NCCAM EXPLORATORY/DEVELOPMENTAL GRANT FOR CLINICAL STUDIES (R21) RELEASE DATE: July 17, 2003 PA NUMBER: PAR-03-153 (see addendum NOT-CA-04-006) March 2, 2006 (NOT-OD-06-046) Effective with the June 1, 2006 submission date, all R03, R21, R33 and R34 applications must be submitted through using the electronic SF424 (R&R) application. Accordingly, the portion of this funding opportunity relating to these mechanisms expires on the date indicated below. Other mechanisms relating to this announcement will continue to be accepted using paper PHS 398 applications until the stated expiration date below, or transition to electronic application submission. Replacement R21 (PAR-06-091), funding opportunity announcement has been issued for the submission date of June 1, 2006 and submission dates thereafter. See NOT-OD-06-048 for information on May 1, 2006 Submission Date for AIDS and AIDS-related R03 and R21 Applications. EXPIRATION DATE: March 2, 2006 National Center for Complementary and Alternative Medicine (NCCAM) ( CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER(S): 93.213 THIS PAR CONTAINS THE FOLLOWING INFORMATION o Purpose of the PAR o Research Objectives o Mechanism(s) of Support o Eligible Institutions o Individuals Eligible to Become Principal Investigators o Special Requirements 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 PAR The National Center for Complementary and Alternative Medicine (NCCAM) invites high quality exploratory/developmental clinical research grant applications, in all domains of complementary and alternative medicine (CAM), in order to provide preliminary data that can be used as a foundation for larger clinical studies. NCCAM defines five domains of complementary and alternative medicine, which are alternative medical systems; biologically-based therapies; energy medicine; manipulative and body-based therapies; and mind-body medicine. These are described more fully in the NCCAM five-year strategic plan (2001-2005) While many CAM therapies are in extensive use by the public, few have been thoroughly tested for safety and/or efficacy. One of the primary missions of NCCAM is to support clinical research to test the efficacy of CAM therapies being used by the public. However, before investing in a large clinical study to test the efficacy of a CAM therapy, it is necessary to first provide preliminary data from pilot studies and small phase I and phase II trials as a basis for such a larger clinical study. Thus, an important goal of this exploratory/developmental research grant solicitation is to provide independent investigators, at all career levels, with the opportunity to design rigorous feasibility and developmental projects in the clinical area that will serve as the basis for planning and scientifically justifying larger clinical research projects to test the efficacy of CAM therapies. If the results from preliminary studies submitted in response to this program announcement, along with published reports in the literature, support the performance of a larger clinical study, then a future grant application soliciting support for such a study can be submitted through the research project grant (R01) mechanism. Examples of types of investigations appropriate for this clinical exploratory/developmental program announcement include, but are not limited to the following: o Feasibility studies to test and optimize parameters such as accrual rates, acceptance of randomization, compliance, delivery of the intervention, appropriate inclusion/exclusion criteria, and optimization of the overall protocol design for planned clinical trials. o Studies to develop and validate testing of biological and behavioral outcome measures in humans for use in CAM clinical research. These could include development and/or validation of both the measurement procedure itself and delivery to subjects. Examples include optimization of imaging methods and enzymatic assays; development and validation of behavioral assessment tools to be used in clinical trials, as well as development and validation of self report questionnaires and survey instruments to be used in CAM epidemiological and health services research, including health outcomes research. o Studies to determine if the effect sizes described in the literature or clinically significant effect sizes can be achieved. o Small clinical trials to determine safety, toxicity, pharmacokinetics, pharmacodynamics and the optimal dosage of an intervention as a prelude to a larger efficacy trial. If the total enrollment required is greater than approximately 60 subjects, the applicant is strongly encouraged to contact an NCCAM Program Officer to discuss whether the R21 or R01 mechanism is most appropriate for the study. o Qualitative research, such as detailed case studies and patient and health care provider interviews or ethnographic/ethnobotanical studies, to describe diagnostic and treatment approaches; to explore patient and health care provider preferences, beliefs and attitudes; and to investigate the relevance of those approaches to future clinical studies. Preliminary data are not required as a prerequisite for submission in response to this announcement, because part of the goal of this program announcement is to produce the preliminary data as the first necessary step in the process required for planning a larger clinical study. However, a clear rationale for the study must be presented. A rigorous project design is required as well. A thorough summary of the published literature that justifies initiating the specific clinical project proposed must be presented in the grant application. In addition, applicants should describe their future research plans as they relate to how the results of this exploratory/developmental research will lead to a larger clinical study. Furthermore, applicants should provide justification regarding why it is important to perform this larger clinical study in the context of the present knowledge of clinical research on CAM therapies. Large Phase II trials or Phase III trials, with the goal of determining efficacy of a CAM therapy, should not be submitted in response to this announcement. Such proposals should be submitted as research project (R01) grants. Exploratory/developmental CAM basic and preclinical studies, including mechanistic studies in humans, should not be submitted in response to this program announcement. Instead such studies should be submitted in response to the NCCAM program announcement on "Basic and Preclinical Research on Complementary and Alternative Medicine" (PA-02-124) ( RESEARCH OBJECTIVES The research objective of this PA is to encourage the submission of high quality, preliminary studies that will provide a solid foundation and justification for larger clinical studies to determine the efficacy of CAM therapies in all five CAM research domains. MECHANISM OF SUPPORT This NCCAM PA will use the NCCAM R21 (Exploratory/Developmental Project) award mechanism (see Please note that this is different from the NIH-wide R21 program. The NCCAM R21 award is an exploratory/developmental research grant for support of pilot and feasibility CAM research designed to provide investigators with an opportunity to produce preliminary data in support of a larger project that may be submitted in the future as a research project(R01)grant application. The NIH-wide R21 program emphasizes research characterized by novel ideas that may differ substantially from current thinking in a field and thus bear considerable risk of failure. While novel ideas are certainly welcome in response to this specific program announcement, the emphasis is more on providing solid data to support justification for a future clinical study. For R21 grants awarded through this program announcement, applicants may request a project period of up to three years with a combined budget for direct costs of up $400,000 for the three-year period. The budget request should be tailored to the needs of the project. For example, you may request $100,000 in the first year, $200,000 in the second year and $100,000 in the third year. However, no more than $250,000 direct costs may be requested in any single year. These grants may not be renewed. However, two revisions of a previously reviewed exploratory/developmental R21 grant may be submitted as defined in NIH Policy at Competing continuation of projects developed under this grant mechanism should be submitted through the R01 research grant mechanism. As an applicant, you will be solely responsible for planning, directing, and executing the proposed project. Facilities and Administrative (F&A) costs will be awarded based on the negotiated rate at the time of award. Although the program is provided for in the financial plans of the NCCAM, the award of grants pursuant to the PAR is contingent upon the availability of funds for this purpose. This PAR uses just-in-time concepts. It uses the modular budgeting formats (see This program does not require cost sharing as defined in the current NIH Grants Policy Statement at ELIGIBLE INSTITUTIONS You may submit (an) application(s) if your institution has any of the following characteristics: o For-profit or non-profit organizations o Public or private institutions, such as universities, colleges, hospitals, and laboratories o Units of State and local governments o Eligible agencies of the Federal government o Domestic or foreign o Faith-based or community-based organizations INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with their institution to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH programs. SPECIAL REQUIREMENTS In addition to the required Federal Citations listed below related to clinical research, applicants submitting applications in response to this announcement should also follow the NCCAM Policy on Terms of Award for Clinical Trials, where applicable. If the clinical study will involve a natural product, then the applicant must follow the NCCAM Policy Announcement on Quality of Natural Products: WHERE TO SEND INQUIRIES We encourage your inquiries concerning this Program Announcement and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into three areas: scientific/research, review of application issues, and financial or grants management issues: o For scientific/research questions: Please contact the appropriate NCCAM program officer listed on this website: o Direct your questions about review of applications to: Martin Goldrosen, Ph.D. Chief, Office of Scientific Review National Center for Complementary and Alternative Medicine National Institutes of Health 6707 Democracy Blvd., Suite 401 Bethesda, MD 20892 (for express/courier service use 20817) Telephone: (301) 594 2014 Fax: (301) 480 2419 Email: o Direct your questions about financial or grants management matters to: Ms. Victoria Carper Grants Management Branch National Center for Complementary and Alternative Medicine 6707 Democracy Blvd., Suite 401 Bethesda, MD 20892 (for express/courier service use 20817) Telephone: Fax: 301 480 2419 Email: SUBMITTING AN APPLICATION Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). The PHS 398 is available at in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 710-0267, Email: APPLICATION RECEIPT DATES: Applications submitted in response to this program announcement will be accepted at the standard application deadlines, which are available at Application deadlines are also indicated in the PHS 398 application kit. SUPPLEMENTAL INSTRUCTIONS FOR NCCAM EXPLORATORY/DEVELOPMENTAL GRANT FOR CLINICAL STUDIES (R21)APPLICATIONS: All application instructions outlined in the PHS 398 application kit are to be followed, along with the following requirements for R21 applications: 1. R21 applications will use the "MODULAR GRANT" and "JUST-IN-TIME" concepts, with direct costs requested in $25,000 modules. Applicants may request a project period of up to three years with a combined budget for direct costs of up $400,000 for the three-year period. For example, you may request $100,000 in the first year, $200,000 in the second year and $100,000 in the third year. The request should be tailored to the needs of your project. However, no more than $250,000 may be requested in any single year. 2. Although preliminary data are not required for an R21 application, they may be included. 3. Sections a-d of the Research Plan of the R21 application may not exceed 20 pages, including tables and figures. 4. R21 appendix materials should be limited, as is consistent with the exploratory nature of the R21 mechanism, and should not be used to circumvent the page limit for the research plan. Copies of appendix material will only be provided to the primary reviewers of the application and will not be reproduced for wider distribution among reviewers. The following materials may be included in the appendix: o Up to five publications, including manuscripts (submitted or accepted for publication), abstracts, patents, or other printed materials directly relevant to the project. These may be stapled as sets. o Surveys, questionnaires, and data collection instruments. These may be stapled as sets. o Original glossy photographs or color images of gels, micrographs, etc., provided that a photocopy (may be reduced in size) is also included within the 20-page limit of items a-d of the research plan. SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: Applications requesting up to $250,000 per year in direct costs must be submitted in a modular grant format. The modular grant format simplifies the preparation of the budget in these applications by limiting the level of budgetary detail. Applicants request direct costs in $25,000 modules. Section C of the research grant application instructions for the PHS 398 (rev. 5/2001) at includes step-by-step guidance for preparing modular grants. Additional information