Path: utzoo!attcan!uunet!bionet!GENBANK.BIO.NET!kristoff From: kristoff@GENBANK.BIO.NET (Dave Kristofferson) Newsgroups: bionet.sci-resources Subject: NIH Guide, vol. 19, no. 39, pt. 2, 2 November 1990 Message-ID: Date: 6 Nov 90 00:07:19 GMT Sender: kristoff@genbank.bio.net Lines: 1178 REQUEST FOR COOPERATIVE AGREEMENTS APPLICATIONS: RFA: AI-91-01 RE-ISSUANCE OF RFA-87-AI-14 DATED 2/87 P.T. 34; K.W. 0740012, 1002008, 1002045 MOLECULARLY TARGETED APPROACHES TO ANTIVIRAL THERAPY NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES Letter of Intent Receipt Date: November 28, 1990 Application Receipt Date: January 17, 1991 The National Institute of Allergy and Infectious Diseases (NIAID) invites applications for research that applies an understanding of the molecular biology of virus replication and pathogenesis to the development of antiviral agents that are targeted to inhibit specific viral functions. Therapeutic and prophylactic agents (other than vaccines) that specifically inhibit virus replicative functions without interfering with normal cellular processes are likely to provide clinical benefit with minimal toxicity. Research on any virus that is a human pathogen or that serves as a model for a human pathogen, except for human immunodeficiency virus (HIV) and/or other retroviruses, is an appropriate subject for a proposal. Research on HIV antiviral agents is the subject of a separate initiative. Successful applicant(s) funded under this Request for Applications (RFA) will be supported through Cooperative Agreements. Cooperative Agreements are awarded to both nonprofit and for-profit organizations and institutions. This type of solicitation is utilized when it is desired to encourage investigator-initiated research projects in areas of special importance to the NIH and where substantial programmatic involvement by staff is anticipated. This RFA solicitation represents a single competition, with a specified deadline for receipt of applications. There are no plans to reissue this RFA at any future time. All applications received in response to the RFA will be reviewed by the same NIAID Initial Review Group (IRG) and by the National Advisory Allergy and Infectious Diseases Council. The deadline for the receipt of applications in response to this RFA is January 17, 1991. Applications should be prepared and submitted in accordance with the aims and requirements as set forth in the remainder of this document. I. BACKGROUND INFORMATION The Division of Microbiology and Infectious Diseases (DMID), NIAID, invites applications for Cooperative Agreements to support research projects to develop molecularly targeted agents as inhibitors of virus infection. Viral infections account for significant morbidity and mortality, as well as economic loss, in the United States and the rest of the world. NIAID continues to play a central role in the development of vaccines and therapies for viral diseases. DMID has targeted the control of infections caused by cytomegalovirus and other herpesviruses, papillomaviruses, hepatitis viruses and respiratory viruses as a high priority. (The Division of AIDS has responsibility for the control of HIV and other retroviral infections). DMID sponsors programs for both in vitro and animal model preclinical evaluation, as well as clinical trials of promising experimental therapies. Since there is a desperate public health need for effective, nontoxic agents for antiviral therapy, NIAID would like to stimulate research on the design and discovery of novel antiviral agents. The search for effective therapeutic agents to combat these serious infections was long delayed by the widely-held belief that the intracellular nature of virus replication made the development of clinically useful drugs improbable. More recently, as knowledge of the molecular mechanisms of virus replication and pathogenesis has become available, it is evident that there are both virus-coded and virus-induced functions which may be specifically, or at least selectively, inhibited. The efficacy of acyclovir at inhibition of herpes simplex infection is a dramatic example and has resulted in significant industrial support for the development of derivatives of acyclovir and some other nucleosides. However, the detailed understanding of the mechanisms of virus replication and the three-dimensional structure of virions and virus proteins that is rapidly accumulating should be exploited to investigate additional innovative approaches to the design of molecularly targeted antivirals. Infectious processes, which may provide vulnerable targets, include virus adsorption and entry, the synthesis and processing of nucleic acids and proteins, transport of macromolecules, assembly of progeny virions, the identification of viral markers on infected cells, and the spread of virus to uninfected cells. It may also be possible to target latently infected cells. Preliminary studies in this area have already been reported although the majority of novel approaches have been directed at HIV. Advances in crystallographic molecular modelling have led to the ability to predict the tertiary structure of the active sites of viral particles and enzymes and illustrate the interaction of these entities with known inhibitors. This ability has already led to the design of novel inhibitors for the HIV protease and rhinovirus adsorption and uncoating. "Anti-sense" oligonucleotides complementary to important viral regulatory or coding sequences inhibit virus replication in tissue culture and may also be effective in vivo. Selective inhibition of enzymes encoded by the viral genome, as well as cellular enzymes whose synthesis is enhanced as a result of infection, has been achieved in several instances. Molecular identification of the cellular receptors for virus adsorption should permit the design of agents that block the first stage of virus infection. Immunoliposomes have been developed on the assumption that they may reduce drug toxicity by enabling specific and selective delivery. These and other imaginative approaches to the development of targeted antiviral therapies are made possible by the recent explosion in our knowledge of the molecular details of virus replication and pathogenesis. II. RESEARCH GOALS AND SCOPE The purpose of this RFA is to stimulate research in the development of novel molecularly targeted approaches to antiviral therapy. This includes strategies for both the design of novel specific agents and development of methods for selective drug delivery. The strategies proposed should involve a molecular rationale for anticipated antiviral activity without significant concomitant cellular and/or organism toxicity. The preparation and testing of derivatives of previously identified nucleoside analogue antiviral agents does not constitute a novel approach. However, investigators may propose