INTERDISCIPLINARY RESEARCH TEAMS FOR MOLECULAR TARGET ASSESSMENT Release Date: November 10, 1999 RFA: CA-00-001 National Cancer Institute Letter of Intent Receipt Date: February 1, 2000 Application Receipt Date: March 15, 2000 PURPOSE The purpose of this initiative is to discover, develop and validate the research tools that will make mechanism assessment in clinical trials and preclinical cancer models a reality. Preclinical and clinical research with novel agents for cancer treatment and prevention requires usable tools to determine that the intended molecular target has been affected by the agent. This initiative's major objective is the development of methods to assess the effects of interventions directed at specific molecular targets that produce the cancer phenotype or are associated with it. We seek molecular assays, molecular and cellular imaging probes, and other tools that provide information on the extent to which molecular targets are affected in vivo by interventions in preclinical models and in proof-of-principle early clinical trials. This Request for Applications (RFA) invites investigators to form Interdisciplinary Research Teams. These Teams should include investigators with expertise in critical biological processes that encompass high-priority targets for cancer treatment or prevention; in chemistry; in molecular and cellular imaging science and technology; in invasive and/or non-invasive evaluation of the molecular effects of drugs; in preclinical models; and in early clinical trials. A Team may have investigators from several institutions; these may include the intramural programs of the NIH. Teams may focus on more than one target and may utilize agents originating from any source (industrial, academic and government). For whatever targets it selects, each Team will advance knowledge of the pertinent biology, defining what events are most likely to be informative in the context of this initiative's goals, and focus on the development of relevant and practical assays, probes, and other tools to assess the effects of drugs on that target class in vivo. These Teams will define the molecular basis for these research tools and develop and validate novel biochemical, pathological, pharmacologic, immunologic, molecular, or imaging methods and reagents to measure the effect of new target-directed drugs in proof-of-principle laboratory models and clinical trials. These methods and reagents must, therefore, be suitable for in vivo use in animal models and in human beings. Examples of target areas include, but are not limited to, angiogenesis, invasion and metastases, and other microenvironmental processes; signal transduction; cell-cycle control; apoptosis; immune effectors; antimutagenesis (e.g. reverse mutations at specifically mutated gene targets) and antioxidant response elements. Public Briefing Date: November 17, 1999 An initial informational session for those investigators planning to submit applications in response to this RFA will be held on Wednesday, November 17, 1999 from 7:00 AM to 8:30 AM at the Washington Hilton, Jefferson West Room, Washington DC. Representatives from the NCI's extramural research programs, Grants Administration Branch, and Division of Extramural Activities will be available to provide information and to answer questions relevant to applications responding to this RFA. Investigators who are unable to attend should request transcripts. Investigators who want transcripts or plan to attend should contact the IDB administrator for the NCI program staff member listed under INQUIRIES by November 15, 1999 to confirm their attendance (or request a transcript) and to obtain further information regarding the meeting site. 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 RFA, Interdisciplinary Research Teams for Molecular Target Assessment, is related to the priority area of cancer prevention and treatment. Potential applicants may obtain a copy of "Healthy People 2000" at http://odphp.osophs.dhhs.gov/pubs/hp2000. ELIGIBILITY REQUIREMENTS Applications may be submitted by for-profit and non-profit organizations, public and private, U.S. and foreign, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal government. Racial/ethnic minority individuals, persons with disabilities, and women are encouraged to apply as Principal Investigators. In order to be considered for review, an application for a U54 must have three or more related, interactive research projects that provide an interdisciplinary, yet thematic, approach to the problems to be investigated. Applications will not be accepted that include research activities focused exclusively on clinical research or exclusively on basic research, or that include epidemiological or large-scale clinical trials. MECHANISM OF SUPPORT This RFA will use the National Institutes of Health (NIH) cooperative specialized center (U54) award mechanism. The U54 mechanism may support any part of a full range of research development from very basic to clinical. The U54 is a cooperative agreement, an assistance mechanism (rather than an acquisition mechanism) in which substantial NIH scientific and/or programmatic involvement with the awardee is anticipated during the performance of the activities. Under a cooperative agreement, the NIH's purpose is to support and stimulate the recipient's activities by involvement in and otherwise working jointly with the award recipient in a partner role. NIH staff work cooperatively with the award recipients in a partner role and do not assume direction, prime responsibility, or a dominant role in the activity. Details of the responsibilities, relationships, and governance of the activities to be funded under the cooperative agreements awarded for this Program are discussed below under "Terms and Conditions of Award." The total project period for an application submitted in response to this RFA may not exceed five years. The anticipated award date is December 1, 2000. This RFA is a one-time solicitation. At this time the NCI has not determined whether or how this solicitation will be continued beyond the present RFA. If it is determined that there is a continuing program need, the NCI will either invite recipients of awards under this RFA to submit competitive continuation cooperative agreement applications for review or re-issue the RFA for re-competition. If the NCI does not continue the program, awardees will be able to submit grant applications through existing investigator- initiated grant programs. FUNDS AVAILABLE It is anticipated that an estimated total of $6.3 million (including direct costs and costs for facilities and administration) will be available for the first year of the program, which will support approximately 6-8 Teams, although the actual funding plan will depend upon the scientific opportunities presented and are contingent upon the availability of funds and the receipt of a sufficient number of applications of outstanding scientific and technical merit. An applicant may request a project period of up to five years. Because the nature and scope of the proposed research will vary, it is anticipated that the sizes of the awards will also vary. RESEARCH OBJECTIVES Background The discovery of putative molecular targets and their exploitation in cancer drug discovery present clinical researchers with striking opportunities, as well as some difficult challenges. In brief, how are these targets and agents directed at them to be validated? What does target-based drug discovery imply for the clinical trials methodology of the future? Will it change the nature of endpoints for Phase I and Phase II trials or for deciding how much drug is enough for individual patients? Three basic principles underlie the present initiative: 1. Since the purpose of drug discovery is to develop effective and selective agents for the prevention and treatment of cancer in people, then ultimate validation of a target can occur only in the clinic. 