CLINICAL RESEARCH CONSORTIUM TO IMPROVE RESUSCITATION OUTCOMES RELEASE DATE: July 2, 2003 (see NOT-HL-03-012) RFA: HL-04-001 (Reissued as RFA-HL-10-006) National Heart, Lung, and Blood Institute (NHLBI) (http://www.nhlbi.nih.gov/) National Institute of Neurological Disorders and Stroke (NINDS) (http://www.ninds.nih.gov/) Institute of Circulatory and Respiratory Health (ICRH), Canadian Institutes of Health Research (CIHR) (http://www.cihr-irsc.gc.ca) CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER(S): 93.837 (NHLBI), 93.853 (NINDS) LETTER OF INTENT RECEIPT DATE: October 16, 2003 APPLICATION RECEIPT DATE: November 13, 2003 THIS RFA CONTAINS THE FOLLOWING INFORMATION: o Purpose of this RFA o Research Objectives o Mechanism(s) of Support o Funds Available o Eligible Institutions o Individuals Eligible to Become Principal Investigators o Special Requirements 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 RFA provides support for the establishment of a Resuscitation Research Consortium to conduct clinical research in the areas of cardiopulmonary arrest and traumatic injury leading to arrest. This Clinical Research Consortium (the Consortium), consisting of up to seven Regional Clinical Centers (RCCs) and a Data and Coordinating Center (DCC), will provide the necessary infrastructure to conduct multiple collaborative trials to aid rapid translation of promising scientific and clinical advances to improve resuscitation outcomes. Trials may evaluate existing or new therapies (such as pharmacologic interventions, strategies of fluid resuscitation, and the use of immunomodulators), defined or proposed clinical management strategies (such as bleeding control strategies, the use of cerebral protection and neurologic preservation, metabolically directed therapies, and alternative CPR approaches), or a combination of the two. For the purpose of this document, cardiopulmonary arrest is defined as primary cardiopulmonary collapse. Traumatic arrest is defined as trauma leading to or threatening cardiopulmonary collapse. Resuscitation research is defined as the field of investigation that attempts to provide the best and most effective treatment for arrest patients. RESEARCH OBJECTIVES Nature of the Research Problem: Current resuscitation practice is based largely on empirical observation and findings from animal research. Few controlled studies have been conducted in people to establish the actual benefit of interventions presently employed. Results of basic research that have improved our understanding of the complex biochemical pathways involved in arrest-related ischemia and reperfusion in the heart and brain have not yet greatly affected resuscitation procedures and subsequent patient outcomes. Both the immediate pre- and post-resuscitation dysfunctional periods represent critical periods that are under- investigated and that may be amenable to therapeutic interventions to improve patient survival. The timing and selection of resuscitative interventions and the ability to administer them effectively pose scientific and logistic challenges shared by both trauma and cardiopulmonary arrest investigators. Pertinent Background Information Establishing Need for the Research: To date, resuscitation-oriented research in people has failed to fulfill expectations generated by recent promising animal results. Translating the results of basic science and enabling technology research that hold promise for reducing arrest-related morbidity and mortality into clinical research and practice is vital for improving public health. In recognition of the need to improve resuscitation outcomes and to decrease the public health burden associated with traumatic injury and cardiopulmonary arrest, the NHLBI, NICHD, NIGMS, NINDS, FDA and DOD cosponsored the Post-Resuscitation and Initial Utility in Life Saving Efforts (PULSE) workshop on June 29-30, 2000 (http://www.nhlbi.nih.gov/meetings/pulse/). A major recommendation of this workshop was to form a research consortium that would allow for the rapid testing of promising therapeutic strategies in appropriate populations of arrest patients. In response to this workshop recommendation, NHLBI released a Request for Information (RFI) [Collaborative Clinical Research Consortium To Improve Resuscitation Outcomes NOT-HL-02-002 (http://grants.nih.gov/grants/guide/notice-files/NOT-HL-02-002.html)] soliciting comments to identify obstacles to clinical resuscitation research. Responses received from professional organizations, established research groups, and individual scientists indicated that testing of resuscitation strategies requires both targeted pilot studies and randomized controlled trials. Respondents felt that current clinical resuscitation research is impeded by a lack of infrastructure to allow enrollment of an adequate number of patients and overcome the substantial initial investment required for conducting patient-oriented research. Other barriers to resuscitation research include the lack of mechanisms to facilitate rapid testing and implementation of promising experimental approaches in the clinical arena, the absence of a uniform definition of successful resuscitation outcomes, and issues of obtaining informed consent from arrest patients. The ICRH has also recognized the need to invest in research concerning clinical resuscitation strategies. Traumatic injuries continue to be a huge burden on the Canadian health care system, especially when leading to cardiopulmonary arrest. In those circumstances where cardiopulmonary arrest occurs outside of the hospital, early and effective resuscitation is key to improving patient survival and rehabilitation. ICRH supports the recommendations of the PULSE report and recent work by the NHLBI to conceptualize the Clinical Research Consortium initiative. In order to promote collaboration between Canada and the United States on clinical resuscitation trials, ICRH will also support the initiative. In sum, the recommendation of the PULSE workshop and responses to the RFI indicate that success in performing clinical resuscitation research requires both infrastructure and project support. The major advantages of establishing a consortium include: a) coordination between community emergency services and research centers; b) development of uniform methods for diagnosis and monitoring to more precisely characterize the natural history and presentation of cardiopulmonary and traumatic arrest; c) development and implementation of standard definitions; d) enhancement of patient and facility resources to ensure rapid, efficient, and cost-effective patient recruitment and enrollment; e) cooperative sharing of data and the use of central core laboratories; f) close scientific and administrative collaboration among participating centers; g) effective monitoring by the data and coordination center for quality, timeliness and adherence to protocols; and h) effective monitoring by the DSMB for patient safety. Lastly, the Consortium provides a vehicle to rapidly disseminate results to the research and practice communities. Scientific Knowledge to be Achieved Through Research Supported by this Program: The general aim of this Consortium will be to conduct multiple collaborative clinical protocols to evaluate strategies to treat arrest patients, with an emphasis on out-of-hospital arrest. Objectives of this Research Program: The primary objective of each study conducted by the Consortium will be to: o Provide a knowledge base that will improve therapeutic decision- making by testing approaches to management of cardiopulmonary arrest and life-threatening trauma. Other objectives of the Consortium will be to: o Develop methods for predicting individual response to interventions. o Evaluate and correlate various