to extend a preliminary approach, such as those listed above in Section I, or apply such an approach to a different system. Investigators will choose the virus and system they prefer for these studies, but the selected virus should either be a clinically important human pathogen or serve as a model for a human viral pathogen. Possible choices include, but are not limited to: hepatitis B, C, and D virus, papillomavirus, cytomegalovirus, herpes simplex virus, varicella zoster virus, influenza viruses, respiratory syncytial virus, parainfluenza, rotavirus, coxsackievirus, and rhinovirus. The development of agents inhibitory to HIV and other retroviruses is the focus of a separate RFA and, therefore, proposals to target HIV will not be accepted in response to this initiative. III. MECHANISM OF SUPPORT A. Award(s) will be made as Cooperative Agreements. These are assistance relationships with substantial involvement of NIAID staff, as outlined under Part IV, "Terms of Award". Universities, medical colleges, hospitals, and laboratories or other public, private, or for-profit institutions are eligible. B. NIAID anticipates making ten to fifteen awards as a result of this request. However, the number of awards to be made is dependent upon receipt of a sufficient number of applications of high scientific merit and upon the availability of funds. If appropriate, collaboration with other investigators or institutions is encouraged. It is expected that the initial year's awards for successful applications will average $150,000 in direct costs, however, individual awards may be higher or lower. Awards will be made for a project period of up to five years. (When the applicant institution is outside the United States, awards will be limited to three years.) The earliest possible award date is July 1, 1991. It is the intent of DMID to fund a group of proposals that will ensure that a variety of approaches and virus systems will be investigated. The specific recommendations for proposals to receive awards will be made by a staff committee. Committee members will be the Director, DMID and the chiefs of the Antiviral Research Branch, the Enteric Diseases Branch, the Respiratory Diseases Branch, and the Sexually Transmitted Diseases Branch. Criteria will be technical excellence and program balance. NIAID has no plans to reissue this announcement. IV. TERMS OF AWARD: AWARDEE RIGHTS AND RESPONSIBILITIES; NATURE OF PARTICIPATION OF NIAID STAFF Under the Cooperative Agreement, a partner relationship between the recipient of the award and NIAID exists in which the applicant is responsive to the requirements and conditions set forth in the RFA. Specifically, the Principal Investigator defines the details for the project within the guidelines of the RFA, retains primary responsibility for the performance of the scientific activity, and agrees to accept close assistance of NIAID staff in all aspects of scientific and technical management of the project in accordance with the terms mutually agreed upon prior to the award. The applicant must define the research objectives and approaches in accord with his/her own interests and perceptions of novel and exploitable molecular approaches to the development of specific novel antiviral agents and must develop the details of the research design following the guidance given in this RFA. The awardee is to plan and conduct the research stipulated in the application and to ensure that the results obtained are analyzed and published in a timely manner. The data obtained will be the property of the awardee. Assistance via Cooperative Agreement differs from the traditional research grant in that, in addition to the normal programmatic and administrative stewardship responsibilities, the component awarding the Cooperative Agreement anticipates substantial programmatic involvement during performance of the project. The staff assistance mandated by the cooperative agreement mechanism will permit NIAID staff to participate in, but not direct, the research to ensure that important disease targets are addressed. A member of the NIAID staff will serve as Scientific Coordinator and will participate as a member of the research team. The Scientific Coordinator will be the Chief, Antiviral Research Branch, DMID. The Scientific Coordinator will interact closely with the Principal Investigators and Co-investigators in the overall research planning and in data analysis. During performance of the award the NIAID Scientific Coordinator may provide appropriate assistance by participating in the design of research group activities; advising in the selection of sources or resources, replacement of staff; coordinating or participating in collection and/or analysis of data; and advising in management and technical performance. The Scientific Coordinator may organize the further evaluation, both in vitro and in animal models, of agents resulting from this research. However the role of NIAID will be to facilitate and not to direct the activities. Specifically, it is presently envisioned that the NIAID will be actively engaged in the coordination of all components including assisting the awardees in: 1. Collaborative participation in overall research planning and data analysis. Specifically, the NIAID Scientific Coordinator may suggest studies within the scope of the award's objectives and research activities; may present to the investigators experimental findings from published sources or from contract projects in support of these suggestions; may participate in the design of experiments and may participate in the analysis of results. 2. Provision of needed resources and information that may not be otherwise available to the investigator. This may include the provision of data from testing conducted in resource contract laboratories. 3. In the event that an awardee's research results in a procedure or a product that requires testing of a nature beyond the awardee's capabilities, the NIAID Scientific Coordinator may provide resources available to the Institute for comprehensive preclinical efficacy evaluations. DMID has facilities to evaluate compounds in vitro for activity against panels of herpesviruses (HSV-1, HSV-2, CMV, VZV, and EBV), respiratory viruses (influenza A, influenza B, parainfluenza, respiratory syncytial virus, adenovirus, and measles), and hepatitis B. Compounds are also evaluated for toxicity for stationary and exponentially growing primary human fibroblasts and for activity against multiple strains of each virus which include recent clinical isolates and drug-resistant strains. DMID also supports animal models for most of the above-listed viruses as well as human and rabbit papillomaviruses. For example, the awardee may devise an agent that inhibits the expression of cloned respiratory syncytial virus or hepatitis B virus genes in vitro. The NIAID Scientific Coordinator can arrange for the agent to receive more extensive in vitro testing as well as evaluation in a cotton rat animal model for RSV infections or a woodchuck model for hepatitis B infection. In addition, the awardee may want NIAID to assist in the eventual clinical testing of the agent. Alternatively, the awardee may pursue testing of his/her agent independently. 