SECTION C OF THE PHS 398 (REVISION 5/2001) AVAILABLE AT http://grants.nih.gov/grants/funding/phs398/phs398.html. PURPOSE The National Center for Complementary and Alternative Medicine (NCCAM) announces the availability of funds to support research into interactions between botanical substances and prescription drugs used in the treatment of human immunodeficiency virus (HIV) infection and its complications. Research findings published in the medical literature suggest harmful interactions between botanicals and antiretroviral medications; however some reports also suggest beneficial effects from botanical/drug combinations. The widespread use of botanicals by persons with HIV-infection and the concomitant use of pharmaceutical drugs pose risks to effective treatment for HIV-infection and support the need for this initiative. In addition, reports of beneficial interactions need to be investigated. This initiative is intended to stimulate investigator-initiated biomedical research on botanical/drug interactions in vitro, in animal models, and in phase I/II clinical studies relevant to the treatment of HIV-infection and its complications. Research supported by this initiative is expected to prevent adverse botanical/drug interactions during therapy for HIV-infection and its complications, establish possible synergistic combinations of botanicals with pharmaceutical drugs, and increase our knowledge of the mechanisms of action of botanicals. The information developed on interactions between botanical substances and pharmaceutical agents used in the treatment of HIV-infection and its complications is expected to provide the public and health professionals with the information necessary to make appropriate treatment choices. 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 Request for Applications (RFA), Botanical/Drug Interactions in HIV, 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/. 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 and local government, and eligible agencies of the Federal government. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. MECHANISM OF SUPPORT This RFA will use the National Institutes of Health (NIH) R01 and R21 award mechanisms. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. This RFA is a one- time solicitation. Future revised applications will compete with all investigator- initiated applications and be reviewed according to the customary peer review procedures. The anticipated award date is September 2002. Specific application instructions have been modified to reflect "MODULAR GRANT" and "JUST_IN_TIME" streamlining efforts that have been adopted by the NIH. Complete and detailed instructions and information on Modular Grant applications have been incorporated into the PHS 398 (rev. 5/2001). Additional information on Modular Grants can be found at http://grants.nih.gov/grants/funding/modular/modular.htm. FUNDS AVAILABLE The NCCAM intends to commit approximately $600,000 total costs in FY 2002 to fund one or two R21 and one or two R01 grants in response to this RFA. An R21 applicant may request a project period of up to two years and a budget of up to $125,000 direct costs per year. An R01 applicant may request a project period of up to three years and a budget of up to $375,000 direct costs per year. The use of modular budgets applies to research grant applications requesting up to $250,000 direct costs per year. Because the nature and scope of the research proposed may vary, it is anticipated that the size of each award will also vary. Although the financial plans of the NCCAM provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications. At this time, it is not known if this RFA will be reissued. RESEARCH OBJECTIVES The main objectives of this initiative are to gain information that can help to prevent adverse botanical/drug interactions during therapy for HIV- infection and its complications, to establish possible synergistic combinations of botanicals with pharmaceutical drugs used in treating HIV- infection and its complications, and to increase our knowledge of the mechanisms of action of botanicals. BACKGROUND Complementary and alternative medicine (CAM) practices are described as those not presently considered an integral part of conventional medicine. Eisenberg et al. estimated that 40% of the general population uses CAM and that 18% of individuals taking prescription drugs concurrently use herbs, high-dose vitamins, or both. They estimated that 15 million adults are at risk for potential drug-dietary supplement interactions, and that fewer than 40% of patients surveyed disclosed their CAM use to their physicians. For persons living with HIV/AIDS, estimates of CAM use range from 41% to 84%, with 21% to 27% of participants in various surveys reporting the use of herbs in addition to antiretroviral medication. In several surveys, only 43% to 67% of persons living with HIV/AIDS reported that their doctors were aware of their CAM use and in one study, 25% of patients reported that the prescribing physician was unaware of their CAM use at all. At the same time, increasing numbers of physicians are referring patients to CAM providers or prescribing CAM interventions themselves. The frequency and extent of adverse drug reactions, or even positive effects due to concurrent use is unknown. Given the complex