CBER_BEST-_Blood_and_Blood_Product_Safety_Surveillance_Statement_of_Work.pdf

The CBER Biologics Effectiveness and Safety (BEST) Initiative:

Blood and Blood Product Safety Surveillance

Statement of Work (SOW) July 21, 2017

Table of Contents

1. Introduction

1.1 Background

1.2 Biologics Effectiveness and Safety (BEST) Contract Objectives

2. Task Description(s)

2.1 Task 1: Program and Task Management

2.1.1 Management Plan

2.1.2 Monthly Status Reports (MSRs)

2.1.3 Kickoff Meeting

2.1.4 Annual In-Person Meeting…………………………………………………………………………………………………...7

2.1.5 WorkGroup Meetings

2.1.6 Administrative Requirements………………………………………………………………………..……………………………8

2.1.6 Risk Management

2.1.7 Facilities

2.1.8 Delivery Instructions for Deliverables

2.2. Task 2: Transition Services

2.2.1 Transition-out

2.3. Task 3: Establish Organization and Infrastructure ……………………………………………………………...…11

2.4. Task 4: Data, Tools and Resource Requirements ……………………………………………………………………12

2.5. TASK 5: Conduct Safety Queries and Studies of Blood and Blood Products and Build Biovigilance Capabilities

3. Contract Constraints

4. OTHER Requirements

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. As part of its mission, the FDA conducts monitoring of the safety of regulated products.

In response to the FDA Amendments Act of 2007 (FDAAA 2007) with the goal to build an active postmarket risk identification and analysis system, the FDA established the Sentinel system and built a national electronic data system for monitoring the safety of FDA-regulated medical products.

Sentinel is a distributed database system consisting of numerous data partners who retain operational control over their data within a secure environment; the Sentinel Operations Center manages, receives and processes FDA questions in the form of queries and returns summary results back to the FDA in a secure environment. Sentinel is currently run under a five-year contract awarded to Harvard Pilgrim Health Care Institute in 2014. The FDA Center for Biologics Evaluation and Research (CBER) established the Postlicensure Rapid Immunization Safety Monitoring (PRISM) system, within Sentinel, specifically to conduct active postmarket risk identification studies and analyses of vaccine safety. CBER also established the Blood Safety Continuously Active Network (BloodSCAN) as an active postmarket risk identification and analysis system within Sentinel for evaluating the safety of blood and blood products. CBER uses the Sentinel system to conduct some of its epidemiological studies as part of its regulatory responsibilities.

CBER has also conducted a number of epidemiological studies outside of the Sentinel system.

CBER’s Office of Biostatistics and Epidemiology (OBE) initiated postmarket safety studies working collaboratively with federal partners such as the Veterans Health Administration, Indian Health Services and Center for Medicare and Medicaid Services (CMS). Since 2005, FDA has conducted studies with CMS in the areas of vaccine and blood safety and in 2013 in vaccine effectiveness.

OBE has conducted numerous epidemiological studies with private sector partners, such as HealthCore. And these successful collaborations resulted in a number of completed safety studies, peer-reviewed publications and contributed to FDA regulatory decision-making. In 2016, CBER funded a study using artificial intelligence, natural language processing and advanced analytics to evaluate biologic product adverse event reports to more efficiently analyze and review reported adverse events and trends in reports to support and enhance our postmarket safety surveillance work.

CBER is initiating this contract action as part of its Biologics Effectiveness and Safety (BEST) initiative, in its continuing efforts to develop additional active postmarket risk identification and analysis systems to address surveillance and epidemiological study challenges unique to our regulated biologic products. CBER’s BEST initiative expands our work beyond current partners (CMS and in Sentinel) to provide CBER with new data sources; common data models (CDMs); tools and methods; infrastructure, capabilities and capacity with the goal of providing deliverables in a more cost-effective, efficient, and timely manner. Overall, the CBER BEST system will be built for conducting surveillance, effectiveness and safety studies in three areas including: 1) Blood and blood product safety as part of FDA’s efforts to build a national biovigilance program; 2) New, innovative approaches to postmarket safety and effectiveness studies for biologic products to include approaches and applications such as query tools, robotics, machine learning, artificial intelligence (AI), natural language processing (NLP) and others to automate blood and blood product adverse event reporting; and 3) Biologics effectiveness and safety surveillance efforts that may include vaccines, blood and blood products, tissues, and other biologic products.

This SOW addresses the first area listed above to build capabilities and capacity for conducting: 1) Blood and blood product safety surveillance as part of FDA’s efforts to build a national biovigilance program. Accordingly, FDA’s goal with BEST is to gain access to new sources of electronic health record (EHR) data or similar sources providing more detailed clinical patient information than claims data for patients treated in outpatient and inpatient settings; as well as new common data models (CDM) that CBER’s Sentinel program is not currently using, including the Observational Medical Outcomes Partnership(OMOP) model that can accommodate EHR and richer patient clinical data than available in claims data; as well as new tools and methods, infrastructure, capabilities and capacity to conduct this work.

