Full Text RR-95-002 NATIONAL GENE VECTOR LABORATORIES NIH GUIDE, Volume 23, Number 40, November 18, 1994 RFA: RR-95-002 P.T. 34 Keywords: Genetics Gene Therapy+ National Center for Research Resources National Cancer Institute National Heart, Lung, and Blood Institute National Institute of Diabetes and Digestive and Kidney Diseases Letter of Intent Receipt Date: December 15, 1994 Application Receipt Date: February 21, 1995 PURPOSE The National Center for Research Resources (NCRR), together with the National Cancer Institute (NCI), the National Heart, Lung, and Blood Institute (NHLBI), and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) as cosponsors, invite applications to establish National Gene Vector Laboratories to enhance research leading to successful gene therapy of single- and multiple-gene disorders. For purposes of this solicitation, the term "vector" is used in the broadest sense to refer to any vehicle designed to deliver genetic material into human somatic cells. The National Gene Vector Laboratories will provide shared resources to facilitate optimal vector production of clinical grade vectors for human gene therapy research. The overall goals are to provide vectors for the prevention, treatment, and cure of a wide variety of medical conditions through gene therapy. HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," a PHS-led national activity for setting priority areas. This Request for Applications (RFA), National Gene Vector Laboratories, is related to many of the priority areas discussed in this publication. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0) or "Healthy People 2000" (Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202 783-3238). ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic, but not foreign, 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. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Program Directors. MECHANISM OF SUPPORT The administrative and funding instrument to be used for this program will be the NIH Animal (Mammalian and Nonmammalian) Model, and Animal and Biological Materials Resource Cooperative Agreement (U42), 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 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. Details of the responsibilities, relationships, and governance of the projects to be funded under cooperative agreement(s) are discussed later in this document under the section "Terms and Conditions of Award." The total project period for applications submitted in response to the present RFA may not exceed five years. The anticipated award date is August 1, 1995. Because the nature and scope of the activity proposed in response to this RFA may vary, it is anticipated that the size of an award will vary also. Awards and 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 NCRR and cosponsoring Institutes, awards pursuant to this RFA are contingent upon the availability of funds for this purpose. This RFA is currently anticipated to be a one-time solicitation. However, if it is determined that there is a sufficient continuing need, the NCRR will invite new applicants and recipients of awards under this RFA to submit competitive new and/or competitive continuation cooperative agreement applications for review according to the procedures described in REVIEW CONSIDERATIONS. FUNDS AVAILABLE Approximately $3.5 million in total costs will be available in Fiscal Year 1995 for the first year of support of meritorious applications submitted in response to this RFA . It is anticipated that between one and three awards will be made. RESEARCH OBJECTIVES Background Recent understanding of molecular biology, combined with breakthroughs in virology and gene transfer techniques, have led to new approaches to the treatment of both inherited and acquired diseases. Diseases thought to be amenable to gene therapy include, but are not limited to, single gene disorders such as cystic fibrosis, Gaucher disease, adenosine deaminase deficiency, immune deficiencies, hemoglobinopathies, hemophilias, hyperlipidemias, and multifactorial disorders such as cancer, hypertension, diabetes, heart disease, and pulmonary diseases. In addition, diseases such as acquired immunodeficiency syndrome (AIDS) and malignancies require suitable vector development, production, and distribution to enhance research leading to effective treatment. Gene therapy for such diseases requires the development of suitable vectors to transfer new genetic material to target cells. Somatic cells such as lung, muscle, liver, neuronal, and bone marrow stem cells, as well as tumor cells, are important targets for gene therapy. An array of viral vectors are under investigation for use in such treatments. In addition, liposome formulations have been approved as vehicles for the delivery of DNA. The technical requirements and the expense of vector development, production, and safety testing have limited the capacity of clinical investigators to proceed with implementation of gene therapy. Just as collaborative efforts have facilitated the testing of gene therapy for cystic fibrosis, optimal progress in treatment of other diseases would be enhanced by national cooperation for the production and distribution of vectors for gene therapy. In addition, centralizing such facilities will reduce the cost barrier for the production of vectors and therefore, enhance development of vectors for rare disorders where commercialization is not cost effective. Objectives and Scope The objective of this RFA is to solicit applications for cooperative agreements to support national laboratories for vector production, maintenance, and distribution for use in gene therapy. The rapid advancements in the field of molecular genetics have led to the identification and characterization of many genes and their products. In addition, investigators are ready to initiate clinical trials for promising gene therapies and patients are anticipating being participants in these studies. There is difficulty in bringing these scientific breakthroughs to clinically applicable therapies. Failure