SOCIAL AND BEHAVIORAL RESEARCH ON NEW BIOMEDICAL METHODS FOR HIV/STD PREVENTION RELEASE DATE: August 14, 2002 RFA: HD-02-020 National Institute of Child Health and Human Development (NICHD) (http://www.nichd.nih.gov) LETTER OF INTENT RECEIPT DATE: February 23, 2003 APPLICATION RECEIPT DATE: March 21, 2003 THIS RFA CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA o Research Objectives o Mechanism of Support o Funds Available o Eligible Institutions o Individuals Eligible to Become Principal Investigators o Where to Send Inquiries o Letter of Intent o Submitting an Application o Peer Review Process o Review Criteria o Receipt and Review Schedule o Award Criteria o Required Federal Citations PURPOSE OF THIS RFA This Request for Applications (RFA) reissues and expands the research scope of an RFA first issued on February 1, 2000 on the acceptability of new methods, especially topical microbicides, designed for the prevention of HIV and/or other STDs. The ultimate goal of the research is to improve the development, evaluation, dissemination, and use of new products through an increased understanding of factors that affect use of such products, including improved approaches to assessing those factors. RESEARCH OBJECTIVES Background This RFA calls for expanded research on social and behavioral issues pivotal to the development, evaluation, and eventual widespread use of new methods, especially topical microbicides, for HIV/STD protection for both men and women. Substantial research efforts currently seek to develop new biomedical strategies for preventing sexual transmission of HIV and other STDs, including gene therapies that alter permissiveness, monoclonal antibodies, inhibitors from natural products, vaccines to stimulate local protection, agents that interfere with viral and pathogen attachment and fusion to cellular membranes, cell adhesion factors, hormone or other receptors. Many of these approaches will require active participation by users who must correctly and consistently apply or insert a product in order to obtain protection. Because the effectiveness of such products will depend upon adoption and maintenance of new behaviors, social and behavioral research is needed on factors related to product use in the context of clinical trials and among varied target populations once such products are shown to be effective. There is, however, little work that can provide estimates of how a new method, no matter its mechanism of action or mode of delivery, will be integrated into the "calculus of conscious choice" that individuals are purported to use when deciding upon protection. For the purposes of this RFA, "acceptability" is defined as the probability that a method will be used correctly and consistently in a defined population. Method characteristics, user characteristics, partner characteristics, external influences such as the service delivery system and marketing, and the socio-cultural context in which the potential users live, all work together to determine the actual initiation and the continued use of a method. Actual use produces both feedback to the user and information into the socio-cultural context for other likely users. The goal of this RFA is to stimulate research to inform the development and dissemination of effective methods for disease protection that are acceptable to those whose sexual behavior places them in need of protection. Research on acceptability of methods is different from, although related to, research about the methods" safety and efficacy. A demonstrably effective and safe product may find no market, or may encounter other, more subjective obstacles to its actual adoption and use (c.f. IUDs in the U.S.). Users may be willing to accept a lower efficacy for a product that they can use covertly, or to accept an undesirable texture or unpleasant side effects for a product that works extremely well. Sometimes, people feel forced to choose the "least worst alternative." The actual product, its viscosity, color, smell, taste, application method, the quantity necessary for efficacious use, and duration of effectiveness may also influence acceptability and use. Other aspects of the product, such as its actual or perceived effect on sexual pleasure, may also have an impact. Finally, there are many parties besides the person using the product who may have opinions that could influence adoption and continued use. These include partners or potential partners, friends and family, health care providers, health system managers, and manufacturers of products. The sexual beliefs, practices, and norms of a group may influence acceptability at the individual level as well. The relative influence of these various parties and factors may vary among cultures, as well as among potential users of different ages and relationship statuses (Hardy et al., 1998). Past research on acceptability has typically followed one of several models, appropriate to different stages of product development and introduction. Behavioral studies can be embedded within the various phases of clinical trials used to evaluate the safety and efficacy of new products. This approach can provide valuable information about users" actual experience with a method. However, selective recruitment of participants into clinical trials and selective retention during the trials present challenges. Hence, findings from such efforts may be limited in their capacity to address use of a product after commercial introduction. Hypothetical product acceptability studies determine potential user responses to a product that is not yet developed and/or proven safe for use in the target population. This type of research provides the opportunity for early input from potential users about a new method, however, asking individuals to evaluate their probable use of a hypothetical method generally has not been successful in predicting actual use of a method. Studies using analogous materials may not generalize to the product once it is on the market. Although each of these models of acceptability research is flawed