Fifty-Sixth ACBTSA Meeting November 17, 2022 - Meeting Summary

Executive Summary

The Advisory Committee on Blood and Tissue Safety and Availability (ACBTSA) held its 56th meeting to discuss three agenda items: data in support of a recommendation to update the HIV Organ Policy Equity Act (HOPE) Act, establishment of a Tissue Tracking Working Group, and presentations on the Alloantibody Exchange.  The update to the HOPE Act is intended to expand access of HIV-positive to HIV-positive organ transplantation. The ACBTSA received presentations on the legislative background, data on kidney and liver transplants, heart transplants, and lung transplants. The ABCTSA voted to approve the recommendation. The ACBTSA also received a presentation for a proposed Tissue Tracking Working Group, which they approved. Finally, the Advisory Committee also heard two presentations on the Alloantibody Registry & Exchange and approved a recommendation to pledge support for the endeavor.

Meeting Summary

Welcome and Opening Remarks

Claudia Cohn provided a few brief welcoming remarks, and Jim Berger conducted roll call to confirm quorum.

Opening Remarks

Claudia Cohn, MD, PhD, University of Minnesota

Claudia Cohn introduced the three main topics covered in this meeting: the HOPE Act, the formation of a working group by the ACBTSA to address tissue donation tracking, and the Red Blood Cell Antibody Exchange.

Enacted in 2013, the HOPE Act called for the development and publication of research criteria relating to transplantation of HIV-positive organs into HIV-positive individuals. Significant work under the auspices of the HOPE Act has resulted in particular successes in kidney and liver transplants. The HOPE Act Working Group has developed revised recommendations on the transplantation of other organs for ACBTSA to consider.

Approximately 3 million allograft tissues have been transplanted from 50,000 donors to approximately 2.5 million recipients; given this volume, Cohn stated that current tissue tracking and safety measures are inadequate. There are gaps in traceability for tissues by end users, and there are currently no requirements for adverse event reporting by consignees or end users. Two Centers for Disease Control (CDC)-led investigations have highlighted these gaps including a 2015 Mycoplasma hominis investigation and a 2021 Mycobacteria tuberculosis investigation. The ABCTSA made recommendations in 2015 to address these gaps, and will discuss the possibility of assembling a working group to develop new recommendations.

Background and History of the HOPE ACT

Dorry Segev, MD, PhD, Director, Center for Surgical and Transplant Applied Research, New York University Langone Health

2010 HIV Landscape and Transplantation

In 2010, promising results were reported in the field of HIV organ transplantation, specifically related to HIV-negative donors to HIV-positive recipients (D-/R+). Positive outcomes were reported in a kidney transplant study and a liver transplant study from a multicenter National Institutes of Health (NIH) trial, which were published in 2010 and 2012. These studies showed that survivability benefits were comparable among HIV-negative and positive-recipients. Another 2010 study in South Africa showed successful transplant results for HIV-positive donors to HIV-positive recipients (D+/R+).

Dorry Segev noted that during the period in which these studies were published, wait lists were growing for organ transplants for all candidates, including HIV-positive candidates. He emphasized that when a D+/R+ organ donation occurred outside the United States., it helped all candidates because everyone moved forward on the wait list. Within the United States, HIV-positive organs were discarded because of U.S. law, and as a result, HIV-positive patients on the organ donation wait list died. The 1984 National Organ Transplant Act (updated in 1988) 42 U.S.C 274(b) Section 372(b) prohibits “the acquisition of organs that are infected with the etiologic agent for acquired immune deficiency syndrome.” Segev underscored that HIV is the only infection named in the Code of Federal Regulations; all others are governed by the Organ Procurement and Transplantation Network (OPTN), which does not forbid any other donor infections, including hepatitis C virus (HCV).

Legislative History

In order to update the U.S. law, a new bill needed to be brought before Congress. Brian Boyarsky (The Johns Hopkins School of Medicine) conducted research for a prospective bill that outlined the number of potential donors, number of lives that could be saved, and cost savings in the Medicare program. This study demonstrated that 300-500 potential HIV-positive donors were dying per year whose organs could have helped more than 1,000 HIV-positive recipients. The study also noted that each organ donation saved an estimated half a million dollars in Medicare costs. The study received significant media attention, including a story on the front page of the New York Times.

The HOPE Act (P.L. 113-51) was first drafted in March of 2012. HHS provided technical assistance throughout the year, and a final draft was prepared for passage during the following year. Patient groups, transplant organizations, and HIV/AIDS advocacy communities endorsed the legislation, including the American Medical Association. The HOPE Act then garnered bipartisan support in both the U.S. House of Representatives and the Senate. President Obama signed the HOPE Act into law on November 21, 2013. The HOPE Act stipulated that D+/R+ donations would be allowed under research protocols for the first two years of enactment and then reassessed by HHS in 2015. The 2015 federal regulations were then updated to add experience criteria for participating transplant and HIV physicians.

