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RFA-DA-03-015: IMMUNOTHERAPY FOR ADDICTION TREATMENT: SBIR/STTR INITIATIVE IMMUNOTHERAPY FOR ADDICTION TREATMENT: SBIR/STTR INITIATIVE RELEASE DATE: December 30, 2002 RFA NUMBER: DA-03-015 National Institute on Drug Abuse (NIDA) (http://www.nida.nih.gov) LETTER OF INTENT RECEIPT DATE: March 24, 2003 APPLICATION RECEIPT DATE: April 23, 2003 THIS REQUEST FOR APPLICATIONS (RFA) CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA o Research Objectives o Mechanisms of Support o Funds Available o Eligible Institutions o Individuals Eligible to Become Principal Investigators o Where to Send Inquiries ? Letter of Intent o Submitting an Application o Peer Review Process o Review Criteria o Receipt and Review Schedule o Award Criteria o Required Federal Citations NOTICE: This Request for Application (RFA) must be read in conjunction with the current OMNIBUS SOLICITATION OF THE NATIONAL INSTITUTES OF HEALTH, CENTERS FOR DISEASE CONTROL AND PREVENTION, AND FOOD AND DRUG ADMINISTRATION FOR SMALL BUSINESS INNOVATION RESEARCH (SBIR) AND SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) GRANT APPLICATIONS (see https://grants.nih.gov/grants/funding/sbirsttr1/index.pdf). The solicitation contains information about the SBIR and STTR programs, regulations governing the programs, and instructional information for submission. Applicants are required to use the PHS398 forms for all SBIR and STTR submissions. Helpful information for advice and preparation of the application can be obtained at: https://grants.nih.gov/grants/funding/sbirgrantsmanship.pdf. All of the instructions within the OMNIBUS SBIR/STTR SOLICITATION apply with the following exceptions: o Special receipt dates o Initial review convened by the (insert IC) Division of Extramural Activities o Additional review considerations The title and number of this RFA must be typed on line 2 of the face page of the application. PURPOSE OF THIS RFA This RFA encourages small businesses, or small businesses in collaboration with research institutions, to develop effective methods for the large-scale production and clinical testing of monoclonal antibodies or vaccines as therapeutic agents for drug or nicotine addiction and/or overdose. Because the RFA is focused on the advanced phase development of these therapies, applicants should already have access to a new molecular entity (NME), either for active or passive immunization, which is in the advanced stages of preclinical development and is ready to begin the process for translation into clinical trials (large scale GMP production of the entity, toxicity testing, formulation development, stability testing and clinical evaluation). The small business should be conversant with the requirements for the Investigational New Drug (IND) filing of such an entity and should have access to a clinical site. The clinical site could be a part of the small business, the research institution involved in the project, or a subcontractor site. RESEARCH OBJECTIVES Background There has been a great deal of research in the past ten years on the production of monoclonal antibodies and vaccines for the treatment of drug and nicotine abuse. Monoclonal antibodies have been reported as possible treatment agents through passive immunization for PCP, methamphetamine, MDMA, and cocaine overdose and may also serve to minimize abuse and prevent relapse. New vaccines are being developed as therapies for drug or nicotine cessation and relapse prevention. However, the transition of a new molecular entity, or NME (a term which is applied by the Food and Drug Administration to both new pharmaceutical and immunological agents) from the preclinical phase to the clinical phase of development requires large-scale production of the NME and toxicity testing. The requirements are described in the most recent FDA Guidance for Industry documents for vaccines and monoclonal antibodies (http://www.fda.gov/cber/gdlns/cmcvacc.pdf and http://www.fda.gov/cber/gdlns/mab032901.pdf) and constitute a major commitment of resources. Recent advances in the production methods for monoclonal antibodies and vaccines have led to the discovery and preclinical development of new entities intended for the treatment of drug overdose and relapse prevention and cocaine and nicotine addiction. Although preclinical research on new therapies for active or passive immunization for substance abuse disorders has been reported in the literature, the need exists for the advanced phase development and validation of technologies for the bulk scale production of new monoclonal antibodies or vaccines in quantities large enough for clinical trials, and for the design and implementation of clinical trials using immunotherapy for treatment of substance abuse disorders. Major difficulties in the large-scale production of these types of NMEs arise from contaminants such as animal proteins and viruses, culture media constituents, and purification problems. Alternative methods to antibody and immunoconjugate production, which minimize these problems or avoid them altogether, would provide faster and more efficient manufacture of the NME and involve less toxicity testing and therefore less time and expense to obtain a marketable product. Current procedures such as the development of antibodies in bioreactors are costly and time-consuming, with potential for contamination and purification problems. New developments in proteomics should facilitate a more rapid and efficient production method. The testing of these products in human clinical trials will establish the proof-of-concept that active immunization is an effective way of preventing or controlling drug or nicotine addiction and/or relapse and that passive immunization will prevent the adverse health effects of drug overdoses caused by cocaine, methamphetamine, PCP, or MDMA abuse in emergency room overdose situations. Objectives and Scope The goal of this RFA is to facilitate the development of a monoclonal antibody or vaccine for a drug overdose and