to accommodate the urgent need for vector production and distribution constitutes a barrier to progress in the field of gene therapy. Through this cooperative agreement initiative, national laboratories will be supported to develop plans and methods to produce and distribute gene therapy vectors for protocols that have received FDA approval and/or have either been determined not to require or have been recommended for approval by the Recombinant DNA Advisory Committee (RAC) and received approval from the Director of the NIH. Highest priority for use of the facilities will be given to projects that have received peer-reviewed grant support. These vectors would have been developed and had preclinical testing supported by NIH funding. Facilities must demonstrate expertise in production of gene therapy vectors that meet FDA criteria for human use. Facilities must address which of the currently approved vectors including retroviral, adenoviral, adeno-associated viral, and/or cationic liposomes will be produced at the facility, and must address how they will incorporate new technologies in the future. Facilities must have the capability to produce several vectors simultaneously and provide information regarding maximal capabilities. SPECIAL REQUIREMENTS These cooperative agreements (U42s) will require cooperation among the NCRR scientific coordinator, the participating Institute and Center (IC) program administrators, and the Program Directors of each vector production facility in order to assure smooth interactions among awardee organizations. To promote the development of a collaborative program among the award recipients, a number of issues need to be addressed in their applications as discussed below. The following terms and conditions will be incorporated into the award statement and provided to the Program Director as well as the institutional official at the time of award. Terms and Conditions 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. The administrative and funding instrument used for this program is a cooperative agreement (U42), 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 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 resides with the awardee(s) for the project as a whole, although specific tasks and activities in carrying out the project(s) will be shared among the awardees and the IC participants. 1. Awardee Rights and Responsibilities The Program Directors and an associate from each institution will plan and design the details of the project including appropriate methods for defining and operating the vector laboratories. They will retain primary responsibility for the performance of the activity. Program Directors and associates must form and agree to participate as members of the National Gene Vector Laboratories Steering Committee. Program Directors will appoint outside experts to balance the composition and size of the Steering Committee so that the total percentage of NIH representatives does not exceed 40 percent of the membership. Each member of the Steering Committee, including the outside experts, will have one vote. The Program Directors, in cooperation with the other Steering Committee members, are responsible for developing the details of the operating policies of the National Gene Vector Laboratories, including definition of objectives and approaches, planning, implementation, and interaction with other Program Directors, and assurance of scientific integrity. The Steering Committee will elect a Chairperson from among the participating Program Directors. Rules governing the selection and tenure of the Chairperson and outside experts will also be established by the Steering Committee. The facility represented by the elected chairperson will then be designated as the Coordinating Facility for purposes of submitting applications for use of all facilities. That facility will also be responsible for the paperwork involved in Steering Committee meetings including preparing meeting agendas, chairing meetings, writing and distributing minutes, and notifying successful and unsuccessful applicants for use of the resource of decisions made and providing the written rationale for such. The Chairperson of the Steering Committee must present an update of activities at each meeting. In order to accomplish this obligation, each Program Director is responsible for timely preparation and submission of his or her individual update to the Chairperson of the Steering Committee who will prepare a summary for presentation at the time of each Steering Committee meeting for incorporation into the minutes. 2. I/C Staff Responsibilities One representative from the NCRR will be designated to serve as the NIH Scientific Coordinator to the cooperative agreement. The NIH Scientific Coordinator and one program administrator from each cosponsoring Institute will serve on the Steering Committee in order to bring that individual's unique perspective on a given categoric disease for which the individual oversees basic genetic research. In consultation with awardees, these individuals may convene workshops or sponsor seminars within existing meetings to update the Program Directors on advances in gene therapy accomplished through NIH support. While each of the four participating IC representatives will attend and have a vote on the Steering Committee, according to the organization of the Committee, their cumulative votes will never exceed 40 percent. As members of the Steering Committee, the NIH Scientific Coordinator and the other IC program administrators attend and participate in all meetings and assist in developing operating policies, quality control procedures, and consistent policies for dealing with recurring situations that require cooperative action. The NIH Scientific Coordinator will assist in coordinating the activities of the awardees and in facilitating exchange of information. The role of the NIH Scientific Coordinator and Institute program administrators, as detailed throughout these terms of cooperation, is to assist and facilitate, but not to direct activities of the National Gene Vector Laboratories. The NIH Scientific Coordinator and the Institute program administrators act as liaisons to the NIH and as information resources about research activities in gene identification and gene therapy. The NIH representatives may also act as "catalysts," bringing together groups with characterized vectors and groups with the requisite resources and expertise to implement high quality clinical research. The Steering Committee coordinates and facilitates the activities supported by these cooperative agreements. 