BEST will be part of the growing and evolving network of CBER postmarket safety and effectiveness analysis systems in the Sentinel program and may not repeat work currently underway in Sentinel but is intended to expand CBER’s postmarket safety and effectiveness work, capabilities and capacity in the areas listed above. Access to large sources of patient data, especially inpatient data in Electronic Health Record (EHR) format or similar data sources providing more detailed clinical patient information than claims data (or with rapid access to medical chart data), and a new CDM that CBER’s Sentinel program is not currently using, including the Observational Medical Outcomes Partnership(OMOP) model, that can accommodate EHR and richer patient clinical data than available in claims data, is required. The proposed FDA work may be conducted under a number of possible organizational structures, collaborations and arrangements. Data holder(s) or other organization(s) may have their own team of epidemiologists, subject matter experts, bioinformaticists, programmers and others who are experienced in conducting postmarket pharmacoepidemiological safety studies for drugs and biologics. Alternatively, the Contractor may partner with other organizations, such as contract research organizations, academic partners, data partners, or others who have their own teams or may assemble its own team of such experts, which might serve as a Coordinating Center to manage the overall program work.

1.2 BIOLOGICS EFFECTIVENESS AND SAFETY (BEST) CONTRACT OBJECTIVES AND SCOPE

The primary goal of this Contract is to develop, build and gain access to new infrastructure and data, methods and tools, and resources to better conduct EHR-type surveillance-based safety studies for blood and blood products (i.e. transfused blood components and plasma derivatives) regulated by CBER as part of FDA’s efforts to build a hemovigilance component of a national biovigilance system.

Objectives

The objectives of this contract are:

1. To provide the resources and support to establish a Coordinating Center that enables CBER to conduct active surveillance using a distributed data model or similar approach

2. To build capabilities and capacity for conducting: 1) Blood and blood product safety surveillance as part of FDA’s efforts to build a national biovigilance program

3. To provide access to data source(s) that covers millions of patients to conduct active blood and blood product postmarket safety and effectiveness studies

4. To provide a new common data model that CBER’s Sentinel program is not currently using including the Observational Medical Outcomes Partnership(OMOP) model that can accommodate EHR and richer patient clinical data

5. To provide FDA with capabilities to analyze patient data using query tools, tools to conduct epidemiological studies, as well as Contractor experts who can provide necessary knowledge to conduct and coordinate efforts.

Scope

The Contractor shall, independently and not as an agent of the Government provide all necessary personnel to assist in the development of capabilities for conducting blood safety surveillance and related epidemiological studies. Specifically, the primary objectives are to:

1. Establish a Coordinating Center using a distributed data model or similar approach with the resources such as access to new large patient data sources, CDMs, query tools and methods, and relevant experts to conduct blood and blood product postmarket product safety and effectiveness assessments.

2. Provide tools with capabilities to conduct rapid queries or simple safety studies using data that include identifying patients with an exposure to the biologic product and outcomes of interest and to conduct moderately complex query studies using cohort identification tools (control, treated populations, age stratification, and others) and evaluate unadjusted exposure. Ability to compare, correlate outcomes in different populations..

3. Provide capabilities to conduct highly complex epidemiological studies using a protocol that includes comparisons between cohort populations, and such methods as cohort designs, self-controlled risk intervals, and others and be able to validate coded exposure and outcome data using Medical Record Review.

4. To access incidence and case fatality rates of severe transfusion-related adverse events (AE) (e.g. TRALI, TACO, Sepsis, HTRs, PTP, thrombosis and others) among blood component transfusion recipients) and thrombotic events and other AEs s to be determined with FDA among recipients of plasma derivative products

5. To obtain incidence rates of severe transfusion-associated adverse events by specific blood products transfused ( i.e., red blood cells, plasma, platelets, clotting factors, immune globulins and others to be determined with FDA) and by blood component processing (e.g., leukocyte reduction, irradiation, pathogen-reduction, etc.), quantity of product transfused, demographics of recipients, clinical diagnoses and procedures, and other possible risk factors.

6. To evaluate transfusion by component or product type, processing, quantity used, product age, etc., donor characteristics, recipient risk factors for occurrence of severe AEs or effectiveness.

7. Provide FDA staff training sessions on use of the methods and tools, data conducting queries and studies and Contractor resources developed to execute the indicated tasks to conduct postmarket safety and effectiveness studies.

2. TASK DESCRIPTION(S)

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

2.1 TASK 1: PROGRAM AND TASK MANAGEMENT

The Contractor’s Program Manager and the Principal Investigator (PI) shall provide Program Management (PM) for the Biologics Effectiveness and Safety Contract requirements. These PM responsibilities shall include what is necessary to plan, structure, coordinate, schedule, manage, communicate, report, and steward all respective tasks and activities throughout the Contract’s period of performance.

The Contractor shall ensure smooth operations between its Coordinating Center, Data source(s) / partners, and work collaboratively with the FDA to ensure delivery of coordination activities such as kick-off meetings, bi-monthly telecons, monthly reports, and in-person meetings; and identify projects, develop protocols, reviewing deliverables such as protocols, interim analyses, interim reports and final reports.

