COMPLEMENTARY/ALTERNATIVE MEDICINE (CAM) AT THE END OF LIFE FOR CANCER AND/OR HIV/AIDS Release Date: January 16, 2001 RFA: RFA-AT-01-002 National Center for Complementary and Alternative Medicine (http://nccam.nih.gov) National Cancer Institute (http://www.nci.nih.gov/) National Institute of Allergy and Infectious Disease (http://www.niaid.nih.gov/default.htm) National Institute of Mental Health (http://www.nimh.nih.gov/) National Institute of Nursing Research (http://www.ninr.nih.gov/) Letter of Intent Receipt Date: February 26, 2001 Application Receipt Date: April 12, 2001 THIS RFA USES THE "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. IT INCLUDES DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS RFA PURPOSE The National Center for Complementary and Alternative Medicine (NCCAM) invites research grant applications to generate scientific knowledge on complementary and alternative medicine (CAM) therapies that will lead to improved care for individuals at the end of life. The intent of this initiative is to generate research that has the potential to improve the quality of life for individuals with cancer and/or HIV/AIDS who are at the end of life. For the purposes of this request for application (RFA), CAM is defined as healthcare practices that are not an integral part of conventional medicine. Currently, CAM practices may be grouped into five major domains: (1) alternative medical systems, (2) mind-body interventions, (3) biologically- based treatments, (4) manipulative and body-based methods, and (5) energy therapies. A classification of CAM approaches may be found on the NCCAM website at: (http://nccam.nih.gov/health/whatiscam/) 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 RFA entitled CAM Therapies at the End of Life for Cancer and/or HIV/AIDS is related to the priority areas of cancer and HIV/AIDS. 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 governments, and eligible agencies of the Federal government. Proposed foreign grants must have the potential to advance knowledge that will benefit the United States and must propose opportunities for unusual talent resources, populations, or environmental conditions that are not readily available in the United States. See POLICIES GOVERNING FOREIGN INSTITUTIONS AND INTERNATIONAL ORGANIZATIONS (PHS GPS 9505) for further guidelines for foreign applications (http://grants.nih.gov/grants/policy/gps/app4.htm). Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply. MECHANISMS OF SUPPORT This RFA will use the National Institutes of Health (NIH) R01 and NCCAM’s R21 award mechanism. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. The total project period for an application submitted in response to this RFA may not exceed 2 years for the R21 or 4 years for the R01. This RFA is a one-time solicitation, and the anticipated award date is September, 2001. R01 Applications. R01 awards will vary in size and duration reflecting the nature and scope of the research proposed. Future unsolicited competing continuation applications will compete with all investigator-initiated applications and be reviewed according to customary peer review. R21 Applications. The objective of the exploratory/developmental mechanism (R21) is to encourage applications from individuals who are interested in testing innovative or conceptually creative ideas that are scientifically sound and may advance treatment options at the end of life with CAM approaches. Another objective is to encourage initial development that is necessary to provide a basis for future research project applications. Exploratory/developmental studies are not intended for large-scale undertakings or to support or supplement ongoing research. Instead, investigators are encouraged to explore the feasibility of an innovative research question or approach that may not yet be sufficiently justified through existing research to compete as a standard research project grant (e.g., R01), and to develop a research basis for a subsequent application through other mechanisms. These grants are non-renewable, and the continuation of projects developed under the R21 program will be through the traditional unsolicited (R01) grant programs. FUNDS AVAILABLE The Institutes and Centers (ICs) intend to commit approximately $2.25 million (up to $1 million allocated for AIDS) for this activity in FY01 to fund new competitive grants in response to this RFA. The total cost over 4 years for this initiative is estimated at $9 million (up to $4 million allocated for AIDS). An applicant may request a project period of up to 2 years and a budget for total costs of up to $200,000 per year for the R21 or a project period of up to 4 years and a budget for total costs of up to $500,000 per year for the RO1. Because the nature and scope of the research proposed may vary, it is anticipated that the size of each award will also vary. NINR is specifically interested in applications investigating holistic approaches that use mind/body interventions in persons