LRCC_SOW_(10-July-15).doc

Transfusion-Transmissible Infections (TTI) Monitoring System (TTIMS)

Laboratory & Risk Factor Database Coordinating Center (LRCC) Statement of Work (SOW)

July 10, 2015

1. Introduction

1.1 Background

The U.S. Food and Drug Administration (FDA) is responsible for protecting the public health by assuring the safety, efficacy, and security of human and veterinary drugs, biological products, medical devices, tobacco products, our nation’s food supply, cosmetics and products that emit radiation. The FDA is also responsible for advancing the public health by helping to speed innovations that make medicines, devices, products, and foods more effective, safer, and more affordable; and helping the public get the accurate, science-based information they need to use medicines and foods to improve their health.

During its July 2, 2013 meeting, the Department of Health and Human Services (DHHS) Blood, Organ, and Tissue Senior Executive Council (BOTSEC), which includes representation from Department of Health and Human Services, Office of the Assistant Secretary of Health (DHHS/OASH), Centers for Disease Control and Prevention (CDC), National Institutes of Health (NIH), Centers for Medicare & Medicaid Services (CMS), Health Resources Services Administration (HRSA), Food and Drug Administration (FDA), HHS-Assistant Secretary for Planning and Evaluation (ASPE), HHS-Assistant Secretary for Preparedness and Response (ASPR), and Agency for Healthcare Research and Quality (AHRQ), unanimously voted to enhance monitoring of Transfusion-Transmissible Infections (TTIs) in the US.

The TTIMS will build on the NIH National Heart Lung Blood Institute’s REDS-II Transfusion-Transmitted Retrovirus Study (REDS) procedures established for centralization of proprietary blood center operational data, successful coordination of standardized data definitions, collection, analysis, and reporting of baseline epidemiologic and risk factor data for > 50 % of the United States (US) donor base. At present, no single comprehensive blood donor or recipient surveillance system exists in the United States to monitor TTIs, such as Human Immunodeficiency Virus (HIV), Hepatitis B (HBV), and Hepatitis C (HCV) in such a large donor population. Subsequently, the external Federal DHHS Advisory Committee on Blood and Tissue Safety and Availability (ACBTSA) met in December 2013 and concurred with the BOTSEC and recommended that DHHS establish “an ongoing, integrated, coordinated, and nationally representative U.S. transfusion transmissible infections monitoring system.”

The FDA requires the establishment of a Transfusion-Transmissible Infection Monitoring System (TTIMS) through two separate complimentary contracts consisting of an integrated, comprehensive Donation Database Coordinating Center (DDCC) system and a Laboratory and Risk Factor Coordinating Center (LRCC), the subject of this statement of work, to provide in-depth laboratory assessment of donors who have confirmed markers for TTIs of interest.

The TTIMS program will build on the infrastructure and initial consensus infectious disease testing classification algorithms that were developed for the REDS-II Transfusion Transmitted Viral Infection (TTVI) Marker Prevalence and Risk Factor Study. The program will support the collection of integrated risk factor data and disease marker surveillance information across different blood collection organizations. Furthermore, systematically collected and combined data are critical for this national surveillance effort.

This effort requires close coordination between the DDCC and LRCC to ensure timely confidential data transfers and to achieve the aims of the TTIMS project. Blood collection organizations interested in participating in TTIMS will participate in both the LRCC and DDCC data collection efforts. In particular, blood collection organizations will share relevant donor data and blood specimens collected by their organization, with both Contractors for compilation and evaluation of TTI risks. The Contractor shall identify, survey, characterize, and provide risk factor and other data on HIV and incident HCV and HBV blood donors.