in some ways, research designs that combine models in creative ways may yield more robust results about the acceptability of new products and the factors that influence acceptability. Studies of acceptability also should attend to the full range of factors that influence the ultimate, consistent, and continued use of a product, including the motivation of the individual and the couple to avoid unwanted consequences of their sexual behavior, the context in which the individual or couple is living, and the medical/health care service delivery they expect to encounter in their daily lives. The placement and timing of acceptability studies within clinical trials attendant upon the development of new methods need further efforts to adequately address these issues. Research Scope This RFA invites research that will contribute to an improved understanding of the acceptability of methods to prevent HIV and other STDs. The ultimate goal of the research is to gain insight into the acceptability of new prevention methods, including microbicidal methods currently undergoing development and testing. Studies may examine acceptability directly, through acceptability studies using new methods in development or testing, or indirectly, through studies of the acceptability of potential methods using existing methods as models. Qualitative studies are particularly welcomed. The choice of models for potential methods must be theoretically informed, but may include contraceptive methods as well as existing STD/HIV prevention methods, such as the female condom. Methodological studies aimed at improving measurement and research design are also appropriate. Studies within ongoing networks of clinical trials are particularly welcomed. Applications may propose research designs that encompass any or all of the models described under "Background," or may propose new models for research. Applications may propose research in the context of clinical trials, general clinical or population samples, or a combination of these. Acceptability research may not be appropriate or efficient to conduct in Phase I clinical trials, where the safety of the product is tested among a highly select group. However, Phase II and Phase III trials may, in some cases, be appropriate contexts for such work. Proposed methodologies should be appropriate to the questions under study, and may consist of qualitative or quantitative approaches or an integration of these modalities. Qualitative research may be particularly appropriate for some questions, especially those requiring exploration of sensitive and complex issues. Such research could reveal user perspectives on the salient attributes of new products and attitudes towards public and private health care delivery systems and public health messages. In all cases, strict attention must be paid to the ethical considerations related to the potential for respondents" exposure to any possible negative consequences of participation in research. Collaborations among clinical trial investigators, product developers, service providers, and social and behavioral science researchers are strongly encouraged. Investigators participating in and those willing to cooperate with NIH-funded HIV-related research networks are particularly encouraged to apply. Topics of particular interest include, but are not limited to: I. Product-related o Studies of the acceptability of specific products or classes of products, and the characteristics (tactile or sensory, real and perceived) that influence acceptability among various populations. o Expansion of our understanding of the acceptability of method delivery systems (e.g., insertion, ingestion, injection) and formulations (e.g., gel, film, foam) in different cultures and populations. o Examination of the extent to which dual protection against pregnancy and disease enhances or deters acceptability of any new product or method. II. User-related o Exploration of the relationship between knowledge and attitudes of different types of health care providers and the adoption of new prevention modalities by patients and clients. Identification of factors associated with more rapid diffusion of accurate knowledge of new technologies among health care providers. o Improvement of our understanding of how and when external factors (e.g., friends, family, community, media, service providers) influence the acceptability of methods, and how, when, and with whom individuals communicate about methods and method use. o Assessment of how individuals and couples make tradeoffs among factors such as efficacy, side effects, pleasure, and the mechanics of use in making choices about adoption and continued use, and how decision-making on preventive methods occurs in couples at all stages of relationships. o Calibration of the influence of individuals" past history of contraceptive and prophylaxis use, pregnancy, and disease experience upon their acceptance and use of new methods. o Evaluation of the impact of the routine use of lubricants or other sexual aids on supporting or deterring the use of new prevention modalities such as microbicides. o Evaluation of the impact of the use of new prevention modalities (e.g., microbicides) on extant methods (e.g., male condoms). o Qualitative research on people"s understanding of what a microbicide actually is and how it works, and the relationship between that understanding and acceptability of products. This includes consideration of cultural variations in beliefs and perceptions. o Studies to better understand the relationship between sexual behavior (i.e., specific acts) and product use, especially in the context of Phase II and III trials. III. Information-related o Exploration of the types of messages and delivery modalities most effective for different groups to facilitate their understanding, acceptance, and use of methods. This could include marketing strategies. o Expansion of how public health messages concerning the risk of exposure to disease and other, potentially negative outcomes of sexual intercourse are understood and balanced