with HIV/AIDS who are at the end of life. Although the financial plans of The Institutes and Centers (ICs) 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. The earliest anticipated award date will be September 1, 2001. RESEARCH OBJECTIVES Background: The goal of palliative care is to provide for unmet physical, psychosocial, and spiritual needs of terminally ill patients and their families.1 The most important concerns expressed by hospice patients are the existential, spiritual, familial, physical, and emotional aspects of illness; however, these concerns are rarely the focus of care at the end of life.2 If cure is not an option, maintaining quality of life and controlling symptoms may be more appropriate than potentially distressing treatments that offer limited, temporary improvement at the cost of physical and emotional suffering. Social and cultural forces are demanding that conventional medicine offer a more holistic approach3 that conveys empathy and compassion to the sick and dying4and assists individuals sustain dignity and well-being in their final days.5 Therefore, treatment options for individual who are dying should be expanded and their emotional, social, cultural, and spiritual needs addressed. At a 1997 meeting on symptoms of terminal illness that was sponsored by six NIH Institutes and the former Office of Alternative Medicine, palliative care was described as care that takes place in a context where cure is no longer possible and disease modification provides diminishing returns. 6 Symptoms are complex and include physical (fatigue and pain) and psychological distress, and subjective measures should expand beyond absence of pain or functional status to include spiritual states, peacefulness, or sense of life completion. The report from that workshop is available at http://www.ninr.nih.gov/end-of-life.htm. A subsequent Program Announcement was published in December, 1997, PA-98-019 entitled Management of Symptoms at the End of Life (http://grants.nih.gov/grants/guide/pa-files/PA-98-019.html). Currently, NCCAM cosponsors a Program Announcement entitled Quality of Life for individuals at the End of Life (http://grants.nih.gov/grants/guide/pa-files/PA-00-127.html). Many of the objectives for research from that program announcement are subsumed within this focused request for applications. Public awareness of the limitations of end of life care and interest in improving treatment at the end of life is growing. In October, 1999, a Congressional hearing entitled Improving Care at the End of Life with Complementary Medicine reviewed use of these modalites. In September, 2000, a television documentary entitled "On Our Own Terms- Moyers on Dying in America" and a Time cover story Dying on our Own Terms focused our nation on these issues. 7,8 In November, 2000, a newly formed End of Life Research Interest Group at the National Institute’s of Health and the primary Institutes that comprise the group (National Institute of Nursing Research, National Cancer Institute, National Institute on Aging, and NCCAM) sponsored an open forum entitled The End of Our Lives: Guiding the Research Agenda . The panelist and participants discussed the need for research, including exploration of ethnic disparities in end of life care. Therefore, this initiative responds to the public demand to increase programs for and research on the end-of-life care, including CAM interventions. This initiative will focus specifically on clinical studies of CAM modalities for related to cancer and/or HIV/AIDS because CAM is widely used by these patients with advanced disease and should be evaluated. Cancer brings fear and hope9 along with 10therapeutic interventions with toxicities and sometimes limitations to control or cure disease. These factors may be driving the search by patients for alternatives.11 Although CAM is used at various stages along the disease continuum, patients with cancer report using CAM by 4 to 6 months after diagnosis when ongoing treatment outcomes may be uncertain;12,13 after a diagnosis with a poor prognosis,14 with recurrence or disease progression14-16, or at the advanced stages of disease.15-18 In studies conducted in different countries of patients with terminal cancer, use of CAM ranged from 7% (70% would have used it if available)19 to 26% and 60% in Canada,13,18,20 63 to 64% in Hong Kong21 and Taiwan,22 61% in Austria15, and 58% in Germany17 and 42% in Norway.12 In several surveys, use was equal among men and women20-22 but greater among younger patients.20,22 Herbs and herbal teas (Essiac, echinacea, Traditional Chinese Medicines) were used predominately,20,21 but patients often could not identify the herbs or pills and referred to these as medication not prescribed by their doctor.19,22 The other most commonly used agents were vitamins and minerals (beta carotene, melatonin, enzymes, hydrazine, coenzyme-Q10)13,20, mind-body approaches (imagery/visualization, faith healing, meditation)13, and biologics (cartilage and mushrooms)13. Most