measures of functional outcome for resuscitation survivors. o Develop collaborations between community emergency service providers and clinical research centers to permit out-of-hospital resuscitation research. o Facilitate the training of resuscitation and emergency medicine physicians in clinical investigation. Types of Research and Experimental Approaches: Each RCC applicant must demonstrate the capability to implement out-of- hospital research protocols and enroll the required number of cardiopulmonary arrest and trauma patients. It is expected that the Consortium will test equal numbers of cardiopulmonary arrest and trauma resuscitation protocols. For the purposes of the RCC application, two well-developed intervention protocols must be proposed. One protocol must focus on cardiopulmonary arrest, and the other on trauma. Both protocol proposals must aim to significantly improve clinical outcomes. Protocols will be of relatively short duration (on average less than two years) and well focused. Many therapeutic trials will include phase I and/or II clinical trials. Final protocols will be selected by majority vote of the Steering Committee. Studies conducted by the Consortium may respond to urgent needs by testing new treatment strategies, providing data for planning larger trials or addressing conflicting results of previous clinical investigations. Examples of Research Topics: Relevant areas may include, but are not limited to, the following scientific needs and considerations: o Evaluation of pharmacologic interventions to address a three-phase (electrical, circulatory, and metabolic) approach to resuscitation. o Evaluation of optimal strategies of fluid resuscitation including permissive hypotension, timing of initiation of infusion, and use of alternative fluids. o Use of immunomodulators in improving clinical outcomes by altering systemic and/or regional inflammatory responses accompanying shock or shock-like states. o Evaluation of bleeding control strategies. o Use of cerebral protection and neurologic preservation, with an emphasis on functional outcome. o Evaluation of metabolically directed therapies, such as a rapid induction of moderate systemic hypothermia and other novel methods to reduce metabolic demands in the immediate post-arrest/resuscitation interval. o Evaluation of alternative CPR approaches including device-assisted CPR. o Evaluation of oxygen delivery systems and methods for airway protection. Project Organization: The Clinical Research Consortium will consist of the following components: the NIH in cooperation with ICRH, up to seven Regional Clinical Centers (RCCs), a Data and Coordinating Center (DCC), a Study Chair, a Steering Committee and its subcommittees, a Protocol Review Committee (PRC), and a Data and Safety Monitoring Board (DSMB). The responsibilities of each component of the consortium are described below. NIH: NHLBI will be responsible for overseeing the organization of the Consortium and thus will be substantially involved with the awardees in a partnership, consistent with the cooperative agreement support mechanism. NHBLI will routinely consult ICRH staff on management of the Consortium and will on a regular basis discuss progress, documentation, and shared goals related to this initiative. The NHLBI Program Official will monitor patient recruitment and study progress, and ensure disclosure of conflicts of interest and adherence to NHLBI policies. NHLBI will appoint the Study Chair and all members of the PRC and the DSMB. The Study Chair, who may or may not be a PI from one of the RCCs, will be responsible for ensuring that there are well-documented policies, procedures, and bylaws to guide all aspects of Consortium activities and operations. The Study Chair will also be ultimately responsible for the prioritization and finalization of study protocols. The Consortium leadership (NHLBI, NINDS and ICRH Program Officials, Consortium Study Chair, and all PIs from the RCCs and DCC) will establish procedures to: a) assure adequate protection of the rights and safety of patients involved in the research; b) guarantee the quality and integrity of the resulting data; c) maintain accurate and timely information on each study; and d) provide interim study summaries to the DSMB as requested. This oversight must be in compliance with all federal regulations and NIH/NHLBI policies. CIHR: ICRH will provide and administer a portion of the funds for RCCs awarded to successful principal investigators located in Canada. ICRH staff will work with NHLBI to assess responsiveness, collaborate with the NHLBI concerning peer review process and administration, and advise the NHLBI on matters related to the management of the Clinical Research Consortium. Regional Clinical Centers (RCCs): As a group, RCCs will likely represent major medical centers with an established associated network of clinical sites or field centers. It is expected that individual RCCs will vary in nature and experience, and thus may represent both different patient populations and expertise in the area of resuscitation medicine. Therefore, the primary center must demonstrate both clinical science excellence and expertise in either cardiopulmonary arrest or trauma resuscitation, and a proven ability to recruit a population that includes patients from either urban or rural areas. As a whole, the Consortium intends to enroll patients from both urban and rural communities, and to perform research in the areas of both cardiopulmonary and trauma arrest resuscitation. However, for practical reasons, it is not required that each RCC represent all aspects of the arrest population, or demonstrate a facility in all areas of arrest investigation. The Principal Investigator (PI) at each RCC will be responsible for proposing protocols, estimating their costs, participating in their overall development, conducting the research, assuring quality of patient care and protocol adherence, assuring the accurate and timely transmission of data collected in conjunction with the DCC, and disseminating research findings. To provide peer reviewers and NHLBI/ICRH staff with sufficient information regarding the capabilities of the investigators, each applicant for a RCC must submit two protocol proposals. A proposed study may or may not ultimately be adopted by the Consortium as one of its protocols. The proposals are requested to serve as an indicator of the applicant's ability to participate in the development and design of protocols for cooperative clinical investigations. It is anticipated that the Steering Committee will include the protocols submitted by the funded RCCs in their consideration of topics for actual studies. Research plans should propose questions that could be examined cooperatively. Protocols should be written specifically for this Consortium to serve as a key factor in evaluation of the application. Applicants should outline the rationale and background of each proposed study, study design and protocol, eligibility criteria and initial sample size and power calculations. In order to avoid speculation about the enrollment potential of other RCCs in the actual Consortium, study design should be based on the available local patient population, not on the potential recruitment to be afforded by the Consortium as a whole. Furthermore, RCC applicants should indicate how their disciplinary and methodological perspectives could contribute to such a cooperative research effort. A protocol budget should be included with each proposal and should include an estimated per-patient enrollment cost; however, protocol costs should be excluded from the requested RCC budget. Data and Coordinating Center (DCC): The DCC will be responsible for the coordination, administration, and support