4. Prior approval of changes of key personnel including the Principal Investigator and co-investigators. 5. The NIAID Scientific Coordinator will organize an annual symposium in Bethesda, Maryland, at which the principal investigators will discuss their progress. This will facilitate overall program planning and development, the evaluation of the feasibility of the attempted approaches, and will promote productive interactions among the successful applicants. The NIAID Scientific Coordinator will also ensure the participation in this symposium of investigators from other NIAID preclinical and clinical programs to provide the most relevant antiviral expertise possible to facilitate planning for future research and expedite the design and development of novel antiviral agents. Funds for travel to this meeting should be included in the budget. 6. In addition to the annual symposium, the NIAID Scientific Coordinator will interact informally with the principal investigators through additional meetings, averaging once a year, at the Principal Investigator's institution as well as by regular telephone and written communication. It is anticipated that decisions in all activities outlined above, as well as changes in research direction, will be reached by consensus of the Principal Investigator and the NIAID Scientific Coordinator. Such changes may be occasioned by the emerging clinical importance of different infections or the suitability of developed approaches for the design of antiviral therapies for other infections. The manner of reaching this consensus and the decision-making authority will rest with the Principal Investigator. However, if a dispute should arise, the decision of a three-member arbitration team will be binding. One member of this team will be chosen by the Principal Investigator and the second will be chosen by the NIAID Scientific Coordinator. These two members of the arbitration team will select the third member. Although the NIAID Scientific Coordinator may participate in discussions on planning and evaluation, the recipients of these awards will be responsible entirely for the design, conduct, and evaluation of their proposed research. The NIAID Scientific Coordinator will not direct, nor be liable for, the awardee's research activities. The awardee will be responsible for publishing and disseminating the results of his/her studies. In the event that collaborative studies with NIAID grantees, awardees, or contractors, are undertaken (as described above), the NIAID Scientific Coordinator may assist in the design of study protocols and evaluation of data. 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. V. METHOD OF APPLICATION A. LETTER OF INTENT Prospective applicants are asked to submit, by November 28, 1990, a short letter of intent that includes a descriptive title of the proposed research, and the names and affiliation(s) of proposed key investigators. The letter of intent is requested in order to provide an indication of the number and scope of applications to be reviewed. The letter of intent does not commit the sender to submit an application, nor is it a requirement for submission of an application. The letter of intent should be sent to: Dr. Olivia Preble Chief, Microbiology and Immunology Review Section Program and Project Review Branch National Institute of Allergy and Infectious Diseases National Institutes of Health Westwood Building, Room 3A10 Bethesda, MD 20892 Telephone: (301) 496-8208 B. Format of Applications 1. Applications must be submitted on form PHS 398 (Rev. 10/88, 9/89), the application form for research grants. Application kits are available at most institutional business offices or may be obtained from the Office of Grants Inquiries, Room 449, Westwood Building, Division of Research Grants, NIH. The format and detail applicable to regular research grant applications should be followed, and the requirements specified under Review Criteria (VII.C.) must be fulfilled. 2. For purposes of identification and processing, mark "yes" in item 2 on the face page of the application and type in the words COOPERATIVE AGREEMENT FOR MOLECULARLY TARGETED APPROACHES TO ANTIVIRAL THERAPY and the RFA number AI-91-01. The RFA label (found in the 10/88 revision of application form PHS 398) must be affixed to the bottom of the face page of the original copy of the application. Failure to use this label could result in delayed processing of your application such that it will not reach the review committee in time for review. 3. The research proposed should describe plans to accommodate the RFA research program requirements and NIAID staff involvement. Note that the applications will be judged by the stated review criteria (see section VIII.C.). C. Application Procedure 1. The completed original application and four (4) exact copies should be sent or delivered to: Division of Research Grants National Institutes of Health Westwood Building, Room 240 Bethesda, MD 20892** TWO (2) ADDITIONAL COPIES MUST BE SENT TO: Dr. Olivia Preble Chief, Microbiology and Immunology Review Section Program and Project Review Branch National Institute of Allergy and Infectious Diseases National Institutes of Health Westwood Building, Room 3A10 Bethesda, MD 20892 Telephone: (301) 496-8208 VI. CONSEQUENCES OF LATE APPLICATIONS AND DUPLICATE SUBMISSIONS To ensure their review, applications must be received by both the Division of Research Grants (DRG) and Dr. Olivia Preble by January 17, 1991. Applications received after the above date will be returned without review. If the application submitted in response to this RFA is substantially similar to a research grant application already submitted to the NIH for review, but has not yet been reviewed, the applicant will be asked to withdraw either the pending application or the new one. Simultaneous submission of identical applications will not be allowed, nor will essentially identical applications be reviewed by different review committees. Therefore, an application cannot be submitted in response to this RFA that is essentially identical to one that has already been 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. VII. REVIEW PROCEDURES AND CRITERIA A. Assignment of Applications: Applications will be received by the NIH DRG and assigned to NIAID. B. Review Procedures: Applications will be reviewed by NIAID staff to determine administrative and programmatic responsiveness to this RFA; those judged to be non-responsive will be returned