patients used one modality for less than 3 months.20-22 Among patients with metastatic melanoma, mistletoe, herbs, metabolic therapies, and mental and spiritual approaches were used at the later stage whereas homeopathy was used at the earlier stage of disease.15 For HIV/AIDS, the overall prevalence of use of CAM therapies across 12 surveys totaling 1480 individuals in the US (with the exception of one study) ranged from 27% to 100%, and the most popular CAM therapies used were vitamins, massage, acupuncture and imagery.23 A more recent survey reported the one-year prevalence was 67.8%, and herbals were the most widely used.24 Similarly, a recent survey of 912 individuals in Australia with HIV/AIDS found prevalence of CAM use was 56%, and use was greatest for nutritional supplements, massage, herbs and meditation/visualization. 25 An observational study of 1016 AIDS patients in the U.S. found that aerobic exercise (48%), prayer (56%), massage (54%), acupuncture (48%), meditation (46%), support groups (42%), visualization and imagery (34%), breathing exercises (33%), spiritual activities (33%), and other exercise (33%) were the most frequently used CAM therapies.26 Advanced stage of illness has been associated with CAM use.27 Despite the frequency of use, clinical research is not reported to support the use of these approaches. 23,26 Hope may be the single greatest reason individuals with cancer and HIV/AIDS seek CAM therapies, although reasons for hope are not well measured nor is the term well-defined.28 Among cancer patients, CAM use has been classified into several themes: hope after conventional therapy fails; hope for disease control, cure, and survival; control of pain and symptoms; and for general quality of life13,20-22. Among HIV/AIDS patients, the three greatest motivations for using CAM include hope to strengthen resistance to the disease, hope to strengthen the body, and the desire to supplement conventional care.23 Other reasons include hope to fight HIV or boost immunity; prevent weight loss, nausea or diarrhea; and relieve stress or depression.24 Cancer patients frequently do not understand their prognosis and tend to overestimate their probability of long-term survival. Their limited understanding of prognosis and subsequent treatment options may not reflect their true values for quality versus quantity of life. In a large cohort of terminally ill cancer patients, those who believed they would survive for at least 6 months were more than twice as likely (odds ratio =2.6; 95% confidence interval 1.8, 3.7) to favor aggressive, life saving treatments than patients who believed they had a small chance (as little as 10%) of not surviving for 6 months.29 In contrast, the most frequent concern of patients who had AIDS or were receiving long-term care or dialysis was the fear of the unwanted application of technology to prolong their life.30 CAM therapies are widely used for HIV/AIDS and cancer; however, the literature does not report widespread use of a broad spectrum of CAM for other conditions such as systemic lupus erythematosus, Alzheimer’s disease, or multiple sclerosis, each of which might otherwise be appropriate targets for studies of palliative CAM. Therefore, this initiative will focus on the potential role of a spectrum of CAM approaches for patients with life-threatening illness due to cancer and HIV/AIDS. Integrated programs, holistic regimens, or individual CAM approaches may provide additional tools for the palliative care setting. In the first systematic review of CAM for palliative care, Pan et al. suggest that some approaches may be useful for treating prevalent symptoms in terminally ill patients (pain, dyspnea, and nausea/vomiting). Massage, relaxation/imagery, hypnosis, or transcutaneous electrical nerve stimulation therapy may augment traditional analgesics for pain management whereas acupuncture, acupressure, and relaxation may be useful in treating dyspnea.31 For the field to advance however, future studies must have larger sample sizes, reliable blinding, and specific, clinically relevant outcome measures that include the effect on concomitant conventional therapy. 31 As the evidence evolves, those CAM therapies that prove beneficial can be integrated into interdisciplinary healthcare and provide an option for continued care and observation in the conventional setting. Thus, patients may not be forced to seek hope outside the conventional setting, the therapeutic armamentarium may be expanded, and the physical, psychosocial, and spiritual needs of patients would be better addressed. OBJECTIVES: The primary objective of this research initiative is to identify and evaluate CAM interventions for patients with advanced, terminal disease associated with cancer or HIV/AIDS. Possible patient outcomes would include: 1) Managing or reducing the symptoms associated with the conditions of end stage disease for cancer and HIV/AIDS, 2) Preventing or reducing side effects of medications such as antiretrovirals, steroids, and