2. Clinical trials of agents emanating from a target-based drug discovery process should focus on endpoints that assess whether the drug has affected its putative target. 3. To make such trials possible, we must develop informative assays, tools, reporter cassettes, probes suitable for molecular and cellular imaging, and other tools that will reveal an agent's effect on its target and that are practical for use in the clinic. What is needed is the ability to assess in vivo the molecular and cellular pharmacology effects of drug on its target, or on pathways regulated by the target, and correlate these observations with the clinical effects of drug administration. These correlations, or the absence of them, will have important implications for judging the validity of the target and for optimizing drug administration regimens. The need to assess target effects is made even more urgent by new classes of agents (for example, drugs that interfere with metastasis or angiogenesis) that may exert effects on cancer, precancer, or high risk tissue that take a long time to become clinically apparent. For such classes of agents, assessment of target effects may provide badly needed surrogate endpoints of drug activity. Direct assessment of effects on molecular targets and the downstream consequences of drug- target interaction may, in fact, be the only practicable methods of deciding on appropriate doses and schedules for certain drug classes. Confirming that the hoped-for biologic effect is achieved, or assessing reasons for failure to achieve it, will be critical in proof-of-principle preclinical and clinical trials to avoid the expense and futility of carrying ineffective agents into full-scale clinical development. Thus the discovery, development, and validation of accurate and practical methods for assessing whether an agent has affected its target is a matter of the highest priority. The impressive progress of target identification and drug discovery efforts in academia and industry has clearly outpaced the development of practical research tools to provide informative molecular endpoints in preclinical and clinical research. The development of clinically useful probes for the molecular effects of drug administration, whether these are assessed by analyses of body fluids or tissue specimens in the laboratory, by non-invasive in vivo imaging, or by other techniques, will require interdisciplinary research teams with broad expertise covering many areas of science and technology. This initiative is intended to provide the critical translational bridge between drug discovery and clinical trials by supporting highly interdisciplinary teams, each oriented toward biological mechanisms that seem highly relevant to cancer biology and currently constitute high-priority targets for drug discovery. As an example, a number of methods have been proposed for in vivo assessment of the effect of angiogenesis inhibitors. These have included 1) dynamic MR or Doppler ultrasound imaging studies to measure alterations in blood flow; 2) biopsy specimens to assay apoptosis in malignant and endothelial cells; and 3) bioassays to assess plasma effects in ex vivo models of angiogenesis. These have not been studied systematically in the pre-clinical efficacy models that are being used to provide evidence supporting the further development of agents with a putative anti-angiogenic mechanism. Informative and efficient clinical evaluation of this class of agents will surely require in vivo measures of the extent to which the agents are affecting their putative targets. Moreover, the appropriate endpoint of drug effect may depend not only on the class of agent (e.g., angiogenesis inhibitor) but on the specific molecular target that the agent interacts with (e.g., VEGF-R). Thus the development of research tools suitable for clinical use is likely to be scientifically and technically challenging. Interdisciplinary Research Teams (Teams) are expected to address directly the translational links between target-based drug discovery and mechanism-based clinical testing. They will focus on discovering, assessing, and validating clinically usable assays, probes, and other tools to make this connection a reality. The intent is to develop research tools that will, directly and indirectly, revolutionize all stages of research relating to the development of drugs to treat or prevent cancer. NCI expects that these Teams will serve as important resources to other investigators developing new agents. For example, they are likely to collaborate with others by making the results of their research - information, reagents, and techniques - available to other institutions. They will also provide training to enable other investigators to implement newly developed tools and technologies at their own sites. The Teams are expected to have productive interactions with many other groups in academia, industry, and government. The expertise in the Teams should make them very attractive collaborators for industry and academic researchers involved in target discovery and validation and in early clinical trials. They will also work closely with the staff of several NCI programs (Developmental Therapeutics Program, Cancer Therapy Evaluation Program, Diagnostic Imaging Program, Cancer Diagnosis Program and the Chemoprevention Program). Related NCI Initiatives The following Web sites present detailed information on other related NCI initiatives in drug discovery for treatment and prevention of cancer, clinical trials, and imaging programs that may interact with a proposed Team: Molecular Targeted Drug Discovery Grants. The output of this initiative will be a spectrum of new agents. The preclinical development of these agents will require suitable assays and probes to assess how targets are affected in pre clinical models and in the clinic. The Teams are logical collaborators with drug discovery groups in this endeavor (https://grants.nih.gov/grants/guide) The National Cooperative Drug Discovery Groups (NCDDG). (https://grants.nih.gov/grants/guide/rfa-files/RFA-CA-99-010.html). The Rapid Access to Intervention Development (RAID) program focuses on the pre-clinical development of anti-cancer drugs and biologics. Modifications of RAID that would provide support for production of diagnostic probes for research purposes are under consideration. (http://dtp.nci.nih.gov) In vivo Cellular and Molecular Imaging Centers. These centers for functional imaging may provide collaborative resources for Team efforts. (https://grants.nih.gov/grants/guide/rfa-files/RFA-CA-99-004.html) Small-Animal Imaging Resource Program. These may be an important resource for Teams funded in this initiative, since they will provide access to specialized resources and expertise. RFA for imaging in therapeutic studies (https://grants.nih.gov/grants/guide/rfa-files/RFA-CA-98-023.html) QuickTrials for Prostate Cancer Therapy (currently pilot testing in prostate cancer). (https://grants.nih.gov/grants/guide/pa-files/PA-99-070.html) Grants submitted to the Clinical Oncology SEP (http://www.drg.nih.gov/Review/irgdesc.asp#CONC) Early Therapeutics Development Cooperative Agreements/Contracts (Phase I and Phase II). These contracts will include provisions for the support of correlative and mechanistic study components of early clinical trials. (http://ctep.cancer.gov) SPORES. (http://spores.nci.nih.gov/) Cancer Diagnosis Program What's New (http://www-cdp.ims.nci.nih.gov) Related initiatives in cancer prevention include: Contract-based chemoprevention drug development program (http://dcp.nci.nih.gov/CB/#MAA) Rapid Access to Preventive Intervention Development (RAPID) (http://dcp.nci.nih.gov/CB/rapid.htm) Chemopreventive agent drug discovery grants