to the applicant without review. Those applications considered responsive to the RFA may be subjected to a triage review by an NIAID peer review group to determine their scientific merit relative to the other applications in response to the RFA. The NIH will withdraw from competition those applications judged by the triage peer review group to be noncompetitive for award and will notify the applicant principal investigator and the institutional business official. Those applications judged to be competitive for award will be reviewed for scientific and technical merit by a Review Committee convened by the Division of Extramural Activities, NIAID, during March 1991. The second level of review will be provided by the National Advisory Allergy and Infectious Diseases Council in May 1991. C. Review Criteria: The factors to be considered in scientific evaluation of the applications are: 1. Originality and scientific merit of research approach, design, and methodology as well as the potential scientific, technical, or medical significance of the proposed research. 2. Research experience and competence of the Principal Investigator and staff to conduct the proposed studies. 3. Adequacy of time (effort) that the Principal Investigator and staff would devote to the proposed studies. 4. Adequacy of facilities. 5. Reasonableness of proposed costs. The review criteria listed above will be those used by the initial review group. In selecting applications for funding, while scientific merit is of prime consideration, applications also will be evaluated for programmatic relevance and importance. VIII. FUTURE FUNDING This is a one-time request for applications. NIAID has no plans to reissue this announcement at any future date. IX. INQUIRIES Investigators seeking information relevant to this RFA should contact Dr. Catherine Laughlin at the address below. Questions regarding review procedures should be addressed to Dr. Preble, at the address given in Section V.A. Dr. Catherine Laughlin Chief, Antiviral Research Branch Division of Microbiology and Infectious Diseases National Institute of Allergy and Infectious Diseases Westwood Building, Room 753 Bethesda, MD 20892 Telephone: (301) 496-8285 This program is supported under authorization of the Public Health Service Act, Sec. 301(c), Public Law 78-410; as amended. The catalog of Federal Domestic Assistance citation is Sec. 93.856, Microbiology and Infectious Diseases Research. Awards will be administered under PHS grant policies and Federal Regulations 42 CFR Part 52 and 45 CFR Part 74. This program is not subject to the intergovernmental review REQUEST FOR APPLICATIONS: RFA RFA: HL-90-09-H CARDIOVASCULAR DEVICE-CENTERED INFECTIONS P.T. 34; K.W. 0715040, 0740035, 0715125 NATIONAL HEART, LUNG, AND BLOOD INSTITUTE* NATIONAL SCIENCE FOUNDATION Letter of Intent Receipt Date: December 3, 1990 Application Receipt Date: January 14, 1991 PURPOSE The Devices and Technology Branch (DTB), Division of Heart and Vascular Diseases of the National Heart, Lung, and Blood Institute (NHLBI), and the Section of Bioengineering and Environmental Systems of the Engineering Directorate, National Science Foundation (NSF), invite grant applications for support of interdisciplinary research (Biomedical Sciences and Bioengineering) on the mechanisms, prevention, and treatment of infections developing in and around permanently implanted cardiovascular devices in humans. BACKGROUND Foreign bodies have long been known to be infection- potentiating, but mechanisms to explain this phenomenon are not clearly defined. Infection in close proximity to a valve (endocarditis) occurs in 1-4% of patients with mechanical or bioprosthetic heart valves. One to 6% of patients with prosthetic vascular grafts develop a graft- associated infection. However, in patients with total artificial hearts (TAHs) or ventricular assist devices (VADs) implanted for periods longer than 3 months, the incidence of infection has been reported as 25-100%. It is likely that this high incidence stems in part from the existence of external drive-lines which serve as portals of entry for microorganisms despite all efforts at prevention. Some of the newer VAD systems currently undergoing preclinical testing will require no external drive-lines. This advance is expected to reduce but not eliminate the risk of implant- related infections in patients receiving these new devices. Infection in patients with TAHs or VADs is commonly associated with thromboembolism, and there is evidence that these two complications are interrelated. Ultrastructural studies of TAHs examined following autopsy in several human subjects have demonstrated failure of tissue integration and diffuse adhesive bacterial colonization of biomaterial surfaces. At device retrieval, thrombotic material has been observed, especially in the region of the valve struts and at the connections between the device and the great vessels. In addition, patients have suffered embolic stroke, and thromboembolic material has been observed in other organs, especially the kidney. These thrombi and emboli are frequently infected. An association between thrombosis and infection has long been observed in a number of clinical conditions, which include implanted prosthetic heart valves and prosthetic vascular grafts, and several mechanisms have been proposed for this. A thrombus forms an ideal nidus for bacteria to adhere and multiply in a nutrient environment. Conversely, certain bacteria can induce activation and aggregation of platelets or leukocytes, and activation of factors in the coagulation and complement cascades, thus favoring thrombosis. These mechanisms may result in a vicious cycle between thrombosis and infection, each increasing the likelihood of the other, especially in a chronic setting. Proteins that mediate adhesion of certain cells, such as platelets and endothelial cells, to one another and to other surfaces include fibronectin, laminin, vitronectin, von Willebrand factor, and certain collagen types. The role of these and other proteins in bacterial adhesion has not been fully defined. Finally, TAH implantation has been associated with alterations in complement and leukocyte functions, perhaps contributing to the high risk of periprosthetic and intraprosthetic infection in these patients. OBJECTIVES AND SCOPE This special grant program is for support of interdisciplinary research approaches to the problem of infections associated with implanted prosthetic cardiovascular devices. Molecular, structural, and computational biology approaches to the life and medical sciences are encouraged: these may deal with the nature of the interaction between bacterial surface components, the biomaterial surface, and molecules mediating bacterial adhesion, growth, and colonization on biomaterials. Other approaches, especially employing the concepts