chemotherapy/radiotherapy, and 3) Enhancing the psychological, social, and spiritual well-being and quality of life at the end-of life. RESEARCH FOCUS Applications should focus on evaluating CAM therapies alone or in combination with other conventional treatment modalities. Integrated programs, holistic regimens, or diverse approaches with CAM interventions including, but not limited to, aromatherapy, music therapy, spirituality, massage and physical approaches, acupuncture, innovative psychosocial support interventions, botanicals (ie, drug-like therapies of single herbs or complex herbal formulas), vitamins and/or minerals, special dietary approaches, or energy approaches (ie, Reiki, therapeutic touch) are appropriate for investigation. The research must be oriented toward the most critically needed areas of CAM research, and toward collaborative activities that address new innovative possibilities in CAM research. Applicants should provide a compelling, research-based rationale for the CAM modality under investigation. For those CAM modalities that have limited or no published research, investigators should include evidence from rigorous studies conducted in patient populations assessing similar outcomes with the modality. Clinical trials of botanicals could be supported by some preliminary evidence of efficacy with patterns of traditional use, case series, preclinical, or pilot clinical data against cancer or for palliation of symptoms or side-effects. SPECIAL REQUIREMENTS 1. Study Design: Research applications should be hypothesis-driven and include developmental pilot studies or phase I - II clinical trials aimed at expanding the therapeutic and palliative care options beyond technologic and conventional pharmacologic treatments with CAM approaches. Studies might include patients who refuse to participate in conventional Phase I trials, who are ineligible for protocols of conventional therapy, or who have no further treatment options but wish and warrant further treatment. The applicant institution must document their experience and capacity to recruit and retain study participants; provide a description of the population currently available for the proposed protocol; describe the procedures for screening this population to identify eligible individuals, for recruiting these individuals into the trial; and describe proposed mechanisms for monitoring accrual performance and criteria for continued participation by each participating institution. The project should provide new knowledge that can be generalized beyond the program being studied, including methodological issues that constrain research into the care of the dying. It is expected that some of this work will lead to definitive Phase III trials in which the efficacy of the CAM interventions could be proven. However, Phase III studies (defined below), surveys, health services research, epidemiologic, and basic science studies will not be accepted for this RFA. 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 some clinical outcome. The definition includes interventions given for disease prevention, prophylaxis, diagnosis, or therapy. 2. Linkages to the CAM community: The applicant should document that linkages to the relevant CAM communities exist and that certified or licensed CAM practitioners will provide appropriate input for the research. Ideally, the project would include conventional and CAM practitioners working as an interdisciplinary team. 3. 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). NCCAM requires that all masked clinical trials, regardless of size, establish an independent data and safety monitoring board (DSMB). Funds should be budgeted for these activities. They should not duplicate internal review and monitoring systems that are already in place at the institution. 4. Adverse Events Reporting: All studies should have a structured adverse event determination, monitoring and reporting system, including standardized forms and protocols for referring and/or treating subjects experiencing adverse events. The proposed schedule for reporting adverse events to the DSMB, the NCCAM Program Officer and/or the FDA should be described. 5. Product Characterization and Dose: Quality control of the source material for dietary supplements should be addressed and if possible, from one batch. Capsule formulation should be justified (ie, tablet, powder, soft gel capsule), and product specification for the identity, purity, strength, and dissolution of each product discussed. The batch should be well-characterized in terms of plant species identification (ie, mass spec, HPLC, or chemical fingerprinting), processing (good harvesting and manufacturing practices), and bioactivity markers. If several batches are used, procedures to minimize lot-to-lot variability should be described. The purity of plant products should be documented with testing of heavy metals, pesticide, other plant(s) contaminants. Authentication and characterization of the material will assure reproducibility for future trials. Dosing must be carefully considered. If the dosage is not established but based on traditional use, a citation(s) from a well-recognized, accessible source to support the proposed dosage should be referenced. If the dosage deviates from traditional use, this decision should be justified. The potential for or known drug-herb-vitamin interactions should be discussed, and a thorough literature review of the traditional contraindication for the plant and/or the major components described, including the risks for vulnerable populations. 