http://www.nci.nih.gov/dcb/cpcb.htm) Prostate, Lung, Colon and Ovary (PLCO) trial (http://dcp.nci.nih.gov/PLCO/) Chemoprevention in high risk genetic cohorts (https://grants.nih.gov/grants/guide/rfa-files/RFA-CA-98-012.html) Early Detection Research Network (EDRN) (http://dcp.nci.nih.gov/cbrg/edrn.html) Pivotal Clinical Trials for Chemoprevention Agent Development (https://grants.nih.gov/grants/guide/rfa-files/RFA-CA-98-001.html) EDRN Biomarker validation laboratories (https://grants.nih.gov/grants/guide/rfa-files/RFA-CA-99-008.html) Objectives The central objective of the Teams supported by this initiative the Teams will be to discover, develop, and validate clinically practical tools and methodologies for assessing the effect of molecularly targeted agents against their putative targets. Some of the essential steps in this process will include the following: 1. Selecting one or more cancer-relevant targets or pathways for which agents are under development and will be available for evaluation 2. Establishing effective collaborations to enhance the synergy of the proposed Team and leverage other available resources 3. Identifying how agents directed at high-priority targets affect molecular/cell biology/cellular pharmacology endpoints and develop practical ways of assaying these effects in clinical settings. Activities that a Team may choose to undertake to achieve the translational goals of this research may include, but are not limited to, some or all of the following: a. Invasive techniques that require acquisition of relevant cells (e.g., from cancers, preinvasive neoplastic lesions, or fields at risk for cancer) by biopsy, aspiration or plasmapheresis: this material can then be evaluated by a variety of molecular and/or immunohistochemical approaches to determine whether the targeted pathway has been affected. b. Invasive techniques that require temporary placement of catheters (e.g. microdialysis) c. Techniques for imaging molecular and cellular processes: examples include MRI, positron emission tomography(PET) or other techniques based on radiotracers, or ultrasound or optical imaging. d. Non-invasive techniques that utilize reporter cassettes for genetic manipulations that can provide additional imaging options 4. Evaluating and validating the assays, probes, and other techniques it develops in in vivo preclinical models, for assessing such matters as target inhibition, inhibition of biochemical processes downstream from the target; the effect of pharmacokinetics on pharmacodynamics and the establishment of exposure-effect relationships; and the establishment of dose/schedule combinations suitable for clinical trials. 5. Evaluating and validating the tools and methodologies in proof-of- principle early clinical trials of molecularly targeted agents in patients with malignancies, premalignant conditions, or cancer risk factors (genetic, infectious or environmental), as appropriate. Effective collaboration of laboratory and clinical scientists is critical for the success of these translational efforts. Depending on the chosen target/process and the availability of agents, clinical trials may not be feasible in the initial funding year, but the NCI anticipates that expeditious progress will permit Teams to initiate proof-of-principle clinical research by the third year of funding. 6. Exploring new scientific insights into drug mechanisms and determinants of response 7. Exploring new approaches to early clinical trials methodology; for example, the use of alternate trial designs and endpoints, or exploring designs based on molecular classifications of tumor rather than histology 8. Willingness to share information via publications, meetings and support of training activities and to disseminate new reagents and techniques discovered under this initiative to other investigators. When dissemination of attractive new reagents to other research groups seems desirable, the NCI will facilitate this by providing additional support to the originating laboratory. Team investigators are expected to participate in NCI-sponsored working groups focused on high-priority targets. Awardees are encouraged to file patent applications in a timely manner in order to permit timely presentation and publication of results. Scope This RFA invites investigators to form interdisciplinary Teams with expertise in the several scientific and technical areas mentioned previously, and elaborated upon below, that are critical to the success of this initiative. The Principal Investigator may draw innovative expertise from wherever it may exist; investigators need not be limited to a single institution. Collaborating investigators may be from academic, industrial, or government institutions (including NIH intramural scientists and non-US sites). In their plans to evaluate novel research tools, investigators may incorporate new molecularly targeted agents for treatment or prevention originating from any source (in-house, other academic, industry, NCI). This RFA, however, does not provide support/funding for synthesis/production of therapeutic agents, . See "Related NCI Initiatives" for a list of available initiatives that support agent synthesis/production. The following is a list of specific research topic areas relevant to treatment or prevention of cancer that are considered to be responsive to this RFA. Additionally, these topics identify areas where research at the basic/clinical interface is deemed essential to the potential development of new agents: o Signal transduction o Angiogenesis o Invasion and metastases o Cell-cycle control o Apoptosis o Immune effectors o Antimutagenesis at specific mutated genes o Antioxidation response elements This list is not meant to be all-inclusive and prospective applicants are encouraged to discuss program relevance issues with program staff cited under INQUIRIES. The specific membership and structure of each Team will be determined by the research plans of the applicant. Although the relevant components will be determined by the selected target(s), NCI expects that innovative approaches to most target classes may entail inclusion of diverse expertise including some or all of the following: o Basic biology pertaining to the target (molecular, cellular, immunologic, biochemical expertise related to the selected target/pathways/mechanisms) o Synthetic chemistry (for congeners, labeled agents or novel vectors) and/or radiochemistry (for agents suitable for imaging) o In vivo models suitable for assessment of the relevant target effects. The capacity to select and carry out this research effectively should be supported by the clarity of the plans or the track record as evidenced by publications or peer-reviewed recognition (funding) for in vivo pharmacodynamic studies or specific studies in therapy or prevention on the part of the proposed project/core leader. o Pharmacokinetics and pharmacodynamics (expertise in designing sampling strategies, assays using appropriate analytic techniques, quality assurance and data analysis); o Early clinical trials of investigational agents with invasive and non- invasive correlative studies: although it is likely that for most targets, clinical research will not be feasible early in the period of support, NCI hopes that the Team will make enough progress to initiate clinical research by the third year of funding; experience in the daily management and treatment of patients with various malignant tumors; experience with persons at risk for invasive cancer; assessment of eligibility/evaluability of these subjects in clinical trials; experience in recruiting, obtaining informed consent and evaluating subjects receiving investigational agents; commitment to investing intellectual effort with basic science colleagues focused on novel molecular targets. Access to a patient care and service facility that serves