Experience Criteria as a Barrier to Transplantation Equity and Access

A multicenter pilot study was launched in 2016 to determine if D+/R+ transplantation in the United States was feasible, safe, and effective. The NIH also funded two U01 trials for kidney and liver transplantation in this population. Dorry Segev noted that D+/R+ transplantations increased; however, far fewer transplants occurred than originally anticipated by the drafters of the HOPE Act.

The 2015 HOPE Act update stipulated that the minimum combined experience required of the transplant and HIV physicians on a transplant team is five organ-specific cases over four years. Dorry Segev pointed out that these guidelines substantially limit the available programs to conduct transplants. In 2022, this guideline encompasses:

39.8 percent of kidney programs

25.9 percent of liver programs

2.7 percent of lung programs

1.4 percent of heart programs

0 percent of pancreas programs.

Dorry Segev noted that a study was conducted in 2015 to compare experienced centers with non-experienced ones, which demonstrated that there was no difference in survival rates for HIV negative recipients and HIV positive recipients.

Dorry Segev underscored that the current guidelines are problematic. Only a handful of centers can perform D+/R+ transplants, which impacts equity and access to transplantation throughout the United States. Fewer HIV-positive patients receive transplants because fewer organ procurement organizations (OPOs) are incentivized to pursue HIV-positive organ donors. Additionally, OPOs typically pursue donors where multiple organs can be used; however, because D+/R+ lung/heart/pancreas transplant programs are almost nonexistent, this creates an extra disincentive for OPOs. Dorry Segev stated that the current regulations increase stigma, create regulatory burden, and interfere with the innovative and patient-centered personalized spirit of organ transplantation.

Kidney and Liver HOPE Transplant Data

Christine Durand, MD, Associate Professor, Johns Hopkins University School of Medicine

Overview

The HOPE in Action Consortium is multicenter study involving 35 transplant centers across the United States. Their objective is to determine if D+/R+ transplantation is safe and effective. Each center is required to receive a variance, or permission, from OPTN to conduct these transplants. A pilot kidney and liver study was conducted by this consortium from 2016-2019; an NIH U01 kidney transplant study was conducted from 2018-2019; and an NIH U01 liver transplant study began in 2019 and is still ongoing.

Transplant Risks

Christine Durand explained the potential risks for D+/R+ transplantation. One of the main risks is HIV superinfection, in which an organ donor passes a new HIV infection with drug resistance to the recipient. Another risk is HIV-associated end-organ disease. HOPE in Action also considered risks of other donor-derived infections, as well as allograft rejection.

Study Design

Patients are enrolled in HOPE in Action studies under a few specific criteria: they must have no opportunistic infections, their kidney CD4 T-cell count greater than 200, and their liver CD4 T-cell count greater than 100. The study compared D-/R+ recipients to D+/R+ recipients. Donor inclusion criteria includes: no opportunistic infections, any HIV viral load or CD4 T-cell count, and an effective antiretroviral protocol for the recipient to avoid possible HIV superinfections. Because OPOs handled the pairing of donors (HIV-positive and HIV-negative) and recipients instead of the study team, Christine Durand called this a “naturally” randomized trial.

Christine Durand noted that, as an unexpected benefit of the study, organs were acquired from deceased donors with false-positive HIV screening test results. U.S. donors are typically tested for HIV by antibody test and nucleic acid test, which are designed to capture acute HIV infections. However, these assays have a false positive rate of 0.1-0.5 percent, and with more than 20,000 donors tested per year, this testing regime consistently produces false positives. The study team defined false positives as patients with no medical history of HIV, no risk factors, and only one of the two tests yielding an HIV-positive result. Prior to the HOPE Act, these donations were discouraged, and little time was allocated to conduct confirmatory testing; nonetheless, HOPE in Action is able to conduct this confirmatory testing within their research studies.

The primary endpoint for the HOPE in Action studies is patient survival. Secondary outcomes included graft failure, serious adverse events, HIV breakthrough, and other infections. As of October 2022, 185 donors have participated in the study. This includes 128 HIV-positive donors and 57 false positive donors.