1.2 TTIMS Governance Framework

Oversight and governance of TTIMS will be provided by the US FDA Contracting Officer’s Representative (COR) within the CBER Office of Biostatistics and Epidemiology. The Contractor shall establish the TTIMS Steering/Monitoring Committee (aka the Committee) within 30 calendar days of contract award, to work with FDA and CDC representatives (including statisticians) to study historical trends. Data analyses and reports provided by the Contractor will be reviewed by the COR and Committee members comprised of the Principal Investigators (PI), and Co-PI representing participating blood center organizations, DDCC and LRCC personnel, and experts from stakeholder Department of Health and Human Services (DHHS) Agencies, including, FDA, NIH, and CDC.

The Committee shall meet no less than every month by teleconference and in person at least twice a year. Unforeseen circumstances may arise requiring additional communication, which would likely be by teleconference.

If necessary, the COR will form smaller subcommittees and executive subcommittees to address issue specific priorities. The Contractor shall report back with findings and recommendations for discussion and any necessary action by the Committee/subcommittees. The Government Officials on the Committee (NHLBI, FDA and CDC) will provide necessary information to the appropriate internal Federal Agencies. The Contractor shall receive feedback on the reports they generate, as well as any weaknesses and make recommended changes.

1.3 TTIMS LRCC Objective

The TTIMS LRCC project purpose is to serve as the biostatistical and analytical center for all analyses relevant to the evaluation and monitoring of HIV (Incident and prevalent), HCV (incident) and HBV (incident) positive blood donors. Specifically the primary objectives of this Contract are to:

· Evaluate and monitor risk factor characteristics of donations confirmed positive for TTIs

· Compare/analyze risk factor data to that obtained in the REDS-II TTVI Marker Prevalence and Risk Factor Study

· Integrate risk factor data and disease marker surveillance information across different blood collection organizations

· Provide logistical support for the TTIMS project and for the Committee/Subcommittee meetings, conferences, and donation(s) transfer/shipment.

2. Task Description(s)

The following tasks constitute the performance of work expectations for LRCC support.

2.1 Task 1: Establish TTIMS LRCC Protocols, Procedures, and Repository

a. The Contractor shall work collaboratively with the Committee and the DDCC Contractor to develop and finalize the LRCC project protocols and the LRCC applicable sections of the TTIMS Manual of Operations (MOP). Procedures shall address at a minimum the following: laboratory procedures, ongoing bio-specimen collection and maintenance procedures for the repository, data collection, shipping and storage, management and tracking, consensus definitions, security, transfer, and sharing considerations.

b. The Contractor shall develop and implement secure and robust data collection, data quality control, tracking, management, and storage procedures for TTI-positive blood donor related data and bio-specimens relevant to the HIV and incident hepatitis infected blood donors’ evaluations

c. The Contractor shall create a centralized repository of samples from HIV-positive blood donations to serve future uses such as availability for HIV evolutionary geneticists investigating changes in HIV virulence and pathogenicity over time and shall be ready for investigation if an emerging agent of concern is identified or for virus discovery in general.

Table 1 Task 1 Deliverables/ Work Products

2.2. Task 2: Coordinate Identification, Characterization & Monitoring of TTI-Positive (HIV, HCV, and HBV) Blood Donations The Contractor shall perform the following activities in support of Task 2:

a. Coordinate, identify, enroll, characterize, and monitor HIV (prevalent and incident), HBV (incident) and HCV (incident) positive blood donors by participating blood collection organization(s)

b. Evaluate and monitor trends in incidence and TTI-positive donor characteristics (demographic, geographic, temporal, and risk factors) in accordance with procedures delineated in the MOP

c. Evaluate and monitor risk factor characteristics of donations confirmed positive for HIV or recently positive for HBV or HCV at participating blood collection organization(s)

d. Develop and perform standardized risk interview survey(s), in accordance with administrative processes such as review and approval by Institutional Review Boards (IRBs) and Office of Management and Budget (OMB), as specified in Section 3.