on modular grants is available at SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten 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) Two copies should also be sent to: Martin Goldrosen, Ph.D. Chief, Office of Scientific Review National Center for Complementary and Alternative Medicine National Institutes of Health 6707 Democracy Blvd., Suite 401 Bethesda, MD 20892 (for express/courier service use 20817) APPLICATION PROCESSING: Applications must be mailed on or before the receipt dates described at The CSR will not accept any application in response to this Program Announcement 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. Although there is no immediate acknowledgement of the receipt of an application, applicants are generally notified of the review and funding assignment within 8 weeks. PEER REVIEW PROCESS Applications submitted for this PA will be assigned on the basis of established PHS referral guidelines. An appropriate scientific review group within NCCAM convened in accordance with the standard NIH peer review procedures ( 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 Advisory Council for Complementary and Alternative Medicine. 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: o Significance o Approach o Innovation o Investigator o Environment The scientific review group will address and consider each of these criteria in assigning the application's overall score, weighting them as appropriate for each application. 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. In addition, preliminary data are not required as a prerequisite for submission in response to this announcement, because part of the goal of this program announcement is to produce the preliminary data as the first necessary step in the process required for planning a larger clinical study. 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? Specifically, does the applicant describe how the results of this exploratory/development research will lead to the development of a larger clinical study? Does the applicant provide justification as to why it is important to perform this larger clinical study in the context of the present knowledge of clinical research on CAM therapies? 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? Does the applicant provide a thorough summary of the published literature that justifies initiating this specific clinical project? Is a clear rationale for the study presented? Is a rigorous study design described? INNOVATION: Does the project employ novel concepts, approaches or methods? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? INVESTIGATOR: Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers (if any)? ENVIRONMENT: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, the following items will be considered in the determination of scientific merit and the priority score: PROTECTION OF HUMAN SUBJECTS FROM RESEARCH RISK: The involvement of human subjects and protections from research risk relating to their participation in the proposed research will be assessed. (See criteria included in the section on Federal Citations, below). INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research will be assessed. Plans for the recruitment and retention of subjects will also be evaluated. (See Inclusion Criteria in the sections on Federal Citations, below). CARE AND USE OF VERTEBRATE ANIMALS IN RESEARCH: If vertebrate animals are to be used in the project, the five items described under Section f of the PHS 398 research grant application instructions (rev. 5/2001) will be assessed. ADDITIONAL CONSIDERATIONS DATA SHARING: The adequacy of the proposed plan to share data. BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. AWARD CRITERIA Applications submitted in response to a PAR will compete for available funds with all other recommended applications. The following will be considered in making funding decisions: o Scientific merit of the proposed project as determined by peer review o Availability of funds o Relevance to program priorities REQUIRED FEDERAL CITATIONS HUMAN SUBJECTS PROTECTION: Federal regulations (45CFR46) require that applications and proposals involving human subjects must be evaluated with reference to the risks to the subjects, the adequacy of protection against these risks, the potential benefits of the research to the subjects and others, and the importance of the knowledge gained or to be gained. 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: INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported clinical research projects unless a clear and compelling justification is provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing clinical research should read the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research - Amended, October, 2001," published in the NIH Guide for Grants and Contracts on October 9, 2001 (; a complete copy of the updated Guidelines are available at 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 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 HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research on hESCs can be found at and at Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (see 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 Applicants may wish to place data collected under this PA in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award. STANDARDS FOR PRIVACY OF INDIVIDUALLY IDENTIFIABLE HEALTH INFORMATION: The Department of Health and Human Services (DHHS) issued final modification to the "Standards for Privacy of Individually Identifiable Health Information", the "Privacy Rule," on August 14, 2002. The Privacy Rule is a federal regulation under the Health Insurance Portability and Accountability Act (HIPAA) of 1996 that governs the protection of individually identifiable health information, and is administered and enforced by the DHHS Office for Civil Rights (OCR). Those who must comply with the Privacy Rule (classified under the Rule as "covered entities") must do so by April 14, 2003 (with the exception of small health plans which have an extra year to comply). Decisions about applicability and implementation of the Privacy Rule reside with the researcher and his/her institution. The OCR website ( provides information on the Privacy Rule, including a complete Regulation Text and a set of decision tools on "Am I a covered entity?" Information on the impact of the HIPAA Privacy Rule on NIH processes involving the review, funding, and progress monitoring of grants, cooperative agreements, and research contracts can be found at 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 AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal Domestic Assistance at and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The NIH Grants Policy Statement can be found at 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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