treatment indication, or drug or nicotine addiction treatment indication, respectively. New technologies are emerging for the large-scale and cost-effective production of monoclonals and vaccines, and it is reasonable to consider that these advances could be applied to their development. The objective of this RFA is to provide the support necessary to successfully transition a NME for immunotherapy for drug or nicotine abuse from the preclinical to the clinical phase, through utilization of improved technology approaches, and to support the clinical safety and efficacy testing of the NME. Because the program is designed to provide support to bridge the critical translation of the NME from the laboratory into the clinic, this RFA is suitable for applicants who already have access to an NME for immunotherapy that has been adequately characterized in animal models, and is ready for clinical development. MECHANISMS OF SUPPORT This RFA uses the SBIR (R43,R44) and STTR (R41,R42) mechanisms, which are set-aside programs. As an applicant, you will be solely responsible for planning, directing, and executing the proposed project. Future competing continuation applications based on this project will compete with all SBIR/STTR applications and will be reviewed according to the customary peer review procedures. The anticipated award date is (insert month, date, year). Applications may be submitted for support as Phase I STTR (R41) or Phase I SBIR (R43) grants; Phase II STTR (R42) or Phase II SBIR (R44) grants; or the SBIR/STTR FAST-TRACK option as described in the OMNIBUS SBIR/STTR SOLICITATION. Phase II applications in response to this RFA will only be accepted as competing continuations of previously funded NIH Phase I SBIR/STTR awards. The Phase II application must be a logical extension of the Phase I research but not necessarily a Phase I project supported in response to this RFA. Fast Track applications will benefit from expedited evaluation of progress following the Phase I feasibility study for transition to Phase II funding for expanded developmental work. PROJECT PERIOD AND AMOUNT OF AWARD The OMNIBUS SBIR/STTR SOLICITATION indicates the statutory guidelines of funding support and project duration periods for SBIR and STTR Phase I and Phase II awards. Because the duration and cost of research for the development of a new immunotherapeutic agent (large-scale production under Good Manufacturing Practices (GMP), toxicity testing needed to support initial human safety testing, and costs associated with the implementation and execution of safety and efficacy trials) is likely to exceed that routinely awarded for SBIR/STTR grants. However, a well-justified application under this RFA will be considered with a Phase I project period of up to 2 years and a budget not to exceed $1,000,000 ($500,000 per year), and a Phase II project period of up to 3 years and a budget not to exceed $2,000,000 (approximately $700,000 per year). Total costs include direct costs, F&A, and a fixed fee. FUNDS AVAILABLE The NIDA intends to commit approximately $1,000,000 in FY 2003 to fund 2 new grants in response to this RFA under the SBIR/STTR set-aside funding mechanism. Because the nature and scope of the research proposed may vary, it is anticipated that the size of each award will also vary. Although the financial plans of NIDA provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications. ELIGIBLE INSTITUTIONS Eligibility requirements are described in the OMNIBUS SBIR/STTR SOLICITATION. Only small business concerns are eligible to submit applications. A small business concern is one that, on the date of award for both Phase I and Phase II agreements, meets ALL of the criteria as described in the SBIR/STTR OMNIBUS SOLICITATION. INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with their institution to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH programs. On an SBIR application, the principal investigator must have his/her primary employment (more than 50%) with the small business at the time of award and for the duration of the project. The PI on an STTR application may be employed with the small business concern or the participating non-profit research institution as long as s/he has a formal appointment with or commitment to the applicant small business concern, which is characterized by an official relationship between the small business concern and that individual. Consultant and Contractual Costs Because the resources required for the successful development of an immunotherapeutic agent are highly specialized, the total amount of consultant costs and contractual costs requested by applicants may exceed the statutory guidelines. Requests in excess of the guidelines must be fully justified. WHERE TO SEND INQUIRIES We encourage your inquiries concerning this RFA and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into three areas: scientific/research, peer review, and financial or grants management issues. o Direct your questions about scientific/research issues to: Jamie Biswas, Ph.D. Division of Treatment Research and Development National Institute on Drug Abuse/NIH/DHHS 6001 Executive Boulevard, Room 4123, MSC 9551 Bethesda, MD 20892-9551 Telephone: (301) 443-8096 FAX: (301) 443-9649 Email: jb168r@nih.gov o Direct your questions about peer review issues to: Teresa Levitin, Ph.D. Office of Extramural Affairs National Institute on Drug Abuse/NIH/DHHS 6001 Executive Boulevard, Room 3158, MSC 9547 Bethesda, Maryland 20892-9547 Telephone: (301) 443-2755 FAX: (301) 443-0538 Email: tl25u@nih.gov o Direct your questions about financial or grants management issues to: Gary Fleming, J.D., M.A. Grants Management Branch National Institute on Drug Abuse/NIH/DHHS 6001 Executive Boulevard, Room 3131 Bethesda, MD 20892-9541 Telephone: (301) 443-6710 FAX: (301) 594-6849 E-mail: GF6S@NIH.GOV LETTER OF INTENT Prospective applicants are asked to submit a letter of intent by that includes the following information: ? Descriptive title of the proposed research ? Name, address, and