and methods of modern cell and molecular biology, are encouraged. Applications should have a substantive content in engineering. This may include the development of new engineering techniques or the novel application of existing ones. Research projects involving human subjects, animal models, or other experimental approaches may be focused on: (1) the etiology, pathogenesis, and natural history of device-centered infections, including the relationship to thromboembolism; (2) elucidation of possible predisposing factors for their development; and/or (3) potential approaches to improved prevention, monitoring, and treatment of such infections. In order for applicants to be responsive to this Request for Applications (RFA), the research should have a strong interdisciplinary component. NSF support is contingent on a strong bioengineering contribution. This may include mathematical modeling, instrumentation, tissue engineering, or any novel engineering technique that may help characterize or understand the mechanisms. The routine use or modification of state-of-the- art technology by itself will not qualify. In addition, the investigative approach should include one or more of the following areas: microbiology, immunology, infectious diseases, cardiovascular diseases, molecular biology, cell biology, pathology, and rheology. Applications might include, but are not limited to, the following: o Investigation of mechanisms for monitoring, producing, or enhancing the development of a biological (cellular or acellular) layer on the inner and outer surfaces of a circulatory support device with the object of inhibiting device-centered infections; with available methods for gene transfer and expression, attempt the alteration of the functions of leukocytes, endothelial cells, or other cells with the object of making them more resistant to infection. o Examining the role of the bacterial cell surface glycocalyx or other surface molecules in the specificity of the adhesion of certain bacteria to certain polymers or metals. o Investigation of bacterial adhesion to cardiovascular implants by delineating binding sites on the surface of biomaterials for bacteria or for extracellular molecules mediating bacterial adhesion; determine the specificity of binding sites for specific types of bacteria or proteins; investigate techniques for saturating these binding sites or synthesizing new materials, which have fewer binding sites for bacteria, or for molecules mediating their adhesion. o Examination and defining the molecular basis of plasma and extracellular matrix proteins in bacterial adhesion and colonization on biomaterials. These proteins include fibrinogen, fibronectin, laminin, vitronectin, von Willebrand factor, and various collagen types. o Investigating the relation between infection and thrombosis by studying the basic mechanisms whereby certain microorganisms activate blood coagulation, fibrinolysis, and complement. o Evaluating the changes in T- and B- lymphocytes, macrophages, neutrophils, lymphokines, complement, and other components of the immune system in response to interaction between well-characterized biomaterials and blood or tissues under controlled conditions; evaluate the role these abnormalities may play in device-related infections. o Examining the production and possible effect on susceptibility to infection of oxygen-free radicals released following contact of biomaterials with blood and other tissues. o Using in vitro, ex vivo, or in vivo models plus monitoring and visualization, evaluation of the role of physical properties (e.g., smoothness vs. roughness, porosity, compliance, surface-free energy) or chemical composition of various biomaterials, as elements influencing adhesion and proliferation of microorganisms on a biomaterial or device and in the development of an intraluminal and extraluminal layer of host cells formed in response to device implantation. o Evaluation of the use of new monitoring techniques, including in-vivo visualization, to characterize changes in surface phenomena. o Evaluation of mass transport and fluid mechanical factors (e.g., shear stress, stasis, recirculation) in the adhesion, colonization, and localization of bacteria on devices in contact with blood. Applicants are not required to include the above-mentioned topics and are encouraged to consider other avenues of investigation that have the potential of yielding significant information regarding mechanisms of biomaterial- centered infections. To be responsive to this RFA, applications must describe experimental conditions that simulate those encountered by implanted cardiovascular devices. Attention should be given to appropriate statistical design of the study. Although not a requirement, the inclusion of NHLBI-DTB primary reference materials (low-density polyethylene and silica-free polydimethylsiloxane) in the research plan is encouraged. Arrangements for procuring these materials may be made by contacting Dr. Paul Didisheim at the address and phone number listed at the end of this announcement. Also, if the research involves infectivity or adhesiveness of specific strains of microorganisms, these should be known to play significant roles in device-related infections in man. Engineering approaches proposed should have general applicability. In any studies involving human subjects, women and minority individuals must be included in the study population; otherwise a clear rationale for their exclusion must be provided in the application. Minority institutions are encouraged to apply, and other institutions are encouraged to establish collaborative arrangements with minority institutions. EXCLUSIONS Applications aimed primarily at examining the biological problem of infections with non-cardiovascular implants (e.g., orthopedic, dental, eye, ear) will not be considered responsive to this RFA. This solicitation will not support large-scale clinical trials. While interdisciplinary research is required, this should not be in the form of a large number of projects which would constitute a program project. Applicants may request equipment; however, funds will not be provided to equip a laboratory or for major, expensive items. Specifically, funds will not be provided for the purchase of expensive cardiovascular devices. MECHANISM OF SUPPORT The support mechanism for this program will be the traditional, individual research grant as administered by the NHLBI and NSF. A committee comprised of NHLBI and NSF staff will determine which agency will fund the most highly rated applications. Although approximately $1.0 million total costs (direct plus indirect) for this program is included in the financial requests for fiscal year 1991, award of grants pursuant to this RFA is contingent upon receipt of funds for this purpose. The hope is to award up to five grants under this