pharmaceutical regimens of antiretroviral therapy and the large numbers of patients who are taking both botanicals and antiretrovirals or other medications to treat complications, the risk of interactions may be substantial. Interactions between botanicals and drugs may be classified as pharmacokinetic or pharmacodynamic. Pharmacokinetic interactions result in a change in the amount of available drug through an effect on the absorption, transport, distribution, metabolism or excretion of the drug. Pharmacodynamic interactions alter the pharmacologic effect of the drug and may be inhibitory, additive, or synergistic. P-glycoprotein, important to cellular transport, and the cytochrome P450 enzyme system have significant roles in the metabolism of HIV medications. P-glycoprotein's action in intestinal cell wall, hepatocytes, and renal tubular cells affects drug absorption and excretion in bile and urine. The cytochrome P450 system contains several families of isoenzymes with the most important for antiretroviral drug metabolism being 3A4 (CYP3A4). The cytochrome enzyme system metabolizes most of the pharmaceuticals currently used in the treatment of HIV and many of the investigational drugs in development, as well as being an important pathway for the metabolism of certain botanical substances. Recent research regarding interaction between herbs and pharmaceuticals used to treat HIV-infection demonstrate the real dangers of combining herbal therapies with antiretroviral therapy. In a study with healthy volunteers, St. John's wort decreased blood levels of the protease inhibitor indinavir to levels that in patients on therapy for HIV-infection could lead to treatment failure. St. John's wort is known to induce CYP3A4 for which protease inhibitors are substrates. A separate study demonstrated an interaction between garlic and another protease inhibitor, saquinavir, that is known to be a substrate for CYP3A4. Healthy volunteers were given saquinavir alone followed by garlic tablets in doses equivalent to culinary amounts of garlic. Garlic lowered the blood levels of saquinavir not only while it was being taken, but also after a washout period. In vitro studies of the effect of garlic on CYP3A4 yield conflicting results some inducing and some suppressing activity of CYP3A4. The exact mechanism of this interaction is not known and may be due to the induction of CYP3A4 or P-glycoprotein. This herb/drug interaction also poses the risk of treatment failure in patients on therapy for HIV, even if they are only eating garlic. Since Milk thistle, ginseng, and skullcap are known to affect CYP450 metabolism in vitro, they also may interact with medications used to treat HIV-infection. In addition, the possibility of botanical/drug interactions having beneficial effects on the treatment of HIV-infection should be investigated. In a clinical study, use of a mushroom extract enhanced the effect of ddI. Also, an anecdotal report in an HIV community newspaper claims benefit from the use of olive leaf extract in combination with 3TC. Research is needed to understand better the documented and potential interactions, as well as to identify additional herb/drug combinations that may pose risks or offer benefits. The award of research grants through this program will permit exploration of the range of possible interactions. Goals The proposed initiative is expected to stimulate investigator-initiated biomedical research on botanical/drug interactions in vitro, in animal models, and in phase I/II or case control clinical studies. The phase I/II clinical studies are expected to examine the pharmacokinetics or pharmacodynamics of the botanical/drug combination in contrast to these parameters when the botanical or drug is administered alone. This RFA invites proposals designed to explore the cellular and molecular effects of botanical interactions with proprietary drugs, or studies which may help to predict the effects of the botanicals on drug action and metabolism in vivo. Case control studies should be aimed at elucidating the relationship between a botanical product and specific events (adverse or beneficial) in the presence of a proprietary drug. Studies may include biomarkers such as CD4 counts or viral loads as secondary outcome measures. SPECIAL REQUIREMENTS The NCCAM does not usually accept research applications in the botanical category that focus on the isolation of active ingredients from herbal preparations, except when this is necessary for identification and standardization of optimal whole products, when comparisons are being made to the complex product, or to investigate metabolic pathways and mechanisms of action as part of the proposed research project. Therefore, conventional drug discovery and drug development approaches using botanicals as the source are not considered to be within the scope of this RFA. It is the responsibility of the applicant to document the characterization, standardization, and quality control of the botanical products chosen. Research projects can be basic (mechanistic) or clinical studies other than Phase III trials. For the purpose of this RFA, a Phase III trial is defined as a broadly based prospective investigation usually involving a substantial number of human subjects either at a single site or at multiple sites. The primary objective of such trials is to evaluate an experimental intervention in comparison with a standard or control intervention, or to compare two or more existing treatments. In Phase III trials, the primary endpoint is usually a significant change in an identified clinical outcome. The definition includes interventions given for disease prevention, prophylaxis, diagnosis, or therapy. 