Government and Regulations

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The US Department of Veterans Affairs (VA) has partnered with academic medical centers and programs since 1946 to provide clinical training for physician residents. Ranking second in federal graduate medical education (GME) funding to the Centers for Medicare and Medicaid Services (CMS), the $850 million VA GME budget annually reimburses > 250 GME-sponsoring institutions (affiliates) of 8000 GME programs for the clinical training of 49,000 individual residents rotating through > 11,000 full-time equivalent (FTE) positions.¹ The VA also distributes $1.6 billion to VA facilities to offset the costs of conducting health professions education (HPE) (eg, facility infrastructure, salary support for VA instructors and preceptors, education office administration, and instructional equipment).² The VA financial and educational contributions account for payment of 11% of resident positions nationally and allow academic medical centers to be less reliant on CMS GME funding.^3,4 The VA contributions also provide opportunities for GME expansion,^1,5,6 educational innovations,^5,7 interprofessional and team-based care,^8,9 and quality and safety training.^10,11 The Table provides a comparison of CMS and VA GME reimbursability based on activity.

GME financing is complex, particularly the formulaic approach used by CMS, the details of which are often obscured in federal regulations. Due to this complexity and the $16 billion CMS GME budget, academic publications have focused on CMS GME financing while not fully explaining the VA GME policies and processes.^4,12-14 By comparison, the VA GME financing model is relatively straightforward and governed by different statues and VA regulations, yet sharing some of the same principles as CMS regulations. Given the challenges in CMS reimbursement to fully support the cost of resident education, as well as the educational opportunities at the VA, the VA designs its reimbursement model to assure that affiliates receive appropriate payments.^4,12,15 To ensure the continued success of VA GME partnerships, knowledge of VA GME financing has become increasingly important for designated institutional officers (DIOs) and residency program directors, particularly in light of recent investigations into oversight of the VA’s reimbursement to academic affiliates.^16-18 This report describes VA GME reimbursement and, where applicable, VA and CMS reimbursement policies are compared to highlight similarities, differences, and common principles.

VA AUTHORITY

While the VA’s primary mission is “to provide a complete hospital medical service for the medical care and treatment of veterans,”early VA leaders recognized the importance of affiliating with the nation’s academic institutions.¹⁹ In 1946, the VA Policy Memorandum Number 2 established a partnership between the VA and the academic medical community.²⁰ Additional legislation authorized specific agreements with academic affiliates for the central administration of salary and benefits for residents rotating at VA facilities. This process, known as disbursement, is an alternative payroll mechanism whereby the VA reimburses the academic affiliate for resident salary and benefits and the affiliate acts as the disbursing agent, issuing paychecks to residents.^21,22

Resident FUNDING

By policy, with rare exceptions, the VA does not sponsor residency programs due to the challenges of providing an appropriate patient mix of age, sex, and medical conditions to meet accreditation standards.⁴ Nearly all VA reimbursements are for residents in affiliate-sponsored programs, while just 1% pays for residents in legacy, VA-sponsored residency programs at 2 VA facilities. The VA budget for resident (including fellows) salary and benefits is managed by the VA Office of Academic Affiliations (OAA), the national VA office responsible for oversight, policy, and funding of VA HPE programs.

Resident Salaries and Benefits

VA funding of resident salary and benefits are analogous with CMS direct GME (DGME), which is designed to cover resident salary and benefits costs.^4,14,23 CMS DGME payments depend on a hospital’s volume of CMS inpatients and are based on a statutory formula, which uses the hospital’s resident FTE positions, the per-resident amount, and Medicare’s share of inpatient beds (Medicare patient load) to determine payments.¹² The per-resident amount is set by statute, varies geographically, and is calculated by dividing the hospital’s allowable costs of GME (percentage of CMS inpatient days) divided by the number of residents.^12,24

By comparison, the VA GME payment reimburses for each FTE based on the salary and benefits rate set by the academic affiliate. Reimbursement is calculated based on resident time spent at the VA multiplied by a daily salary rate. The daily salary rate is determined by dividing the resident’s total compensation (salary and benefits) by the number of calendar days in an academic year. Resident time spent at the VA facility is determined by obtaining rotation schedules provided by the academic affiliate and verifying resident clinical and educational activity during scheduled rotations.

Indirect Medical Education Funding

In addition to resident salary and benefits, funds to offset the cost of conducting HPE are provided to VA facilities. These funds are intended to improve and maintain necessary infrastructure for all HPE programs not just GME, including education office administration needs, teaching costs (ie, a portion of VA preceptors salary), and instructional equipment.

figure.png

The Veterans Equitable Resource Allocation (VERA) is a national budgeting process for VA medical facilities that funds facility operational needs such as staff salary and benefits, infrastructure, and equipment.² The education portion of the VERA, the VERA Education Support Component (VESC), is not managed by the OAA, but rather is distributed through the VERA model to the general budget of VA facilities hosting HPE (Figure). VESC funding in the VA budget is based on labor mapping of physician time spent in education; other labor mapping categories include clinical care, research, and administration. VA facility VESC funding is calculated based on the number of paid health profession trainees (HPTs) from all professions, apportioned according to the number of FTEs for physician residents and VA-paid HPTs in other disciplines. In fiscal year 2024, VA facilities received $115,812 for each physician resident FTE position and $84,906 for each VA-paid, non-GME FTE position.

The VESC is like CMS's indirect GME funding, termed Indirect Medical Education (IME), an additional payment for each Medicare patient discharged reflecting teaching hospitals’ higher patient care costs relative to nonteaching hospitals. Described elsewhere, IME is calculated using a resident-to-bed ratio and a multiplier, which is set by statute.^4,25 While IME can be used for reimbursement for some resident clinical and educational activities(eg, research), VA VESC funds cannot be used for such activities and are part of the general facility budget and appropriated per the discretion of the medical facility director.

ESTABLISHING GME PARTNERSHIPS

An affiliation agreement establishes the administrative and legal requirements for educational relationships with academic affiliates and includes standards for conducting HPE, responsibilities for accreditation standards, program leadership, faculty, resources, supervision, academic policies, and procedures. The VA uses standardized affiliation agreement templates that have been vetted with accrediting bodies and the VA Office of General Counsel.

A disbursement agreement authorizes the VA to reimburse affiliates for resident salary and benefits for VA clinical and educational activities. The disbursement agreement details the fiscal arrangements (eg, payment in advance vs arrears, salary, and benefit rates, leave) for the reimbursement payments. Veterans Health Administration (VHA) Directive 1400.05 provides the policy and procedures for calculating reimbursement for HPT educational activities.²⁶

The VA facility designated education officer (DEO) oversees all HPE programs and coordinates the affiliation and disbursement agreement processes.²⁷ The DEO, affiliate DIO, residency program director, and VA residency site director determine the physician resident FTE positions assigned to a VA facility based on educational objectives and availability of educational resources at the VA facility, such as patient care opportunities, faculty supervisors, space, and equipment. The VA facility requests for resident FTE positions are submitted to the OAA by the facility DEO.

Once GME FTE positions are approved by the OAA, VA facilities work with their academic affiliate to submit the physician resident salary and benefit rate. Affiliate DIOs attest to the accuracy of the salary rate schedule and the local DEO submits the budget request to the OAA. Upon approval, the funds are transferred to the VA facility each fiscal year, which begins October 1. DEOs report quarterly to the OAA both budget needs and excesses based on variations in the approved FTEs due to additional VA rotations, physician resident attrition, or reassignment.

Resident Position Allocation

VA GME financing provides flexibility through periodic needs assessments and expansion initiatives. In August and December, DEOs collaborate with an academic affiliate to submit reports to the OAA confirming their projected GME needs for the next academic year. Additional positions requests are reviewed by the OAA; funding depends on budget and the educational justification. The OAA periodically issues GME expansion requests for proposal, which typically arise from legislation to address specific VA workforce needs. The VA facility DEO and affiliate GME leaders collaborate to apply for additional positions. For example, a VA GME expansion under the Veterans Access, Choice, and Accountability Act of 2014 added 1500 GME positions in 8 years for critically needed specialties and in rural and underserved areas.⁵ The Maintaining Internal Systems and Strengthening Outside Networks (MISSION) Act of 2018 authorized a pilot program for VA to fund residents at non-VA facilities with priority for Indian Health Services, Tribes and Tribal Organizations, Federally Qualified Health Centers, and US Department of Defense facilities to provide access to veterans in underserved areas.⁶

The VA GME financing system has flexibility to meet local needs for additional resident positions and to address broader VA workforce gaps through targeted expansion. Generally, CMS does not fund positions to address workforce needs, place residents in specific geographic areas, or require the training of certain types of residents.⁴ However, the Consolidated Appropriations Act of 2021 has provided the opportunity to address rural workforce needs.²⁸

Reimbursement

The VA provides reimbursement for clinical and educational activities performed in VA facilities for the benefit of veterans as well as research, didactics, meetings and conferences, annual and sick leave, and orientation. The VA also may provide reimbursement for educational activities that occur off VA grounds (eg, the VA proportional share of a residency program’s didactic sessions). The VA does not reimburse for affiliate clinical duties or administrative costs, although a national policy allows VA facilities to reimburse affiliates for some GME overhead costs.²⁹

CMS similarly reimburses for residency training time spent in patient care activities as well as orientation activities, didactics, leave, and, in some cases, research.^4,30,31 CMS makes payments to hospitals, which may include sponsoring institutions and Medicare-eligible participating training sites.^4,30,31 For both the VA and CMS, residents may not be counted twice for reimbursement by 2 federal agencies; in other words, a resident may not count for > 1 FTE.^4,30-32

GME Oversight

VA GME funding came under significant scrutiny. At a 2016 House Veterans Affairs Committee hearing, Representative Phil Roe, MD (R-Tennessee), noted that no process existed at many VA facilities for “determining trainee presence” and that many VA medical centers had “difficulty tracking resident rotations”¹⁶ A VA Office of the Inspector General investigation recommended that the VA implement policies and procedures to improve oversight to “ensure residents are fully participating in educational activities” and that the VA is “paying the correct amount” to the affiliate.¹⁷ A 2020 General Accountability Office report outlined unclear policy guidance, incomplete tracking of resident activities, and improper fiscal processes for reimbursement and reconciliation of affiliate invoices.¹⁸

eappendix.png

In response, the OAA created an oversight and compliance unit, revised VHA Directive 1400.05 (the policy for disbursement), and improved resident tracking procedures.²⁶ The standard operating procedure that accompanied VHA Directive 1400.05 provides detailed information for the DEO and VA facility staff for tracking resident clinical and educational activities. FTE counts are essential to both VA and CMS for accurate reimbursement. The eAppendix and the Table provide a guide to reimbursable activities in the VA for the calculation of reimbursement, with a comparison to CMS.^33,34 The OAA in cooperation with other VA staff and officers periodically conducts audits to assess compliance with disbursement policy and affiliate reimbursement accuracy.

In the VA, resident activities are captured on the VA Educational Activity Record, a standardized spreadsheet to track activities and calculate reimbursement. Each VA facility hosting resident physicians manually records resident activity by the half-day. This process is labor intensive, involving both VA and affiliate staff to accurately reconcile payments. To address the workload demands, the OAA is developing an online tool that will automate aspects of the tracking process. Also, to ensure adequate staffing, the OAA is in the process of implementing an office optimization project, providing standardized position descriptions, an organizational chart, and staffing levels for DEO offices in VA facilities.

This report describes the key policies and principles of VA GME financing, highlighting the essential similarities and differences between VA and CMS. Neither the VA nor CMS regulations allow for reimbursement for > 1 FTE position per resident, a principle that underpins the assignment of resident rotations and federal funding for GME and are similar with respect to reimbursement for patient care activities, didactics, research, orientation, and scholarly activity. While reimbursable activities in the VA require physical presence and care of veteran patients, CMS also limits reimbursement to resident activities in the hospital and approved other settings if the hospital is paying for resident salary and benefits in these settings. The VA provides some flexibility for offsite activities including didactics and, in specific circumstances, remote care of veteran patients (eg, teleradiology).

The VA and CMS use different GME financing models. For example, the CMS calculations for resident FTEs are complex, whereas VA calculations reimburse the salary and benefits as set by the academic affiliate. The VA process accounts for local variation in salary rates, whereas the per-resident amount set by CMS varies regionally and does not fully account for differences in the cost of living.²⁴ Because all patients in VA facilities are veterans, VA calculations for reimbursement do not involve ratios of beds like the CMS calculations to determine a proportional share of reimbursement. The VA GME expansion tends to be more directed to VA health workforce needs than CMS, specifying the types of programs and geographic locations to address these needs.

The VA regularly reevaluates how affiliates are reimbursed for VA resident activity, balancing compliance with VA policies and the workload for VA and its affiliates. The VA obtains input from key stakeholders including DEOs, DIOs, and professional organizations such as the Association of American Medical Colleges and the Accreditation Council for Graduate Medical Education.^35,36

Looking ahead, the VA is developing an online tool to improve the accuracy of affiliate reimbursement. The VA will also implement a standardized staffing model, organizational structure, and position descriptions for DEO offices. These initiatives will help reduce the burden of tracking and verifying resident activity and continue to support the 77-year partnership between VA and its affiliated institutions.

table.png

The US Department of Veterans Affairs (VA) has partnered with academic medical centers and programs since 1946 to provide clinical training for physician residents. Ranking second in federal graduate medical education (GME) funding to the Centers for Medicare and Medicaid Services (CMS), the $850 million VA GME budget annually reimburses > 250 GME-sponsoring institutions (affiliates) of 8000 GME programs for the clinical training of 49,000 individual residents rotating through > 11,000 full-time equivalent (FTE) positions.¹ The VA also distributes $1.6 billion to VA facilities to offset the costs of conducting health professions education (HPE) (eg, facility infrastructure, salary support for VA instructors and preceptors, education office administration, and instructional equipment).² The VA financial and educational contributions account for payment of 11% of resident positions nationally and allow academic medical centers to be less reliant on CMS GME funding.^3,4 The VA contributions also provide opportunities for GME expansion,^1,5,6 educational innovations,^5,7 interprofessional and team-based care,^8,9 and quality and safety training.^10,11 The Table provides a comparison of CMS and VA GME reimbursability based on activity.

GME financing is complex, particularly the formulaic approach used by CMS, the details of which are often obscured in federal regulations. Due to this complexity and the $16 billion CMS GME budget, academic publications have focused on CMS GME financing while not fully explaining the VA GME policies and processes.^4,12-14 By comparison, the VA GME financing model is relatively straightforward and governed by different statues and VA regulations, yet sharing some of the same principles as CMS regulations. Given the challenges in CMS reimbursement to fully support the cost of resident education, as well as the educational opportunities at the VA, the VA designs its reimbursement model to assure that affiliates receive appropriate payments.^4,12,15 To ensure the continued success of VA GME partnerships, knowledge of VA GME financing has become increasingly important for designated institutional officers (DIOs) and residency program directors, particularly in light of recent investigations into oversight of the VA’s reimbursement to academic affiliates.^16-18 This report describes VA GME reimbursement and, where applicable, VA and CMS reimbursement policies are compared to highlight similarities, differences, and common principles.

VA AUTHORITY

While the VA’s primary mission is “to provide a complete hospital medical service for the medical care and treatment of veterans,”early VA leaders recognized the importance of affiliating with the nation’s academic institutions.¹⁹ In 1946, the VA Policy Memorandum Number 2 established a partnership between the VA and the academic medical community.²⁰ Additional legislation authorized specific agreements with academic affiliates for the central administration of salary and benefits for residents rotating at VA facilities. This process, known as disbursement, is an alternative payroll mechanism whereby the VA reimburses the academic affiliate for resident salary and benefits and the affiliate acts as the disbursing agent, issuing paychecks to residents.^21,22

Resident FUNDING

By policy, with rare exceptions, the VA does not sponsor residency programs due to the challenges of providing an appropriate patient mix of age, sex, and medical conditions to meet accreditation standards.⁴ Nearly all VA reimbursements are for residents in affiliate-sponsored programs, while just 1% pays for residents in legacy, VA-sponsored residency programs at 2 VA facilities. The VA budget for resident (including fellows) salary and benefits is managed by the VA Office of Academic Affiliations (OAA), the national VA office responsible for oversight, policy, and funding of VA HPE programs.

Resident Salaries and Benefits

VA funding of resident salary and benefits are analogous with CMS direct GME (DGME), which is designed to cover resident salary and benefits costs.^4,14,23 CMS DGME payments depend on a hospital’s volume of CMS inpatients and are based on a statutory formula, which uses the hospital’s resident FTE positions, the per-resident amount, and Medicare’s share of inpatient beds (Medicare patient load) to determine payments.¹² The per-resident amount is set by statute, varies geographically, and is calculated by dividing the hospital’s allowable costs of GME (percentage of CMS inpatient days) divided by the number of residents.^12,24

By comparison, the VA GME payment reimburses for each FTE based on the salary and benefits rate set by the academic affiliate. Reimbursement is calculated based on resident time spent at the VA multiplied by a daily salary rate. The daily salary rate is determined by dividing the resident’s total compensation (salary and benefits) by the number of calendar days in an academic year. Resident time spent at the VA facility is determined by obtaining rotation schedules provided by the academic affiliate and verifying resident clinical and educational activity during scheduled rotations.

Indirect Medical Education Funding

In addition to resident salary and benefits, funds to offset the cost of conducting HPE are provided to VA facilities. These funds are intended to improve and maintain necessary infrastructure for all HPE programs not just GME, including education office administration needs, teaching costs (ie, a portion of VA preceptors salary), and instructional equipment.

figure.png

The Veterans Equitable Resource Allocation (VERA) is a national budgeting process for VA medical facilities that funds facility operational needs such as staff salary and benefits, infrastructure, and equipment.² The education portion of the VERA, the VERA Education Support Component (VESC), is not managed by the OAA, but rather is distributed through the VERA model to the general budget of VA facilities hosting HPE (Figure). VESC funding in the VA budget is based on labor mapping of physician time spent in education; other labor mapping categories include clinical care, research, and administration. VA facility VESC funding is calculated based on the number of paid health profession trainees (HPTs) from all professions, apportioned according to the number of FTEs for physician residents and VA-paid HPTs in other disciplines. In fiscal year 2024, VA facilities received $115,812 for each physician resident FTE position and $84,906 for each VA-paid, non-GME FTE position.

The VESC is like CMS's indirect GME funding, termed Indirect Medical Education (IME), an additional payment for each Medicare patient discharged reflecting teaching hospitals’ higher patient care costs relative to nonteaching hospitals. Described elsewhere, IME is calculated using a resident-to-bed ratio and a multiplier, which is set by statute.^4,25 While IME can be used for reimbursement for some resident clinical and educational activities(eg, research), VA VESC funds cannot be used for such activities and are part of the general facility budget and appropriated per the discretion of the medical facility director.

ESTABLISHING GME PARTNERSHIPS

An affiliation agreement establishes the administrative and legal requirements for educational relationships with academic affiliates and includes standards for conducting HPE, responsibilities for accreditation standards, program leadership, faculty, resources, supervision, academic policies, and procedures. The VA uses standardized affiliation agreement templates that have been vetted with accrediting bodies and the VA Office of General Counsel.

A disbursement agreement authorizes the VA to reimburse affiliates for resident salary and benefits for VA clinical and educational activities. The disbursement agreement details the fiscal arrangements (eg, payment in advance vs arrears, salary, and benefit rates, leave) for the reimbursement payments. Veterans Health Administration (VHA) Directive 1400.05 provides the policy and procedures for calculating reimbursement for HPT educational activities.²⁶

The VA facility designated education officer (DEO) oversees all HPE programs and coordinates the affiliation and disbursement agreement processes.²⁷ The DEO, affiliate DIO, residency program director, and VA residency site director determine the physician resident FTE positions assigned to a VA facility based on educational objectives and availability of educational resources at the VA facility, such as patient care opportunities, faculty supervisors, space, and equipment. The VA facility requests for resident FTE positions are submitted to the OAA by the facility DEO.

Once GME FTE positions are approved by the OAA, VA facilities work with their academic affiliate to submit the physician resident salary and benefit rate. Affiliate DIOs attest to the accuracy of the salary rate schedule and the local DEO submits the budget request to the OAA. Upon approval, the funds are transferred to the VA facility each fiscal year, which begins October 1. DEOs report quarterly to the OAA both budget needs and excesses based on variations in the approved FTEs due to additional VA rotations, physician resident attrition, or reassignment.

Resident Position Allocation

VA GME financing provides flexibility through periodic needs assessments and expansion initiatives. In August and December, DEOs collaborate with an academic affiliate to submit reports to the OAA confirming their projected GME needs for the next academic year. Additional positions requests are reviewed by the OAA; funding depends on budget and the educational justification. The OAA periodically issues GME expansion requests for proposal, which typically arise from legislation to address specific VA workforce needs. The VA facility DEO and affiliate GME leaders collaborate to apply for additional positions. For example, a VA GME expansion under the Veterans Access, Choice, and Accountability Act of 2014 added 1500 GME positions in 8 years for critically needed specialties and in rural and underserved areas.⁵ The Maintaining Internal Systems and Strengthening Outside Networks (MISSION) Act of 2018 authorized a pilot program for VA to fund residents at non-VA facilities with priority for Indian Health Services, Tribes and Tribal Organizations, Federally Qualified Health Centers, and US Department of Defense facilities to provide access to veterans in underserved areas.⁶

The VA GME financing system has flexibility to meet local needs for additional resident positions and to address broader VA workforce gaps through targeted expansion. Generally, CMS does not fund positions to address workforce needs, place residents in specific geographic areas, or require the training of certain types of residents.⁴ However, the Consolidated Appropriations Act of 2021 has provided the opportunity to address rural workforce needs.²⁸

Reimbursement

The VA provides reimbursement for clinical and educational activities performed in VA facilities for the benefit of veterans as well as research, didactics, meetings and conferences, annual and sick leave, and orientation. The VA also may provide reimbursement for educational activities that occur off VA grounds (eg, the VA proportional share of a residency program’s didactic sessions). The VA does not reimburse for affiliate clinical duties or administrative costs, although a national policy allows VA facilities to reimburse affiliates for some GME overhead costs.²⁹

CMS similarly reimburses for residency training time spent in patient care activities as well as orientation activities, didactics, leave, and, in some cases, research.^4,30,31 CMS makes payments to hospitals, which may include sponsoring institutions and Medicare-eligible participating training sites.^4,30,31 For both the VA and CMS, residents may not be counted twice for reimbursement by 2 federal agencies; in other words, a resident may not count for > 1 FTE.^4,30-32

GME Oversight

VA GME funding came under significant scrutiny. At a 2016 House Veterans Affairs Committee hearing, Representative Phil Roe, MD (R-Tennessee), noted that no process existed at many VA facilities for “determining trainee presence” and that many VA medical centers had “difficulty tracking resident rotations”¹⁶ A VA Office of the Inspector General investigation recommended that the VA implement policies and procedures to improve oversight to “ensure residents are fully participating in educational activities” and that the VA is “paying the correct amount” to the affiliate.¹⁷ A 2020 General Accountability Office report outlined unclear policy guidance, incomplete tracking of resident activities, and improper fiscal processes for reimbursement and reconciliation of affiliate invoices.¹⁸

eappendix.png

In response, the OAA created an oversight and compliance unit, revised VHA Directive 1400.05 (the policy for disbursement), and improved resident tracking procedures.²⁶ The standard operating procedure that accompanied VHA Directive 1400.05 provides detailed information for the DEO and VA facility staff for tracking resident clinical and educational activities. FTE counts are essential to both VA and CMS for accurate reimbursement. The eAppendix and the Table provide a guide to reimbursable activities in the VA for the calculation of reimbursement, with a comparison to CMS.^33,34 The OAA in cooperation with other VA staff and officers periodically conducts audits to assess compliance with disbursement policy and affiliate reimbursement accuracy.

In the VA, resident activities are captured on the VA Educational Activity Record, a standardized spreadsheet to track activities and calculate reimbursement. Each VA facility hosting resident physicians manually records resident activity by the half-day. This process is labor intensive, involving both VA and affiliate staff to accurately reconcile payments. To address the workload demands, the OAA is developing an online tool that will automate aspects of the tracking process. Also, to ensure adequate staffing, the OAA is in the process of implementing an office optimization project, providing standardized position descriptions, an organizational chart, and staffing levels for DEO offices in VA facilities.

This report describes the key policies and principles of VA GME financing, highlighting the essential similarities and differences between VA and CMS. Neither the VA nor CMS regulations allow for reimbursement for > 1 FTE position per resident, a principle that underpins the assignment of resident rotations and federal funding for GME and are similar with respect to reimbursement for patient care activities, didactics, research, orientation, and scholarly activity. While reimbursable activities in the VA require physical presence and care of veteran patients, CMS also limits reimbursement to resident activities in the hospital and approved other settings if the hospital is paying for resident salary and benefits in these settings. The VA provides some flexibility for offsite activities including didactics and, in specific circumstances, remote care of veteran patients (eg, teleradiology).

The VA and CMS use different GME financing models. For example, the CMS calculations for resident FTEs are complex, whereas VA calculations reimburse the salary and benefits as set by the academic affiliate. The VA process accounts for local variation in salary rates, whereas the per-resident amount set by CMS varies regionally and does not fully account for differences in the cost of living.²⁴ Because all patients in VA facilities are veterans, VA calculations for reimbursement do not involve ratios of beds like the CMS calculations to determine a proportional share of reimbursement. The VA GME expansion tends to be more directed to VA health workforce needs than CMS, specifying the types of programs and geographic locations to address these needs.

The VA regularly reevaluates how affiliates are reimbursed for VA resident activity, balancing compliance with VA policies and the workload for VA and its affiliates. The VA obtains input from key stakeholders including DEOs, DIOs, and professional organizations such as the Association of American Medical Colleges and the Accreditation Council for Graduate Medical Education.^35,36

Looking ahead, the VA is developing an online tool to improve the accuracy of affiliate reimbursement. The VA will also implement a standardized staffing model, organizational structure, and position descriptions for DEO offices. These initiatives will help reduce the burden of tracking and verifying resident activity and continue to support the 77-year partnership between VA and its affiliated institutions.

table.png

The US Department of Veterans Affairs (VA) has partnered with academic medical centers and programs since 1946 to provide clinical training for physician residents. Ranking second in federal graduate medical education (GME) funding to the Centers for Medicare and Medicaid Services (CMS), the $850 million VA GME budget annually reimburses > 250 GME-sponsoring institutions (affiliates) of 8000 GME programs for the clinical training of 49,000 individual residents rotating through > 11,000 full-time equivalent (FTE) positions.¹ The VA also distributes $1.6 billion to VA facilities to offset the costs of conducting health professions education (HPE) (eg, facility infrastructure, salary support for VA instructors and preceptors, education office administration, and instructional equipment).² The VA financial and educational contributions account for payment of 11% of resident positions nationally and allow academic medical centers to be less reliant on CMS GME funding.^3,4 The VA contributions also provide opportunities for GME expansion,^1,5,6 educational innovations,^5,7 interprofessional and team-based care,^8,9 and quality and safety training.^10,11 The Table provides a comparison of CMS and VA GME reimbursability based on activity.

GME financing is complex, particularly the formulaic approach used by CMS, the details of which are often obscured in federal regulations. Due to this complexity and the $16 billion CMS GME budget, academic publications have focused on CMS GME financing while not fully explaining the VA GME policies and processes.^4,12-14 By comparison, the VA GME financing model is relatively straightforward and governed by different statues and VA regulations, yet sharing some of the same principles as CMS regulations. Given the challenges in CMS reimbursement to fully support the cost of resident education, as well as the educational opportunities at the VA, the VA designs its reimbursement model to assure that affiliates receive appropriate payments.^4,12,15 To ensure the continued success of VA GME partnerships, knowledge of VA GME financing has become increasingly important for designated institutional officers (DIOs) and residency program directors, particularly in light of recent investigations into oversight of the VA’s reimbursement to academic affiliates.^16-18 This report describes VA GME reimbursement and, where applicable, VA and CMS reimbursement policies are compared to highlight similarities, differences, and common principles.

VA AUTHORITY

While the VA’s primary mission is “to provide a complete hospital medical service for the medical care and treatment of veterans,”early VA leaders recognized the importance of affiliating with the nation’s academic institutions.¹⁹ In 1946, the VA Policy Memorandum Number 2 established a partnership between the VA and the academic medical community.²⁰ Additional legislation authorized specific agreements with academic affiliates for the central administration of salary and benefits for residents rotating at VA facilities. This process, known as disbursement, is an alternative payroll mechanism whereby the VA reimburses the academic affiliate for resident salary and benefits and the affiliate acts as the disbursing agent, issuing paychecks to residents.^21,22

Resident FUNDING

By policy, with rare exceptions, the VA does not sponsor residency programs due to the challenges of providing an appropriate patient mix of age, sex, and medical conditions to meet accreditation standards.⁴ Nearly all VA reimbursements are for residents in affiliate-sponsored programs, while just 1% pays for residents in legacy, VA-sponsored residency programs at 2 VA facilities. The VA budget for resident (including fellows) salary and benefits is managed by the VA Office of Academic Affiliations (OAA), the national VA office responsible for oversight, policy, and funding of VA HPE programs.

Resident Salaries and Benefits

VA funding of resident salary and benefits are analogous with CMS direct GME (DGME), which is designed to cover resident salary and benefits costs.^4,14,23 CMS DGME payments depend on a hospital’s volume of CMS inpatients and are based on a statutory formula, which uses the hospital’s resident FTE positions, the per-resident amount, and Medicare’s share of inpatient beds (Medicare patient load) to determine payments.¹² The per-resident amount is set by statute, varies geographically, and is calculated by dividing the hospital’s allowable costs of GME (percentage of CMS inpatient days) divided by the number of residents.^12,24

By comparison, the VA GME payment reimburses for each FTE based on the salary and benefits rate set by the academic affiliate. Reimbursement is calculated based on resident time spent at the VA multiplied by a daily salary rate. The daily salary rate is determined by dividing the resident’s total compensation (salary and benefits) by the number of calendar days in an academic year. Resident time spent at the VA facility is determined by obtaining rotation schedules provided by the academic affiliate and verifying resident clinical and educational activity during scheduled rotations.

Indirect Medical Education Funding

In addition to resident salary and benefits, funds to offset the cost of conducting HPE are provided to VA facilities. These funds are intended to improve and maintain necessary infrastructure for all HPE programs not just GME, including education office administration needs, teaching costs (ie, a portion of VA preceptors salary), and instructional equipment.

figure.png

The Veterans Equitable Resource Allocation (VERA) is a national budgeting process for VA medical facilities that funds facility operational needs such as staff salary and benefits, infrastructure, and equipment.² The education portion of the VERA, the VERA Education Support Component (VESC), is not managed by the OAA, but rather is distributed through the VERA model to the general budget of VA facilities hosting HPE (Figure). VESC funding in the VA budget is based on labor mapping of physician time spent in education; other labor mapping categories include clinical care, research, and administration. VA facility VESC funding is calculated based on the number of paid health profession trainees (HPTs) from all professions, apportioned according to the number of FTEs for physician residents and VA-paid HPTs in other disciplines. In fiscal year 2024, VA facilities received $115,812 for each physician resident FTE position and $84,906 for each VA-paid, non-GME FTE position.

The VESC is like CMS's indirect GME funding, termed Indirect Medical Education (IME), an additional payment for each Medicare patient discharged reflecting teaching hospitals’ higher patient care costs relative to nonteaching hospitals. Described elsewhere, IME is calculated using a resident-to-bed ratio and a multiplier, which is set by statute.^4,25 While IME can be used for reimbursement for some resident clinical and educational activities(eg, research), VA VESC funds cannot be used for such activities and are part of the general facility budget and appropriated per the discretion of the medical facility director.

ESTABLISHING GME PARTNERSHIPS

An affiliation agreement establishes the administrative and legal requirements for educational relationships with academic affiliates and includes standards for conducting HPE, responsibilities for accreditation standards, program leadership, faculty, resources, supervision, academic policies, and procedures. The VA uses standardized affiliation agreement templates that have been vetted with accrediting bodies and the VA Office of General Counsel.

A disbursement agreement authorizes the VA to reimburse affiliates for resident salary and benefits for VA clinical and educational activities. The disbursement agreement details the fiscal arrangements (eg, payment in advance vs arrears, salary, and benefit rates, leave) for the reimbursement payments. Veterans Health Administration (VHA) Directive 1400.05 provides the policy and procedures for calculating reimbursement for HPT educational activities.²⁶

The VA facility designated education officer (DEO) oversees all HPE programs and coordinates the affiliation and disbursement agreement processes.²⁷ The DEO, affiliate DIO, residency program director, and VA residency site director determine the physician resident FTE positions assigned to a VA facility based on educational objectives and availability of educational resources at the VA facility, such as patient care opportunities, faculty supervisors, space, and equipment. The VA facility requests for resident FTE positions are submitted to the OAA by the facility DEO.

Once GME FTE positions are approved by the OAA, VA facilities work with their academic affiliate to submit the physician resident salary and benefit rate. Affiliate DIOs attest to the accuracy of the salary rate schedule and the local DEO submits the budget request to the OAA. Upon approval, the funds are transferred to the VA facility each fiscal year, which begins October 1. DEOs report quarterly to the OAA both budget needs and excesses based on variations in the approved FTEs due to additional VA rotations, physician resident attrition, or reassignment.

Resident Position Allocation

VA GME financing provides flexibility through periodic needs assessments and expansion initiatives. In August and December, DEOs collaborate with an academic affiliate to submit reports to the OAA confirming their projected GME needs for the next academic year. Additional positions requests are reviewed by the OAA; funding depends on budget and the educational justification. The OAA periodically issues GME expansion requests for proposal, which typically arise from legislation to address specific VA workforce needs. The VA facility DEO and affiliate GME leaders collaborate to apply for additional positions. For example, a VA GME expansion under the Veterans Access, Choice, and Accountability Act of 2014 added 1500 GME positions in 8 years for critically needed specialties and in rural and underserved areas.⁵ The Maintaining Internal Systems and Strengthening Outside Networks (MISSION) Act of 2018 authorized a pilot program for VA to fund residents at non-VA facilities with priority for Indian Health Services, Tribes and Tribal Organizations, Federally Qualified Health Centers, and US Department of Defense facilities to provide access to veterans in underserved areas.⁶

The VA GME financing system has flexibility to meet local needs for additional resident positions and to address broader VA workforce gaps through targeted expansion. Generally, CMS does not fund positions to address workforce needs, place residents in specific geographic areas, or require the training of certain types of residents.⁴ However, the Consolidated Appropriations Act of 2021 has provided the opportunity to address rural workforce needs.²⁸

Reimbursement

The VA provides reimbursement for clinical and educational activities performed in VA facilities for the benefit of veterans as well as research, didactics, meetings and conferences, annual and sick leave, and orientation. The VA also may provide reimbursement for educational activities that occur off VA grounds (eg, the VA proportional share of a residency program’s didactic sessions). The VA does not reimburse for affiliate clinical duties or administrative costs, although a national policy allows VA facilities to reimburse affiliates for some GME overhead costs.²⁹

CMS similarly reimburses for residency training time spent in patient care activities as well as orientation activities, didactics, leave, and, in some cases, research.^4,30,31 CMS makes payments to hospitals, which may include sponsoring institutions and Medicare-eligible participating training sites.^4,30,31 For both the VA and CMS, residents may not be counted twice for reimbursement by 2 federal agencies; in other words, a resident may not count for > 1 FTE.^4,30-32

GME Oversight

VA GME funding came under significant scrutiny. At a 2016 House Veterans Affairs Committee hearing, Representative Phil Roe, MD (R-Tennessee), noted that no process existed at many VA facilities for “determining trainee presence” and that many VA medical centers had “difficulty tracking resident rotations”¹⁶ A VA Office of the Inspector General investigation recommended that the VA implement policies and procedures to improve oversight to “ensure residents are fully participating in educational activities” and that the VA is “paying the correct amount” to the affiliate.¹⁷ A 2020 General Accountability Office report outlined unclear policy guidance, incomplete tracking of resident activities, and improper fiscal processes for reimbursement and reconciliation of affiliate invoices.¹⁸

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In response, the OAA created an oversight and compliance unit, revised VHA Directive 1400.05 (the policy for disbursement), and improved resident tracking procedures.²⁶ The standard operating procedure that accompanied VHA Directive 1400.05 provides detailed information for the DEO and VA facility staff for tracking resident clinical and educational activities. FTE counts are essential to both VA and CMS for accurate reimbursement. The eAppendix and the Table provide a guide to reimbursable activities in the VA for the calculation of reimbursement, with a comparison to CMS.^33,34 The OAA in cooperation with other VA staff and officers periodically conducts audits to assess compliance with disbursement policy and affiliate reimbursement accuracy.

In the VA, resident activities are captured on the VA Educational Activity Record, a standardized spreadsheet to track activities and calculate reimbursement. Each VA facility hosting resident physicians manually records resident activity by the half-day. This process is labor intensive, involving both VA and affiliate staff to accurately reconcile payments. To address the workload demands, the OAA is developing an online tool that will automate aspects of the tracking process. Also, to ensure adequate staffing, the OAA is in the process of implementing an office optimization project, providing standardized position descriptions, an organizational chart, and staffing levels for DEO offices in VA facilities.