of all clinical research activities at the direction of NIH program staff. These activities include, but are not limited to, administrative support for the Consortium Study Chair, scientific leadership and committees, reimbursement for patient accrual, and organization of investigator meetings. The DCC will assist in final protocol development, provide statistical leadership for study design, and prepare operational timetables. The DCC will develop data collection system and manuals of operations, determine sampling and randomization schemes, and assist in defining primary and secondary outcomes and analytical approaches for the protocols. The DCC will subcontract to external laboratories as needed, coordinate with suppliers of drugs, and arrange for the preparation and packaging of medications. The DCC will manage and distribute all protocol funds. The DCC will develop procedures for quality control, training and certification, and data management. It will monitor the quality and quantity of data received from the RCCs, provide relevant reports to the NHLBI, RCCs, and Steering Committee, and serve as a central repository for study data. The DCC will prepare protocols for submission to the PRC, and to the FDA, CMS, or other government agencies as required, and prepare confidential data analyses and reports for the DSMB. The DSMB, with DCC support, will develop stopping rules. The DCC will support manuscript preparation through data analysis, statistical consultation, editorial support, and meeting coordination. It will schedule and make arrangements for all meetings of established committees and boards. The DCC will be subject to annual administrative review. The Consortium will require an interactive information technology system for identifying eligible arrest patients, evaluating investigator performance and protocol adherence, maintaining real time data accuracy and quality, training of personnel on a regular basis and in remote locations, and, most importantly, for assuring the highest quality of medical care for patients involved in Consortium protocols. This approach to information management provides the benefit of instant, reliable communication channels, accelerates the inclusion of key participants and medical experts, and reduces non-productive time spent traveling. Such a system will be based on teleconferencing and will allow for multi-site participants to effectively and precisely share and compare both research data and medical information. It must be modifiable as protocols demand and medical technology advances. Thus, a high degree of technical flexibility is both a priority and a requirement. Plans for an information technology system must be included in the DCC application and must be universally implemented across RCCs. Up to $275,000 total costs will be provided to the DCC in the first year for acquisition, installation, and other costs associated with necessary information technology equipment and software. Up to $250,000 total costs will be available with NHLBI approval over the following four years for system upgrades and maintenance. Steering Committee: The Steering Committee will be the main governing body of the Consortium. Voting members of the Steering Committee include, at a minimum, the Study Chair, and the PIs of the RCCs and the DCC (or their designated alternate). The NHLBI and NINDS Program Officials and an ICRH designate will be non-voting members of the Steering Committee. The Study Chair will be appointed by NHLBI and may or may not be a PI at a participating RCC or the DCC. The Study Chair will plan network activities, oversee its functions, conduct SC meetings, and cast tie- breaking votes in that committee. The Steering Committee will develop and ensure compliance with Consortium policies and procedures, identify and prioritize topics for investigation, evaluate protocols proposed by the RCCs, and develop consensus protocols for submission to the PRC. The Steering Committee will ensure that studies are properly conducted and monitored, that data are appropriately analyzed and interpreted, and that study results are reported in the scientific literature in a timely manner and disseminated to those directly involved in the care of arrest patients. Subcommittees consisting of qualified individuals from the RCCs, DCC, and NHLBI/NINDS/ICRH may be established by the Steering Committee to perform specific functions such as publications and presentations or quality control. Protocol Review Committee (PRC): The PRC will be appointed by, and responsible to, NHLBI in consultation with ICRH. It will consist of a Chairperson and scientists with expertise in basic and clinical research, clinical trial design, biostatistics, enabling technologies, outcome measures, and other areas of expertise as needed. The exact number and duration of protocols supported in the five-year program will depend on the nature and extent of the investigations proposed by the Consortium's Steering Committee. The PRC will evaluate protocols proposed by the Steering Committee based on the importance of the question to be addressed, scientific merit of the experimental design and approach, feasibility, appropriateness for the consortium, and consistency with NHLBI/ICRH missions and policies. The PRC will provide a written critique of each proposal and a final recommendation to the NHLBI/ICRH. All study protocols performed by the Consortium must be recommended by the PRC and approved by the NHLBI/ICRH before initiation. Each RCC is expected to participate in at least two protocols per year after the first year. Data and Safety Monitoring Board (DSMB): NHLBI, in consultation with ICRH, will establish a DSMB in accordance with established policies to ensure data quality and participant safety and to provide independent advice to the NHLBI regarding progress and the appropriateness of continuing each study (see http://www.nhlbi.nih.gov/funding/policies/dsmb_inst.htm ). Suggested Time Table for Research Agenda Administration: Phase I (3 months) will be devoted to planning and development of the Consortium organizational infrastructure (including committee structure), and to protocol selection, development and prioritization, thus establishing a cohesive research agenda. Objectives for the planning and development stage are to select the Study Chair and Steering Committee leadership, determine patient eligibility criteria for initial clinical trials, develop data acquisition and consent forms, define terms and outcome measures, develop a manual of operations, questionnaires, procedures for quality control, determine priorities for protocol development, and begin to develop specific protocols. The PIs, through the Steering Committee, will lead the planning effort, with the assistance of the NHLBI Program Official. Phase II (3-6 months) will consist of staff training in data acquisition procedures, protocol completion, IRB approval, and initial enrollment for the first study. Phase III (6-54 months) will involve the ongoing process of protocol development and implementation. Enrollment for the first study will begin as soon as a protocol is approved and resources become available. The DCC will oversee the management of data and the distribution of protocol funds. It will also support manuscript preparation through data analysis, statistical consultation, editorial tasks, and coordination of meetings. The main results paper for each clinical trial will be collaboratively prepared by the investigators and submitted for publication. Complete patient records will be audited by the DCC on a regular basis. Phase IV consists of final data analysis and manuscript preparation. MECHANISM OF SUPPORT This RFA will use NIH U01 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 