6. Investigational New Drug (or Device) applications (INDs): It is the sole responsibility of the applicant to obtain all necessary clearances from the Food and Drug Administration as required. It is expected that applicants will have started the IND process, if required, well before submission of the application. In addition, applicants are strongly encouraged to consult their local Institutional Review Boards (IRBs) concerning IND status and the IRB approval process. 7. Institutional Support: Applicants are encouraged to make use of ongoing research efforts where feasible. The institution should demonstrate a strong commitment to the stability and success of the project. The application must provide a plan that addresses how the institutional commitment will be established and sustained, how it will maintain accountability for promoting scientific progress, and how the research effort will be given a high priority within the institution relative to other research efforts. The institution should demonstrate commitment to the scientific value of the proposed research be in the form of commitments to recruit scientific talent, provision of discretionary resources to the applicant, assignment of clinical and research space, or other ways to be proposed by the applicant. Applicants from institutions that have a General Clinical Research Center (GCRC) for conducting the proposed research may wish to identify these programs as a resource for use or for ongoing clinical trials. Furthermore, Hospice Programs and/or National Cancer Institute (NCI) designated Community Clinical Oncology Programs (CCOP) would be appropriate sources of cooperation for identifying and recruiting the study population as well as administering the intervention and data collection. A letter of agreement from the GCRC or CCOP Principal Investigator and/or the Hospice program director or Principal Investigator should be included with the application. Any cooperating sites would be considered subcontractors of the main application and their budgets included in the application. 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 biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification are 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 research involving human subjects should read the UPDATED "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research," published in the NIH Guide for Grants and Contracts on August 2, 2000 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html); a complete copy of the updated Guidelines are available at http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm: The revisions relate to NIH defined Phase III clinical trials and require: a) all applications or proposals and/or protocols to 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) all investigators to report accrual, and to conduct and report 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 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. Reviewers are cautioned that their anonymity may be compromised when they directly access an Internet site. LETTER OF INTENT Prospective applicants are asked to submit a letter of intent by February 26, 2001 that includes a descriptive title of the proposed research, the name, address, and telephone number of the Principal Investigator, the identities of other key personnel and participating institutions, and the number and title of the RFA in response to which the application may be submitted. Although 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. The letter of intent is to be sent to: Mary Ann Richardson, DrPH National Center for Complementary and Alternative Medicine National Institutes of Health 6707 Democracy Boulevard, Suite 106 Bethesda, MD 20892-5475 Phone: 301-402-1272 FAX: 301-480-3621 Email: marich@od.nih.gov APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants. These forms are available at most institutional offices of sponsored research and from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/710-0267, email: GrantsInfo@nih.gov. Applications are also available on the World Wide Web at http://grants.nih.gov/grants/forms.htm. 