This report describes the key policies and principles of VA GME financing, highlighting the essential similarities and differences between VA and CMS. Neither the VA nor CMS regulations allow for reimbursement for > 1 FTE position per resident, a principle that underpins the assignment of resident rotations and federal funding for GME and are similar with respect to reimbursement for patient care activities, didactics, research, orientation, and scholarly activity. While reimbursable activities in the VA require physical presence and care of veteran patients, CMS also limits reimbursement to resident activities in the hospital and approved other settings if the hospital is paying for resident salary and benefits in these settings. The VA provides some flexibility for offsite activities including didactics and, in specific circumstances, remote care of veteran patients (eg, teleradiology).

The VA and CMS use different GME financing models. For example, the CMS calculations for resident FTEs are complex, whereas VA calculations reimburse the salary and benefits as set by the academic affiliate. The VA process accounts for local variation in salary rates, whereas the per-resident amount set by CMS varies regionally and does not fully account for differences in the cost of living.²⁴ Because all patients in VA facilities are veterans, VA calculations for reimbursement do not involve ratios of beds like the CMS calculations to determine a proportional share of reimbursement. The VA GME expansion tends to be more directed to VA health workforce needs than CMS, specifying the types of programs and geographic locations to address these needs.

The VA regularly reevaluates how affiliates are reimbursed for VA resident activity, balancing compliance with VA policies and the workload for VA and its affiliates. The VA obtains input from key stakeholders including DEOs, DIOs, and professional organizations such as the Association of American Medical Colleges and the Accreditation Council for Graduate Medical Education.^35,36

Looking ahead, the VA is developing an online tool to improve the accuracy of affiliate reimbursement. The VA will also implement a standardized staffing model, organizational structure, and position descriptions for DEO offices. These initiatives will help reduce the burden of tracking and verifying resident activity and continue to support the 77-year partnership between VA and its affiliated institutions.

Word to the Nation: Guard zealously your right to serve in the Armed Forces, for without them, there will be no other rights to guard.

  John F. Kennedy ¹

The title of this Veterans Day editorial is a paraphrase of the legendary folk artist Pete Seeger’s protest song popularized during the Vietnam War. On January 27, 1973, in the wake of the widespread antiwar movement, Secretary of Defense Melvin Laird announced an end to the dreaded draft.²

For nearly 50 years, the all-volunteer military was celebrated as an outstanding achievement that professionalized the armed services and arguably made the US military among the most highly trained and effective fighting forces in the world. That was until an ongoing recruitment crisis threatened to write a different and far more disturbing conclusion to what the government had heralded as a “success story.”³

The recruiting crisis is a complicated problem with many facets that have received increasing attention from journalists, the media, experts, think tanks, and the government. Given this complexity, this will be a 2-part editorial: This column examines the scope of the crisis and the putative causes of the problem with recruiting Americans to serve in uniform. The next column will examine the potential impact of the shortage of service members on federal health care practice.

The Recruiting Crisis

Over the past several years, nearly every branch of the armed forces has struggled with recruitment, especially the Army. In April of this year, the US Department of Defense (DoD) reported that the Army, Navy, and Air Force would all fail to meet recruitment goals; only the Marines and Space Forces were expected to reach their targets.⁴ At the end of its fiscal year (October 1), the Army acknowledged that its 55,000 recruits were 10,000 fewer soldiers than it had aimed to enlist.⁵ But this was still more people joining the ranks than in 2022 when the Army was 15,000 recruits below the mark.⁶

Challenging Trends

There are many putative causes and proposed solutions for the recruitment crisis. Among the most serious is a marked drop in the American public’s confidence in the military. A June 2023 Gallup poll found that only 60% of citizens expressed “a great deal” or “quite a lot” of confidence in the military. This was the nadir of a 5-year decline that this year reached the lowest point since 1997/1998.⁷ For many Americans in and out of uniform, the ignoble end to the long war in Afghanistan leaving behind friends and allies contrary to the military ethos is cited as a significant contributor to both the loss of confidence in the military and the recruiting crisis.⁸

These cultural developments reinforce each other. Now, many veterans do not want their relatives and friends to follow them into the armed services. A 2021 survey by the Military Family Advisory Network found that slightly more than 60% of veterans and active-duty service members would recommend a military career to a potential recruit. This was down from 75% in 2019.⁹ Veterans cite a variety of reasons for discouraging their fellow citizens from serving, including low pay compared with civilian employment, especially in a labor-hungry job market; and the military failure to fulfill health care promises, housing, and other social services, especially for the growing number experiencing mental health disorders related to their service.¹⁰

Two facts about recruitment heighten the negative impact of some veterans’ change of attitude toward joining the services. First, since the end of the draft, military life in the US has become a family tradition. Published in 2011, a Pew Research Center study found that even then, a decreasing number of Americans had a family connection to the military. More respondents aged ≥ 50 years had a parent, child, spouse, or sibling who had served compared with those aged 30 to 49 years and those aged 18 to 29 (77%, 57%, and 33%, respectively).¹¹ Second, since the end of the draft, far fewer Americans have had military experience. Only 1% of the nation is currently in military service, and the veteran population is steadily declining. In 1980, 18% of adult Americans were veterans; 20 years later, that number is only 7%.¹² This makes it less likely that a high school or college student will have a personal or even a passing relationship with a teacher, coach, or other mentoring adult who is or has been a military member. This demographic discrepancy has generated what sociologists call the military-civilian gap.¹⁰ That division has been manipulated in the increasingly vehement culture wars and generational struggles that are splitting the country.¹²

This relatively recent sociological trend is reflected in a growing lack of interest among many young Americans in armed forces service. A DoD survey of participants aged 16 to 24 years regarding their intention to serve in the military found that 89% were probably not going to pursue a career in uniform. More than 65% of respondents indicated that the possibility of physical injury, death, or psychological trauma was the primary deterrent for considering enlisting.¹³ The latter barrier is directly related to our work as practitioners caring for service members and veterans, and through our compassion and competence, we may help bridge the widening divide between the military and civilian spheres. These numbers speak to the unwilling; there is also a significant group of Americans who want to serve yet are unable to due to their history, diagnoses, or condition.¹⁴ Their motivation to be military members in the face of the recruitment challenges highlighted here present federal practitioners with ethical questions that will be the subject of the next column.

Armed Forces and Veterans Day

This column’s epigraph is from President John F. Kennedy, a decorated World War II Navy combat veteran who decreed Armed Forces Day an official holiday a decade before conscription ended.¹ The commemoration was to thank and honor all individuals currently serving in the military for their patriotism and sacrifice. President Kennedy’s Word to the Nation could not be timelier on Veterans Day 2023. The data reviewed here raise profound questions as to where tomorrow’s service members and the veterans of the future will come from, and how we will persuade them that though there are real risks to military service, the rewards are both tangible and transcendent.

Word to the Nation: Guard zealously your right to serve in the Armed Forces, for without them, there will be no other rights to guard.

  John F. Kennedy ¹

The title of this Veterans Day editorial is a paraphrase of the legendary folk artist Pete Seeger’s protest song popularized during the Vietnam War. On January 27, 1973, in the wake of the widespread antiwar movement, Secretary of Defense Melvin Laird announced an end to the dreaded draft.²

For nearly 50 years, the all-volunteer military was celebrated as an outstanding achievement that professionalized the armed services and arguably made the US military among the most highly trained and effective fighting forces in the world. That was until an ongoing recruitment crisis threatened to write a different and far more disturbing conclusion to what the government had heralded as a “success story.”³

The recruiting crisis is a complicated problem with many facets that have received increasing attention from journalists, the media, experts, think tanks, and the government. Given this complexity, this will be a 2-part editorial: This column examines the scope of the crisis and the putative causes of the problem with recruiting Americans to serve in uniform. The next column will examine the potential impact of the shortage of service members on federal health care practice.

The Recruiting Crisis

Over the past several years, nearly every branch of the armed forces has struggled with recruitment, especially the Army. In April of this year, the US Department of Defense (DoD) reported that the Army, Navy, and Air Force would all fail to meet recruitment goals; only the Marines and Space Forces were expected to reach their targets.⁴ At the end of its fiscal year (October 1), the Army acknowledged that its 55,000 recruits were 10,000 fewer soldiers than it had aimed to enlist.⁵ But this was still more people joining the ranks than in 2022 when the Army was 15,000 recruits below the mark.⁶

Challenging Trends

There are many putative causes and proposed solutions for the recruitment crisis. Among the most serious is a marked drop in the American public’s confidence in the military. A June 2023 Gallup poll found that only 60% of citizens expressed “a great deal” or “quite a lot” of confidence in the military. This was the nadir of a 5-year decline that this year reached the lowest point since 1997/1998.⁷ For many Americans in and out of uniform, the ignoble end to the long war in Afghanistan leaving behind friends and allies contrary to the military ethos is cited as a significant contributor to both the loss of confidence in the military and the recruiting crisis.⁸

These cultural developments reinforce each other. Now, many veterans do not want their relatives and friends to follow them into the armed services. A 2021 survey by the Military Family Advisory Network found that slightly more than 60% of veterans and active-duty service members would recommend a military career to a potential recruit. This was down from 75% in 2019.⁹ Veterans cite a variety of reasons for discouraging their fellow citizens from serving, including low pay compared with civilian employment, especially in a labor-hungry job market; and the military failure to fulfill health care promises, housing, and other social services, especially for the growing number experiencing mental health disorders related to their service.¹⁰

Two facts about recruitment heighten the negative impact of some veterans’ change of attitude toward joining the services. First, since the end of the draft, military life in the US has become a family tradition. Published in 2011, a Pew Research Center study found that even then, a decreasing number of Americans had a family connection to the military. More respondents aged ≥ 50 years had a parent, child, spouse, or sibling who had served compared with those aged 30 to 49 years and those aged 18 to 29 (77%, 57%, and 33%, respectively).¹¹ Second, since the end of the draft, far fewer Americans have had military experience. Only 1% of the nation is currently in military service, and the veteran population is steadily declining. In 1980, 18% of adult Americans were veterans; 20 years later, that number is only 7%.¹² This makes it less likely that a high school or college student will have a personal or even a passing relationship with a teacher, coach, or other mentoring adult who is or has been a military member. This demographic discrepancy has generated what sociologists call the military-civilian gap.¹⁰ That division has been manipulated in the increasingly vehement culture wars and generational struggles that are splitting the country.¹²

This relatively recent sociological trend is reflected in a growing lack of interest among many young Americans in armed forces service. A DoD survey of participants aged 16 to 24 years regarding their intention to serve in the military found that 89% were probably not going to pursue a career in uniform. More than 65% of respondents indicated that the possibility of physical injury, death, or psychological trauma was the primary deterrent for considering enlisting.¹³ The latter barrier is directly related to our work as practitioners caring for service members and veterans, and through our compassion and competence, we may help bridge the widening divide between the military and civilian spheres. These numbers speak to the unwilling; there is also a significant group of Americans who want to serve yet are unable to due to their history, diagnoses, or condition.¹⁴ Their motivation to be military members in the face of the recruitment challenges highlighted here present federal practitioners with ethical questions that will be the subject of the next column.

Armed Forces and Veterans Day

This column’s epigraph is from President John F. Kennedy, a decorated World War II Navy combat veteran who decreed Armed Forces Day an official holiday a decade before conscription ended.¹ The commemoration was to thank and honor all individuals currently serving in the military for their patriotism and sacrifice. President Kennedy’s Word to the Nation could not be timelier on Veterans Day 2023. The data reviewed here raise profound questions as to where tomorrow’s service members and the veterans of the future will come from, and how we will persuade them that though there are real risks to military service, the rewards are both tangible and transcendent.

Word to the Nation: Guard zealously your right to serve in the Armed Forces, for without them, there will be no other rights to guard.

  John F. Kennedy ¹

The title of this Veterans Day editorial is a paraphrase of the legendary folk artist Pete Seeger’s protest song popularized during the Vietnam War. On January 27, 1973, in the wake of the widespread antiwar movement, Secretary of Defense Melvin Laird announced an end to the dreaded draft.²

For nearly 50 years, the all-volunteer military was celebrated as an outstanding achievement that professionalized the armed services and arguably made the US military among the most highly trained and effective fighting forces in the world. That was until an ongoing recruitment crisis threatened to write a different and far more disturbing conclusion to what the government had heralded as a “success story.”³

The recruiting crisis is a complicated problem with many facets that have received increasing attention from journalists, the media, experts, think tanks, and the government. Given this complexity, this will be a 2-part editorial: This column examines the scope of the crisis and the putative causes of the problem with recruiting Americans to serve in uniform. The next column will examine the potential impact of the shortage of service members on federal health care practice.

The Recruiting Crisis

Over the past several years, nearly every branch of the armed forces has struggled with recruitment, especially the Army. In April of this year, the US Department of Defense (DoD) reported that the Army, Navy, and Air Force would all fail to meet recruitment goals; only the Marines and Space Forces were expected to reach their targets.⁴ At the end of its fiscal year (October 1), the Army acknowledged that its 55,000 recruits were 10,000 fewer soldiers than it had aimed to enlist.⁵ But this was still more people joining the ranks than in 2022 when the Army was 15,000 recruits below the mark.⁶

Challenging Trends

There are many putative causes and proposed solutions for the recruitment crisis. Among the most serious is a marked drop in the American public’s confidence in the military. A June 2023 Gallup poll found that only 60% of citizens expressed “a great deal” or “quite a lot” of confidence in the military. This was the nadir of a 5-year decline that this year reached the lowest point since 1997/1998.⁷ For many Americans in and out of uniform, the ignoble end to the long war in Afghanistan leaving behind friends and allies contrary to the military ethos is cited as a significant contributor to both the loss of confidence in the military and the recruiting crisis.⁸

These cultural developments reinforce each other. Now, many veterans do not want their relatives and friends to follow them into the armed services. A 2021 survey by the Military Family Advisory Network found that slightly more than 60% of veterans and active-duty service members would recommend a military career to a potential recruit. This was down from 75% in 2019.⁹ Veterans cite a variety of reasons for discouraging their fellow citizens from serving, including low pay compared with civilian employment, especially in a labor-hungry job market; and the military failure to fulfill health care promises, housing, and other social services, especially for the growing number experiencing mental health disorders related to their service.¹⁰

Two facts about recruitment heighten the negative impact of some veterans’ change of attitude toward joining the services. First, since the end of the draft, military life in the US has become a family tradition. Published in 2011, a Pew Research Center study found that even then, a decreasing number of Americans had a family connection to the military. More respondents aged ≥ 50 years had a parent, child, spouse, or sibling who had served compared with those aged 30 to 49 years and those aged 18 to 29 (77%, 57%, and 33%, respectively).¹¹ Second, since the end of the draft, far fewer Americans have had military experience. Only 1% of the nation is currently in military service, and the veteran population is steadily declining. In 1980, 18% of adult Americans were veterans; 20 years later, that number is only 7%.¹² This makes it less likely that a high school or college student will have a personal or even a passing relationship with a teacher, coach, or other mentoring adult who is or has been a military member. This demographic discrepancy has generated what sociologists call the military-civilian gap.¹⁰ That division has been manipulated in the increasingly vehement culture wars and generational struggles that are splitting the country.¹²

This relatively recent sociological trend is reflected in a growing lack of interest among many young Americans in armed forces service. A DoD survey of participants aged 16 to 24 years regarding their intention to serve in the military found that 89% were probably not going to pursue a career in uniform. More than 65% of respondents indicated that the possibility of physical injury, death, or psychological trauma was the primary deterrent for considering enlisting.¹³ The latter barrier is directly related to our work as practitioners caring for service members and veterans, and through our compassion and competence, we may help bridge the widening divide between the military and civilian spheres. These numbers speak to the unwilling; there is also a significant group of Americans who want to serve yet are unable to due to their history, diagnoses, or condition.¹⁴ Their motivation to be military members in the face of the recruitment challenges highlighted here present federal practitioners with ethical questions that will be the subject of the next column.

Armed Forces and Veterans Day

This column’s epigraph is from President John F. Kennedy, a decorated World War II Navy combat veteran who decreed Armed Forces Day an official holiday a decade before conscription ended.¹ The commemoration was to thank and honor all individuals currently serving in the military for their patriotism and sacrifice. President Kennedy’s Word to the Nation could not be timelier on Veterans Day 2023. The data reviewed here raise profound questions as to where tomorrow’s service members and the veterans of the future will come from, and how we will persuade them that though there are real risks to military service, the rewards are both tangible and transcendent.

Traditional manufacturing concentrates capacity into a few discrete locations while applying lean and just-in-time philosophies to maximize profit during times of somewhat predictable supply and demand. This approach exposed nationwide vulnerabilities even during local crises, such as the United States saline shortages following closure of a single plant in Puerto Rico following Hurricane Maria in 2017.¹ Interruptions to the supply chain due to pandemic plant closure, weather, politics, or surge demand can cause immediate and lasting shortages. Nasal swabs were a clear example.

At the onset of COVID-19, 2 companies—Puritan in Guilford, Maine, and Copan in Italy—manufactured nearly all of the highly specialized nasopharyngeal (NP) swabs singled out by the Centers for Disease Control and Prevention (CDC) and the US Food and Drug Administration (FDA) to test patients for COVID-19. Demand for swabs skyrocketed as the virus spread, and they became unattainable. The lack of swabs meant patients went undiagnosed. Without knowing who was positive, people with symptoms and known contacts were presumed positive and quarantined, impacting isolated patients, the health care professionals treating them, and the entire US economy.

3-Dimensional Printing Solutions

Manufacturing NP swabs is not trivial. Their simple shape conceals complexity and requires highly specialized equipment. The lead time for one non-US machine manufacturer was > 6 months at the start of the pandemic.

Digital manufacturing/3-dimensional (3D) printing represented a potential solution to the supply chain crisis.² Designers created digital blueprints for 3D-printed goods, face masks, face shields, and ventilator splitters were rapidly created and shared.^3,4 Scrambling to fill the critical need for NP swabs, many hospitals, businesses, and academic centers began 3D printing swabs. This effort was spearheaded by University of South Florida (USF) and Northwell Health researchers and clinicians, who designed and tested a 3D-printed NP swab from photocurable resin that was printable on 2 models of Formlabs printers.⁵ Several other 3D-printed NP swab designs soon followed. This innovation and problem-solving renaissance faced several challenges well known to traditional manufacturers of regulated products but novel to newcomers.

The first challlenge was that these NP swabs predate FDA oversight of medical device development and manufacturing and no testing standards existed. Designers began casting prototypes out without guidance about the critical features and clinical functions required. Many of these designs did not have a clinical evaluation pathway to test safety and efficacy.

The second challlenge was that these swabs were being produced by facilities not registered with the FDA. This raised concerns about the quality of unlisted medical products developed and manufactured at novel facilities.

The third challenge was that small-scale novel approaches may offset local shortages but could not address national needs. The self-organized infrastructure for this crisis was ad hoc, local, and lacked coordinated federal support. This led to rolling shortages of these materials for years.

Two studies were performed early in the pandemic. The first study evaluated 4 prototypes of different manufacturer designs, finding excellent concordance among them and their control swab.⁶ A second study demonstrated the USF swab to be noninferior to the standard of care.⁷ Both studies acknowledged and addressed the first challenge for their designs.

COLLABORATIONS

Interagency

Before the pandemic, the US Department of Veterans Affairs (VA) had been coordinating with the FDA, the National Institutes of Health (NIH), and the nonprofit America Makes to bring medical product development and manufacturing closer to the point of care.

At the outset of the COVID-19 pandemic, the collaboration was formalized to address new challenges.⁸ The objectives of this collaboration were the following: (1) host a digital repository for 3D-printed digital designs for personal protectice equipment and other medical supplies in or at risk of shortage; (2) provide scientifically based ratings for designs according to clinical and field testing; and (3) offer education to health care workers and the public about the digital manufacturing of medical goods and devices.^4,9

A key output of this collaboration was the COVID 3D Trusted Repository For Users And Suppliers Through Testing (COVID 3D TRUST), a curated archive of designs. In most cases, existing FDA standards and guidance formed the basis of testing strategies with deviations due to limited access to traditional testing facilities and reagents.

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To address novel NP swabs, working with its COVID 3D TRUST partners, the VA gathered a combined list of clinical- and engineering-informed customer requirements and performed a hazard analysis. The result was a list of design inputs for NP swabs and 8 standard test protocols to evaluate key functions (Table).¹⁰ These protocols are meant to benchmark novel 3D-printed swabs against the key functions of established, traditionally manufactured swabs, which have a long record of safety and efficacy. The protocols, developed by the VA and undergoing validation by the US Army, empower and inform consumers and provide performance metrics to swab designers and manufacturers. The testing protocols and preliminary test results developed by the VA are publicly available at the NIH.¹¹

Intra-agency

The use of the inputs and verification tests noted in the Table may reduce the risk of poor design but were inadequate to evaluate the clinical safety and efficacy of novel swabs. Recognizing this, the VA Office of Healthcare Innovation and Learning (OHIL) and the Office of Research and Development (ORD) launched the Nasal Swab Objective and Statistical Evaluation (NOSE) study to formally evaluate the safety and efficacy of 3D-printed swabs in the field. This multisite clinical study was a close collaboration between the OHIL and ORD. The OHIL provided the quality system and manufacturing oversight and delivery of the swabs, and the ORD provided scientific review, research infrastructure, human subjects oversight, administrative support, and funding and fiscal oversight. The OHIL/ORD collaboration resulted in the successful completion of the NOSE study.

This study (manuscript under preparation) yielded two 3D-printing production processes and swab designs that had comparable performance to the standard of care, were manufacturable compliant with FDA guidelines, and could be produced at scale in a distributed manner. This approach directly addressed the 3 challenges described earlier.

LESSONS LEARNED

Swabs were an example of supply challenges in the pandemic, but advanced manufacturing (notably, digital designs leading to 3D-printed solutions) also served as a temporary solution to device and product shortages during the COVID-19 pandemic. Digital designs and 3D printing as manufacturing techniques have the following key advantages: (1) they are distributed in nature, both in the breadth of locations that have access to these manufacturing platforms and in the depth of material choice that can be used to fabricate products, which alleviates the threat of a disaster impacting manufacturing capacity or a material stream; (2) they do not require retooling of machinery so new products can deploy rapidly and on demand; and (3) the speed of digital iteration, printing, and revision allows for rapid product development and production.

There also are notable disadvantages to these techniques. First, because 3D printing is a newer technology, there is less general depth of knowledge regarding design and material choice for additive manufacturing. Second, the flexibility of 3D printing means that operators must increase awareness of the factors that might cause the fabrication of a part to fail in either printing or postprocessing. Third, there are significant gaps in understanding how materials and manufacturing processes will perform in high-stakes settings such as health care, where performance and biocompatibility may be critical to support life-sustaining functions. Fourth, digital files are vulnerable to intentional or unintentional alteration. These alterations might weaken design integrity and be imperceptible to the manufacturer or end user. This is a prevalent challenge in all open-source designs.

The pandemic materialized quickly and created vast supply chain challenges. To address this crisis, it was clear that the average 17-year interval between research and translation in the US was unacceptable. The VA was able to accelerate swiftly many existing processes to meet this need, build new capabilities, and establish new practices for the rapid evaluation and deployment of health care products and guidance. This agile and innovative cooperation was critical in the success of the VA’s national support for pandemic solutions.

Finally, although COVID 3D TRUST was able to provide testing of submitted designs, this collaboration was not a substitute for the “peacetime” process of manufacturing site registration with the FDA and product listing. COVID 3D TRUST could evaluate designs only, not the production process, safety, and efficacy.

CALLS TO ACTION

The pandemic's impact on medical supply chain security persists, as does the need for greater foresight and crisis preparation. We must act now to avoid experiencing again the magnitude of fatalities (civilian and veteran) and the devastation to the US economy and livelihoods that occurred during this single biological event. To this end, creating a digital stockpile of federally curated, crisis-ready designs for as-needed distribution across our US industrial base would offer a second line of defense against life-threatening supply chain interruptions. The realization of such a digital stockpile requires calls to action among multiple contributors.

Collaborations

The VA’s Fourth Mission is to improve the nation’s preparedness for response to war, terrorism, national emergencies, and natural disasters. The VA does this by developing plans and taking actions to ensure continued service to veterans, as well as to support national, state, and local emergency management, public health, safety, and homeland security efforts.

The VA partnership with the FDA and NIH during the pandemic enabled successful coordination among federal agencies. Numerous other agencies, including the US Department of Defense (DoD), the Biomedical Advanced Research and Development Authority (BARDA), and the Defense Advanced Research Projects Agency (DARPA), also developed and executed successful initiatives.^12-14 The joint awareness and management of these efforts, however, could be strengthened through more formal agreements and processes in peacetime. The VA/FDA/NIH Memorandum of Understanding is a prototype example of each agency lending its subject matter expertise to address a host of pandemic challenges collectively, cooperatively, and efficiently.⁸

Public-private partnerships (eg, VA/FDA/NIH and America Makes) led to coordinated responses for crisis readiness. The Advanced Manufacturing Crisis Product Response Program, a multipartner collaboration that included VA, addressed 7 crisis scenarios, 3 of which were specifically related to COVID-19.¹⁵ In addition, both BARDA and DARPA had successful public-private collaborations, and the DoD supported national logistics and other efforts.^12-14 Clearly, industry and government both recognize complementary synergies: (1) the depth of resources of US industry; and (2) the national resources, coordination, and clinical insight available through federal agencies that can address the challenges of future crises quickly and efficiently.

When traditional supply chains and manufacturing processes failed during the pandemic, new techniques were exploited to fill the unmet material needs. Novel techniques and product pathways, however, are untested or undeveloped. The collaboration between the ORD and OHIL in support of NP swab testing and production is an example of bringing research insight, regulated product development, and manufacturing together to support a complete product life cycle.

Joint Awareness and Management

The VA continues to refine the joint awareness and management (JAM) process of products from ideation to translation, to shorten the time from research to product delivery. JAM is a VA collaborative committee of partners from ORD research offices and technology transfer program, and the OHIL Office of Advanced Manufacturing, which seeks additional support and guidance from VHA clinical service lines, VA Office of General Council, and VA Office of Acquisitions, Logistics, and Construction.

This team enables the rapid identification of unmet veteran health care product needs. In addition, JAM leverages the resources of each group to support products from problem identification to solution ideation, regulated development, production, and delivery into clinical service lines. While the concept of JAM arose to meet the crisis needs of the pandemic, it persists in delivering advanced health care solutions to veterans.

A Proposed Plan

The next national crisis is likely to involve and threaten national health care security. We propose that federal agencies be brought together to form a federally supported digital stockpile. This digital stockpile must encompass, at minimum, the following features: (1) preservation of novel, scalable medical supplies and products generated during the COVID-19 pandemic, to avoid the loss of this work; (2) clinical maturation of those existing supplies and products to refine their features and functions under the guidance of clinical, regulatory, and manufacturing experts—and validate those outputs with clinical evidence; (3) manufacturing maturation of those existing supplies and products, such that complete design and production processes are developed with the intent to distribute to multiple public manufacturers during the next crisis; (4) a call for new designs/intake portal for new designs to be matured and curated as vulnerabilities are identified; (5) supply chain crisis drills executed to test public-private preparedness to ensure design transfer is turnkey and can be engaged quickly during the next crisis; and (6) public-private engagement to develop strategy, scenarios, and policy to ensure that when supply chains next fail, additional surge capacity can be quickly added to protect American lives and health care, and that when supply chains resume, surge capacity can be redirected or stood down to protect the competitive markets.

This digital stockpile can complement and be part of the Strategic National Stockpile. Whereas the Strategic National Stockpile is a reserve of physical products that may offset product shortages, the digital stockpile is a reserve of turnkey, transferable designs that may offset supply chain disruptions and production-capacity shortages.

CONCLUSIONS

The success of 3D-printed NP swabs is a specific example of the importance of collaborations across industry, government, innovators, and researchers. More important than a sole product, however, these collaborations demonstrated the potential for game-changing approaches to how public-private partnerships support the continuity of health care operations nationally and prevent the potential for unnecessary loss of life due to capacity and supply chain disruptions.

As the largest health care system in the US, the VA has a unique capability to lead in the assessment of other novel 3D-printed medical devices in partnership with the FDA. The VA has a unique patient-centered perspective on medical device efficacy, and as a government institution, it is a trusted independent source for medical device evaluation. The VA’s role in the evaluation of 3D-printed medical devices will benefit veterans and their families, clinicians, hospitals, and the broader public by providing a gold-standard evaluation for the growing medical 3D-printing industry to follow. By creating new pathways and expectations for how federal agencies maintain crisis preparedness—such as establishing a digital stockpile—we can be equipped to serve the US health care system and minimize the effects of supply chain disruptions.

Traditional manufacturing concentrates capacity into a few discrete locations while applying lean and just-in-time philosophies to maximize profit during times of somewhat predictable supply and demand. This approach exposed nationwide vulnerabilities even during local crises, such as the United States saline shortages following closure of a single plant in Puerto Rico following Hurricane Maria in 2017.¹ Interruptions to the supply chain due to pandemic plant closure, weather, politics, or surge demand can cause immediate and lasting shortages. Nasal swabs were a clear example.

At the onset of COVID-19, 2 companies—Puritan in Guilford, Maine, and Copan in Italy—manufactured nearly all of the highly specialized nasopharyngeal (NP) swabs singled out by the Centers for Disease Control and Prevention (CDC) and the US Food and Drug Administration (FDA) to test patients for COVID-19. Demand for swabs skyrocketed as the virus spread, and they became unattainable. The lack of swabs meant patients went undiagnosed. Without knowing who was positive, people with symptoms and known contacts were presumed positive and quarantined, impacting isolated patients, the health care professionals treating them, and the entire US economy.

3-Dimensional Printing Solutions

Manufacturing NP swabs is not trivial. Their simple shape conceals complexity and requires highly specialized equipment. The lead time for one non-US machine manufacturer was > 6 months at the start of the pandemic.

Digital manufacturing/3-dimensional (3D) printing represented a potential solution to the supply chain crisis.² Designers created digital blueprints for 3D-printed goods, face masks, face shields, and ventilator splitters were rapidly created and shared.^3,4 Scrambling to fill the critical need for NP swabs, many hospitals, businesses, and academic centers began 3D printing swabs. This effort was spearheaded by University of South Florida (USF) and Northwell Health researchers and clinicians, who designed and tested a 3D-printed NP swab from photocurable resin that was printable on 2 models of Formlabs printers.⁵ Several other 3D-printed NP swab designs soon followed. This innovation and problem-solving renaissance faced several challenges well known to traditional manufacturers of regulated products but novel to newcomers.

The first challlenge was that these NP swabs predate FDA oversight of medical device development and manufacturing and no testing standards existed. Designers began casting prototypes out without guidance about the critical features and clinical functions required. Many of these designs did not have a clinical evaluation pathway to test safety and efficacy.

The second challlenge was that these swabs were being produced by facilities not registered with the FDA. This raised concerns about the quality of unlisted medical products developed and manufactured at novel facilities.

The third challenge was that small-scale novel approaches may offset local shortages but could not address national needs. The self-organized infrastructure for this crisis was ad hoc, local, and lacked coordinated federal support. This led to rolling shortages of these materials for years.

Two studies were performed early in the pandemic. The first study evaluated 4 prototypes of different manufacturer designs, finding excellent concordance among them and their control swab.⁶ A second study demonstrated the USF swab to be noninferior to the standard of care.⁷ Both studies acknowledged and addressed the first challenge for their designs.

COLLABORATIONS

Interagency

Before the pandemic, the US Department of Veterans Affairs (VA) had been coordinating with the FDA, the National Institutes of Health (NIH), and the nonprofit America Makes to bring medical product development and manufacturing closer to the point of care.

At the outset of the COVID-19 pandemic, the collaboration was formalized to address new challenges.⁸ The objectives of this collaboration were the following: (1) host a digital repository for 3D-printed digital designs for personal protectice equipment and other medical supplies in or at risk of shortage; (2) provide scientifically based ratings for designs according to clinical and field testing; and (3) offer education to health care workers and the public about the digital manufacturing of medical goods and devices.^4,9

A key output of this collaboration was the COVID 3D Trusted Repository For Users And Suppliers Through Testing (COVID 3D TRUST), a curated archive of designs. In most cases, existing FDA standards and guidance formed the basis of testing strategies with deviations due to limited access to traditional testing facilities and reagents.

table.png

To address novel NP swabs, working with its COVID 3D TRUST partners, the VA gathered a combined list of clinical- and engineering-informed customer requirements and performed a hazard analysis. The result was a list of design inputs for NP swabs and 8 standard test protocols to evaluate key functions (Table).¹⁰ These protocols are meant to benchmark novel 3D-printed swabs against the key functions of established, traditionally manufactured swabs, which have a long record of safety and efficacy. The protocols, developed by the VA and undergoing validation by the US Army, empower and inform consumers and provide performance metrics to swab designers and manufacturers. The testing protocols and preliminary test results developed by the VA are publicly available at the NIH.¹¹

Intra-agency

The use of the inputs and verification tests noted in the Table may reduce the risk of poor design but were inadequate to evaluate the clinical safety and efficacy of novel swabs. Recognizing this, the VA Office of Healthcare Innovation and Learning (OHIL) and the Office of Research and Development (ORD) launched the Nasal Swab Objective and Statistical Evaluation (NOSE) study to formally evaluate the safety and efficacy of 3D-printed swabs in the field. This multisite clinical study was a close collaboration between the OHIL and ORD. The OHIL provided the quality system and manufacturing oversight and delivery of the swabs, and the ORD provided scientific review, research infrastructure, human subjects oversight, administrative support, and funding and fiscal oversight. The OHIL/ORD collaboration resulted in the successful completion of the NOSE study.

This study (manuscript under preparation) yielded two 3D-printing production processes and swab designs that had comparable performance to the standard of care, were manufacturable compliant with FDA guidelines, and could be produced at scale in a distributed manner. This approach directly addressed the 3 challenges described earlier.

LESSONS LEARNED

Swabs were an example of supply challenges in the pandemic, but advanced manufacturing (notably, digital designs leading to 3D-printed solutions) also served as a temporary solution to device and product shortages during the COVID-19 pandemic. Digital designs and 3D printing as manufacturing techniques have the following key advantages: (1) they are distributed in nature, both in the breadth of locations that have access to these manufacturing platforms and in the depth of material choice that can be used to fabricate products, which alleviates the threat of a disaster impacting manufacturing capacity or a material stream; (2) they do not require retooling of machinery so new products can deploy rapidly and on demand; and (3) the speed of digital iteration, printing, and revision allows for rapid product development and production.

There also are notable disadvantages to these techniques. First, because 3D printing is a newer technology, there is less general depth of knowledge regarding design and material choice for additive manufacturing. Second, the flexibility of 3D printing means that operators must increase awareness of the factors that might cause the fabrication of a part to fail in either printing or postprocessing. Third, there are significant gaps in understanding how materials and manufacturing processes will perform in high-stakes settings such as health care, where performance and biocompatibility may be critical to support life-sustaining functions. Fourth, digital files are vulnerable to intentional or unintentional alteration. These alterations might weaken design integrity and be imperceptible to the manufacturer or end user. This is a prevalent challenge in all open-source designs.

The pandemic materialized quickly and created vast supply chain challenges. To address this crisis, it was clear that the average 17-year interval between research and translation in the US was unacceptable. The VA was able to accelerate swiftly many existing processes to meet this need, build new capabilities, and establish new practices for the rapid evaluation and deployment of health care products and guidance. This agile and innovative cooperation was critical in the success of the VA’s national support for pandemic solutions.

Finally, although COVID 3D TRUST was able to provide testing of submitted designs, this collaboration was not a substitute for the “peacetime” process of manufacturing site registration with the FDA and product listing. COVID 3D TRUST could evaluate designs only, not the production process, safety, and efficacy.

CALLS TO ACTION

The pandemic's impact on medical supply chain security persists, as does the need for greater foresight and crisis preparation. We must act now to avoid experiencing again the magnitude of fatalities (civilian and veteran) and the devastation to the US economy and livelihoods that occurred during this single biological event. To this end, creating a digital stockpile of federally curated, crisis-ready designs for as-needed distribution across our US industrial base would offer a second line of defense against life-threatening supply chain interruptions. The realization of such a digital stockpile requires calls to action among multiple contributors.

Collaborations

The VA’s Fourth Mission is to improve the nation’s preparedness for response to war, terrorism, national emergencies, and natural disasters. The VA does this by developing plans and taking actions to ensure continued service to veterans, as well as to support national, state, and local emergency management, public health, safety, and homeland security efforts.

The VA partnership with the FDA and NIH during the pandemic enabled successful coordination among federal agencies. Numerous other agencies, including the US Department of Defense (DoD), the Biomedical Advanced Research and Development Authority (BARDA), and the Defense Advanced Research Projects Agency (DARPA), also developed and executed successful initiatives.^12-14 The joint awareness and management of these efforts, however, could be strengthened through more formal agreements and processes in peacetime. The VA/FDA/NIH Memorandum of Understanding is a prototype example of each agency lending its subject matter expertise to address a host of pandemic challenges collectively, cooperatively, and efficiently.⁸

Public-private partnerships (eg, VA/FDA/NIH and America Makes) led to coordinated responses for crisis readiness. The Advanced Manufacturing Crisis Product Response Program, a multipartner collaboration that included VA, addressed 7 crisis scenarios, 3 of which were specifically related to COVID-19.¹⁵ In addition, both BARDA and DARPA had successful public-private collaborations, and the DoD supported national logistics and other efforts.^12-14 Clearly, industry and government both recognize complementary synergies: (1) the depth of resources of US industry; and (2) the national resources, coordination, and clinical insight available through federal agencies that can address the challenges of future crises quickly and efficiently.