anticipated award date is July 1, 2004. Applications that are not funded in the competition described in this RFA may be resubmitted as NEW investigator-initiated applications using the standard receipt dates for NEW applications described in the instructions to the PHS 398 application. This RFA uses just-in-time concepts. This program does not require cost sharing as defined in the current NIH Grants Policy Statement at http://grants.nih.gov/archive/grants/policy/nihgps_2001/part_i_1.htm. The NIH (U01) is a cooperative agreement award mechanism in which the Principal Investigator retains the primary responsibility and dominant role for planning, directing, and executing the proposed project, with NIH staff being substantially involved as a partner with the Principal Investigator, as described under the section "Cooperative Agreement Terms and Conditions of Award". Applications submitted by foreign institutions can request facilities and administrative (F&A) costs up to a maximum of eight percent. Please see the web site http://grants.nih.gov/grants/guide/notice-files/NOT-OD-01-028.html for more information on allowable F&A costs for foreign grants and domestic grants with foreign components. FUNDS AVAILABLE NHLBI intends to commit approximately $7 million (total costs) in FY 2004, and up to $38 million (total costs) over a five-year period. In addition, NINDS intends to commit approximately $5 million (total costs) over a five-year period. ICRH intends to commit approximately $2.5 million over a five-year period toward meritorious grants from Canadian institutions. Applicants who wish to have their projects considered for funding by ICRH should include with their application a letter stating that their application and summary statement may be shared with ICRH. These funds are intended to support up to eight new grants in response to this RFA including up to seven RCCs and one DCC for a period of five years. Budget information for RCC and DCC applicants is contained in the sections on budget requirements below. Although the financial plans of the 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. At this time, it is not known if this RFA will be reissued. 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 Foreign institutions may apply as primary grantees or may participate as part of a domestic application. o Eligible agencies of the Federal government Applicants may choose to apply as a RCC, DCC, or as both a RCC and DCC. If an institution is applying for both a RCC and DCC, two separate applications from two different PIs should be submitted. 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 the appropriate 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/CIHR programs. SPECIAL REQUIREMENTS The Consortium will be a collaborative effort that will require frequent interactions of awardees among each other and with NHLBI/ICRH. Applicants should explicitly indicate their willingness to: o Participate in Steering Committee meetings (expected to occur approximately four times per year in Bethesda, Maryland), site visits required by the NHLBI/ICRH, and regular telephone conference calls; o Cooperate with other awardees in the development and design of research protocols; o Abide by common definitions, common methods for patient selection and enrollment, and common protocols, procedures, tests, and reporting forms as chosen by majority vote of the Steering Committee; o Actively seek to implement each network-wide protocol approved by the PRC and NHLBI/ICRH; o Comply with study policies and quality assurance measures approved by the Steering Committee; o Agree to oversight of the study by a DSMB; o Accept awards from the DCC for the support of research based on per- patient (capitated) rates and actual numbers of subjects enrolled, followed, and completing the study (RCCs only); o Accept, manage and distribute awards for the support of research based on the number of protocols developed, initiated, and carried out (DCC only); o Transmit study data to the DCC in a timely and accurate manner (RCCs only); o Report all adverse events in accordance with procedures established by the Steering Committee and NHLBI/ICRH policies; o Cooperate with other awardees in the publication of study results and the eventual release to the scientific community of study procedures and other resources; o Develop and implement plans for the dissemination of study results to physicians involved in the care of arrest patients; o Participate in studies of the cost effectiveness of therapeutic interventions should the NHLBI/ICRH choose to implement such research within the Consortium; and o Accept the Cooperative Agreement Terms and Conditions of Award given below. Cooperative Agreement Terms and Conditions of Award The cooperative agreement is an award instrument establishing an "assistance" relationship (in contrast to an "acquisition" relationship) between NHLBI and a recipient, in which substantial NHLBI scientific and/or programmatic involvement with the recipient is anticipated during performance of the activity. The purpose of NHLBI involvement is to support and/or stimulate the recipient's activity by acting as a "partner", while avoiding a dominant role, direction, or prime responsibility. The terms and conditions below, elaborate on these actions and responsibilities, and the awardee agrees to these collaborative actions with the NHLBI Project Scientist to achieve the project objectives. It is anticipated that these terms and conditions will enhance the relationship between the NHLBI staff and the principal investigator(s), and will facilitate the successful conduct and completion of the study. These agreements will be in addition to, and not in lieu of, the relevant NIH procedures for grants administration. The terms will be as follows: 1. The awardee(s) will have lead responsibilities in all aspects of the study, including any modification of study design, conduct of the study, quality control, data analysis and interpretation, preparation of publications, and collaboration with other investigators, unless otherwise provided for in these terms or by action of the Steering Committee. 2. The NHLBI Project Scientist will serve on the Steering Committee; he/she or other NHLBI scientists may serve on other study committees, when appropriate. The NHLBI Project Scientist (and other NHLBI scientists) may work with awardees on issues coming before the Steering Committee and, as appropriate, other committees, e.g., recruitment, intervention, follow-up, quality control, adherence to protocol, assessment of problems affecting the study and possible changes in protocol, interim data and safety monitoring, final data analysis and interpretation, preparation of publications, and development of solutions to major problems such as insufficient participant enrollment. 3. Awardee(s) agree to the governance of the study through a Steering Committee. Steering Committee voting membership shall consist of the principal investigators (i.e., cooperative agreement awardees), the NHLBI Project Scientist, and the Chairperson. Meetings of the Steering Committee will ordinarily be held by telephone conference call or in the metropolitan Washington Area. 4. A Data and Safety Monitoring Board will be appointed by the Director, NHLBI to provide overall monitoring of interim data and safety issues; the Steering Committee will nominate members for this Board. Meetings of the Data and Safety Monitoring Board will ordinarily be held in Bethesda. An NHLBI scientist other than the NHLBI Project Scientist shall serve as Executive Secretary to the Board. An independent Protocol Review Committee, established by the NHLBI, will provide peer review for each network protocol. Because the Board serves as an independent group advisory to the NHLBI, study investigators will not communicate with Board members regarding study issues, except as authorized by the Board's Executive Secretary. 