program. The specific amount to be funded, however, will depend on the merit and scope of the applications received and the availability of funds. Since a variety of approaches would represent valid responses to this announcement, it is anticipated that there will be a range of costs among individual grants awarded. If collaborative arrangements involve sub-contracts with other institutions, the NHLBI Grants Operations Branch should be consulted regarding procedures to be followed (tel: 301-496-7255). Following initiation of the program, NHLBI and NSF will jointly sponsor annual meetings to encourage exchange of information among investigators who participate in this program. In the budget for the grant application, applicants should request ADDITIONAL TRAVEL FUNDS for a one-day meeting each year, to be held in the Washington, D.C. area. Applicants should also include a statement in their applications indicating their willingness to participate in these meetings. Applicants, who will plan and execute their own research programs, are requested to furnish their own estimates of the time required to achieve the objectives of the proposed research project. Up to FIVE YEARS of support may be requested. At the end of the official award period, renewal applications may be submitted through the regular grant programs of the NIH or NSF. It is anticipated that support for the present program will begin in July 1991. Administrative adjustments in project period and/or amount of support may be required at the time of the award. All current policies and requirements that govern the research grant programs of NIH and NSF will apply to grants awarded under this RFA. Awards to foreign institutions will be made only for research of very unusual merit, need and promise, and in accordance with Public Health Service and NSF policy governing such awards. REVIEW PROCEDURES AND CRITERIA Review Method: Upon receipt, applications will be reviewed for their responsiveness to the objectives of this RFA by NIH and NSF staffs. If an application is judged unresponsive, the applicant will be contacted and given the opportunity to withdraw the application, or have it considered for the regular NIH or NSF grant programs. If an application submitted in response to this RFA is substantially similar to a research grant application already submitted to the NIH or NSF for review, but has not yet been reviewed, the applicant will be asked to withdraw either the pending application or the new one. Simultaneous submission of identical applications will not be allowed, nor will essentially identical applications be reviewed by different review committees. Therefore, an application cannot be submitted in response to this RFA that is essentially identical to one that has already been 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. Those applications that are judged to be responsive will be reviewed for scientific and technical merit by an invited review group convened by the Division of Extramural Affairs, NHLBI. The review group will be composed of mostly nonfederally employed reviewers with expertise that will include the disciplines represented by the applications. Applications will be reviewed in competition with each other on a nation-wide basis. This RFA solicitation is a single competition and has one specific deadline for receipt of applications. Review Criteria: The factors to be considered in the evaluation of scientific and engineering merit of each application will be similar to those used in the review of traditional research project grant applications, including: o the novelty, originality and feasibility of the approach and the merit of the experimental design o clear indication of an interdisciplinary approach encompassing a substantive and innovative bioengineering component o the competence of the principal investigator and collaborators to accomplish the proposed research, and the commitment and time they will devote to the project o the suitability of the facilities to perform the proposed research, including laboratories, instrumentation, and data management systems o the appropriateness of the requested budget for the work proposed. METHOD OF APPLICATION Letter of intent: Prospective applicants are asked to submit a letter of intent to apply to this RFA. This letter should include the names of any participating institutions and all investigators, together with a descriptive title. Such a letter of intent is not binding and it will not enter into the review of any application. Letters of intent are requested solely for planning purposes. The NHLBI and NSF Staff will not provide responses to such letters. Letters of intent to apply to this RFA should be received no later than December 3, 1990, and should be addressed to: Dr. Charles L. Turbyfill Review Branch Division of Extramural Affairs National Heart, Lung, and Blood Institute Westwood Building, Room 553 NIH, Bethesda, MD 20892 Format for Applications: Submit applications on form PHS-398 (revised 10/88), the application form for the traditional NIH research project grant. Copies of this form are available in the applicant institution's office of sponsored research, or may be obtained from the following: Office of Grants Inquiries Division of Research Grants Westwood Building, Room 449 NIH, Bethesda, MD 20892 Use the conventional format for research project grant applications and ensure that points identified in the section above on "Review Procedures and Criteria" are fulfilled. Applications that contain prior work supported by the NSF must include a "Results from prior support" statement. To identify the application as a response to this RFA, CHECK "YES" on item 2 of page 1 of the application and enter the title "Cardiovascular Device-Centered Infections", and enter the RFA number HL-90-09-H in the space provided. THE RFA LABEL FOUND IN THE FORM PHS-398 APPLICATION KIT MUST BE AFFIXED TO THE BOTTOM OF THE FACE PAGE OF THE ORIGINAL COMPLETED APPLICATION FORM PHS-398. FAILURE TO USE THIS LABEL COULD RESULT IN DELAYED PROCESSING OF YOUR APPLICATION SUCH THAT IT MAY NOT REACH THE REVIEW COMMITTEE IN TIME FOR REVIEW. Application Procedure: Send or deliver the completed, signed application and four (4) complete photocopies of it to the following, making sure that the original application with the RFA label attached is on top: Division of Research Grants Westwood Building, Room 240 National Institutes of Health Bethesda, MD 20892** SEND TWO ADDITIONAL COPIES OF THE APPLICATION TO DR. CHARLES TURBYFILL AT THE ADDRESS LISTED UNDER "LETTER OF INTENT". IT IS IMPORTANT TO SEND THESE TWO COPIES AT THE SAME TIME AS THE ORIGINAL AND FOUR COPIES ARE SENT TO THE DIVISION OF RESEARCH GRANTS, OTHERWISE THE NHLBI CANNOT GUARANTEE THAT THE APPLICATION WILL BE REVIEWED IN COMPETITION FOR THIS RFA. Applications must be received by January 14, 