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 NCCAM staff. MODULAR GRANT applications request direct costs in $25,000 modules. The total direct costs must be requested in accordance with the program guidelines and the modifications made to the standard PHS 398 application instructions described below: (a) PHS 398 o FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs in $25,000 increments. The total cost may be up to a maximum of $500,000 [Modular Direct Cost Total plus Facilities and Administrative (F&A) costs] for the initial budget period. Items 8a and 8b should be completed indicating the Direct and Total Costs for the entire proposed period of support. o DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD - Do not complete Form Page 4 of the PHS 398. It is not required and will not be accepted with the application. o BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT - Do not complete the categorical budget table on Form Page 5 of the PHS 398. It is not required and will not be accepted with the application. o NARRATIVE BUDGET JUSTIFICATION - Prepare a Modular Grant Budget Narrative page. (See http://grants.nih.gov/grants/funding/modular/modular.htm for sample pages.) At the top of the page, enter the total direct costs requested for each year. This is not a Form page. Under Personnel, list all project personnel, including their names, percent of effort, and roles on the project. No individual salary information should be provided. However, the applicant should use the NIH appropriation language salary cap and the NIH policy for graduate student compensation in developing the budget request. For Consortium/Contractual costs, provide an estimate of total costs (direct plus facilities and administrative) for each year, each rounded to the nearest $1,000. List the individuals/organizations with whom consortium or contractual arrangements have been made, the percent effort of all personnel, and the role on the project. Indicate whether the collaborating institution is foreign or domestic. The total cost for a consortium/contractual arrangement is included in the overall requested modular direct cost amount. Include the Letter of Intent to establish a consortium. Applicants are strongly encouraged to request the same number of modules for each year of funding. Provide an additional narrative budget justification for any variation in the number of modules requested. o BIOGRAPHICAL SKETCH - The Biographical Sketch provides information used by reviewers in the assessment of each individual's qualifications for a specific role in the proposed project, as well as to evaluate the overall qualifications of the research team. A biographical sketch is required for all key personnel, following the instructions below. No more than three pages may be used for each person. A sample biographical sketch may be viewed at http://grants.nih.gov/grants/funding/modular/modular.htm. - Complete the educational block at the top of the form page; - List position(s) and any honors; - Provide information, including overall goals and responsibilities, on research projects ongoing or completed during the last three years. - List selected peer-reviewed publications, with full citations; o CHECKLIST - This page should be completed and submitted with the application. If the F&A rate agreement has been established, indicate the type of agreement and the date. All appropriate exclusions must be applied in the calculation of the F&A costs for the initial budget period and all future budget years. o The applicant should provide the name and phone number of the individual to contact concerning fiscal and administrative issues if additional information is necessary following the initial review. (b) Mailing Procedures The RFA label available in the PHS 398 (rev. 4/98) application form must be affixed to the bottom of the face page of the application. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title, and number, must be typed on Line 2 of the face page of the application form and the YES box must be marked. The sample RFA label available at: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been modified to allow for this change. Please note this is in pdf format. Submit a signed, original of the application, including the Checklist, and four (4) signed photocopies of the application in one package to: CENTER FOR SCIENTIFIC REVIEW (formerly Division of Research Grants) 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, send one (1) additional copy of the application to: Chief, Review Branch National Center for Complementary and Alternative Medicine National Institutes of Health 6707 Democracy Boulevard, Suite 106 Bethesda, MD 20892-5475 It is important to send this copy at the same time that the original and four copies are sent to the Center for Scientific Review (CSR). Applications must be received by April 12, 2001. 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 the 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. In addition to the criteria list below, the initial review group will examine: the appropriateness of proposed project budget and duration; the adequacy of plans to include subjects of both genders, minorities (and their subgroups), and children as appropriate for the scientific goals of the research, and plans for the recruitment and retention of subjects; the provisions for the protection of human and animal subjects; and the safety of the research environment. 