The Contractor shall:

• Develop a plan on processes and procedures for collaborating with FDA in study design and analysis. Details of the collaboration will by mutual decision of all collaborative parties. Collaboration includes sharing summary data findings, interpretation of findings, review of manuscripts, design of protocols, and co-authorship of publications.

The order of listing authors on each publication shall be determined on a case-by-case basis, by mutual decision of all collaborative parties and shall reflect appropriately each author's contribution to the project. Where there is no agreement on the above items, the FDA Contracting Officer, through the FDA COR, shall provide the final decision.

• Provide access to a data source(s) with millions of patient electronic health records (EHRs) or similar data sources providing more detailed clinical patient information than claims data; the infrastructure, tools and methods, staffing, expertise and ability to identify and characterize transfusion-associated adverse events for blood and blood products; and the ability to conduct medical chart review to confirm findings.

• Generate a document providing information as to which key personnel w i l l be used on each project and the percentage of time and staff member effort and contribution to the program on a per-task basis.

Additionally, the Contractor shall provide Program Management services to establish control, management, monitoring, and notification mechanisms for Biologics Effectiveness and Safety System Contract requirements. Moreover, the Contactor shall work with the Government Contracting Officer (CO), Contracting Officer’s Representative (COR), and subject matter experts (SMEs) to ensure that tasks stay on track and important milestones are met.

Representative activities include, but are not limited to:

• Administering the program;

• Throughout the period of performance, developing, maintaining, modifying, and updating plans to include: risk management plans, staffing plan, Standard Operating Procedures (SOP), Protocols, and Others;

• Preparing a Management Plan (MP) describing the technical approach, organizational resources and management controls throughout execution.

• Preparing and maintaining the Program Management Plan;

• Preparing monthly progress and financial reports;

• Establishing notification mechanisms for acceptance by the FDA;

• Complying with reporting requirements;

• Following escalation procedures for problems, issues, and recommendations, as encountered;

• Safeguarding information;

• Managing Contractor staff and provide sub-contractor management;

• Coordinating tasks and working collaboratively with FDA CBER staff to carry out the work of the contract;

• Attending an annual face-to-face meeting with FDA CBER staff at the FDA White Oak Campus;

• Communicating, presenting and publishing of any BEST project findings shall be done in coordination and with the concurrence of FDA CBER and the FDA COR;

• Ensuring proper exit criteria are followed when Contractor employees leave projects;

• Providing risk mitigation;

• Conducting and participating in progress meetings, facility meetings, training meetings, performance meetings, program/project reviews, management briefings, stakeholder presentations, demonstration meetings, transition meetings, and COR site visits, and post requirements meetings as may be required;

• Responding to ad hoc data calls to refine or confirm project findings or address FDA questions or concerns concerning project findings; and

• Provide training to FDA staff on data sources, study approaches or methods and tools employed and developed as part of the specific tasks. The specific type of training shall be determined based on the tools and methods developed and may include development of training manuals, conduct training sessions, provide presentations or provide other similar activities.

2.1.1 MANAGEMENT PLAN

The Contractor shall deliver a Management Plan. The Management Plan (MP) shall include a Work Breakdown Structure (WBS), which shall contain all of the work elements described. The WBS elements shall also illustrate the sequence and resources required for each work package.

Additionally, the MP shall include a schedule that details activities, dependencies and timeframes for meeting FDA objectives and deliverables; an organizational chart identifying relationships, authorities, and responsibilities. The MP shall include a description of the management controls that the Contractor shall employ to meet the performance, cost, and schedule requirements; and other areas the Contractor deems relevant and important to the management of the Contract.

The MP shall address all the action items from any Kickoff Meetings and other follow-on meetings, as appropriate. The Contactor shall update the MP when re-planning any activities. Changes to the MP are subject to approval by the COR.

2.1.2 MONTHLY STATUS REPORTS (MSRS)

The Contractor shall provide a written Monthly Report (MSR) to the FDA COR, incorporating all tasks at a high level and their progress. Within the first 30 calendar days after award, the Government and the Contractor shall design and agree upon a standard reporting format and timeframe. At a minimum, unless otherwise specified, each MSR shall contain the following information:

• The previous month’s progress

• Deviance from previous month’s planned progress (either positive or negative)

• The current month’s planned progress

• Issues and recommendations

• Performance and Cost Report (P&CR): the P&CR shall include all recurring and non-recurring costs, cumulative cost, total labor hours, and cumulative labor hours for each task area for the previous month

• Program risks, risk mitigation plans, risk mitigation actions taken and resolution of risks.

• Status of deliverables

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.

2.1.3 KICKOFF MEETING

Following the contract award, the Contractor shall conduct a kickoff meeting at the FDA for the BEST Blood and Blood Safety Surveillance Contract. The kickoff meeting shall be conducted to introduce the Contractor team, discuss roles, responsibilities, other relevant issues and the contractor’s approach to meeting the requirements of the SOW.

