RFA-CA-00-002: MOLECULAR TARGET DRUG DISCOVERY FOR CANCER

Department of Health
and Human Services (HHS)

NIH... Turning Discovery Into Health^®

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MOLECULAR TARGET DRUG DISCOVERY FOR CANCER Release Date: February 16, 2000 RFA: CA-00-002 National Cancer Institute Letter of Intent Receipt Date: June 6, 2000 Application Receipt Date: July 18, 2000 PURPOSE The National Cancer Institute (NCI) defines new, extraordinary research opportunities through stated goals in a "Bypass Budget". Among the priorities of the 2001 Bypass Budget was to identify and use molecular targets for the discovery and clinical testing of new anticancer agents based on the molecular mechanisms that underlie neoplastic transformations, cancer growth and metastasis. Accordingly, the Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, NCI, and the Chemoprevention Agent Development Research Group, the Division of Cancer Prevention, NCI invite cooperative agreement applications to exploit molecular targets for drug discovery. New insights into our understanding of cancer cell biology provide a new opportunity for a fundamental re-ordering of approaches to cancer drug discovery. Rather than depending on in vitro and in vivo screens for antiproliferative activity, investigators can now focus on new molecular targets and pathways essential for the development and maintenance of the cancer phenotype. As a result, the NCI is reorganizing its drug development programs from early drug discovery phases to the conduct of clinical trials in order to bring forward new types of agents based on strong rationales. The plan also involves changes in the clinical evaluation of new agents that will include appropriate measurements to verify target modulation. Projects are acceptable at all stages of development, including mature projects as well as novel insights at an early investigational stage. However, the cooperative agreements, herein described, should be projects that are more developed and comprehensive. In addition to this RFA, the NCI announces the following three related program announcements in molecular target drug discovery for cancer treatment and prevention: Small Business Innovation Research (SBIR, R43) and Small Business Technology Transfer Programs (STTR, R41) (see http://grants.nih.gov/grants/guide/pa-files/PAR-00-061.html), which are directed to those of the small business community who need assistance in launching commercial products, Exploratory/Development Grant (R21) awards (see http://grants.nih.gov/grants/guide/pa-files/PAR-00-060.html) for pilot projects for which preliminary data are lacking that would make the project competitive for a regular research grant, Competing Supplements for existing NCI awardees (see http://grants.nih.gov/grants/guide/pa-files/PAR-00-062.html), which can be used to extend the goals of active grants to include studies related to drug discovery. Also see the HomePages of either the Developmental Therapeutics Program (http://dtp.nci.nih.gov) or the Chemoprevention Agent Development Group (http://dcp.nci.nih.gov/cb) for further information or contact individuals listed under INQUIRIES of this RFA. Further information on research opportunities regarding molecular targets in drug discovery can be found in the NCI ByPass Budget, The Nation’s Investment in Cancer Research: A Budget Proposal for Fiscal Year 2001 at http://2001.cancer.gov. The purpose of this Request for Applications (RFA) is to reorganize the front end or gateway to drug discovery. Investigators are being asked to identify a novel molecular target, to validate the target as a basis for cancer drug discovery, and to develop an assay for the target. Given the fact that some investigators may already have considerable preliminary data on a signaling pathway, they nevertheless may not have focused on the point of greatest vulnerability in the pathway and therefore, perhaps the optimal point of drug attack. This RFA would support an investigator to validate a target and develop an assay based on the target. Applicants may address targets related to the treatment of established cancers, or the prevention of molecular changes which may cause cancer. Investigators may use their own creativity in defining their approach. For example, some may prefer to 1) use a genetic, structural biology or molecular biology approach to target identification/validation using information from genetic studies or studies of pathways, whereas others may prefer to 2) identify the function of a cellular target after first finding the target as a result of exploring binding patterns of natural products or other ligands to the novel target. Once targets are identified and validated, they will be developed into high- throughput screens by the applicant or through collaborative arrangements, potentially using NCI contract research resources, with appropriate safeguards for intellectual property. The RFA requires that the proposed target (s) in each application be novel and not addressed by drugs already approved for clinical use. A special feature of this Molecular Target Drug Discovery (MTDD) effort will be the ability for grants funded through this RFA to be eligible for administrative supplements to add structural biology studies, create targeted libraries, acquire pre-existing libraries, or screen compounds following negotiation of appropriate collaboration agreements. These activities may of course be a part of the initial application if the Principal Investigator (PI) has data convincing to the peer review committee that the proposed target has sufficient validation. Alternatively, awardees will have access to NCI- supported contract research resources that may facilitate their studies. Applications will be submitted to the NIH and will be reviewed by the NCI according to the criteria established for this RFA as described below under REVIEW CONSIDERATIONS. 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, Molecular Target Drug Discovery for Cancer, is related to priority areas of human cancer treatment and prevention. 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 domestic for-profit and non-profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and Local governments, and eligible agencies of the Federal Government. Applications may also be submitted by a foreign institution or an intramural laboratory from the National Institutes of Health. For this RFA, NIH investigators may submit applications, but they may not request or receive funds from this program. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as principal investigators. MECHANISM OF SUPPORT The administrative and funding instrument to be used for awards for non-NIH applicants will be a cooperative agreement (U01), an "assistance" mechanism (rather than an "acquisition" mechanism) in which substantial NIH scientific and/or programmatic involvement with the awardee is anticipated during performance of the activity. Under the cooperative agreement, the NCI’s role is to support and/or stimulate the recipient"s activity by working jointly with the award recipient as a partner, but it is not to assume direction, prime responsibility, or a dominant role in the activity. Details of the responsibilities, relationships and governance of the study to be funded under a cooperative agreement are discussed later in this document under the section "Terms and Conditions of Award." There is no intent, real or implied, for NCI staff to direct an awardee’s activities or to limit the freedom of investigators. Assistance via cooperative agreement differs from the research project grant in that the government component (NCI) awarding the cooperative agreement anticipates a partnership relationship that will enhance the efficiency and effectiveness of an awardee’s efforts. The total project period requested for applications submitted in response to this RFA may not exceed four years. The earliest anticipated award date is April 1, 2001. Because the nature and scope of the research proposed in response to this RFA may vary, it is anticipated that the size of awards will vary. The number of awards and the level of support depend on receipt of a sufficient number of applications of high scientific merit. Although this program is provided for in the financial plans of the NCI, awards pursuant to this RFA are contingent upon the availability of funds for this purpose. Unless otherwise noted, all NIH grants policies apply. No funds from the amount set aside for this RFA will be used to support intramural projects from NIH. For further budget information pertaining specifically to NIH intramural applications, see section APPLICATION PROCEDURES below regarding Additional Instructions for Intramural Project Applicants. This RFA is a one-time solicitation. To enable a continuing flow of applications to this initiative, NCI anticipates continued support in the future through a Program Announcement with NCI review (PAR). FUNDS AVAILABLE The NCI has budgeted $3 million total costs (direct plus facilities and administrative costs) for the first year of funding, subject to the availability of funds. It is expected that NCI will make 8-10 awards for periods up to four years. The number of awards and individual level of support are dependent on the receipt of a sufficient number and diversity of applications with high scientific merit. Program balance and diversity of topics will be factors in selecting applications for award. Budget requests should be justified and commensurate with the needs of the project. Those in excess of $500,000 total costs for the first year must be carefully justified, and the projects must be highly meritorious. Annual budgets for years two to four should not exceed the first year budget plus a 3% yearly increase. Equipment needs, especially in future years, must be well justified. Although no funds from the amount set aside for this RFA will be used to support intramural projects, NIH intramural project applicants must verify that the amount of the resources allocated from intramural sources does not exceed $300,000 direct costs. For further budget information pertaining specifically to NIH intramural applications, see APPLICATION PROCEDURES , below regarding Additional Instructions for NIH Intramural Applicants." RESEARCH OBJECTIVES Background The past 20 years have seen an explosion in the understanding of how cancer cells work. Specific molecules have been identified which cause the initiation and progressive growth of tumors. From this work, a fundamental re-ordering of the approach to drug discovery and development for the treatment and prevention of cancer has emerged. There is the opportunity to move away from screening agents by their effects on tumor cell growth, in vivo or in vitro, and targets that have been thoroughly exploited. While it remains true that these methods might continue to be the basis for the development of clinically useful agents, these agents may not be the best lead compounds that effect a particular pathway of biologic importance specific for cancer establishment or progression. Drugs discovered by these early methods have historically demonstrated clear limitations in clinical efficacy. The hope is that drugs targeting new, specific molecular lesions in cancer cells will provide more effective therapy or prevention approaches, alone or in combination with other agents. The focus of attention in this new approach to cancer drug discovery is a compound’s effect against a novel molecular target, or a target operating in a defined biochemical pathway, with the intent of causing a gain or loss in function to reverse, stop, or delay cancer progression. The cancer cell selectivity of lead compounds should be enhanced by screens based on a novel target or a critical pathway that represents a true Achilles heel. The evaluation of drugs in the clinic which have emerged from these types of approaches is beginning. Examples would include the farnesyl transferase inhibitors (FTIs), protein kinase (PK) antagonists of various sorts, matrix metalloprotease inhibitors, and growth factor receptor or other effector antagonists (endothelin, tamoxifen, TRAIL, etc.). It is striking that in this process the pharmaceutical industry has clearly seized a defining role in expeditiously advancing potentially useful compounds to a clinical test. However, in each of the instances cited, the pioneering studies on the targets to which these drugs are directed occurred largely (if not exclusively) in the academic sector. Objectives and Scope The goal of this RFA is the discovery and validation of molecular targets for cancer prevention or treatment intervention which can be developed into drug discovery assays. Identification of a potential target might present varying degrees of difficulty, but validation (an indication of a target’s predictive capacity to aid in the selection of clinical drugs) is apt to be uniformly more problematic. Leads for many existing clinical drugs were not discovered through the use of macro-molecular targets but rather through in vivo or in vitro anti-proliferative assays. Accordingly, the cornerstone of this effort is the validation of targets of demonstrated importance. At minimum, a target should be identified (de novo, or from the literature), a validation plan outlined, and a conception of how the validated target could be developed into a drug assay. Approaches and projects appropriate for this RFA should be in three general areas as follows: First, investigative activities establishing a molecule as a potential cancer drug discovery target can have as its focus any aspect of early dysplasia or cancer cell biology that may reveal a vulnerability in the cancer cell. These might include cell cycle checkpoints, DNA repair, cell stress, or cell death pathways, cassettes of altered transcription factor activity, or activation of pathways allowing cell growth in hypoxic or hypo-vascularized conditions. Oncogenic viral targets also would be appropriate. In fact, any difference between a cancer and normal cell could potentially be exploitable as a therapeutic maneuver. Modern science has afforded numerous opportunities to demonstrate the likely value of this approach. These include: (1) engineered animals of various sorts (transgene-expressing, knock-out, etc.), (2) smart assays designed to give information, not only about phenotypic alteration, such as growth arrest or cell death, but also about the effect on particular molecular targets of pathways known or suspected to have biological relevance to cancer, (3) array technology, where the action of a candidate drug lead against its target can be placed rapidly in the context of expected action against other cellular and indeed organ-specific molecules, and (4) cancer gene discovery programs, such as the Cancer Genome Anatomy Project (CGAP) (http://www.ncbi.nlm.nih.gov/CGAP), which has identified numerous mutational sites in cancer cells, some of which are possibly unique to specific types of cancer. Accordingly, a requirement is to establish that a molecular target likely affects important aspects of cancer cell function. Second, the validation of new molecular targets, with the intent of discovering new agents for the treatment or prevention of cancer, is an important and necessary activity. At present, science appears to offer too many targets. Therefore, projects should focus on determining which of these numerous potential defects are sites of critical vulnerability which could be exploited for intervention. Ideally one would expect to demonstrate that manipulation of the target function would cause a phenotypic change in the cancer cell. Clearly if a prime target is fully validated, such that the target can be used to totally exploit a unique difference between a healthy and a cancerous cell, control of cancer would then only await the discovery of a drug molecule through a systematic screening and/or drug design program, in real laboratory experience, validation occurs in stages or degrees. Demonstration of some phenotypic or functional change that is desirable, such as elimination or reversal of dysplasia, tumor shrinkage or change in a validated surrogate marker, would provide evidence of the importance of a target. Approaches to target validation might involve the use of antisense or engineered animals, such as transgene-expressing or gene knock-outs. Small, bioactive molecules, obtained either from natural products libraries or from chemical libraries, may be used as ligands to select and validate proteins from arrays. If an investigator chooses to utilize crude extracts of natural products, as from the NCI Active Repository, expertise must be available for chemical fractionation of the extracts. Thus, validation can be conceptualized as a series of milestones. A proposal to reach validation milestones could be responsive to this RFA. There are many good rationales for selecting targets, but validation requires considerable imagination and skill on the part of the investigator. Therefore, also responsive to this RFA would be an insightful and clever validation of a target suggested by others as a possible intervention point. While it is true that the ultimate validation can only come from a successful clinical trial, having information on the importance of the target prior to the trial should provide important feedback in case therapies are ineffective. Third, the target system should be amenable to conversion into a screen for effectors of the target’s function (at minimum on a laboratory scale), or the molecular structure determined through biophysical techniques as a prelude to drug discovery studies. These aspects are critical components which would form the thrust of any molecularly focused drug discovery effort. The practical nature of drug discovery research is of high importance. While the desirability of this approach might seem obvious, the tools for accomplishing this task are only now becoming routinely available. These include sequence information defining the primary structure of relevant target proteins or other macromolecules, expression vectors for their large scale production, biophysical (e.g., X-ray and NMR) and computational techniques to allow the determination of three-dimensional structure, advances in screening technology to allow ever increasing speed and efficiency in assessing large numbers of candidate structures, and combinatorial chemistry to generate large numbers of candidate drug structures. A Molecular Target Analysis Group made up of each of the MTDD Principal Investigators, as well as ad hoc members, and NCI Extramural Program Staff, will meet at least twice yearly to evaluate targets selected from MTDD efforts. The Molecular Target Analysis Group will recommend criteria for defining and validating appropriate drug discovery targets as well as determining when a putative target is appropriate for development into a high- throughput screen. The NCI will facilitate the identification of sources and establish distribution systems for compound libraries, database resources, and information systems to disseminate non-proprietary data and information to the research community. Access to NCI contract research resources will be a distinguishing feature of MTDD awards. To facilitate communication among the MTDD participants, NCI will establish and maintain an Internet-based mechanism for rapid data and document transmission and electronic communications. In order to assure that novel ideas and inventions are rapidly developed to the benefit of the public, it is understood that intellectual property protection may be needed for some of the data and materials resulting from grantee labors. Resources potentially available to MTDD grantees, if not a part of the initial individual application, include but certainly are not limited to the following: o Expression of Target: Successful applicants whose program requires production of quantities of expressed target protein for either structure elucidation and/or assays will be eligible for supplements to achieve this goal. This will be accomplished either through production at their own institution or at a contract research facility using constructs emanating from the applicant’s laboratory. Authority for granting these supplements will rest with NCI Program staff. o Structural Analysis of Target: Applicants will be encouraged to describe in the application, when it exists, ongoing relationships with structural biologists who will be responsible for structure determination using relevant physical techniques such as X-ray crystallography or NMR. At a point in the progress of a project when structural analysis might seem appropriate, funds for support of biophysical studies may be requested. Lacking that initial collaboration, grantees could obtain supplemental funding through, for example, a consortium arrangement with a structural biologist. When the opportunity for structural analysis presents itself, funds will be flexibly available to stimulate this interaction as needed. Authority for implementation of the supplements will rest with NCI Program staff. o Access to Chemistry/Screening: Following definition of a candidate assay relevant to a target, efforts to create libraries of compounds and conduct screening activities that are based on the target’s structure may be undertaken. This effort could use contract research resources available to NCI, but would be paired by NCI staff in their management with the MTDD investigator. In the event that an MTDD project produces its own libraries, these would remain the property of the originator. NCI may take the lead in developing specific "made to order" libraries or libraries may emerge from existing collections available to NCI. All new libraries funded from an outside source under the overall umbrella of an MTDD grant will be the property of the originating PI, but may be offered to additional MTDD grantees or other peer-reviewed, NCI-sponsored drug discovery efforts under appropriate Material Transfer Agreements. Screening might also be supported by contract research resources in the event it cannot be done in the originating PI’s laboratory, or it might be conducted by supplementation of the award to include the cost of screening. Authority