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. 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? For Exploratory/Developmental (R21) Research Projects, what is the likelihood that the research will contribute to the development of interdisciplinary programs or more mature research endeavors? o Degree to which the research will improve our understanding of how we can narrow the gap between what is known and what is currently used as end of life treatments; o Likelihood of the development of interventions that can be applied to a variety of conditions and in a range of settings; (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? o Extent to which the project builds-on or establishes meaningful linkages between CAM practitioners, researchers, and conventional practitioners; o Plans for dissemination and implementation of findings within and outside of the grantee’s organization. (3) INNOVATION: Does the project employ novel concepts, approaches or method? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? (4) INVESTIGATORS: Is each 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)? o Incorporation of appropriate CAM expertise, including certified or licensed CAM practitioners, throughout the design and execution stage is encouraged; (5) ENVIRONMENT: Does the scientific environment in which the work will be done contribute to the probability of success of the project? Do the proposed studies take advantage of unique features of the scientific environment or employ useful collaborative arrangements? o Demonstration of substantial institutional commitment by the health care organization/system to the CAM intervention, including use of in-kind support and letters of support from clinical and administrative staff; o Adequacy of facilities to perform the proposed research, including clinical facilities and data management systems, when needed; 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 26, 2001 Application Receipt Date: April 12, 2001 Council Review: August, 2001 Earliest Anticipated Start Date: September, 2001 AWARD CRITERIA Applications will compete for available funds with all other recommended applications submitted in response to this RFA. The following will be considered in making funding decisions: o The quality of the proposed project as determined by peer review; o Availability of funds; and o The research priorities of the NCCAM. INQUIRIES Inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding specific PROGRAMMATIC ISSUES to: Christopher M. Gordon, PhD Chief, Secondary HIV Prevention & Treatment Adherence Division of Mental Disorders, Behavioral Research & AIDS National Institute of Mental Health National Institutes of Health 6001 Executive Boulevard, Bethesda, MD 20892-9621 Telephone: 301-443-1613 Fax: 301-443-9719 E-mail: cgordon1@mail.nih.gov Ann R. Knebel, RN, DNSc Division of Extramural Activities National Institute of Nursing Research Building 45, Room 3AN12, MSC 6300 Bethesda, MD 20892-6300 Telephone: (301) 594-5966 FAX: (301) 480-8260 Email: aknebel@nih.gov Katherine W. Muth, R.N., M.S. Nurse Consultant Office of the Associate Director Treatment Research Program Division of AIDS, NIAID 6700-B Rockledge Drive, Room 5215 Bethesda, MD 20892 Ph: (301)496-1189 FAX: (301)435-9282 E-mail: KMuth@niaid.nih.gov Mary Ann Richardson, DrPH Program Officer, National Center for Complementary and Alternative Medicine National Institutes of Health 6707 Democracy Boulevard, Suite 106 Bethesda, MD 20892-5475 Telephone: 301-402-1272 Fax: 301-480-3621 E-mail: marich@mail.nih.gov Wendy B. Smith, PhD Program Manager, Research Development and Support Program Office of Cancer Complementary and Alternative Medicine Office of the Deputy Director for Extramural Science National Cancer Institute Telephone: 301-435-7980 FAX: 301-480-0075 E-mail: wsmith@mail.nih.gov Direct inquiries regarding FISCAL MATTERS to: Ms. Victoria Putprush Grants Administration Branch National Center for Complementary and Alternative Medicine National Institutes of Health 6707 Democracy Boulevard, Suite 106 Bethesda, MD 20892-5475 Telephone: 301-594-9102 Fax: 301-480-3621 E-mail: vp8g@nih.gov Mr. Robert Tarwarter Office of Grants and Contracts Management National Institute of Nursing Research Building 45, Room Number 3AN12, MSC 6300 Bethesda, MD 20892-6300 Telephone: (301) 594-2807 FAX: (301) 480-8260 Email: Robert_tarwater@nih.gov Direct Inquiries regarding REVIEW ISSUES to: Chief, Review Branch National Center for Complementary and Alternative Medicine National Institutes of Health 6707 Democracy Boulevard, Suite 106 Bethesda, MD 20892-5475 Telephone: 301-496-4252 Fax: 301-480-3621 Email: TBA AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.213 and 93.361. 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 and contract recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people. REFERENCES 1. Seely JF, Mount BM. Palliative medicine and modern technology. Canadian Medical Association Journal. 