2.1.4 ANNUAL IN-PERSON MEETING

The Contractor shall schedule and conduct an annual in-person meeting with FDA personnel a t t he F D A W h it e O ak Cam pu s i n S i l v e r S p r i n g , MD to discuss Contractor’s performance under the contract; and provide a presentation of recently completed or in-progress individual collaborative study or studies .

2.1.5 WORKGROUP MEETINGS AND DELIVERABLES

The Contractor shall work collaboratively with FDA Staff and the COR and shall establish project workgroups and participate in bi-monthly telecons. The Contractor shall participate in the processes and meetings that support the overall efforts of the FDA BEST System program, including general management-related meetings, and meetings related to specific tasks. Generally, there are meetings of the Contractor and FDA Staff working group meetings on an approximately bi-monthly basis. The Contractor shall participate in different capacities, such as leading discussions; contributing questions and answers; raising issues, risks and concerns; and developing and giving presentations.

The contractor shall schedule and provide administrative support for task workgroup 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. Minutes shall be of sufficient detail to accurately document meeting date and location, meeting purpose, items discussed, decisions made, attendees, and action items, and shall be delivered within FDA document repositories.

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

e. Prepare a Draft Contract Technical Report for FDA review and comment and a Final Technical Report consisting of a description of work performed and results obtained for the entire contract period of performance, lessons learned in sufficient detail to describe comprehensively the results achieved. The Final Technical Report shall incorporate FDA comments and input.

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

2.1.6 ADMINISTRATIVE REQUIREMENTS

The Contractor shall ensure smooth operations between its Coordinating Center, Data holders / partners, and work collaboratively with the FDA to ensure delivery of activities such as kick-off meetings, bi-monthly telecons for project meetings, monthly reports, and in-person meetings; and developing query forms, executing and completing queries, generating query reports, developing protocols, generating protocol-based study reports, reviewing deliverables such as protocols, interim analyses, interim reports and final reports.

The Contractor shall:

• Have the ability to contact a sample of physicians and/or patients on an ad hoc basis for information beyond what is available in automated data sources.

• Generate a Key Personnel Document providing information as to which key personnel w i l l be used on each project and identifying the percentage of time and staff member effort and contribution to the program on a per-project basis.

Table 1: Task 1 Meetings

Table 2: Task 1 Deliverables/ Work Products

2.1.7 RISK MANAGEMENT

The Contractor shall identify and report for resolution to the Government any issues that prevent the Contractor from performing the work in any task that the Contractor is unable to resolve independently.

For each Task, the Contractor shall document and report the risks and opportunities within a risk registry. The Contractor shall maintain the risk registry and provide it to the COR on request.

Task Meeting / Activity Title Location(s) Estimated Occurrences

Receiving Organization

Task 1 1. Kick-Off Meeting FDA White Oak Campus, Bldg 71 or teleconference

Once : Within 10-calendar days of award

COR

Task 1 2. Annual In-person Meeting FDA White Oak Campus, Bldg 71 One per year COR

Task 1 3. Workgroup Meetings Teleconference Bi-Monthly COR, FDA Project Staff

Task Deliverable/Work Product Title Due Date Quantity / Frequency Delivered To

Task 1 1. Management Plan Initially reviewed at Kick- Off Meeting

Once, Ongoing COR

Task 1 2. Monthly Status Reports 5th calendar day of each month Monthly COR

Task 1

3. Workgroup Conference Calls, Meeting Minutes By 10th calendar day following the meeting Monthly COR, FDA project

Staff

Task 1 4. Workgroup Agendas 5 calendar days prior to the meeting Monthly COR, FDA project

Staff

Task 1

5. Central Electronic Repository of Meeting Minutes/ Calls/Action Items

Last business day of the month Ongoing COR, FDA project

Staff

Task 1 6. Draft Technical Report

Draft due 30 calendar days before the last day of the period of performance

One COR

Task 1 7. Final Technical Report Final due at the end of period of performance

One COR

Task 1 8. Abstracts and Presentations 5 business days prior to submission or presentation

Anticipate one per year COR

Task 1 9. Reports and Manuscripts 30 calendar days prior to the agreed date

Anticipate one per year COR

Task 1 10. Key Personnel Document 1 month after award date Once COR

The risk registry shall contain, at a minimum:

• Issue Number: a sequential numbering of all issues;

• Severity: assessment of issue severity i.e., likelihood and consequences (High/Medium/Low)

• Date Found: – date that issue was identified by the Contractor;

• Duration: number of days that issue has been open;

• Status: representing issue status as open or closed. The Contractor shall maintain a complete list of all issues – no issues typically should be deleted from the Contractor’s delivered list;

• Title: short description of issue;

• Updated: date for updated status;

• Details: narrative description of activities that have been completed to resolve issue;

• Assigned To: identify Government POC or Contractor that is assigned to resolve the issue;

• Solution or Workaround: description of the actions and activities taken to resolve or mitigate issue the issue.

