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Case Western Reserve University Tuberculosis Research Unit
  Integrating research to combat the global TB epidemic
 
 

Objectives


Overview of Contract Objectives
Full Statement of Work

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Overview of Contract Objectives


(Statement of work as stipulated in the NIH original Request for Proposal (January 6, 2006) & contract award (May 1, 2007)

Introduction

This contract will establish and support the Tuberculosis Research Unit (TBRU), a multi-disciplinary, multi-national consortium of investigators and institutions with expertise in the areas of epidemiology, microbiology, and immunity, to conduct clinical studies on host-pathogen interactions in tuberculosis (TB). The overall goal of the clinical studies to be carried out by the TBRU is to fill critical gaps in translational TB research and to provide tools needed to advance new health care interventions in TB endemic countries.

The TBRU must include:

  1. At least one country outside of the United States (U.S.) in which TB is endemic and foreign clinical sites with an established infrastructure capable of conducting the clinical studies, including local investigators experienced in the conduct of multi-disciplinary human clinical studies in TB, laboratory facilities and personnel to perform protocol-specific tests, and access to relevant patient populations
  2. A Data Management Center for the collection, storage, quality control, and evaluation of all data derived from the clinical studies
  3. A Specimen Repository for the storage and inventory of mycobacterial strains and human-derived materials

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Scope

The Contractor shall design, conduct and direct clinical studies in human TB to establish markers to:

  1. Identify individuals at highest risk for progression to TB disease after infection with Mycobacterium tuberculosis (Mtb)
  2. Characterize correlates of response to therapy and vaccination that can establish useful early estimates of clinical efficacy of new health care interventions
  3. Eventually contribute to the identification of new diagnostic tests and improved therapeutic and vaccination strategies

A Data Management Center for the collection, storage, quality control, and evaluation of all data derived from the clinical studies shall be provided by the Contractor, and shall include:

  1. Establish and direct the TBRU consortium.
  2. Develop the overall Clinical Study Plan, including proposed studies and timelines for completion.
  3. Provide an infrastructure for the overall scientific, technical and administrative management of the clinical studies.
  4. Provide clinical study oversight for all clinical sites and studies.
  5. Establish and direct the projects and activities of the Specimen Repository of clinical samples.
  6. Establish and direct the projects and activities of the Data Management Center.
  7. Solicit for and evaluate the technical merit and proposed costs for additional clinical sites that should need to be added during the contract, execute and manage studies at these sites, and assess subcontractor performance.
  8. Provide for an orderly transition to a successor contractor or to the Government at the end of the contract period of performance.

To meet these objectives, the following organization has been developed:


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Full Statement of Work - Tuberculosis Research Unit (TBRU) – NO1-AI70022 / HHSN266200700022C


Introduction

This contract will establish and support the Tuberculosis Research Unit (TBRU), a multi-disciplinary, multi-national consortium of investigators and institutions with expertise in the areas of epidemiology, microbiology, and immunity, to conduct clinical studies on host-pathogen interactions in tuberculosis (TB). The overall goal of the clinical studies to be carried out by the TBRU is to fill critical gaps in translational TB research and to provide tools needed to advance new health care interventions in TB endemic countries.

The TBRU must include:

  1. At least one country outside of the United States (U.S.) in which TB is endemic (see Dye et al. http://jama.ama-assn.org/cgi/content/full/282/7/677), and foreign clinical sites with an established infrastructure capable of conducting the clinical studies, including local investigators experienced in the conduct of multi-disciplinary human clinical studies in TB, laboratory facilities and personnel to perform protocol-specific tests, and access to relevant patient populations;
  2. A Data Management Center for the collection, storage, quality control, and evaluation of all data derived from the clinical studies; and
  3. A Specimen Repository for the storage and inventory of mycobacterial strains and human-derived materials