for implementation of chemistry or screening efforts would rest with NCI Program staff. o Access to Preclinical Drug Development: A key issue in early compound development may be the toxicologic, pharmacologic and/or pharmaceutic properties of a lead. NCI-directed contract research resources may be made available to assess initial pharmacologic or pharmaceutical features of leads, or of subsequent versions of the lead that may have included efforts to optimize in vivo efficacy, pharmacology or formulation attributes. Advice concerning the suitability of the molecule(s) for these studies may be sought from the NCI Program Director. SPECIAL REQUIREMENTS 1. Definitions ARBITRATION PANEL: A panel that is formed to review any scientific or programmatic disagreement, within the scope of the awards supported under this RFA, between U01 awardees or NIH intramural projects and the NCI. The panel will be composed of three members: one selected by the Molecular Target Analysis Group (excluding the NCI staff representatives) or the individual U01 awardee or NIH intramural program in case of an individual dispute, a second member selected by NCI staff, and a third members selected by the prior selected members. For U01 awardees, this special arbitration procedure in no way affects the awardee’s right to appeal an adverse action that is otherwise appealable in accordance with the PHS regulations at 42 CFR part 50, Subpart D and HHS regulation at 45 CFR Part 16. AWARDEE: The institution to which the MTDD project (U01) is awarded. COOPERATIVE AGREEMENT (U01): An assistance mechanism, rather than an acquisition mechanism, in which substantial NCI scientific and/or programmatic involvement is anticipated during performance of the activity. Under the cooperative agreement, the NCI purpose is to support and/or facilitate the activity by involvement in, and otherwise working jointly with, the awardee in a partner role, but NCI is not to assume direction, prime responsibility, or a dominant role in the activity. DRUG: In the context of this RFA, a term used broadly to encompass synthetic agents, natural products and biological products designed to treat and/or prevent cancer. INTELLECTUAL PROPERTY (IP): Inventions which may result from the discovery of new targets, design of new assays or models, or discovery of new agents effective for the treatment or prevention of cancer. However, works of authorship, which can be copyrighted, and trademarks are also included. MOLECULAR TARGET DRUG DISCOVERY (MTDD) awards: Cooperative agreements or NIH intramural projects which are designed to discover, validate, and utilize as a screening model, new molecular targets that are important for cancer and exploitable for new drug discovery. MOLECULAR TARGET: For the purpose of this RFA, an entity, which could be a protein, a receptor or enzyme, or a cellular process or a pathway, that is essential for the establishment and maintenance of the cancer phenotype. Within the context of this RFA, molecular targets to be investigated should not include those already exploited by clinically available drugs. PRINCIPAL INVESTIGATOR: The scientist who is designated by the applicant institution or NIH intramural laboratory to direct the MTDD project. The PI will assume responsibility and accountability to the applicant institution and the NCI for the performance and proper conduct of the MTDD project in accordance with the terms and conditions specified in this RFA. NCI PROGRAM OFFICIAL: The senior staff member of the Grants and Contracts Operations Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, or the Chemoprevention Agent Development Research Group, the Division of Cancer Prevention, who provides leadership and guidance for the overall MTDD Program within NCI, maintains overall scientific balance for the Program, ensures that it is consistent with the NCI mission of treatment or prevention, and performs the normal stewardship activities. NCI PROGRAM SCIENTIST: A science administrator of the NCI extramural staff, appointed after award by the NCI Program Official, who participates as a member of an MTDD Group, interacts scientifically with the Group and facilitates the role of the NCI as a partner in the Group. MOLECULAR TARGET ANALYSIS GROUP: A committee which will include the PI or their designated representatives from each U01 or NIH intramural project selected under this RFA. NCI Program Scientists will serve as non-voting members. Its purpose will be to apply its collective knowledge to accelerate the pace of identification of new molecular targets for drug discovery and to exchange information among its members. The Molecular Target Analysis Group and their collaborators will participate in recommending guidelines and standards for the discovery and validation of new targets, II. Other Considerations A. The Principal Investigator or designated representative should plan to attend twice yearly meetings of the Molecular Target Analysis Group. B. The Principal Investigator must state in the application a willingness to participate in the Molecular Target Analysis Group and provide a commitment to sharing data and reagents as recommended by the NCI staff. C. The Principal Investigator must state in the application a willingness to accept participation of NCI staff during performance of the award as outlined below under NCI Extramural Staff Responsibilities . D. Patent Coverage. Since the discovery of new targets, assays and improved anticancer treatments is the objective of this effort and since transfer of intellectual property to industrial laboratories for extended developmental purposes is facilitated by the existence of adequate patent coverage, it is essential that applicants provide plans to assure such coverage. Also, according to the terms of this RFA, the NCI staff may recommend that reagents and assays, which may be considered IP, be transferred to another party for assay development or screening purposes. Each applicant must therefore 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. A plan should be developed for transfer of materials embodying intellectual property to other parties upon recommendation by NCI. 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, Vol. 19, No. 23, June 22, 1990. A formal statement of patent procedures and plan for transfer of materials embodying intellectual property to other parties as well as a detailed description of procedures to be followed for resolution of legal problems which may develop, signed and dated by the organizational official authorized to enter into intellectual property arrangements for each applicant and collaborators, if any, must be developed. The signed agreement must be submitted prior to award to Dr. John Beisler at the address provided at the GCOB web site, http://dtp.nci.nih.gov (On the panel, left side, click on "Funding", then scroll down to "Staff"). Applicants proposing to access the Natural Products Repository of the NCI must obtain and execute the Natural Products Repository Material Transfer Agreement prior to receiving an award. Similarly, applicants proposing to access the synthetic repository of the NCI must obtain and execute the synthetic Material Transfer Agreement prior to receiving an award. These agreement forms are available at http://dtp.nci.nih.gov (On the panel, left side, click on "Organization", select "Natural Products Branch", select "Natural Products Repository", then