e. Coordinate with the DDCC Contractor and participating blood collection organizations regarding collecting, tracking, shipping (including freight), storage, and retrieval of all positive biospecimens necessary for lab characterizations

f. Coordinate with the DDCC and participating blood collection organizations to conduct follow-up investigations triggered by significant changes in TTI incidence/prevalence rates and risk factors

g. Conduct risk factor interviews by donor counselors via telephone on all HIV infections in order to determine if changes in the prevalence of risk behaviors associated with HIV are related to changes in compliance with the donor health history questionnaire, risk behaviors of donors, or simply in the demographics of donors who present to donate

h. Conduct risk factor interviews by donor counselors via telephone with donors exhibiting validated NAT-only test results for HBV and HCV infection since the likely “recency” of infection creates an opportunity to pinpoint actual exposures that led to infection

i. Establish procedures and processes within the protocol identified in 2.1.a to ensure that participating blood collection organizations perform all follow-up investigations triggered by significant changes in transfusion-transmissible viral infection incidence, prevalence, rates, and risk factors

j. Develop an Analytical Plan detailing the methodology for risk factor analyses, genotyping/drug resistance analyses, and pertinent demographic, geographical and temporal trend analyses. Specifically the plan shall:

i. Include a description of significant changes in transfusion-transmissible viral infection risk factors, which could potentially trigger in-depth evaluation of the determinants underlying these changes

ii. Identify routinely produced data reports to be provided for Committee evaluation

Table 2 Task 2 Deliverables/ Work Products

2.3. TASK 3: Perform laboratory testing, Data Collection and Management pertinent to characterization of HIV, HCV, & HBV-positive donors

The Contractor shall perform the following activities in support of Task 3:

a. Closely collaborate/coordinate with the DDCC to ensure data transfers, cross-talk between datasets, and integration of efforts

b. The contractor shall lead the task of integrating risk factor data and disease marker surveillance information across different blood collection organizations by closely working with the DDCC to obtain donation/donor data information

c. Perform sequencing of HIV (prevalent and incident), HBV, and HCV viruses from donors with newly acquired infections to monitor evolving molecular epidemiology of viruses in the donor population, drug resistance profiles of HIV, and to help ensure that donor screening assays are optimized to detect circulating strains of infections

d. Perform “recency” testing of HIV antibody positive donations to distinguish more recently acquired from longer-standing HIV infections, and improve classification of HIV incidence and provide data quarterly to allow the DDCC to optimally classify HIV-positive donors as incident or prevalent cases:

i. Apply HIV "recency" tests to all HIV seropositive samples obtained from the TTIMS program, as well as historical HIV+ samples provided by participating blood centers to assess baseline data over time for HIV “recency” among donors.

ii. Establish the performance of available "recency" assays in antibody positive donations for which an alternate measure of “recency” is available (e.g. prior recent seronegative or NAT yield donation to validate use of “recency” testing to distinguish recently acquired from longer-standing HIV infections among HIV seropositive donors unknown infection history.

e. Perform necessary follow-up and supplemental testing within seven (7) calendar days of initial discovery of positive results to confirm the presence of HIV, HCV or HBV infection to allow the DDCC to optimally classify donors’ infection status

Table 3 Task 3 Deliverables/ Work Products

2.4. Task 4: Perform TTIMS Logistic Support

The contractor shall schedule and provide administrative support for Committee and Subcommittee meetings. In performing this task the Contractor shall:

a. Prepare and distribute agendas to include conference call-in information

b. Prepare and distribute review materials

c. Take and distribute minutes and action items to meeting participants

d. Track and maintain a central repository of minutes and action items and associated materials relating to all meetings/calls

e. Disseminate scientific reports at scientific venues and to relevant FDA or HHS advisory committees.

f. Prepare a Draft Technical Report and a Final Technical Report consisting of a description of work performed and results obtained for the entire contract period of performance in sufficient detail to describe comprehensively the results achieved.

g. Prepare abstracts, presentations, reports, and manuscripts for publication derived from analyses under the contract.