2.1.8 FACILITIES

The Contractor shall provide all facilities and equipment necessary to accomplish the Contract requirements as specified herein. Additionally the Contractor shall ensure that electronic data and medical record data is securely stored, transferred and handled, and retained and protected for future study purposes.

2.1.9 DELIVERY INSTRUCTIONS FOR DELIVERABLES

Unless otherwise specified, all deliverables, reports or copies of reports shall be delivered to the COR.

Requirements for inspection and acceptance are as follows:

• The Government will inspect and accept the services provided to ensure they meet the requirements detailed in the relevant Contract tasks.

• The Government will accept products and services only if they conform to all terms and conditions of the Contract.

• The Government will provide written notification of acceptance or rejection within ten (10) calendar days of receiving the service.

• The Government will reject non-conforming products and services. The Contractor shall correct any deficiencies within thirty (30) calendar days of when the Government issues the rejection notice. If the Contractor cannot correct the deficiencies within this time frame, the Contractor shall immediately notify the COR of the reason for the delay and provide a proposed corrective action plan within ten (10) calendar days.

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 (via email) to the responsible party and the FDA, and have identified dates for completion.

2.2. TASK 2: TRANSITION SERVICES

TRANSITION ACTIVITIES TAKE PLACE TO EFFICIENTLY TRANSITION ALL ACTIVITIES FROM AN INCUMBENT

CONTRACTOR TO THE NEW CONTRACTOR. CURRENTLY, THERE IS NO INCUMBENT CONTRACTOR SINCE

THIS IS A NEW CONTRACT. TRANSITION-OUT PLAN

The Contractor shall provide transition-out activities of contracted activities and services to the Federal Government or to a follow-on Contractor by the end of the contract period of performance.

During this period, the Contractor shall ensure no degradation in support provided under the contract. Between the turnover date designated by the COR and the end of the contract period of performance, the outgoing Contractor shall ensure all contract activities are closed out and provide sustainment support to complete the transition.

Representative deliverables include, but are not limited to:

• Providing the FDA with current versions of all documentation developed (i.e. Standard Operating Procedures and Manual of Operations)

• Providing the FDA with a current inventory of all Government-Furnished Equipment (GFE) and Government Furnished Information (GFI) utilized by the Contractor along with full support in the reconciliation of this inventory

• Providing the follow-on contractor with the ability to “shadow” and participate in technical exchange meetings and opportunities to facilitate the transfer of information, processes, and data needed to continue the services being performed by the Contractor

• The Contractor shall develop and submit to the COR a Transition-Out Plan that shall include but not be limited to the following elements:

• Roles and responsibilities for contractor’s staff during the transition, including the identification of a transition lead;

• Transition-out schedule and milestones for completing transition-out activities

• Define schedule for transition-out progress reviews, and define processes for identifying problems, and for ensuring prompt problem resolution;

• Identify methodology used for conducting and ensuring a seamless transition

• Identify activities to acclimate the successor contractor

The Contractor shall conduct and provide and inventory of government-funded equipment (GFE) and government-furnished information (GFI).

Table 3: Task 2 Deliverables/ Work Products

2.3 Task 3: Establish Organization and Infrastructure

Task Deliverable/Work Product Title Due Date Quantity /

Frequency Delivered To

Task 2 1. Transition-Out Plan 120 calendar days prior to period of performance end date

One COR

Task 2 2. GFE and GFI Inventory 120 calendar days prior to period of performance end date

One COR

The primary goal of this Contract is to gain access to new data sources, CDMs, methods and tools, infrastructure a resources to conduct surveillance and epidemiologic safety studies that promote OBE’s mission to assure the safety of blood and blood products.

During the course of the contract period of performance, the Contractor shall establish the organizational structure, such as a coordinating center, and infrastructure to provide a work plan(s) and a cost estimate(s) to conduct each blood and blood product safety study requested. The Contractor shall not proceed with the work plan until written approval is given by both the Contracting Officer and COR. The following describe in greater detail Contractor activities for each of the objectives of the Contract.

General Requirements: Please note that the requirements below refer largely to blood and blood products.

Organization and Resource Requirements. The Contractor shall:

• Establish a Coordination Center (CC) or similar organizational structure consisting of a team of experts such as epidemiologists, clinical and subject matter experts, bioinformaticists, programmers, project managers and others.

• Be capable of executing the work of the tasks including but not limited to identifying the data necessary to conduct the work; developing the study protocols and programming and conducting the required development of methods or tools and/or postmarket pharmacoepidemiological analyses and safety studies for biologics.

• Provide an EHR data resource or similar sources providing more detailed clinical patient information than claims data for patients treated in outpatient and inpatient settings that can best support population-based studies of blood or blood products and is available for linking each patient to all relevant medical care data including enrollment status, biologic product exposure data, coded medical outcomes, and vital records (desired, but not required). For biologics licensed for distribution in the US see http://www.fda.gov/CBER/products.htm and for vaccines see http://www.fda.gov/CBER/vaccine/licvacc.htm.