a substantial cancer patient population and, if the facility is not part of the parent institution, documentation of a consortium agreement with an associated institution that assures adequate access to cancer patients for clinical research o Prevention and treatment: for agents/targets suitable for chemoprevention development o Molecular and cellular imaging (small animal and human): ability to perform investigational imaging (possibly with novel imaging agents) for research purposes and to evaluate study results with other measures of drug effect and/or treatment outcome o Interventional radiology (for identification of suitable patients and sample acquisition; ability to obtain tissue and radiologic evaluations for research purposes) o Pathology and molecular analysis of tissues: expertise in a variety of techniques for analysis of target relevant alterations in human tissues o Enhanced topical/endoscopic imaging for preinvasive neoplasia Organizational Structure In order to provide the greatest flexibility for organizing research efforts in these cooperative agreements, the PI should organize the investigators and resources into the following required elements: 1. Research Projects Each Team application must provide details for at least three Research Projects, which together represent experimental approaches to the discovery and/or development of assays, probes, and other tools suitable for use in preclinical models and clinical research. In addition, Research Projects may conduct research on the biologic and pharmacodynamic aspects of target interactions, to enable assessment of how agents affect the target. All of the Research Projects must be related to one or more specific molecular targets for anticancer agents. Research Projects should not focus on developing molecular assessment tools for agents that are already approved for clinical use. Teams should plan to continually select the most promising research approaches that are likely to have impact on the development of clinically useful probes. The flexibility of the Team is intended to promote the discontinuance of research projects demonstrating little or no translational significance and to promote initiation of new projects with greater potential. 2. Core Services The Team is encouraged to develop and maintain core resources that are essential for the conduct of this research. Core Services may include resources that may already be available at the institution and do not need further development/research. Examples of potential Core Services include animal cores, imaging resources, pharmacology, pathology, clinical data monitoring services, and statistical support. An Administrative Core is required and is responsible for administrative management and coordination of meetings and other activities within the Team and with other potential collaborators such as industry and NCI and other funded Teams. By definition, the Principal Investigator of the Team also serves as the Principal Investigator of the Administrative Core. The administrative core may encompass the other service cores, or, if they are separately organized, each service core must provide resources to at least two Research Projects and/or Pilot Projects. 3. Pilot (Developmental) Projects Every Team must allocate a significant effort to support pilot projects that take maximum advantage of new research opportunities. Such projects may be collaborative among scientists within one or more Teams, or with scientists outside the Team. If a clinical trial is not described as one of the Research Projects, at least one Pilot Project should outline the general plan for a (future) clinical trial that incorporates the methodologies, techniques, and probes to be developed in the research projects, along with a mechanism-specific novel agent. Each application should propose an institutional review process for selecting pilot projects for funding that generate feasibility data and have the most promising translational research potential. These funds are intended to remain flexible and to support studies of a limited duration, e.g., two years or less. The expectation is that successful feasibility studies will replace full projects that are not progressing satisfactorily with regard to translational research objectives within the Team. The team of scientists that participates in the Team may, therefore, change through the course of the research. Framing experiments as pilot projects permits maximal flexibility to proceed in the directions that seem most scientifically fruitful to the investigators. It is expected that individual pilot projects would have small budgets since the majority of the personnel and equipment involved may be supported by the Research Projects and Cores and funds would only be needed for supplies, animals, etc. The expectation is that successful feasibility studies will allow the new approaches and reagents developed in this initiative to become a core function and/or be distributed more widely to other investigators studying similar targets. Further information on the structure and organization of the grant application is provided in the Supplemental Application Instructions (see URL: http://ctep.info.nih.gov) The research activities included in these cooperative agreements are explicitly translational and are, of necessity, highly interdisciplinary. A Team should be able to deal expertly with such matters as cancer biology and target selection, chemistry, pharmacokinetics and pharmacodynamics, cellular and molecular imaging, in vivo animal models, and early clinical trials that are centered on hypothesis validation and proof of principle. A Planning Committee with appropriate representation from each Team and from NCI Program Staff will be established to help coordinate the activities and exchange information and techniques among the Teams (see below). SPECIAL REQUIREMENTS Terms and Conditions of Award Cooperative agreements are assistance mechanisms and are subject to the same administrative requirements as grants. The following Terms and Conditions of Award are in addition to, and not in lieu of, otherwise applicable OMB administrative guidelines, HHS grant administration regulations in 45 CFR Part 74 and 92 and administered under the NIH Grants Policy Statement. The administrative and funding instrument used for this program is a cooperative centers agreement (U54), an "assistance" mechanism (rather than an "acquisition" mechanism) in which substantial NIH scientific and programmatic involvement with the awardee is anticipated during the grant award. The NIH purpose is to support and stimulate the activity by working jointly with the recipient in a partner role, but it is not to assume direction, prime responsibility or a dominant role in the activity. The prime responsibility for the research resides with the awardees, although some activities may be carried out as a collaboration among the awardees with coordination and facilitation by NCI program staff. 