Table 4 Task 4 Deliverables/ Work Products

2.5. task 5: Communication and Outreach

The Contractor shall act as a member of and actively participate in the TTIMS Committee and any assigned Subcommittees. Moreover, the contractor shall provide regular updates on work accomplished to the Committee and other identified stakeholders.

The Contractor shall be responsible for leading discussions, participating in discussions, contributing questions and answers, raising and addressing issues, risks and concerns, developing and giving presentations, and other active oral and written communications.

The Contractor’s Principal Investigator (PI) shall attend face-to-face semi-annual Committee meetings located at Silver Spring, Maryland (1-day duration each) with the first meeting conducted within two months of contract award. Moreover, the Contractor’s Principal Investigator (PI) shall attend all Committee and Subcommittee conference calls, at least once per month for the duration of the contract period of performance. The Contractor shall:

1.5.1 Quality Control and Site Visits

The LRCC Contractor shall conduct a minimum of two (2) site visits during the contract period to one of the participating blood collection organizations to address and remedy any issues encountered in the conduct of TTIMS activities related to the evaluation of the HIV, HCV and HBV positive donors.

1.5.2 External Collaborations

The Contractor shall collaborate with other Government Agencies and blood organizations. The Contactor shall submit requests for external collaborations and investigations to the COR and Committee for review and approval. All external collaboration requests shall be sent via written communication (e.g. email). The Contractor shall enable external collaborations and investigations that propose to use existing TTIMS data or resources to address additional research questions, as approved by the COR and the Committee.

Table 5 Task 5 Meetings Table 6 Task 5 Deliverables/ Work Products

2.6. Task 6: Project/Contract Management

1.6.1 Facilities

The Contractor shall provide facilities and equipment necessary to work with infectious materials, in order to accomplish the requirements as specified in task areas 3.1 through 3.4. Specifically, the Contractor shall provide facilities and equipment (i.e. BSL-3 facility) to complete biohazard containment procedures, which is required when working with infectious materials. Additionally the Contractor shall provide the capacities to store biological/infectious materials and specimens at -70 C (minus 70 degrees Celsius). Lastly, the Contractor shall ensure that electronic medical record data is captured, and retained and protected for future study purposes.

1.6.2 Project Meetings and Status Reporting

The Contractor shall provide project/contract management to ensure that tasks stay on track and milestones, performance measures deliverables and work products are met. The Contractor shall participate in a kickoff meeting within 10-calendar days of contract award. The purpose of the kickoff meeting is to introduce the contractor staff to the Government and discuss the contractor’s approach to meeting the requirements of the SOW.

The Contractor shall deliver a monthly status report (MSR) to the COR on the 5th calendar day of each month following the end of the previous calendar month. At a minimum the MSR shall contain the following information:

a. An overview of work completed, in progress, and planned for each task

b. Identification of problem areas with recommended remedial actions

c. Challenges, issues, and risks Lastly, the Contractor shall ensure that all deliverables are sent in electronic formats (i.e. Microsoft Office or Adobe PDF) for the COR’s inspection/acceptance.

1.6.3 Quality Control

The Contractor shall deliver high quality data and information; follow FDA Statutes, Guidance, and Good Manufacturing Processes (GMP’s); which are required of all licensed blood collection organizations operating within the United States and deliver high quality written materials (technical documents, analyses, reports, etc.). See Appendix A, Quality Assurance Surveillance Plan (QASP) for performance standard matrix. The Contractor shall provide comprehensive, clear analyses and interpretation of trends and their effects.

a. Information shall reflect state-of-the-industry practices and current applicable regulatory requirements.

b. The Contractor shall take the lead in developing documents and shall incorporate a high level of quality assurance and responsiveness.

c. The Contractor shall not receive more than two customer complaints regarding documents prepared within any twelve-month period of performance.

d. Reports and technical documents shall be delivered within the time frame specified with minimal errors and need for corrections.

e. The Contractor shall ensure the following:

· That its staff have the requisite subject matter expertise and skill sets

· Key Personnel shall be on board within 30-calendar days of award

In addition, the Contractor shall be proactive in informing the designated CBER COR of any issues, problems and recommendations that shall be addressed in order for the overall effective accomplishment of contract goals and deliverables. Recommendations for actions that need to be taken by FDA staff, or other Contractors shall be clearly defined and communicated (in writing) to the responsible party and the FDA, and have identified dates for completion.