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. NIH policy requires data and safety monitoring for all clinical trials 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). The NIH has also released "Further Guidance On A Data And Safety Monitoring For Phase I and Phase II Trials", NIH Guide, June 5, 2000: http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-038.html. In addition, NCCAM requires that all masked clinical trials, regardless of size, establish an independent data and safety monitoring board. The Data Safety Monitoring Guidelines for NCCAM-supported clinical trials are available at: http://nccam.nih.gov/research/policies/datasafety/index.htm. Funds should be budgeted for these activities. They should not duplicate internal review and monitoring systems that are already in place at the institution. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported 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 It is the policy of NIH that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines" on the Inclusion of Children as Participants in Research Involving Human Subjects that was published in the NIH Guide for Grants and Contracts, March 6, 1998, and is available at the following URL address: http://grants.nih.gov/grants/guide/notice-files/not98-024.html. Investigators also may obtain copies of these policies from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. 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. This policy announcement is found in the NIH Guide for Grants and Contracts Announcement dated June 5, 2000, at the following website: http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html. URLS IN NIH GRANT APPLICATIONS OR APPENDICES All applications and proposals for NIH funding must be self-contained within specified page limitations. For R01 applications, the limit for Items a-d in the Research Plan is 25 pages, while R21 applications have a limit of 15 pages. Unless otherwise specified in an NIH solicitation, internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Reviewers are cautioned that their anonymity may be compromised when they directly access an Internet site. 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 RFA 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. LETTER OF INTENT Prospective applicants are asked to submit 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 this RFA. Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows NCCAM staff to estimate the potential review workload and plan the review. Mail/Fax letters of intent on or before February 28, 2002 to: Morgan N. Jackson, M.D., M.P.H. National Center for Complementary and Alternative Medicine National Institutes of Health 6707 Democracy Blvd., Suite 106 Bethesda, MD 20892-5475 Telephone: (301) 402-1278 FAX: (301) 480-3621 Email: mj145m@nih.gov APPLICATION PROCEDURES The PHS 398 research grant application instructions and forms (rev. 5/2001) at http://grants.nih.gov/grants/funding/phs398/phs398.html must be used in applying for these grants. This version of the PHS 398 is available in an interactive, searchable format. For further assistance contact GrantsInfo, Telephone 301/710-0267, Email: GrantsInfo@nih.gov. SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS 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 NIH staff. The research grant application form PHS 398 (rev. 5/2001) at http://grants.nih.gov/grants/funding/phs398/phs398.html is to be used in applying for these grants, with modular budget instructions provided in Section C of the application instructions. R21 APPLICATION GUIDELINES o The purpose of the NCCAM's Exploratory/Developmental Research (R21) grant mechanism is to provide investigators, at all career levels, with a funding opportunity for exploring the feasibility, as well as the development, of projects investigating botanical/drug interactions in HIV. The R21 mechanism is specifically intended to support innovative ideas where preliminary data, as evidence of feasibility, are sparse or do not exist. These grants are not intended for large-scale undertakings or to support or supplement ongoing research. Rather, R21-supported projects are intended to serve as a basis for planning and strengthening future investigator-initiated research project grant applications (R01). It is important to note that, while originality of approach and potential significance of the proposed research are major considerations in evaluation for funding R21 grants, the applicant is also responsible for presenting the background literature that provides some basis for the approach and developing a rigorous research plan. o For R21 applications, Direct Costs are limited to a maximum of $125,000 per year for a maximum of two years. Direct Costs requested for the proposed period may not exceed $250,000. Direct costs should be requested in increments of $25,000 (Modular Budget). Total Costs should equal the modular Direct Costs plus Facilities and Administrative (F&A) costs. The