scroll down to and select "Material Transfer Agreement"). For information concerning the NCI synthetic or natural product repositories go to the Developmental Therapeutics web site, http://dtp.nci.nih.gov (On the panel, left side, click on "Samples and Services"). For applications involving natural products, the applicant must provide a formal statement signed by an authorized representative of the applicant institution which assures that an equitable portion of royalties or profits arising from drugs discovered, if any, will be returned to indigenous peoples, research collaborators, research institutions or governmental entities as appropriate, in the country of origin of the natural product sample from which the drug was derived. Plans for the procurement of proper collection and export permits must be provided. The signed document must be submitted prior to award to Dr. Gordon Cragg at the Developmental Therapeutics Program web site, http://dtp.nci.nih.gov (On the panel, left side, click on "Organization", select "Natural Products Branch" then click on "Organization/ Staff Directory"). A plan must be developed for disposition of natural products samples, chemical libraries, etc., in conformance with Terms and Conditions of Award below. The signed document must be submitted prior to award to Dr. John Beisler at the address provided at the GCOB web site, http://dtp.nci.nih.gov. The four documents listed above will not be included with review material, and therefore, will NOT be required at the time of application. However, awards will not be made until they are received and approved by NCI. E. An NIH intramural scientist (IMS) may serve as a PI on a project, and for supported projects an IMS or their designated representative will serve on the Molecular Target Analysis Group for recommending guidelines and standards for the discovery and validation of new targets. However, an IMS may not receive salary, equipment, supplies, or other remuneration from this RFA. The IMS must obtain approval of their respective NIH Institute Scientific Director to allocate resources to the project. This letter must specify that no more than $300,000 direct costs of intramural resources will be allocated to the project and provide assurance that the conduct of the project will comply with the Department of Health and Human Services (DHHS) regulations for vertebrate animal and human subjects research. The participation of an IMS is independent of and unrelated to the role of the NCI Program Official as described below in Terms and Conditions of Award . III. TERMS AND CONDITIONS OF AWARD The following terms and conditions will be incorporated into the U01 award statement, and will be provided to the PI and awardee institutional official at the time of award or to the PI of the NIH intramural project and NIH Institute Scientific Director at the time of selection for participation. Failure to abide by any of the TERMS AND CONDITIONS OF AWARD pertaining to awardee responsibilities as stipulated, may result in reduction of funding, withholding of support, or suspension or termination of award. 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 Parts 74 and 92, and other HHS, PHS, and NIH Grant Administration policy statements. (Part 92 applies when state and local government are eligible to apply as a domestic organization .) A. The administrative and funding instrument used for the non-NIH intramural applicants is the cooperative agreement (U01), an assistance mechanism (rather than as acquisition mechanism) in which substantial NIH scientific and programmatic involvement with the awardee is anticipated during performance of the activity. Under the cooperative agreement, the NIH purpose is to support and/or stimulate the recipient’s activity by involvement in and otherwise working jointly with the award recipient in a partner role, but it is not to assume direction, prime responsibility, or a dominant role in the activity. Consistent with this concept, the dominant role and prime responsibility for the activity supported by a cooperative agreement resides with the awardee for the project as a whole, although specific tasks and activities in carrying out the studies will be shared by the awardee and NCI. NIH intramural project applicants will be supported by intramural resources. B. Awardee Rights and Responsibilities 1. The PI is the scientist who is designated by the awardee institution or NIH intramural laboratory to direct the MTDD project. The PI will have primary authority and responsibility to define objectives and approaches, and to plan and conduct the proposed research. The PI will assume responsibility and accountability to the awardee institution and to the NCI for performance and proper conduct of the research in accordance with the TERMS AND CONDITIONS OF AWARD. 2. The PI or designated representative will serve as a voting member of the Molecular Target Analysis Group and will attend meetings as scheduled. 3. As stated in the RFA, the PI will be responsible for accepting the NCI molecular target goals, procedures, and policies. Included, but not limited to, would be the transfer of molecular target and screening assays to a third party, such as an NCI contract-based resource, for the purpose of developing and/or utilizing high-throughput screening. 4. Awardees will retain custody of, and have primary rights to, data developed under awards, subject to Government rights of access consistent with current HHS, PHS, and NIH policies. Under the terms of OMB Circular A-110, data generated by grantees is now subject to the Freedom of Information Act. Assays and use of novel molecular targets developed under the U01s may be considered unique research resources. The policy of the PHS is to make available to the public results and accomplishments of activities that it funds. All awardees must adhere to PHS policy for distribution of unique research resources produced with PHS funding, which was published in the Federal Register on December 23, 1999 [64 FR 72090] and is available on the Internet at: http://www.ott.nih.gov/policy/rt_guide_final.html. Publication or oral presentation of work done under this agreement will require appropriate acknowledgment of NCI support: see Acknowledgment of Federal Funding (Section 507) in the Notice of Legislative Mandates Contained in the FY2000 Omnibus Appropriations http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-010.html . Dissemination of information or synthetic or natural substances supplied by NCI will require clearance by NCI to assure conformity with existing confidentiality agreements with suppliers. 5. Possessory rights of physical materials, such as natural product samples and chemical libraries acquired during the course of the research, rests with the applicant. For samples governed by a Materials Transfer Agreement (MTA), disposition will be determined in consultation, and with approval of, NCI. Transfer of samples to other parties or collaborators can only be done if the other party(ies) agree to the MTA through being a signatory of the MTA. Prior to award the applicant must formulate a policy for final disposition of the samples and ownership rights in the event that the samples are transferred to other parties who use them to make discoveries. 