1991. An application not received by this date will be considered ineligible Timetable: Letter of Intent December 3, 1990 Application Receipt Date January 14, 1991 Review by National Heart, Lung, and Blood Advisory Council and NSF Staff May 23-24, 1991 Anticipated Award Date July 1, 1991 Inquiries: Inquiries regarding this announcement may be directed to the following: Dr. Paul Didisheim Norman Caplan Head, Biomaterials Program Section Head Devices and Technology Branch Bioengineering and Division of Heart and Vascular Environmental Systems Diseases National Science Foundation National Heart, Lung, and 1800 G Street Blood Institute Washington, D.C. 20550 Federal Building, Room 312 Telephone: (202) 357-7955 7550 Wisconsin Avenue Bethesda, MD 20892 Telephone: (301) 496-1586 *This program is described in the Catalog of Federal Domestic Assistance number 93.837, Heart and Vascular Diseases. Awards will be made under the authority of the Public Health Services Act, Section 301 (42 USC 241) and administered under PHS grant policies and Federal regulations, most specifically 42 CFR Part 52 and 45 CFR Part 74. This program is not subject to the intergovernmental review requirements of Executive Order 12372, or to Health CLINICAL TRIAL PLANNING GRANT FOR DIGESTIVE AND NUTRITIONAL DISEASES RFA AVAILABLE: DK-91-02 P.T. 34; K.W. 0755015, 0715085, 0715135, 0710095 National Institute of Diabetes and Digestive and Kidney Diseases Application Receipt Date: January 22, 1991 PURPOSE The Division of Digestive Diseases and Nutrition of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) invites applications for Planning Grants (R21) to support the development of single center or multicenter clinical trials in digestive and nutritional diseases. Areas of particular importance include obesity, inflammatory bowel disease, irritable bowel syndrome, helicobacter pylori, primary biliary cirrhosis, and sclerosing cholangitis. It is anticipated that three planning grant awards will be made. BACKGROUND Recent advances in basic biomedical research have provided new insights into the pathogenesis of many nutritional and digestive diseases. These advances have led to new possibilities for therapeutic intervention in these diseases. New therapies or interventions are best evaluated in prospective, randomized controlled clinical trials. However, the planning, design, conduct, and analysis of clinical trials are difficult. Each step in the process requires major commitment of effort and time, financial support, and multidisciplinary expertise. As a consequence, opportunities can be lost to identify and rigorously evaluate important new therapeutic possibilities. In the area of digestive diseases and nutrition there are several diseases or conditions that warrant studies of new therapeutic interventions. Digestive and nutritional diseases or conditions of importance for which there are currently no satisfactory long-term therapies include severe obesity, inflammatory bowel disease, irritable bowel syndrome, primary biliary cirrhosis, and sclerosing cholangitis. These are important conditions that affect many Americans and cause considerable morbidity and mortality. Primary biliary cirrhosis, for example, is an autoimmune disease of the liver that largely affects women and leads slowly but inexorably to cirrhosis and death from liver failure. Primary biliary cirrhosis is the leading single indication for liver transplantation in adults. Despite these features, there is currently no therapy of proven benefit for primary biliary cirrhosis. In recent years, several small clinical trials in primary biliary cirrhosis have reported some benefit of several agents including ursodeoxycholic acid, chlorambucil, cyclosporine A, methotrexate, prednisone, and colchicine. While results from several of these studies have been promising, they have not been convincing enough to provide firm guidance for therapy of patients with this important disease. It is obvious, however, that one or several of these agents could be adequately evaluated in a proper, large, multicenter randomized controlled trial. Clinical Trial Planning Grants have been designed to aid investigators in designing clinical trials in important areas of digestive and nutritional diseases. These Planning Grants will support the development of a clinical trial research plan. This grant also provides a means for early peer review of the rationale and need for the trial. OBJECTIVES AND SCOPE The overall goal of this Request for Applications (RFA) is to encourage experienced clinical investigators in digestive and nutritional diseases to undertake prospective, randomized, controlled, single-center or multicenter trials in the treatment of digestive and nutritional diseases. The NIDDK Clinical Trial Planning Grant has been designed to help support the extensive planning that should precede any well-designed single-center or multicenter clinical trial. The grant provides a mechanism for early peer review of the rationale and need for the trial as well as support for the development of a detailed Manual of Procedures. In addition, a limited number of patients can be recruited to test the operational aspects of the trial. It is expected that this Planning Grant RFA will be followed by a program announcement within twelve months from the funding of grants in response to this initial RFA, for applications to perform single-center or multicenter clinical trials. Applications in response to this latter announcement will be required to provide detailed information regarding the rationale, experimental design, protocols and procedures, analytical techniques, facilities and environment, adequacy of the proposed administrative procedures, and collaborative arrangements for the trial. A well documented Manual of Procedures will also need to be part of the latter submission. The actual funding of a single-center or multicenter clinical trial will be contingent on the excellence and feasibility of the proposed trial, programmatic needs, and on the availability of designated funds. PREPARATION OF THE APPLICATION General instructions for the preparation of applications contained in Grant Application Form PHS 398 (Revised 10/88) are to be used in preparing Planning Grant (R21) applications. Item 2 should state "RFA # DK-91-02 Clinical Trial Planning Grant for Digestive and Nutritional Diseases." Applicants from institutions that have a General Clinical Research Center (GCRC) funded by the NIH National Center for Research Resources may wish to identify the GCRC as a resource for conducting the proposed research. In such a case, a letter of agreement from either the GCRC program director or principal investigator should be included with the application. ELIGIBILITY REQUIREMENTS All applicants must be qualified nutritionists, gastroenterologists, hepatologists, or surgeons, with