5. Awardees will retain custody of and have primary rights to their data developed under these awards, subject to Government rights of access consistent with current HHS, PHS, and NIH policies. The collaborative protocol and governance policies will call for the continued submission of data centrally to the coordinating center for a collaborative database; the submittal of copies of the collaborative datasets to each principal investigator upon completion of the study; procedures for data analysis, reporting and publication; and procedures to protect and ensure the privacy of medical and genetic data and records of individuals. The NHLBI Project Scientist, on behalf of the NHLBI, will have the same access, privileges and responsibilities regarding the collaborative data as the other members of the Steering Committee. 6. Support or other involvement of industry or any other third party in the study -- e.g., participation by the third party; involvement of study resources or citing the name of the study or NHLBI support; or special access to study results, data, findings or resources -- may be advantageous and appropriate. However, except for licensing of patents or copyrights, support or involvement of any third party will occur only following notification of and concurrence by NHLBI. 7. Study investigators are encouraged to publish and to release publicly and disseminate results and other products of the study, in accordance with study protocols and governance. Within three years of the end of the period of NHLBI support for the project, data not previously released and other study materials or products not previously distributed, are to be made available to individuals who are not study investigators, provided such release is consistent with the study protocol and governance and with paragraph 6. In addition, study investigators must establish a plan for making data sets and materials available to the scientific community and to the NHLBI immediately upon completion of the three year period following the end of the period of NHLBI support. 8. The NHLBI reserves the right to terminate or curtail the study (or an individual award) in the event of (a) failure to develop or implement a mutually agreeable collaborative protocol, (b) substantial shortfall in participant recruitment, follow-up, data reporting, or quality control, (c) major breach of the protocol or substantive changes in the agreed-upon protocol with which NHLBI cannot concur, (d) attaining of a major study endpoint before schedule with persuasive statistical significance, or (e) human subject ethical issues that may dictate a premature termination. 9. Upon completion of the project, awardees are expected to put their intervention materials and procedure manuals into the public domain and/or make them available to other investigators, according to the approved plan for making data and materials available to the scientific community and the NHLBI, for the conduct of research at no charge other than the costs of reproduction and distribution. 10. Any disagreement that may arise in scientific/programmatic matters (within the scope of the award), between award recipients and the NHLBI may be brought to arbitration. An arbitration panel will be composed of three members--one selected by the Steering Committee (with the NHLBI member not voting) or by the individual awardee in the event of an individual disagreement, a second member selected by NHLBI, and the third member selected by the two prior members. This special arbitration procedure in no way affects the awardee's right to appeal an adverse action that is otherwise appealable in accordance with the PHS regulations at 42 CFR part 50, Subpart D and HHS regulation at 45 CFR part 16, or the rights of NHLBI under applicable statutes, regulations and terms of the award. 11. These special terms of award are in addition to and not in lieu of otherwise applicable OMB administrative guidelines, HHS Grant Administration Regulations at 45 CFR part 74, and other HHS, PHS, and NIH grant administration policy statements. Awards made from ICRH will be held to similar terms and conditions as outlined above. 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: Tracey Hoke, M.D., Sc.M. Division of Heart and Vascular Diseases National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room 9198 Bethesda, MD 20892-7940 Telephone: (301) 435-0515 FAX: (301) 480-1454 Email: firstname.lastname@example.org Mary Ellen Michel, Ph.D. NINDS/NIH Neuroscience Center, Room 2209, MSC 9525 6001 Executive Boulevard Bethesda, MD 20892-9525 (301) 496-1447 Email: email@example.com o Direct your questions about peer review issues to: Anne Clark, Ph.D. Chief, Review Branch National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room 7214, MSC 7924 Bethesda, MD 20892 (20817 for express/courier service) Telephone: (301) 435 0270 FAX: (301) 480 3541 Email: firstname.lastname@example.org o Direct your questions about financial or grants management matters to: David Reiter Grants Operations Branch National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room Bethesda, MD 20892 Telephone: (301) 435-0144 Email: email@example.com For any questions directed to ICRH please contact: Elissa Hines Reimer Senior Associate Institute of Circulatory and Respiratory Health Telephone: (613) 954-0544 Email: firstname.lastname@example.org 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 IC 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 by mail or email to Anne Clark at the above address. In addition, for this RFA, principal investigators located in Canada are requested to notify ICRH of their intent to apply by sending an email to email@example.com by 10/16/2003. 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 http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact Grants Info, Telephone (301) 435-0714, Email: GrantsInfo@nih.gov. SUPPLEMENTAL INSTRUCTIONS EXPECTATION OF COOPERATION Applicants should indicate their willingness and ability to participate in the stated aspects of the Consortium. Departmental and Institutional Commitments: The local department and institutional commitment to collaborative resuscitation research and to the prioritization of Consortium research must be clearly documented by providing letters to the PI and by citing evidence of past support. This institutional assurance to provide support should address areas such as fiscal administration, personnel management, space allocation, procurement, planning, equipment and budgeting and should include IRB assurance of a willingness to consider participation in resuscitation research. REGIONAL CLINICAL CENTERS Minimum Application Requirements for Regional Clinical Center (RCC) Applications: o The PI and research team at each RCC must have a history of previous successful clinical research. o The applicant must provide evidence of recent research productivity in previous or present clinical trials, especially of a cooperative, multi- center nature. Specifically, contributions in key areas such as protocol design, patient recruitment, data analysis and interpretation, and publication are important. o The applicant must have a minimum of 500 arrest (cardiopulmonary and/or trauma) cases annually. These cases must be suitable for resuscitation research. Applicants are expected to provide information regarding the nature of the available patient population including numbers of arrest cases over the past five years, type of arrest (cardiopulmonary vs. traumatic), average response time (both in terms of time from 911 call to