1. Awardee responsibilities: a. Awardees will have primary responsibility for the project as a whole, including research design and conduct, data collection, data quality control, data analysis and interpretation and preparation of publications, as well as collaborations with other awardees. Awardees will retain primary rights to the data developed under these awards, subject to government rights of access consistent with current HHS, PHS, and NIH policies. However, awardees must be committed to making the assays and probes they develop available to the cancer research community. b. Awardees agree to participate on common projects identified by the Planning Committee on common research interests that address a specific basic and/or clinical research problem. c.b. Each Team (a Team consists of the investigators in a single grant award) should plan regular meetings (no less than monthly) to discuss the progress and directions of its research and to insure that the necessary interdisciplinary interactions are taking place. For Teams including members from other institutions, plans to extend meetings via teleconferencing, videoconferencing or web conferencing (for more frequent meetings) as well as face-to-face meetings (semiannually or quarterly) should be described. dc. The Principal Investigator and other designated investigators will attend an Annual Meeting to be organized by NCI staff in Washington D.C. In addition, the PI will be a voting member of the Planning Committee which meets twice a year (one meeting will be coordinated with the Annual Meeting). The support for attendance at these meetings will be provided through the Team's award. The Team should request support for attending these meetings within their travel budget. ed. Each Team will submit biannual progress reports to the NCI that describe activities and accomplishments during the previous funding period. f. NIH intramural scientists, if any are included in a Team, will not receive additional budgeted support from this award mechanism. They should arrange support for their participation in this initiative through the usual NIH intramural mechanisms. ge. Intellectual Property Since the discovery of new and improved research tools for the evaluation of the molecular effects of anticancer treatments is the objective of this effort and active involvement by commercial laboratories is facilitated by the existence of adequate patent coverage, it is essential that applicants provide plans to assure such coverage. In order to encourage timely presentation and publication of results, the Awardees are encouraged to file patent applications in a timely manner. The situation may be complicated by the involvement of multiple institutions. Each applicant Team must provide a detailed description of the approach to be used for obtaining patent coverage and for licensing where appropriate, in particular where the invention may involve investigators from more than one institution. Procedures must be described for resolution of legal problems should they arise. Your attention is drawn to P.L. 96-517 as amended by P.L. 98-620 and 37 CFR Part 401. Instructions were also published in the NIH Guide for Grants and Contracts (NIH Guide, Vol. 19, No. 23, June 22, 1990). All Awardees must adhere to the policy for distribution of unique research resources produced with PHS funding, published in the NIH Guide for Grants and Contracts (NIH Guide, Vol. 25, No. 23, July 12, 1996). The Guide can be accessed electronically at https://grants.nih.gov/grants/guide/index.html. Procedures must be described, which address how Awardees will approach such distribution, including acknowledgment of the terms of any related technology licenses or sponsored research agreements which Institution may have. Awardees shall include the following terms concerning intellectual property rights, or provide an alternative plan. NCI acknowledges that some commercial collaborators that are members of applicant Teams, or who provide agents to applicant Teams, may require that Institution agree to grant to them certain intellectual property rights, as described by the terms below. If Institution voluntarily agrees to the described terms, then they should appear in the Institution's Team application. NCI recognizes that Institutions' ability to access agents from commercial collaborators for this effort may be limited absent such a voluntary agreement, or a substantially similar independent agreement between Institution and commercial collaborators providing agents. However, in no event will the award of a cooperative agreement be dependent upon the described terms' being part of an Institution's Team application. Rather, Institution's Team application may provide Institution's own plan for accessing agents from commercial collaborators. In no event, however, will an award be made absent incorporation of either the terms below, or Institution's own plan. "Institution agrees to grant to commercial collaborator: (i) a paid-up nonexclusive, nontransferable, royalty-free, world-wide license to all Institution Inventions for research purposes only; and (ii) a time- limited first option to negotiate an exclusive, world-wide royalty- bearing license for all commercial purposes, including the right to sub-license, to all Institution Inventions on terms to be negotiated in good faith by the collaborator and Institution. The collaborator shall notify Institution, in writing, of its interest in obtaining such an exclusive license to any Institution Invention within six (6) months of the collaborator's receipt of notice of such Institution Invention(s). In the event that a collaborator fails to so notify Institution, or elects not to obtain an exclusive license, then the collaborator's option shall expire with respect to that Institution Invention, and Institution will be free to dispose of its interests in such Institution Invention in accordance with Institution's policies. If Institution and collaborator fail to reach agreement within ninety (90) days, (or such additional period as collaborator and Institution may agree) on the terms for an exclusive license for a particular Institution Invention, then for a period of six (6) months thereafter Institution shall not offer to license the Institution Invention to any third party on materially better terms than those last offered to collaborator without first offering such terms to collaborator, in which case collaborator shall have a period of thirty (30) days in which to accept or reject the offer. Institution agrees that notwithstanding anything contained herein to the contrary, any inventions, discoveries or innovations, whether patentable or not, which are not Subject Inventions as defined in 35 USC 201(e), arising out of any unauthorized use of the collaborator's agent and/or any modifications to the agent, shall be the property of the collaborator (hereinafter "Collaborator Inventions"). Institution will promptly notify the collaborator in writing of any such Collaborator Inventions and, at collaborator's request and expense, Institution will cause to be assigned to collaborator all right, title and interest in and to any such collaborator inventions and provide collaborator with assignment or other documents). Institution may also be conducting other research using the agent under the authority of a separate Material transfer Agreement (MTA) with the collaborator. Inventions arising thereunder shall be subject to the terms of the MTA, and not to this clause." * 35 USC (E) The term "Subject Invention" means any invention of the contractor first conceived or first actually reduced to practice in the performance of work under a funding agreement. h. Protection of Proprietary Data The ability to publish new results in a timely and intellectually unconstrained manner is fundamental to the academic enterprise. This need must be balanced with the legitimate requirements of commercial collaborators to protect the proprietary or confidential information that they provide concerning their proprietary agents. Commercial collaborators also may require exclusive access to the raw and primary data generated in studies of their agents. Therefore, NCI urges that the following statement also be incorporated in Team applications: "Raw and primary data may be provided exclusively to the NCI, industrial collaborators, and the FDA, as appropriate. This provision shall not affect the investigators' right to disseminate their research findings through publications or presentations." 