against desires for pleasure or pleasing a partner. IV. Methodological o Development of better approaches to constructing hypothetical acceptability measures that will effectively predict actual use. This could include the design and testing of questions concerning acceptability included within Phase II and/or Phase III clinical trials. o Formulation of valid and reliable measures of product use and associated sexual behaviors for use in clinical trials and post-marketing evaluations. These include both behavioral and biological measures. o Assessment of variations in usage patterns within clinical trials across individuals and trial settings. o Elucidation of processes by which individuals from populations likely to be targeted for recruitment into efficacy or effectiveness trials understand the terms of participation, including their grasp of such concepts as random assignment, placebo control, investigational therapy/modality, and risk- benefit. o Identification of barriers to and facilitators of enrollment and retention in clinical trials of topical microbicides. These might include perceived benefits, financial gain, altruism, and peer pressure from friends or partners, among other things. MECHANISM OF SUPPORT This RFA will use the NIH individual research project grant (R01) award mechanism. As an applicant you will be solely responsible for planning, directing, and executing the proposed project. This RFA is a one-time solicitation. Future unsolicited, competing continuation applications based on this project will compete with all investigator-initiated applications and will be reviewed according to the customary peer review procedures. The earliest anticipated award date is September 2003. This RFA uses just-in-time concepts. It also uses the modular budgeting formats (see https://grants.nih.gov/grants/funding/modular/modular.htm). For this RFA, use only the modular format. FUNDS AVAILABLE The NICHD intends to commit approximately $1 million in total costs [Direct plus Facilities and Administrative (F & A) costs] in FY 2003 to fund three to five new and/or competitive continuation grants responsive to this RFA. An applicant may request a project period of up to five years and a budget for direct costs of up to $300,000 per year (F & A costs for subcontracts are included within this cap). Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary. Although the financial plans of the NICHD 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 National Institute of Allergy and Infectious Diseases (NIAID) also has an interest in this RFA as it pertains to (1) microbicide research and development - in particular studies of valid, reliable, efficient ways to assess product adherence and sexual behavior, especially in developing country populations, as well as (2) studies of microbicide acceptability useful for guiding product development, especially in the context of later phase clinical trials. The NIAID may consider funding grant applications that fall within these scientific areas, but cannot commit funds at this time. ELIGIBLE INSTITUTIONS You may submit an application 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 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. WHERE TO SEND INQUIRIES We encourage inquiries concerning this RFA and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into three areas: scientific/research, peer review, and financial or grants management issues: o Direct your questions about scientific/research issues to: Susan Newcomer, Ph.D. Demographic and Behavioral Sciences Branch National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 8B07, MSC 7510 Bethesda, MD 20892-7510 Telephone: 301-435-6981 Email: Snewcomer@nih.gov o Direct your questions about peer review issues to: Robert Stretch, Ph.D. Director, Division of Scientific Review National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 5B01, MSC 7510 Bethesda, MD 20892-7510 Telephone: 301-496-1485 Email: stretchr@nih.gov o Direct your questions about financial or grants management matters to: Kathy Hancock Grants Management Branch National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 8A17M, MSC 7510 Bethesda, MD 20892-7510 Telephone: 301-496-5482 Email: Hancockk@nih.gov LETTER OF INTENT Prospective applicants are asked to submit a letter of intent that includes the following information: o Descriptive title of the proposed research o Name, address, and telephone number of the Principal Investigator o Names of other key personnel o Participating institutions o 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 NICHD staff to estimate the potential review workload and plan the review. The letter of intent is to be sent by the date listed at the beginning of this document. The letter of intent should be sent to: Susan Newcomer, Ph.D. Demographic and Behavioral Sciences Branch National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 8B07, MSC 7510 Bethesda, MD 20892-7510 Telephone: 301-435-6981 Email: Snewcomer@nih.gov 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 https://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact GrantsInfo, Telephone 301-710-0267, Email: GrantsInfo@nih.gov. SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: All applications in response to this RFA must be submitted in a modular 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 https://grants.nih.gov/grants/funding/phs398/phs398.html includes step-by-step guidance for preparing modular grants. Additional information on modular grants is available at https://grants.nih.gov/grants/funding/modular/modular.htm. For the purposes of this RFA, all applications must be submitted in the modular grant format. USING THE RFA LABEL: 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: https://grants.nih.gov/grants/funding/phs398/label-bk.pdf. 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) At the time of submission, two additional copies of the application must be sent to: Robert Stretch, Ph.D. Director, Division of Scientific Review National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 5B01, MSC 7510 Bethesda, MD 20892-7510 Rockville, MD 20852 (for express/courier service) APPLICATION PROCESSING: Applications must be received by the application receipt date listed in the heading of this RFA. 