Study Outcomes

The NIH HOPE in Action kidney and liver studies are ongoing. These studies are closely monitored by a Data Safety and Monitoring Board (DSMB) and no concerns or safety signals have emerged. Current study data indicate a survival benefit for HIV-positive recipients of HIV-positive and HIV-negative organs. One study analyzed the results from 92 donors contributing 177 organs (131 kidneys and 46 livers) between 2016-2020. Of these donors, 58 were HIV-positive and 34 had false-positive HIV test results. In addition, 30 percent of donors had an unknown HIV infection that was only discovered through testing after they died. Of the remainder of HIV-positive donors, 90 percent received antiretroviral (ART) treatment. There were no major differences in comorbidities between the HIV-positive and HIV false-positive groups. HIV-positive donors were more likely to have coinfections, such as hepatitis B virus, cytomegalovirus (CMV), or syphilis—which are manageable diseases in transplant contexts. Most donors did not have AIDS based on their CD4 T-cell counts. Christine Durand noted that drug resistance is prevalent due to broad access to ART; 42 percent had some drug resistance, but not to the fundamental aspects of ART, which the study team considered predictable and manageable.

NIH Kidney Pilot Study

In the NIH kidney pilot study, 14 centers conducted 75 kidney transplants encompassing 25 D+/R+ and 50 D-/R+ transplantation procedures. The median follow-up time was 1.7 years. No deaths were reported, and graft survival (transplantation with subsequent dialysis) was over 90 percent. There were no differences reported between transplant groups for serious adverse events, hospitalizations due to infections, opportunistic infections, HIV breakthrough, cancer incidence, or one-year renal function.

Allograft rejection was the most common complication among both donor groups. Overall, 36 percent of recipients experienced rejection. In some cases, this led to the failure of the kidney and return to dialysis. There was a higher rejection rate for HIV-positive donors (50 percent vs 29 percent for HIV-negative donors) and Christine Durand emphasized that further study was needed; however, the study still clearly demonstrated a survival benefit. Organ rejection is a known complication in HIV-negative recipients, as well.

NIH Liver Pilot Study

In the NIH liver pilot study, 9 centers conducted 45 liver transplants encompassing 24 D+/R+ and 21 D-/R+ transplantation procedures. Six deaths were reported in for the HIV-positive donor group and 2 in the HIV-negative donor group. Christine Durand noted that investigators expected these results, as deaths are more common in liver transplant patients, overall. There was an 83 precent one-year survival in the HIV-positive donor group and a 100 percent survival in the HIV-negative donor group. Christine Durand pointed out that these results were better than the original NIH multisite pilot study. There were no differences in serious adverse events or HIV breakthrough between the two groups. There were more opportunistic infections in the HIV-positive group, which were common and generally manageable. Cancers were present in both groups, but Christine Durand noted that this did not constitute a safety signal.

HIV Superinfection Assessment

Researchers also examined HIV virology in D+/R+ transplants to look for further evidence of HIV superinfections. They studied 14 donor-recipient kidney pairs and 8 liver donor-recipient pairs. Even in a case with a patient who stopped ART and had a high viral load, no evidence of donor infection was found. Overall, no evidence of superinfections from transplantation was reported in this study.

Conclusions

Christine Durand stated that the evidence supports the conclusion that HIV D+/R+ kidney transplantation is safe. There is excellent patient and graft survival and no signal of increased HIV-related complications such as superinfection or opportunistic infection. The evidence also supports the conclusion that HIV D+/R+ liver transplantation is safe. There is good patient and grant survival, which is better than historical cohorts. There are no signs of HIV-related complications such as superinfection or opportunistic infections.

Heart HOPE Transplant Data

Marcus Pereira, MD, Assistant Professor of Medicine Medical Director, Transplant Infectious Disease Program, Columbia University Irving Medical Center

Overview

People living with HIV have an elevated risk for cardiovascular disease, including a 61 percent increased risk of heart failure with reduced ejection fraction. Marcus Pereira noted that since ART has become widespread, the elevated risk indicates a need for advanced heart failure therapies in this population, even when controlling for medical and social risk factors.

These therapies are comprised of either heart transplant or ventricular-assistive devices. Ventricular-assistive devices are currently available for those living with HIV. A 2021 study found that there was no difference in survival between HIV-positive and HIV-negative patients using ventricular-assistive devices. However, Marcus Pereira underscored that heart transplantation remains the most favorable treatment for individuals with end-stage heart failure.

Heart transplantation for people living with HIV has slowly increased. Prior to 2004, transplantation was considered a contraindication for this population. A total of 114 heart transplants have been performed across 57 centers. There were 7 combined heart-kidney transplants and one heart-liver transplant. Marcus Pereira noted that Columbia University Irving Medical Center has performed 14 transplants; four patients since have died—one in the first year. Candidate selection criteria for Columbia and other centers involve ensuring well-controlled HIV, a lack of opportunistic infections, and a CD4 T-cell count greater than 200—which are similar to the HOPE in Action kidney and liver transplantation criteria.

Relevant Studies

A 2019 study assessed 41 HIV-positive individuals who received a ventricular-assistive device as a bridge to a transplantation procedure versus those who received transplantation alone. Survival rates were 85.9 percent for the first year and 77.3 percent for five years—with no difference in rates for those who received ventricular-assistive devices. Overall, survival rates were not significantly different from HIV-negative populations.