patient contact and from patient contact to arrival at hospital), percent achieving return of spontaneous circulation, and percent admitted to hospital, and percent discharged from the hospital. o The applicant must have an established program with experience in identifying and treating arrest and trauma patients and a designated facility for this purpose. o Each RCC must designate a research coordinator with adequate percent effort. Description of this individual's training, experience and involvement in clinical research should be provided. o The applicant must demonstrate the willingness and ability to participate in a cooperative manner with other RCCs, the DCC, and the NHLBI and ICRH in the development of research protocols, statistical methods, uniform data collection and data transfer. o The departmental and institutional commitment to collaborative consortium research should be clearly documented by providing letters to the PI and by citing evidence of past support. o The applicant must provide a plan for community representation in Consortium activities. This may include both lay people as well representatives of various organizations involved in local emergency medical systems. The plan should address how the representatives' inclusion will make a substantive contribution to the overall success of the Consortium. o The applicant should plan and budget for two members of the investigative team to attend four Steering Committee meetings per year in Bethesda, MD. Each meeting will be approximately two days in length. During these meetings, the Steering Committee will determine the operating policies of the Consortium, discuss on-going research, formulate the collaborative research plan, and discuss the implications of their research with interested parties outside of the Consortium who may be invited by the Steering Committee as the occasion warrants. Clinical Trial Agreement (CTA): When a pharmaceutical or device collaborator (third party) provides a study agent/device to the Consortium, a CTA will be negotiated describing respective responsibilities and rights. The agreement will include, but is not limited to, IND/IDE sponsorship, safety and data monitoring, and access to data. Third party agreements must be developed and implemented by the NHLBI/ICRH. Informed Consent: Patients who meet the eligibility criteria for a protocol may be unresponsive and incapable of providing consent at the time of enrollment. Further, the interventions being evaluated may need to be applied immediately (or have a small therapeutic window) to be effective, prohibiting any delay to obtain consent from next of kin. Therefore, NHLBI anticipates that certain protocols will be conducted under the regulations for exception from informed consent for emergency research (21 CFR 50.24) (see http://www.fda.gov/oc/ohrt/irbs/appendixb.html). These regulations have obligations for the investigators, the IRBs and NHLBI. The activities associated with fulfilling the requirements of those regulations can be substantial and vary by community. Applicants should anticipate undertaking research requiring an exception from informed consent and should allocate sufficient time and resources for the process, plan to work proactively with their IRBs, and develop community contacts, which can facilitate public input. Applicants for each RCC should present the following information: For each year, each RCCs should request core budget costs only. Estimated protocol implementation costs should be based on the proposals presented in the applicant's research plan, but should not be included in the RCC budget request. A table should be included showing estimated costs per patient for conducting each proposed protocol. The budget for each protocol should be developed on a cost-per-patient basis and include all direct costs and the associated protocol facilities and administrative costs. Costs of drugs or laboratory tests that are not clinically indicated (i.e., are not eligible for third-party reimbursement as part of routine clinical care) should be part of the per-patient cost of conducting a protocol. Applications should identify the potential source(s) for any drugs or substances that are being considered for clinical protocols that are currently unavailable commercially. It should be noted that funds will not be provided for the purchase of expensive medical equipment such as echocardiographic or magnetic resonance imaging systems. If any of the protocols proposed by RCC applicants includes obtaining blood or tissue samples, the applicant should delineate how such specimens will be handled and analyzed. In the event that a central laboratory is required to analyze specimens, the RCCs will be responsible for obtaining the sample(s) and the cost of obtaining them will be part of the RCCs per-patient expense. The cost of shipping, analyzing, and storage, as well as training of personnel and quality control will be the responsibility of the DCC. All protocol proposals should include implementation budgets; however, costs for protocols should not be included in the RCC core budget request. Investigators should prepare budgets only for their own RCC to conduct the proposed protocols, and not for the entire Consortium. The yearly protocol budget for the applicant's center should include: a) the number of patients available for each of the proposed protocol at the applicant's center; b) costs per patient for obtaining community consent in order to facilitate emergency research; and c) costs for recruitment and retention of the specified number of patients. Note that ongoing annual budgets for protocols will be based on the protocols approved by the PRC and the Consortium Steering Committee. Continuation and level of funding for each RCC will be based on actual recruitment and overall performance. Awards will be subject to annual administrative review. Budget Requirements for RCC Applications: RCC applicants should consider the following additional issues regarding budgets. The underlying concept of the Consortium is that a RCC core effort is essential to maintain the infrastructure required to perform multiple clinical trials. Based on this approach, it is estimated that the individual RCC will require a minimum level of effort to sustain the organizational aspects of the Consortium. It is also expected that the type and complexity of each RCC will vary. RCCs may represent compact urban clinical centers or extensive rural networks, and may require individualized staffing models in order to operate effectively. Therefore, each RCC applicant should submit a request for a CORE BUDGET between $350,000 and $500,000 total costs per year. Requests must be submitted with appropriate justification. It is anticipated that this core budget will include the following personnel categories: PI and Co-Investigators, Study Coordinators, Data Management/Teaching and Training Coordinator, Secretary/Administrator, Community/Policy Leadership Liaison, and EMS Leadership Liaison. A minimum of 25% effort for the PI at each RCC is required. Appropriate effort for other key personnel, travel costs for two people to attend approximately four trips each year to attend Steering Committee meetings in Bethesda, MD, and other travel related to Consortium operations (such as DSMB meetings and site visits) should be included with appropriate justification. In addition to the RCC core budget, each RCC will be provided funds for protocol implementation and participation (enrollment) by the DCC. This support will be provided for each protocol on a per-patient basis. The precise number of protocols conducted over the five years will be determined by the Consortium Steering Committee and will depend on a number of factors including scientific