6. In order that samples be fully evaluated for anticancer potential after the awardee has concluded its evaluation, but before the samples are transferred to other parties for evaluation in other therapeutic areas, it is requested that the awardee provide lists of completed samples to an NCI Program Scientist, who may facilitate additional biological evaluation in NCI’s contract-based screening facilities or at an additional testing resource of mutual agreement to NCI and the awardee. 7. The NCI recognizes that most countries retain interest in samples collected within their domains. In the event that an applicant may propose study of natural products from foreign sources, a formal statement of agreement, prior to an award, must be provided to NCI, signed by an authorized representative of their institution and that of their collaborators, if any, for equitable return of benefits such as profits or royalties derived from discoveries supported by this award to indigenous peoples, research collaborators, cooperating institutions or governmental entities in the countries of origin, as appropriate to their contributions. C. NCI Extramural Staff Responsibilities 1. The NCI Program Official will select an NCI Program Scientist, from the extramural but not the intramural staff, for each MTDD following award. NCI will participate as a non-voting member of the Molecular Target Analysis Group and will be represented by Program Scientists. During performance of the award, through the NCI Program Scientist, the NCI may provide appropriate assistance by participating in the design of activities. In all cases, the role of NCI will be to assist and facilitate and not to direct activities. 2. The NCI Program Scientist, as well as any other MTDD group member, may assist in research planning, may suggest studies within the scope of the MTDD"s objectives and research activities, may present to the MTDD experimental findings from published sources or from contract projects in support of these suggestions, may participate in the design of experiments agreed to by the MTDD, may advise in the selection of sources for resources, may advise in management and technical performance, and may participate in the analysis of results. However, the NCI Program Scientist will not conduct laboratory studies. 3. Upon recommendation of the NCI Program Scientist, NCI may utilize its drug development resources in support of activities when such resources may be required on an occasional basis. The following is a list or resources that may be supplied if they become desirable during performances, are not anticipated as a continuing need, and are readily available. a. Reference compounds for standardization of test systems, as analytical standards, and for related purposes. b. Needed resources such as test materials and information. c. Data from testing conducted in resource contract laboratories. d. Laboratory testing capacity in NCI’s current contract-based resources. e. Searches of computer files of materials, chemical structures and biological activity. Information provided will be restricted by any confidentially agreement between the Government and suppliers of such materials or information. f. Experimental animals and cultured cells, if available, to projects which do not require these items on a regular basis. Projects which require animals and cells on a regular basis must budget these items in the application. D. Collaborative Responsibilities Molecular Target Analysis Group: NCI Program Scientists, the Program Official and Principal Investigators for U01 awards and NIH intramural projects will form a Molecular Target Analysis Group as defined below. An arbitration system, as detailed below, will be available to resolve any disagreement which may arise between NIH Program Scientists and the members of the Molecular Target Analysis Group. The Molecular Target Analysis Group will be composed of the PI from each U01 or NIH intramural project or their designated representatives plus non-voting representatives selected by the voting members. The NCI Program staff will attend as non-voting members. A Chair, not from the NCI extramural staff, will be selected by the Molecular Target Analysis Group. The Molecular Target Analysis Group or NCI may, when it is deemed to be necessary, invite additional, ad hoc, non-voting advisors to the meetings. The Molecular Target Analysis Group will meet at least twice annually. One meeting will be in the Bethesda area and the other at a time and place agreed upon by the Molecular Target Analysis Group and the NCI. A planning meeting of the Molecular Target Analysis Group will be convened by the NCI program staff shortly after the U01 awards are made and the NIH intramural projects are selected. At this planning meeting, a Chair will be selected and the Group may: -draft a charter to detail policies and procedures and agree on terms of the charter -set a plan for location and time of future meetings -review criteria for validation of a molecular target as a site of vulnerability for drug discovery At subsequent meetings the Group will evaluate molecular target data presented by individual PI s. As a Group they will determine the status of various target projects and facilitate the research efforts for target validation and drug discovery for each project presented. The Molecular Target Analysis Group may establish subcommittees, as it deems appropriate, NCI staff may serve on subcommittees. In summary, the purpose of the Molecular Target Analysis Group is to apply its collective knowledge to accelerate the pace of identification of new molecular targets for drug discovery. Members of the Molecular Target Analysis Group and their collaborators will participate in recommending guidelines and standards for the discovery and validation of new targets, and will have the advantage of access to resources, information, technologies, ideas, and expertise to facilitate their research. As targets are developed and validated, the NCI will provide a mechanism to disseminate information to the research community, with appropriate safeguards for protection of intellectual property. The ideal outcome from these efforts would be the discovery of a new generation of agents useful for the treatment and/or prevention of cancer. The NCI will have the option to cross-file or independently file an application for investigational clinical trial (e.g., and Investigational New Drug Application [INDA] to the United States Food and Drug Administration) of any invention resulting from these NCI supported cooperative agreements. Reports of data required for inclusion in INDAs and Clinical Brochures and for cross-filing purposes shall be submitted promptly by the PI to an NCI Program Scientist upon request. Such reports shall include background information, methods, results, and conclusions. They will be subject to approval and revision by NCI and may be augmented with test results from other government- sponsored projects prior to submission to the appropriate regulatory agency. E. Arbitration Panel Any disagreement that may arise on scientific/programmatic issues (within the scope of the U01 award or NIH intramural project), between the awardees and the NCI Extramural Program staff may be brought to arbitration. An arbitration panel will be composed of three members: one selected by the Molecular Target Analysis Group, or by the U01 awardee or NIH intramural project in the event of an individual disagreement, a second member selected by the NCI, and third member agreed upon by the other two. For U01 awardees, this special arbitration procedure in no way affects the awardee’s right to appeal an adverse action that is otherwise appealable in accordance with the PHS regulations at 42 CFR Part 50, Subpart D and HHS regulation at 45 CFR Part 16. 