3. Collaborative Responsibilities Steering Committee The members of the Steering Committee will establish the functions of the Steering Committee, its method of operation, quality control assurance, cooperation among Program Directors, the NIH, and users of the facilities. The Steering Committee will also make provisions for an arbitration panel as described below. Criteria for accession and discontinuance of use of the facility will also be delineated. The Committee will then reach a consensus on these issues and generate three documents: one outlining its functions, handling of quality control issues, mode of cooperation of among awardees, the NIH, and the users of the facilities, conflict of interest, and mode of operation; a second enumerating criteria and procedures for accession and discontinuance of use of the facility for a given vector; and a third which will serve as an application form for investigators wishing to use the facility. The Steering Committee will meet three times during the first year of the awards and twice annually, thereafter. Program Directors are also responsible for formulating consistent policies for dealing with recurring situations that require coordinated action through participation by the Program Directors and any other designated representatives at Steering Committee meetings. Steering Committee meetings should be scheduled in close sequence with RAC meetings in order to avoid unnecessary delays in setting priorities and approving vectors. 4. Arbitration Any disagreement that may arise on scientific/programmatic matters within the scope of the award, between award recipients and the NIH may be brought to arbitration. An arbitration panel of external consultants will be created, and convened as needed, to resolve any irreconcilable differences of opinion related to scientific/programmatic matters among awardees and the NIH with respect to implementation of a proposed operating policy or other problems that may arise. The panel will include one member selected by the Program Directors, one member selected by the NIH representatives, and a third member chosen by the other two members of the arbitration panel. These special arbitration procedures in no way affect the awardee's right to appeal an adverse determination in accordance with PHS regulations at 42 CFR part 50, subpart D and HHS regulations at 45 CFR part 16. Applicants should anticipate probable areas of conflict and put forward an arbitration plan in their applications. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their subpopulations must be included in all NIH supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification is provided that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This new policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43) and supersedes and strengthens the previous policies (Concerning the Inclusion of Women in Study Populations, and Concerning the Inclusion of Minorities in Study Populations), which have been in effect since 1990. The new policy contains some new provisions that are substantially different from the 1990 policies. All investigators proposing research involving human subjects should read the "NIH Guidelines For Inclusion of Women and Minorities as Subjects in Clinical Research," which have been published in the Federal Register of March 28, 1994 (FR 59 14508-14513), and reprinted in the NIH Guide for Grants and Contracts of March 18, 1994, Volume 23, Number 11. Investigators may obtain copies of the policy from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. LETTER OF INTENT Prospective applicants are asked to submit, by December 15, 1994, a letter of intent that includes a descriptive title of the proposed project, the name, address and telephone number of the Program Director, the identities of other key personnel and participating institutions, and the number and title of the RFA in response to which the application may be submitted. Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information is helpful in planning for the review of applications. It allows IC staff to estimate the potential review workload and avoid conflict of interest in the review. The letter of intent is to be sent to: Dorothy D. Sogn, M.D. General Clinical Research Centers Program National Center for Research Resources Westwood Building, Room 10A-07 5333 Westbard Avenue Bethesda, MD 20892-4500** Telephone: (301) 594-7945 FAX: (301) 594-7929 APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 9/91) is to be used in applying for these cooperative agreements. These forms are available at most institutional offices of sponsored research; from the Office of Grants Information, Division of Research Grants, National Institutes of Health, 5333 Westbard Avenue, Room 449, Bethesda, MD 20892-4500, telephone 301/710-0267; and from the program administrators listed under INQUIRIES. The general instructions for format, budget issues, etc., in the application packet should be followed except for the following. The Research Plan (Sections A-D) may not exceed 150 pages, and must address the issues 1. through 4. listed below as well as points discussed in the Review Criteria section of this RFA. The budget pages of the application must address points raised under item 6. below. Special Application Requirements 1. Resources a. A detailed description of the facility and its compliance with current Good Manufacturing Practices as put forth by the Food and Drug Administration should be included. Access to animal and