When traditional supply chains and manufacturing processes failed during the pandemic, new techniques were exploited to fill the unmet material needs. Novel techniques and product pathways, however, are untested or undeveloped. The collaboration between the ORD and OHIL in support of NP swab testing and production is an example of bringing research insight, regulated product development, and manufacturing together to support a complete product life cycle.

Joint Awareness and Management

The VA continues to refine the joint awareness and management (JAM) process of products from ideation to translation, to shorten the time from research to product delivery. JAM is a VA collaborative committee of partners from ORD research offices and technology transfer program, and the OHIL Office of Advanced Manufacturing, which seeks additional support and guidance from VHA clinical service lines, VA Office of General Council, and VA Office of Acquisitions, Logistics, and Construction.

This team enables the rapid identification of unmet veteran health care product needs. In addition, JAM leverages the resources of each group to support products from problem identification to solution ideation, regulated development, production, and delivery into clinical service lines. While the concept of JAM arose to meet the crisis needs of the pandemic, it persists in delivering advanced health care solutions to veterans.

A Proposed Plan

The next national crisis is likely to involve and threaten national health care security. We propose that federal agencies be brought together to form a federally supported digital stockpile. This digital stockpile must encompass, at minimum, the following features: (1) preservation of novel, scalable medical supplies and products generated during the COVID-19 pandemic, to avoid the loss of this work; (2) clinical maturation of those existing supplies and products to refine their features and functions under the guidance of clinical, regulatory, and manufacturing experts—and validate those outputs with clinical evidence; (3) manufacturing maturation of those existing supplies and products, such that complete design and production processes are developed with the intent to distribute to multiple public manufacturers during the next crisis; (4) a call for new designs/intake portal for new designs to be matured and curated as vulnerabilities are identified; (5) supply chain crisis drills executed to test public-private preparedness to ensure design transfer is turnkey and can be engaged quickly during the next crisis; and (6) public-private engagement to develop strategy, scenarios, and policy to ensure that when supply chains next fail, additional surge capacity can be quickly added to protect American lives and health care, and that when supply chains resume, surge capacity can be redirected or stood down to protect the competitive markets.

This digital stockpile can complement and be part of the Strategic National Stockpile. Whereas the Strategic National Stockpile is a reserve of physical products that may offset product shortages, the digital stockpile is a reserve of turnkey, transferable designs that may offset supply chain disruptions and production-capacity shortages.

CONCLUSIONS

The success of 3D-printed NP swabs is a specific example of the importance of collaborations across industry, government, innovators, and researchers. More important than a sole product, however, these collaborations demonstrated the potential for game-changing approaches to how public-private partnerships support the continuity of health care operations nationally and prevent the potential for unnecessary loss of life due to capacity and supply chain disruptions.

As the largest health care system in the US, the VA has a unique capability to lead in the assessment of other novel 3D-printed medical devices in partnership with the FDA. The VA has a unique patient-centered perspective on medical device efficacy, and as a government institution, it is a trusted independent source for medical device evaluation. The VA’s role in the evaluation of 3D-printed medical devices will benefit veterans and their families, clinicians, hospitals, and the broader public by providing a gold-standard evaluation for the growing medical 3D-printing industry to follow. By creating new pathways and expectations for how federal agencies maintain crisis preparedness—such as establishing a digital stockpile—we can be equipped to serve the US health care system and minimize the effects of supply chain disruptions.

Traditional manufacturing concentrates capacity into a few discrete locations while applying lean and just-in-time philosophies to maximize profit during times of somewhat predictable supply and demand. This approach exposed nationwide vulnerabilities even during local crises, such as the United States saline shortages following closure of a single plant in Puerto Rico following Hurricane Maria in 2017.¹ Interruptions to the supply chain due to pandemic plant closure, weather, politics, or surge demand can cause immediate and lasting shortages. Nasal swabs were a clear example.

At the onset of COVID-19, 2 companies—Puritan in Guilford, Maine, and Copan in Italy—manufactured nearly all of the highly specialized nasopharyngeal (NP) swabs singled out by the Centers for Disease Control and Prevention (CDC) and the US Food and Drug Administration (FDA) to test patients for COVID-19. Demand for swabs skyrocketed as the virus spread, and they became unattainable. The lack of swabs meant patients went undiagnosed. Without knowing who was positive, people with symptoms and known contacts were presumed positive and quarantined, impacting isolated patients, the health care professionals treating them, and the entire US economy.

3-Dimensional Printing Solutions

Manufacturing NP swabs is not trivial. Their simple shape conceals complexity and requires highly specialized equipment. The lead time for one non-US machine manufacturer was > 6 months at the start of the pandemic.

Digital manufacturing/3-dimensional (3D) printing represented a potential solution to the supply chain crisis.² Designers created digital blueprints for 3D-printed goods, face masks, face shields, and ventilator splitters were rapidly created and shared.^3,4 Scrambling to fill the critical need for NP swabs, many hospitals, businesses, and academic centers began 3D printing swabs. This effort was spearheaded by University of South Florida (USF) and Northwell Health researchers and clinicians, who designed and tested a 3D-printed NP swab from photocurable resin that was printable on 2 models of Formlabs printers.⁵ Several other 3D-printed NP swab designs soon followed. This innovation and problem-solving renaissance faced several challenges well known to traditional manufacturers of regulated products but novel to newcomers.

The first challlenge was that these NP swabs predate FDA oversight of medical device development and manufacturing and no testing standards existed. Designers began casting prototypes out without guidance about the critical features and clinical functions required. Many of these designs did not have a clinical evaluation pathway to test safety and efficacy.

The second challlenge was that these swabs were being produced by facilities not registered with the FDA. This raised concerns about the quality of unlisted medical products developed and manufactured at novel facilities.

The third challenge was that small-scale novel approaches may offset local shortages but could not address national needs. The self-organized infrastructure for this crisis was ad hoc, local, and lacked coordinated federal support. This led to rolling shortages of these materials for years.

Two studies were performed early in the pandemic. The first study evaluated 4 prototypes of different manufacturer designs, finding excellent concordance among them and their control swab.⁶ A second study demonstrated the USF swab to be noninferior to the standard of care.⁷ Both studies acknowledged and addressed the first challenge for their designs.

COLLABORATIONS

Interagency

Before the pandemic, the US Department of Veterans Affairs (VA) had been coordinating with the FDA, the National Institutes of Health (NIH), and the nonprofit America Makes to bring medical product development and manufacturing closer to the point of care.

At the outset of the COVID-19 pandemic, the collaboration was formalized to address new challenges.⁸ The objectives of this collaboration were the following: (1) host a digital repository for 3D-printed digital designs for personal protectice equipment and other medical supplies in or at risk of shortage; (2) provide scientifically based ratings for designs according to clinical and field testing; and (3) offer education to health care workers and the public about the digital manufacturing of medical goods and devices.^4,9

A key output of this collaboration was the COVID 3D Trusted Repository For Users And Suppliers Through Testing (COVID 3D TRUST), a curated archive of designs. In most cases, existing FDA standards and guidance formed the basis of testing strategies with deviations due to limited access to traditional testing facilities and reagents.

table.png

To address novel NP swabs, working with its COVID 3D TRUST partners, the VA gathered a combined list of clinical- and engineering-informed customer requirements and performed a hazard analysis. The result was a list of design inputs for NP swabs and 8 standard test protocols to evaluate key functions (Table).¹⁰ These protocols are meant to benchmark novel 3D-printed swabs against the key functions of established, traditionally manufactured swabs, which have a long record of safety and efficacy. The protocols, developed by the VA and undergoing validation by the US Army, empower and inform consumers and provide performance metrics to swab designers and manufacturers. The testing protocols and preliminary test results developed by the VA are publicly available at the NIH.¹¹

Intra-agency

The use of the inputs and verification tests noted in the Table may reduce the risk of poor design but were inadequate to evaluate the clinical safety and efficacy of novel swabs. Recognizing this, the VA Office of Healthcare Innovation and Learning (OHIL) and the Office of Research and Development (ORD) launched the Nasal Swab Objective and Statistical Evaluation (NOSE) study to formally evaluate the safety and efficacy of 3D-printed swabs in the field. This multisite clinical study was a close collaboration between the OHIL and ORD. The OHIL provided the quality system and manufacturing oversight and delivery of the swabs, and the ORD provided scientific review, research infrastructure, human subjects oversight, administrative support, and funding and fiscal oversight. The OHIL/ORD collaboration resulted in the successful completion of the NOSE study.

This study (manuscript under preparation) yielded two 3D-printing production processes and swab designs that had comparable performance to the standard of care, were manufacturable compliant with FDA guidelines, and could be produced at scale in a distributed manner. This approach directly addressed the 3 challenges described earlier.

LESSONS LEARNED

Swabs were an example of supply challenges in the pandemic, but advanced manufacturing (notably, digital designs leading to 3D-printed solutions) also served as a temporary solution to device and product shortages during the COVID-19 pandemic. Digital designs and 3D printing as manufacturing techniques have the following key advantages: (1) they are distributed in nature, both in the breadth of locations that have access to these manufacturing platforms and in the depth of material choice that can be used to fabricate products, which alleviates the threat of a disaster impacting manufacturing capacity or a material stream; (2) they do not require retooling of machinery so new products can deploy rapidly and on demand; and (3) the speed of digital iteration, printing, and revision allows for rapid product development and production.

There also are notable disadvantages to these techniques. First, because 3D printing is a newer technology, there is less general depth of knowledge regarding design and material choice for additive manufacturing. Second, the flexibility of 3D printing means that operators must increase awareness of the factors that might cause the fabrication of a part to fail in either printing or postprocessing. Third, there are significant gaps in understanding how materials and manufacturing processes will perform in high-stakes settings such as health care, where performance and biocompatibility may be critical to support life-sustaining functions. Fourth, digital files are vulnerable to intentional or unintentional alteration. These alterations might weaken design integrity and be imperceptible to the manufacturer or end user. This is a prevalent challenge in all open-source designs.

The pandemic materialized quickly and created vast supply chain challenges. To address this crisis, it was clear that the average 17-year interval between research and translation in the US was unacceptable. The VA was able to accelerate swiftly many existing processes to meet this need, build new capabilities, and establish new practices for the rapid evaluation and deployment of health care products and guidance. This agile and innovative cooperation was critical in the success of the VA’s national support for pandemic solutions.

Finally, although COVID 3D TRUST was able to provide testing of submitted designs, this collaboration was not a substitute for the “peacetime” process of manufacturing site registration with the FDA and product listing. COVID 3D TRUST could evaluate designs only, not the production process, safety, and efficacy.

CALLS TO ACTION

The pandemic's impact on medical supply chain security persists, as does the need for greater foresight and crisis preparation. We must act now to avoid experiencing again the magnitude of fatalities (civilian and veteran) and the devastation to the US economy and livelihoods that occurred during this single biological event. To this end, creating a digital stockpile of federally curated, crisis-ready designs for as-needed distribution across our US industrial base would offer a second line of defense against life-threatening supply chain interruptions. The realization of such a digital stockpile requires calls to action among multiple contributors.

Collaborations

The VA’s Fourth Mission is to improve the nation’s preparedness for response to war, terrorism, national emergencies, and natural disasters. The VA does this by developing plans and taking actions to ensure continued service to veterans, as well as to support national, state, and local emergency management, public health, safety, and homeland security efforts.

The VA partnership with the FDA and NIH during the pandemic enabled successful coordination among federal agencies. Numerous other agencies, including the US Department of Defense (DoD), the Biomedical Advanced Research and Development Authority (BARDA), and the Defense Advanced Research Projects Agency (DARPA), also developed and executed successful initiatives.^12-14 The joint awareness and management of these efforts, however, could be strengthened through more formal agreements and processes in peacetime. The VA/FDA/NIH Memorandum of Understanding is a prototype example of each agency lending its subject matter expertise to address a host of pandemic challenges collectively, cooperatively, and efficiently.⁸

Public-private partnerships (eg, VA/FDA/NIH and America Makes) led to coordinated responses for crisis readiness. The Advanced Manufacturing Crisis Product Response Program, a multipartner collaboration that included VA, addressed 7 crisis scenarios, 3 of which were specifically related to COVID-19.¹⁵ In addition, both BARDA and DARPA had successful public-private collaborations, and the DoD supported national logistics and other efforts.^12-14 Clearly, industry and government both recognize complementary synergies: (1) the depth of resources of US industry; and (2) the national resources, coordination, and clinical insight available through federal agencies that can address the challenges of future crises quickly and efficiently.

When traditional supply chains and manufacturing processes failed during the pandemic, new techniques were exploited to fill the unmet material needs. Novel techniques and product pathways, however, are untested or undeveloped. The collaboration between the ORD and OHIL in support of NP swab testing and production is an example of bringing research insight, regulated product development, and manufacturing together to support a complete product life cycle.

Joint Awareness and Management

The VA continues to refine the joint awareness and management (JAM) process of products from ideation to translation, to shorten the time from research to product delivery. JAM is a VA collaborative committee of partners from ORD research offices and technology transfer program, and the OHIL Office of Advanced Manufacturing, which seeks additional support and guidance from VHA clinical service lines, VA Office of General Council, and VA Office of Acquisitions, Logistics, and Construction.

This team enables the rapid identification of unmet veteran health care product needs. In addition, JAM leverages the resources of each group to support products from problem identification to solution ideation, regulated development, production, and delivery into clinical service lines. While the concept of JAM arose to meet the crisis needs of the pandemic, it persists in delivering advanced health care solutions to veterans.

A Proposed Plan

The next national crisis is likely to involve and threaten national health care security. We propose that federal agencies be brought together to form a federally supported digital stockpile. This digital stockpile must encompass, at minimum, the following features: (1) preservation of novel, scalable medical supplies and products generated during the COVID-19 pandemic, to avoid the loss of this work; (2) clinical maturation of those existing supplies and products to refine their features and functions under the guidance of clinical, regulatory, and manufacturing experts—and validate those outputs with clinical evidence; (3) manufacturing maturation of those existing supplies and products, such that complete design and production processes are developed with the intent to distribute to multiple public manufacturers during the next crisis; (4) a call for new designs/intake portal for new designs to be matured and curated as vulnerabilities are identified; (5) supply chain crisis drills executed to test public-private preparedness to ensure design transfer is turnkey and can be engaged quickly during the next crisis; and (6) public-private engagement to develop strategy, scenarios, and policy to ensure that when supply chains next fail, additional surge capacity can be quickly added to protect American lives and health care, and that when supply chains resume, surge capacity can be redirected or stood down to protect the competitive markets.

This digital stockpile can complement and be part of the Strategic National Stockpile. Whereas the Strategic National Stockpile is a reserve of physical products that may offset product shortages, the digital stockpile is a reserve of turnkey, transferable designs that may offset supply chain disruptions and production-capacity shortages.

CONCLUSIONS

The success of 3D-printed NP swabs is a specific example of the importance of collaborations across industry, government, innovators, and researchers. More important than a sole product, however, these collaborations demonstrated the potential for game-changing approaches to how public-private partnerships support the continuity of health care operations nationally and prevent the potential for unnecessary loss of life due to capacity and supply chain disruptions.

As the largest health care system in the US, the VA has a unique capability to lead in the assessment of other novel 3D-printed medical devices in partnership with the FDA. The VA has a unique patient-centered perspective on medical device efficacy, and as a government institution, it is a trusted independent source for medical device evaluation. The VA’s role in the evaluation of 3D-printed medical devices will benefit veterans and their families, clinicians, hospitals, and the broader public by providing a gold-standard evaluation for the growing medical 3D-printing industry to follow. By creating new pathways and expectations for how federal agencies maintain crisis preparedness—such as establishing a digital stockpile—we can be equipped to serve the US health care system and minimize the effects of supply chain disruptions.

The Veterans Health Administration (VHA) clinicians, clinician-investigators, and investigators perform basic and translational research for the benefit of our nation and are widely recognized for treating patients and discovering cures.^1,2 In May 2020, the US Department of Veterans Affairs (VA) launched the VA Science and Health Initiative to Combat Infectious and Emerging Life-Threatening Diseases (VA SHIELD). The goal of this novel enterprise was to assemble a comprehensive specimen and data repository for emerging life-threatening diseases and to address future challenges. VA SHIELD was specifically charged with creating a biorepository to advance research, improve diagnostic and therapeutic capabilities, and develop strategies for immediate deployment to VA clinical environments. One main objective of VA SHIELD is to harness the clinical and scientific strengths of the VA in order to create a more cohesive collaboration between preexisting clinical research efforts within the VA.

ANATOMY OF VA SHIELD

The charge and scope of VA SHIELD is unique.³ As an entity, this program leverages the strengths of the diverse VHA network, has a broad potential impact on national health care, is positioned to respond rapidly to national and international health-related events, and substantially contributes to clinical research and development. In addition, VA SHIELD upholds VA’s Fourth Mission, which is to contribute to national emergencies and support emergency management, public health, safety, and homeland security efforts.

VA SHIELD is part of the VA Office of Research and Development (ORD). The coordinating center (CC), headquartered in Cleveland, Ohio, is the central operational partner, leading VA SHIELD and interacting with other important VA programs, including laboratory, clinical science, rehabilitation, and health services. The VA SHIELD CC oversees all aspects of operations, including biospecimen collection, creating and enforcing of standard operating procedures, ensuring the quality of the samples, processing research applications, distribution of samples, financing, and progress reports. The CC also initiates and maintains interagency collaborations, convenes stakeholders, and develops strategic plans to address emerging diseases.

The VA SHIELD Executive Steering Committee (ESC) is composed of infectious disease, biorepository, and public health specialists. The ESC provides scientific and programmatic direction to the CC, including operational activities and guidance regarding biorepository priorities and scientific agenda, and measuring and reporting on VA SHIELD accomplishments.

The primary function of the Programmatic and Scientific Review Board (PSRB) is to evaluate incoming research proposals for specimen and data use for feasibility and make recommendations to the VA SHIELD CC. The PSRB evaluates and ensures that data and specimen use align with VA SHIELD ethical, clinical, and scientific objectives.

VA SHIELD IN PRACTICE

VA SHIELD consisted of 11 specimen collection sites (Atlanta, GA; Boise, ID; Bronx, NY; Cincinnati, OH; Cleveland, OH; Durham, NC; Houston, TX; Los Angeles, CA; Mountain Home, TN; Palo Alto, CA; and Tucson, AZ), a data processing center in Boston, MA, and 2 central biorepositories in Palo Alto, CA, and Tucson, AZ. Information flow is a coordinated process among specimen collection sites, data processing centers, and the biorepositories. Initially, each local collection site identifies residual specimens that would have been discarded after clinical laboratory testing. These samples currently account for the majority of biological material within VA SHIELD via a novel collection protocol known as “Sweep,” which allows residual clinical discarded samples as well as samples from patients with new emerging infectious and noninfectious diseases of concern to be collected at the time of first emergence and submitted to VA SHIELD during the course of routine veteran health care.³ These clinical discarded samples are de-identified and transferred from the clinical laboratory to VA SHIELD. The VA Central Institutional Review Board (cIRB) has approved the use of these samples as nonhuman subject research. Biological samples are collected, processed, aliquoted, shipped to, and stored at the central biorepository sites.

The Umbrella amendment to Sweep that has been approved also by the VA cIRB, will allow VA SHIELD sites to prospectively consent veterans and collect biospecimens and additional clinical and self-reported information. The implementation of Umbrella could significantly enhance collection and research. Although Sweep is a onetime collection of samples, the Umbrella protocol will allow the longitudinal collection of samples from the same patient. Additionally, the Umbrella amendment will allow VA SHIELD to accept samples from other preexisting biorepositories or specimen collections.

Central Biorepositories

VA SHIELD has a federated organization with 2 central specimen biorepositories (Palo Alto, CA and Tucson, AZ), and an enterprise data processing center (Boston, MA). The specimen biorepositories receive de-identified specimens that are stored until distribution to approved research projects. The samples and data are linked using an electronic honest broker system to protect privacy, which integrates de-identified specimens with requested clinical and demographic data as needed for approved projects. The honest broker system is operated by independent personnel and does not have vested interest in any studies being performed under VA SHIELD. The integration of sample and associated data is done only as needed when characterization of the donor/participant is necessary byresearch aims or project outcomes. The process is facilitated by a nationally supported laboratory information management system (LIMS), managed by the VA SHIELD data center, that assists with all data requests. The clinical and demographic data are collected from VA electronic health record (EHR), available through VA Corporate Data Warehouse (CDW) and VA Informatics and Computing Infrastructure (VINCI) as needed and integrated with the biorepository samples information for approved VA SHIELD studies. The CDW is the largest longitudinal EHR data collection in the US and has the ability to provide access to national clinical and demographic data.

figure.png

VA SHIELD interacts with multiple VA programs and other entities (Figure). For example, Surveillance Platform for Enteric and Respiratory Infectious Organisms at United States Veterans Affairs Medical Centers (SUPERNOVA) is a network of 5 VA medical centers supported by the Centers for Disease Control and Prevention.⁴ Its initial goal was to perform surveillance for acute gastroenteritis. In 2020, SUPERNOVA shifted to conduct surveillance for COVID-19 variants among veterans.⁵ VA SHIELD also interacts with VHA genomic surveillance and sequencing programs: the VA Sequencing Collaborations United for Research and Epidemiology (SeqCURE) and VA Sequencing for Research Clinical and Epidemiology (SeqFORCE), described by Krishnan and colleagues.⁶

Working Groups

To encourage research projects that use biospecimens, VA SHIELD developed content-oriented research working groups. The goal is to inspire collaborations between VA scientists and prevent redundant or overlapping projects. Currently working groups are focused on long COVID, and COVID-19 neurology, pathogen host response, epidemiology and sequencing, cancer and cancer biomarkers, antimicrobial resistance, and vector-borne diseases. Working groups meet regularly to discuss projects and report progress. Working groups also may consider samples that might benefit VA health research and identify potential veteran populations for future research. Working groups connect VA SHIELD and investigators and guide the collection and use of resources.

From inception, VA SHIELD has discussed best practices for human research subject protection, how to ensure veterans’ privacy and protecting personal health information, and how to assess the benefit-risk ratio of veterans who participate in the biorepository. Ethical principles on access to and use of veteran data are embedded in human subject protection plans and patient consent. The PSRB is responsible for reviewing specimen use and data access requests in accordance with established programmatic and scientific goals. The PSRB balances limited sample availability by prioritizing requests to ensure utilization of biospecimens occurs in accordance with the guidelines, protocols, and strategic objectives of VA SHIELD.

We recognize the significant ethical concerns for biobanking of specimens. However, there is no general consensus or guideline that addresses all of the complex ethical issues regarding biobanking.⁷ To address these ethical concerns, we applied the VA Ethical Framework Principles for Access to and Use of Veteran Data principles to VA SHIELD, including all parties who oversee the access to, sharing of, or the use of data, or who access or use its data.⁸

Conclusions

The VA has assembled a scientific enterprise dedicated to combating emerging infectious diseases and other threats to our patients. This enterprise has been modeled in its structure and oversight to support VA SHIELD. The establishment of a real-time biorepository and data procurement system linked to clinical samples is a bold step forward to address current and future challenges. Similarly, the integration and cooperation of multiple arms within the VA that transcend disciplines and boundaries promise to shepherd a new era of system-wide investigation. In the future, VA SHIELD will integrate with other existing government agencies to advance mutual scientific agendas. VA SHIELD has established the data and biorepository infrastructure to develop innovative and novel technologies to address future challenges. The alignment of basic science, clinical, and translational research goals under one governance is a significant advancement compared with previous models of research coordination.

VA SHIELD was developed to meet an immediate need; it was also framed to be a research enterprise that harnesses the robust clinical and research environment in VHA. The VA SHIELD infrastructure was conceptualized to harmonize specimen and data collection across the VA, allowing researchers to leverage broader collection efforts. Building a biorepository and data collection system within the largest integrated health care system has the potential to provide a lasting impact on VHA and on our nation’s health.

Acknowledgments

The authors wish to acknowledge Ms. Daphne Swancutt for her contribution as copywriter for this manuscript. The authors wish to acknowledge the VA SHIELD investigators: Mary Cloud Ammons, David Beenhouwer, Sheldon T. Brown, Victoria Davey, Abhinav Diwan, John B. Harley, Mark Holodniy, Vincent C. Marconi, Jonathan Moorman, Emerson B. Padiernos, Ian F. Robey, Maria Rodriguez-Barradas, Jason Wertheim, Christopher W. Woods.

The Veterans Health Administration (VHA) clinicians, clinician-investigators, and investigators perform basic and translational research for the benefit of our nation and are widely recognized for treating patients and discovering cures.^1,2 In May 2020, the US Department of Veterans Affairs (VA) launched the VA Science and Health Initiative to Combat Infectious and Emerging Life-Threatening Diseases (VA SHIELD). The goal of this novel enterprise was to assemble a comprehensive specimen and data repository for emerging life-threatening diseases and to address future challenges. VA SHIELD was specifically charged with creating a biorepository to advance research, improve diagnostic and therapeutic capabilities, and develop strategies for immediate deployment to VA clinical environments. One main objective of VA SHIELD is to harness the clinical and scientific strengths of the VA in order to create a more cohesive collaboration between preexisting clinical research efforts within the VA.

ANATOMY OF VA SHIELD

The charge and scope of VA SHIELD is unique.³ As an entity, this program leverages the strengths of the diverse VHA network, has a broad potential impact on national health care, is positioned to respond rapidly to national and international health-related events, and substantially contributes to clinical research and development. In addition, VA SHIELD upholds VA’s Fourth Mission, which is to contribute to national emergencies and support emergency management, public health, safety, and homeland security efforts.

VA SHIELD is part of the VA Office of Research and Development (ORD). The coordinating center (CC), headquartered in Cleveland, Ohio, is the central operational partner, leading VA SHIELD and interacting with other important VA programs, including laboratory, clinical science, rehabilitation, and health services. The VA SHIELD CC oversees all aspects of operations, including biospecimen collection, creating and enforcing of standard operating procedures, ensuring the quality of the samples, processing research applications, distribution of samples, financing, and progress reports. The CC also initiates and maintains interagency collaborations, convenes stakeholders, and develops strategic plans to address emerging diseases.

The VA SHIELD Executive Steering Committee (ESC) is composed of infectious disease, biorepository, and public health specialists. The ESC provides scientific and programmatic direction to the CC, including operational activities and guidance regarding biorepository priorities and scientific agenda, and measuring and reporting on VA SHIELD accomplishments.

The primary function of the Programmatic and Scientific Review Board (PSRB) is to evaluate incoming research proposals for specimen and data use for feasibility and make recommendations to the VA SHIELD CC. The PSRB evaluates and ensures that data and specimen use align with VA SHIELD ethical, clinical, and scientific objectives.

VA SHIELD IN PRACTICE

VA SHIELD consisted of 11 specimen collection sites (Atlanta, GA; Boise, ID; Bronx, NY; Cincinnati, OH; Cleveland, OH; Durham, NC; Houston, TX; Los Angeles, CA; Mountain Home, TN; Palo Alto, CA; and Tucson, AZ), a data processing center in Boston, MA, and 2 central biorepositories in Palo Alto, CA, and Tucson, AZ. Information flow is a coordinated process among specimen collection sites, data processing centers, and the biorepositories. Initially, each local collection site identifies residual specimens that would have been discarded after clinical laboratory testing. These samples currently account for the majority of biological material within VA SHIELD via a novel collection protocol known as “Sweep,” which allows residual clinical discarded samples as well as samples from patients with new emerging infectious and noninfectious diseases of concern to be collected at the time of first emergence and submitted to VA SHIELD during the course of routine veteran health care.³ These clinical discarded samples are de-identified and transferred from the clinical laboratory to VA SHIELD. The VA Central Institutional Review Board (cIRB) has approved the use of these samples as nonhuman subject research. Biological samples are collected, processed, aliquoted, shipped to, and stored at the central biorepository sites.

The Umbrella amendment to Sweep that has been approved also by the VA cIRB, will allow VA SHIELD sites to prospectively consent veterans and collect biospecimens and additional clinical and self-reported information. The implementation of Umbrella could significantly enhance collection and research. Although Sweep is a onetime collection of samples, the Umbrella protocol will allow the longitudinal collection of samples from the same patient. Additionally, the Umbrella amendment will allow VA SHIELD to accept samples from other preexisting biorepositories or specimen collections.

Central Biorepositories

VA SHIELD has a federated organization with 2 central specimen biorepositories (Palo Alto, CA and Tucson, AZ), and an enterprise data processing center (Boston, MA). The specimen biorepositories receive de-identified specimens that are stored until distribution to approved research projects. The samples and data are linked using an electronic honest broker system to protect privacy, which integrates de-identified specimens with requested clinical and demographic data as needed for approved projects. The honest broker system is operated by independent personnel and does not have vested interest in any studies being performed under VA SHIELD. The integration of sample and associated data is done only as needed when characterization of the donor/participant is necessary byresearch aims or project outcomes. The process is facilitated by a nationally supported laboratory information management system (LIMS), managed by the VA SHIELD data center, that assists with all data requests. The clinical and demographic data are collected from VA electronic health record (EHR), available through VA Corporate Data Warehouse (CDW) and VA Informatics and Computing Infrastructure (VINCI) as needed and integrated with the biorepository samples information for approved VA SHIELD studies. The CDW is the largest longitudinal EHR data collection in the US and has the ability to provide access to national clinical and demographic data.

figure.png

VA SHIELD interacts with multiple VA programs and other entities (Figure). For example, Surveillance Platform for Enteric and Respiratory Infectious Organisms at United States Veterans Affairs Medical Centers (SUPERNOVA) is a network of 5 VA medical centers supported by the Centers for Disease Control and Prevention.⁴ Its initial goal was to perform surveillance for acute gastroenteritis. In 2020, SUPERNOVA shifted to conduct surveillance for COVID-19 variants among veterans.⁵ VA SHIELD also interacts with VHA genomic surveillance and sequencing programs: the VA Sequencing Collaborations United for Research and Epidemiology (SeqCURE) and VA Sequencing for Research Clinical and Epidemiology (SeqFORCE), described by Krishnan and colleagues.⁶

Working Groups

To encourage research projects that use biospecimens, VA SHIELD developed content-oriented research working groups. The goal is to inspire collaborations between VA scientists and prevent redundant or overlapping projects. Currently working groups are focused on long COVID, and COVID-19 neurology, pathogen host response, epidemiology and sequencing, cancer and cancer biomarkers, antimicrobial resistance, and vector-borne diseases. Working groups meet regularly to discuss projects and report progress. Working groups also may consider samples that might benefit VA health research and identify potential veteran populations for future research. Working groups connect VA SHIELD and investigators and guide the collection and use of resources.

From inception, VA SHIELD has discussed best practices for human research subject protection, how to ensure veterans’ privacy and protecting personal health information, and how to assess the benefit-risk ratio of veterans who participate in the biorepository. Ethical principles on access to and use of veteran data are embedded in human subject protection plans and patient consent. The PSRB is responsible for reviewing specimen use and data access requests in accordance with established programmatic and scientific goals. The PSRB balances limited sample availability by prioritizing requests to ensure utilization of biospecimens occurs in accordance with the guidelines, protocols, and strategic objectives of VA SHIELD.

We recognize the significant ethical concerns for biobanking of specimens. However, there is no general consensus or guideline that addresses all of the complex ethical issues regarding biobanking.⁷ To address these ethical concerns, we applied the VA Ethical Framework Principles for Access to and Use of Veteran Data principles to VA SHIELD, including all parties who oversee the access to, sharing of, or the use of data, or who access or use its data.⁸

Conclusions

The VA has assembled a scientific enterprise dedicated to combating emerging infectious diseases and other threats to our patients. This enterprise has been modeled in its structure and oversight to support VA SHIELD. The establishment of a real-time biorepository and data procurement system linked to clinical samples is a bold step forward to address current and future challenges. Similarly, the integration and cooperation of multiple arms within the VA that transcend disciplines and boundaries promise to shepherd a new era of system-wide investigation. In the future, VA SHIELD will integrate with other existing government agencies to advance mutual scientific agendas. VA SHIELD has established the data and biorepository infrastructure to develop innovative and novel technologies to address future challenges. The alignment of basic science, clinical, and translational research goals under one governance is a significant advancement compared with previous models of research coordination.

VA SHIELD was developed to meet an immediate need; it was also framed to be a research enterprise that harnesses the robust clinical and research environment in VHA. The VA SHIELD infrastructure was conceptualized to harmonize specimen and data collection across the VA, allowing researchers to leverage broader collection efforts. Building a biorepository and data collection system within the largest integrated health care system has the potential to provide a lasting impact on VHA and on our nation’s health.

Acknowledgments

The authors wish to acknowledge Ms. Daphne Swancutt for her contribution as copywriter for this manuscript. The authors wish to acknowledge the VA SHIELD investigators: Mary Cloud Ammons, David Beenhouwer, Sheldon T. Brown, Victoria Davey, Abhinav Diwan, John B. Harley, Mark Holodniy, Vincent C. Marconi, Jonathan Moorman, Emerson B. Padiernos, Ian F. Robey, Maria Rodriguez-Barradas, Jason Wertheim, Christopher W. Woods.

The Veterans Health Administration (VHA) clinicians, clinician-investigators, and investigators perform basic and translational research for the benefit of our nation and are widely recognized for treating patients and discovering cures.^1,2 In May 2020, the US Department of Veterans Affairs (VA) launched the VA Science and Health Initiative to Combat Infectious and Emerging Life-Threatening Diseases (VA SHIELD). The goal of this novel enterprise was to assemble a comprehensive specimen and data repository for emerging life-threatening diseases and to address future challenges. VA SHIELD was specifically charged with creating a biorepository to advance research, improve diagnostic and therapeutic capabilities, and develop strategies for immediate deployment to VA clinical environments. One main objective of VA SHIELD is to harness the clinical and scientific strengths of the VA in order to create a more cohesive collaboration between preexisting clinical research efforts within the VA.

ANATOMY OF VA SHIELD

The charge and scope of VA SHIELD is unique.³ As an entity, this program leverages the strengths of the diverse VHA network, has a broad potential impact on national health care, is positioned to respond rapidly to national and international health-related events, and substantially contributes to clinical research and development. In addition, VA SHIELD upholds VA’s Fourth Mission, which is to contribute to national emergencies and support emergency management, public health, safety, and homeland security efforts.

VA SHIELD is part of the VA Office of Research and Development (ORD). The coordinating center (CC), headquartered in Cleveland, Ohio, is the central operational partner, leading VA SHIELD and interacting with other important VA programs, including laboratory, clinical science, rehabilitation, and health services. The VA SHIELD CC oversees all aspects of operations, including biospecimen collection, creating and enforcing of standard operating procedures, ensuring the quality of the samples, processing research applications, distribution of samples, financing, and progress reports. The CC also initiates and maintains interagency collaborations, convenes stakeholders, and develops strategic plans to address emerging diseases.

The VA SHIELD Executive Steering Committee (ESC) is composed of infectious disease, biorepository, and public health specialists. The ESC provides scientific and programmatic direction to the CC, including operational activities and guidance regarding biorepository priorities and scientific agenda, and measuring and reporting on VA SHIELD accomplishments.

The primary function of the Programmatic and Scientific Review Board (PSRB) is to evaluate incoming research proposals for specimen and data use for feasibility and make recommendations to the VA SHIELD CC. The PSRB evaluates and ensures that data and specimen use align with VA SHIELD ethical, clinical, and scientific objectives.

VA SHIELD IN PRACTICE

VA SHIELD consisted of 11 specimen collection sites (Atlanta, GA; Boise, ID; Bronx, NY; Cincinnati, OH; Cleveland, OH; Durham, NC; Houston, TX; Los Angeles, CA; Mountain Home, TN; Palo Alto, CA; and Tucson, AZ), a data processing center in Boston, MA, and 2 central biorepositories in Palo Alto, CA, and Tucson, AZ. Information flow is a coordinated process among specimen collection sites, data processing centers, and the biorepositories. Initially, each local collection site identifies residual specimens that would have been discarded after clinical laboratory testing. These samples currently account for the majority of biological material within VA SHIELD via a novel collection protocol known as “Sweep,” which allows residual clinical discarded samples as well as samples from patients with new emerging infectious and noninfectious diseases of concern to be collected at the time of first emergence and submitted to VA SHIELD during the course of routine veteran health care.³ These clinical discarded samples are de-identified and transferred from the clinical laboratory to VA SHIELD. The VA Central Institutional Review Board (cIRB) has approved the use of these samples as nonhuman subject research. Biological samples are collected, processed, aliquoted, shipped to, and stored at the central biorepository sites.

The Umbrella amendment to Sweep that has been approved also by the VA cIRB, will allow VA SHIELD sites to prospectively consent veterans and collect biospecimens and additional clinical and self-reported information. The implementation of Umbrella could significantly enhance collection and research. Although Sweep is a onetime collection of samples, the Umbrella protocol will allow the longitudinal collection of samples from the same patient. Additionally, the Umbrella amendment will allow VA SHIELD to accept samples from other preexisting biorepositories or specimen collections.