the demonstrated ability to recruit adequate numbers of patients. Applicants for a Planning Grant for a multicenter clinical trial must have demonstrated expertise in the many complex features of conducting a multicenter study. If participating centers are proposed, they must have an adequate patient load and demonstrate ability to adhere to clinical trial protocols and procedures. All applicants are responsible for obtaining and maintaining the appropriate Investigational New Drug Application from the Food and Drug Administration and the appropriate assurance and certification from their Institutional Review Boards on Human Subjects. Only costs that are not usual costs for the normal care of patients entered in the trial may be requested as research costs to the grant application. The NIH places special emphasis on the need for inclusion of minorities and women in studies of diseases which disproportionately affect them and also requires that applicants give added attention, where feasible and appropriate, to their inclusion in other clinical studies. For proposed population-based studies that include neither women nor minorities, a clear rationale for not including them must be provided. In attempting to include either group in a particular study, attention must be paid to such issues as research design and sample size. TERMS OF THE AWARD Applications for single-center or multicenter clinical trial Planning Grants should request up to 1 year duration and a maximum of $50,000 in direct cost. Three Planning Grants may be awarded. Funding decisions will be based in part on relative merit recommendation of the IRG and in part on programmatic needs as determined by the National Diabetes and Digestive and Kidney Diseases Advisory Council and by the staff of the Division of Digestive Diseases and Nutrition. The award of applications submitted in response to this RFA is contingent on the actual availability of funds and receipt of applications deemed worthy of support by the accepted NIH peer review process. REVIEW PROCEDURES All applications submitted in response to this RFA will be evaluated for scientific and technical merit by an initial review group convened for this purpose by the Division of Extramural Activities, NIDDK. REVIEW CRITERIA In evaluating a Clinical Trial Planning Grant Application, the Initial Review Group (IRG) will consider the criteria outlined below. The greatest weight will be given to Items I, IV and V. I.Rationale A. Clinical importance of the disease or condition being studied. B. Rationale for therapy being applied. C. Ethical considerations of treatment. II.Experimental Design A. Merit of the study design. B. Appropriateness of intervention groups. C. Plans to minimize bias through randomization, statification, choice of controls, and masking of treatment or results. D. Identification of appropriate primary and secondary outcomes for the tri E. Recognition of possible problems inherent in the design and the adequacy of plans for dealing with them. III. Experimental Procedures and Plans for Patient Participation A. Quality of plans (even if broadly described) for recruitment and retention of patients, identification of eligibility and exclusion criteria, and standardization and maintenance of quality control among participating centers. B. Patient protection, including informed consent and monitoring data for safety and efficacy. Plans for early termination if it becomes necessary. C. Documentation of potential availability of patients at each of the participating centers. D. Plans for the preparation of a Manual of Procedures that must be submitted with any future application for actual conduct of the randomized controlled trials. IV. Plans for Data Analysis A. Rationale and validity of sample size. B. General methods to be used for data analyses. V. Planned Preliminary Studies A. Suitability for providing the necessary supporting data. B. Feasibility particularly in conducting preliminary studies. C. Provisions not made for needed preliminary information. VI. Investigators A. Professional credentials of the organizers indicating experience in such areas as: 1. The problem under study 2. Clinical trial administration 3. Methodology 4. Adequate and similar patient recruitment potential of participants 5. The proposed procedures. B. Professional credentials of the participating center investigators in the clinical problem and in clinical trial participation. Verification of the cooperating investigators and their institutions should be included. VII. Budget The budget should be itemized on page 4 and justified on page 5 of the application. The total direct cost budget may not exceed $50,000 and may not exceed a 12-month period. Examples of typical use of these funds include: A. Travel expenses of personnel assisting in preparation of the Manual of Procedures B. Secretarial assistance C. Consultant fees D. Preliminary studies to refine trial procedures, document recruitment potential, etc. E. Office supplies F. Communication expenses. METHOD OF APPLYING The regular research grant application form PHS-398 (revised 10/88) must be used. The RFA label available in the application kit must be affixed to the bottom of the face page. Failure to use this label could result in delayed processing of your application. There will be a single receipt date of January 22, 1991. Applications received after that date will be returned. Earliest possible funding will be December 1991. Submit a signed, typewritten original of the application, including the Checklist and four (4) signed, exact photocopies, in one package to: DIVISION OF RESEARCH GRANTS National Institutes of Health Westwood Building, Room 240 Bethesda MD 20892** IMPORTANT: At time of submission, two (2) additional copies of the application should be sent under separate cover to: CHIEF, REVIEW BRANCH Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases Room 406, Westwood Building Bethesda MD 20892 Applications must be received by January 22, 1991. If an application is received after that date, it will not be accepted and will be returned. Potential applicants should write or phone the individual listed below for the full RFA document. Tommie S. Tralka Director, Clinical Trials Program Division of Digestive Diseases and Nutrition Westwood Bldg., Rm 3A-15 5333 Westbard Ave. Bethesda, MD 20892 Telephone: (301) 496-9717 This program is described in the Catalog of Federal Domestic Assistance No. 93,848, Digestive Diseases and Nutrition. Awards will be made under the authority of the Public Health Service Act, Title III, Section 301 (Public Law 78-410, as amended; 42 USC 241) and administered under PHS grant policies and Federal Regulations 42 CFR Part 52 and CFR Part 74. This program is not subject to the intergovernmental review requirements Brought to you by Super Global Mega Corp .com