A retrospective study also published in 2019 looked at transplants for HIV-positive patients at 16 centers between 2000-2016. Inclusion criteria for heart transplants in this population were similar to those at Columbia. Marcus Pereira noted that most patients were on alternatives to protease inhibitors in order to avoid complications from other inhibitors used in transplantation. Many received ventricular-assistive support prior to transplantation. The survival rate was approximately 90 percent in the first year, which is similar to the rate of HIV-negative heart transplant recipients. Survival rates for the three- and five-year marks were slightly lower than HIV-negative recipients. Rejection rates did not appear to be significantly associated with ART regimens, even those including protease inhibitors. Infectious complications did not appear to be any more prevalent than the general population.

Implementation

Based on accumulated experience in this field, Marcus Pereira reported that Columbia was comfortable proceeding with D+/R+ heart transplantations. Columbia developed study protocols over a two-year period from 2018-2020. The COVID-19 pandemic has delayed this program. Meanwhile, Montefiore Medical Center conducted their first D+/R+ heart transplant in June of 2022.

Overall, a growing number of D-/R+ heart transplant procedures have been performed since 2005. Retrospective analysis shows comparable survival rates at one year to the general population, but potentially worse outcomes at three and five years. Inclusion criteria typically include stable HIV virologic control. HIV does not seem to be a complicating factor in post-transplant outcomes. Marcus Pereira pointed out that more research is needed on rates of allograft vasculopathy and transplant rejection. He stated that D+/R+ are an important next step in increasing access to heart transplantation in this population.

Lung HOPE Transplant Data

Ghady Haidar, MD, Assistant Professor of Medicine, Division of Infectious Diseases, Transplant ID Program, University of Pittsburgh and UPMC

Overview

Ghady Haider opened his presentation by noting that there are significantly less data for lung transplantation in HIV-positive populations as compared to kidney, liver, and heart transplants. There have been no D+/R+ lung transplants as of yet; however, some D-/R+ lung transplants have been performed, with the first completed in 2004. Lung transplantation to HIV-positive recipients have slowly increased; in 2021, 16 lung transplants were performed for HIV-positive recipients, the largest annual number to date.

Relevant Studies

A 2019 retrospective international study identified seven lung transplants in HIV-positive patients between 2009-2016, and four of these were double lung transplants. These patients were all virally suppressed with median CD4 counts of 638. Similar to other HIV-positive transplant patients, their drug regimens needed to be changed to avoid protease inhibitors. The patients also received varied immunosuppressive therapies, which are common in transplant procedures. These transplant procedures were done either to address Idiopathic Pulmonary Fibrosis (IPF) and interstitial lung disease or chronic obstructive pulmonary disease (COPD). Ghady Haider observed that survival rates for these patients were essentially identical to those in HIV-negative populations. Deaths occurred from non-HIV related causes that are typical in lung transplant patients, such as adenovirus and Klebsiella pneumoniae. Non-fatal infection rates were common and similar to HIV-negative populations, as well.

Another recently published study of HIV-positive lung transplantations from Europe assessed 68 lung transplant centers. This study identified 22 lung transplant recipients, of which the most common reason for transplantation was pulmonary arterial hypertension. A majority were double lung transplants and received immunosuppressive therapies. All transplant candidates were virally suppressed and had manageable CD4 counts before and after transplantation. Some transplant candidates shifted their ART regimen to avoid interactions with protease inhibitors. Median follow-up was two years. Eight of the 22 patients had post-transplant infections, which Haidar observed was remarkably low. He noted that the infections and organ rejection rates matched fairly closely with HIV-negative populations. Three patients had cancer, one of which was likely HIV-related. Four of the 22 patients died, and two of these deaths occurred within three months of the procedure due to hemorrhagic shock and graft failure; Ghady Haidar noted that this unfortunate outcome is not exclusive to the HIV-positive patients. Overall, however, the survival rate for these patients at one, three, and five years was 79 percent. More than half the patients were active and independent at last follow up.

UPMC Experience

The University of Pittsburgh Medical Center (UPMC) has performed seven D-/R+ lung transplants between 2009-2020. All patients were virally undetectable at the time of their procedure and the median CD4 count was 728. Four patients changed their ART regimen in anticipation of transplantation. All patients received immunosuppressive therapies. Six of the seven procedures were double lung transplants. Reasons for the procedure ranged from COPD, IPF, and pulmonary hypertension. Survival rates were similar to other studies—one year survival was 85 percent and three-year survival was 100 percent. The one death reported was not due to HIV-related causes. At follow-up all patients remained virally suppressed. Patients experienced a median of nine post-operation infections, but none were related to HIV. Ghady Haidar reported that, overall, both HIV-negative and HIV-positive patients had similar numbers of post-operative infections.