virology facilities as well as any necessary computer facilities should be documented. For current FDA guidance related to facilities for gene therapy, contact: Division of Establishment Licensing 1401 Rockville Pike, HFM-205 Rockville, MD 20852-1448 Telephone: (301) 594-2049 For information about Good Manufacturing Practices refer to Title 21 of the Code of Federal Regulations (CFR), sections 210-211 and 610. For information about Good Laboratory Practices refer to the CFR Title 21, section 58. Pertinent portions of the CFR can be ordered from: The Government Printing Office Superintendent of Documents Washington, DC 20402 Telephone: (202) 783-3238 b. Documentation must be provided of the maximum number of vectors that may be produced and maintained simultaneously and per year. 2. Scientific Expertise and Experience in Vector Production a. Documentation of experience in vector production and expertise in virology and molecular genetics should be provided. An understanding of important trends in gene therapy research and incorporation of new technologies in the future should also be documented. b. Documentation should be provided regarding which of the current vector technologies (retroviral, adenoviral, adeno-associated viral, and/or liposome components) will be performed at the facility. A detailed description of vector production methodology should also be provided and should include plans to establish and maintain a master cell bank of a producer cell line. c. Knowledge of, and ability to adhere to, FDA guidelines for quality control and safety testing for microbial contamination, endogenous and recombinant replication-competent retroviruses, and other viral contaminants of vectors at all stages of development and maintenance (including post distribution monitoring) should be outlined. d. Methods of certification of supernatants and final products should be described and outside sources of safety testing should be identified. Human somatic cell gene therapy involves the administration to patients of materials considered biological products, and thus subject to regulation by the Center for Biologics Evaluation and Research (CBER), FDA. Investigational New Drug (IND) applications are filed concerning clinical use of such products. Investigators planning clinical studies in these areas or preclinical and animal studies in support of future applications should inform themselves concerning the types of preclinical studies that are appropriate for such biological products. CBER has prepared a document entitled, "Points to Consider in Human Somatic Cell Therapy (1991)," which provides guidance in this area. Other relevant Points to Consider documents should also be consulted. These may include: "Points to Consider in the Production and Testing of New Drugs and Biological Produced by Recombinant DNA technology (1985);" "Points to Consider in the Characterization of Cell Lines Used to Produce Biologicals (1987);" "Points to Consider in the Manufacture and Testing of Monoclonal Antibody Products for Human Use (1987);" and "Points to Consider in the Collection, Processing, and Testing of Ex- Vivo Activated Mononuclear Leukocytes for Administration to Humans (1989)." Copies of Points to Consider documents are available from: The Division of Congressional and Public Affairs CBER HFM-12 1401 Rockville Pike, Suite 200 N Rockville, MD 20852-1448 Telephone: (301) 594-0830 CBER staff are also available for questions about which types of therapies are covered, for consultation, or for arrangement of pre- IND meetings at (301) 594-0830. 3. Collaborative Abilities a. Applicants should propose detailed plans for how to organize the cooperative resource. The function of the Steering Committee, including its mode of operation and methods of handling quality control and conflicts of interest, should be described. Suggested requirements for access to, and termination of use of, the facilities should be elaborated. Include proposed methods to be used to apply for access to the resources, both to have a vector developed from a gene sequence and to petition to use a vector for clinical studies. Issues of intellectual property and authorship of and plans for publications should be addressed. b. Methods should be proposed for establishing an inventory of vectors and their respective stages of development, as well as procedures for maintaining and distributing products and tracking the status of clinical studies. c. Rules for access to the laboratory should be proposed and the relationship between users and investigators proposing studies defined. d. A description should be provided concerning how the availability of the resource will be made known to the scientific community (e.g., notices of availability in scientific journals, displays at national meetings, etc.). If necessary, costs for these activities should be included in the budget. e. Outside experts will be added to the Steering Committee to balance its composition. Applicants should describe the types of expertise, but not individuals, needed to balance the composition of the Steering Committee. 4. Adherence to Terms of Cooperation a. Because the Terms of Cooperation discussed above will be included in all awards issued as a result of the RFA, it is critical that each applicant include specific plans for responding to these terms. b. Plans should describe clearly how applicants plan to interact with the other awardees involved in the cooperative agreement and describe how they will comply with the involvement of the NIH representatives. c. The expertise required for an effective Steering Committee should be proposed as well as how the Steering Committee would function to identify priorities for accessing the resources. d. Plans should describe the role of the Steering Committee in coordinating activities of the cooperative laboratories, establishing policies and priorities, and reviewing progress. 