telephone number of the Principal Investigator ? Names of other key personnel ? Participating institutions ? Number and title of this RFA Although a letter of intent is not required, is not binding, and does not affect the review of a subsequent application, the information that it contains allows NIDA staff to estimate the potential review workload and plan the review. The letter of intent is to be sent by the date listed at the beginning of this document. The letter of intent should be addressed to: Director Office of Extramural Affairs National Institute on Drug Abuse/NIH/DHHS 6001 Executive Blvd, Room 3158, MSC 9547 Bethesda, MD 20892-9551 Rockville, MD 20852 (for express/courier service) Telephone: (301) 443-2755 FAX: (301) 443-0538 Email: tl25u@nih.gov SUBMITTING AN APPLICATION The PHS 398 research grant application (rev. 5/2001) must be used for all Phase I, Phase II and Fast-Track applications (new and revised.) Instructions and forms are available at https://grants.nih.gov/grants/funding/phs398/phs398.html. Prepare your application in accordance with the SBIR/STTR Omnibus Solicitation and Chapter VI of the PHS 398. The NIH will return applications that are not submitted on the 5/2001 version of the PHS 398. For further assistance contact GrantsInfo, Telephone: (301) 710-0267, Email:GrantsInfo@nih.gov. USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 5/2001) application form must be affixed to the bottom of the face page of the application. Type the RFA number on the label. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. The RFA label is also available at: https://grants.nih.gov/grants/funding/phs398/label-bk.pdf. SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of the application, including the checklist, and three signed photocopies in one package to: Center for Scientific Review National Institutes of Health 6701 Rockledge Drive, Room 1040, MSC 7710 Bethesda, MD 20892-7710 Bethesda, MD 20817 (for express/courier service) At the time of submission, two additional copies of the application must be sent to: Director Office of Extramural Affairs National Institute on Drug Abuse/NIH/DHHS 6001 Executive Blvd., Room 3158, MSC 9547 Bethesda, MD 20892-9547 Rockville, MD 20852 (for express/courier service) RECEIPT OF APPLICATIONS. Applications must be received by the receipt date listed on the first page of this announcement. The Center for Scientific Research (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 a substantial revision of an application already reviewed, but such application must include an Introduction addressing the previous critique. PEER REVIEW PROCESS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by NIDA. Incomplete and/or non-responsive applications will be returned to the applicant without further consideration. If the application is not responsive to the RFA, CSR staff may contact the applicant to determine whether to return the application to the applicant or submit it to compete with other applications submitted in response to the next available receipt date of the OMNIBUS SOLICITATION. An appropriate scientific review group convened in accordance with the standard NIH peer review procedures (http://www.csr.nih.gov/refrev.htm) will evaluate applications for scientific and technical merit. As part of the initial merit review, all applications will: o Receive a written critique o Undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of applications under review, will be discussed and assigned a priority score o Those that receive a priority score will undergo a second-level review by the appropriate national advisory council or board. REVIEW CRITERIA The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. In the written comments, reviewers will be asked to discuss the following aspects of your application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals: o Significance o Approach o Milestones and Proof of Principle o Innovation o Investigator o Environment The scientific review group will address and consider each of these criteria in assigning your application's overall score, weighting them as appropriate for each application. Your application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, you may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. Review criteria are described in the NIH Omnibus Solicitation and available on the web at the following URL address: https://grants.nih.gov/grants/funding/sbirsttr1/index.pdf ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, your application will also be reviewed with respect to the following: SIGNIFICANCE: Will the product arising from this research address a clinical need in the targeted patient population? APPROACH: Does the applicant have access to the new molecular entity (NME)? Does the applicant have access to a clinical site for clinical trials? Has the applicant or applicant organization provided a Data and Safety Monitoring Plan for the clinical studies? INNOVATION: Will the production of the proposed monoclonal antibody or vaccine utilize an innovative method, or methods, which will allow for the reasonably cost effective and efficient large scale production of the immunotherapeutic agent? Is the product expected to improve the treatment of substance abuse and its consequences? INVESTIGATOR: Is the PI knowledgeable in FDA requirements for Investigational New Drug (IND) filing? Does the applicant have experience in the development and clinical testing of immunotherapies? ENVIRONMENT: Has the site experience in producing entities under Good Manufacturing Practices (GMP)? Is the facility set up for the large scale GMP manufacture, purifications, and formulation of a therapeutic entity? PROTECTIONS: The adequacy of the proposed protection for humans, animals, or the environment, to the extent they may be adversely affected by the project proposed in the application. INCLUSION: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. (See Inclusion Criteria included in the section on Federal