Appendix D

Relevant National Academies Studies and Historical and Ongoing VCA Work

This report appreciates and builds upon prior work done related to vascularized composite allotransplantation (VCA), organ transplantation, clinical trials, small populations, ethics, and trust in science. Below are brief descriptions of previous National Academies of Sciences, Engineering, and Medicine (the National Academies) reports that are relevant to the study charge that helped ground this report in lessons learned from other disciplines, including the larger discipline of organ transplantation, followed by previous work specific to VCA that is referenced and expanded upon throughout the report.

Previous National Academies Reports

Previous reports that examined the discipline of organ transplantation were key providers of information to this report.

The National Academies published a report in 2017 titled Opportunities for Organ Donor Intervention Research: Saving Lives by Improving the Quality and Quantity of Organs for Transplantation. This report focused on issues within the U.S. organ transplantation system, including research on deceased donor organs and ethical, legal, and regulatory challenges. It provided recommendations on how to conduct ethical and respectful organ donor interventions that ensure transparency for transplant candidates who might receive a transplant, and opportunities to sustain and improve the public’s trust in the process of organ donation and transplantation (NASEM, 2017). While most related research on organ donation has concentrated on improving transplantation techniques and recipient outcomes,

the field of organ donor intervention research aims to maximize the number of usable organs available for transplantation by improving the quality and quantity of organs retrieved from deceased donors. Although outcomes for transplant recipients have improved, and the number of organs transplanted has increased, the demand for organs far exceeds the supply (NASEM, 2017). Several factors contribute to this shortage, including the number of willing donors and the condition of donated organs (NASEM, 2017).

In 2021 the National Academies held a workshop, Exploring the State of the Science of Solid Organ Transplantation and Disability¸ to examine disability associated with organ transplantation. Speakers presented on clinical aspects of posttransplantation recovery and described the implications for physical, cognitive, and psychosocial functioning in adults and children (NASEM, 2021). Workshop participants discussed how transplant recipients commonly experience considerable impairments related to health factors, medication side effects, organ rejection, or other setbacks that can cause functional limitations. (NASEM, 2021).

Finally, Realizing the Promise of Equity in the Organ Transplantation System was published in 2022 and provides recommendations to improve fairness, equity, transparency, and the cost-effectiveness in the donor organ system (NASEM, 2022). The report states that the U.S. organ transplant system, while showing significant growth in the number of transplants performed, faces a critical shortage of organs. Despite successes in organ donation and transplantation, the system is riddled with inconsistencies and unfairness. People’s chance of getting a transplant depends heavily on factors such as race, income, and location, not simply medical need. The report focused on three main areas: unequal access to transplants, inconsistent system performance, and underuse of donated organs. The report primarily focused on solid organ transplantation, but noted the following about VCA:

An additional relevant National Academies study is A National Trauma Care System: Integrating Military and Civilian Trauma Systems to Achieve Zero Preventable Deaths After Injury, published in 2016. The report discussed a learning health system for improving military and civilian trauma care, including recommendations for the White House, the Department of Defense, the Department of Veteran Affairs, the Department of Health and Human Services, the Department of Homeland Security, and the Department of Transportation to promote collaboration and avoid unnecessary death (NASEM, 2016).

Other Previous and Ongoing VCA Work

This report also builds upon VCA-specific work over the last two decades. These are briefly summarized below and referenced throughout the report.

American Society for Reconstructive Surgery and International Society of Vascularized Composite Transplantation Working Groups

The American Society for Reconstructive Surgery, in collaboration with the International Society of Vascularized Composite Transplantation (ISVCA), has created working groups specific to hand transplantation, face transplantation, and chronic rejection. The hand transplant working group is focused on evaluating functional and patient-reported outcome metrics. The face transplant group reviews specific measurements, including examining challenges in coverage and a lack of clear standards. The chronic rejection group is tasked with establishing a working definition of chronic rejection in VCAs (Kaufman et al., 2020).

Banff Foundation for Allograph Pathology

The Banff Allograft Pathology Consensus Process is an international forum that uses a consensus process to develop international transplant pathology classification systems. The first meeting was held in 1991 to develop a universally recognized schema for the pathologic assessment of rejection in kidney transplantation (Racusen et al., 1999; Schneider et al., 2016). The standardization of the rejection language created by the Banff enables objective histopathologic endpoints for international communication, clinical reporting, and preclinical and clinical studies. The collaborative effort across international centers to standardize the language of rejection and implement evidence-based medicine collected has led to continued and responsive evaluation and enhanced patient care. An additional Banff VCA meeting was held in 2007 with the goal of standardizing criteria for the

characterization and reporting of severity and types of rejection. The 2007 Banff VCA working classification for skin containing VCA is the standard for diagnosis of rejection (Cendales et al., 2008; Schneider et al., 2016).