award is nonrenewable and may not be used to supplement an ongoing project. o Do not exceed a total of fifteen pages for Items a-d in the Research Plan. Tables and figures are included in the page limitation. Applications that exceed the page limitation or NIH requirements for type size and margins (refer to PHS 398 application for details) will be returned to the applicant without further consideration. The fifteen-page limitation does not include Items e-i (Human Subjects, Vertebrate Animals, Literature Cited, Consortia, and Consultants). o Color illustrations or original photographs may be included in an Appendix. These are allowed only if there are copies of black and white figures appearing in the body of the application. No other appendix material is permitted. o Applications not following the above instructions will be returned to the applicant without review. The RFA label available in the PHS 398 (rev. 5/2001) application form must be affixed to the bottom of the face page of the application. Type the RFA number on the label. 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 and number must be typed on line 2 of the face page of the application form and the YES box must be marked. The RFA label is also available at: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf. Submit a typewritten, signed original of the application, including the Checklist, 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. Martin Goldrosen Director, Scientific Review Branch National Center for Complementary and Alternative Medicine 6707 Democracy Blvd., Suite 106 Bethesda, MD 20892-5475 Telephone: (301) 594-2014 FAX: (301) 480-2419 Email: mg85x@nih.gov Applications must be received by March 28, 2002. 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 the CSR and responsiveness by NCCAM. Incomplete and/or non-responsive applications will be returned to the applicant without further consideration. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the NCCAM in accordance with the review criteria stated below. As part of the initial merit review, all applications will receive a written critique and may undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of the applications under review, will be discussed, assigned a priority score, and receive a second level review by the NCCAM National 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 the application 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 assigning the overall score, weighting them as appropriate for each application. Note that the application does not need to be strong in all categories to be judged likely to have 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. (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 methods? 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? Because the exploratory grant mechanism (R21) is designed to support innovative ideas, preliminary data as evidence of feasibility of the project are not required. However, the applicant does have the responsibility for developing a sound research plan approach, including appropriate statistical analyses and sample size calculations where appropriate. Innovation of the project and potential significance of the proposed research will be major considerations in the evaluation of this mechanism. In addition to the above criteria, in accordance with NIH policy, all applications will also be reviewed with respect to the following: o The adequacy of plans to include both genders, minorities and their subgroups, and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. o The reasonableness of the proposed budget and duration in relation to the proposed research. o 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. Schedule Letter of Intent Receipt Date: February 28, 2002 Application Receipt Date: March 28, 2002 Council Review: August 2002 Earliest Anticipated Start Date: September 2002 AWARD CRITERIA Award criteria that will be used to make award decisions include: o scientific merit (as determined by peer review) o availability of funds o programmatic priorities. INQUIRIES Inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or answer questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Morgan N. Jackson, M.D., M.P.H. National Center for Complementary and Alternative Medicine 6707 Democracy Blvd., Suite 106 Bethesda, MD 20892-5475 Telephone: (301) 402-1278 FAX: (301) 480-3621 Email: mj145m@nih.gov Direct inquiries regarding review issues to: Dr. Martin Goldrosen Director, Scientific Review Branch National Center for Complementary and Alternative Medicine 6707 Democracy Blvd., Suite 106 Bethesda, MD 20892-5475 Telephone: (301) 594-2014 FAX: (301) 480-2419 Email: mg85x@nih.gov Direct inquiries regarding fiscal matters to: Mrs. Victoria Carper Grants Management Officer National Center for Complementary and Alternative Medicine National Institutes of Health 6707 Democracy Blvd., Suite 106 Bethesda, MD 20892-5475 Phone: 301-594-9102 Fax: 301-480-3621 Email: vp8g@nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.213. Awards are made under authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and administered under NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The PHS strongly encourages all grant recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.

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