2. NCI Staff responsibilities: a. Program Staff consists of the NCI Program Director and additional representatives from each of the following Programs: Cancer Therapy Evaluation Program, Chemopreventive Agent Development Program, Developmental Therapeutics Program, Diagnostic Imaging Program, and Cancer Diagnosis Program. The Program Director will identify specific Program Staff to participate in the roles described below: a. Three (the Program Director and the Associate Directors of the NCI Developmental Therapeutics Program and Cancer Diagnosis Program) will serve as voting members of the Planning Committee. b. Specified program staff have substantial coordinating scientific roles based on their knowledge of other related NIH supported research and resource activities. Program staff will work closely as Program staff have substantial coordinating scientific roles based on their knowledge of other related NIH supported research and resource activities Program Staff will work closely as research coordinators with individual investigators and NIH intramural scientists to facilitate collaborations with other NCI-funded research groups to leverage the resources available for this effort. The NCI Program Staff will assist in the coordination of activities that involve all the awardees, such as annual meetings and Planning Committee meetings. They will also assist the research efforts of the Team by facilitating access to fiscal and intellectual resources provided by industry, private foundations and NIH intramural scientists. As required, when projects are not making headway, Program Staff, through the NCI Program Director will help reprogram research efforts within the peer-reviewed scope of work, including options to modify or terminate projects, by mutual consent between a Team and NCI. cb. The NCI Program Director will interact with each Team, evaluating the progress of that particular Team, coordinate research approaches between Teams, and contribute to the adjustment of research projects or approaches as warranted. The NCI Program Director will assist and facilitate this process and not direct it. The NCI Program Director will also provide assistance in reviewing and commenting on all major transitional changes of an individual Team's activities prior to implementation to assure consistency with the goals of this RFA. dc. The NCI Program Director will coordinate this activity with other ongoing studies supported by NCI to avoid duplication of effort and to encourage sharing and collaboration in the development of new clinically useful reagents and methodologies for molecular target assessment. The NCI Program Director will coordinate access to other resources from NCI including NCI sponsored agents for preclinical and clinical testing, drug screening, preclinical toxicology testing, assistance in IND filing, etc. ed. CTEP Assistance in Protocol Development: When a proof-of-principle clinical trial to be supported by this initiative is planned, a detailed protocol mutually acceptable to the Team and to the CTEP Protocol Review Committee (PRC) will be prepared. Communication at the various stages of protocol development is encouraged to promote protocol development and implementation. Protocols utilizing NCI-sponsored agents should be preceded by a written Letter of Intent (LOI) from the Team declaring interest in conducting a particular study. The LOI mechanism is designed for preliminary review and is recommended to expedite protocol development and implementation and to facilitate agreement on study priority and design (for further discussion of these mechanisms see the DCTD Investigator's Handbook available at the CTEP Web page at the following URL: (http://ctep.info.nih.gov/handbook/index.html). fe. CTEP Review of Proposed Clinical Research. All Team protocols, including protocols utilizing agents not sponsored by NCI, will be reviewed by the PRC, which meets weekly and is chaired by the Associate Director, CTEP. Ad hoc reviewers, external to NCI, will be utilized when deemed appropriate by the PRC chairperson. Following the review of the protocol by the PRC, the NCI Program Director will provide the Team with a consensus review that describes recommended modifications and other suggestions, as appropriate (see the Investigator's Handbook for further information regarding protocol review at CTEP). NCI will not provide investigational drugs or permit expenditure of NCI funds for a protocol that it has not approved. An Investigational Drug Branch Senior Clinical Investigator will serve as the Scientific Coordinator for designated agents for clinical trials and will be available to assist the Team in developing a mutually acceptable protocol, consistent with the research interests, abilities and strategic plans of the Team and of the NCI. gf. The NCI Program Director will organize an annual meeting of all funded investigators to share progress and research insights that may benefit all of the projects. In addition, he/she will be responsible for organizing biannual meetings of the Planning Committee. hg. NCI Program Staff will assist, where warranted, in data analyses, interpretations, and the dissemination of study findings to the research community and health care recipients including co-authorship of the publication of results of studies conducted by the Teams, subject to NIH publication policies. 3. Collaborative responsibilities: The Planning Committee will provide overall coordination of the Teams; voting members will consist of the Team Principal Investigators, 3 additional non- NCI scientists selected by the PIs and 3 NCI Program Staff. Additional Program Staff and scientists other than PI's may attend as non-voting members of the Planning Committee where additional expertise may be required. A non- NIH An extramural chairperson for the Planning Committee will be chosen by a majority vote of the Principal Investigators. The Planning Committee will identify the need for collaborations either within or outside the Teams and the need to redirect certain efforts as mandated by establishment of sufficient data to reach conclusions, data supporting alternative approaches, or experience proving that the proposed research is no longer feasible. Some Teams will have common research interests that address a specific basic and/or clinical research problem; research focus groups may be formed to conduct coordinated research activities identified by the Planning Committee. The Planning Committee will make recommendations regarding targets and possible research tools. It will also seek input from the scientific research communities and consider how to have an impact on drug development in the larger community. The Team investigators must be willing to consider addressing future scientific needs discussed by the Planning Committee. The Planning Committee will apprise NCI program staff on scientific opportunities, emerging needs or impediments to progress. The Planning Committee will meet twice yearly, once at the annual meeting of the entire Team. The purpose of these meetings is to share scientific information, assess scientific progress, identify new research opportunities and potential avenues of collaborations such as with industry, private foundations and/or NIH intramural scientists, establish priorities that will accelerate the translation of preclinical findings into clinical applications, reallocate resources and conduct the business of the cooperative research program. 4. Arbitration: When agreement between an awardee and NCI staff cannot be reached on scientific/programmatic issues that may arise after the award, an arbitration panel will be formed. The panel will consist of one person selected by the awardee, one person selected by NCI staff, and a third person selected by these two members. The decision of the arbitration panel, by majority vote, will be binding. This special arbitration procedure in no way affects the right of an awardee to appeal an adverse action in accordance with PHS regulations at 42 CFR Part 50, Subpart D, and HHS regulations at 45 CFR Part 16. 