In 2022 the Banff VCA Working Group’s reported on the first revision of the 2007 scoring system (Cendales et al., 2024). The report was the result of a unanimous determination by the working group and investigators and clinicians from the VCA and transplant community that the vascular changes were to be included in the first revision. This represents an ongoing advance in the discipline, improving the ability to integrate vascular changes to the classification to provide a more accurate diagnosis of acute/active chronic rejection in a skin-containing VCA. It is expected that the revisions will motivate studies that can validate the changes and lead to additional modifications in the future. This would also stimulate reproducibility studies, as well as studies to test the criteria with respect to predicting graft outcomes. The goal of the classification is also to guide therapy and improve outcomes. In keeping with the Banff process, subsequent avenues will be the inclusion of chronic rejection and antibody-mediated rejection in addition to the requirement of further research on molecular studies, interobserver reproducibility, and diagnostic impact.

Bethesda, Maryland, Summit Conference

In 2019 a gathering of experts convened in Bethesda, Maryland, for a summit conference to discuss the value of VCA procedures and developed a set of consensus guidelines (Tintle et al., 2022). For face and hand transplants, they discussed the indications, complications, and outcomes of the procedures. For face transplantation, the relevant outcome measures discussed included eating capabilities, motor function, hot/cold discrimination, health-related quality of life, and depression symptoms. For hand transplantation, the group discussed certain complications, such as the development of chronic kidney disease that may require dialysis or a kidney transplant. Experts also discussed life satisfaction post transplant compared to pre transplant for hand transplantation recipients. Scores ranged from 25/100 to 75/100 pre transplant and rose to 79/100 to 100/100 post transplant. (See Chapter 4 for more information on inclusion/exclusion criteria, Chapter 5 for more information on complications, and Chapter 6 for outcome metrics.) The group also discussed costs and financing for face and hand transplantations, noting that estimates of total cost and comparisons to other reconstructive techniques are challenging to quantify (Tintle et al., 2022).

The Brocher Bioethics Working Group

In 2017 the first international workshop on bioethics in VCAs was organized by the Brocher Foundation. This group was created to provide recommendations for improvement based on meaningful debates between experts (Magill et al., 2019). The group discussed 12 key ethical considerations related to VCAs: candidate vulnerabilities; patient experiences; justice and respect for dignity; privacy concerns; procurement, allocation, and policy issues; subject selection; risk–benefit issues; program standards; informed consent; physician and program responsibility and accountability for outcomes, public trust, and perception; patient responsibility and accountability; and exit strategies. Following the discussions, a survey was submitted for 60 VCA stakeholders in order to gain insight into the importance of bioethical challenges in the community (Magill et al., 2019).

The Chauvet Workgroup

The Chauvet Workgroup, supported by the ISVCA, was tasked with examining the psychological impact of VCAs and addressing psychosocial domains through an interdisciplinary platform for the development of psychosocial guidelines using a multicenter collaborative approach. The workgroup met for the first time in Paris, France, in 2014, and has had follow-up meetings in 2016 and 2018 (ISVCA, n.d.; Kumnig et al., 2022).

OPTN Vascularized Composite Allotransplantation Committee

The Organ Procurement and Transplantation Network (OPTN) has formed a VCA committee, made up of 18 current members, charged with considering the implications of allocation, procurement, distribution, and transplantation. The committee attempts to improve access to VCAs and improve the overall outcomes of transplant recipients. This committee focuses on all forms of VCA, not solely face and hand transplants. To date, it has implemented 10 proposals, including guidance on membership requirements for VCA programs, eliminating the use of regions in VCA distributions, and updates to optimizing VCA recovery (OPTN, n.d.).

Policy Institute at King’s College London and AboutFace Two-Step Delphi Study

In 2024, a group of experts in VCA, convened by the Policy Institute at King’s College London, completed a two-step Delphi study and produced 52 international consensus recommendations for face transplantations (Longo et al., 2024). This was the first major international, multidisciplinary

consensus conference on face transplantation. The recommendations were divided into nine categories: patient assessment and selection, indications, social support networks, clinical framework, surgical considerations, data on patient progress and outcomes, definitions of failure and success, public image and perception, and financial sustainability. The results also exposed areas of controversy that would require more research before a recommendation could be made. The formal recommendations were made based on greater than 75 percent agreement among experts. Statements that did not reach 75 percent agreement after two rounds of Delphi were considered dissensus (Longo et al., 2024).

REFERENCES

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