Central Biorepositories

VA SHIELD has a federated organization with 2 central specimen biorepositories (Palo Alto, CA and Tucson, AZ), and an enterprise data processing center (Boston, MA). The specimen biorepositories receive de-identified specimens that are stored until distribution to approved research projects. The samples and data are linked using an electronic honest broker system to protect privacy, which integrates de-identified specimens with requested clinical and demographic data as needed for approved projects. The honest broker system is operated by independent personnel and does not have vested interest in any studies being performed under VA SHIELD. The integration of sample and associated data is done only as needed when characterization of the donor/participant is necessary byresearch aims or project outcomes. The process is facilitated by a nationally supported laboratory information management system (LIMS), managed by the VA SHIELD data center, that assists with all data requests. The clinical and demographic data are collected from VA electronic health record (EHR), available through VA Corporate Data Warehouse (CDW) and VA Informatics and Computing Infrastructure (VINCI) as needed and integrated with the biorepository samples information for approved VA SHIELD studies. The CDW is the largest longitudinal EHR data collection in the US and has the ability to provide access to national clinical and demographic data.

figure.png

VA SHIELD interacts with multiple VA programs and other entities (Figure). For example, Surveillance Platform for Enteric and Respiratory Infectious Organisms at United States Veterans Affairs Medical Centers (SUPERNOVA) is a network of 5 VA medical centers supported by the Centers for Disease Control and Prevention.⁴ Its initial goal was to perform surveillance for acute gastroenteritis. In 2020, SUPERNOVA shifted to conduct surveillance for COVID-19 variants among veterans.⁵ VA SHIELD also interacts with VHA genomic surveillance and sequencing programs: the VA Sequencing Collaborations United for Research and Epidemiology (SeqCURE) and VA Sequencing for Research Clinical and Epidemiology (SeqFORCE), described by Krishnan and colleagues.⁶

Working Groups

To encourage research projects that use biospecimens, VA SHIELD developed content-oriented research working groups. The goal is to inspire collaborations between VA scientists and prevent redundant or overlapping projects. Currently working groups are focused on long COVID, and COVID-19 neurology, pathogen host response, epidemiology and sequencing, cancer and cancer biomarkers, antimicrobial resistance, and vector-borne diseases. Working groups meet regularly to discuss projects and report progress. Working groups also may consider samples that might benefit VA health research and identify potential veteran populations for future research. Working groups connect VA SHIELD and investigators and guide the collection and use of resources.

From inception, VA SHIELD has discussed best practices for human research subject protection, how to ensure veterans’ privacy and protecting personal health information, and how to assess the benefit-risk ratio of veterans who participate in the biorepository. Ethical principles on access to and use of veteran data are embedded in human subject protection plans and patient consent. The PSRB is responsible for reviewing specimen use and data access requests in accordance with established programmatic and scientific goals. The PSRB balances limited sample availability by prioritizing requests to ensure utilization of biospecimens occurs in accordance with the guidelines, protocols, and strategic objectives of VA SHIELD.

We recognize the significant ethical concerns for biobanking of specimens. However, there is no general consensus or guideline that addresses all of the complex ethical issues regarding biobanking.⁷ To address these ethical concerns, we applied the VA Ethical Framework Principles for Access to and Use of Veteran Data principles to VA SHIELD, including all parties who oversee the access to, sharing of, or the use of data, or who access or use its data.⁸

Conclusions

The VA has assembled a scientific enterprise dedicated to combating emerging infectious diseases and other threats to our patients. This enterprise has been modeled in its structure and oversight to support VA SHIELD. The establishment of a real-time biorepository and data procurement system linked to clinical samples is a bold step forward to address current and future challenges. Similarly, the integration and cooperation of multiple arms within the VA that transcend disciplines and boundaries promise to shepherd a new era of system-wide investigation. In the future, VA SHIELD will integrate with other existing government agencies to advance mutual scientific agendas. VA SHIELD has established the data and biorepository infrastructure to develop innovative and novel technologies to address future challenges. The alignment of basic science, clinical, and translational research goals under one governance is a significant advancement compared with previous models of research coordination.

VA SHIELD was developed to meet an immediate need; it was also framed to be a research enterprise that harnesses the robust clinical and research environment in VHA. The VA SHIELD infrastructure was conceptualized to harmonize specimen and data collection across the VA, allowing researchers to leverage broader collection efforts. Building a biorepository and data collection system within the largest integrated health care system has the potential to provide a lasting impact on VHA and on our nation’s health.

Acknowledgments

The authors wish to acknowledge Ms. Daphne Swancutt for her contribution as copywriter for this manuscript. The authors wish to acknowledge the VA SHIELD investigators: Mary Cloud Ammons, David Beenhouwer, Sheldon T. Brown, Victoria Davey, Abhinav Diwan, John B. Harley, Mark Holodniy, Vincent C. Marconi, Jonathan Moorman, Emerson B. Padiernos, Ian F. Robey, Maria Rodriguez-Barradas, Jason Wertheim, Christopher W. Woods.

The COVID-19 virus and its associated pandemic have highlighted the urgent need for a national infrastructure to rapidly identify and respond to emerging pathogens. The importance of understanding viral population dynamics through genetic sequencing has become apparent over time, particularly as the vaccine responses, clinical implications, and therapeutic effectiveness of treatments have varied substantially with COVID-19 variants.^1,2

table.png

As the largest integrated health care system in the US, the US Department of Veterans Affairs (VA) is uniquely situated to help with pandemic detection and response. This article highlights 2 VA programs dedicated to COVID-19 sequencing at the forefront of pandemic response and research: VA Sequencing for Research Clinical and Epidemiology (SeqFORCE) and VA Sequencing Collaborations United for Research and Epidemiology (SeqCURE) (Table).

VA SeqFORCE

VA SeqFORCE was established March 2021 to facilitate clinical surveillance of COVID-19 variants in the US veteran population and in VA employees. VA SeqFORCE consists of 9 Clinical Laboratory Improvement Amendment (CLIA)–certified laboratories in VA medical centers, including the VA Public Health Reference Laboratory in Palo Alto, California, and 8 Veterans Health Administration (VHA) clinical laboratories (Los Angeles, California; Boise, Idaho; Iowa City, Iowa; Bronx, New York; West Haven, Connecticut; Indianapolis, Indiana; Denver, Colorado; and Orlando, Florida).³ Specimen standards (eg, real-time polymerase chain reaction [RT-PCR] cycle threshold [Ct] ≤ 30, minimum volume, etc) and clinical criteria (eg, COVID-19–related deaths, COVID-19 vaccine escape, etc) for submitting samples to VA SeqFORCE laboratories were established, and logistics for sample sequencing was centralized, including providing centralized instructions for sample preparation and to which VA SeqFORCE laboratory samples should be sent.

These laboratories sequenced samples from patients and employees with COVID-19 to understand patterns of variant evolution, vaccine, antiviral and monoclonal antibody response, health care–associated outbreaks, and COVID-19 transmission. As clinically relevant findings, such as monoclonal antibody treatment failure, emerged with novel viral variants, VA SeqFORCE was well positioned to rapidly detect the emergent variants and inform better clinical care of patients with COVID-19. Other clinical indications identified for sequencing within VA SeqFORCE included outbreak investigation, re-infection with COVID-19 > 90 days but < 6 months after a prior infection, extended hospitalization of > 21 days, death due to COVID-19, infection with a history of recent nondomestic travel, rebound of symptoms after improvement on oral antiviral therapy, and epidemiologic surveillance.

VA SeqFORCE laboratories use a variety of sequencing platforms, although a federated system was developed that electronically linked all laboratories using a software system (PraediGene, Bitscopic) for sample management, COVID-19 variant analytics, and automated result reporting of clade and lineage into the Veterans Health Information Systems and Technology Architecture (VistA) Computerized Patient Record System. In addition, generated nucleic acid sequence alignment through FASTA consensus sequence files have been archived for secondary research analyses. By archiving the consensus sequences, retrospective studies within the VA have the added benefit of being able to clinically annotate investigations into COVID-19 variant patterns. As of August 2023, 43,003 samples containing COVID-19 have been sequenced, and FASTA file and metadata upload are ongoing to the Global Initiative on Sharing Avian Influenza Data, which houses > 15 million COVID-19 files from global submissions.

VA SeqFORCE’s clinical sequencing efforts have created opportunities for multicenter collaboration in variant surveillance. In work from December 2021, investigators from the James J. Peters VA Medical Center in Bronx, New York, collaborated with the VHA Pathology and Laboratory Medicine Services and Public Health national program offices in Washington, DC, to develop an RT-PCR assay to rapidly differentiate Omicron from Delta variants.⁴ Samples from VA hospitals across the nation were used in this study.

Lessons from VA SeqFORCE have also been cited as inspiration to address COVID-19 clinical problems, including outbreak investigations in hospital settings and beyond. Researchers at the Iowa City VA Health Care System, for example, proposed a novel probabilistic quantitative method for determining genetic-relatedness among COVID-19 viral strains in an outbreak setting.⁵ They extended the scope of work to develop COVID-19 outbreak screening tools combining publicly available algorithms with targeted sequencing data to identify outbreaks as they arise.⁶ We expect VA SeqFORCE, in conjunction with its complement VA SeqCURE, will continue to further pandemic surveillance and response.

VA SeqCURE

As the research-focused complement to VA SeqFORCE, VA SeqCURE is dedicated to a broader study of the COVID-19 genome through sequencing. Established January 2021, the VA SeqCURE network consists of 6 research laboratories in Boise, Idaho; Bronx, New York; Cleveland, Ohio; Durham, North Carolina; Iowa City, Iowa; and Temple, Texas.

Samples are collected as a subset of the broader VA Science and Health Initiative to Combat Infectious and Emerging Life-Threatening Diseases (VA SHIELD) biorepository sweep protocol for discarded blood and nasal swab specimens of VHA patients hospitalized with COVID-19, as described by Epstein and colleagues.^7-9 While VA SeqFORCE sequences samples positive for COVID-19 by RT-PCR with a Ct value of ≤ 30 for diagnostic purposes, VA SeqCURE laboratories sequence more broadly for nondiagnostic purposes, including samples with a Ct value > 30. The 6 VA SeqCURE laboratories generate sequencing data using various platforms, amplification kits, and formats. To ensure maximum quality and metadata on the sequences generated across the different laboratories, a sequence intake pipeline has been developed, adapting the ViralRecon bioinformatics platform.¹⁰ This harmonized analysis pipeline accommodates different file formats and performs quality control, alignment, variant calling, lineage assignment, clade assignment, and annotation. As of August 2023, VA SeqCURE has identified viral sequences from 24,107 unique specimens. Annotated COVID-19 sequences with the appropriate metadata will be available to VA researchers through VA SHIELD.

Research projects include descriptive epidemiology of COVID-19 variants in individuals who receive VHA care, COVID-19 vaccine and therapy effectiveness, and the unique distribution of variants and vaccine effectiveness in rural settings.³ True to its core mission, members of the VA SeqCURE consortium have contributed to the COVID-19 viral sequencing literature over the past 2 years. Researchers also are accessing VA SeqCURE to study COVID-19 persistence and rebound among individuals with mild disease taking nirmatrelvir/ritonavir compared with other COVID-19 therapeutics and untreated controls. Finally, COVID-19 samples and their sequences are stored in the VA SHIELD biorepository, which leverages these samples and data to advance scientific understanding of COVID-19 and future emerging infectious diseases.^7-9

Important work from investigators at the Central Texas Veterans Health Care System confronted the issue of whole genome sequencing data from COVID-19 samples with low viral loads, a common issue with COVID-19 sequencing. They found that yields of 2 sequencing protocols, which generated high-sequence coverage, were enhanced further by combining the results of both methods.¹¹ This project, which has potentially broad applications for sequencing in research and clinical settings, is an example of VA SeqCURE’s efforts to address the COVID-19 pandemic. The VA SeqCURE program has substantial potential as a large viral sequencing repository with broad geographic and demographic representation, such that future large-scale sequencing analyses may be generated from preexisting nested cohorts within the repository.

NEXT STEPS

Promising new directions of clinical and laboratory-based research are planned for VA SeqFORCE and VA SeqCURE. While the impact of COVID-19 and other viruses with epidemic potential is perhaps most feared in urban settings, evidence suggests that the distribution of COVID-19 in rural settings is unique and associated with worse outcomes.^12,13 Given the wide catchment areas of VA hospitals that encompass both rural and urban settings, the VA’s ongoing COVID-19 sequencing programs and repositories are uniquely positioned to understand viral dynamics in areas of differing population density.

While rates of infection, hospitalization, and death resulting from COVID-19 have substantially dropped, the long-term impact of the pandemic is just beginning to be recognized in conditions such as long COVID or postacute COVID-19 syndrome. Long COVID has already proven to be biologically multifaceted, difficult to diagnose, and unpredictable in identifying the most at-risk patients.^14-16 Much remains to be determined in our understanding of long COVID, including a unified definition that can effectively be used in clinical settings to diagnose and treat patients. However, research indicates that comorbidities common in veterans, such as diabetes and cardiovascular disease, are associated with worse long-term outcomes.^17,18 Collaborations between VA scientists, clinicians, and national cooperative programs (such as a network of VHA long COVID clinics) create an unmatched opportunity for VA SeqFORCE and VA SeqCURE programs to provide insight into a disease likely to become a chronic disease outcome of the pandemic.

With VA SeqFORCE and VA SeqCURE programs, the VA now has infrastructure ready to respond to new infectious diseases. During the mpox outbreak of 2022, the VA Public Health Reference Laboratory received > 80% of all VA mpox samples for orthopox screening and mpox confirmatory testing. A subset of these samples underwent whole genome sequencing with the identification of 10 unique lineages across VA, and > 200 positive and 400 negative samples have been aliquoted and submitted to VA SHIELD for research. Furthermore, the VA SeqFORCE and VA SeqCURE sequencing processes might be adapted to identify outbreaks of multidrug-resistant organisms among VA patients trialed at other institutions.¹⁹ We are hopeful that VA SeqFORCE and VA SeqCURE will become invaluable components of health care delivery and infection prevention at the hospital level and beyond.

Finally, the robust data infrastructure and associated repositories of VA SeqFORCE and VA SeqCURE may be leveraged to study noninfectious diseases. Research groups are starting to apply these programs to cancer sequencing. We anticipate that these efforts may have a substantial impact on our understanding of cancer epidemiology and region-specific risk factors for malignancy, given the size and breadth of VA SeqFORCE and VA SeqCURE. Common oncogenic mutations identified through these programs could be targets for precision oncology therapeutics. Similarly, we envision applications of the VA SeqFORCE and VA SeqCURE data infrastructures and repositories toward other precision medicine fields, including pharmacogenomics and nutrition, to tailor interventions to meet the specific individual needs of veterans.

CONCLUSIONS

The productivity of VA SeqFORCE and VA SeqCURE programs over the past 2 years continues to increase in response to the COVID-19 pandemic. We anticipate that they will be vital components in our nation’s responses to infectious threats and beyond.

The COVID-19 virus and its associated pandemic have highlighted the urgent need for a national infrastructure to rapidly identify and respond to emerging pathogens. The importance of understanding viral population dynamics through genetic sequencing has become apparent over time, particularly as the vaccine responses, clinical implications, and therapeutic effectiveness of treatments have varied substantially with COVID-19 variants.^1,2

table.png

As the largest integrated health care system in the US, the US Department of Veterans Affairs (VA) is uniquely situated to help with pandemic detection and response. This article highlights 2 VA programs dedicated to COVID-19 sequencing at the forefront of pandemic response and research: VA Sequencing for Research Clinical and Epidemiology (SeqFORCE) and VA Sequencing Collaborations United for Research and Epidemiology (SeqCURE) (Table).

VA SeqFORCE

VA SeqFORCE was established March 2021 to facilitate clinical surveillance of COVID-19 variants in the US veteran population and in VA employees. VA SeqFORCE consists of 9 Clinical Laboratory Improvement Amendment (CLIA)–certified laboratories in VA medical centers, including the VA Public Health Reference Laboratory in Palo Alto, California, and 8 Veterans Health Administration (VHA) clinical laboratories (Los Angeles, California; Boise, Idaho; Iowa City, Iowa; Bronx, New York; West Haven, Connecticut; Indianapolis, Indiana; Denver, Colorado; and Orlando, Florida).³ Specimen standards (eg, real-time polymerase chain reaction [RT-PCR] cycle threshold [Ct] ≤ 30, minimum volume, etc) and clinical criteria (eg, COVID-19–related deaths, COVID-19 vaccine escape, etc) for submitting samples to VA SeqFORCE laboratories were established, and logistics for sample sequencing was centralized, including providing centralized instructions for sample preparation and to which VA SeqFORCE laboratory samples should be sent.

These laboratories sequenced samples from patients and employees with COVID-19 to understand patterns of variant evolution, vaccine, antiviral and monoclonal antibody response, health care–associated outbreaks, and COVID-19 transmission. As clinically relevant findings, such as monoclonal antibody treatment failure, emerged with novel viral variants, VA SeqFORCE was well positioned to rapidly detect the emergent variants and inform better clinical care of patients with COVID-19. Other clinical indications identified for sequencing within VA SeqFORCE included outbreak investigation, re-infection with COVID-19 > 90 days but < 6 months after a prior infection, extended hospitalization of > 21 days, death due to COVID-19, infection with a history of recent nondomestic travel, rebound of symptoms after improvement on oral antiviral therapy, and epidemiologic surveillance.

VA SeqFORCE laboratories use a variety of sequencing platforms, although a federated system was developed that electronically linked all laboratories using a software system (PraediGene, Bitscopic) for sample management, COVID-19 variant analytics, and automated result reporting of clade and lineage into the Veterans Health Information Systems and Technology Architecture (VistA) Computerized Patient Record System. In addition, generated nucleic acid sequence alignment through FASTA consensus sequence files have been archived for secondary research analyses. By archiving the consensus sequences, retrospective studies within the VA have the added benefit of being able to clinically annotate investigations into COVID-19 variant patterns. As of August 2023, 43,003 samples containing COVID-19 have been sequenced, and FASTA file and metadata upload are ongoing to the Global Initiative on Sharing Avian Influenza Data, which houses > 15 million COVID-19 files from global submissions.

VA SeqFORCE’s clinical sequencing efforts have created opportunities for multicenter collaboration in variant surveillance. In work from December 2021, investigators from the James J. Peters VA Medical Center in Bronx, New York, collaborated with the VHA Pathology and Laboratory Medicine Services and Public Health national program offices in Washington, DC, to develop an RT-PCR assay to rapidly differentiate Omicron from Delta variants.⁴ Samples from VA hospitals across the nation were used in this study.

Lessons from VA SeqFORCE have also been cited as inspiration to address COVID-19 clinical problems, including outbreak investigations in hospital settings and beyond. Researchers at the Iowa City VA Health Care System, for example, proposed a novel probabilistic quantitative method for determining genetic-relatedness among COVID-19 viral strains in an outbreak setting.⁵ They extended the scope of work to develop COVID-19 outbreak screening tools combining publicly available algorithms with targeted sequencing data to identify outbreaks as they arise.⁶ We expect VA SeqFORCE, in conjunction with its complement VA SeqCURE, will continue to further pandemic surveillance and response.

VA SeqCURE

As the research-focused complement to VA SeqFORCE, VA SeqCURE is dedicated to a broader study of the COVID-19 genome through sequencing. Established January 2021, the VA SeqCURE network consists of 6 research laboratories in Boise, Idaho; Bronx, New York; Cleveland, Ohio; Durham, North Carolina; Iowa City, Iowa; and Temple, Texas.

Samples are collected as a subset of the broader VA Science and Health Initiative to Combat Infectious and Emerging Life-Threatening Diseases (VA SHIELD) biorepository sweep protocol for discarded blood and nasal swab specimens of VHA patients hospitalized with COVID-19, as described by Epstein and colleagues.^7-9 While VA SeqFORCE sequences samples positive for COVID-19 by RT-PCR with a Ct value of ≤ 30 for diagnostic purposes, VA SeqCURE laboratories sequence more broadly for nondiagnostic purposes, including samples with a Ct value > 30. The 6 VA SeqCURE laboratories generate sequencing data using various platforms, amplification kits, and formats. To ensure maximum quality and metadata on the sequences generated across the different laboratories, a sequence intake pipeline has been developed, adapting the ViralRecon bioinformatics platform.¹⁰ This harmonized analysis pipeline accommodates different file formats and performs quality control, alignment, variant calling, lineage assignment, clade assignment, and annotation. As of August 2023, VA SeqCURE has identified viral sequences from 24,107 unique specimens. Annotated COVID-19 sequences with the appropriate metadata will be available to VA researchers through VA SHIELD.

Research projects include descriptive epidemiology of COVID-19 variants in individuals who receive VHA care, COVID-19 vaccine and therapy effectiveness, and the unique distribution of variants and vaccine effectiveness in rural settings.³ True to its core mission, members of the VA SeqCURE consortium have contributed to the COVID-19 viral sequencing literature over the past 2 years. Researchers also are accessing VA SeqCURE to study COVID-19 persistence and rebound among individuals with mild disease taking nirmatrelvir/ritonavir compared with other COVID-19 therapeutics and untreated controls. Finally, COVID-19 samples and their sequences are stored in the VA SHIELD biorepository, which leverages these samples and data to advance scientific understanding of COVID-19 and future emerging infectious diseases.^7-9

Important work from investigators at the Central Texas Veterans Health Care System confronted the issue of whole genome sequencing data from COVID-19 samples with low viral loads, a common issue with COVID-19 sequencing. They found that yields of 2 sequencing protocols, which generated high-sequence coverage, were enhanced further by combining the results of both methods.¹¹ This project, which has potentially broad applications for sequencing in research and clinical settings, is an example of VA SeqCURE’s efforts to address the COVID-19 pandemic. The VA SeqCURE program has substantial potential as a large viral sequencing repository with broad geographic and demographic representation, such that future large-scale sequencing analyses may be generated from preexisting nested cohorts within the repository.

NEXT STEPS

Promising new directions of clinical and laboratory-based research are planned for VA SeqFORCE and VA SeqCURE. While the impact of COVID-19 and other viruses with epidemic potential is perhaps most feared in urban settings, evidence suggests that the distribution of COVID-19 in rural settings is unique and associated with worse outcomes.^12,13 Given the wide catchment areas of VA hospitals that encompass both rural and urban settings, the VA’s ongoing COVID-19 sequencing programs and repositories are uniquely positioned to understand viral dynamics in areas of differing population density.

While rates of infection, hospitalization, and death resulting from COVID-19 have substantially dropped, the long-term impact of the pandemic is just beginning to be recognized in conditions such as long COVID or postacute COVID-19 syndrome. Long COVID has already proven to be biologically multifaceted, difficult to diagnose, and unpredictable in identifying the most at-risk patients.^14-16 Much remains to be determined in our understanding of long COVID, including a unified definition that can effectively be used in clinical settings to diagnose and treat patients. However, research indicates that comorbidities common in veterans, such as diabetes and cardiovascular disease, are associated with worse long-term outcomes.^17,18 Collaborations between VA scientists, clinicians, and national cooperative programs (such as a network of VHA long COVID clinics) create an unmatched opportunity for VA SeqFORCE and VA SeqCURE programs to provide insight into a disease likely to become a chronic disease outcome of the pandemic.

With VA SeqFORCE and VA SeqCURE programs, the VA now has infrastructure ready to respond to new infectious diseases. During the mpox outbreak of 2022, the VA Public Health Reference Laboratory received > 80% of all VA mpox samples for orthopox screening and mpox confirmatory testing. A subset of these samples underwent whole genome sequencing with the identification of 10 unique lineages across VA, and > 200 positive and 400 negative samples have been aliquoted and submitted to VA SHIELD for research. Furthermore, the VA SeqFORCE and VA SeqCURE sequencing processes might be adapted to identify outbreaks of multidrug-resistant organisms among VA patients trialed at other institutions.¹⁹ We are hopeful that VA SeqFORCE and VA SeqCURE will become invaluable components of health care delivery and infection prevention at the hospital level and beyond.

Finally, the robust data infrastructure and associated repositories of VA SeqFORCE and VA SeqCURE may be leveraged to study noninfectious diseases. Research groups are starting to apply these programs to cancer sequencing. We anticipate that these efforts may have a substantial impact on our understanding of cancer epidemiology and region-specific risk factors for malignancy, given the size and breadth of VA SeqFORCE and VA SeqCURE. Common oncogenic mutations identified through these programs could be targets for precision oncology therapeutics. Similarly, we envision applications of the VA SeqFORCE and VA SeqCURE data infrastructures and repositories toward other precision medicine fields, including pharmacogenomics and nutrition, to tailor interventions to meet the specific individual needs of veterans.

CONCLUSIONS

The productivity of VA SeqFORCE and VA SeqCURE programs over the past 2 years continues to increase in response to the COVID-19 pandemic. We anticipate that they will be vital components in our nation’s responses to infectious threats and beyond.

The COVID-19 virus and its associated pandemic have highlighted the urgent need for a national infrastructure to rapidly identify and respond to emerging pathogens. The importance of understanding viral population dynamics through genetic sequencing has become apparent over time, particularly as the vaccine responses, clinical implications, and therapeutic effectiveness of treatments have varied substantially with COVID-19 variants.^1,2

table.png

As the largest integrated health care system in the US, the US Department of Veterans Affairs (VA) is uniquely situated to help with pandemic detection and response. This article highlights 2 VA programs dedicated to COVID-19 sequencing at the forefront of pandemic response and research: VA Sequencing for Research Clinical and Epidemiology (SeqFORCE) and VA Sequencing Collaborations United for Research and Epidemiology (SeqCURE) (Table).

VA SeqFORCE

VA SeqFORCE was established March 2021 to facilitate clinical surveillance of COVID-19 variants in the US veteran population and in VA employees. VA SeqFORCE consists of 9 Clinical Laboratory Improvement Amendment (CLIA)–certified laboratories in VA medical centers, including the VA Public Health Reference Laboratory in Palo Alto, California, and 8 Veterans Health Administration (VHA) clinical laboratories (Los Angeles, California; Boise, Idaho; Iowa City, Iowa; Bronx, New York; West Haven, Connecticut; Indianapolis, Indiana; Denver, Colorado; and Orlando, Florida).³ Specimen standards (eg, real-time polymerase chain reaction [RT-PCR] cycle threshold [Ct] ≤ 30, minimum volume, etc) and clinical criteria (eg, COVID-19–related deaths, COVID-19 vaccine escape, etc) for submitting samples to VA SeqFORCE laboratories were established, and logistics for sample sequencing was centralized, including providing centralized instructions for sample preparation and to which VA SeqFORCE laboratory samples should be sent.

These laboratories sequenced samples from patients and employees with COVID-19 to understand patterns of variant evolution, vaccine, antiviral and monoclonal antibody response, health care–associated outbreaks, and COVID-19 transmission. As clinically relevant findings, such as monoclonal antibody treatment failure, emerged with novel viral variants, VA SeqFORCE was well positioned to rapidly detect the emergent variants and inform better clinical care of patients with COVID-19. Other clinical indications identified for sequencing within VA SeqFORCE included outbreak investigation, re-infection with COVID-19 > 90 days but < 6 months after a prior infection, extended hospitalization of > 21 days, death due to COVID-19, infection with a history of recent nondomestic travel, rebound of symptoms after improvement on oral antiviral therapy, and epidemiologic surveillance.

VA SeqFORCE laboratories use a variety of sequencing platforms, although a federated system was developed that electronically linked all laboratories using a software system (PraediGene, Bitscopic) for sample management, COVID-19 variant analytics, and automated result reporting of clade and lineage into the Veterans Health Information Systems and Technology Architecture (VistA) Computerized Patient Record System. In addition, generated nucleic acid sequence alignment through FASTA consensus sequence files have been archived for secondary research analyses. By archiving the consensus sequences, retrospective studies within the VA have the added benefit of being able to clinically annotate investigations into COVID-19 variant patterns. As of August 2023, 43,003 samples containing COVID-19 have been sequenced, and FASTA file and metadata upload are ongoing to the Global Initiative on Sharing Avian Influenza Data, which houses > 15 million COVID-19 files from global submissions.

VA SeqFORCE’s clinical sequencing efforts have created opportunities for multicenter collaboration in variant surveillance. In work from December 2021, investigators from the James J. Peters VA Medical Center in Bronx, New York, collaborated with the VHA Pathology and Laboratory Medicine Services and Public Health national program offices in Washington, DC, to develop an RT-PCR assay to rapidly differentiate Omicron from Delta variants.⁴ Samples from VA hospitals across the nation were used in this study.

Lessons from VA SeqFORCE have also been cited as inspiration to address COVID-19 clinical problems, including outbreak investigations in hospital settings and beyond. Researchers at the Iowa City VA Health Care System, for example, proposed a novel probabilistic quantitative method for determining genetic-relatedness among COVID-19 viral strains in an outbreak setting.⁵ They extended the scope of work to develop COVID-19 outbreak screening tools combining publicly available algorithms with targeted sequencing data to identify outbreaks as they arise.⁶ We expect VA SeqFORCE, in conjunction with its complement VA SeqCURE, will continue to further pandemic surveillance and response.

VA SeqCURE

As the research-focused complement to VA SeqFORCE, VA SeqCURE is dedicated to a broader study of the COVID-19 genome through sequencing. Established January 2021, the VA SeqCURE network consists of 6 research laboratories in Boise, Idaho; Bronx, New York; Cleveland, Ohio; Durham, North Carolina; Iowa City, Iowa; and Temple, Texas.

Samples are collected as a subset of the broader VA Science and Health Initiative to Combat Infectious and Emerging Life-Threatening Diseases (VA SHIELD) biorepository sweep protocol for discarded blood and nasal swab specimens of VHA patients hospitalized with COVID-19, as described by Epstein and colleagues.^7-9 While VA SeqFORCE sequences samples positive for COVID-19 by RT-PCR with a Ct value of ≤ 30 for diagnostic purposes, VA SeqCURE laboratories sequence more broadly for nondiagnostic purposes, including samples with a Ct value > 30. The 6 VA SeqCURE laboratories generate sequencing data using various platforms, amplification kits, and formats. To ensure maximum quality and metadata on the sequences generated across the different laboratories, a sequence intake pipeline has been developed, adapting the ViralRecon bioinformatics platform.¹⁰ This harmonized analysis pipeline accommodates different file formats and performs quality control, alignment, variant calling, lineage assignment, clade assignment, and annotation. As of August 2023, VA SeqCURE has identified viral sequences from 24,107 unique specimens. Annotated COVID-19 sequences with the appropriate metadata will be available to VA researchers through VA SHIELD.

Research projects include descriptive epidemiology of COVID-19 variants in individuals who receive VHA care, COVID-19 vaccine and therapy effectiveness, and the unique distribution of variants and vaccine effectiveness in rural settings.³ True to its core mission, members of the VA SeqCURE consortium have contributed to the COVID-19 viral sequencing literature over the past 2 years. Researchers also are accessing VA SeqCURE to study COVID-19 persistence and rebound among individuals with mild disease taking nirmatrelvir/ritonavir compared with other COVID-19 therapeutics and untreated controls. Finally, COVID-19 samples and their sequences are stored in the VA SHIELD biorepository, which leverages these samples and data to advance scientific understanding of COVID-19 and future emerging infectious diseases.^7-9

Important work from investigators at the Central Texas Veterans Health Care System confronted the issue of whole genome sequencing data from COVID-19 samples with low viral loads, a common issue with COVID-19 sequencing. They found that yields of 2 sequencing protocols, which generated high-sequence coverage, were enhanced further by combining the results of both methods.¹¹ This project, which has potentially broad applications for sequencing in research and clinical settings, is an example of VA SeqCURE’s efforts to address the COVID-19 pandemic. The VA SeqCURE program has substantial potential as a large viral sequencing repository with broad geographic and demographic representation, such that future large-scale sequencing analyses may be generated from preexisting nested cohorts within the repository.

NEXT STEPS

Promising new directions of clinical and laboratory-based research are planned for VA SeqFORCE and VA SeqCURE. While the impact of COVID-19 and other viruses with epidemic potential is perhaps most feared in urban settings, evidence suggests that the distribution of COVID-19 in rural settings is unique and associated with worse outcomes.^12,13 Given the wide catchment areas of VA hospitals that encompass both rural and urban settings, the VA’s ongoing COVID-19 sequencing programs and repositories are uniquely positioned to understand viral dynamics in areas of differing population density.

While rates of infection, hospitalization, and death resulting from COVID-19 have substantially dropped, the long-term impact of the pandemic is just beginning to be recognized in conditions such as long COVID or postacute COVID-19 syndrome. Long COVID has already proven to be biologically multifaceted, difficult to diagnose, and unpredictable in identifying the most at-risk patients.^14-16 Much remains to be determined in our understanding of long COVID, including a unified definition that can effectively be used in clinical settings to diagnose and treat patients. However, research indicates that comorbidities common in veterans, such as diabetes and cardiovascular disease, are associated with worse long-term outcomes.^17,18 Collaborations between VA scientists, clinicians, and national cooperative programs (such as a network of VHA long COVID clinics) create an unmatched opportunity for VA SeqFORCE and VA SeqCURE programs to provide insight into a disease likely to become a chronic disease outcome of the pandemic.

With VA SeqFORCE and VA SeqCURE programs, the VA now has infrastructure ready to respond to new infectious diseases. During the mpox outbreak of 2022, the VA Public Health Reference Laboratory received > 80% of all VA mpox samples for orthopox screening and mpox confirmatory testing. A subset of these samples underwent whole genome sequencing with the identification of 10 unique lineages across VA, and > 200 positive and 400 negative samples have been aliquoted and submitted to VA SHIELD for research. Furthermore, the VA SeqFORCE and VA SeqCURE sequencing processes might be adapted to identify outbreaks of multidrug-resistant organisms among VA patients trialed at other institutions.¹⁹ We are hopeful that VA SeqFORCE and VA SeqCURE will become invaluable components of health care delivery and infection prevention at the hospital level and beyond.

Finally, the robust data infrastructure and associated repositories of VA SeqFORCE and VA SeqCURE may be leveraged to study noninfectious diseases. Research groups are starting to apply these programs to cancer sequencing. We anticipate that these efforts may have a substantial impact on our understanding of cancer epidemiology and region-specific risk factors for malignancy, given the size and breadth of VA SeqFORCE and VA SeqCURE. Common oncogenic mutations identified through these programs could be targets for precision oncology therapeutics. Similarly, we envision applications of the VA SeqFORCE and VA SeqCURE data infrastructures and repositories toward other precision medicine fields, including pharmacogenomics and nutrition, to tailor interventions to meet the specific individual needs of veterans.

CONCLUSIONS

The productivity of VA SeqFORCE and VA SeqCURE programs over the past 2 years continues to increase in response to the COVID-19 pandemic. We anticipate that they will be vital components in our nation’s responses to infectious threats and beyond.

The COVID-19 pandemic emphasized the need for rapid response research in health care. The robust enterprise approach used by the US Department of Veterans Affairs (VA), termed VA Research, is meeting these needs by using existing outstanding data resources and interdisciplinary collaborations.¹ In the first 7 months of 2021 alone, while many US health care systems struggled with limited data, VA Research published more than 300 unique and instrumental research papers addressing urgent questions about transmission, vaccination, therapeutics, and health impacts of COVID-19 on its high-risk population.¹ The ability to leverage the VA electronic health record (EHR) and Corporate Data Warehouse (CDW)—a fully established data system bringing together test results, prescriptions, and complete patient health records, readily accessible and updated daily—was substantial.

With more than 9 million veterans enrolled in care at 171 medical centers and 1113 outpatient facilities across the US and its territories, the CDW provides an unprecedented opportunity to examine outcomes in real time. This allowed research groups such as the VA St Louis Health Care System Research and Education Service to build a cohort of 181,280 veterans with diabetes and positive COVID-19 test results within a 6-month period in 2021 to study the incidence of new diagnoses of diabetes after COVID-19 infection.² Similarly, the Clinical Epidemiology Program (CEP) at VA White River Junction Health Care System built a cohort of 1,363,180 veterans who received at least 1 COVID-19 vaccine by March 7, 2021, to analyze coverage and effectiveness of those vaccines.³ This time-sensitive research was possible because the VA had the data and tools in place. Moreover, the the CEP quickly built an infrastructure to make its cohort and programming codes available to researchers in and outside the VA, resulting in additional significant research.⁴

The innovation and speed of COVID-19 vaccine development and distribution in the US were unprecedented. The rapid discovery and implementation of multiple preventives and therapeutics for COVID-19 could not have been possible without shared information within a competitive industry. VA studies added significantly to understanding the clinical performance of the messenger RNA (mRNA) COVID-19 vaccines, antivirals, and monoclonal treatments in a real-world setting. For example, a vaccine coverage study by VA Research illustrated how successful vaccination for COVID-19 at the VA has been in protecting a diverse community of patients from hospitalization and death, particularly the highly comorbid, racial and ethnic minorities, and other high-risk populations.³ The study demonstrated the power of the VA system to generate robust and compelling clinical endpoint effectiveness data across a broad range of high-risk groups.

This success is promising. However, the COVID-19 pandemic is not over, and the next could prove even more challenging. For example, through a recent partnership with the US Department of Defense (DoD), the VA was able to rapidly analyze the effectiveness of previous smallpox vaccination efforts in the military for preventing mpox infections.⁵ We should take this opportunity to think creatively about ways to improve our existing infrastructure based on what we have learned.