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 are provided that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing research involving human subjects should read the "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 the NIH Guide for Grants and Contracts, Volume 23, Number 11, March 18, 1994, available on the web at: https://grants.nih.gov/grants/guide/notice-files/not94-100.html. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of NIH that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines on the Inclusion of Children as Participants in Research Involving Human Subjects" that was published in the NIH Guide for Grants and Contracts, March 6, 1998, and is available on the Web at https://grants.nih.gov/grants/guide/notice-files/not98-024.html. Investigators also may obtain copies of these policies from the program staff listed under INQUIRES. LETTER OF INTENT Prospective applicants are asked to submit a letter of intent that includes: a descriptive title of the proposed research and the respective projects; the name, address, email address and telephone number of the Principal Investigator; the identities of other key personnel and participating institutions; and the 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 subsequent applications, the information that it contains allows NCI 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 the program staff listed under INQUIRIES by February 1, 2000. APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these awards. These forms are available at most institutional offices of sponsored research and from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/710-0267, E-mail: grantsinfo@nih.gov. The 398 kit may also be found at https://grants.nih.gov/grants/forms.htm Additional instructions for preparing a U54 grant application are available by FAX from the program staff listed under INQUIRIES and on the Internet at http://ctep.info.nih.gov/newpage1.htm. THESE INSTRUCTIONS MUST BE USED IN PREPARING AN APPLICATION IN RESPONSE TO THE RFA. Submission Procedures The RFA label available in the PHS 398 (rev. 4/98) application form must be affixed to the bottom of the face page of the application. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. 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 (20817 FOR EXPRESS SERVICE) At the time of submission, two additional copies of the application must also be sent to: Ms. Toby Friedberg Referral Officer Division of Extramural Activities National Cancer Institute 6116 Executive Boulevard, Room 8062, MSC 8239 Rockville, MD 20852 (express service) Bethesda, MD 20892-8239 Applications must be received by March 15, 2000. If an application is received after that date, it will be returned to the applicant without review. The Center for Scientific Review (CSR) will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. The CSR will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of substantial revisions of applications already reviewed, but such applications must include an introduction addressing the previous critique. Applications must meet all eligibility requirements as described above and must address all programmatic requirements (see Special Requirements above) in the RFA. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by CSR and responsiveness to the RFA by NCI staff. Incomplete and/or non-responsive applications will be returned to the applicant without further consideration. Any application that does not meet the minimum application requirements as set forth under APPLICATION PROCEDURES will be considered unresponsive to the RFA. Responsiveness includes, but is not limited to, the program relevance of the proposed research projects and pilot projects being proposed to access core facilities, as determined by NCI. 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 NCI in accordance with the review criteria stated below. As part of the initial merit review, a process may be used by the scientific review group in which all applications receive a written critique and only those applications deemed to have the highest scientific merit will be discussed, assigned a priority score, and receive a second level review by the NCAB. Review Criteria The goals of NIH supported research are to advance our understanding of biological systems, improve the control of disease and enhance health. The reviewers will comment on the following general aspects of the application in order to judge the likelihood that the proposed research will have an impact on these goals. Note that the application does not need to be strong in all the general categories to be judged likely to have a major scientific impact and deserve a high priority score. For example, important work that is essential to move a field forward may not be innovative by its nature. The factors to be considered in the evaluation of all applications are given below. A. Individual Research Projects: 1. Significance: How important are the selected target(s)/pathway(s)/mechanism(s)? Are the selected targets considered high priority for the development of anticancer agents? Will development of the proposed assays, probes, and other tools improve the clinical development of the agents? What will be the effect of these studies on the concepts or methods that drive this field? 2. Approach: Are the conceptual framework, design, methods, and analyses adequately developed, well-integrated, and appropriate to the aims of the project? How effective is the strategy for selecting assessment tools? Have preclinical models been proposed in which the agents demonstrate activity? Have the investigators considered the appropriate negative and positive controls? Are there adequate plans to assess the feasibility of the probes and assays to be developed, and to correlate their readout with useful preventive or therapeutic activity in these models? Are there plans to describe the operating characteristics and quality control procedures for the reagents to be developed? Will the design of preclinical experiments permit conclusions that will be applicable to scheduling of drug administration and timing of effect assessment in clinical trials? Does the investigator identify potential limitations in currently available models and possible approaches to rectifying them? 3. Innovation: Does the project employ novel concepts, approaches or methods? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? Does the project study new factors or parameters that will impact drug development and evaluation? 4. Investigator: Is there understanding of the design of relevant laboratory studies? Does the training, experience, qualifications, accomplishments and availability of the proposed Investigators and evidence of ability, organizational structure and availability to function as a team demonstrate capacity in the following areas as is pertinent to the proposed research (not all need to be included): o Basic biology pertaining to the target (molecular, cellular, immunologic) o Synthetic chemistry and/or radiochemistry o In vivo models o Pharmacokinetics and pharmacodynamics in preclinical and clinical experiments o Clinical research incorporating novel biological and/or pharmacodynamic endpoints o Molecular and cellular imaging (small animal and human) o Interventional radiology o Pathologic and molecular analysis of tissues o Enhanced topical/endoscopic imaging for preinvasive neoplasia 5. Environment: Is there related experience of the organization including project descriptions and pertinent efforts for any sponsor (commercial, government or non-profit)? In particular, is there evidence of experience with preclinical and clinical evaluation of investigational agents? Is there an explanation of how the organization will provide support and