• The Contractor shall provide documentation that the Contractor either owns the data or has legal rights to access and disclose analyses of the data to third parties such as the FDA.

• Provide a new common data model that CBER’s Sentinel program is not currently using including the Observational Medical Outcomes Partnership(OMOP) model that can accommodate EHR and richer patient clinical data than available in claims data.

• Provide a document demonstrating full disclosure of HIPAA-compliant data collection, coding, secure handling and configuration methods to allow FDA to appropriately interpret findings.

• Summarize the data and results of analyses for FDA use. FDA will require no patient-, provider-, or health plan- specific identifiers. The de-identification of the data shall be solely the responsibility of the Contractor.

• Establish Contract Workgroups consisting of members from the Coordination Center (CC) or similar organizational structures described in the Contract and FDA Staff. In addition the CC team shall consist of at least one member with clinical or specific expertise in the blood transfusion area such as hematology, transfusion medicine, etc. FDA staff will provide questions to be addressed and Workgroup members shall work collaboratively to design and complete studies as specified in Task 5.

http://www.fda.gov/CBER/vaccine/licvacc.htm

• Develop and provide detailed work plan describing the overall approach to be used to conduct the proposed blood product safety studies describing including application of available patient data, query and study methods and tools, along with overall management of the workgroup, Contractor staffing and resources to work collaboratively with FDA staff to complete the proposed queries and protocol-based studies as described in Task 5.

Table 4: Task 3 Deliverables/ Work Products

2.4 TASK 4: DATA, TOOLS AND RESOURCE REQUIREMENTS

The conduct of postmarket blood safety surveillance and safety studies under the BEST system requires the Contractor to conduct queries and more complex studies of blood products and development of new innovative methods. This shall require the Contractor to have access to EHR data (or similar data sources providing more detailed clinical patient information than claims data) covering millions of patients; a new CDM that CBER’s Sentinel program is not currently using, including the Observational Medical Outcomes Partnership (OMOP) model, that can accommodate EHR and richer patient clinical data than available in claims; the necessary tools for data queries and analyses and the resources such as technical expertise, infrastructure and organizational structure to support this endeavor.

The Contractor shall develop and update the BEST manual of operating procedures (MOP) and protocols to ensure it accurately reflects current and ongoing contract activities. FDA staff will review the draft MOP and protocol documents provide input for incorporation into the final document. The Contractor shall obtain and meet all required review, approval and standards processes that comply with all relevant institutional, federal, state, and local laws and regulations to conduct the work such as data and information technology security, such as Federal Information Security Management Act (FISMA), Health

Task Deliverable/Work Product Title Due Date Quantity /

Frequency Delivered To

Task 3

1. Establish Coordinating Center 1 month after award date Once COR

Task 3

2. Provide document that the Contractor either owns the data or has legal rights to access and disclose analyses

1 month after award date Once COR

Task 3

3.Provide a document demonstrating full disclosure of HIPAA-compliant data collection, coding, secure handling and configuration methods

1 month after award date Once COR

Task 3

4. Establish Project Workgroup 1 month after award date Once COR

Task 3

5. Detailed work plan for conducting blood product safety studies

1 month after award date Ongoing, One per project

COR

Insurance Portability and Accountability Act (HIPAA), Institutional Review Boards (IRB) and any others identified in the contract. These procedures (i.e. the MOP) shall address at a minimum the following:

secure data collection, handling processes, sharing, ownership; management and tracking, consensus definitions, secure data transfer procedures, and sharing considerations for data summaries.

The Contractor shall:

• Provide access to large dataset(s) with millions of patient EHRs or similar data sources providing more detailed clinical patient information than claims data and deliver the capability to analyze and assess the incidence, mortality and risk factors for occurrence of severe transfusion-related and plasma derivative-related adverse events in the United States.

• Provide a new common data model for formatting and analyzing patient data that CBER’s Sentinel program is not currently using including the Observational Medical Outcomes Partnership (OMOP) model that can accommodate EHR and richer patient clinical data than claims data alone.

• Provide a data resource that is automated with capabilities to link each patient to all relevant EHR data including enrollment status, transfusion exposure, coded medical outcomes, vital records, etc. The Co ntracto r data, tools methods and resources shall provide(but not be limited to) the following:

• Data Sources that demonstrate completeness, timeliness, and accessibility, including estimated times from service delivery to accessibility of data via queries;

• Have the ability to identify products by type, lot identification number, or other applicable descriptors.

• Provide level of detail to examine temporal relationships between product administration/and associated adverse events/outcomes. Examples include, but are not limited to:

o Anaphylaxis after immune globulin intravenous (IGIV) and other plasma derivatives, and other blood products by age group.

o Thrombotic events following product administration.

o Assess ability to identify blood products by type, number of transfused units, lot identification number, or other applicable descriptors.

• Provide patient populations permitting long-term longitudinal follow-up of most patients for acute or delayed severe adverse events and capture related outpatient prescription exposures and health provider encounters, linked longitudinally to each patient and shall include blood transfusions and plasma derivative treatments from a variety of settings (inpatient, outpatient, emergency, etc.).