Conclusions

Ghady Haidar observed that management of HIV-positive lung transplant recipients was essentially identical to HIV-negative recipients, provided they adhere to ART. He noted that issues related to ART can be managed by pharmacists and HIV physicians. Complications appear to be driven by the lung transplants themselves, not HIV. Ghady Haidar pointed out that more research is needed to understand issues surrounding HIV-positive lung donations; there may be unknown risks for infection, given the limited clinician experience with these procedures. UPMC had planned to conduct D+/R+ lung transplants, but the pandemic has delayed this work.

Discussion on HOPE Act Recommendation

Discussion of Presentations

Claudia Cohn opened discussion of the HOPE Act Recommendation in context of the presentations by Dorry Segev, Christine Durand, Marcus Pereira, and Ghady Haidar. Jed Gorlin posed a question regarding the poor rate of organ donation among ethnic minorities and how outreach to these communities might be improved in order to increase acceptance of organ donation. He also inquired whether HIV-positive rates in these communities differed from others. Ghady Haidar noted that he published a study describing an initiative to increase donation rates through the distribution of organ donor cards to people living with HIV. A subsequent survey of these card recipients showed a marked increase in donor registration to 47 percent, which was the approximate participation rate in the state. The donation card asks for a reason if a person does not want to become a donor; 21 percent replied that this was due to HIV infection. Ghady Haidar observed that this response provides an opportunity to educate donors that HIV infection is not a hindrance on organ donation. Dorry Segev added that this education also includes community engagement with potential donors prior to a terminal event and discussion with families and loved ones in the intensive care unit (ICU) progressing toward brain death. He reiterated that OPOs have not pursued HIV-positive donors due to restrictions in the current guidelines and should be encouraged to engage with families to increase donation rates.

Biree Andemariam inquired if there were circumstances in which a donor was thought to be HIV-negative but actually turned out to do be positive. She noted that a study of cases like these may help clinicians, researchers, and policymakers understand the safety implications for HIV-negative recipients willing to take an organ donation from an HIV-positive donor. Dorry Segev responded that a handful of cases exist but are quite rare. A high profile 2007 case occurred in Chicago. Christine Durand pointed out that this case led to the dual testing regime as a failsafe. He observed that new legislation would be required to allow D+/R- donations to occur if researchers decide to study the issue further. Marcus Pereira noted that researchers followed a 2009 D+/R- case in New York and found no complications. He stated that preparations could be made to avoid complications as has been done with donors with HCV. Daryl Kor inquired about the perceptions of HIV-positive patients receiving HIV-positive donor organs. Christine Durand surveyed participants in a multicenter study and found that there was a high willingness to receive HIV-positive donor organs. She stated that there was an even higher willingness to take these organs than from donors who had documented risk behaviors. Gary Marklin asked if there were HIV-positive donors who were registered as donors after cardiac death (DCD). Christina Durand noted that, overall, about 10 percent of HIV-positive donors were DCD.

HOPE Act Recommendation Text

The Committee reviewed the recommendation text and held a discussion on revisions prior to voting to approve the recommendation. The recommendation text is as follows:

For the transplantation of organs from HIV-positive donors into HIV-positive recipients:

Kidneys and Livers – remove statutory “NIH Research Criteria and IRB” requirement (with no special restrictions other than the applicable OPTN kidney and liver policies).

All other organs including thoracic organs – remove statutory “NIH Research Criteria” requirement BUT recommend the Secretary direct the OPTN to develop and implement the following new special policies:

1. OPTN organ-specific variance for each organ other than kidneys and livers

2. Additional organ-specific candidate criteria and transplant program requirements analogous (but not “identical”) to the NIH Research Criteria developed specifically for the unique patient safety and outcomes monitoring characteristics of transplants other than kidneys and livers in HIV patients

3. Additional organ-specific OPTN outcomes monitoring for candidates of organs other than kidneys and livers on the Waiting List and recipients following transplantation

4. Each center/institution must have an IRB-approved protocol that will include measures of outcomes and safety

5. When multiple organs are transplanted simultaneously, the default approach will be to use the guidelines of the organ with more conservative policies

The OPTN should develop and implement the above-listed new special policies within 15 months of receiving this request from the Secretary of Health and Human Services

These criteria will be reviewed and re-evaluated 2 years after implementation.

Jed Gorlin asked if removing the research requirement would have any unintended detrimental effect on available funding for research. Dorry Segev responded that the updated recommendation should not have a direct impact on funding since many transplantation procedures receive non-research funds. Biree Andemariam questioned if the text related to OPTN organ-specific committees making relevant organ-specific policies was directly relevant to lifting the experience criteria to allow more discretion in organ donations in HIV-positive populations; Dorry Segev responded affirmatively and stated that this puts those judgments in the hands of specifically relevant decision-makers at OPTN. Elisa Gordon inquired about what the OPTN variance would entail. Dorry Segev responded that any center that wished to perform HIV-positive organ transplants would need to apply for the OPTN variance, but experience requirements would be under the purview of OPTN based on the new recommendation.