Citations, below) BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. RECEIPT AND REVIEW SCHEDULE Letter of Intent Receipt Date: March 24, 2003 Application Receipt Date: April 23, 2003 Peer Review Date: June/July/August 2003 Council Review: September 2003 Earliest Anticipated Start Date: September 30, 2003 AWARD CRITERIA Award criteria that will be used to make award decisions include: o Scientific merit of the proposed project as determined by peer review o Availability of funds o Relevance to program priorities Phase II applications will be selected for funding based on the following: o Quality of the proposed project as determined by peer review o Assessment of Phase I progress o Determination that the Phase I goals were achieved o The project's potential for commercial success o Availability of funds Fast Track Phase II applications may be funded following submission of: o The Phase I progress report o Other documents necessary for continuation REQUIRED FEDERAL CITATIONS MONITORING PLAN AND DATA SAFETY AND MONITORING BOARD: Research components involving Phases I and II clinical trials must include provisions for assessment of patient eligibility and status, rigorous data management, quality assurance, and auditing procedures. In addition, it is NIH policy that all clinical trials require data and safety monitoring, with the method and degree of monitoring being commensurate with the risks (NIH Policy for Data Safety and Monitoring, NIH Guide for Grants and Contracts, June 12, 1998: https://grants.nih.gov/grants/guide/notice-files/not98-084.html). INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported clinical research projects unless a clear and compelling justification is provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing clinical research should read the AMENDMENT "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research - Amended, October, 2001," published in the NIH Guide for Grants and Contracts on October 9, 2001 (https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines are available at https://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm. The amended policy incorporates: the use of an NIH definition of clinical research; updated racial and ethnic categories in compliance with the new OMB standards; clarification of language governing NIH-defined Phase III clinical trials consistent with the new PHS Form 398; and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH-defined Phase III clinical trials that: a) all applications or proposals and/or protocols must provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable; and b) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS: The NIH maintains a policy that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines" on the inclusion of children as participants in research involving human subjects that is available at https://grants.nih.gov/grants/funding/children/children.htm. HIV/AIDS COUNSELING AND TESTING POLICY FOR THE NATIONAL INSTITUTE ON DRUG ABUSE: Researchers funded by NIDA who are conducting research in community outreach settings, clinical, hospital settings, or clinical laboratories and have ongoing contact with clients at risk for HIV infection, are strongly encouraged to provide HIV risk reduction education and counseling. HIV counseling should include offering HIV testing available on-site or by referral to other HIV testing services. Persons at risk for HIV infection including injecting drug users, crack cocaine users, and sexually active drug users and their sexual partners. For more information see https://grants.nih.gov/grants/guide/notice-files/NOT-DA-01-001.html. NATIONAL ADVISORY COUNCIL ON DRUG ABUSE RECOMMENDED GUIDELINES FOR THE ADMINISTRATION OF DRUGS TO HUMAN SUBJECTS: The National Advisory Council on Drug Abuse recognizes the importance of research involving the administration of drugs to human subjects and has developed guidelines relevant to such research. Potential applicants are encouraged to obtain and review these recommendations of Council before submitting an application that will administer compounds to human subjects. The guidelines are available on NIDA's Home Page at www.nida.nih.gov under the Funding, or may be obtained by calling (301) 443-2755. REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS: NIH policy requires education on the protection of human subject participants for all investigators submitting NIH proposals for research involving human subjects. You will find this policy announcement in the NIH Guide for Grants and Contracts Announcement, dated June 5, 2000, at https://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html. HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research on hESCs can be found at https://grants.nih.gov/grants/stem_cells.htm and at https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html. Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (see http://escr.nih.gov). It is the responsibility of the applicant to provide the official NIH identifier(s)for the hESC line(s)to be used in the proposed research. Applications that do not provide this information will be returned without review. PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at https://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this RFA in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award. URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site. HEALTHY PEOPLE 2010: The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This RFA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople. AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal Domestic Assistance No. 93.279 and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. 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 described at https://grants.nih.gov/grants/policy/policy.htm and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. The PHS strongly encourages all grant recipients to provide a smoke-free workplace and discourage the use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.

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