A Role for VA Research in Efficacy

The US Food and Drug Administration (FDA) Reauthorization Act of 2017 requires that manufacturers submit evidence establishing a product’s benefits (effectiveness) outweigh its risks (safety) before it can be promoted and distributed.⁶ As such, the FDA has been obligated by external stakeholders and Congress to be more explicit and transparent about benefit-risk profile supporting its decisions on licensure. This process led to requiring more phase 4 postmarketing observational studies for safety and effectiveness.⁷ Although the FDA postlicensure system remains vigilant toward safety, effectiveness information is limited due to insufficient reporting (with exceptions of manufacturer studies for new indications or to exhibit superior comparative effectiveness). The agency typically relies on a static set of efficacy data generated prelicensure with a dynamic and evolving set of safety data accrued postlicensure to support its assessment that benefits outweigh risks.

For example, operating in near real time, postauthorization safety monitoring systems, led by the Centers for Disease Control and Prevention and other federal systems, identified a safety signal for thrombosis following the Janssen COVID-19 vaccination. Distribution was quickly paused, the safety signal was investigated, the magnitude of the risk was characterized, new language describing the risk and providing guidance regarding clinical management was included in labeling, and distribution was resumed, all within a few weeks. This remarkable success demonstrated how timely the safety system can operate to evaluate risk.

In contrast, the duration and extent of protection against COVID-19 variants are largely limited to the assessment of immune biomarker surrogates. Such clinical effectiveness data are urgently needed for the FDA’s Center for Biologics Evaluation and Research and Center for Drug Evaluation and Research to make accurate benefit-risk assessments and continue to conclude the balance is favorable. As we prepare for the next pandemic, we must consider plans for monitoring postauthorization/postlicensure effectiveness as well as safety in real time. VA Research is ideally situated for this task.

Published studies on effectiveness at the VA serve as a prototype and could lead the way to initiating those preparations.^4,8-11 One of the striking features of the VA system that became apparent in the preparation of the mRNA vaccine study was the speed at which an enormous volume of COVID-19 testing data were produced. This enabled implementation of methodologically sound test-negative and case-control analysis. Analyses sufficiently powered to conclude mRNA vaccines were highly effective when used in real-world conditions among a diverse population from nearly every state and territory during a period in which multiple COVID-19 variants were already circulating.³ This is unique to the VA and would not be possible for any other US health care system. With planning, the VA system could produce product-specific, real-world evidence of effectiveness comparable to the timeliness and quality of the safety data currently produced to support regulatory benefit-risk assessments. For example, the VA conducted an effectiveness study of tixagevimab/cilgavimab for preventing COVID-19 during the initial Omicron surge, which is continually updated while Omicron circulates and repeatable for different subvariants.¹²

The FDA continues to collaborate with the VA on demonstration projects to evaluate the impact of available vaccines and treatment against COVID-19 variants. The VA has also initiated several large-scale sequencing programs for COVID-19 specimens that will support these efforts, including VA Science and Health Initiative to Combat Infectious and Emerging Life-Threatening Diseases (VA SHIELD), VA Sequencing for Research Clinical and Epidemiology (SeqFORCE), and VA Sequencing Collaborations United for Research and Epidemiology (SeqCURE).^13,14 Successful proof-of-concept studies using these data could provide a template for VA and other medical systems/databases to report effectiveness in near real time.

Interagency Collaboration

The potential advantages of federal agencies working with the VA to build an infrastructure capable of generating real-world evidence effectiveness analyses in near real time is not limited to needs that will arise in the next pandemic. For example, generating randomized, placebo-controlled, clinical trial endpoint data on the effectiveness of new variant vaccines will be difficult from a feasibility and ethical standpoint. Combining the VA’s robust virus sequencing program with preexisting mechanisms, such as expanded access studies (allowed under FDA Investigational New Drug regulations), researchers could enable a large-scale effective evaluation program of vaccination with variant or universal COVID-19 vaccines, using rapidly accruing effectiveness data.

The pandemic created opportunities to advance innovative approaches to medical product development. Some have advocated these innovative approaches should proceed together toward a seamless convergence between the domains of medical research and clinical care. A shift toward expecting, as a matter of routine, effectiveness data to be generated in near real time and made available for benefit-risk assessment would be a useful step in that direction.

Expanding and sharing analytical platforms, including methodology and programming codes, will allow increased access to rapidly refreshed real-world data. A common adaptive platform of complete and continuously updated data will also enable a wider community of researchers to create multiple investigatory groups simultaneously accessing fully de-identified data for concurrent observational studies. In turn, researchers need to have programming, study design, and methodology ready in an open-source platform. An efficient platform would also require the adoption of artificial intelligence, natural language processing, imaging processing, and quantum computing for validation and improved data quality.

COVID-19 has demonstrated the need for open science data synchronization with universal access for faster action and improved outcomes able to gain public confidence. OpenSafely (UK), a software platform for analysis of EHR data that is shared automatically and openly for scientific review and efficient reuse, created a cohort of about 23.4 million records for observational review of monoclonal COVID-19 treatments. To keep pace with the UK, Israel, and other nationalized systems, the US would benefit from duplicating this example of coordination between federal agencies and their data repositories. For example, combining data between the DoD, which captures active military health care data through TRICARE, and VA, which follows postmilitary discharge, would create datasets encompassing complete life spans. Additionally, expanding the National COVID Cohort Collaborative (N3C) program—one of the largest collections of clinical data related to COVID-19 symptoms and patient outcomes in the US—to include EHR data from DoD, VA, Medicare, and Test to Treat initiative partners would further expand research capabilities. This could be accomplished through a framework of anonymized, readily available, harmonized data. EHRs with synchronized datasets from every health care practitioner—independent pharmacies, primary care physicians, and hospitals—could all work to create a de-identified, comprehensive, continuously updated, near real-time dataset accessible to all federal researchers.

Conclusions

The VA has been lauded for its rapid, effective response to the current pandemic. The successful management and prescription of vaccines and treatment to the largely high-risk veteran population was possible because of the existing data framework within the VA. VA Research continues to build and refine infrastructure to improve speed, quality, and value of data analytics. We can do more. Expanding partnerships to use existing VA data strategies in designing a cooperative national data alliance would deliver necessary progress to research and public health.

Acknowledgments

The authors thank Jeff Roberts, MD, for his insight on the US Food and Drug Administration, its responsibilities, and the potential benefit of real world data to its missions.

The COVID-19 pandemic emphasized the need for rapid response research in health care. The robust enterprise approach used by the US Department of Veterans Affairs (VA), termed VA Research, is meeting these needs by using existing outstanding data resources and interdisciplinary collaborations.¹ In the first 7 months of 2021 alone, while many US health care systems struggled with limited data, VA Research published more than 300 unique and instrumental research papers addressing urgent questions about transmission, vaccination, therapeutics, and health impacts of COVID-19 on its high-risk population.¹ The ability to leverage the VA electronic health record (EHR) and Corporate Data Warehouse (CDW)—a fully established data system bringing together test results, prescriptions, and complete patient health records, readily accessible and updated daily—was substantial.

With more than 9 million veterans enrolled in care at 171 medical centers and 1113 outpatient facilities across the US and its territories, the CDW provides an unprecedented opportunity to examine outcomes in real time. This allowed research groups such as the VA St Louis Health Care System Research and Education Service to build a cohort of 181,280 veterans with diabetes and positive COVID-19 test results within a 6-month period in 2021 to study the incidence of new diagnoses of diabetes after COVID-19 infection.² Similarly, the Clinical Epidemiology Program (CEP) at VA White River Junction Health Care System built a cohort of 1,363,180 veterans who received at least 1 COVID-19 vaccine by March 7, 2021, to analyze coverage and effectiveness of those vaccines.³ This time-sensitive research was possible because the VA had the data and tools in place. Moreover, the the CEP quickly built an infrastructure to make its cohort and programming codes available to researchers in and outside the VA, resulting in additional significant research.⁴

The innovation and speed of COVID-19 vaccine development and distribution in the US were unprecedented. The rapid discovery and implementation of multiple preventives and therapeutics for COVID-19 could not have been possible without shared information within a competitive industry. VA studies added significantly to understanding the clinical performance of the messenger RNA (mRNA) COVID-19 vaccines, antivirals, and monoclonal treatments in a real-world setting. For example, a vaccine coverage study by VA Research illustrated how successful vaccination for COVID-19 at the VA has been in protecting a diverse community of patients from hospitalization and death, particularly the highly comorbid, racial and ethnic minorities, and other high-risk populations.³ The study demonstrated the power of the VA system to generate robust and compelling clinical endpoint effectiveness data across a broad range of high-risk groups.

This success is promising. However, the COVID-19 pandemic is not over, and the next could prove even more challenging. For example, through a recent partnership with the US Department of Defense (DoD), the VA was able to rapidly analyze the effectiveness of previous smallpox vaccination efforts in the military for preventing mpox infections.⁵ We should take this opportunity to think creatively about ways to improve our existing infrastructure based on what we have learned.

A Role for VA Research in Efficacy

The US Food and Drug Administration (FDA) Reauthorization Act of 2017 requires that manufacturers submit evidence establishing a product’s benefits (effectiveness) outweigh its risks (safety) before it can be promoted and distributed.⁶ As such, the FDA has been obligated by external stakeholders and Congress to be more explicit and transparent about benefit-risk profile supporting its decisions on licensure. This process led to requiring more phase 4 postmarketing observational studies for safety and effectiveness.⁷ Although the FDA postlicensure system remains vigilant toward safety, effectiveness information is limited due to insufficient reporting (with exceptions of manufacturer studies for new indications or to exhibit superior comparative effectiveness). The agency typically relies on a static set of efficacy data generated prelicensure with a dynamic and evolving set of safety data accrued postlicensure to support its assessment that benefits outweigh risks.

For example, operating in near real time, postauthorization safety monitoring systems, led by the Centers for Disease Control and Prevention and other federal systems, identified a safety signal for thrombosis following the Janssen COVID-19 vaccination. Distribution was quickly paused, the safety signal was investigated, the magnitude of the risk was characterized, new language describing the risk and providing guidance regarding clinical management was included in labeling, and distribution was resumed, all within a few weeks. This remarkable success demonstrated how timely the safety system can operate to evaluate risk.

In contrast, the duration and extent of protection against COVID-19 variants are largely limited to the assessment of immune biomarker surrogates. Such clinical effectiveness data are urgently needed for the FDA’s Center for Biologics Evaluation and Research and Center for Drug Evaluation and Research to make accurate benefit-risk assessments and continue to conclude the balance is favorable. As we prepare for the next pandemic, we must consider plans for monitoring postauthorization/postlicensure effectiveness as well as safety in real time. VA Research is ideally situated for this task.

Published studies on effectiveness at the VA serve as a prototype and could lead the way to initiating those preparations.^4,8-11 One of the striking features of the VA system that became apparent in the preparation of the mRNA vaccine study was the speed at which an enormous volume of COVID-19 testing data were produced. This enabled implementation of methodologically sound test-negative and case-control analysis. Analyses sufficiently powered to conclude mRNA vaccines were highly effective when used in real-world conditions among a diverse population from nearly every state and territory during a period in which multiple COVID-19 variants were already circulating.³ This is unique to the VA and would not be possible for any other US health care system. With planning, the VA system could produce product-specific, real-world evidence of effectiveness comparable to the timeliness and quality of the safety data currently produced to support regulatory benefit-risk assessments. For example, the VA conducted an effectiveness study of tixagevimab/cilgavimab for preventing COVID-19 during the initial Omicron surge, which is continually updated while Omicron circulates and repeatable for different subvariants.¹²

The FDA continues to collaborate with the VA on demonstration projects to evaluate the impact of available vaccines and treatment against COVID-19 variants. The VA has also initiated several large-scale sequencing programs for COVID-19 specimens that will support these efforts, including VA Science and Health Initiative to Combat Infectious and Emerging Life-Threatening Diseases (VA SHIELD), VA Sequencing for Research Clinical and Epidemiology (SeqFORCE), and VA Sequencing Collaborations United for Research and Epidemiology (SeqCURE).^13,14 Successful proof-of-concept studies using these data could provide a template for VA and other medical systems/databases to report effectiveness in near real time.

Interagency Collaboration

The potential advantages of federal agencies working with the VA to build an infrastructure capable of generating real-world evidence effectiveness analyses in near real time is not limited to needs that will arise in the next pandemic. For example, generating randomized, placebo-controlled, clinical trial endpoint data on the effectiveness of new variant vaccines will be difficult from a feasibility and ethical standpoint. Combining the VA’s robust virus sequencing program with preexisting mechanisms, such as expanded access studies (allowed under FDA Investigational New Drug regulations), researchers could enable a large-scale effective evaluation program of vaccination with variant or universal COVID-19 vaccines, using rapidly accruing effectiveness data.

The pandemic created opportunities to advance innovative approaches to medical product development. Some have advocated these innovative approaches should proceed together toward a seamless convergence between the domains of medical research and clinical care. A shift toward expecting, as a matter of routine, effectiveness data to be generated in near real time and made available for benefit-risk assessment would be a useful step in that direction.

Expanding and sharing analytical platforms, including methodology and programming codes, will allow increased access to rapidly refreshed real-world data. A common adaptive platform of complete and continuously updated data will also enable a wider community of researchers to create multiple investigatory groups simultaneously accessing fully de-identified data for concurrent observational studies. In turn, researchers need to have programming, study design, and methodology ready in an open-source platform. An efficient platform would also require the adoption of artificial intelligence, natural language processing, imaging processing, and quantum computing for validation and improved data quality.

COVID-19 has demonstrated the need for open science data synchronization with universal access for faster action and improved outcomes able to gain public confidence. OpenSafely (UK), a software platform for analysis of EHR data that is shared automatically and openly for scientific review and efficient reuse, created a cohort of about 23.4 million records for observational review of monoclonal COVID-19 treatments. To keep pace with the UK, Israel, and other nationalized systems, the US would benefit from duplicating this example of coordination between federal agencies and their data repositories. For example, combining data between the DoD, which captures active military health care data through TRICARE, and VA, which follows postmilitary discharge, would create datasets encompassing complete life spans. Additionally, expanding the National COVID Cohort Collaborative (N3C) program—one of the largest collections of clinical data related to COVID-19 symptoms and patient outcomes in the US—to include EHR data from DoD, VA, Medicare, and Test to Treat initiative partners would further expand research capabilities. This could be accomplished through a framework of anonymized, readily available, harmonized data. EHRs with synchronized datasets from every health care practitioner—independent pharmacies, primary care physicians, and hospitals—could all work to create a de-identified, comprehensive, continuously updated, near real-time dataset accessible to all federal researchers.

Conclusions

The VA has been lauded for its rapid, effective response to the current pandemic. The successful management and prescription of vaccines and treatment to the largely high-risk veteran population was possible because of the existing data framework within the VA. VA Research continues to build and refine infrastructure to improve speed, quality, and value of data analytics. We can do more. Expanding partnerships to use existing VA data strategies in designing a cooperative national data alliance would deliver necessary progress to research and public health.

Acknowledgments

The authors thank Jeff Roberts, MD, for his insight on the US Food and Drug Administration, its responsibilities, and the potential benefit of real world data to its missions.

The COVID-19 pandemic emphasized the need for rapid response research in health care. The robust enterprise approach used by the US Department of Veterans Affairs (VA), termed VA Research, is meeting these needs by using existing outstanding data resources and interdisciplinary collaborations.¹ In the first 7 months of 2021 alone, while many US health care systems struggled with limited data, VA Research published more than 300 unique and instrumental research papers addressing urgent questions about transmission, vaccination, therapeutics, and health impacts of COVID-19 on its high-risk population.¹ The ability to leverage the VA electronic health record (EHR) and Corporate Data Warehouse (CDW)—a fully established data system bringing together test results, prescriptions, and complete patient health records, readily accessible and updated daily—was substantial.

With more than 9 million veterans enrolled in care at 171 medical centers and 1113 outpatient facilities across the US and its territories, the CDW provides an unprecedented opportunity to examine outcomes in real time. This allowed research groups such as the VA St Louis Health Care System Research and Education Service to build a cohort of 181,280 veterans with diabetes and positive COVID-19 test results within a 6-month period in 2021 to study the incidence of new diagnoses of diabetes after COVID-19 infection.² Similarly, the Clinical Epidemiology Program (CEP) at VA White River Junction Health Care System built a cohort of 1,363,180 veterans who received at least 1 COVID-19 vaccine by March 7, 2021, to analyze coverage and effectiveness of those vaccines.³ This time-sensitive research was possible because the VA had the data and tools in place. Moreover, the the CEP quickly built an infrastructure to make its cohort and programming codes available to researchers in and outside the VA, resulting in additional significant research.⁴

The innovation and speed of COVID-19 vaccine development and distribution in the US were unprecedented. The rapid discovery and implementation of multiple preventives and therapeutics for COVID-19 could not have been possible without shared information within a competitive industry. VA studies added significantly to understanding the clinical performance of the messenger RNA (mRNA) COVID-19 vaccines, antivirals, and monoclonal treatments in a real-world setting. For example, a vaccine coverage study by VA Research illustrated how successful vaccination for COVID-19 at the VA has been in protecting a diverse community of patients from hospitalization and death, particularly the highly comorbid, racial and ethnic minorities, and other high-risk populations.³ The study demonstrated the power of the VA system to generate robust and compelling clinical endpoint effectiveness data across a broad range of high-risk groups.

This success is promising. However, the COVID-19 pandemic is not over, and the next could prove even more challenging. For example, through a recent partnership with the US Department of Defense (DoD), the VA was able to rapidly analyze the effectiveness of previous smallpox vaccination efforts in the military for preventing mpox infections.⁵ We should take this opportunity to think creatively about ways to improve our existing infrastructure based on what we have learned.

A Role for VA Research in Efficacy

The US Food and Drug Administration (FDA) Reauthorization Act of 2017 requires that manufacturers submit evidence establishing a product’s benefits (effectiveness) outweigh its risks (safety) before it can be promoted and distributed.⁶ As such, the FDA has been obligated by external stakeholders and Congress to be more explicit and transparent about benefit-risk profile supporting its decisions on licensure. This process led to requiring more phase 4 postmarketing observational studies for safety and effectiveness.⁷ Although the FDA postlicensure system remains vigilant toward safety, effectiveness information is limited due to insufficient reporting (with exceptions of manufacturer studies for new indications or to exhibit superior comparative effectiveness). The agency typically relies on a static set of efficacy data generated prelicensure with a dynamic and evolving set of safety data accrued postlicensure to support its assessment that benefits outweigh risks.

For example, operating in near real time, postauthorization safety monitoring systems, led by the Centers for Disease Control and Prevention and other federal systems, identified a safety signal for thrombosis following the Janssen COVID-19 vaccination. Distribution was quickly paused, the safety signal was investigated, the magnitude of the risk was characterized, new language describing the risk and providing guidance regarding clinical management was included in labeling, and distribution was resumed, all within a few weeks. This remarkable success demonstrated how timely the safety system can operate to evaluate risk.

In contrast, the duration and extent of protection against COVID-19 variants are largely limited to the assessment of immune biomarker surrogates. Such clinical effectiveness data are urgently needed for the FDA’s Center for Biologics Evaluation and Research and Center for Drug Evaluation and Research to make accurate benefit-risk assessments and continue to conclude the balance is favorable. As we prepare for the next pandemic, we must consider plans for monitoring postauthorization/postlicensure effectiveness as well as safety in real time. VA Research is ideally situated for this task.

Published studies on effectiveness at the VA serve as a prototype and could lead the way to initiating those preparations.^4,8-11 One of the striking features of the VA system that became apparent in the preparation of the mRNA vaccine study was the speed at which an enormous volume of COVID-19 testing data were produced. This enabled implementation of methodologically sound test-negative and case-control analysis. Analyses sufficiently powered to conclude mRNA vaccines were highly effective when used in real-world conditions among a diverse population from nearly every state and territory during a period in which multiple COVID-19 variants were already circulating.³ This is unique to the VA and would not be possible for any other US health care system. With planning, the VA system could produce product-specific, real-world evidence of effectiveness comparable to the timeliness and quality of the safety data currently produced to support regulatory benefit-risk assessments. For example, the VA conducted an effectiveness study of tixagevimab/cilgavimab for preventing COVID-19 during the initial Omicron surge, which is continually updated while Omicron circulates and repeatable for different subvariants.¹²

The FDA continues to collaborate with the VA on demonstration projects to evaluate the impact of available vaccines and treatment against COVID-19 variants. The VA has also initiated several large-scale sequencing programs for COVID-19 specimens that will support these efforts, including VA Science and Health Initiative to Combat Infectious and Emerging Life-Threatening Diseases (VA SHIELD), VA Sequencing for Research Clinical and Epidemiology (SeqFORCE), and VA Sequencing Collaborations United for Research and Epidemiology (SeqCURE).^13,14 Successful proof-of-concept studies using these data could provide a template for VA and other medical systems/databases to report effectiveness in near real time.

Interagency Collaboration

The potential advantages of federal agencies working with the VA to build an infrastructure capable of generating real-world evidence effectiveness analyses in near real time is not limited to needs that will arise in the next pandemic. For example, generating randomized, placebo-controlled, clinical trial endpoint data on the effectiveness of new variant vaccines will be difficult from a feasibility and ethical standpoint. Combining the VA’s robust virus sequencing program with preexisting mechanisms, such as expanded access studies (allowed under FDA Investigational New Drug regulations), researchers could enable a large-scale effective evaluation program of vaccination with variant or universal COVID-19 vaccines, using rapidly accruing effectiveness data.

The pandemic created opportunities to advance innovative approaches to medical product development. Some have advocated these innovative approaches should proceed together toward a seamless convergence between the domains of medical research and clinical care. A shift toward expecting, as a matter of routine, effectiveness data to be generated in near real time and made available for benefit-risk assessment would be a useful step in that direction.

Expanding and sharing analytical platforms, including methodology and programming codes, will allow increased access to rapidly refreshed real-world data. A common adaptive platform of complete and continuously updated data will also enable a wider community of researchers to create multiple investigatory groups simultaneously accessing fully de-identified data for concurrent observational studies. In turn, researchers need to have programming, study design, and methodology ready in an open-source platform. An efficient platform would also require the adoption of artificial intelligence, natural language processing, imaging processing, and quantum computing for validation and improved data quality.

COVID-19 has demonstrated the need for open science data synchronization with universal access for faster action and improved outcomes able to gain public confidence. OpenSafely (UK), a software platform for analysis of EHR data that is shared automatically and openly for scientific review and efficient reuse, created a cohort of about 23.4 million records for observational review of monoclonal COVID-19 treatments. To keep pace with the UK, Israel, and other nationalized systems, the US would benefit from duplicating this example of coordination between federal agencies and their data repositories. For example, combining data between the DoD, which captures active military health care data through TRICARE, and VA, which follows postmilitary discharge, would create datasets encompassing complete life spans. Additionally, expanding the National COVID Cohort Collaborative (N3C) program—one of the largest collections of clinical data related to COVID-19 symptoms and patient outcomes in the US—to include EHR data from DoD, VA, Medicare, and Test to Treat initiative partners would further expand research capabilities. This could be accomplished through a framework of anonymized, readily available, harmonized data. EHRs with synchronized datasets from every health care practitioner—independent pharmacies, primary care physicians, and hospitals—could all work to create a de-identified, comprehensive, continuously updated, near real-time dataset accessible to all federal researchers.

Conclusions

The VA has been lauded for its rapid, effective response to the current pandemic. The successful management and prescription of vaccines and treatment to the largely high-risk veteran population was possible because of the existing data framework within the VA. VA Research continues to build and refine infrastructure to improve speed, quality, and value of data analytics. We can do more. Expanding partnerships to use existing VA data strategies in designing a cooperative national data alliance would deliver necessary progress to research and public health.

Acknowledgments

The authors thank Jeff Roberts, MD, for his insight on the US Food and Drug Administration, its responsibilities, and the potential benefit of real world data to its missions.

The Million Veteran Program (MVP) was launched in 2011 by the US Department of Veterans Affairs (VA) to enroll at least 1 million veterans in a longitudinal cohort to better understand how genes, lifestyle, military experience, and environmental exposures interact to influence health and illness and ultimately enable precision health care. The MVP has established a national, centralized infrastructure for recruitment and enrollment, biospecimen and data collection and storage, data generation and curation, and secure data access. When the COVID-19 pandemic hit in 2020, the MVP was leveraged to support research utilizing the following key infrastructure components: (1) MVP recruitment and enrollment platform to provide support for COVID-19 vaccine and treatment trials and to collect COVID-19 data from MVP participants; (2) using MVP Phenomics for COVID-19 research data cleaning and curation, assisting with the development of a VA Severity Index for COVID-19, and forming 6 scientific working groups to coordinate COVID-19 research questions; and (3) the VA/MVP and US Department of Energy (DOE) partnership to assist in responding to COVID-19 research questions identified by the US Food and Drug Administration (FDA). This article describes these infrastructure components in more detail and highlights key findings from the MVP COVID-19 research efforts.

MVP Infrastructure

The Veterans Health Administration (VHA) Office of Research and Development (ORD) oversaw efforts to develop the VA Coronavirus Research Volunteer List (the COVID-19 registry). To support the registry, the MVP leveraged its infrastructure to facilitate a rapid response. The MVP is designed as a full-service and centralized recruitment and enrollment platform. This includes MVP office oversight; MVP coordinating centers that manage the centralized platform; an information center that handles inbound and outbound calls; an informatics system built for recruitment and enrollment monitoring and tracking; and a network of more than 70 participating MVP sites with dedicated staff to conduct recruitment and enrollment activities. The MVP used its informatics infrastructure to support secure data storage for the registry volunteer information. MVP coordinating center staff worked with the COVID-19 registry to invite > 125,000 MVP participants from approximately 20 MVP sites. Additionally, MVP information center staff made > 4000 calls to prospective registry volunteers. This work resulted in 1300 volunteers agreeing to be contacted by COVID-19 vaccine clinical trial study teams (including Moderna, Janssen, AstraZeneca, and Novavax). About 20 MVP site staff (spanning 14 MVP sites) also were deployed to support COVID-19 work for clinical care capabilities or vaccine trials.

New Data Collection

The MVP protocol was approved by the VA Central Institutional Review Board (IRB) in 2011. As part of initial enrollment in MVP, participants consented to recontact for additional self-report information along with access to their electronic health record (EHR). This allows for the linkage of EHR and survey response data, thus providing a comprehensive understanding of health history before and after a self-reported COVID-19 diagnosis. Between May 2020 and September 2021, the MVP COVID-19 survey was distributed to existing MVP participants via mail, telephone, and email with the ability to complete the survey by paper and pencil or through the MVP online system. Dissemination of the survey was approved by the VA Central IRB in 2020, with nearly 730,000 eligible MVP participants contacted. As of June 2022, 255,737 MVP participants (35% of the eligible cohort) had completed the survey; 86% completed a paper survey while 14% completed it online. Respondents were primarily older (≥ 65 years); 90% were male; close to 7% reported Hispanic ethnicity, and 11% reported Black race.

Findings from this survey provide insight into pandemic behaviors not consistently captured in EHRs, such as psychosocial aspects, including social and emotional support, loss of tangible and intangible resources, as well as COVID-19–related behaviors, such as social distancing and self-protective practices.¹ MVP COVID-19 survey data combined with veteran EHRs, responses to other MVP surveys, and genetic data enable MVP researchers to better understand epidemiological, clinical, and psychosocial aspects of the disease. Future COVID-19 studies may use self-reported survey responses to enrich understanding about the effects of the disease on a veteran’s daily life, and possibly validate existing EHR COVID-19 diagnoses and hospitalization findings. This comprehensive data resource provides a unique opportunity to identify new targets for disease prevention, treatment, and management with an emphasis on individual variability in genes, environment, and lifestyle.

COVID-19 Research

In early 2020, the burden of COVID-19 on the US was unprecedented, and little was known about risk factors for severe COVID-19 and deaths. The MVP Phenomics team quickly responded with a large-scale phenome-wide association study (PheWAS) of > 1800 phenotypes (physical and biochemical traits) and COVID-19 progression. Its goal was to characterize risk factors and outcomes associated with COVID-19 disease progression.² Data curation and assembly occurred rapidly through integrated efforts led by MVP and VA COVID-19 initiatives. The MVP utilized its phenomics core resource to understand the progression of COVID-19 defined by SARS-CoV-2 infection, hospitalization, intensive care unit admission, and 30-day mortality using VA EHR data.

To broaden disease progression data curation and fit the specific needs of the VA, we operationalized and validated the World Health Organization clinical severity scale and used VA EHR data to create the VA Severity Index for COVID-19 (VASIC).³ The VASIC category is now part of the MVP core data repository, where volumes of data from multiple activities are integrated through an automated process to create monthly research-ready data cubes. These activities include extensive data curation, mapping, phenotyping, and adjudication that are performed to curate oxygen supplementation status and other procedures related to treatment that are processed and understood in real time. The data cubes were provisioned to MVP COVID-19 researchers. In addition, the VASIC scale variable is now integrated within the larger VA system for all researchers to use as part of its wider COVID-19 initiative. The VA Centralized Interactive Phenomics Resource (CIPHER) phenomics library now hosts the details of VASIC, codes, metadata, and related COVID-19 data products for all VA communities. In partnership with CIPHER and other internal and external COVID-19 initiatives, the MVP continues to play an integral part for the VA and beyond in the development of a phenomics algorithm for long COVID, or post-acute COVID-19 syndrome (PACS).

Host Genetics in COVID-19

As the SARS-CoV-2 virus continued to spread globally, it became clear that the symptoms and severity of infection experienced by patients varied across a broad spectrum, from being asymptomatic carriers to experiencing severe symptoms in 1 or more organ systems in the body, resulting in death. This variability suggested that host genetics and other host factors may play a role in determining the severity of COVID-19 infection. The MVP dataset, with genetic and health information on > 600,000 MVP participants, provided an ideal dataset to explore host contributions to COVID-19.

In late spring 2020, the MVP executive committee issued a call to the MVP research community to propose study aims around the COVID-19 pandemic that could leverage the phenotypic and genetic data and resources. The MVP quickly formed 6 rapid-response scientific working groups. Their mission was to cultivate collaboration and inclusivity and to coordinate COVID-19 research questions. A steering committee composed of the MVP executive committee, staff from computational environments, working group cochairs, and an administrator, who was responsible for daily oversight of the working groups. In addition, the ORD COVID-19 steering committee reviewed and approved research activities to ensure scientific rigor, as well as alignment with overall ongoing research activities.

table.png

The MVP COVID-19 working groups included dozens of researchers who used MVP data to identify disease mechanisms; understand the impact of host genetics on susceptibility, morbidity, and mortality; and identify potential targets for treatments and therapies. The working groups were further supported by MVP analysts to work cross-functionally on genomics, phenomics, statistical genetics, and PheWAS. Each working group chair was responsible for prioritizing concepts and moving them forward in coordination with the MVP and ORD COVID-19 steering committees. An overview of the MVP COVID-19 working groups follows (Table).^4-9

Druggable genome. This working group researched drug-repurposing opportunities to prevent severe COVID-19, defined as hospitalization with oxygen therapy (high flow), intubation, mechanical ventilation, vasopressors, dialysis, or death from COVID-19; and prevent complications in patients hospitalized by COVID-19.

Pharmacogenomics. This working group focused on 2 main aims: the impact of apolipoprotein L1 risk variants on acute kidney injury (AKI) and death in Black veterans with COVID-19; and pharmacogenetic analysis of remdesivir-induced liver chemistry abnormalities.

Disease mechanisms. Understanding the underlying pathways and mechanisms behind COVID-19 has been a difficult but important challenge overall in the scientific community. This working group investigated specific genetic markers and effects on COVID-19, including polygenic predisposition to venous thromboembolism associated with increased COVID-19 susceptibility; renal comorbidities and new AKI and unfavorable outcomes among COVID-19–positive sickle cell trait carriers; and mucin 5B, oligomeric mucus/gel-forming gene polymorphism, and protective effects in COVID-19 infection.

Genomics for risk prediction, polygenic risk scores, and mendelian randomization. Risk prediction for COVID-19 has been widely studied mostly aiming at comorbidities and preexisting conditions. The MVP cohort provided a unique opportunity to understand how genetic information can enhance our understanding of COVID-19 risk. This working group focused on: (1) ABO blood group typing and the protective effects of the O blood group on COVID-19 infection; (2) polygenic risk scores and COVID-19 outcomes; (3) human leukocyte antigen typing and COVID-19 outcomes; and (4) a transcriptome-wide association study of COVID-19–positive MVP participants.

Genome-Wide Association Study (GWAS) and Downstream Analysis. This working group performed GWAS of the main COVID-19 outcomes. Results from GWAS unveiled new genetic loci to suggest further investigation on these candidate genes. The results were used by other MVP COVID-19 working groups for their activities. The results also contributed to external collaborations, such as the COVID-19 Host Genetics Initiative.

COVID-19–Related PheWAS. This working group focused on understanding the potential clinical significance of genetic variants associated with susceptibility to, or outcomes of, COVID-19 infection. They worked to identify traits that share genetic variants associated with severe COVID-19 from the Host Genetics Initiative. The group also studied the phenotypic consequences of acquired mosaic chromosomal alterations with early data linking to COVID-19 susceptibility.

COVID-19 Research Partnerships

In 2016, the VA and DOE formed an interagency partnership known as Computational Health Analytics for Medical Precision to Improve Outcomes Now (CHAMPION) to demonstrate the power of combining the VA EHR system, MVP genetic data, and clinical research expertise with DOE high-performance computing infrastructure and artificial intelligence expertise. The VA EHR captures longitudinal care information on veterans with records that go back decades. Furthermore, the VA covers the costs of medications and provides a variety of services through the Veterans Benefits Administration. As a result, VA data include medications used by patients before, during, and after COVID-19. Similarly, the VA has comprehensive vital records, whereas other large health systems do not capture events such as death after patients leave the hospital.

The DOE Oak Ridge National Laboratory (ORNL) in Tennessee securely maintains this rich database for the VA. The ORNL Summit supercomputer can complete trillions of calculations per second to provide critical and timely analyses, applying the most advanced and powerful artificial intelligence methods, which would not be possible in more conventional research settings. CHAMPION taught the VA and DOE how to bring their disparate research cultures together for innovative collaborative investigation. Moreover, this collaboration produced a cadre of VA and DOE scientists familiar with VA patient data and experienced in conducting joint research successfully and integrating omics data with clinical data for a better mechanistic understanding. Because of this preexisting collaboration between the VA and DOE, interagency teams were prepared at the start of the COVID-19 pandemic.^10-15

During the pandemic, the FDA and VA conducted research together. One joint study found that the bradykinin storm is likely to play a role in many COVID-19 symptoms. Using VA data, researchers compared COVID-19 testing patterns, positive test results, and 30-day mortality rates by race and ethnicity among VA patients.^10,11These findings demonstrated the higher burden COVID-19 placed on Black and Hispanic communities, not fully explained by underlying health conditions, access to medical care, or geographic locale.¹¹

Other recently completed studies have developed and validated short-term mortality indices in individuals with COVID-19 based on their preexisting conditions, assessed the generalizability of VA COVID-19 experiences to the US population, and evaluated the effectiveness of hydroxychloroquine with and without azithromycin in VA patients with COVID-19.^12,15 A recent study demonstrated the benefit of prophylactic anticoagulation at initial hospitalization.¹⁴

The VA also provided the FDA with daily reports on aggregate VA COVID-19 cases and their distribution across the VA system, demographics of VA patients with COVID-19, and analyses of predictive models for positive test results and death. The VA regularly sent the FDA aggregated data showing patterns of medication use and retrospective analyses of the effectiveness of certain medications (including remdesivir and some antithrombotic agents). The FDA used these data along with other data to understand the scope of the pandemic and to predict drug shortages or needs for additional medical equipment, including ventilators. This information was critical at the start of the pandemic.

Limitations

For the most part, MVP infrastructure and partnerships were efficiently leveraged to significantly advance our understanding of the biological basis of COVID-19 and to develop treatments and vaccines. However, there were a few limitations that may have slowed timely and optimal outcomes. An issue not limited to the MVP or VA was the continual evolution of the pandemic and its response. This included evolving definitions of disease, symptomatology, testing, vaccines, and public health recommendations. Keeping pace with the emerging knowledge from these domains was a struggle for the entire scientific community. A more discrete limitation was the number of participants in the MVP with positive COVID-19 test results and positive symptoms; however, this was mitigated by partnering with other groups like the COVID-19 Host Genetics Initiative to increase study participant numbers. Finally, there were logistical and regulatory challenges associated with coordination of national clinical trial recruitment across a VA system with > 100 discrete hospitals.

Conclusions

Having a centralized infrastructure for recruitment and enrollment, including a national research volunteer registry, information center, research staff, and coordinating centers, can allow for expedited enrollment in vaccine and treatment trials in the face of future public health emergencies. VA assets, including its rich EHR and MVP, the world’s largest genomic cohort, have contributed to improving our understanding and management of COVID-19. MVP’s ready-to-respond research infrastructure embedded within the country’s largest national health care system allows for both the facilitation of the research work and applications of the research findings into practice. Findings from the MVP COVID-19 working groups have yielded compelling results, particularly around genetic variants among various racial and ethnic groups. Looking ahead, the VA and DOE are launching a new joint project on long COVID that will include developing a gold-standard definition for long COVID. The ORD has established a Partnered Research Program to facilitate collaborations with industry to speed up clinical trials, and the MVP will continue to contribute toward expanding scientific knowledge to improve the management of COVID-19.

