Full Text HL-95-012 LUNG SPECIFIC DRUG DELIVERY SYSTEMS FOR TUBERCULOSIS TREATMENT NIH GUIDE, Volume 24, Number 1, January 13, 1995 RFA: HL-95-012 P.T. 34 Keywords: Pulmonary Diseases 0740022 Microbiology National Heart, Lung, and Blood Institute Letter of Intent Receipt Date: February 24, 1995 Application Receipt Date: April 7, 1995 PURPOSE The National Heart, Lung, and Blood Institute (NHLBI) invites grant applications to encourage research on novel approaches to therapy, adjuvants to therapy, and prophylaxis of tuberculosis (TB), using the lung as the site of drug delivery. The primary objective of this special grant program is to develop new modalities of treatment for pulmonary TB based on delivery of the therapeutic agent(s) directly to the lung. HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," a PHS-led national activity for setting priority areas. This Request for Applications (RFA), Lung Specific Drug Delivery Systems for Enhanced TB Treatment, is related to the priority area of immunization and infectious diseases. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0) or "Healthy People 2000" (Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202-783-3238). ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign for-profit and non-profit institutions, public and private, such as universities, colleges, hospitals, laboratories, units of state and local governments and eligible agencies of the Federal government. Foreign institutions are not eligible for the First Independent Research Support and Transition (FIRST) award (R29). Applications from minority individuals women and new investigators are encouraged. All current policies and requirements that govern the research grant programs of the NIH will apply to grants awarded under this RFA. Awards under this announcement to foreign institutions will be made only for research of very unusual merit, need, and promise, and in accordance with Public Health Service policy governing such awards. Among the disciplines and expertise that may be appropriate for this research program are molecular pharmacology, physical chemistry, cell biology, biochemistry, virology, molecular biology, molecular immunology, infectious diseases, pathology, and pulmonary medicine. MECHANISM OF SUPPORT The support mechanism for this program will be the National Institutes of Health (NIH), individual research grant (R01) and the FIRST award (R29). While multidisciplinary approaches are encouraged, it is not the intent of this announcement to solicit applications for large studies encompassing a variety of individual subprojects, i.e., program projects. If collaborative arrangements through subcontracts with other institutions are planned, consult the program staff listed under INQUIRIES. Upon initiation of the program, the NHLBI will sponsor periodic meetings to encourage exchange of information among investigators who participate in this program. In the budget for the grant application, applicants should request travel funds for a one-day meeting each year, most likely to be held in Bethesda, Maryland. 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 expected to furnish their own estimates of time required to achieve the objectives of the proposed research project. Up to five years of support may be requested for R01s; five years are required for FIRST awards. Requested budgets for FIRST awards may not exceed those specified in the FIRST award guidelines. Because a variety of approaches would represent valid responses to this RFA, it is anticipated that there will be a range of costs among individual grants awarded. This RFA is a one-time solicitation. Future unsolicited competing continuation applications may be submitted for peer review and competition for support through the regular grant program of the NIH. It is anticipated that support for this program will begin in September 1995. Administrative adjustments in project period and/or amount may be required at the time of the award. 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. If so, a letter of agreement from the GCRC program director and principal investigator should be included with the application. The National Institute of Allergy and Infectious Diseases (NIAID) also has interest in developing new delivery systems and new therapeutic agents for the treatment of tuberculosis. Therefore, applications that are of mutual interest are likely to be given a secondary assignment to NIAID in accordance with the NIH referral guidelines. FUNDS AVAILABLE Although financial plans for fiscal year 1995 include approximately $2,500,000 for the total cost of the program for the first year, award of grants pursuant to this RFA is contingent upon receipt of funds for this purpose. It is anticipated that no more than 10 awards will be issued under this program. The specific number to be funded will, however, depend on the merit and scope of the applications received and the availability of funds. RESEARCH OBJECTIVES Background The spread of tuberculosis (TB) has reemerged as an urgent health problem. Rates for this disease have been increasing since the mid 1980s in association with the HIV epidemic. Recent projections of TB rates made by the Centers for Disease Control suggest that, worldwide, the current high rate of new TB cases in the population is likely to increase over the next 10 years. For industrialized countries, including the United States TB case rates are expected to remain stable or perhaps increase slightly over the next decade. The number of new active cases of TB reported annually in the U.S. population is now approximately 10/100,000 (new cases/100,000 people in the general population), with extremely high rates in HIV infected study populations, about 800/100,000. Current methods of treatment are far from optimal and better ones are being sought to overcome the increasing spread of TB and the problem of incompletely treated TB that contributes to the emergence of drug resistant strains. Since many patients with TB may have significant social problems, compliance with drug therapy is frequently difficult. The development of targeted drug delivery to the lungs as a means of treating TB is desirable for several reasons. Although TB is a systemic disease that can potentially affect any organ system, the lung is the major portal of entry for Mycobacterium tuberculosis (Mtb) and thereby the site of the initial immune response as well as an important site of reactivation disease. Technology for lung specific drug delivery systems is now at a point where aerosols and aerosols combined with liposomes and possibly timed-release methodology may offer advantages for more effective treatment and prevention of TB. Conventional antituberculous medications frequently have serious side effects. Although single drugs