1.6.4 Transition Out

A smooth and orderly transition-out between the incumbent Contractor and the successor Contractor or Government is necessary to ensure minimum disruption to vital FDA business. The Contractor shall submit and execute a Transition-Out plan to ensure business continuity for the FDA in the event that a new Contractor is chosen. At a minimum, this Transition-Out Plan shall include the following:

a. Transition-Out Plan and Schedule;

b. Inventory of documentation to be turned over;

c. Submission of knowledge transfer documentation to include current and up-to-date Standard Operating Procedures and MOP;

d. Participate in all transition-in activities with successor Contractor;

e. Provide “shadowing” and participate in knowledge transfer meetings and opportunities to facilitate the transfer of information, processes, and data needed to continue the services being performed by the Contractor;

f. Identify, track and discuss with the Government any known problems, risks or issues associated with the transition – Deliverables, Inspection and Acceptance.

2. Contract Constraints

The following constraints are applicable to this contract:

1. Blood Donor Survey modifications shall be recommended by the Committee and approved by the COR following receipt of all necessary administrative/regulatory approvals. This includes applicable Institutional Review Boards (IRBs), and Office of Management and Budget (OMB).

2. Blood collection organizations will collect, process, and store bio-specimens until the LRCC coordinates the shipments.

3. The LRCC shall provide the necessary freezers, containers, and other supplies to the DDCC and other participating blood collection organizations to properly and safely transfer the bio-specimens.

4. The Contractor shall ensure that all administrative and regulatory approvals are obtained as described in the MOP and LRCC Protocol by any participating blood collection organizations before TTIMS data collection begins. These include but are not limited to those that address human subject considerations; and clearances including applicable Institutional Review Boards (IRBs), and Office of Management and Budget (OMB).

5. The DDCC Contractor will provide a unique identification number (ID) for each donor allowing donors to be longitudinally followed and individual donations and components identified in the databases maintained by the DDCC and LRCC. These unique identifiers will accompany the data files transmitted from the DDCC to the LRCC and vice versa.

i. The identity of the blood donors will be known only to the blood center investigator (s) and will not be provided to the LRCC. Participating blood collection organization shall maintain the link between the unique study donor ID and the donor identification information to allow the center to contact the donor for appropriate follow-up.

ii. The link between study donor ID and donor name or other identifiers shall be kept in a secured location at the participating blood centers.

6. Interim data used in technical progress reports and other reports developed for the purpose of study monitoring and shall not be released publicly. Premature release of such data could result in interpretations that prove to be unreliable or invalid once the study is completed and the full context for the data is known and lead the public and medical practitioners to pursue inappropriate measures.

7. Legend for Technical Progress Reports Containing Interim Study Data

i. The Contractor shall incorporate the following legend on the cover of technical progress reports and reports containing interim study data that are prepared for internal and confidential use by the Committee or other Committees such as the Blood Product Advisory Committee or the Advisory Committee on Blood & Tissue Safety & Availability:

· "The data, if any, contained in this report/deliverable are preliminary and may contain un-validated findings. These data are not intended for public use. Public use of these data could create erroneous conclusions which, if acted upon, could threaten public health or safety."

8. The computer programs, data management systems, databases, and other resources developed through this contract shall comply with data standards and procedures established by DHHS and FDA (per http://www.fda.gov/ForIndustry/DataStandards/default.htm).