expertise to this project and the proposed PI? Is there prior experience of the PI/Organization with multi-institutional research projects, or is there a clear plan to organize multi-institutional research projects if they are proposed? Is there experience or well defined plans for completing correlative studies in trials of anti-cancer agents, including recruitment of patients with accessible tissue, integration/scheduling of imaging resources, pathology resources and pharmacology resources proposed in prior studies? Are there plans for Team members to make intellectual investments in the relevant disciplines to permit true multidisciplinary collaborations? Has sufficient effort been committed to permit the clinical researchers to attend presentations at the basic science laboratory meetings? Have the basic scientists planned to attend relevant clinical meetings at the institution to review the course of trials and imaging experiments? Does the preparation of the projects indicate that experts from different backgrounds communicated with each other in writing the grant application? B. Cores 1. Qualifications, experience and commitment of key personnel in the services provided by the core unit, as well as their ability to devote the required time and effort in providing services to the Team 2. Appropriateness of the use of the core services by the budgeted projects 3. Adequate plans for charge back and priority management procedures for service/technical core units C. Developmental/Pilot Projects 1. Are the specific plans for developmental funds consistent with the Team's overall goals and priorities? Do the Pilot Projects interact with the Research Projects and Cores? 2. Does the quality of the pilot projects proposed by the Team demonstrate the effectiveness of the selection process? D. Overall Program Organization and Capability: 1. Significance: Does the Team address an important target/pathway/mechanism? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? 2. Approach: Are the conceptual framework, design, methods, and analyses adequately developed, well-integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? 3. Innovation: Does the project employ novel concepts, approaches or methods? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? 4. Investigators: Are the Principal Investigator and collaborators appropriately trained and well suited to carry out this work? Does the research experience of the PI demonstrate expertise in the biologic target/pathway/mechanism? Is the work proposed appropriate to the experience level of the key investigator and other researchers? Is the Principal Investigator committed to devote the required time and effort to the Team? Does the PI demonstrate willingness to work and collaborate with other Team Programs as appropriate and with NCI assistance in the manner summarized in this RFA. 5. Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Are resources such as space, equipment, preclinical models, technical and clinical capabilities described that are needed for the success of the research? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? 6. In addition, the criteria for reviewing the Team as an integrated effort are: a. Overall strength of the Team in terms of the combined strength of the research projects, pilot projects and core units, and the significance of the application to the objectives of the Program outlined in this RFA; b. Leadership ability and scientific stature of the Principal Investigator, particularly, but not exclusively in the area of the proposed research, and his/her ability to meet the Team's demands of time and effort; c. An appropriate organizational and administrative structure for effective attainment of Team objectives that considers arrangements for internal quality control of ongoing research, the allocation of funds, day-to-day management, contractual agreements, if applicable, and internal communication among investigators; d. Demonstrated institutional commitment to the Team and its objectives in terms of providing research facilities and management support. E. The initial review group will also examine: the appropriateness of the proposed project budget and duration; the adequacy of plans to include both genders and minorities and their subgroups as appropriate for the scientific goals of the research and plans for the recruitment and retention of subjects; the adequacy of plans for including children as appropriate for the scientific goals of the research, or justification for exclusion; the provisions for the protection of human and animal subjects; and the safety of the research environment. FE. Overall Evaluation and Scoring of Applications The individual Research Projects will be assigned numerical priority scores while the Cores and Pilot Projects will be rated superior, satisfactory, or NRFC, without numeric scores. A single numerical priority score will then be assigned to the Team application as a whole after discussing all of the review elements listed above. The score will be based on the overall quality of the Research Projects, the Developmental/ Pilot Projects, the overall effectiveness and adequacy of shared resources, the overall program organization and capability, the plans for interactions with the Team, and the potential for validation and integration of research tools into new drug development programs. AWARD CRITERIA Applications recommended by the National Cancer Advisory Board will be considered for award based on a) scientific and technical merit as determined by peer review; b) program balance, including, in this RFA, the need for Teams that address different targets/processes; and c) availability of funds. Schedule Letter of Intent Receipt Date: February 1, 2000 Application Receipt Date: March 15, 2000 Peer Review: June/July 2000 Review by NCAB: September 2000 Earliest Anticipated Award Date: December 1, 2000 INQUIRIES Written and telephone inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues and address the letter of intent to: Louise Grochow, M.D. Chief, Investigational Drug Branch, CTEP, DCTD National Cancer Institute Executive Plaza North, Room 715 6130 Executive blvd Rockville, MD 20850 Email: grochowl@ctep.nci.nih.gov Telephone: (301) 496-1196 FAX: (301) 402 0428 Please FAX requests for supplemental instructions to Marylou Macgregor IDB Administrator: Marylou Macgregor (email: macgregorm@ctep.nci.nih.gov). Direct inquiries regarding review issues to: Ms. Toby Friedberg Referral Officer Division of Extramural Activities National Cancer Institute 6116 Executive Boulevard, Room 8062, MSC 8239 Rockville, MD 20852 (express service) Bethesda, MD 20892-8239 Telephone (301) 496-3428 Fax: (301) 402-0275 Email: tf12w@nih.gov Direct inquiries regarding fiscal matters to: Ms. Carolyn Mason Grants Administration Branch National Cancer Institute 6120 Executive Boulevard Room 243 Bethesda, MD 20892-7340 Rockville, MD 20852 (for express/courier service) Telephone: (301)496-7800 ext 259 Fax:(301) 496-8601 Email: cm113g@nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.394, cancer treatment. Awards are made under authorization of Sections 301 and 405 of the Public Health Service Act as amended, (42 USC 241 and 284) and administered under NIH grants policies and Federal Regulations 42 CFR Parts 52 and 45 CFR Parts 74 and 92. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The PHS strongly encourages all grant and contract recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.
Weekly TOC for this Announcement
NIH Funding Opportunities and Notices
Office of Extramural Research (OER) |
National Institutes of Health (NIH) 9000 Rockville Pike Bethesda, Maryland 20892 |
Department of Health and Human Services (HHS) |
||||||||
Note: For help accessing PDF, RTF, MS Word, Excel, PowerPoint, Audio or Video files, see Help Downloading Files. |