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Scope
  1. The Contractor shall design, conduct and direct clinical studies in human TB to establish markers to:
    1. Identify individuals at highest risk for progression to TB disease after infection with Mycobacterium tuberculosis (Mtb);
    2. Characterize correlates of response to therapy and vaccination that can establish useful early estimates of clinical efficacy of new health care interventions; and
    3. Eventually contribute to the identification of new diagnostic tests and improved therapeutic and vaccination strategies
  2. The resources/studies to be provided under this contract shall be performed either directly by the Contractor or indirectly through subcontractors. At a minimum, the Contractor shall:
    1. Establish and direct the TBRU consortium.
    2. Develop the overall Clinical Study Plan, including proposed studies and timelines for completion.
    3. Provide an infrastructure for the overall scientific, technical and administrative management of the clinical studies.
    4. Provide clinical study oversight for all clinical sites and studies.
    5. Establish and direct the projects and activities of the Specimen Repository of clinical samples.
    6. Establish and direct the projects and activities of the Data Management Center.
    7. Solicit for and evaluate the technical merit and proposed costs for additional clinical sites that should need to be added during the contract, execute and manage studies at these sites, and assess subcontractor performance.
    8. Provide for an orderly transition to a successor contractor or to the Government at the end of the contract period of performance.

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Statement of Work

Independently, and not as an agent of the Government, the Contractor shall furnish all the necessary services, qualified professional and technical personnel, volunteer and patient populations, material, major equipment, and facilities, not otherwise provided by the Government as needed to perform the work described below. The exact types of studies to be performed by the Contractor may vary and all study activities, documents, and procedures shall be implemented after discussion with and concurrence by, the NIAID Project Officer. The timeline or schedule for initiation of all clinical studies shall be determined in collaboration with the NIAID Project Officer. The Contractor shall inform the NIAID Project Officer of any unforeseen circumstances that may delay timely completion or progress of study activities.

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  1. Establishment and Maintenance of the Tuberculosis Research Unit (TBRU) - The Contractor shall establish and direct a collaboration of scientific and clinical investigators and institutions with expertise and experience in the conduct of multi-disciplinary, multi-national TB research to design and conduct clinical studies in TB endemic countries. The Contractor shall utilize established collaborations with qualified, experienced U.S. and/or non U.S. institutions to provide technical expertise, infrastructure, and data management for human clinical studies in TB endemic countries. The scientific, clinical and technical infrastructure of the TBRU shall consist of the following:
    1. Clinical Study Sites - The number of clinical study sites necessary to carry out the Clinical Study Plan are described in paragraph 2., below. This must include a site in at least one (1) country in which TB is endemic. The clinical study sites in TB endemic areas must provide, at a minimum, the following:
      1. Clinical investigators, nurse coordinators and other clinical and technical personnel experienced in the design and conduct of clinical studies of human TB, including: patient screening, recruitment and retention; adherence to Good Clinical Practices (GCP) and host country requirements and regulations governing the safe and ethical conduct of research involving human subjects; assessment and reporting of adverse events; management of study products; collection and quality control of study data; and maintenance and storage of research records;
      2. Facilities and personnel to carry out study-specific laboratory testing and storage of patient samples;
      3. Access to a patient pool adequate to ensure the timely screening and enrollment of eligible study participants in accordance with study-specific requirements and within established timelines; and
      4. Clinical and technical personnel with experience in complex human studies of HIV-negative, HIV-positive and HIV-TB co-infected adult and pediatric TB patients as well as healthy adult and pediatric volunteers.
    2. Study Design, Implementation and Management - Provide scientific, clinical and technical personnel with expertise and experience in designing, conducting, and directing multi-disciplinary, multi-national clinical studies of TB, including epidemiology, microbiology and immunity.
    3. TBRU Data Management Center - The Data Management Center shall include experts in statistics and database management, as well as project management. The Data Management Center shall carry out the following functions:
      1. Design, maintenance and quality control of a database system for the receipt and storage of all clinical study data;
      2. Provide expertise and assistance to the TBRU protocol teams in the statistical design of study protocols, the development of statistical analysis plans, and the analysis of study data;
      3. Participate in the preparation of interim and final analyses of clinical study data.
      4. Manage and coordinate oversight of all regulatory and clinical aspects of the studies conducted by the TBRU with NIAID/DMID’s Offices of Regulatory and Clinical Activities.
    4. TBRU Specimen Repository - The Contractor shall establish a repository of patient specimens from TBRU clinical studies, to be housed at a central location, to be available for additional laboratory studies that are relevant to the goals of this contract and for which tools may become available at a later date in the contract period. This repository will not serve the TB research community as a whole. However, samples will remain available to the Contractor, the TBRU clinical study sites, and outside collaborators as well as the NIAID TB contract community, to maximize information that can be obtained from this limited resource. The TBRU Specimen Repository shall:
      1. Receive, ship, store, package and inventory mycobacterial strains and human-derived materials from the clinical studies conducted under this contract. Samples may contain, but are not limited to, sera, sputa, saliva, blood and blood derived products, tissue and genetic material for use by the Contractor and any subcontractor in the conduct of studies outlined in this Statement of Work.
      2. Redistribute stored samples to the TBRU clinical study sites. Shipping of human derived materials shall be in accordance with current interstate commerce regulations and international ethics and commerce laws.
      3. Establish and maintain a database of study-specific patient and volunteer information on these samples. The database must capture sufficient information to characterize samples clinically while maintaining subject data confidentiality, but allow transfer of non-personal sample data between participating clinical study sites.