Vote

Marilyn Levi made a motion for the Committee to accept the recommendation. 11 members voted yes. The motion passed.

Tissue Biovigilance Systems Presentation

Timothy L. Pruett, MD, Professor of Surgery and Internal Medicine, University of Minnesota

World Health Organization’s Project NOTIFY

The World Health Organization’s (WHO’s) project NOTIFY is a global initiative for the vigilance and surveillance of substances of human origin. Timothy Pruett, who participates in this initiative, stated that NOTIFY became interested in a recent tuberculosis (TB) outbreak as a result of 113 patients receiving TB-contaminated bone graft products in the United States, as outlined in this article. Of those, 77 percent showed evidence of TB disease, 50 percent were hospitalized, 43 percent required an operative procedure, and 8 percent died. Because there was only one tissue processor for the donor products, investigators were able to locate the source of contamination; however, tissues from donors are often sent to multiple tissue processors, indicating a true need for improved traceability of human tissues.

2009 PHS Analysis

The ACBTSA conducted a biovigilance gap analysis in 2009, which advocated for a comprehensive and integrated patient safety program to collect, analyze, and report on the outcomes of collection and transfusion and transplantation of blood components and derivatives, cells, tissues, and organs. In response, the Public Health Service (PHS) released a report, Biovigilance in the United States, which identified and recommended 16 areas where donor products could be better monitored. Eight areas involved blood, six involved tissue, and two involved organs. Timothy Pruett noted that, since 2009, monitoring in these areas were only partially implemented. A 2011 report proposed more public/private collaboration to accomplish this task, but this did not advance due to lack of funding.

The tissues portion of the gap analysis highlighted several issues. There was limited information on the potential for human cells, tissues, and tissue-based products (HCT/P) to transmit infectious disease as well as what causes of disease can be attributable to HCT/P. Regulations governing HCT/P adverse event reports do not cover healthcare facilities or providers, which limits the mechanisms for tracking HCT/P to recipients.

Timothy Pruett stated that since 2009, cell-based therapeutics have evolved significantly, which increases challenges for oversight and biovigilance. Regenerative medicine researchers have advanced organogenesis and the production of complex structures for metabolic control. Unregulated stem cell labs have opened across the United States. Gene therapies have also expanded significantly, with more industry involvement. Timothy Pruett observed that although these endeavors often involve synthetic production, the interest in allo-products continues to be high. Advanced biopreservation techniques have also evolved, allowing for complex, viable cellular products (and pathogens) to be preserved for long periods of time and distributed worldwide.

Proposed Tissue Tracking Work Group

Timothy Pruett underscored that there is a continuing traceability problem between donors and recipients as documented in the 2022 briefing to the CDC on TB and M. hominis transmissions in tissues. There is also no adverse reporting for the consignees or end users of HCT/P products. This status quo presents an ongoing risk of patient harm, especially in products that contain viable cells.

Prompted by the recent TB outbreak from contaminated tissue, Timothy Pruett proposed a new biovigilance gap analysis of safety issues for when HCT/P are derived from one person and implanted or used by another. Such an analysis would identify effective chains of custody both in organ donation as well as live cells. The goal of this analysis, according to Timothy Pruett, would be to build consensus on areas of improvement in HCT/P safety in the United States and generate a proposal deemed feasible for providers and regulators.

The proposed tissue tracking work group would involve all federal entities involved in tissue donation, including the Food and Drug Administration’s (FDA’s) Center for Biologics Evaluation and Research (CBER), CDC, ACBTSA, Office of the National Coordinator for Health Information Technology (ONC), and other related HHS agencies. Private partners would include OPO, tissue bank processors/manufacturers/distributors, healthcare systems that deal with electronic medical records, recipients of HCT/P, and professional organizations. Timothy Pruett pointed out that outpatient HCT/P surveillance is not part of the OPO system and may require this organization’s involvement, as well.

Discussion on Formation of Tissue Tracking Work Group

Claudia Cohn opened a discussion on Timothy Pruett’s proposal. Susan Galel noted that the Joint Commission has a requirement for tissue tracking in accredited facilities and inquired what gaps a potential work group would monitor that are present in this realm, if any. She also wondered if other licensing organizations should also be involved with the proposed work group. Sridhar Basavaraju responded that, as part of the TB investigation, gaps were identified in traceability for these facilities, despite accreditation. Susan Galel advocated for accreditation agencies to be brought into discussion with a potential Work Group, as well.