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 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 in the NIH Guide for Grants and Contracts, Volume 23, Number 11, March 18, 1994, available on the web at the following URL address: http://grants.nih.gov/grants/guide/notice-files/not94-100.html. Investigators may also obtain copies of the policy from the program staff mentioned in the GCOB web site, http://dtp.nci.nih.gov. 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 clear and compelling scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the NIH Policy and Guidelines on the Inclusion of Children as Participants in Research Involving Human Subjects that was published in the NIH Guide for Grants and Contracts, March 6, 1998, and is available at the following URL address: http://grants.nih.gov/grants/guide/notice-files/not98-024.html. As part of the scientific and technical merit evaluation of the research plan, reviewers will be instructed to address the adequacy of plans for including children as appropriate for the scientific goals of the research, or justification for exclusion. LETTER OF INTENT Prospective applicants are asked to submit, by June 6, 2000, a letter of intent (by mail, FAX or e-mail) that includes a descriptive title of the proposed research, name, address, and telephone number of the Principal Investigator, identities of other key personnel and participating institutions, and 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 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 INQUIRES by the letter of intent receipt date listed in the heading of this RFA. APPLICATION PROCEDURES Applicants for either U01 awards or NIH Intramural projects must use the research grant application form PHS 398 (rev. 4/98). Alternatively, NIH intramural project applicants must follow the directions in Additional Instructions for NIH Intramural Project Applicants" below. Application kits are available at most institutional offices of sponsored research and may be obtained 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. PHS 398 application kits are also available at: http://grants.nih.gov/grants/funding/phs398/forms_toc.html. All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view Internet sites. Reviewers are cautioned that their anonymity may be compromised when they directly access an Internet site (see http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-004.html). SPECIAL INSTRUCTIONS FOR ALL APPLICANTS 1. Specific issues related to cooperative agreements must be addressed as follows. o Applicants must budget (i.e., based on a city centrally located in the USA) for travel and per diem expenses for Molecular Target Analysis Group meetings. In the first year, applicants should plan for two investigators, the principal investigator and an additional senior investigator, to attend two Molecular Target Analysis Group meetings. In the second and subsequent years, applicants should plan for the PI to attend two Molecular Target Analysis Group meetings per year. o Applicants must include their specific plans for responding to the "Terms and Conditions of Award" section. Applicants should state their willingness to collaborate and share data freely with the other MTDD awardees, to participate in planning and to serve on the Molecular Target Analysis Group and be bound by its decisions for setting the standards for characterization and validation, and to be able and willing to share data and communicate with each other and the NCI in an Internet environment. Applicants should also describe how they will comply with the involvement of an NCI Program Scientist. 2. Additional Materials to Include in the Application 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, MOLECULAR TARGET DRUG DISCOVERY FOR CANCER, and number, RFA CA-00-002, must be typed on line 2 of the face page of the application form and the YES box must be marked. 3. Application Format to Follow The format outlined in the form PHS 398 kit should be followed except for the additional materials listed below which should be included in the indicated order after the LITERATURE CITED section. o Acceptance of NCI Staff participation as described in NCI Extramural Staff Responsibilities . o A statement by the PI accepting participation on the Molecular Target Analysis Group and implementing, if applicable, the goals, procedures and policies agreed upon by the Molecular Target Analysis Group. o A plan for patent coverage and licensing, for transfer of material embodying intellectual property to other parties, for resolution of legal problems should they arise. o An assurance plan to return benefits to the country of origin in the use of natural products. o A plan for the disposition of natural products samples and chemical libraries. U01 applicants (NIH intramural project applicants must use the address in section 3, Additional Instructions for NIH Intramural Project Applicants" below), should submit a typewritten, signed original of the application, including the checklist, and three signed photocopies, in one package to: CENTER FOR SCIENTIFIC REVIEW NATIONAL INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710 BETHESDA, MD 20892-7710 BETHESDA, MD 20817 (for express/courier service) At the time of submission, two additional signed photocopies 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 Bethesda, MD 20892-8239 Rockville, MD 20852 (for express/courier service) Applications must be received by July 18, 2000. If a U01 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 U01 application in response to this RFA that is essentially the same as a research project application 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 a substantial revision of an application already reviewed, but such an application must follow the guidance in the PHS Form 398 application instructions for the preparation of revised applications, including an introduction addressing the previous critique. ADDITIONAL INSTRUCTIONS FOR NIH INTRAMURAL PROJECT APPLICANTS The research grant application form PHS 398 (rev. 4/98) is also to be used by NIH intramural project applicants in applying for these grants. Applications kits are available may be obtained 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. For those applicants with internet access, the 398 kit may be found at http://grants.nih.gov/grants/funding/phs398/forms_toc.html. The PHS 398 application form should be used with the following modifications: o On the Face Page, fill out only items 1., 2., 3.