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  2. Clinical Study Plan
    1. Clinical Study Plan Development - Within sixty (60) calendar days after contract award, provide a comprehensive Clinical Study Plan for a maximum of five (5) clinical studies over the course of the contract, including clinical study proposals and timelines, for a systematic approach to address the questions delineated in paragraph b., below.
      1. Clinical studies will be conducted in TB endemic countries and will ensure the substantial involvement of local investigators in study design, development and analysis. In addition, the data generated should be relevant to TB health care practices and research in these endemic countries.
      2. The TBRU will design and conduct studies in the following areas:
        1. Characterization of the human immune response to Bacillus Calmette Gu1rin (BCG) in target populations, such as children, to better define expectation and clinical endpoints for new TB vaccines in general;
        2. Characterization of immune responses in persons who successfully control infection with Mtb versus those who progress to active disease to facilitate selection of at-risk persons for clinical studies and the development of diagnostics;
        3. Characterization of human immune responses or other biological markers in response to drug therapy to define early markers of efficacy and possible approaches for combining drug therapy with vaccination strategies; and
        4. Kinetics of human immune responses after vaccination and infection to facilitate selection of boosting strategies for vaccine studies.
      3. The Clinical Study Plan shall include:
        1. The scientific basis for the approaches and methodologies selected to address the three questions delineated in paragraph b., below, including a summary of the state of the science in each area;
        2. A description of relevant knowledge gaps and a discussion of those knowledge gaps to be addressed by the Clinical Study Plan; and
        3. A discussion of potential problems or obstacles to addressing these knowledge gaps and proposed approaches to overcoming any such problems and obstacles.
      4. The Clinical Study Plan shall also include detailed protocols for each clinical study including:
        1. Scientific basis/rationale;
        2. Study design, including sample size, inclusion and exclusion criteria, clinical endpoints and their relevance to answering the questions being addressed by the study;
        3. A detailed statistical analysis plan;
        4. A discussion of how the clinical study will advance translational TB research and inform host country health care practices;
        5. A description of any proposed collaborations with academia and/or industry for proposed studies involving the use of experimental diagnostics, therapeutics or vaccines, including the conduct of any proposed clinical studies in conjunction with planned or ongoing clinical trials supported through other mechanisms and sponsored by other entities;
        6. A plan for the identification, recruitment and retention of study participants; and
        7. Detailed timelines for protocol development, initiation, completion and analysis of final study data.
    2. Research Questions to be Addressed in the Clinical Study Plan - The Contractor shall perform clinical studies to answer specific questions in human TB as specified in the Statement of Work, below. Clinical studies may incorporate, where appropriate, the utilization of experimental and/or approved drugs, vaccines and/or diagnostics to define and validate markers that will provide improved information for human clinical studies for TB interventions.
      1. Why do most HIV negative persons successfully control Mtb infection while some progress to active tuberculosis disease?
        1. The study design shall allow longitudinal assessment, in one or more TB endemic countries, of immunological, biochemical, microbiological, host genetic or other biochemical markers that identify various stages of infection and disease in HIV negative adult and pediatric populations.
        2. Study outcomes shall provide epidemiological data for the characterization of disease prevalence and incidence, and transmission dynamics of Mtb strains.
        3. Studies may include evaluation of one or more promising diagnostic tests made available through collaborations with the research community to maximize information obtained from clinical studies.
        4. Studies shall maximize utilization of local expertise to conduct assays and analyses with human derived specimens.
        5. Study results should provide data that have the potential to inform local TB care practices.
        6. Study endpoints shall be of sufficient practical nature to have the potential to aid in the development of diagnostic test(s) to identify persons at highest risk for progressing from Mtb infection to active TB disease.
      2. Why does BCG protect some individuals and not others from TB disease and what are the kinetics of the immune response after vaccination with BCG versus after infection with Mtb?
        1. Studies shall be conducted in one or more TB endemic countries that routinely use BCG vaccination as part of their control strategies.
        2. Study design shall include pediatric populations and may include HIV+ or HIV- TB co-infected individuals.
        3. Study design shall include identification and characterization of the kinetics of the immune response after vaccination versus after infection with Mtb.
        4. Study results should provide data that have the potential to inform local TB care practices.
        5. Study endpoints shall be of sufficient practical nature to have the potential to aid in the development of clinical endpoints for the evaluation of novel vaccine candidates and to inform expectations for benchmarks in clinical vaccine development for TB.
        6. Study endpoints shall be of sufficient practical nature to have the potential to aid in the development of diagnostic tests to identify immune competent persons infected with Mtb and not be compromised by standard BCG vaccination or presence of other mycobacteria.
        7. Study design shall not include extended observational studies of TB incidence as a result of BCG vaccination.
      3. What immune responses or other biological markers that predict relevant clinical outcomes can be measured in response to drug therapy or vaccines?
        1. Clinical studies shall be conducted in one or more TB endemic countries.
        2. Study design may include HIV co-infected individuals.
        3. Studies may be conducted with existing or novel drugs or vaccines, available through the research community, as part of early stage human clinical studies or as part of Phase I or Phase II clinical trials.
        4. Study design shall include a comprehensive panel of immunological and other biological evaluations to maximize information content derived from these studies. These laboratory studies may be conducted in TB non-endemic countries, if appropriate.
        5. Study results are expected to contribute to the identification of early surrogate markers of efficacy. It is expected that more than one marker will have to be utilized to estimate clinical efficacy of vaccines and/or drug therapies.