The Million Veteran Program (MVP) was launched in 2011 by the US Department of Veterans Affairs (VA) to enroll at least 1 million veterans in a longitudinal cohort to better understand how genes, lifestyle, military experience, and environmental exposures interact to influence health and illness and ultimately enable precision health care. The MVP has established a national, centralized infrastructure for recruitment and enrollment, biospecimen and data collection and storage, data generation and curation, and secure data access. When the COVID-19 pandemic hit in 2020, the MVP was leveraged to support research utilizing the following key infrastructure components: (1) MVP recruitment and enrollment platform to provide support for COVID-19 vaccine and treatment trials and to collect COVID-19 data from MVP participants; (2) using MVP Phenomics for COVID-19 research data cleaning and curation, assisting with the development of a VA Severity Index for COVID-19, and forming 6 scientific working groups to coordinate COVID-19 research questions; and (3) the VA/MVP and US Department of Energy (DOE) partnership to assist in responding to COVID-19 research questions identified by the US Food and Drug Administration (FDA). This article describes these infrastructure components in more detail and highlights key findings from the MVP COVID-19 research efforts.

MVP Infrastructure

The Veterans Health Administration (VHA) Office of Research and Development (ORD) oversaw efforts to develop the VA Coronavirus Research Volunteer List (the COVID-19 registry). To support the registry, the MVP leveraged its infrastructure to facilitate a rapid response. The MVP is designed as a full-service and centralized recruitment and enrollment platform. This includes MVP office oversight; MVP coordinating centers that manage the centralized platform; an information center that handles inbound and outbound calls; an informatics system built for recruitment and enrollment monitoring and tracking; and a network of more than 70 participating MVP sites with dedicated staff to conduct recruitment and enrollment activities. The MVP used its informatics infrastructure to support secure data storage for the registry volunteer information. MVP coordinating center staff worked with the COVID-19 registry to invite > 125,000 MVP participants from approximately 20 MVP sites. Additionally, MVP information center staff made > 4000 calls to prospective registry volunteers. This work resulted in 1300 volunteers agreeing to be contacted by COVID-19 vaccine clinical trial study teams (including Moderna, Janssen, AstraZeneca, and Novavax). About 20 MVP site staff (spanning 14 MVP sites) also were deployed to support COVID-19 work for clinical care capabilities or vaccine trials.

New Data Collection

The MVP protocol was approved by the VA Central Institutional Review Board (IRB) in 2011. As part of initial enrollment in MVP, participants consented to recontact for additional self-report information along with access to their electronic health record (EHR). This allows for the linkage of EHR and survey response data, thus providing a comprehensive understanding of health history before and after a self-reported COVID-19 diagnosis. Between May 2020 and September 2021, the MVP COVID-19 survey was distributed to existing MVP participants via mail, telephone, and email with the ability to complete the survey by paper and pencil or through the MVP online system. Dissemination of the survey was approved by the VA Central IRB in 2020, with nearly 730,000 eligible MVP participants contacted. As of June 2022, 255,737 MVP participants (35% of the eligible cohort) had completed the survey; 86% completed a paper survey while 14% completed it online. Respondents were primarily older (≥ 65 years); 90% were male; close to 7% reported Hispanic ethnicity, and 11% reported Black race.

Findings from this survey provide insight into pandemic behaviors not consistently captured in EHRs, such as psychosocial aspects, including social and emotional support, loss of tangible and intangible resources, as well as COVID-19–related behaviors, such as social distancing and self-protective practices.¹ MVP COVID-19 survey data combined with veteran EHRs, responses to other MVP surveys, and genetic data enable MVP researchers to better understand epidemiological, clinical, and psychosocial aspects of the disease. Future COVID-19 studies may use self-reported survey responses to enrich understanding about the effects of the disease on a veteran’s daily life, and possibly validate existing EHR COVID-19 diagnoses and hospitalization findings. This comprehensive data resource provides a unique opportunity to identify new targets for disease prevention, treatment, and management with an emphasis on individual variability in genes, environment, and lifestyle.

COVID-19 Research

In early 2020, the burden of COVID-19 on the US was unprecedented, and little was known about risk factors for severe COVID-19 and deaths. The MVP Phenomics team quickly responded with a large-scale phenome-wide association study (PheWAS) of > 1800 phenotypes (physical and biochemical traits) and COVID-19 progression. Its goal was to characterize risk factors and outcomes associated with COVID-19 disease progression.² Data curation and assembly occurred rapidly through integrated efforts led by MVP and VA COVID-19 initiatives. The MVP utilized its phenomics core resource to understand the progression of COVID-19 defined by SARS-CoV-2 infection, hospitalization, intensive care unit admission, and 30-day mortality using VA EHR data.

To broaden disease progression data curation and fit the specific needs of the VA, we operationalized and validated the World Health Organization clinical severity scale and used VA EHR data to create the VA Severity Index for COVID-19 (VASIC).³ The VASIC category is now part of the MVP core data repository, where volumes of data from multiple activities are integrated through an automated process to create monthly research-ready data cubes. These activities include extensive data curation, mapping, phenotyping, and adjudication that are performed to curate oxygen supplementation status and other procedures related to treatment that are processed and understood in real time. The data cubes were provisioned to MVP COVID-19 researchers. In addition, the VASIC scale variable is now integrated within the larger VA system for all researchers to use as part of its wider COVID-19 initiative. The VA Centralized Interactive Phenomics Resource (CIPHER) phenomics library now hosts the details of VASIC, codes, metadata, and related COVID-19 data products for all VA communities. In partnership with CIPHER and other internal and external COVID-19 initiatives, the MVP continues to play an integral part for the VA and beyond in the development of a phenomics algorithm for long COVID, or post-acute COVID-19 syndrome (PACS).

Host Genetics in COVID-19

As the SARS-CoV-2 virus continued to spread globally, it became clear that the symptoms and severity of infection experienced by patients varied across a broad spectrum, from being asymptomatic carriers to experiencing severe symptoms in 1 or more organ systems in the body, resulting in death. This variability suggested that host genetics and other host factors may play a role in determining the severity of COVID-19 infection. The MVP dataset, with genetic and health information on > 600,000 MVP participants, provided an ideal dataset to explore host contributions to COVID-19.

In late spring 2020, the MVP executive committee issued a call to the MVP research community to propose study aims around the COVID-19 pandemic that could leverage the phenotypic and genetic data and resources. The MVP quickly formed 6 rapid-response scientific working groups. Their mission was to cultivate collaboration and inclusivity and to coordinate COVID-19 research questions. A steering committee composed of the MVP executive committee, staff from computational environments, working group cochairs, and an administrator, who was responsible for daily oversight of the working groups. In addition, the ORD COVID-19 steering committee reviewed and approved research activities to ensure scientific rigor, as well as alignment with overall ongoing research activities.

table.png

The MVP COVID-19 working groups included dozens of researchers who used MVP data to identify disease mechanisms; understand the impact of host genetics on susceptibility, morbidity, and mortality; and identify potential targets for treatments and therapies. The working groups were further supported by MVP analysts to work cross-functionally on genomics, phenomics, statistical genetics, and PheWAS. Each working group chair was responsible for prioritizing concepts and moving them forward in coordination with the MVP and ORD COVID-19 steering committees. An overview of the MVP COVID-19 working groups follows (Table).^4-9

Druggable genome. This working group researched drug-repurposing opportunities to prevent severe COVID-19, defined as hospitalization with oxygen therapy (high flow), intubation, mechanical ventilation, vasopressors, dialysis, or death from COVID-19; and prevent complications in patients hospitalized by COVID-19.

Pharmacogenomics. This working group focused on 2 main aims: the impact of apolipoprotein L1 risk variants on acute kidney injury (AKI) and death in Black veterans with COVID-19; and pharmacogenetic analysis of remdesivir-induced liver chemistry abnormalities.

Disease mechanisms. Understanding the underlying pathways and mechanisms behind COVID-19 has been a difficult but important challenge overall in the scientific community. This working group investigated specific genetic markers and effects on COVID-19, including polygenic predisposition to venous thromboembolism associated with increased COVID-19 susceptibility; renal comorbidities and new AKI and unfavorable outcomes among COVID-19–positive sickle cell trait carriers; and mucin 5B, oligomeric mucus/gel-forming gene polymorphism, and protective effects in COVID-19 infection.

Genomics for risk prediction, polygenic risk scores, and mendelian randomization. Risk prediction for COVID-19 has been widely studied mostly aiming at comorbidities and preexisting conditions. The MVP cohort provided a unique opportunity to understand how genetic information can enhance our understanding of COVID-19 risk. This working group focused on: (1) ABO blood group typing and the protective effects of the O blood group on COVID-19 infection; (2) polygenic risk scores and COVID-19 outcomes; (3) human leukocyte antigen typing and COVID-19 outcomes; and (4) a transcriptome-wide association study of COVID-19–positive MVP participants.

Genome-Wide Association Study (GWAS) and Downstream Analysis. This working group performed GWAS of the main COVID-19 outcomes. Results from GWAS unveiled new genetic loci to suggest further investigation on these candidate genes. The results were used by other MVP COVID-19 working groups for their activities. The results also contributed to external collaborations, such as the COVID-19 Host Genetics Initiative.

COVID-19–Related PheWAS. This working group focused on understanding the potential clinical significance of genetic variants associated with susceptibility to, or outcomes of, COVID-19 infection. They worked to identify traits that share genetic variants associated with severe COVID-19 from the Host Genetics Initiative. The group also studied the phenotypic consequences of acquired mosaic chromosomal alterations with early data linking to COVID-19 susceptibility.

COVID-19 Research Partnerships

In 2016, the VA and DOE formed an interagency partnership known as Computational Health Analytics for Medical Precision to Improve Outcomes Now (CHAMPION) to demonstrate the power of combining the VA EHR system, MVP genetic data, and clinical research expertise with DOE high-performance computing infrastructure and artificial intelligence expertise. The VA EHR captures longitudinal care information on veterans with records that go back decades. Furthermore, the VA covers the costs of medications and provides a variety of services through the Veterans Benefits Administration. As a result, VA data include medications used by patients before, during, and after COVID-19. Similarly, the VA has comprehensive vital records, whereas other large health systems do not capture events such as death after patients leave the hospital.

The DOE Oak Ridge National Laboratory (ORNL) in Tennessee securely maintains this rich database for the VA. The ORNL Summit supercomputer can complete trillions of calculations per second to provide critical and timely analyses, applying the most advanced and powerful artificial intelligence methods, which would not be possible in more conventional research settings. CHAMPION taught the VA and DOE how to bring their disparate research cultures together for innovative collaborative investigation. Moreover, this collaboration produced a cadre of VA and DOE scientists familiar with VA patient data and experienced in conducting joint research successfully and integrating omics data with clinical data for a better mechanistic understanding. Because of this preexisting collaboration between the VA and DOE, interagency teams were prepared at the start of the COVID-19 pandemic.^10-15

During the pandemic, the FDA and VA conducted research together. One joint study found that the bradykinin storm is likely to play a role in many COVID-19 symptoms. Using VA data, researchers compared COVID-19 testing patterns, positive test results, and 30-day mortality rates by race and ethnicity among VA patients.^10,11These findings demonstrated the higher burden COVID-19 placed on Black and Hispanic communities, not fully explained by underlying health conditions, access to medical care, or geographic locale.¹¹

Other recently completed studies have developed and validated short-term mortality indices in individuals with COVID-19 based on their preexisting conditions, assessed the generalizability of VA COVID-19 experiences to the US population, and evaluated the effectiveness of hydroxychloroquine with and without azithromycin in VA patients with COVID-19.^12,15 A recent study demonstrated the benefit of prophylactic anticoagulation at initial hospitalization.¹⁴

The VA also provided the FDA with daily reports on aggregate VA COVID-19 cases and their distribution across the VA system, demographics of VA patients with COVID-19, and analyses of predictive models for positive test results and death. The VA regularly sent the FDA aggregated data showing patterns of medication use and retrospective analyses of the effectiveness of certain medications (including remdesivir and some antithrombotic agents). The FDA used these data along with other data to understand the scope of the pandemic and to predict drug shortages or needs for additional medical equipment, including ventilators. This information was critical at the start of the pandemic.

Limitations

For the most part, MVP infrastructure and partnerships were efficiently leveraged to significantly advance our understanding of the biological basis of COVID-19 and to develop treatments and vaccines. However, there were a few limitations that may have slowed timely and optimal outcomes. An issue not limited to the MVP or VA was the continual evolution of the pandemic and its response. This included evolving definitions of disease, symptomatology, testing, vaccines, and public health recommendations. Keeping pace with the emerging knowledge from these domains was a struggle for the entire scientific community. A more discrete limitation was the number of participants in the MVP with positive COVID-19 test results and positive symptoms; however, this was mitigated by partnering with other groups like the COVID-19 Host Genetics Initiative to increase study participant numbers. Finally, there were logistical and regulatory challenges associated with coordination of national clinical trial recruitment across a VA system with > 100 discrete hospitals.

Conclusions

Having a centralized infrastructure for recruitment and enrollment, including a national research volunteer registry, information center, research staff, and coordinating centers, can allow for expedited enrollment in vaccine and treatment trials in the face of future public health emergencies. VA assets, including its rich EHR and MVP, the world’s largest genomic cohort, have contributed to improving our understanding and management of COVID-19. MVP’s ready-to-respond research infrastructure embedded within the country’s largest national health care system allows for both the facilitation of the research work and applications of the research findings into practice. Findings from the MVP COVID-19 working groups have yielded compelling results, particularly around genetic variants among various racial and ethnic groups. Looking ahead, the VA and DOE are launching a new joint project on long COVID that will include developing a gold-standard definition for long COVID. The ORD has established a Partnered Research Program to facilitate collaborations with industry to speed up clinical trials, and the MVP will continue to contribute toward expanding scientific knowledge to improve the management of COVID-19.

The Million Veteran Program (MVP) was launched in 2011 by the US Department of Veterans Affairs (VA) to enroll at least 1 million veterans in a longitudinal cohort to better understand how genes, lifestyle, military experience, and environmental exposures interact to influence health and illness and ultimately enable precision health care. The MVP has established a national, centralized infrastructure for recruitment and enrollment, biospecimen and data collection and storage, data generation and curation, and secure data access. When the COVID-19 pandemic hit in 2020, the MVP was leveraged to support research utilizing the following key infrastructure components: (1) MVP recruitment and enrollment platform to provide support for COVID-19 vaccine and treatment trials and to collect COVID-19 data from MVP participants; (2) using MVP Phenomics for COVID-19 research data cleaning and curation, assisting with the development of a VA Severity Index for COVID-19, and forming 6 scientific working groups to coordinate COVID-19 research questions; and (3) the VA/MVP and US Department of Energy (DOE) partnership to assist in responding to COVID-19 research questions identified by the US Food and Drug Administration (FDA). This article describes these infrastructure components in more detail and highlights key findings from the MVP COVID-19 research efforts.

MVP Infrastructure

The Veterans Health Administration (VHA) Office of Research and Development (ORD) oversaw efforts to develop the VA Coronavirus Research Volunteer List (the COVID-19 registry). To support the registry, the MVP leveraged its infrastructure to facilitate a rapid response. The MVP is designed as a full-service and centralized recruitment and enrollment platform. This includes MVP office oversight; MVP coordinating centers that manage the centralized platform; an information center that handles inbound and outbound calls; an informatics system built for recruitment and enrollment monitoring and tracking; and a network of more than 70 participating MVP sites with dedicated staff to conduct recruitment and enrollment activities. The MVP used its informatics infrastructure to support secure data storage for the registry volunteer information. MVP coordinating center staff worked with the COVID-19 registry to invite > 125,000 MVP participants from approximately 20 MVP sites. Additionally, MVP information center staff made > 4000 calls to prospective registry volunteers. This work resulted in 1300 volunteers agreeing to be contacted by COVID-19 vaccine clinical trial study teams (including Moderna, Janssen, AstraZeneca, and Novavax). About 20 MVP site staff (spanning 14 MVP sites) also were deployed to support COVID-19 work for clinical care capabilities or vaccine trials.

New Data Collection

The MVP protocol was approved by the VA Central Institutional Review Board (IRB) in 2011. As part of initial enrollment in MVP, participants consented to recontact for additional self-report information along with access to their electronic health record (EHR). This allows for the linkage of EHR and survey response data, thus providing a comprehensive understanding of health history before and after a self-reported COVID-19 diagnosis. Between May 2020 and September 2021, the MVP COVID-19 survey was distributed to existing MVP participants via mail, telephone, and email with the ability to complete the survey by paper and pencil or through the MVP online system. Dissemination of the survey was approved by the VA Central IRB in 2020, with nearly 730,000 eligible MVP participants contacted. As of June 2022, 255,737 MVP participants (35% of the eligible cohort) had completed the survey; 86% completed a paper survey while 14% completed it online. Respondents were primarily older (≥ 65 years); 90% were male; close to 7% reported Hispanic ethnicity, and 11% reported Black race.

Findings from this survey provide insight into pandemic behaviors not consistently captured in EHRs, such as psychosocial aspects, including social and emotional support, loss of tangible and intangible resources, as well as COVID-19–related behaviors, such as social distancing and self-protective practices.¹ MVP COVID-19 survey data combined with veteran EHRs, responses to other MVP surveys, and genetic data enable MVP researchers to better understand epidemiological, clinical, and psychosocial aspects of the disease. Future COVID-19 studies may use self-reported survey responses to enrich understanding about the effects of the disease on a veteran’s daily life, and possibly validate existing EHR COVID-19 diagnoses and hospitalization findings. This comprehensive data resource provides a unique opportunity to identify new targets for disease prevention, treatment, and management with an emphasis on individual variability in genes, environment, and lifestyle.

COVID-19 Research

In early 2020, the burden of COVID-19 on the US was unprecedented, and little was known about risk factors for severe COVID-19 and deaths. The MVP Phenomics team quickly responded with a large-scale phenome-wide association study (PheWAS) of > 1800 phenotypes (physical and biochemical traits) and COVID-19 progression. Its goal was to characterize risk factors and outcomes associated with COVID-19 disease progression.² Data curation and assembly occurred rapidly through integrated efforts led by MVP and VA COVID-19 initiatives. The MVP utilized its phenomics core resource to understand the progression of COVID-19 defined by SARS-CoV-2 infection, hospitalization, intensive care unit admission, and 30-day mortality using VA EHR data.

To broaden disease progression data curation and fit the specific needs of the VA, we operationalized and validated the World Health Organization clinical severity scale and used VA EHR data to create the VA Severity Index for COVID-19 (VASIC).³ The VASIC category is now part of the MVP core data repository, where volumes of data from multiple activities are integrated through an automated process to create monthly research-ready data cubes. These activities include extensive data curation, mapping, phenotyping, and adjudication that are performed to curate oxygen supplementation status and other procedures related to treatment that are processed and understood in real time. The data cubes were provisioned to MVP COVID-19 researchers. In addition, the VASIC scale variable is now integrated within the larger VA system for all researchers to use as part of its wider COVID-19 initiative. The VA Centralized Interactive Phenomics Resource (CIPHER) phenomics library now hosts the details of VASIC, codes, metadata, and related COVID-19 data products for all VA communities. In partnership with CIPHER and other internal and external COVID-19 initiatives, the MVP continues to play an integral part for the VA and beyond in the development of a phenomics algorithm for long COVID, or post-acute COVID-19 syndrome (PACS).

Host Genetics in COVID-19

As the SARS-CoV-2 virus continued to spread globally, it became clear that the symptoms and severity of infection experienced by patients varied across a broad spectrum, from being asymptomatic carriers to experiencing severe symptoms in 1 or more organ systems in the body, resulting in death. This variability suggested that host genetics and other host factors may play a role in determining the severity of COVID-19 infection. The MVP dataset, with genetic and health information on > 600,000 MVP participants, provided an ideal dataset to explore host contributions to COVID-19.

In late spring 2020, the MVP executive committee issued a call to the MVP research community to propose study aims around the COVID-19 pandemic that could leverage the phenotypic and genetic data and resources. The MVP quickly formed 6 rapid-response scientific working groups. Their mission was to cultivate collaboration and inclusivity and to coordinate COVID-19 research questions. A steering committee composed of the MVP executive committee, staff from computational environments, working group cochairs, and an administrator, who was responsible for daily oversight of the working groups. In addition, the ORD COVID-19 steering committee reviewed and approved research activities to ensure scientific rigor, as well as alignment with overall ongoing research activities.

table.png

The MVP COVID-19 working groups included dozens of researchers who used MVP data to identify disease mechanisms; understand the impact of host genetics on susceptibility, morbidity, and mortality; and identify potential targets for treatments and therapies. The working groups were further supported by MVP analysts to work cross-functionally on genomics, phenomics, statistical genetics, and PheWAS. Each working group chair was responsible for prioritizing concepts and moving them forward in coordination with the MVP and ORD COVID-19 steering committees. An overview of the MVP COVID-19 working groups follows (Table).^4-9

Druggable genome. This working group researched drug-repurposing opportunities to prevent severe COVID-19, defined as hospitalization with oxygen therapy (high flow), intubation, mechanical ventilation, vasopressors, dialysis, or death from COVID-19; and prevent complications in patients hospitalized by COVID-19.

Pharmacogenomics. This working group focused on 2 main aims: the impact of apolipoprotein L1 risk variants on acute kidney injury (AKI) and death in Black veterans with COVID-19; and pharmacogenetic analysis of remdesivir-induced liver chemistry abnormalities.

Disease mechanisms. Understanding the underlying pathways and mechanisms behind COVID-19 has been a difficult but important challenge overall in the scientific community. This working group investigated specific genetic markers and effects on COVID-19, including polygenic predisposition to venous thromboembolism associated with increased COVID-19 susceptibility; renal comorbidities and new AKI and unfavorable outcomes among COVID-19–positive sickle cell trait carriers; and mucin 5B, oligomeric mucus/gel-forming gene polymorphism, and protective effects in COVID-19 infection.

Genomics for risk prediction, polygenic risk scores, and mendelian randomization. Risk prediction for COVID-19 has been widely studied mostly aiming at comorbidities and preexisting conditions. The MVP cohort provided a unique opportunity to understand how genetic information can enhance our understanding of COVID-19 risk. This working group focused on: (1) ABO blood group typing and the protective effects of the O blood group on COVID-19 infection; (2) polygenic risk scores and COVID-19 outcomes; (3) human leukocyte antigen typing and COVID-19 outcomes; and (4) a transcriptome-wide association study of COVID-19–positive MVP participants.

Genome-Wide Association Study (GWAS) and Downstream Analysis. This working group performed GWAS of the main COVID-19 outcomes. Results from GWAS unveiled new genetic loci to suggest further investigation on these candidate genes. The results were used by other MVP COVID-19 working groups for their activities. The results also contributed to external collaborations, such as the COVID-19 Host Genetics Initiative.

COVID-19–Related PheWAS. This working group focused on understanding the potential clinical significance of genetic variants associated with susceptibility to, or outcomes of, COVID-19 infection. They worked to identify traits that share genetic variants associated with severe COVID-19 from the Host Genetics Initiative. The group also studied the phenotypic consequences of acquired mosaic chromosomal alterations with early data linking to COVID-19 susceptibility.

COVID-19 Research Partnerships

In 2016, the VA and DOE formed an interagency partnership known as Computational Health Analytics for Medical Precision to Improve Outcomes Now (CHAMPION) to demonstrate the power of combining the VA EHR system, MVP genetic data, and clinical research expertise with DOE high-performance computing infrastructure and artificial intelligence expertise. The VA EHR captures longitudinal care information on veterans with records that go back decades. Furthermore, the VA covers the costs of medications and provides a variety of services through the Veterans Benefits Administration. As a result, VA data include medications used by patients before, during, and after COVID-19. Similarly, the VA has comprehensive vital records, whereas other large health systems do not capture events such as death after patients leave the hospital.

The DOE Oak Ridge National Laboratory (ORNL) in Tennessee securely maintains this rich database for the VA. The ORNL Summit supercomputer can complete trillions of calculations per second to provide critical and timely analyses, applying the most advanced and powerful artificial intelligence methods, which would not be possible in more conventional research settings. CHAMPION taught the VA and DOE how to bring their disparate research cultures together for innovative collaborative investigation. Moreover, this collaboration produced a cadre of VA and DOE scientists familiar with VA patient data and experienced in conducting joint research successfully and integrating omics data with clinical data for a better mechanistic understanding. Because of this preexisting collaboration between the VA and DOE, interagency teams were prepared at the start of the COVID-19 pandemic.^10-15

During the pandemic, the FDA and VA conducted research together. One joint study found that the bradykinin storm is likely to play a role in many COVID-19 symptoms. Using VA data, researchers compared COVID-19 testing patterns, positive test results, and 30-day mortality rates by race and ethnicity among VA patients.^10,11These findings demonstrated the higher burden COVID-19 placed on Black and Hispanic communities, not fully explained by underlying health conditions, access to medical care, or geographic locale.¹¹

Other recently completed studies have developed and validated short-term mortality indices in individuals with COVID-19 based on their preexisting conditions, assessed the generalizability of VA COVID-19 experiences to the US population, and evaluated the effectiveness of hydroxychloroquine with and without azithromycin in VA patients with COVID-19.^12,15 A recent study demonstrated the benefit of prophylactic anticoagulation at initial hospitalization.¹⁴

The VA also provided the FDA with daily reports on aggregate VA COVID-19 cases and their distribution across the VA system, demographics of VA patients with COVID-19, and analyses of predictive models for positive test results and death. The VA regularly sent the FDA aggregated data showing patterns of medication use and retrospective analyses of the effectiveness of certain medications (including remdesivir and some antithrombotic agents). The FDA used these data along with other data to understand the scope of the pandemic and to predict drug shortages or needs for additional medical equipment, including ventilators. This information was critical at the start of the pandemic.

Limitations

For the most part, MVP infrastructure and partnerships were efficiently leveraged to significantly advance our understanding of the biological basis of COVID-19 and to develop treatments and vaccines. However, there were a few limitations that may have slowed timely and optimal outcomes. An issue not limited to the MVP or VA was the continual evolution of the pandemic and its response. This included evolving definitions of disease, symptomatology, testing, vaccines, and public health recommendations. Keeping pace with the emerging knowledge from these domains was a struggle for the entire scientific community. A more discrete limitation was the number of participants in the MVP with positive COVID-19 test results and positive symptoms; however, this was mitigated by partnering with other groups like the COVID-19 Host Genetics Initiative to increase study participant numbers. Finally, there were logistical and regulatory challenges associated with coordination of national clinical trial recruitment across a VA system with > 100 discrete hospitals.

Conclusions

Having a centralized infrastructure for recruitment and enrollment, including a national research volunteer registry, information center, research staff, and coordinating centers, can allow for expedited enrollment in vaccine and treatment trials in the face of future public health emergencies. VA assets, including its rich EHR and MVP, the world’s largest genomic cohort, have contributed to improving our understanding and management of COVID-19. MVP’s ready-to-respond research infrastructure embedded within the country’s largest national health care system allows for both the facilitation of the research work and applications of the research findings into practice. Findings from the MVP COVID-19 working groups have yielded compelling results, particularly around genetic variants among various racial and ethnic groups. Looking ahead, the VA and DOE are launching a new joint project on long COVID that will include developing a gold-standard definition for long COVID. The ORD has established a Partnered Research Program to facilitate collaborations with industry to speed up clinical trials, and the MVP will continue to contribute toward expanding scientific knowledge to improve the management of COVID-19.

The US Department of Veterans Affairs (VA), through its Office of Research and Development (ORD), supports an extensive and experienced clinical research enterprise, including the first multisite trials in the US.¹ These resources contribute to the ORD support for the largest US integrated health care system, with a primary focus on the care and well-being of veterans. While the history of VA research has facilitated the creation of an experienced and organized research enterprise, the COVID-19 pandemic challenged VA to contribute even more significantly. These challenges became pronounced given the urgency associated with standing up VA sites for both therapeutic and vaccine trials.

VA Clinical Research Enterprise

The VA recognized an early need for an organized research response not only to address operational challenges resulting from COVID-19 but also ensure that the agency would be ready to support new scientific efforts focused specifically on the virus and related outcomes.² As a result, the ORD took decisive action first by establishing itself as a central headquarters for VA COVID-19 research activities, and second, by leveraging existing resources, initiatives, and infrastructure to develop new mechanisms that would ensure that the VA was well positioned to develop or participate in research endeavors being driven by the VA as well federal, industry, and non-VA partners.

Prior to the pandemic, the ORD, through its Cooperative Studies Program (CSP), had strategies to address challenges associated with clinical trial startup and improved efficient conduct.³ For example, the VA Network of Dedicated Enrollment Sites (NODES) is a consortium of 23 VA medical centers (VAMCs) dedicated to rapid startup and recruitment into VA-sponsored clinical trials. NODES provides site-level expertise on clinical trial management, including troubleshooting challenges that may occur during clinical research execution.⁴ Another initiative, Access to Clinical Trials (ACT) for Veterans, engaged industry, academic, patient advocacy, and other partners to identify potential regulatory and operational hurdles to efficient startup activities specific to externally sponsored multisite clinical trials. Under ACT for Veterans, stakeholders emphasized the importance of developing a single VA point of contact for external partners to work with to more efficiently understand and navigate the VA system. In turn, such a resource could be designed to facilitate substantive research and long-term relationships with compatible external partners. Targeted to launch in April 2020, the Partnered Research Program (PRP) was expedited to respond to the pandemic.

During the pandemic, new VA efforts included the creation of the VA CoronavirUs Research and Efficacy Studies (VA CURES) network, initially established as a clinical trial master protocol framework to support and maximize VA-funded COVID-19 trial efficiency.⁵ VA CURES joined the consortium of trials networks funded by the National Heart, Lung, and Blood Institute. It began treatment trials under Accelerating COVID-19 Therapeutic Interventions and Vaccination (ACTIV), specifically ACTIV-4. The VA also partnered with the National Institutes of Allergy and Infectious Diseases (NIAID) by organizing the VA International Coordinating Center (VA ICC) for other ACTIV trials (ACTIV-2 and -3). When approached to startup studies that included veterans and the VA health care system, these capabilities comprised the VA research response.

A Need for a New Approach

As the impact of the pandemic expanded and the need for effective treatments and vaccines grew, national calls were made to assess the capabilities and readiness of available clinical trials networks. Additionally, the US Department of Health and Human Services Biomedical Advanced Research and Development Authority, ACTIV, NIAID Division of Clinical Research and Division of AIDS, and many pharmaceutical companies were starting to roll out trials of new therapeutics and vaccines. These groups approached the VA to help evaluate the safety and efficacy of several therapeutics and vaccines because they recognized several advantages of the VA enterprise, including its position as the nation’s largest integrated health care system, its diverse patient population, and its expertise in conducting clinical trials.

Although the VA was well positioned as an important player in a collaborative investigational approach to COVID-19 research, these trials required startup approaches that were significantly different from those it had employed in traditional, prepandemic, clinical research. Despite the VA being a single federal agency, each VAMC conducting research establishes its own practices to address both operational and regulatory requirements. This structure results in individual units that operate under different standard operating procedures. Efforts must be taken centrally to organize them into a singular network for the entire health care system. During a national crisis, when there was a need for rapid trial startup to answer safety and efficacy questions and participate under a common approach to protocol execution, this variability was neither manageable nor acceptable. Additionally, the intense resource demands associated with such research, coupled with frequent reporting requirements by VA leaders, Congress, and the White House, required that VAMCs function more like a single unit. Therefore, the ORD needed to develop VAMCs’ abilities to work collectively toward a common goal, share knowledge and experience, and capitalize on potential efficiencies concerning legal, regulatory, and operational processes.

table.png

Beginning August 2020, 39 VAMCs joined 7 large-scale collaborative COVID-19 therapeutic and vaccine trials. Through its COVID-19 Research Response Team, the ORD identified, engaged, and directed appropriate resources to support the VAMC under a centralized framework for study management (Table). Centralized management not only afforded VAMCs the opportunity to work more collectively and efficiently but also provided an important advantage by enabling the VA to collect and organize its experiences (and on occasion data) to provide a base for continual learning and improvement efforts. While others have described efforts undertaken across networks to advance learning health systems, the VA’s national scope and integration of research and clinical care allow greater opportunities to learn in a practical setting.⁶

Using surveys, webinars, interviews, and observation from site and VA Central Office personnel, the ORD identified specific variables that prevented the VAMCs from quickly starting up as a clinical trial site. We also documented strategies, solutions, and recommendations for improving startup time lines. These were organized into 8 categories: (1) site infrastructure needs and capabilities; (2) study management roles and responsibilities; (3) educational resources and training; (4) local review requirements and procedures; (5) study design demands; (6) contracting and budgeting; (7) central-level systems and processes; and (8) communication between external partners and within the VA.

Site Infrastructure Needs and Capabilities

A primary impediment to rapid study startup was a lack of basic infrastructure, including staff, space, and the agility necessary for the changing demands of high-priority, high-enrolling trials. This observation is not unique to the VA.⁷ Initially, certain facilities located in hot spots where COVID-19 was more prevalent became high-interest targets for study placement, despite varying degrees of available research infrastructure. Furthermore, pandemic shutdowns and quarantines permitted fewer employees onsite. This resulted in inadequate staffing in personnel needed to support required startup activities and those needed to handle the high volume of study participants who were being recruited, screened, enrolled, and followed. Additionally, as clinical care needs and infection control practices were prioritized, clinical research space was often appropriated for these needs, making it difficult to find the space to conduct trials. Lastly, supply chain issues also posed unique challenges, sometimes making it difficult for participating VAMCs to obtain needed materials, such as IV solution bags of specific sizes and contents, safety injection needles, and IV line filters.

The VA was able to use central purchasing/contracting at coordinating centers or the VA Central Office to support investigators and assist with finding supplies and clinical research space. VAMCs with research operating budgets to cover startup costs were better positioned to handle funding delays. During the pandemic, the ORD further contracted to supply administrative support to research offices to address regulatory and other requirements needed for startup activities. The ability to expand such central contracts to procure clinical research staff and outpatient clinical research space may also prove useful in meeting key needs at a site.

Management Roles and Responsibilities

Ambiguous and variable roles and responsibilities among the various partners and stakeholders represented a challenge given the large-scale, national, or international operations involved in the trials. VA attempts to operate uniformly were further limited given that each sponsor or group had preferred methods for operating and/or organizing work under urgent time lines. For example, one trial involved a coordinating center, a contract research organization, and federal partners that each worked with individual sites. Consequently, VA study teams would receive messages that were conflicting or unclear.

The VA learned that studies need a single “source of truth” and/or central command structure in times of urgency. To mitigate conflicting messages, vaccine trials relied on a clearinghouse through the PRP to interpret requirements or work on behalf of all sites before key actions were taken. For studies with the NIAID, the VA relied on experienced staff at the CSP coordinating center at the Perry Point, Maryland, VAMC before beginning. This approach especially helped with the challenges of understaffing and sites’ lack of familiarity with complex platform trial designs and already-established network practices within the ACTIV-2 and ACTIV-3 studies.

Educational Resources and Training

Since VA participation in externally sponsored, multisite clinical trials traditionally relies on an individual VAMC study team and its local resources, transitioning to centralized approaches for COVID-19 multisite studies created barriers. Many VAMCs were unfamiliar with newer capabilities for more rapid regulatory reviews and approvals involving commercial institutional review boards (IRBs) and central VA information security and privacy reviews. While tools and resources were available to facilitate these processes, real-time use had not been fully tested. As a result, everyone had to learn as they went along.

The simultaneous establishment of workflows required the ORD to centralize operations and provide training and guidance to field personnel. Although many principal investigators and clinical research coordinators had trial experience, training required unlearning previous understandings of requirements to meet urgent time lines. ORD enterprise road maps, central tools, and training materials also were made available on a study-by-study basis. Open communication was vital to train on central study materials while opportunities to discuss, question, and share experiences and ideas were promoted. The ORD also sent regular emails to prepare for upcoming work and/or raise awareness of identified challenges.

The clinical trials were impacted by varying VAMC review requirements and approval processes. Although VA policy defines standard requirements, the timing and procedures are left to the individual facility to determine any local factors to accommodate and/or resource availability. While such an approach is well understood within the VA, external sponsors were not as familiar and assumed a more uniform approach across all sites. In response, some VAMCs established ad hoc research and development committee review procedures, allowing study teams to obtain the necessary reviews in a timely fashion. However, not all VAMCs had the infrastructure (especially when clinical personnel had been redeployed to other priorities) to respond with such agility. One critical role of the VA Central Office coordinating entities was to communicate and manage external sponsor and group expectations surrounding individual site review time lines. However, establishing policies and procedures that focus on streamlining local review processes helped to broadly mitigate the COVID-19 trial challenges.

Study Design Demands

The design of COVID-19 studies combined with the uncertainty of the pandemic required rapid protocol changes and adaptations that were often difficult to deliver. The multinetwork trials that the VA collaborated on were platform or master protocol designs. These designs emphasized overall goals (eg, treating patients requiring intensive care unit care). However, because this trial strategy also introduces complexities that may impact review and execution among those unfamiliar with it, there is a need for increased discussion and understanding of this methodology.⁸ For example, there can be shared control groups, reliance on specific criteria for halting because of safety or futility concerns, or continuation and expansion applied through an external review board. Delays may arise when changes to study protocols occur rapidly or frequently and necessitate new regulatory reviews, negotiation of new agreements, modifications to contracts, changes to entry criteria, etc.