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. PEER REVIEW PROCESS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NICHD. 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 NICHD in accordance with the review criteria stated below. As part of the initial merit review, all applications will: o Receive a written critique o 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 and assigned a priority score o Receive a second level review by the National Advisory Child Health and Human Development Council. REVIEW CRITERIA The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. In the written comments, reviewers will be asked to discuss the following aspects of your application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals: o Significance o Approach o Innovation o Investigator o Environment The scientific review group will address and consider each of these criteria in assigning your application"s overall score, weighting them as appropriate for each application. Your application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, you may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. (1) SIGNIFICANCE: Does your study address an important problem? If the aims of your application are achieved, how do they advance scientific knowledge? 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? Do you acknowledge potential problem areas and consider alternative tactics? (3) INNOVATION: Does your project employ novel concepts, approaches or methods? Are the aims original and innovative? Does your project challenge existing paradigms or develop new methodologies or technologies? (4) INVESTIGATOR: Are you appropriately trained and well suited to carry out this work? Is the work proposed appropriate to your experience level as the principal investigator and to that of other researchers (if any)? (5) ENVIRONMENT: Does the scientific environment in which your 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, your application will also be reviewed with respect to the following: o PROTECTIONS: The adequacy of the proposed protection for humans, animals, or the environment, to the extent they may be adversely affected by the project proposed in the application. o INCLUSION: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. (See Inclusion Criteria included in the section on Federal Citations, below.) o BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. RECEIPT AND REVIEW SCHEDULE Letter of Intent Receipt Date: February 23, 2003 Application Receipt Date: March 21, 2003 Peer Review Date: June/July 2003 Council Review: September 2003 Earliest Anticipated Start Date: September 2003 AWARD CRITERIA 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. REQUIRED FEDERAL CITATIONS MONITORING PLAN AND DATA SAFETY AND MONITORING BOARD: Research components involving Phase I and II clinical trials must include provisions for assessment of patient eligibility and status, rigorous data management, quality assurance, and auditing procedures. In addition, it is NIH policy that all clinical trials require data and safety monitoring, with the method and degree of monitoring being commensurate with the risks (NIH Policy for Data Safety and Monitoring, NIH Guide for Grants and Contracts, June 12, 1998: https://grants.nih.gov/grants/guide/notice-files/not98-084.html). INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported clinical research projects unless a clear and compelling justification is provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing clinical research should read the AMENDMENT "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research - Amended, October, 2001," published in the NIH Guide for Grants and Contracts on October 9, 2001 (https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html), a complete copy of the updated Guidelines is available at https://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm The amended policy incorporates: the use of an NIH definition of clinical research, updated racial and ethnic categories in compliance with the new OMB standards, clarification of language governing NIH-defined Phase III clinical trials consistent with the new PHS Form 398, and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH-defined Phase III clinical trials that: a) all applications or proposals and/or protocols must provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable, and b) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS: The NIH maintains a policy that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines" on the inclusion of children as participants in research involving human subjects that is available at https://grants.nih.gov/grants/funding/children/children.htm. REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS: NIH policy requires education on the protection of human subject participants for all investigators submitting NIH proposals for research involving human subjects. You will find this policy announcement in the NIH Guide for Grants and Contracts Announcement, dated June 5, 2000, at https://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html. 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 https://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. 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 RFA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople. AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal Domestic Assistance Nos. 93.864, and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Awards are made under authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and administered under NIH grants policies described at https://grants.nih.gov/grants/policy/policy.htm and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. 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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