• Access to developed methods and tools for querying the data for exposures, outcomes of interest and allow for derivation and comparison of incidence/prevalence rates in a rapid manner. The Contractor tools shall be able to form cohorts of patient subpopulations to be studied or as comparator groups.

• Tools shall provide for automated/assisted selection of product, diagnostic and procedure codes that map across different coding systems such as ICD-9, ICD-10, Medra, ISBT, Codabar and others.

• Tools shall be able to make epidemiological, statistical comparisons between populations such as controls, treatments, etc. with the capability to identify safety signals or to refine and verify previously identified signals.

• Provide information on cost estimates for conducting Medical chart review, and on processes and procedures to be followed in rapidly conducting chart review using automation and other cutting edge approaches for chart retrieval; case identification; abstraction tools and abstraction process; validation of fields, derivation of positive predictive value, rates and others.

Table 5: Task 4 Deliverables/ Work Products

2.5 TASK 5: Conduct Safety Queries and Studies of Blood and Blood Products and Build Biovigilance Capabilities

The Contractor shall:

a. Work Collaboratively with FDA to identify queries and studies that can be accomplished using contractor provided data and tools addressing specific CBER blood and blood product and adverse event associations o f r e g u l a t o r y s i g n i f i c a n c e .

b. The Contractor shall develop a distributed data analysis system or similar approach that so the Contractor and FDA may use the data to identify trends of severe transfusion-related adverse events over time and assess the epidemiology of blood and blood product safety and utilization, including but not limited to recipients’ demographics, clinical indications, and quantities of transfused products. .

c. The Contractor shall work collaboratively with FDA staff to develop and finalize a query intake form that can be used to quickly collect information needed to run a query and incorporate input from FDA staff. The intake form shall provide areas to accomodate the key question, background, objectives (exposure and outcome), data to be used (number of patients, years, coverage, etc.), clinical setting, proposed diagnosis and procedure codes and methods/analyses, analyses, data/data fields collected, references, and any other relevant information to complete the request. Once the form is completed studies can commence.

d. For simple queries of exposure and outcomes, the Contractor shall provide the capabilities to use tools and methods they have developed to query their data source to address regulatory questions of interest to FDA. The Contractor and FDA shall work collaboratively to complete a query form containing query inputs/parameters, the study shall commence and should be completed in 2 to 7 days. The Contractor shall provide the FDA the query output and result report as a short addendum to the completed form (a few pages) as a deliverable for each query.

Task Deliverable/Work Product Title Due Date Quantity /

Frequency Delivered To

Task 4

1. Methods, Tools and Data resource document

1 month after award date Once COR

Task 4

2. Document on Medical Chart Review

1 month after award date Once COR

e. For moderately complex queries, the Contractor shall also provide capabilities to use their data sources to conduct moderately complex studies to address regulatory questions of interest to FDA including development of a query intake form that can be used to quickly collect information needed to run a query and incorporate input from FDA staff.

The intake form will provide areas to detail the key question, background, objective (exposure and outcome), clinical setting, data to be used (number of patients, years, coverage, etc.), product number and types transfused, cohort populations, correlations between populations, proposed methods/analyses, data/data fields to be used, proposed diagnosis and procedure codes or case definitions to be used, references, and any other relevant information. Use of more complex analyses to compare cohorts, data/data fields collected, references, and any other relevant information to complete the request. Once the form is completed and the terms of the study, mutually agreed upon between the Contractor and FDA, the study can commence and should be completed in 1 to 4 weeks.

Results shall be provided by the Contractor as query output and a short summary report (5-10 pages).

f. For complex, protocol-based studies, the Contractor shall generate a draft written protocol of the blood or blood product(s) and adverse event or health outcome of interest to be studied for review and to accommodate FDA input. The protocol shall address the key question, background, objectives (exposure and outcome), data to be used (number of patients, years, coverage, etc.), product number and types transfused, cohort populations, correlations between populations, proposed methods/analyses, data/data fields to be used, clinical setting, diagnosis and procedure codes or case definitions to be used, references, and any other relevant information. In addition, the protocol shall require medical chart review, preferably using electronic health records, and validation of findings. The protocol shall describe and provide experts to develop the chart abstraction tool, elements to be evaluated, identification of cases, adjudication of differing expert evaluations, and analyses to determine findings such as positive-predictive value, etc. (medical records will not be shared directly with FDA). The study shall calculate the incidence rates of adverse events, data on risk factors such as demographics, procedure or treatment history, and comorbid diseases. Once the protocol is completed and the terms of the protocol mutually agreed upon between the Contractor and FDA the study can commence and should be completed in 4 to 12 months. Contractor shall provide a final report (10-50 pages) describing the study and medical chart review details, results, findings, strengths, limitations or challenges in conducting the study.

g. Work collaboratively with FDA staff to identify and develop the product and adverse event or health outcome of interest pairs to be studied via queries or protocol-based studies. The Contractor shall obtain and meet all required review, approval and standards processes to conduct the work such as Institutional Review Boards (IRB), FSMA, HIPAA, data and information technology security and any others. Contractor personnel performing work under this contract shall satisfy all requirements for appropriate security eligibility in dealing with access to sensitive personal health information and information systems. These procedures shall address at a minimum the following: data collection, ownership, and security; management and tracking, consensus definitions, transfer, and sharing considerations for data summaries.