(leave 3c. blank), 4.and 5. The remainder of the items should be left blank, and the application must not be signed by either the PI or an NIH Institute official. The RFA label must be affixed to the bottom of the Face Page, as described above in section 2. o Do not submit "Other Support", Checklist", "Personnel Report", or "Personal Data" pages. o The PI must obtain the approval of the NIH Institute Scientific Director for applying for collaboration, or for participating as a principal investigator, in the MTDD program under the terms and conditions of the RFA, and for complying with the policies of the Molecular Target Analysis Group. A copy of that letter of approval must be provided as part of a cover letter, addressed to the NCI Referral Officer, for the application. o The budget page should supply the time and effort for each project participant, but no other budget figures should be included. The resources available for the project and the research environment should be carefully described, but no budget figures should be included. The NIH Institute Scientific Director, as part of the letter of approval for participation, must verify that no more than $300,000 direct costs of intramural resources will be allocated to the project described in the application, and provide assurance that the conduct of the project will comply with the DHHS regulations for research involving human subjects (if applicable) and with the PHS policy on vertebrate animal research. o For NIH intramural applicants, a letter of approval must be submitted from their Institute Intramural Scientific Director to allocate resources to the project. o Submit an unsigned, typewritten original of the application, and five photocopies to: Ms. Toby Friedberg Referral Officer Division of Extramural Activities National Cancer Institute 6116 Executive Boulevard, Room 8062, MSC 8239 Bethesda, MD 20892-8239 Rockville, MD 20852 (for express/courier service) Do not send the application or any copies to the Center for Scientific Review. NIH intramural project applications must be received by July 18, 2000. If an application is received after that date, it will be returned to the applicant without review. REVIEW CONSIDERATIONS: Extramural Applications Upon receipt, applications will be reviewed for completeness by CSR and responsiveness by NCI. Incomplete and/or non-responsive applications will be returned to the applicant without further consideration. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the Division of Extramural Activities of the NCI in accordance with the review criteria stated below. As part of the initial merit review, a process will be used by the initial review group in which applications will receive a written critique and undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of the applications under review, will be discussed, assigned a priority score, and receive a second level review by the National Cancer Advisory Board. Review Criteria The goals of NIH-sponsored research are to advance our understanding of biological systems, improve the control of disease, and enhance health. Within this framework, the specific goals of this RFA are the discovery and validation of new molecular targets with the potential for developing assays for the discovery of new agents to treat or prevent cancer. At minimum, a target should be identified (de novo, or from the literature), a validation plan outlined, and a conception of how the validated target can be developed into a drug assay. Meritorious projects will include imaginative intervention points and insightful validation approaches, which overall will reveal an exploitable site of critical vulnerability. The reviewers will comment on the five criteria listed below in their written critiques of the applications in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered by the reviewers in assigning the overall score weighting them as appropriate for each application. Note that the application does not need to be strong in all categories to be judged likely to have a major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. Significance. Does this study address an important problem? 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? Is the proposed molecular target of importance to development and maintenance of the transformed phenotype? Is the target new and not one which has been the object of other evaluative studies? What is the likelihood that assays using this target will lead to a new class of agents for the prevention or treatment of cancer? 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 alternate tactics? How well has the applicant addressed the major goals of the RFA: identification of a novel target, its validation as an intervention point, and assay development? What is the likelihood that a high-throughput screen can be developed with the target? Has the applicant designed an appropriate set of experiments to demonstrate a critical site of vulnerability in the cancer cell which can exploited for treatment or prevention? If crude natural product extracts are proposed, are strategies for compound isolation and identification adequate? If structural biology studies are proposed, are plans adequate for the production of materials and have appropriate collaborations been arranged? If screening is proposed, are data handling procedures adequate, and is the assay validated and appropriate for large- scale or high throughput use? 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? Will the approaches advance the use of new, validated molecular targets for new drug discovery? Investigator. Is the investigator appropriately trained and suited to carry out the project? Is the research proposed appropriate to the experience level of the PI and other researchers (if any)? Environment. Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ valuable collaborative arrangements? Additional Considerations The initial review group will also examine: the appropriateness of the proposed 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 of human and animal subjects, and the safety of the research environment. For intramural applications, all of the above applies except applications will not be reviewed for completeness by CSR, the proposed budget will not be reviewed by the review group. AWARD CRITERIA Extramural applications recommended by the National Cancer Advisory Board will be considered for award based upon (a) scientific and technical merit, (b) program balance, including in this instance, sufficient compatibility of features to make a successful collaborative program a reasonable likelihood, and (c) availability of funds. SCHEDULE Letter of Intent Receipt Date: June 6, 2000 Application Receipt Date: July 18, 2000 Review by NCAB Advisory Board: February 2001 Earliest Anticipated Start Date: April 1, 2001 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 in cancer treatment, inquiries regarding access to the Natural Products Repository and inquiries regarding access to the Synthetic Compound Repository of NCI to the appropriate individuals given in the GCOB web site: http://dtp.nci.nih.gov/ (On the panel, left side, click on "Funding", then scroll down to "Staff") Direct inquiries regarding programmatic issues in cancer prevention to the DCP web site: http://dcp.nci.nih.gov/cb Direct inquiries regarding review issues to: Ms. Toby Friedberg Referral Officer Division of Extramural Activities 6116 Executive Blvd., Room 8062, MSC 8239 National Cancer Institute Bethesda MD 20892-8239 Rockville, MD 20852 (express courier) Telephone (301) 496-3428 Fax: (301) 402-0275 Email: tf12w@nih.gov Direct inquiries regarding fiscal matters to: Ms. Kathleen Shino Grants Administration Branch National Cancer Institute Executive Plaza South 243 Bethesda, MD 20892-7150 Telephone: (301) 496-8635 Fax: (301) 496-8601 Email: shinok@gab.nci.nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.395, Cancer Treatment Research. 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 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.

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