priority, availability of funds, length of the protocols, and ease of enrollment. It is anticipated that after the first year, at least two protocols may be active each year. Clinical Research Skills Development Core (Core): The Consortium presents a rich environment for young investigators to be exposed to and develop additional research skills. To assist the Consortium awards in enhancing the developmental environment for their new clinical investigators, NHLBI will permit applicants for a RCC to request up to $100,000 in total costs per year for a Clinical Research Skills Development Core. A Core is not a required component of an RCC and its absence will not disadvantage an applicant. The priority score on the Core will have no effect on the overall score of an application. If a Consortium application includes an application for a Core, then the Core should be mentioned in both the Abstract and the Table of Contents. Up to four additional pages may be used to describe the proposed Clinical Research Skills Development Core. The Core proposal should be inserted in the Consortium application at the end of the Research Plan. This text will not be counted toward the 25-page limit for the total Research Plan specified by the Form 398 instructions. Requests for Core funds should not be included in the body of Consortium applications as it is expected that this aspect of the Consortium will be supported by supplemental funds. Thus, applicants should provide a separate budget page for the Core and add the cost of the Core as a line item into the total request for funds. Applicants should read the specific requirements and other instructions for applying at http://www.nhlbi.nih.gov/funding/policies/ntwk_skill.htm. DATA AND COORDINATING CENTER: Minimum Application Requirements for Data and Coordinating Center Applications: o The applicant must have demonstrated prior experience as a coordinating center in multi-center studies. o The PI, with other staff, must have appropriate biostatistical, enabling technologies, data management and coordination expertise. o The applicant must have the ability to assist in designing protocols and the data collection system, including secure transmission via the Internet. o The applicant must demonstrate the willingness and ability to cooperate with the Consortium and NHLBI/ICRH staff in all design, data collection and analysis functions. o The applicant must have an established data system to collect and tabulate and analyze statistics. o The applicant should demonstrate the ability to provide multimedia conferencing and collaboration. o The applicant must demonstrate and ability to manage and distribute protocol funds. Budget Requirements for DCC Applications: Applicants for the DCC should prepare budgets for five one-year periods with maximum total allowable costs for the DCC limited to $1,500,000 in the first year and $2,500,000 in years two through five. In addition, the Consortium has budgeted $525,000 total costs during the project period for information technology (multimedia conferencing and collaboration), and $3,000,000 total costs per year for protocols. This cost structure may be modified once the Consortium is finalized and protocols are underway. It is expected that patient care costs will be greatest in years two through five. Total costs may be escalated at three percent annually for future years. For budget purposes, DCC applicants should assume that in the first year all administrative aspects of the Consortium will be organized and at least one protocol will be developed and enrollment started. For subsequent years, applicants may assume that at least two protocols a year will be active (either in the protocol development, implementation, or analysis and writing phase). DCC applicants should include costs for managing the DSMB, the PRC, and the Steering Committee including the cost of DSMB calls and meetings (DSMB meetings will be held two times per year in Bethesda, MD), the cost of PRC conference calls and meetings, and the administrative expenses of weekly Steering Committee conference calls and the four Steering Committee meetings in Bethesda, MD. Costs allowed for the participation of the Study Chair include salary support (up to 20% of the NIH cap), travel expenses and administrative support. The DCC also should include costs for site visits of each of the RCCs over the five- year study period, assuming up to six RCCs and a five-member site visit team for purposes of budget preparation. Cost for financial administration to prepare protocol budgets and to distribute and monitor funds should also be addressed. In addition, RCC applicants must include a statement of willingness to work collaboratively after award with the other funded sites to prepare a joint dissemination plan. DCC applications/proposals should describe methods to coordinate the dissemination planning and implementation. The DCC must include a budget and justification for any additional costs of this collaborative effort. Applications that do not include a dissemination plan will be considered non-responsive and not eligible for review. The awards will be subject to annual administrative review. It is expected that all protocols will be performed in a manner consistent with United States Food and Drug Administration guidelines. 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: http://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 and all five collated sets of appendix material must be sent to Anne Clark at the above address. APPLICATION PROCESSING Applications must be received on or before 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. Although there is no immediate acknowledgement of the receipt of an application, applicants are generally notified of the review and funding assignment within eight weeks. 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. However, when a previously unfunded application, originally submitted as an investigator-initiated application, is to be submitted in response to an RFA, it is to be prepared as a NEW application. That is the application for the RFA must not include an Introduction describing the changes and improvements made, and the text must not be marked to indicate the changes. While the investigator may still benefit from the previous review, the RFA application is not to state explicitly how. PEER REVIEW PROCESS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NHLBI/ICRH. 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 Division of Extramural Affairs, NHLBI, in consultation with ICRH, and in accordance with the review criteria stated below. The roster of the initial review group will be posted on the NHLBI/ICRH home page approximately two weeks prior to the review. As part of the initial merit review, all applications will receive a written critique and undergo a review 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 National Heart, Lung, and Blood Advisory Council. 