5. Budget a. Minimal and maximal staffing patterns and budgets for operation must be outlined; the cost of producing, maintaining, and distributing a representative vector being budgeted separately. b. The Program Director of each funded application will be a member of a Steering Committee that will meet three times in the first year and twice in each subsequent year. Travel funds for Steering Committee meetings should be set aside as a budget line item. For planning purposes, either three trips to Washington DC or one East Coast, one West Coast and one Central U.S. trip in the first year may be proposed. c. In addition to travel funds for institutional personnel, funds should be included to support travel by one outside expert (per applicant) to the Steering Committee meeting twice per year, anticipated travel expenses for workshop/seminar participants, plus any additional travel anticipated for Steering Committee members. d. One awardee institution will be designated as the Coordinating Facility and will have responsibility for certain tasks outlined under Responsibilities of Awardees. Each applicant should provide a budget for these tasks, in the event of being designated the Coordinating Facility. The RFA label available in the application form PHS 398 (rev. 9/91) must be affixed to the bottom of the face page. Failure to use 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 number and title must be typed on line 2a of the face page of the application form. Submit a signed typewritten original of the application, including the checklist, and three signed exact, clear, single-sided photocopies, in one package to: Division of Research Grants National Institutes of Health Westwood Building, Room 240 Bethesda, MD 20892-4500** At the time of submission, send two additional copies of the application to: Dr. Mary Ann Sestili Director, Office of Review National Center for Research Resources Westwood Building, Room 10A-11 Bethesda, Md 20892 Applications must be received by February 21, 1995. Applications received after this date will be returned. The Division of Research Grants (DRG) will not accept any application in response to this RFA that is the same as one currently pending initial review, unless the applicant withdraws the pending application. The DRG will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of substantial revisions of applications already reviewed, but such applications must include an introduction addressing the previous critique. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by DRG and responsiveness by NCRR. Applications that are incomplete or unresponsive will be returned to the applicant without further consideration. Applications must adhere to the page limitations and Special Application Requirements noted under the section APPLICATION PROCEDURES above to be considered responsive. 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 Office of Review, NCRR, in accordance with the review criteria stated below. Following scientific-technical review, the applications will receive a second-level review by the appropriate national advisory councils/boards. As part of the initial merit review, a process (triage) may be used by the initial review group in which applications will be determined to be competitive or non-competitive based on their scientific merit relative to other applications received in response to the RFA. Applications judged to be competitive will be discussed and be assigned a priority score. Applications determined to be non- competitive will be withdrawn from further consideration and the Program Director and the official signing for the applicant organization will be notified. Review Criteria Reviewers will be asked to review the grant applications by considering the following criteria: 1. Scientific and technical merit of the proposed activities and organizational plans for implementing the proposed National Gene Vector Laboratories and the extent to which they address the overall goals and objectives of the RFA. 2. Availability and quality of facilities and resources required for this project. 3. Qualifications, experience, and proposed responsibilities of the Program Director and other key personnel. 4. Plans for effective cooperation and coordination among participating awardees and the NIH. 5. Plans for protection of the rights of human subjects and for inclusion of women and minorities and their subgroups as appropriate to the scientific goals of the activity. Reviewers will also judge the appropriateness of the proposed budget and duration for each meritorious application. AWARD CRITERIA The earliest anticipated date of award is August 1, 1995. Awards will be based primarily on the scientific merit, diversity of vector production capability, and programmatic priorities. Some consideration may also be given to geographic diversity. INQUIRIES Inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Dorothy D. Sogn, M.D. General Clinical Research Centers Program National Center for Research Resources Westwood Building, Room 10A-07 Bethesda, MD 20892-4500 Telephone: (301) 594-7945 FAX: (301) 594-7929 Email: DorothyS@EP.NCRR.NIH.GOV Inese Z. Beitins, M.D. General Clinical Research Centers Program National Center for Research Resources Westwood Building, Room 10A-03 Bethesda, MD 20892-4500 Telephone: (301) 594-7945 FAX: (301) 594-7929 Email: IneseB@EP.NCRR.NIH.GOV Direct inquiries regarding fiscal matters to: Ms. Mary V. Niemiec Office of Grants and Contracts Management National Center for Research Resources Westwood Building, Room 849 Bethesda, MD 20892-4500 Telephone: (301) 594-7955 FAX: (301) 594-7910 Email: MaryN@EP.NCRR.NIH.GOV AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.922. Awards are made under authorization of the Public Health Service Act, Title III, Part A (Public Law 78-410 as amended by public law 99-158, 42 USC 241) and administered under PHS grants policies and Federal Regulations 42 CFR Part 52, 45 CFR Part 74 and 45 CFR 92. This program may be subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The Public Health Service strongly encourages all grant recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people. .
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