Claudia asked committee members if there were any reasons why the ACBTSA should not adopt Timothy Pruett’s proposal to form a Work Group to conduct a gap analysis. Committee members did not voice any concerns.

Alloantibody Exchange Presentation

R. George Hauser, MD, Associate Professor of Laboratory Medicine, Yale University

The goal of the Alloantibody Exchange is proposed system to share alloantibody and antigen data between blood banks. R. George Hauser noted that blood banks share this information as part of patient care, but do not do so online as many electronic health record (EHR) systems operate. The Exchange would pull data from several online providers and store it on cloud servers to facilitate sharing with relevant health care organizations. The Exchange would enable users to learn where blood units containing antibodies and antigens are stored, as well as some blood bank notes about the patient.

Transfusion Safety

In patients, more than 60 percent of red blood cell (RBC) antibodies fall below the level of blood bank detection in a process called evanescence. When blood banks attempt to match blood for a patient whose RBC antibodies have fallen below the level of detection, they may not be aware of which alloantigens they need to match to. A patient in this situation may experience a serious medical complication known as a delayed hemolytic transfusion reaction. George Hauser noted that it can be difficult to get information from various blood banks in a timely fashion when such a scenario occurs. One study documented the high frequency of undetectable antibodies and called for an electronic system to track them, much like the Exchange.

George Hauser observed that EHR records are fragmented as health care systems share records inconsistently across state lines and with other EHR systems. The Exchange is the first attempt to unify blood bank records across the United States. George Hauser stated that the Exchange is a low cost, time saving measure to address this fragmentation problem. The Exchange would not generate any qualitative information about blood banks beyond sharing information about them that would be available via a phone call; however, the Exchange will impose some standardization on identifying antibodies and antigens. He also noted that patient consent is given to the blood bank at the time of transfusion, which should preclude the need for further consent to provide information to the Exchange. George Hauser noted that an upcoming security review will provide recommendations for any needed changes to the consent regime—which he will report to the Work Group.

Support

The Exchange is set up as a 501(c)(3) non-profit in order to act as a neutral third party in collaboration with vendors. George Hauser encouraged the Work Group to support the Exchange at Alloantibody.org. He also requested that Work Group members to contact him and provide examples of letters of support in order to help his organization engage vendors. The goal is to have vendors store patient alloantibody and antigen history from blood banks. George Hauser noted that a growing number of vendors are willing to work with the Exchange, and this will help demonstrate widespread interest and generate more support. Work to develop the Exchange is done primarily by volunteers. Grant support in the form of cloud computing services is provided by Google and Microsoft; this support currently allows blood banks to use the Exchange without incurring costs, but George Hauser pointed out that if the scope of the Exchange increases in scale beyond the next year of operations, additional financial support may be needed.

Next Steps

George Hauser highlighted several vendors that are providing access to alloantibody and antigen data in health care systems. These include Soft Computer, Cerner, Haemonetics, WellSky, Sunquest, and Meditech. He noted that Exchange software enables the generation of reports to reduce barriers to accessing relevant data. George Hauser stated that he has already validated the Soft Computer and Cerner interfaces with the Exchange. Other vendors are still reviewing the Exchange.

The Exchange is also receiving support from other important sectors. Advocacy groups are currently organizing petitions for municipalities to adopt the Exchange. George Hauser stated that 75 percent of the top blood bank directors in the U.S. News and World Report endorse using the Exchange, as well. The Exchange is currently seeking support from patient advocacy communities. George Hauser stated that the Exchange will become available to users after an upcoming legal review. The Exchange is prepared to provide recognition awards to early adopters.

RBC Alloantibody Registry and Data Exchange Report Project

Meghan Walsh, PhD, Rose Li and Associates

Meghan Walsh stated the RBC Alloantibody Registry and Data Exchange report project is meant to inform the work being done by George Hauser on the Exchange. Only one nationwide registry exists abroad, which signals a lack of experience, process knowledge, and barriers to setting up a system—all of which can be systematically investigated. A formal environmental scan is also required to inform the strategic planning toward the planning of national exchange and registry.

This project has four parts: Data Collection, Synthesis, Implementation, and Evaluation. Data Collection involves conducting stakeholder interviews, producing a scoping review, and seeking guidance from subject matter experts (SMEs). Synthesis encompasses the production of a report and identifying barriers and obstacles. Implementation includes the identification and adoption of available implementation options. Evaluation incorporates follow-up research and refinement.

Project Timeline

Phase I of this project will involve a scoping review of published and unpublished literature as well as interviews with SMEs. Phase II will incorporate the construction of interview schedules in addition to formal and informal stakeholder interviews. Phase III will encompass the writing of a final report, which synthesizes findings, identifies barriers, and presents recommendations.