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  3. Protocol Development and Implementation - Following NIAID Project Officer approval of the Clinical Study Plan, provide all necessary personnel, expertise and resources to develop ethical, safe and implementation-ready clinical protocols for all approved studies. Specifically, the Contractor shall carry out the following tasks:
    1. Protocol Development
      1. Coordinate all protocol development activities with the NIAID Project Officer and/or a designated NIAID protocol coordinator.
      2. Establish a protocol team consisting of relevant Contractor and subcontractor personnel and NIAID staff with expertise in aspects of clinical trial development and oversight to provide technical expertise for the development of protocols for the approved clinical studies, and provide for substantial and substantive involvement of local investigators in protocol design and development.
      3. Identify and incorporate, where appropriate, novel diagnostics, drugs and vaccines that may be suitable to address product- or host response-relevant questions as part of the protocol.
      4. Coordinate with NIAID/DMID the establishment of material transfer agreements where appropriate, between NIAID and the product provider.
      5. Evaluate and determine the feasibility and appropriateness for including exploratory assays to maximize the amount of data obtainable from human specimens.
      6. Assure that protocol and final study design provide novel data and do not needlessly duplicate studies conducted by other investigators.
      7. Include request for permission to store specimens for later expansion of laboratory evaluations in the informed consent documents.
      8. Acquire appropriate approvals from local and government ethics committees and/or other human subject protection review boards. Submit Annual Institutional Review Board (IRB) approvals with each Annual Progress Report and the Final Report.
      9. Coordinate approaches for human clinical studies with other NIAID contractors involved in developing preclinical animal efficacy models to provide improved information.
      10. Collaborate with existing NIAID animal model contractors, to be identified by the NIAID Project Officer, throughout this contract term via face-to-face meetings, phone conferences or through inclusion in annual contract meetings to assure that planned TBRU studies have relevance for the improvement of preclinical animal models that are being refined to increase their predictive value for vaccine, drug and diagnostic selection.
    2. Protocol Implementation, Management and Reporting - Upon NIAID Project Officer approval of the final protocols, provide all necessary personnel (such as program officers, clinical monitors, nursing and clinical staff, etc), resources, and facilities to conduct the clinical studies and to satisfy the NIAID clinical terms of award which will apply to all clinical studies conducted as part of this contract:
      http://www.niaid.nih.gov/ncn/pdf/clinterm.pdf.
      1. Clinical Studies Management and Oversight Plan - Develop and submit upon request for NIAID Project Officer approval, a plan for the management and oversight of clinical studies, including policies and procedures to ensure the timely and accurate completion of all clinical studies in compliance with GCP regulations and requirements governing the safe and ethical conduct of research involving human subjects.
      2. Monthly Clinical Study Progress Reports - Prepare and submit Monthly Clinical Study Progress Reports to address:
        1. Progress in accrual of study participants, including problems encountered in recruitment and retention and proposed approaches to resolving any such problems;
        2. Proposed revisions to the established timelines for protocol implementation, including the rationale/justification for the proposed revisions;
        3. Proposed modifications to the approved clinical study protocol and their rationale; and
        4. Any recommendations for curtailing or discontinuing approved clinical studies based on scientific rationale, feasibility and other factors.
      3. Safety Monitoring and Oversight - Conduct safety monitoring and oversight for all clinical studies in collaboration with the NIAID/DMID Office of Clinical Research Affairs and their designated personnel. Submit safety monitoring reports as outlined in each protocol.
      4. Clinical Study Final Reports - Within sixty (60) calendar days of completion of clinical studies, prepare and submit to the NIAID Project Officer a Clinical Study Final Report containing:
        1. The study protocol;
        2. Final study demographics; study results and interpretation;
        3. An assessment of the impact of study findings on the state of the science, the enhancement and/or improvement of approaches to evaluating the safety and efficacy of new diagnostics and therapeutic and vaccine candidates, and the contributions of study findings to informing local TB care practices; and
        4. Publications resulting from each study.