Project queries and studies shall include one or more of the following:

1. Assessment of emerging infectious disease risks that impact blood safety and blood supply issues including but not limited to Zika, dengue, babesiosis, and others.

2 Assessment of emerging technologies that impact blood safety and blood supply issues including but not limited to pathogen inactivation, advances in testing technologies and others identified during Contractor’s assessment.

Table 6: Task 5 Deliverables/ Work Products

*Activity should start within 2 months of the award date

Product / Adverse Event pairs to be studied Because FDA must be responsive to a changing landscape of products and associated risks ( i.e., adverse events, etc.) and benefits (i.e., effectiveness), the BEST system must be flexible and similarly able to respond to safety or effectiveness questions that arise as part of the regulatory review of pre-licensure

Task Deliverable/Work Product Title Due Date Quantity /

Frequency Delivered To

Task 5

1. A distributed data analysis system or similar approach

1 month after Protocol or Analytic Plan completion

Once COR

Task 5 2. IRB Documents and Approval

1 month after Protocol or Analytic Plan completion

Ongoing basis COR

Task 5

3. Query Intake Form for

Simple and Moderately Complex Queries

1 month after award date Once COR

Task 5 4. Simple Queries

Approximately 5 per month*. Due within 10 days after completion of Intake Form and initiation of Query

50 COR

Task 5

5. Completed Query Intake Form and Query Output and Result report

10 days after completion of Intake Form and initiation of Query

50 COR

Task 5 6. Moderately Complex Queries

Approximately 1 per month*. Due within 1 month after initiation of query.

10 COR

Task 5

7. Report for each

Moderately Complex Queries (5-10 pages).

No later than 1 month after Initiation of Query 10 COR

Task 5 8. Complex, Protocol-based Studies

Approximately 2 per year* 2 COR

Task 5

9. Complex, Protocol-based Study Final Report (10-50 pages)

Due Within 12 months of initiation of query/ 2 COR data or through postmarket surveillance or studies. Accordingly, it is not possible at this time or the time of contract award to identify and determine the specific product / adverse event(s) of interest to be studied. However, FDA will work with the Contractor on an ongoing basis to identify the specific product / adverse event(s) of interest to the FDA for study.

As part of its philosophy of product safety throughout the lifecycle, FDA has studied and continues to study a number of blood and blood product adverse event pairs to ensure products continue to have favorable benefit-risk profiles and also, to potentially identify mitigations to further reduce risks.

Blood and Components to potentially study may include but not be limited to: Whole blood, Red Blood Cells, Packed Red Cells, Platelets, Plasma includes additionally process products that have undergone leukocyte reduction (LR), irradiation, pathogen reduction, solvent-treated, and others.

Adverse events or Health Outcomes of Interest to potentially study for blood and blood components may include but not be limited to: Transfusion-related Acute Lung Injury (TRALI), Transfusion-associated Circulatory Overload (TACO), Hemolysis, Hemothrombotic Reactions, Acute Respiratory Distress Syndrome (ARDS), Acute Lung Injury (ALI), Thromboembolic Events (TEE), Transfusion-transmitted infections, Sepsis, and Septic shock.

Blood Products or plasma-derived products to potentially study may include but not be limited to:

Albumin, Intravenous Immune Globulin (IVIg), Intramuscular Immune Globulin, Clotting factors such as Factor VII, Factor VIII, and Factor IX.

Potential associated seious adverse events or Health Outcomes of Interest to study for blood products may include but not be limited to the following: Transfusion-related Acute Lung Injury (TRALI), Transfusion-associated Circulatory Overload (TACO), Hemolysis, Acute Respiratory Distress Syndrome (ARDS), Acute Lung Injury (ALI), Thromboembolic Events (TEE), Transfusion-associated dyspnea (TAD), Allergic reaction (severe), Hypotensive transfusion reaction, Febrile non-hemolytic transfusion reaction (FNHTR), Acute hemolytic transfusion reaction (AHTR), Delayed hemolytic transfusion reaction (DHTR),Delayed serologic transfusion reaction (DSTR), Transfusion-associated graft vs. host disease (TAGVHD),Post-transfusion purpura (PTP), or Transfusion-transmitted infection (TTI).

The focus of this contract is to largely conduct blood safety and biovigilance studies, but in doing so, also build a system that can be used to conduct safety studies for all biologic products. Accordingly, to assess the ability of the BEST system to conduct studies on a broader range of products CBER requires the Contractor perform a portion of the queries (~20%) and one protocol-based study on vaccine and adverse event pairs / or effectiveness outcome(s)..

Vaccines to potentially study may include but not be limited to: Influenza…