can be effective for prophylactic treatment of skin test converters, active disease must be treated using combinations of three or four drugs over a period of at least six to nine months to insure that disease will not recur after treatment is discontinued and to prevent the emergence of resistant strains. Targeted delivery of new formulations, directly to the lungs, could result in high pulmonary levels relative to systemic levels. Thus, increasing effectiveness and decreasing toxicity. Supplementing the dose of agent delivered to the diseased lung, when it is the only clinically involved organ, could make it possible to decrease the duration of treatment in these cases. Because the systemic dose will not be increased, undesirable toxicities would be avoided. Another advantage is that this mode of delivery might make it easier to provide prolonged treatment. It should be possible to design biopolymers or nanoparticles which slowly dissolve and therefore slowly release their drugs to the pulmonary environment. Improved targeted delivery approaches combined with development of new antituberculous drugs or with timed release formulations may reduce the frequency of dose delivery. This would be a major benefit in treating patients in whom it is hard to maintain effective compliance with treatment regimens. For example, longer intervals between treatment would make it easier to deliver directly observed therapy, which is an effective means of getting patients to complete a full course of treatment. Targeted drug delivery may be essential in carrying out future modes of TB therapy such as gene therapy resulting in increased cytokine expression or antisense oligonucleotide therapy blocking protein synthesis. Objectives and Scope The objective of this initiative is to encourage basic research aimed at developing new modalities of treatment for TB, using the lung as the site of drug delivery. Delivery of antituberculous agents to the lung might be used as a means of increasing local concentrations of drug to augment existing, conventional therapy or perhaps the lung could be used as the route of delivery for agents that are intended to work both locally and systemically. It is thought that lowered systemic toxicity provided by this approach would permit much more flexibility for treatment regimens such that smaller, more effective doses may be employed. Conversely, if a lung delivery system is intended as the only route for drug delivery, it would be essential to demonstrate that systemic levels of drug are adequate to treat TB elsewhere in the body. Drugs could be targeted to the lung as opposed to other organs, to airways of a specific size within the lungs, or perhaps to injured or diseased areas as compared to normal ones. Specific cells such as macrophages, endothelial cells, or epithelial cells might be targeted and it should even be possible to deliver drugs to specific organelles within a cell. Potential drug delivery sites could include the alveolar surface itself, or cells on the surface such as macrophages, lymphocytes, or neutrophils. Other targets might include cells and extracellular matrix beneath the epithelium. The nature of the material will affect its fate. For example, insoluble particulate material will largely be taken up by resident alveolar macrophages. Some surfactant phospholipids will be recycled into Type II epithelial cells. Soluble molecules will enter and pass through or between epithelial cells into the extracellular matrix. Some proteins will be found in phagocytic cells in the connective tissue and lymph nodes. Aerosol delivery of therapeutic agents to the lung has been used for many years in the treatment of airways obstructive diseases. Since the 1980s the aerosol application of interferon-alpha (INF-`) has been examined by several groups of investigators for the treatment of various types of lung cancer. Interferon-gamma has also been given to human subjects to activate alveolar macrophages. In general, it seems possible to deliver fairly high concentrations of these agents to the epithelial lung surface and minimize the systemic dose and toxicity. Drugs used in the treatment of TB including rifampin and streptomycin can be encapsulated in liposomes. Drugs such as these could be delivered to the lung in conjunction with antituberculous therapy (administered by mouth or parenterally) to augment therapy or given to replace conventional therapy, if adequate levels can be achieved in all parts of the body. Liposomal preparations of drugs or agents capable of potentiating immune responses may have enhanced uptake by lung cells. Furthermore, it appears to be possible to deliver liposomes by the aerosol route. Surfactant which may be useful as a vehicle for the delivery of other agents can be aerosolized and delivered to the lung. Research topics that could be applicable to the goals of this RFA might include, but are not limited to, the following areas: mechanisms of treatment, drug formulation issues, delivery strategies to get agents to the respiratory tract, targeting strategies to reach particular sites, evaluation of drug delivery and especially, evaluation of effectiveness of lung targeted drug delivery. These issues could be studied at a variety of levels including laboratory modeling animal testing, and human studies. Both animal studies and innovative studies involving human subjects or using human cells or tissues are encouraged. Research involving humans should be formulated in the context of mechanistic studies and should address specific hypotheses. Large scale clinical studies are beyond the scope of this RFA. Pharmacologic agents currently used in antituberculous regimens and agents that appear to show promise for future use are of interest. SPECIAL REQUIREMENTS Applications that propose descriptive studies and do not contain hypothesis driven studies directed at developing lung specific drug delivery systems to aid in the treatment of tuberculosis will not be acceptable. Treatment strategies must be clearly linked to the lung and to specific mechanisms of mycobacterial disease. This program will not support studies directed at development of animal models alone, therefore the models must be applied to the study of lung specific drug delivery strategies for use in the treatment of mycobacterial disease. This RFA is not intended to support in vitro studies of drug screening. Studies to verify that drug in an active state reaches the site intended for deposition should be included. Applications that focus on molecular pharmacologic approaches are of particular interest. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their subpopulations must be included in all NIH supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification is provided that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This new policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43) and supersedes and strengthens the previous policies (Concerning the Inclusion of Women in Study Populations, and Concerning the Inclusion of Minorities in Study Populations) which have been in effect since 1990. The new policy contains some new provisions that are substantially different from the 1990 policies. All investigators proposing research involving human subjects should read the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research", which have been published in the Federal Register of March 28, 1994 (FR 59 14508-14513), and reprinted in the NIH GUIDE FOR GRANTS AND CONTRACTS of March 18, 1994, Volume 23, Number 11. Investigators also may obtain copies of the policy from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. LETTER OF INTENT Prospective applicants are asked to submit, by February 24, 1995, a letter of intent that includes a descriptive title of the proposed research, the name, address, and telephone number of the Principal Investigator, the identities of other key personnel and participating institutions, and the number and title of the RFA in response to which the application may be submitted. Although a letter of intent is not required, is not binding, and does not enter into the review of subsequent applications, the information that it contains allows NIH staff to estimate the potential review workload and to avoid conflict of interest in the review. The letter of intent is to be sent to Dr. C. James Scheirer, at the address listed under INQUIRIES. APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 9/91) is to be used in applying for these grants. These forms are available at most institutional offices of sponsored research and from the Office of Grants Information, Division of Research Grants, National Institutes of Health, The Westwood Building, Room 449, Bethesda, MD 20892, telephone (301) 710-0267. Use the conventional format for research project grant applications and ensure the points identified in the section REVIEW CONSIDERATIONS are fulfilled. To identify the application as a response to this RFA, check "YES" on item 2a of page 1 of the application and enter the title "Lung Specific Drug Delivery Systems for Enhanced TB Treatment" HL-95-012. The RFA label found in 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 the application such that it may not reach the review committee in time for review. Send or deliver the completed application and three signed photocopies in one package to: Division of Research Grants National Institutes of Health Westwood Building, Room 240 Bethesda, MD 20892** Send two additional copies of the application to the Chief, Review Branch, DEA at the address listed under INQUIRIES. It is important to send these two copies at the same time as the original and three 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 April 7, 1995. If an application is received after this date, it will be returned to the applicant without review. The DRG will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. The DRG will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of substantial revisions of applications already reviewed, but such applications must include an introduction addressing the previous critique. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by the DRG and responsiveness to this RFA by the NHLBI. Incomplete applications will be returned without further consideration. If the application is not responsive to the RFA, DRG staff may contact the applicant to determine whether to return the application to the applicant or submit it for review in competition with unsolicited applications at the next review cycle. 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 accordance with the review criteria stated below. As part of the initial merit review, a process (triage) may be used by the initial review group in which applications will be determined to be competitive or non-competitive based on their scientific merit relative to other applications received in response to the RFA. Applications judged to be competitive will be discussed and be assigned a priority score. Applications determined to be non- competitive will be withdrawn from further consideration and the Principal Investigator and the official signing for the applicant organization will be notified. Review Criteria. The factors to be considered in the evaluation of scientific merit of each application will be similar to those used in the review of traditional research project grant applications including the novelty, originality, and feasibility of the approach; the training, experience, and research competence of the investigator(s); the adequacy of the experimental design; the suitability of the facilities; the appropriateness of the requested budget to the work proposed and the adequacy of plans to include both genders and minorities and their subgroups as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. The initial review group will also examine the provisions for the protection of human and animal subjects and the safety of the research environment. AWARD CRITERIA The anticipated date of award is September 29, 1995. In addition to the scientific merit of the applications, awards will be based on responsiveness to the RFA and the availability of resources. INQUIRIES Inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Hannah H. Peavy, M.D. Division of Lung Diseases National Heart, Lung, and Blood Institute Westwood Building, Room 6A09 Bethesda, MD 20892 Telephone: (301) 594-7425 FAX: (301) 594-7487 Email: hpv%nihhwb1.bitnet@cu.nih.gov Direct inquiries regarding review matters to: C. James Scheirer, Ph.D. Division of Extramural Activities National Heart, Lung, and Blood Institute Westwood Building, Room 557 Bethesda, MD 20892 Telephone: (301) 594-7478 FAX: (301) 594-7407 Email: james_scheirer%nihhwb1.bitnet@cu.nih.gov Direct inquiries regarding fiscal matters to: Raymond L. Zimmerman Division of Extramural Affairs National Heart, Lung, and Blood Institute Westwood Building, Room 4A17 Bethesda, MD 20892 Telephone: (301) 594-7420 FAX: (301) 594-7492 Email: raymond_zimmerman%nihhwb1.bitnet@cu.nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance, No. 93.838. Awards are made under authorization of the Public Health Service Act, Title IV, Part A (Public Law 78-410, amended by Public Law 99-158, 42 USC 241 and 285) and administered under PHS grants policies and Federal Regulations 42 CFR 52 and 45 CFR Part 74. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or to review by a Health Systems Agency. The Public Health Service (PHS) strongly encourages all grant recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people. .
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