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  4. Project Management - The Contract shall provide the scientific, technical and administrative infrastructure to ensure the efficient planning, initiation, implementation, and management of all activities carried out under this contract. Infrastructure at the Contractor’s site shall include a Principal Investigator (PI) with responsibility for overall project management and communications, tracking, monitoring and reporting on project status and progress. The PI shall be responsible for recommending modifications to project requirements and timelines, including projects undertaken by subcontractors. This infrastructure shall also include administrative staff with responsibility for financial management and financial reporting on all activities conducted by the Contractor and all subcontractors. Additional activities include:
    1. Communications with NIAID - Assure effective communications with the NIAID Project Officer, Contracting Officer, and NIAID clinical and regulatory staff to include the following:
      1. Conference Calls - Monthly, or more frequently, one-hour conference calls with the NIAID Project Officer, Contracting Officer, Principal Investigator and key Contractor scientific, technical and administrative staff to review the status of all scientific projects, future plans, and issues or problems in study design, implementation or conduct that require immediate attention and resolution.
      2. Annual Meetings - One (1) annual meeting with the NIAID Project Officer, Contracting Officer, Principal Investigator and key contractor/subcontractor scientific and technical staff. Meetings may be held in Bethesda, Maryland, or at the Contractor’s location, and may be held in conjunction with annual meetings for other NIAID TB Program contractors, when appropriate. The date and agenda for the annual meetings shall be established by the Contractor’s PI in consultation with the NIAID Project Officer and the Contracting Officer. Annual meetings will be closed to the public and will include status updates for all projects, a discussion of and suggested solutions to any problems that may have arisen, as well as recommendations for any changes in timelines or projects. The Contractor will submit a meeting summary to the NIAID Project Officer and Contracting Officer within thirty (30) calendar days after the meeting.
    2. Establish a Panel of External Experts - Establish, post-award, with the concurrence of the NIAID Project Officer, a panel of external experts to be available for discussion and recommendations on specific scientific issues that arise during the course of the contract. The experts may be invited to attend annual contract meetings and shall be consulted by the Contractor, through telephone conferences or at annual meetings, on issues that NIAID and the Contractor agree require outside input. Members of the Panel of External Experts will each serve for two (2) years and shall be selected on the basis of the types of expertise the Contractor and NIAID determine is needed to complement the expertise of Contractor and subcontractor staff. Travel and per diem of panel members will be paid for under this contract.
    3. Audits and Reporting of Good Clinical Practices (GCP) - Perform audits to meet FDA required Good Clinical Practices (GCP) standards and submit reports on all such audits to the NIAID Project Officer within thirty (30) calendar days following each audit. NIAID reserves the right to conduct independent audits of the Contractor and its subcontractors, as needed, to evaluate compliance with FDA required GCP standards and expects that all records and staff shall be available for site visits or study-specific audits by NIAID or its designees.