1999;161(9):1120-1121. 2. Greisinger AJ, Lorimor RJ, Aday LA, Winn RJ, Baile WF. Terminally ill cancer patients: Their most important concerns. Cancer Practice. 1997;5(3):147-154. 3. Eskinazi DP. Factors that shape alternative medicine. (editorial). JAMA. 1998;280:1621-1623. 4. Dossey L; Reinventing Medicine. New York: Harper Collins Publisher; 1999. 5. Justice B; A Different Kind of Health: Finding Well-Being Despite Illness. Houston: Peak Press; 1998. 6. National Institutes of Health. Symptoms in Terminal Illness: A Research Workshop. Rockville, Maryland: htt://www.nih.gov/ninr/end-of-life.htm; 1997. 7. Committee on Government Reform Hearing. Improving Care at the End of Life With Complementary Medicine. Washington, DC: U.S. Government Printing Office; 1999. 8. Cloud J. Society: A kinder, gentler death. Time. 2000:61-74. 9. Hoey J. The arrogance of science and the pitfalls of hope. Canadian Medical Association Journal. 1998;159:803-804. 10. Durant JR. Alternative medicine: an attractive nuisance. Journal of Clinical Oncology. 1998;16:1-2. 11. Tannock IF, Warr DG. Unconventional therapies for cancer: a refuge from the rules of evidence? Canadian Medical Association Journal. 1998;159:801-802. 12. Risberg T, Lund E, Wist E, et al. The use of non-proven therapy among patients treated in Norwegian oncological departments: a cross- sectional national multicenter study. European Journal of Cancer. 1995;31A:1785-1789. 13. Verhoef MJ, Hagen N, Pelletier G, Forsyth P. Alternative therapy use in neurologic diseases. Neurology. 1999;52:617-622. 14. Sawyer MG, Gannoni AF, Toogood IR, Antoniou G, Rice M. The use of alternative therapies by children with cancer. Medical Journal of Australia. 1994;160:320-322. 15. Sollner W, Zingg-Schir M, Rumpold G, Fritsch P. Attitude toward alternative therapy, compliance with standard treatment, and need for emotional support in patients with melanoma. Archives of Dermatology. 1997;133:316-321. 16. Lerner IJ, Kennedy BJ. The prevalence of questionable methods of cancer treatment in the United States. CA A Cancer Journal for Clinicians. 1992;42:181-191. 17. Grothey A, Duppe J, Hasenburg A, Voigtmann R. Use of alternative medicine in oncology. Deutsche Medizinische Wochenschrift. 1998;123(31-32):923- 929. 18. Fernandez CV, Stutzer CA, MacWilliam L, Fryer C. Alternative and complementary therapy use in pediatric oncology patients in British Columbia: prevalence and reasons for use and nonuse. Journal of Clinical Oncology. 1998;16:1279-1286. 19. Eidinger RN, Schapira DV. Cancer patients' insight into their treatment, prognosis, and unconventional therapies. Cancer. 1984;53:2736-2740. 20. Oneschuk D, Fennell L, Hanson J, Bruera E. The use of complementary medications by cancer patients attending an outpatient pain and symptom clinic. Journal of Palliative Care. 1998;14(4):21-26. 21. Yuen R, Mak Y, Chan A, Ho P, Lee J. Preliminary study on use of traditional Chinese medicine and other complementary therapies by terminal cancer patients in Hong Kong. Presented at the 12th International Congress on Care of the Terminally Ill: Montreal, Canada. 1998:133. 22. Liu JM, Chu HC, Chin YH, et al. Cross sectional study of use of alternative medicines in Chinese cancer patients. Japanese Journal of Clinical Oncology. 1997;27:37-41. 23. Ernst E. Complementary AIDS therapies: the good, the bad and the ugly. Int J STD AIDS. 1997;8(5):281-285. 24. Fairfield KM , Eisenberg DM, Davis RB, Libman H, Phillips RS. Patterns of use, expenditures, and perceived efficacy of complementary and alternative therapies in HIV-infected patients. Arch Intern Med. 1998;158:2257-2264. 25. de Visser R, Ezzy D, Bartos M. Alternative or complementary? nonallopathic therapies for HIV/AIDS. Altern Therapies. 1000;6(5):44- 52. 26. Greene KB, Berger J, Reeves C, Moffat A, Standish LJ, Calabrese C. Most frequently used alternative and complementary therapies and activities by participants in the AMCOA study. J Assoc Nurses AIDS Care. 1999;10(3):60-73. 27. Greenblatt RM, Hollander H, McMaster JR, Henke CJ. Polypharmacy among patients attending an AIDS clinic: utilization of prescribed, unorthodox, and investigational treatments. J Acq Immune Defic Syndr. 1991;4:136-143. 28. Nekolaichuk CL, Bruera E. On the nature of hope in palliative care. Journal of Palliative Care. 1998;14(1):36-42. 29. Weeks JC, Cook EF, O'Day SJ, et al. Relationship between cancer patients' predictions of prognosis and their treatment preferences. JAMA. 1998;279:1709-1714. 30. Singer PA, Martin DK, Kelner M. Quality of life care: patients' perspectives. JAMA. 1999;281:163-168. 31. Pan C, Morrison R, Ness J, Fugh-Berman A, Leipzig R. Complementary and alternative medicine in the management of pain, dyspnea, and nausea and vomiting near the end of life: a systematic review. J Pain and Symptom Management. 2000;20(5):374-387.

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