While the VA has adopted a quality by design framework, VA investigators noted many missed opportunities related to looking at outcomes with new diagnostics, studies of serology, outcomes related to vaccinations, and understanding the natural history of disease in these trials.⁹ The limited opportunities for investigator input suggested that the advantages offered by platform designs were not maximized during pandemic-focused urgencies. It was unclear whether this barrier was created by a general lack of awareness by sponsors or a lack of opportunities. At the very least, quality by design approaches may help avoid redundancies in documentation or study processes at the central and site levels.

Contracting and Budgeting

Given external sponsorship of COVID-19 trials, efficient contracting and budgeting were critical for a rapid start up. The variability of processes associated with these trials created several challenges that were compounded by issues, such as site sub-agreements and budget documents that did not always go to the correct groups and individuals. Furthermore, the VA’s ability to use contracted resources (eg, tents, trailers, personnel) that external sponsors had built into their contracts was more difficult for VA as a federal agency governed by other statues and policies. This also put VAMCs at a disadvantage from a timing perspective, as the VA often required additional time to find equivalent solutions that met federal regulations.

Although the VA was able to establish contract solutions to some issues, time was still lost while working to secure initial funding. Additionally, for needs such as home phlebotomy—commended for convenience to veterans and research staff—and engaging a specialized research team in the Office of General Counsel, early awareness of protocol needs and sponsor solutions could allow VA to pursue alternatives sooner.

Central-Level Systems and Processes

Not all challenges were at the VAMC level. As the ORD explored solutions, it learned that various tools and study platforms were available but not considered. Applications, such as eConsent, and file-sharing platforms that met existing information security and privacy requirements were needed but had to comply with the Privacy Act of 1974, Federal Information Security Modernization Act, and other requirements. Using sponsor-provided devices, such as drug temperature monitoring equipment, required additional review to ensure that they met system requirements for a national health care system. In addition, the VA uses a clinical trials management review system; however, its implementation was new at the time these trials began. Furthermore, the system engaged with some commercial IRBs but not all. This resulted in additional delays as VAMCs and central resources worked to familiarize themselves with the system and procedures.

The ability to work collaboratively across the VA includes having a framework in which key startup processes are standardized. This allows for efficiency and minimizes variability. Also, all stakeholders should understand the importance of holding discussions to identify appropriate solutions, guidance, and instruction. Finally, the VA must strive to be more nimble when adapting technological, regulatory, and financial processes.

The value of communication—both internal and external—cannot be understated. Minimizing confusion, managing expectations, and ensuring consistent messaging were essential for rapid trial execution. Despite being the second largest federal agency, the VA did not have a seat at the study leadership table for several protocols. When it joined later, several study aspects were set and/or difficult to revise. Challenges affecting time and securing resources have been noted. The ability to plan and then share expectations and responsibilities across and within the respective participating organizations early in the process was perhaps the single factor that was most addressable. The VA enterprise organization and integration with other units could accentuate key communications that would be essential in time-sensitive activities.

VA as a Partner for Future Research

Before the pandemic, the VA had already undertaken a path to enhance its ability to partner as part of the national biomedical research enterprise. The need for COVID-19 therapeutic and vaccine trials accelerated opportunities to plan and develop processes and capabilities to advance this path. As a key strength for VA scientific activities, clinical trials represent a primary medium by which to develop its partnerships. Learning and development have become part of a culture that expedites opportunities for veterans who actively seek ways to contribute to medical knowledge and treatments for their peers and the nation.

CONCLUSIONS

Challenges associated with rapid startup and completion of clinical trials have been discussed for some time. During the pandemic, needs and barriers were magnified because of the heightened urgency for evidence-based therapeutics and vaccines. While the VA faced similar problems as well as those specific to it as a health care system, it had the opportunity to learn and more systematically implement solutions to help in its partnered efforts.¹⁰ As an enterprise, the VA hopes to apply lessons learned, strategies, and best practices to further its goals to enhance veteran access to clinical trials and respond to any future need to quickly establish evidence bases in pandemics and other health emergencies that warrant the rapid implementation of research.

Acknowledgments

The activities reported here were supported by the US Department of Veterans Affairs, Office of Research and Development.

The US Department of Veterans Affairs (VA), through its Office of Research and Development (ORD), supports an extensive and experienced clinical research enterprise, including the first multisite trials in the US.¹ These resources contribute to the ORD support for the largest US integrated health care system, with a primary focus on the care and well-being of veterans. While the history of VA research has facilitated the creation of an experienced and organized research enterprise, the COVID-19 pandemic challenged VA to contribute even more significantly. These challenges became pronounced given the urgency associated with standing up VA sites for both therapeutic and vaccine trials.

VA Clinical Research Enterprise

The VA recognized an early need for an organized research response not only to address operational challenges resulting from COVID-19 but also ensure that the agency would be ready to support new scientific efforts focused specifically on the virus and related outcomes.² As a result, the ORD took decisive action first by establishing itself as a central headquarters for VA COVID-19 research activities, and second, by leveraging existing resources, initiatives, and infrastructure to develop new mechanisms that would ensure that the VA was well positioned to develop or participate in research endeavors being driven by the VA as well federal, industry, and non-VA partners.

Prior to the pandemic, the ORD, through its Cooperative Studies Program (CSP), had strategies to address challenges associated with clinical trial startup and improved efficient conduct.³ For example, the VA Network of Dedicated Enrollment Sites (NODES) is a consortium of 23 VA medical centers (VAMCs) dedicated to rapid startup and recruitment into VA-sponsored clinical trials. NODES provides site-level expertise on clinical trial management, including troubleshooting challenges that may occur during clinical research execution.⁴ Another initiative, Access to Clinical Trials (ACT) for Veterans, engaged industry, academic, patient advocacy, and other partners to identify potential regulatory and operational hurdles to efficient startup activities specific to externally sponsored multisite clinical trials. Under ACT for Veterans, stakeholders emphasized the importance of developing a single VA point of contact for external partners to work with to more efficiently understand and navigate the VA system. In turn, such a resource could be designed to facilitate substantive research and long-term relationships with compatible external partners. Targeted to launch in April 2020, the Partnered Research Program (PRP) was expedited to respond to the pandemic.

During the pandemic, new VA efforts included the creation of the VA CoronavirUs Research and Efficacy Studies (VA CURES) network, initially established as a clinical trial master protocol framework to support and maximize VA-funded COVID-19 trial efficiency.⁵ VA CURES joined the consortium of trials networks funded by the National Heart, Lung, and Blood Institute. It began treatment trials under Accelerating COVID-19 Therapeutic Interventions and Vaccination (ACTIV), specifically ACTIV-4. The VA also partnered with the National Institutes of Allergy and Infectious Diseases (NIAID) by organizing the VA International Coordinating Center (VA ICC) for other ACTIV trials (ACTIV-2 and -3). When approached to startup studies that included veterans and the VA health care system, these capabilities comprised the VA research response.

A Need for a New Approach

As the impact of the pandemic expanded and the need for effective treatments and vaccines grew, national calls were made to assess the capabilities and readiness of available clinical trials networks. Additionally, the US Department of Health and Human Services Biomedical Advanced Research and Development Authority, ACTIV, NIAID Division of Clinical Research and Division of AIDS, and many pharmaceutical companies were starting to roll out trials of new therapeutics and vaccines. These groups approached the VA to help evaluate the safety and efficacy of several therapeutics and vaccines because they recognized several advantages of the VA enterprise, including its position as the nation’s largest integrated health care system, its diverse patient population, and its expertise in conducting clinical trials.

Although the VA was well positioned as an important player in a collaborative investigational approach to COVID-19 research, these trials required startup approaches that were significantly different from those it had employed in traditional, prepandemic, clinical research. Despite the VA being a single federal agency, each VAMC conducting research establishes its own practices to address both operational and regulatory requirements. This structure results in individual units that operate under different standard operating procedures. Efforts must be taken centrally to organize them into a singular network for the entire health care system. During a national crisis, when there was a need for rapid trial startup to answer safety and efficacy questions and participate under a common approach to protocol execution, this variability was neither manageable nor acceptable. Additionally, the intense resource demands associated with such research, coupled with frequent reporting requirements by VA leaders, Congress, and the White House, required that VAMCs function more like a single unit. Therefore, the ORD needed to develop VAMCs’ abilities to work collectively toward a common goal, share knowledge and experience, and capitalize on potential efficiencies concerning legal, regulatory, and operational processes.

table.png

Beginning August 2020, 39 VAMCs joined 7 large-scale collaborative COVID-19 therapeutic and vaccine trials. Through its COVID-19 Research Response Team, the ORD identified, engaged, and directed appropriate resources to support the VAMC under a centralized framework for study management (Table). Centralized management not only afforded VAMCs the opportunity to work more collectively and efficiently but also provided an important advantage by enabling the VA to collect and organize its experiences (and on occasion data) to provide a base for continual learning and improvement efforts. While others have described efforts undertaken across networks to advance learning health systems, the VA’s national scope and integration of research and clinical care allow greater opportunities to learn in a practical setting.⁶

Using surveys, webinars, interviews, and observation from site and VA Central Office personnel, the ORD identified specific variables that prevented the VAMCs from quickly starting up as a clinical trial site. We also documented strategies, solutions, and recommendations for improving startup time lines. These were organized into 8 categories: (1) site infrastructure needs and capabilities; (2) study management roles and responsibilities; (3) educational resources and training; (4) local review requirements and procedures; (5) study design demands; (6) contracting and budgeting; (7) central-level systems and processes; and (8) communication between external partners and within the VA.

Site Infrastructure Needs and Capabilities

A primary impediment to rapid study startup was a lack of basic infrastructure, including staff, space, and the agility necessary for the changing demands of high-priority, high-enrolling trials. This observation is not unique to the VA.⁷ Initially, certain facilities located in hot spots where COVID-19 was more prevalent became high-interest targets for study placement, despite varying degrees of available research infrastructure. Furthermore, pandemic shutdowns and quarantines permitted fewer employees onsite. This resulted in inadequate staffing in personnel needed to support required startup activities and those needed to handle the high volume of study participants who were being recruited, screened, enrolled, and followed. Additionally, as clinical care needs and infection control practices were prioritized, clinical research space was often appropriated for these needs, making it difficult to find the space to conduct trials. Lastly, supply chain issues also posed unique challenges, sometimes making it difficult for participating VAMCs to obtain needed materials, such as IV solution bags of specific sizes and contents, safety injection needles, and IV line filters.

The VA was able to use central purchasing/contracting at coordinating centers or the VA Central Office to support investigators and assist with finding supplies and clinical research space. VAMCs with research operating budgets to cover startup costs were better positioned to handle funding delays. During the pandemic, the ORD further contracted to supply administrative support to research offices to address regulatory and other requirements needed for startup activities. The ability to expand such central contracts to procure clinical research staff and outpatient clinical research space may also prove useful in meeting key needs at a site.

Management Roles and Responsibilities

Ambiguous and variable roles and responsibilities among the various partners and stakeholders represented a challenge given the large-scale, national, or international operations involved in the trials. VA attempts to operate uniformly were further limited given that each sponsor or group had preferred methods for operating and/or organizing work under urgent time lines. For example, one trial involved a coordinating center, a contract research organization, and federal partners that each worked with individual sites. Consequently, VA study teams would receive messages that were conflicting or unclear.

The VA learned that studies need a single “source of truth” and/or central command structure in times of urgency. To mitigate conflicting messages, vaccine trials relied on a clearinghouse through the PRP to interpret requirements or work on behalf of all sites before key actions were taken. For studies with the NIAID, the VA relied on experienced staff at the CSP coordinating center at the Perry Point, Maryland, VAMC before beginning. This approach especially helped with the challenges of understaffing and sites’ lack of familiarity with complex platform trial designs and already-established network practices within the ACTIV-2 and ACTIV-3 studies.

Educational Resources and Training

Since VA participation in externally sponsored, multisite clinical trials traditionally relies on an individual VAMC study team and its local resources, transitioning to centralized approaches for COVID-19 multisite studies created barriers. Many VAMCs were unfamiliar with newer capabilities for more rapid regulatory reviews and approvals involving commercial institutional review boards (IRBs) and central VA information security and privacy reviews. While tools and resources were available to facilitate these processes, real-time use had not been fully tested. As a result, everyone had to learn as they went along.

The simultaneous establishment of workflows required the ORD to centralize operations and provide training and guidance to field personnel. Although many principal investigators and clinical research coordinators had trial experience, training required unlearning previous understandings of requirements to meet urgent time lines. ORD enterprise road maps, central tools, and training materials also were made available on a study-by-study basis. Open communication was vital to train on central study materials while opportunities to discuss, question, and share experiences and ideas were promoted. The ORD also sent regular emails to prepare for upcoming work and/or raise awareness of identified challenges.

The clinical trials were impacted by varying VAMC review requirements and approval processes. Although VA policy defines standard requirements, the timing and procedures are left to the individual facility to determine any local factors to accommodate and/or resource availability. While such an approach is well understood within the VA, external sponsors were not as familiar and assumed a more uniform approach across all sites. In response, some VAMCs established ad hoc research and development committee review procedures, allowing study teams to obtain the necessary reviews in a timely fashion. However, not all VAMCs had the infrastructure (especially when clinical personnel had been redeployed to other priorities) to respond with such agility. One critical role of the VA Central Office coordinating entities was to communicate and manage external sponsor and group expectations surrounding individual site review time lines. However, establishing policies and procedures that focus on streamlining local review processes helped to broadly mitigate the COVID-19 trial challenges.

Study Design Demands

The design of COVID-19 studies combined with the uncertainty of the pandemic required rapid protocol changes and adaptations that were often difficult to deliver. The multinetwork trials that the VA collaborated on were platform or master protocol designs. These designs emphasized overall goals (eg, treating patients requiring intensive care unit care). However, because this trial strategy also introduces complexities that may impact review and execution among those unfamiliar with it, there is a need for increased discussion and understanding of this methodology.⁸ For example, there can be shared control groups, reliance on specific criteria for halting because of safety or futility concerns, or continuation and expansion applied through an external review board. Delays may arise when changes to study protocols occur rapidly or frequently and necessitate new regulatory reviews, negotiation of new agreements, modifications to contracts, changes to entry criteria, etc.

While the VA has adopted a quality by design framework, VA investigators noted many missed opportunities related to looking at outcomes with new diagnostics, studies of serology, outcomes related to vaccinations, and understanding the natural history of disease in these trials.⁹ The limited opportunities for investigator input suggested that the advantages offered by platform designs were not maximized during pandemic-focused urgencies. It was unclear whether this barrier was created by a general lack of awareness by sponsors or a lack of opportunities. At the very least, quality by design approaches may help avoid redundancies in documentation or study processes at the central and site levels.

Contracting and Budgeting

Given external sponsorship of COVID-19 trials, efficient contracting and budgeting were critical for a rapid start up. The variability of processes associated with these trials created several challenges that were compounded by issues, such as site sub-agreements and budget documents that did not always go to the correct groups and individuals. Furthermore, the VA’s ability to use contracted resources (eg, tents, trailers, personnel) that external sponsors had built into their contracts was more difficult for VA as a federal agency governed by other statues and policies. This also put VAMCs at a disadvantage from a timing perspective, as the VA often required additional time to find equivalent solutions that met federal regulations.

Although the VA was able to establish contract solutions to some issues, time was still lost while working to secure initial funding. Additionally, for needs such as home phlebotomy—commended for convenience to veterans and research staff—and engaging a specialized research team in the Office of General Counsel, early awareness of protocol needs and sponsor solutions could allow VA to pursue alternatives sooner.

Central-Level Systems and Processes

Not all challenges were at the VAMC level. As the ORD explored solutions, it learned that various tools and study platforms were available but not considered. Applications, such as eConsent, and file-sharing platforms that met existing information security and privacy requirements were needed but had to comply with the Privacy Act of 1974, Federal Information Security Modernization Act, and other requirements. Using sponsor-provided devices, such as drug temperature monitoring equipment, required additional review to ensure that they met system requirements for a national health care system. In addition, the VA uses a clinical trials management review system; however, its implementation was new at the time these trials began. Furthermore, the system engaged with some commercial IRBs but not all. This resulted in additional delays as VAMCs and central resources worked to familiarize themselves with the system and procedures.

The ability to work collaboratively across the VA includes having a framework in which key startup processes are standardized. This allows for efficiency and minimizes variability. Also, all stakeholders should understand the importance of holding discussions to identify appropriate solutions, guidance, and instruction. Finally, the VA must strive to be more nimble when adapting technological, regulatory, and financial processes.

The value of communication—both internal and external—cannot be understated. Minimizing confusion, managing expectations, and ensuring consistent messaging were essential for rapid trial execution. Despite being the second largest federal agency, the VA did not have a seat at the study leadership table for several protocols. When it joined later, several study aspects were set and/or difficult to revise. Challenges affecting time and securing resources have been noted. The ability to plan and then share expectations and responsibilities across and within the respective participating organizations early in the process was perhaps the single factor that was most addressable. The VA enterprise organization and integration with other units could accentuate key communications that would be essential in time-sensitive activities.

VA as a Partner for Future Research

Before the pandemic, the VA had already undertaken a path to enhance its ability to partner as part of the national biomedical research enterprise. The need for COVID-19 therapeutic and vaccine trials accelerated opportunities to plan and develop processes and capabilities to advance this path. As a key strength for VA scientific activities, clinical trials represent a primary medium by which to develop its partnerships. Learning and development have become part of a culture that expedites opportunities for veterans who actively seek ways to contribute to medical knowledge and treatments for their peers and the nation.

CONCLUSIONS

Challenges associated with rapid startup and completion of clinical trials have been discussed for some time. During the pandemic, needs and barriers were magnified because of the heightened urgency for evidence-based therapeutics and vaccines. While the VA faced similar problems as well as those specific to it as a health care system, it had the opportunity to learn and more systematically implement solutions to help in its partnered efforts.¹⁰ As an enterprise, the VA hopes to apply lessons learned, strategies, and best practices to further its goals to enhance veteran access to clinical trials and respond to any future need to quickly establish evidence bases in pandemics and other health emergencies that warrant the rapid implementation of research.

Acknowledgments

The activities reported here were supported by the US Department of Veterans Affairs, Office of Research and Development.

The US Department of Veterans Affairs (VA), through its Office of Research and Development (ORD), supports an extensive and experienced clinical research enterprise, including the first multisite trials in the US.¹ These resources contribute to the ORD support for the largest US integrated health care system, with a primary focus on the care and well-being of veterans. While the history of VA research has facilitated the creation of an experienced and organized research enterprise, the COVID-19 pandemic challenged VA to contribute even more significantly. These challenges became pronounced given the urgency associated with standing up VA sites for both therapeutic and vaccine trials.

VA Clinical Research Enterprise

The VA recognized an early need for an organized research response not only to address operational challenges resulting from COVID-19 but also ensure that the agency would be ready to support new scientific efforts focused specifically on the virus and related outcomes.² As a result, the ORD took decisive action first by establishing itself as a central headquarters for VA COVID-19 research activities, and second, by leveraging existing resources, initiatives, and infrastructure to develop new mechanisms that would ensure that the VA was well positioned to develop or participate in research endeavors being driven by the VA as well federal, industry, and non-VA partners.

Prior to the pandemic, the ORD, through its Cooperative Studies Program (CSP), had strategies to address challenges associated with clinical trial startup and improved efficient conduct.³ For example, the VA Network of Dedicated Enrollment Sites (NODES) is a consortium of 23 VA medical centers (VAMCs) dedicated to rapid startup and recruitment into VA-sponsored clinical trials. NODES provides site-level expertise on clinical trial management, including troubleshooting challenges that may occur during clinical research execution.⁴ Another initiative, Access to Clinical Trials (ACT) for Veterans, engaged industry, academic, patient advocacy, and other partners to identify potential regulatory and operational hurdles to efficient startup activities specific to externally sponsored multisite clinical trials. Under ACT for Veterans, stakeholders emphasized the importance of developing a single VA point of contact for external partners to work with to more efficiently understand and navigate the VA system. In turn, such a resource could be designed to facilitate substantive research and long-term relationships with compatible external partners. Targeted to launch in April 2020, the Partnered Research Program (PRP) was expedited to respond to the pandemic.

During the pandemic, new VA efforts included the creation of the VA CoronavirUs Research and Efficacy Studies (VA CURES) network, initially established as a clinical trial master protocol framework to support and maximize VA-funded COVID-19 trial efficiency.⁵ VA CURES joined the consortium of trials networks funded by the National Heart, Lung, and Blood Institute. It began treatment trials under Accelerating COVID-19 Therapeutic Interventions and Vaccination (ACTIV), specifically ACTIV-4. The VA also partnered with the National Institutes of Allergy and Infectious Diseases (NIAID) by organizing the VA International Coordinating Center (VA ICC) for other ACTIV trials (ACTIV-2 and -3). When approached to startup studies that included veterans and the VA health care system, these capabilities comprised the VA research response.

A Need for a New Approach

As the impact of the pandemic expanded and the need for effective treatments and vaccines grew, national calls were made to assess the capabilities and readiness of available clinical trials networks. Additionally, the US Department of Health and Human Services Biomedical Advanced Research and Development Authority, ACTIV, NIAID Division of Clinical Research and Division of AIDS, and many pharmaceutical companies were starting to roll out trials of new therapeutics and vaccines. These groups approached the VA to help evaluate the safety and efficacy of several therapeutics and vaccines because they recognized several advantages of the VA enterprise, including its position as the nation’s largest integrated health care system, its diverse patient population, and its expertise in conducting clinical trials.

Although the VA was well positioned as an important player in a collaborative investigational approach to COVID-19 research, these trials required startup approaches that were significantly different from those it had employed in traditional, prepandemic, clinical research. Despite the VA being a single federal agency, each VAMC conducting research establishes its own practices to address both operational and regulatory requirements. This structure results in individual units that operate under different standard operating procedures. Efforts must be taken centrally to organize them into a singular network for the entire health care system. During a national crisis, when there was a need for rapid trial startup to answer safety and efficacy questions and participate under a common approach to protocol execution, this variability was neither manageable nor acceptable. Additionally, the intense resource demands associated with such research, coupled with frequent reporting requirements by VA leaders, Congress, and the White House, required that VAMCs function more like a single unit. Therefore, the ORD needed to develop VAMCs’ abilities to work collectively toward a common goal, share knowledge and experience, and capitalize on potential efficiencies concerning legal, regulatory, and operational processes.

table.png

Beginning August 2020, 39 VAMCs joined 7 large-scale collaborative COVID-19 therapeutic and vaccine trials. Through its COVID-19 Research Response Team, the ORD identified, engaged, and directed appropriate resources to support the VAMC under a centralized framework for study management (Table). Centralized management not only afforded VAMCs the opportunity to work more collectively and efficiently but also provided an important advantage by enabling the VA to collect and organize its experiences (and on occasion data) to provide a base for continual learning and improvement efforts. While others have described efforts undertaken across networks to advance learning health systems, the VA’s national scope and integration of research and clinical care allow greater opportunities to learn in a practical setting.⁶

Using surveys, webinars, interviews, and observation from site and VA Central Office personnel, the ORD identified specific variables that prevented the VAMCs from quickly starting up as a clinical trial site. We also documented strategies, solutions, and recommendations for improving startup time lines. These were organized into 8 categories: (1) site infrastructure needs and capabilities; (2) study management roles and responsibilities; (3) educational resources and training; (4) local review requirements and procedures; (5) study design demands; (6) contracting and budgeting; (7) central-level systems and processes; and (8) communication between external partners and within the VA.

Site Infrastructure Needs and Capabilities

A primary impediment to rapid study startup was a lack of basic infrastructure, including staff, space, and the agility necessary for the changing demands of high-priority, high-enrolling trials. This observation is not unique to the VA.⁷ Initially, certain facilities located in hot spots where COVID-19 was more prevalent became high-interest targets for study placement, despite varying degrees of available research infrastructure. Furthermore, pandemic shutdowns and quarantines permitted fewer employees onsite. This resulted in inadequate staffing in personnel needed to support required startup activities and those needed to handle the high volume of study participants who were being recruited, screened, enrolled, and followed. Additionally, as clinical care needs and infection control practices were prioritized, clinical research space was often appropriated for these needs, making it difficult to find the space to conduct trials. Lastly, supply chain issues also posed unique challenges, sometimes making it difficult for participating VAMCs to obtain needed materials, such as IV solution bags of specific sizes and contents, safety injection needles, and IV line filters.

The VA was able to use central purchasing/contracting at coordinating centers or the VA Central Office to support investigators and assist with finding supplies and clinical research space. VAMCs with research operating budgets to cover startup costs were better positioned to handle funding delays. During the pandemic, the ORD further contracted to supply administrative support to research offices to address regulatory and other requirements needed for startup activities. The ability to expand such central contracts to procure clinical research staff and outpatient clinical research space may also prove useful in meeting key needs at a site.

Management Roles and Responsibilities

Ambiguous and variable roles and responsibilities among the various partners and stakeholders represented a challenge given the large-scale, national, or international operations involved in the trials. VA attempts to operate uniformly were further limited given that each sponsor or group had preferred methods for operating and/or organizing work under urgent time lines. For example, one trial involved a coordinating center, a contract research organization, and federal partners that each worked with individual sites. Consequently, VA study teams would receive messages that were conflicting or unclear.

The VA learned that studies need a single “source of truth” and/or central command structure in times of urgency. To mitigate conflicting messages, vaccine trials relied on a clearinghouse through the PRP to interpret requirements or work on behalf of all sites before key actions were taken. For studies with the NIAID, the VA relied on experienced staff at the CSP coordinating center at the Perry Point, Maryland, VAMC before beginning. This approach especially helped with the challenges of understaffing and sites’ lack of familiarity with complex platform trial designs and already-established network practices within the ACTIV-2 and ACTIV-3 studies.

Educational Resources and Training

Since VA participation in externally sponsored, multisite clinical trials traditionally relies on an individual VAMC study team and its local resources, transitioning to centralized approaches for COVID-19 multisite studies created barriers. Many VAMCs were unfamiliar with newer capabilities for more rapid regulatory reviews and approvals involving commercial institutional review boards (IRBs) and central VA information security and privacy reviews. While tools and resources were available to facilitate these processes, real-time use had not been fully tested. As a result, everyone had to learn as they went along.

The simultaneous establishment of workflows required the ORD to centralize operations and provide training and guidance to field personnel. Although many principal investigators and clinical research coordinators had trial experience, training required unlearning previous understandings of requirements to meet urgent time lines. ORD enterprise road maps, central tools, and training materials also were made available on a study-by-study basis. Open communication was vital to train on central study materials while opportunities to discuss, question, and share experiences and ideas were promoted. The ORD also sent regular emails to prepare for upcoming work and/or raise awareness of identified challenges.

The clinical trials were impacted by varying VAMC review requirements and approval processes. Although VA policy defines standard requirements, the timing and procedures are left to the individual facility to determine any local factors to accommodate and/or resource availability. While such an approach is well understood within the VA, external sponsors were not as familiar and assumed a more uniform approach across all sites. In response, some VAMCs established ad hoc research and development committee review procedures, allowing study teams to obtain the necessary reviews in a timely fashion. However, not all VAMCs had the infrastructure (especially when clinical personnel had been redeployed to other priorities) to respond with such agility. One critical role of the VA Central Office coordinating entities was to communicate and manage external sponsor and group expectations surrounding individual site review time lines. However, establishing policies and procedures that focus on streamlining local review processes helped to broadly mitigate the COVID-19 trial challenges.

Study Design Demands

The design of COVID-19 studies combined with the uncertainty of the pandemic required rapid protocol changes and adaptations that were often difficult to deliver. The multinetwork trials that the VA collaborated on were platform or master protocol designs. These designs emphasized overall goals (eg, treating patients requiring intensive care unit care). However, because this trial strategy also introduces complexities that may impact review and execution among those unfamiliar with it, there is a need for increased discussion and understanding of this methodology.⁸ For example, there can be shared control groups, reliance on specific criteria for halting because of safety or futility concerns, or continuation and expansion applied through an external review board. Delays may arise when changes to study protocols occur rapidly or frequently and necessitate new regulatory reviews, negotiation of new agreements, modifications to contracts, changes to entry criteria, etc.

While the VA has adopted a quality by design framework, VA investigators noted many missed opportunities related to looking at outcomes with new diagnostics, studies of serology, outcomes related to vaccinations, and understanding the natural history of disease in these trials.⁹ The limited opportunities for investigator input suggested that the advantages offered by platform designs were not maximized during pandemic-focused urgencies. It was unclear whether this barrier was created by a general lack of awareness by sponsors or a lack of opportunities. At the very least, quality by design approaches may help avoid redundancies in documentation or study processes at the central and site levels.

Contracting and Budgeting

Given external sponsorship of COVID-19 trials, efficient contracting and budgeting were critical for a rapid start up. The variability of processes associated with these trials created several challenges that were compounded by issues, such as site sub-agreements and budget documents that did not always go to the correct groups and individuals. Furthermore, the VA’s ability to use contracted resources (eg, tents, trailers, personnel) that external sponsors had built into their contracts was more difficult for VA as a federal agency governed by other statues and policies. This also put VAMCs at a disadvantage from a timing perspective, as the VA often required additional time to find equivalent solutions that met federal regulations.

Although the VA was able to establish contract solutions to some issues, time was still lost while working to secure initial funding. Additionally, for needs such as home phlebotomy—commended for convenience to veterans and research staff—and engaging a specialized research team in the Office of General Counsel, early awareness of protocol needs and sponsor solutions could allow VA to pursue alternatives sooner.

Central-Level Systems and Processes

Not all challenges were at the VAMC level. As the ORD explored solutions, it learned that various tools and study platforms were available but not considered. Applications, such as eConsent, and file-sharing platforms that met existing information security and privacy requirements were needed but had to comply with the Privacy Act of 1974, Federal Information Security Modernization Act, and other requirements. Using sponsor-provided devices, such as drug temperature monitoring equipment, required additional review to ensure that they met system requirements for a national health care system. In addition, the VA uses a clinical trials management review system; however, its implementation was new at the time these trials began. Furthermore, the system engaged with some commercial IRBs but not all. This resulted in additional delays as VAMCs and central resources worked to familiarize themselves with the system and procedures.

The ability to work collaboratively across the VA includes having a framework in which key startup processes are standardized. This allows for efficiency and minimizes variability. Also, all stakeholders should understand the importance of holding discussions to identify appropriate solutions, guidance, and instruction. Finally, the VA must strive to be more nimble when adapting technological, regulatory, and financial processes.

The value of communication—both internal and external—cannot be understated. Minimizing confusion, managing expectations, and ensuring consistent messaging were essential for rapid trial execution. Despite being the second largest federal agency, the VA did not have a seat at the study leadership table for several protocols. When it joined later, several study aspects were set and/or difficult to revise. Challenges affecting time and securing resources have been noted. The ability to plan and then share expectations and responsibilities across and within the respective participating organizations early in the process was perhaps the single factor that was most addressable. The VA enterprise organization and integration with other units could accentuate key communications that would be essential in time-sensitive activities.

VA as a Partner for Future Research

Before the pandemic, the VA had already undertaken a path to enhance its ability to partner as part of the national biomedical research enterprise. The need for COVID-19 therapeutic and vaccine trials accelerated opportunities to plan and develop processes and capabilities to advance this path. As a key strength for VA scientific activities, clinical trials represent a primary medium by which to develop its partnerships. Learning and development have become part of a culture that expedites opportunities for veterans who actively seek ways to contribute to medical knowledge and treatments for their peers and the nation.

CONCLUSIONS

Challenges associated with rapid startup and completion of clinical trials have been discussed for some time. During the pandemic, needs and barriers were magnified because of the heightened urgency for evidence-based therapeutics and vaccines. While the VA faced similar problems as well as those specific to it as a health care system, it had the opportunity to learn and more systematically implement solutions to help in its partnered efforts.¹⁰ As an enterprise, the VA hopes to apply lessons learned, strategies, and best practices to further its goals to enhance veteran access to clinical trials and respond to any future need to quickly establish evidence bases in pandemics and other health emergencies that warrant the rapid implementation of research.

Acknowledgments

The activities reported here were supported by the US Department of Veterans Affairs, Office of Research and Development.

The US Department of Veterans Affairs (VA) plays a substantial role in the nation’s public health through the Veterans Health Administration (VHA). Its statutory missions of teaching, clinical care, and research enable it to serve a foundational role in the US biomedical enterprise.¹ Throughout its extensive network of VA medical centers (VAMCs) and partnering academic affiliates, thousands of clinicians and researchers have been trained to improve the lives of veterans and benefit the lives of all Americans. In supporting the largest US integrated health care system, the VA also has numerous capabilities and resources that distinctively position it to produce scientific and clinical results specifically within the context of providing care. The VA has formed partnerships with other federal agencies, industry, and nonprofit entities. Its ability to be a nexus of health care and practice, scientific discovery, and innovative ways to integrate shared interests in these areas have led to many transformative endeavors that save lives and improve the quality of care for veterans and the public.

The COVID-19 pandemic triggered another mission: service in times of national emergency. Known as the Fourth Mission, the VA rapidly shifted to highlight how its health care and research enterprises could apply strengths in a unique, coordinated manner. While the Fourth Mission is typically considered in the context of clinical care, the VA’s movement toward greater integration facilitated the role of research as a key component in efforts under a learning health care model.²

VA Office of Research and Development

Within the VHA, the Office of Research and Development (ORD) develops research policy and oversees interdisciplinary efforts focused on generating evidence to improve veteran health.³ These activities span at least 100 of 171 VAMCs and include thousands of investigators and staff across all major health research disciplines. Many of these investigators are also clinicians who provide patient care and are experts in the prevention, diagnosis, and treatment of diseases and disorders affecting veterans.

The ORD has invested in a range of scientific, operational, regulatory, and technological assets and infrastructure as part of its enterprise. These strengths come from a nearly 100-year history originating as part of a set of hospital-based medical studies. This established the model for a culture of cooperative research within the VA and with external groups who benefit from the VA’s foundational role in multisite clinical trials.^2,4,5 Today, the VA prioritizes bench-to-bedside research covering a broad spectrum of investigations, which are integrated with clinical operations and systems that deliver care.³ The VA supports an extensive range of work that covers core areas in preclinical and clinical studies to health services research, rehabilitation and implementation science, establishing expertise in genomic and data sciences, and more recent activities in artificial intelligence.

In 2017, the ORD began a focused strategy to transform into a national enterprise that capitalized on its place within the VA and its particular ability to translate and implement scientific findings into real impact for veteran health and care through 5 initiatives: (1) enhancing veteran access to high-quality clinical trials; (2) increasing the substantial real-world impact of VA Research; (3) putting VA data to work for veteran health; (4) promoting diversity, equity, and inclusion within our sphere of influence; and (5) building community through research. These activities are interrelated and, where possible, the ORD works with other VA clinical and operational offices to accomplish multiple goals and coordinate within the health care system. As such, the VA continually seeks to increase efficiencies and improve abilities that provide veterans with best-in-class health care. While still in its early stages, this strategy and its initiatives established a path for the ORD response to the pandemic.

Within 2 weeks of the World Health Organization and the US declaring a COVID-19 pandemic, the ORD began to address the developing needs and challenges of the yet unknown emerging public health threat. This included outreach to and contact from federal, academic, and industry partners. At the same time, the ORD maintained its focus and energy to support its ongoing veteran-centric research portfolio and VHA health care system needs across its broad scope of activities.

This article discusses how the pandemic accelerated the VA’s research enterprise strategy and enacted a response, highlighting the advantages and strengths of this direction. We demonstrate how this evolving strategy enabled the VA to quickly leverage partnerships during a health emergency. While the ORD and VA Research have been used interchangeably, we will attempt to distinguish between the office that serves as headquarters for the national enterprise—the ORD—and the components of that enterprise composed of scientific personnel, equipment, operational units, and partners—VA Research. Finally, we present lessons from this experience toward a broader, post–COVID-19, enterprise-wide approach that the VA has for providing evidence-based care. These experiences may enrich our understanding of postpandemic future research opportunities with the VA as a leader and partner who leverages its commitment to veterans to improve the nation’s health.

ORGANIZING THE VA COVID-19 RESEARCH RESPONSE

VA Research seeks to internally standardize and integrate collaborations with clinical and operational partners throughout the agency. When possible, it seeks to streamline partnership efforts involving external groups less familiar with how the VA operates or its policies, as well as its capabilities. This need was more obvious during the pandemic, and the ORD assembled its COVID-19 response quickly.⁶

figure.png

In early January 2020, VA offices, including the ORD, were carefully observing COVID-19. On March 4, 2020, a week before the World Health Organization declared COVID-19 a pandemic, the ORD and its National Research Advisory Council arranged a briefing from VA public health leaders to deal with reported cases of COVID-19 and VA plans. Immediately afterward, the ORD Chief Research and Development Officer gathered a team of experts in clinical research, infectious disease, and public health to strategize a broader research enterprise approach to the pandemic. This group quickly framed 3 key targets: (1) identify critical research questions to prioritize; (2) provide operational guidance to the research community; and (3) uphold VA research staff safety. This discussion led to the creation of a larger ORD COVID-19 Research Response Team that managed activities within this scope. This team included other ORD leaders and staff with operational, scientific, and regulatory expertise charged with enterprise-level planning and execution for all research activities addressing or affected by the pandemic (Figure).