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  5. Facilities, Other Resources, Safety and Training
    1. Provide safe facilities and resources in the U.S. and in non-U.S. countries, and conduct work in accordance with the most recent Guidelines for Biosafety in Microbiological and Biomedical Laboratories (BMBL, Centers for Disease Control and Prevention and the National Institutes of Health, fourth edition, HHS Publication No. [CDC 93-8395, published by the U.S. Government Printing Office, May 1999, Stock Number 017-040-0547-4)), or comparable safety standards in TB endemic countries.
    2. Provide adequate biocontainment facilities and staff with the required training, experience and expertise to operate the facilities and conduct the studies in accordance with the appropriate Biosafety Guidelines for working with pathogenic organisms (see also http://bmbl.od.nih.gov).
    3. Provide adequate and appropriate training, protective garments, equipment and monitoring for all involved personnel to assure safe handling and transport of potentially hazardous microorganisms, blood products or other specimens.
    4. Where applicable, adhere to the current Federal Guidelines for Research Involving Recombinant DNA molecules (http://www4.od.nih.gov/oba/rac/guidelines/guidelines.html).

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  6. Publications, Presentations and Data Dissemination
    1. Major Scientific Findings and Technical Advances for Publication and Presentation - Publish and present to the public all major scientific findings and technical advances no later than six (6) months after internal data verification. Disseminate this information at national and international meetings and, where appropriate to other members of the contract infrastructure within the NIAID TB Program, and adhere to NIH’s Policy on Enhancing Public Access to Archived Publications Resulting from NIH-Funded Research (http://grants2.nih.gov/grants/guide/notice-files/NOT-OD-05-022.html).
    2. Manuscripts and Scientific Meeting Abstracts - Submit manuscripts and scientific meeting abstracts containing data generated under this contract to the NIAID Project Officer for review no less than five (5) calendar days prior to submission for public presentation or publication. NIAID contract support shall be acknowledged in all such publications and presentations. A “publication” is defined as an issue of printed material offered for distribution or any communication or oral presentation of information. The NIAID Project Officer will review all manuscripts/abstracts in a period of time not to exceed five (5) calendar days from receipt to recommend any changes. If review is not completed within this timeframe, the Contractor may proceed with the publication.
    3. Internet Website - Establish and maintain an internet website, referencing the NIAID contract number, that summarizes on-going studies, lists the locations of current clinical study sites, provides contact information for key study staff, summarizes publications and key findings from studies, and provides summaries of workshops or scientific meetings hosted by the Contractor. This website shall be approved by the NIAID Project Officer prior to being offered on the Internet.
    4. Scientific Meetings and Workshops - Plan and conduct bi-annual-scientific meetings/workshops to discuss specific issues relevant to the clinical and scientific areas of TBRU research. These meetings shall involve invited outside experts [in addition to the Panel of External Experts] and result in workshop summaries to be posted on the contract website and submitted to the NIAID Project Officer for posting on public NIAID websites. Travel and per diem will be covered under this contract.

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  7. Final Contract Transition - Provide for a safe, orderly and efficient transition to a successor contractor or to the Government on or before the completion date of the contract.
    1. Submit a Draft Final Transition Plan for review and approval to the NIAID Project Officer six (6) months prior to the completion date of the contract. The Draft Final Transition Plan shall address:
      1. Completion of ongoing clinical studies;
      2. Relocation/disposition of clinical specimens in the repository; and
      3. Contract-developed data files and software systems (with documentation and specifications).
    2. Include a timeline of proposed activities and completion of the transition.
    3. Implement the approved Final Transition Plan to achieve a complete, safe, timely, and orderly transition of contract activities and resources.