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. REVIEW CRITERIA FOR REGIONAL CLINICAL CENTER APPLICATIONS: o Research plan. Appropriateness of proposed protocols, need for the network to accomplish the proposed protocols, relevance and importance of the research questions, preliminary results that justify the proposed end points and sample size, and likelihood that accrual could be accomplished on time. o Qualifications and experience. The expertise, training, and experience of the investigators and staff in clinical trials, evidence of understanding of randomized, multi-center trials, administrative abilities of the Principal Investigator and the level of commitment to the program for the effective function of the Clinical Research Consortium. o Patient access and study population. The access to at least 500 arrest patients; plans for the recruitment and retention of subjects; plans to ensure appropriate representation by ethnic group, age, and gender; the description of competing protocols, and the strategy for allocating patients between them. o Willingness and ability to participate in the Consortium. Applicant institution's history of collaborative research, depth of commitment, willingness to randomize patients, and ability to work with other Consortium Centers and NHLBI. o Institutional resources for patient care and follow-up. Adequacy of institutional resources including personnel, space, and special laboratory facilities. REVIEW CRITERIA FOR DATA AND COORDINATING CENTER APPLICATIONS o Research plan. Demonstrates understanding of the scientific, statistical, logistical, and technical issues underlying multi-center studies, including issues relating to assessment of outcomes relating to use of novel treatments of arrest patients; and demonstrates leadership in study design and statistics, data acquisition and management, data quality control, data analysis, handling and quality control of laboratory specimens, and consortium coordination. o Qualifications and experience. The expertise, training, and experience of the investigators and staff, including the administrative abilities of the Principal Investigator, co-investigator, and the time they plan to devote to the program for the effective coordination of the Consortium. o Study management. The administrative, supervisory, and collaborative arrangements for achieving the goals of the program, including willingness to cooperate with the participating RCCs and the NHLBI. This includes the ability to assist RCCs with recruitment problems to meet enrollment goals. o Willingness and ability to participate in the Consortium. Applicant institution's history of collaborative research, depth of commitment, and ability to work with RCCs and the NHLBI. o Environment. Facilities, equipment, and organizational structure to effectively coordinate Consortium activities and assist RCCs in implementing the Consortium protocols, providing for specialized laboratory testing, and collecting data. This includes but is not limited to development of repositories, conduct of lab tests and studies, and obtaining study drugs or investigational agents or products. 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. REVIEW CRITERIA FOR CLINICAL RESEARCH SKILLS DEVELOPMENT CORES The Clinical Research Skills Development Core will receive a priority score based on the review criteria below, but the priority score will not enter into the overall Consortium application priority score. The Clinical Research Skills Development Core will be evaluated for its effectiveness in developing the skills and clinical research capabilities of new investigators. This will include an evaluation of: o Credentials and track record of the PI, Core Project Leader, and other participating senior investigators. o Methods by which new investigators are to be recruited and selected including plans to recruit women and minority individuals. o Plans for developing the skills of new investigators; the types of skill and technologic development proposed. o Means by which the new investigators' professional development will be achieved. ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, and in accordance with NIH policy, 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. 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. DATA SHARING AND DISSEMINATION PLAN: The adequacy of the proposed DCC plan to share and disseminate data. Applicants must include in their application/proposal a plan for dissemination of research results and such a plan should include: o Identification and description of target audience of the dissemination plan. o Description of the methods to be used to reach the audience. o Appropriate benchmarks for success. o Appropriate additional personnel for developing and implementing the dissemination activities. o An appropriate budget for the proposed dissemination activities for the last year of requested funding. o A statement that the investigators agree to discuss and finalize the dissemination plan with Institute staff prior to its implementation. 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: October 16, 2003 Application Receipt Date: November 13, 2003 Peer Review Date: March 2004 Council Review: May 13, 2004 Earliest Anticipated Start Date: July 1, 2004 AWARD CRITERIA Award criteria that will be used to make award decisions include: o Scientific merit (as determined by peer review) o Availability of funds o Programmatic priorities. 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. http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm MONITORING PLAN AND DATA AND SAFETY 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 and Safety Monitoring, NIH Guide for Grants and Contracts, June 12, 1998: http://grants.nih.gov/grants/guide/notice-files/not98-084.html). INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: It is the policy of the NIH that women and members of minority groups and their sub- populations must be included in all NIH-supported clinical research projects unless a clear and compelling justification is provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing clinical research should read the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research - Amended, October, 2001," published in the NIH Guide for Grants and Contracts on October 9, 2001 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines are available at http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm. The amended policy incorporates: the use of an NIH definition of clinical research; updated racial and ethnic categories in compliance with the new OMB standards; clarification of language governing NIH-defined Phase III clinical trials consistent with the new PHS Form 398; and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH-defined Phase III clinical trials that: a) all applications or proposals and/or protocols must provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable; and b) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS: The NIH maintains a policy that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines" on the inclusion of children as participants in research involving human subjects that is available at http://grants.nih.gov/grants/funding/children/children.htm REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS: NIH policy requires education on the protection of human subject participants for all investigators submitting NIH proposals for research involving human subjects. You will find this policy announcement in the NIH Guide for Grants and Contracts Announcement, dated June 5, 2000, at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html. PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this RFA in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award. 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 (http://www.hhs.gov/ocr/) 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 http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html. 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.healthypeople.gov/Default.htm. ICRH Web Documents: Applicants are encouraged to visit the ICRH website available from the Canadian Institutes of Health Research homepage (www.cihr-irsc.gc.ca) to view the ICRH mandate and related strategic documents. Information about the CIHR Clinical Research initiative is also available by visiting the CIHR homepage and choosing, "Strategic Initiatives" and Clinical Research (available in English and French). 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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