Effective and timely communication was chief among key ORD responsibilities. On March 19, 2020, the Response Team informed the VA Research community about ORD plans for organizing the VA COVID-19 research response.⁷ It also mobilized VA research programs and investigators to support an enterprise approach that would be coordinated centrally. We achieved communication goals by developing a dedicated website, which provided a means to distribute up-to-date notices and guidance, answer frequently asked questions, and alert investigators about research opportunities. The site enabled the field to report on its efforts, which enhanced leadership and community awareness. A working group of ORD and field personnel managed communications. Given the volume of existing non–COVID-19 research, we established a research continuity of operations plan to provide guidelines for study participant and research staff safety. The ORD issued an unprecedented full-stop administrative hold on in-person research activities after the global announcement of the pandemic. This policy provided formal protections for research programs to safeguard staff and research participants and to determine appropriate alternatives to conduct research activities within necessary social distancing, safety, and other clinical care parameters. It also aligned with guidance and requirements that local VAMCs issued for their operations and care priorities.

The Response Team also established a scientific steering committee of VA infectious disease, critical care, informatics, and epidemiology experts to prioritize research questions, identify research opportunities, and evaluate proposals using a modified expeditious scientific review process. This group also minimized duplicate scientific efforts that might be expected from a large pool of investigators simultaneously pursuing similar research questions. Committee recommendations set up a portfolio that included basic science efforts in diagnostics, clinical trials, population studies, and research infrastructure.

Leveraging Existing Infrastructure

Besides quickly organizing a central touchpoint for the VA COVID-19 research response, the ORD capitalized on its extensive nationwide infrastructure. One key component was the Cooperative Studies Program (CSP); the longstanding VA clinical research enterprise that supports the planning and conduct of large multicenter clinical trials and epidemiological studies. The CSP includes experts at 5 data and statistical coordinating centers, a clinical research pharmacy coordinating center, and 4 epidemiological resource centers.⁸ CSP studies provide definitive evidence for clinical practice and care of veterans and the nation. CSP’s CONFIRM trial (CSP 577) is the largest VA interventional study with > 50,000 veterans.⁹ CONFIRM followed the Trial of Varicella Zoster Vaccine for the Prevention of Herpes Zoster and Its Complications (CSP 403), which involved > 38,000 participants to evaluate a vaccine to reduce the burden of illness-associated herpes zoster (shingles). In the study, the vaccine markedly reduced the shingles burden of illness among older adults.¹⁰ These studies highlight the CSP cohort development ability as evidenced by the Million Veteran Program.¹¹

VA Research, particularly through the CSP, contributed to multiple federal actions for COVID-19. The CSP had already established partnerships with federal and industry groups in multisite clinical trials and observational studies. During COVID-19, the ORD established a COVID-19 clinical trial master protocol framework: the VA CoronavirUs Research & Efficacy Studies network.⁹ The CSP also supported studies by the Coronavirus Prevention Network, the National Institute of Allergy and Infectious Disease (NIAID), and the US Food and Drug Administration (FDA). As such, the VA could translate requirements in working with an industry sponsor on the rapid execution of studies within a federal health care system. Much of the success arose when there was either earlier engagement in planning and/or existing familiarity among parties with operational and regulatory requirements.

table_1.png

Before the pandemic, the ORD had also been working on various external partnerships to increase opportunities for veterans in clinical trial participation, particularly for cancer, which Caroff and colleagues discuss further.¹² A newly emerging Partnered Research Program (PRP) offered a strategy for participation in the major COVID-19 vaccine efficacy clinical trials. VA Research, through PRP and CSP, rapidly engaged others and managed critical communication (Table 1). In quickly pivoting to COVID-19 clinical studies, the VA also used the Networks of Dedicated Enrollment Sites (NODES), its site-based, CSP-supported infrastructure of existing investigators and coordinators with clinical, operational, and regulatory proficiency for large trials.^13,14 Together, the CSP and PRP solidified the VA’s scientific, operational, and regulatory support basis for working with industry partners and federal agencies to conduct therapeutic and vaccine trials.

Speed, Knowledge, and Safety

The scope of VA Research partnerships covers several goals but can be broadly categorized in the following ways: research aimed at evaluating the efficacy of new treatments; development of infrastructure to facilitate more rapid and innovative approaches to research; and building connections within the health care system to take an enterprise approach to research.

Activities are not limited to COVID-19. The VA partners with federal entities on research primarily through interagency agreements whose authorities are derived from the Economy Act (31 USC § 1535). For industry and nonfederal groups, the VA enters into Cooperative Research and Development Agreements that are rooted in the Federal Technology Transfer Act (15 USC § 3710). Although the VA has experience in each of these processes, COVID-19 prompted many groups, existing partners and new ones, to engage with the VA. Consequently, the ORD needed to quickly understand the complexities of how to handle such engagements on a larger scale. The VA Research enterprise strategy also focused on facilitating these processes.

As part of VA integration goals, ORD leaders engaged VA clinical leaders, especially in Public Health, Preventive Medicine, Pharmacy Benefits Management, and Pathology and Laboratory services. The ORD also worked closely with operational leaders, including those responsible for the Veterans Integrated Service Networks and VAMC chiefs of staff and network chief medical officers. The ORD’s familiarity with coordinating complex activities for research further helped to organize nonresearch responses for clinical needs and resources to support the VA COVID-19 response. The Office of the Under Secretary for Health recognized VA Research’s critical role as part of the VA health care system. In turn, it served as a major champion to drive success among the active research efforts, especially the partnered efforts, responding to COVID-19. Continuously communicating support and offering resources for the agency’s overall COVID-19 response reinforced the positive impact of VA Research that extended beyond its traditional roles. That is, the research component of VHA was highlighted as an integral part of the COVID-19 response along with its clinical operations. This integrated approach was perhaps best demonstrated in a VHA-wide push to start and conduct the national vaccine efficacy trials.

Other COVID-19 research supported by the ORD included participation in the Mayo Clinic–led convalescent plasma expanded access treatment protocol, which had emerged as a potential therapeutic option.¹⁵ The ORD provided centralized regulatory support to nearly 100 VAMCs, helping to reduce inconsistencies in protocol approval processes for what was hoped to be a promising treatment for COVID-19.¹⁶ This rapid approach to address a real-time treatment option demonstrated the VA Research capability for swift mobilization in an emergency.

The ORD also coordinated with other federal agencies. For example, it collaborated with the US Department of Defense to begin a parallel observational study on COVID-19 infections and potential severe outcomes. The study enrolled > 3000 veterans who are being followed for up to 2 years to better understand the natural history and course of COVID-19.¹⁷ Other interagency efforts focused on vaccine and therapeutic trials, including Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) with the National Institutes of Health. In these activities, VA Research helped increase recruitment, particularly of a more diverse patient population, in helping to assess promising treatments.¹⁰

table_2.png

Motivated by its expanding portfolio of COVID-19 intervention studies, the VA also created a COVID-19 research registry for all VA investigators. This registry included almost 59,000 veterans who indicated a willingness to volunteer for clinical studies. This registry exemplified a long-standing tradition of veterans willing to serve their nation again in a time of need. Iaquinto and colleagues showcased how VHA programs (eg, Office of Healthcare Innovation and Learning) collaborated by expediting a study on 3D-printed swabs to address supply chain shortages. The study, which involved the FDA, showed that the printed swabs were as effective as commercially available ones.¹⁸ It provided evidence supporting the production and dissemination of a greater number of testing swabs to the public while also reducing the cost and time requirements (Table 2).

Altogether, these collaborative efforts advanced a transformative approach within the VA that was already happening but was accelerated by the pandemic. Such activities enabled greater understanding throughout the VA for how research is not merely complementary but an integrated part of how veterans receive health care. By giving opportunities to veterans to participate in studies, especially clinical studies, the VA created a path in which such expectations, understanding, and operations were more fluid.

Future Directions

The VA continues to work for veterans by emphasizing its strategic goals and strengths in clinical, data science, and other pioneering activities at an enterprise level to provide the highest quality evidence for care. These capabilities perpetuate a scientific and learning environment that also builds toward the future by giving junior investigators and others opportunities to work within a national health care setting. In turn, this provides a more focused perspective on endeavors that align with the VA mission through ORD-supported career development, merit review (independent investigator submissions), and CSP.¹⁹ Preclinical, health services, genomic, and implementation research were given insights into more effective operational and methodological partnerships to help inform the health care system. The pandemic also served to strengthen our ability to mobilize and prepare even faster for emergencies and other potential disease outbreaks, including newer pandemic concerns (eg, mpox, Ebola) from research and public health perspectives.

Conclusions

Throughout its 100-year history, VA Research has been a critical, enduring institution within the national medical landscape. The ability to collaborate with partners has helped us to design and create even better processes, optimize and maximize our infrastructure, and learn more about common research interests that can be even more responsive to national health care needs. As an enterprise, VA Research also aims to continually learn and expand on these valuable lessons gained from internal, interagency, and industry collaborations to effectively meet and exceed our mission to serve our veterans.

Acknowledgments

The authors acknowledge Daphne Swancutt for her contribution as copywriter for this manuscript.

The US Department of Veterans Affairs (VA) plays a substantial role in the nation’s public health through the Veterans Health Administration (VHA). Its statutory missions of teaching, clinical care, and research enable it to serve a foundational role in the US biomedical enterprise.¹ Throughout its extensive network of VA medical centers (VAMCs) and partnering academic affiliates, thousands of clinicians and researchers have been trained to improve the lives of veterans and benefit the lives of all Americans. In supporting the largest US integrated health care system, the VA also has numerous capabilities and resources that distinctively position it to produce scientific and clinical results specifically within the context of providing care. The VA has formed partnerships with other federal agencies, industry, and nonprofit entities. Its ability to be a nexus of health care and practice, scientific discovery, and innovative ways to integrate shared interests in these areas have led to many transformative endeavors that save lives and improve the quality of care for veterans and the public.

The COVID-19 pandemic triggered another mission: service in times of national emergency. Known as the Fourth Mission, the VA rapidly shifted to highlight how its health care and research enterprises could apply strengths in a unique, coordinated manner. While the Fourth Mission is typically considered in the context of clinical care, the VA’s movement toward greater integration facilitated the role of research as a key component in efforts under a learning health care model.²

VA Office of Research and Development

Within the VHA, the Office of Research and Development (ORD) develops research policy and oversees interdisciplinary efforts focused on generating evidence to improve veteran health.³ These activities span at least 100 of 171 VAMCs and include thousands of investigators and staff across all major health research disciplines. Many of these investigators are also clinicians who provide patient care and are experts in the prevention, diagnosis, and treatment of diseases and disorders affecting veterans.

The ORD has invested in a range of scientific, operational, regulatory, and technological assets and infrastructure as part of its enterprise. These strengths come from a nearly 100-year history originating as part of a set of hospital-based medical studies. This established the model for a culture of cooperative research within the VA and with external groups who benefit from the VA’s foundational role in multisite clinical trials.^2,4,5 Today, the VA prioritizes bench-to-bedside research covering a broad spectrum of investigations, which are integrated with clinical operations and systems that deliver care.³ The VA supports an extensive range of work that covers core areas in preclinical and clinical studies to health services research, rehabilitation and implementation science, establishing expertise in genomic and data sciences, and more recent activities in artificial intelligence.

In 2017, the ORD began a focused strategy to transform into a national enterprise that capitalized on its place within the VA and its particular ability to translate and implement scientific findings into real impact for veteran health and care through 5 initiatives: (1) enhancing veteran access to high-quality clinical trials; (2) increasing the substantial real-world impact of VA Research; (3) putting VA data to work for veteran health; (4) promoting diversity, equity, and inclusion within our sphere of influence; and (5) building community through research. These activities are interrelated and, where possible, the ORD works with other VA clinical and operational offices to accomplish multiple goals and coordinate within the health care system. As such, the VA continually seeks to increase efficiencies and improve abilities that provide veterans with best-in-class health care. While still in its early stages, this strategy and its initiatives established a path for the ORD response to the pandemic.

Within 2 weeks of the World Health Organization and the US declaring a COVID-19 pandemic, the ORD began to address the developing needs and challenges of the yet unknown emerging public health threat. This included outreach to and contact from federal, academic, and industry partners. At the same time, the ORD maintained its focus and energy to support its ongoing veteran-centric research portfolio and VHA health care system needs across its broad scope of activities.

This article discusses how the pandemic accelerated the VA’s research enterprise strategy and enacted a response, highlighting the advantages and strengths of this direction. We demonstrate how this evolving strategy enabled the VA to quickly leverage partnerships during a health emergency. While the ORD and VA Research have been used interchangeably, we will attempt to distinguish between the office that serves as headquarters for the national enterprise—the ORD—and the components of that enterprise composed of scientific personnel, equipment, operational units, and partners—VA Research. Finally, we present lessons from this experience toward a broader, post–COVID-19, enterprise-wide approach that the VA has for providing evidence-based care. These experiences may enrich our understanding of postpandemic future research opportunities with the VA as a leader and partner who leverages its commitment to veterans to improve the nation’s health.

ORGANIZING THE VA COVID-19 RESEARCH RESPONSE

VA Research seeks to internally standardize and integrate collaborations with clinical and operational partners throughout the agency. When possible, it seeks to streamline partnership efforts involving external groups less familiar with how the VA operates or its policies, as well as its capabilities. This need was more obvious during the pandemic, and the ORD assembled its COVID-19 response quickly.⁶

figure.png

In early January 2020, VA offices, including the ORD, were carefully observing COVID-19. On March 4, 2020, a week before the World Health Organization declared COVID-19 a pandemic, the ORD and its National Research Advisory Council arranged a briefing from VA public health leaders to deal with reported cases of COVID-19 and VA plans. Immediately afterward, the ORD Chief Research and Development Officer gathered a team of experts in clinical research, infectious disease, and public health to strategize a broader research enterprise approach to the pandemic. This group quickly framed 3 key targets: (1) identify critical research questions to prioritize; (2) provide operational guidance to the research community; and (3) uphold VA research staff safety. This discussion led to the creation of a larger ORD COVID-19 Research Response Team that managed activities within this scope. This team included other ORD leaders and staff with operational, scientific, and regulatory expertise charged with enterprise-level planning and execution for all research activities addressing or affected by the pandemic (Figure).

Effective and timely communication was chief among key ORD responsibilities. On March 19, 2020, the Response Team informed the VA Research community about ORD plans for organizing the VA COVID-19 research response.⁷ It also mobilized VA research programs and investigators to support an enterprise approach that would be coordinated centrally. We achieved communication goals by developing a dedicated website, which provided a means to distribute up-to-date notices and guidance, answer frequently asked questions, and alert investigators about research opportunities. The site enabled the field to report on its efforts, which enhanced leadership and community awareness. A working group of ORD and field personnel managed communications. Given the volume of existing non–COVID-19 research, we established a research continuity of operations plan to provide guidelines for study participant and research staff safety. The ORD issued an unprecedented full-stop administrative hold on in-person research activities after the global announcement of the pandemic. This policy provided formal protections for research programs to safeguard staff and research participants and to determine appropriate alternatives to conduct research activities within necessary social distancing, safety, and other clinical care parameters. It also aligned with guidance and requirements that local VAMCs issued for their operations and care priorities.

The Response Team also established a scientific steering committee of VA infectious disease, critical care, informatics, and epidemiology experts to prioritize research questions, identify research opportunities, and evaluate proposals using a modified expeditious scientific review process. This group also minimized duplicate scientific efforts that might be expected from a large pool of investigators simultaneously pursuing similar research questions. Committee recommendations set up a portfolio that included basic science efforts in diagnostics, clinical trials, population studies, and research infrastructure.

Leveraging Existing Infrastructure

Besides quickly organizing a central touchpoint for the VA COVID-19 research response, the ORD capitalized on its extensive nationwide infrastructure. One key component was the Cooperative Studies Program (CSP); the longstanding VA clinical research enterprise that supports the planning and conduct of large multicenter clinical trials and epidemiological studies. The CSP includes experts at 5 data and statistical coordinating centers, a clinical research pharmacy coordinating center, and 4 epidemiological resource centers.⁸ CSP studies provide definitive evidence for clinical practice and care of veterans and the nation. CSP’s CONFIRM trial (CSP 577) is the largest VA interventional study with > 50,000 veterans.⁹ CONFIRM followed the Trial of Varicella Zoster Vaccine for the Prevention of Herpes Zoster and Its Complications (CSP 403), which involved > 38,000 participants to evaluate a vaccine to reduce the burden of illness-associated herpes zoster (shingles). In the study, the vaccine markedly reduced the shingles burden of illness among older adults.¹⁰ These studies highlight the CSP cohort development ability as evidenced by the Million Veteran Program.¹¹

VA Research, particularly through the CSP, contributed to multiple federal actions for COVID-19. The CSP had already established partnerships with federal and industry groups in multisite clinical trials and observational studies. During COVID-19, the ORD established a COVID-19 clinical trial master protocol framework: the VA CoronavirUs Research & Efficacy Studies network.⁹ The CSP also supported studies by the Coronavirus Prevention Network, the National Institute of Allergy and Infectious Disease (NIAID), and the US Food and Drug Administration (FDA). As such, the VA could translate requirements in working with an industry sponsor on the rapid execution of studies within a federal health care system. Much of the success arose when there was either earlier engagement in planning and/or existing familiarity among parties with operational and regulatory requirements.

table_1.png

Before the pandemic, the ORD had also been working on various external partnerships to increase opportunities for veterans in clinical trial participation, particularly for cancer, which Caroff and colleagues discuss further.¹² A newly emerging Partnered Research Program (PRP) offered a strategy for participation in the major COVID-19 vaccine efficacy clinical trials. VA Research, through PRP and CSP, rapidly engaged others and managed critical communication (Table 1). In quickly pivoting to COVID-19 clinical studies, the VA also used the Networks of Dedicated Enrollment Sites (NODES), its site-based, CSP-supported infrastructure of existing investigators and coordinators with clinical, operational, and regulatory proficiency for large trials.^13,14 Together, the CSP and PRP solidified the VA’s scientific, operational, and regulatory support basis for working with industry partners and federal agencies to conduct therapeutic and vaccine trials.

Speed, Knowledge, and Safety

The scope of VA Research partnerships covers several goals but can be broadly categorized in the following ways: research aimed at evaluating the efficacy of new treatments; development of infrastructure to facilitate more rapid and innovative approaches to research; and building connections within the health care system to take an enterprise approach to research.

Activities are not limited to COVID-19. The VA partners with federal entities on research primarily through interagency agreements whose authorities are derived from the Economy Act (31 USC § 1535). For industry and nonfederal groups, the VA enters into Cooperative Research and Development Agreements that are rooted in the Federal Technology Transfer Act (15 USC § 3710). Although the VA has experience in each of these processes, COVID-19 prompted many groups, existing partners and new ones, to engage with the VA. Consequently, the ORD needed to quickly understand the complexities of how to handle such engagements on a larger scale. The VA Research enterprise strategy also focused on facilitating these processes.

As part of VA integration goals, ORD leaders engaged VA clinical leaders, especially in Public Health, Preventive Medicine, Pharmacy Benefits Management, and Pathology and Laboratory services. The ORD also worked closely with operational leaders, including those responsible for the Veterans Integrated Service Networks and VAMC chiefs of staff and network chief medical officers. The ORD’s familiarity with coordinating complex activities for research further helped to organize nonresearch responses for clinical needs and resources to support the VA COVID-19 response. The Office of the Under Secretary for Health recognized VA Research’s critical role as part of the VA health care system. In turn, it served as a major champion to drive success among the active research efforts, especially the partnered efforts, responding to COVID-19. Continuously communicating support and offering resources for the agency’s overall COVID-19 response reinforced the positive impact of VA Research that extended beyond its traditional roles. That is, the research component of VHA was highlighted as an integral part of the COVID-19 response along with its clinical operations. This integrated approach was perhaps best demonstrated in a VHA-wide push to start and conduct the national vaccine efficacy trials.

Other COVID-19 research supported by the ORD included participation in the Mayo Clinic–led convalescent plasma expanded access treatment protocol, which had emerged as a potential therapeutic option.¹⁵ The ORD provided centralized regulatory support to nearly 100 VAMCs, helping to reduce inconsistencies in protocol approval processes for what was hoped to be a promising treatment for COVID-19.¹⁶ This rapid approach to address a real-time treatment option demonstrated the VA Research capability for swift mobilization in an emergency.

The ORD also coordinated with other federal agencies. For example, it collaborated with the US Department of Defense to begin a parallel observational study on COVID-19 infections and potential severe outcomes. The study enrolled > 3000 veterans who are being followed for up to 2 years to better understand the natural history and course of COVID-19.¹⁷ Other interagency efforts focused on vaccine and therapeutic trials, including Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) with the National Institutes of Health. In these activities, VA Research helped increase recruitment, particularly of a more diverse patient population, in helping to assess promising treatments.¹⁰

table_2.png

Motivated by its expanding portfolio of COVID-19 intervention studies, the VA also created a COVID-19 research registry for all VA investigators. This registry included almost 59,000 veterans who indicated a willingness to volunteer for clinical studies. This registry exemplified a long-standing tradition of veterans willing to serve their nation again in a time of need. Iaquinto and colleagues showcased how VHA programs (eg, Office of Healthcare Innovation and Learning) collaborated by expediting a study on 3D-printed swabs to address supply chain shortages. The study, which involved the FDA, showed that the printed swabs were as effective as commercially available ones.¹⁸ It provided evidence supporting the production and dissemination of a greater number of testing swabs to the public while also reducing the cost and time requirements (Table 2).

Altogether, these collaborative efforts advanced a transformative approach within the VA that was already happening but was accelerated by the pandemic. Such activities enabled greater understanding throughout the VA for how research is not merely complementary but an integrated part of how veterans receive health care. By giving opportunities to veterans to participate in studies, especially clinical studies, the VA created a path in which such expectations, understanding, and operations were more fluid.

Future Directions

The VA continues to work for veterans by emphasizing its strategic goals and strengths in clinical, data science, and other pioneering activities at an enterprise level to provide the highest quality evidence for care. These capabilities perpetuate a scientific and learning environment that also builds toward the future by giving junior investigators and others opportunities to work within a national health care setting. In turn, this provides a more focused perspective on endeavors that align with the VA mission through ORD-supported career development, merit review (independent investigator submissions), and CSP.¹⁹ Preclinical, health services, genomic, and implementation research were given insights into more effective operational and methodological partnerships to help inform the health care system. The pandemic also served to strengthen our ability to mobilize and prepare even faster for emergencies and other potential disease outbreaks, including newer pandemic concerns (eg, mpox, Ebola) from research and public health perspectives.

Conclusions

Throughout its 100-year history, VA Research has been a critical, enduring institution within the national medical landscape. The ability to collaborate with partners has helped us to design and create even better processes, optimize and maximize our infrastructure, and learn more about common research interests that can be even more responsive to national health care needs. As an enterprise, VA Research also aims to continually learn and expand on these valuable lessons gained from internal, interagency, and industry collaborations to effectively meet and exceed our mission to serve our veterans.

Acknowledgments

The authors acknowledge Daphne Swancutt for her contribution as copywriter for this manuscript.

The US Department of Veterans Affairs (VA) plays a substantial role in the nation’s public health through the Veterans Health Administration (VHA). Its statutory missions of teaching, clinical care, and research enable it to serve a foundational role in the US biomedical enterprise.¹ Throughout its extensive network of VA medical centers (VAMCs) and partnering academic affiliates, thousands of clinicians and researchers have been trained to improve the lives of veterans and benefit the lives of all Americans. In supporting the largest US integrated health care system, the VA also has numerous capabilities and resources that distinctively position it to produce scientific and clinical results specifically within the context of providing care. The VA has formed partnerships with other federal agencies, industry, and nonprofit entities. Its ability to be a nexus of health care and practice, scientific discovery, and innovative ways to integrate shared interests in these areas have led to many transformative endeavors that save lives and improve the quality of care for veterans and the public.

The COVID-19 pandemic triggered another mission: service in times of national emergency. Known as the Fourth Mission, the VA rapidly shifted to highlight how its health care and research enterprises could apply strengths in a unique, coordinated manner. While the Fourth Mission is typically considered in the context of clinical care, the VA’s movement toward greater integration facilitated the role of research as a key component in efforts under a learning health care model.²

VA Office of Research and Development

Within the VHA, the Office of Research and Development (ORD) develops research policy and oversees interdisciplinary efforts focused on generating evidence to improve veteran health.³ These activities span at least 100 of 171 VAMCs and include thousands of investigators and staff across all major health research disciplines. Many of these investigators are also clinicians who provide patient care and are experts in the prevention, diagnosis, and treatment of diseases and disorders affecting veterans.

The ORD has invested in a range of scientific, operational, regulatory, and technological assets and infrastructure as part of its enterprise. These strengths come from a nearly 100-year history originating as part of a set of hospital-based medical studies. This established the model for a culture of cooperative research within the VA and with external groups who benefit from the VA’s foundational role in multisite clinical trials.^2,4,5 Today, the VA prioritizes bench-to-bedside research covering a broad spectrum of investigations, which are integrated with clinical operations and systems that deliver care.³ The VA supports an extensive range of work that covers core areas in preclinical and clinical studies to health services research, rehabilitation and implementation science, establishing expertise in genomic and data sciences, and more recent activities in artificial intelligence.

In 2017, the ORD began a focused strategy to transform into a national enterprise that capitalized on its place within the VA and its particular ability to translate and implement scientific findings into real impact for veteran health and care through 5 initiatives: (1) enhancing veteran access to high-quality clinical trials; (2) increasing the substantial real-world impact of VA Research; (3) putting VA data to work for veteran health; (4) promoting diversity, equity, and inclusion within our sphere of influence; and (5) building community through research. These activities are interrelated and, where possible, the ORD works with other VA clinical and operational offices to accomplish multiple goals and coordinate within the health care system. As such, the VA continually seeks to increase efficiencies and improve abilities that provide veterans with best-in-class health care. While still in its early stages, this strategy and its initiatives established a path for the ORD response to the pandemic.

Within 2 weeks of the World Health Organization and the US declaring a COVID-19 pandemic, the ORD began to address the developing needs and challenges of the yet unknown emerging public health threat. This included outreach to and contact from federal, academic, and industry partners. At the same time, the ORD maintained its focus and energy to support its ongoing veteran-centric research portfolio and VHA health care system needs across its broad scope of activities.

This article discusses how the pandemic accelerated the VA’s research enterprise strategy and enacted a response, highlighting the advantages and strengths of this direction. We demonstrate how this evolving strategy enabled the VA to quickly leverage partnerships during a health emergency. While the ORD and VA Research have been used interchangeably, we will attempt to distinguish between the office that serves as headquarters for the national enterprise—the ORD—and the components of that enterprise composed of scientific personnel, equipment, operational units, and partners—VA Research. Finally, we present lessons from this experience toward a broader, post–COVID-19, enterprise-wide approach that the VA has for providing evidence-based care. These experiences may enrich our understanding of postpandemic future research opportunities with the VA as a leader and partner who leverages its commitment to veterans to improve the nation’s health.

ORGANIZING THE VA COVID-19 RESEARCH RESPONSE

VA Research seeks to internally standardize and integrate collaborations with clinical and operational partners throughout the agency. When possible, it seeks to streamline partnership efforts involving external groups less familiar with how the VA operates or its policies, as well as its capabilities. This need was more obvious during the pandemic, and the ORD assembled its COVID-19 response quickly.⁶

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In early January 2020, VA offices, including the ORD, were carefully observing COVID-19. On March 4, 2020, a week before the World Health Organization declared COVID-19 a pandemic, the ORD and its National Research Advisory Council arranged a briefing from VA public health leaders to deal with reported cases of COVID-19 and VA plans. Immediately afterward, the ORD Chief Research and Development Officer gathered a team of experts in clinical research, infectious disease, and public health to strategize a broader research enterprise approach to the pandemic. This group quickly framed 3 key targets: (1) identify critical research questions to prioritize; (2) provide operational guidance to the research community; and (3) uphold VA research staff safety. This discussion led to the creation of a larger ORD COVID-19 Research Response Team that managed activities within this scope. This team included other ORD leaders and staff with operational, scientific, and regulatory expertise charged with enterprise-level planning and execution for all research activities addressing or affected by the pandemic (Figure).

Effective and timely communication was chief among key ORD responsibilities. On March 19, 2020, the Response Team informed the VA Research community about ORD plans for organizing the VA COVID-19 research response.⁷ It also mobilized VA research programs and investigators to support an enterprise approach that would be coordinated centrally. We achieved communication goals by developing a dedicated website, which provided a means to distribute up-to-date notices and guidance, answer frequently asked questions, and alert investigators about research opportunities. The site enabled the field to report on its efforts, which enhanced leadership and community awareness. A working group of ORD and field personnel managed communications. Given the volume of existing non–COVID-19 research, we established a research continuity of operations plan to provide guidelines for study participant and research staff safety. The ORD issued an unprecedented full-stop administrative hold on in-person research activities after the global announcement of the pandemic. This policy provided formal protections for research programs to safeguard staff and research participants and to determine appropriate alternatives to conduct research activities within necessary social distancing, safety, and other clinical care parameters. It also aligned with guidance and requirements that local VAMCs issued for their operations and care priorities.

The Response Team also established a scientific steering committee of VA infectious disease, critical care, informatics, and epidemiology experts to prioritize research questions, identify research opportunities, and evaluate proposals using a modified expeditious scientific review process. This group also minimized duplicate scientific efforts that might be expected from a large pool of investigators simultaneously pursuing similar research questions. Committee recommendations set up a portfolio that included basic science efforts in diagnostics, clinical trials, population studies, and research infrastructure.

Leveraging Existing Infrastructure

Besides quickly organizing a central touchpoint for the VA COVID-19 research response, the ORD capitalized on its extensive nationwide infrastructure. One key component was the Cooperative Studies Program (CSP); the longstanding VA clinical research enterprise that supports the planning and conduct of large multicenter clinical trials and epidemiological studies. The CSP includes experts at 5 data and statistical coordinating centers, a clinical research pharmacy coordinating center, and 4 epidemiological resource centers.⁸ CSP studies provide definitive evidence for clinical practice and care of veterans and the nation. CSP’s CONFIRM trial (CSP 577) is the largest VA interventional study with > 50,000 veterans.⁹ CONFIRM followed the Trial of Varicella Zoster Vaccine for the Prevention of Herpes Zoster and Its Complications (CSP 403), which involved > 38,000 participants to evaluate a vaccine to reduce the burden of illness-associated herpes zoster (shingles). In the study, the vaccine markedly reduced the shingles burden of illness among older adults.¹⁰ These studies highlight the CSP cohort development ability as evidenced by the Million Veteran Program.¹¹

VA Research, particularly through the CSP, contributed to multiple federal actions for COVID-19. The CSP had already established partnerships with federal and industry groups in multisite clinical trials and observational studies. During COVID-19, the ORD established a COVID-19 clinical trial master protocol framework: the VA CoronavirUs Research & Efficacy Studies network.⁹ The CSP also supported studies by the Coronavirus Prevention Network, the National Institute of Allergy and Infectious Disease (NIAID), and the US Food and Drug Administration (FDA). As such, the VA could translate requirements in working with an industry sponsor on the rapid execution of studies within a federal health care system. Much of the success arose when there was either earlier engagement in planning and/or existing familiarity among parties with operational and regulatory requirements.

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Before the pandemic, the ORD had also been working on various external partnerships to increase opportunities for veterans in clinical trial participation, particularly for cancer, which Caroff and colleagues discuss further.¹² A newly emerging Partnered Research Program (PRP) offered a strategy for participation in the major COVID-19 vaccine efficacy clinical trials. VA Research, through PRP and CSP, rapidly engaged others and managed critical communication (Table 1). In quickly pivoting to COVID-19 clinical studies, the VA also used the Networks of Dedicated Enrollment Sites (NODES), its site-based, CSP-supported infrastructure of existing investigators and coordinators with clinical, operational, and regulatory proficiency for large trials.^13,14 Together, the CSP and PRP solidified the VA’s scientific, operational, and regulatory support basis for working with industry partners and federal agencies to conduct therapeutic and vaccine trials.

Speed, Knowledge, and Safety

The scope of VA Research partnerships covers several goals but can be broadly categorized in the following ways: research aimed at evaluating the efficacy of new treatments; development of infrastructure to facilitate more rapid and innovative approaches to research; and building connections within the health care system to take an enterprise approach to research.

Activities are not limited to COVID-19. The VA partners with federal entities on research primarily through interagency agreements whose authorities are derived from the Economy Act (31 USC § 1535). For industry and nonfederal groups, the VA enters into Cooperative Research and Development Agreements that are rooted in the Federal Technology Transfer Act (15 USC § 3710). Although the VA has experience in each of these processes, COVID-19 prompted many groups, existing partners and new ones, to engage with the VA. Consequently, the ORD needed to quickly understand the complexities of how to handle such engagements on a larger scale. The VA Research enterprise strategy also focused on facilitating these processes.

As part of VA integration goals, ORD leaders engaged VA clinical leaders, especially in Public Health, Preventive Medicine, Pharmacy Benefits Management, and Pathology and Laboratory services. The ORD also worked closely with operational leaders, including those responsible for the Veterans Integrated Service Networks and VAMC chiefs of staff and network chief medical officers. The ORD’s familiarity with coordinating complex activities for research further helped to organize nonresearch responses for clinical needs and resources to support the VA COVID-19 response. The Office of the Under Secretary for Health recognized VA Research’s critical role as part of the VA health care system. In turn, it served as a major champion to drive success among the active research efforts, especially the partnered efforts, responding to COVID-19. Continuously communicating support and offering resources for the agency’s overall COVID-19 response reinforced the positive impact of VA Research that extended beyond its traditional roles. That is, the research component of VHA was highlighted as an integral part of the COVID-19 response along with its clinical operations. This integrated approach was perhaps best demonstrated in a VHA-wide push to start and conduct the national vaccine efficacy trials.

Other COVID-19 research supported by the ORD included participation in the Mayo Clinic–led convalescent plasma expanded access treatment protocol, which had emerged as a potential therapeutic option.¹⁵ The ORD provided centralized regulatory support to nearly 100 VAMCs, helping to reduce inconsistencies in protocol approval processes for what was hoped to be a promising treatment for COVID-19.¹⁶ This rapid approach to address a real-time treatment option demonstrated the VA Research capability for swift mobilization in an emergency.

The ORD also coordinated with other federal agencies. For example, it collaborated with the US Department of Defense to begin a parallel observational study on COVID-19 infections and potential severe outcomes. The study enrolled > 3000 veterans who are being followed for up to 2 years to better understand the natural history and course of COVID-19.¹⁷ Other interagency efforts focused on vaccine and therapeutic trials, including Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) with the National Institutes of Health. In these activities, VA Research helped increase recruitment, particularly of a more diverse patient population, in helping to assess promising treatments.¹⁰

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Motivated by its expanding portfolio of COVID-19 intervention studies, the VA also created a COVID-19 research registry for all VA investigators. This registry included almost 59,000 veterans who indicated a willingness to volunteer for clinical studies. This registry exemplified a long-standing tradition of veterans willing to serve their nation again in a time of need. Iaquinto and colleagues showcased how VHA programs (eg, Office of Healthcare Innovation and Learning) collaborated by expediting a study on 3D-printed swabs to address supply chain shortages. The study, which involved the FDA, showed that the printed swabs were as effective as commercially available ones.¹⁸ It provided evidence supporting the production and dissemination of a greater number of testing swabs to the public while also reducing the cost and time requirements (Table 2).

Altogether, these collaborative efforts advanced a transformative approach within the VA that was already happening but was accelerated by the pandemic. Such activities enabled greater understanding throughout the VA for how research is not merely complementary but an integrated part of how veterans receive health care. By giving opportunities to veterans to participate in studies, especially clinical studies, the VA created a path in which such expectations, understanding, and operations were more fluid.

Future Directions

The VA continues to work for veterans by emphasizing its strategic goals and strengths in clinical, data science, and other pioneering activities at an enterprise level to provide the highest quality evidence for care. These capabilities perpetuate a scientific and learning environment that also builds toward the future by giving junior investigators and others opportunities to work within a national health care setting. In turn, this provides a more focused perspective on endeavors that align with the VA mission through ORD-supported career development, merit review (independent investigator submissions), and CSP.¹⁹ Preclinical, health services, genomic, and implementation research were given insights into more effective operational and methodological partnerships to help inform the health care system. The pandemic also served to strengthen our ability to mobilize and prepare even faster for emergencies and other potential disease outbreaks, including newer pandemic concerns (eg, mpox, Ebola) from research and public health perspectives.

Conclusions

Throughout its 100-year history, VA Research has been a critical, enduring institution within the national medical landscape. The ability to collaborate with partners has helped us to design and create even better processes, optimize and maximize our infrastructure, and learn more about common research interests that can be even more responsive to national health care needs. As an enterprise, VA Research also aims to continually learn and expand on these valuable lessons gained from internal, interagency, and industry collaborations to effectively meet and exceed our mission to serve our veterans.

Acknowledgments

The authors acknowledge Daphne Swancutt for her contribution as copywriter for this manuscript.