Work on the scoping review will begin in December 2022 and conclude in March 2023. Interviews will proceed from January 2023 until May 2023. Stakeholder meetings will begin in March 2023 and continue into June 2023. Report writing will commence in June of 2023 and conclude in August of 2023. The project is slated for completion in October 2023.

Scoping Review

The scoping review will utilize the Arksey and O’Malley framework and will employ pre-defined inclusion criteria including published and unpublished literature from both the United States and abroad. The scoping review will incorporate topics involving existing exchanges, registries, and data health systems such as system ownership, funding sources, maintenance costs, and standardization efforts. The scoping review will also provide an assessment of the exchange implementation process, such as barriers and obstacles, information security, and examples of success.

Stakeholder Interviews

Meghan Walsh explained that interview schedules will be developed based on advice from SMEs and the RBC Advisory Group, as well as findings from the scoping review. Draft interview schedules will be submitted to the project advisory group for feedback. Rose Li and Associates (RLA) will conduct virtual, semi-structured interviews to identify barriers for success, determine potential pathways for implementation, measure buy-in and engagement, and determine obstacles for success. These stakeholder groups include:

Federal Agencies (FDA, CDC, NIH)

Dutch Registry

Professional Organizations (Sickle Cell Association, American Society of Hematology)

Blood Bank Information System (BBIS) Vendors

Kansas City Officials

Informal interviews may also include:

American Hospital Association

Association for the Advancement of Blood and Biotherapies (AABB)

Electronic Patient Health Records Organizations

Yale Non-Profit Organizations

Central Transfusion Registries in Canada (British Columbia & Yukon)

Discussion

Meghan Walsh noted that the RBC Alloantibody Repository has been chosen for development as part of the HHS Secretary’s “Challenge on Equity” award. It is one of 24 innovative projects selected to advance equity in programs, policies, and processes across the agency. Claudia Cohn inquired if antibody data from blood centers would be included in the Exchange. George Hauser affirmed that they could, but that they would need to revise their agreements with hospitals. Glenn Ramsey advocated to include genotyping information (particularly those approved by the FDA), on the Exchange as well. George Hauser noted that sickle cell genotyping falls under a different section of HIPPA than is being used by the Exchange and would require additional consent. He also indicated that other genotyping profiles may be able to be shared electronically.

Recommendation to Support the Alloantibody Exchange

Claudia Cohn introduced the recommendation detailing a statement by the Work Group to support the Exchange. The Work Group decided to fine tune the language to ensure that the recommendation precisely defined the Work Group’s support. The Work Group was primarily concerned with defining the experts involved, ensuring the appropriate organizations provided oversight, and articulating the need to explore various options for standardization. This language is as follows:

The committee therefore recommends that:

1. A workgroup of blood transfusion experts convened by the ABTSA continue to support the establishment of a US-wide RBC antibody registry.

1.1 This registry may include RBC alloantibody, antigen, and phenotype, genotype data as the capability to include these data are developed.

2. The US-wide RBC antibody registry be overseen by an appropriate party.

3. The Work Group shall explore options for standardizing recording of RBC alloantibodies (e.g., using ISBT-128 codes) in the electronic medical record.

4. The OASH provide a letter of support for the development of the US-wide RBC antibody registry, and

5. The Office of Minority Health provide a letter of support for the development of the US-wide RBC antibody registry.

Vote

Biree Andemariam made a motion for the Committee to accept the recommendation. 11 members voted yes with no dissenting nor abstaining votes. The motion passed.

Summary of Meeting

Claudia Cohn lauded the Work Group for the passage of the recommendation updating the HOPE Act. She noted that developing a Working Group on tissue tracking will improve patient safety. Claudia Cohn also commended the work of the Alloantibody Exchange and congratulated members for the passage of the recommendation supporting the project.

Adjournment

Jim Berger noted that new federal members are awaiting confirmation and will attend the next meeting. He then officially adjourned the meeting at 2:34 PM EDT.

List of Participants

Special Government Employees

Claudia Cohn (ACBTSA Chair), University of Minnesota
Biree Andemariam, UConn Health
Sally Caglioti, Creative Testing Solutions
Susan Galel, Roche Molecular Diagnostics
Ray Goodrich, Colorado State University
Elisa Gordon, Northwestern University
Jed Gorlin, Innovative Blood Resources & University of Minnesota
Mary Gustafson, Plasma Protein Therapeutics Association
Bennie H. Jeng, University of Maryland
Michelle Kameka, Florida International University
Daryl Kor, Mayo Clinic
Jim MacPherson, MacPherson Strategies
Gary Marklin, Mid-America Transplant
Paul Ness, Johns Hopkins University
David Perez, Terumo BCT (retired)
Glenn Ramsey, Northwestern Medicine
Eric Santiago-Justiniano, Fresenius Kabi
Lynne Uhl, Beth Israel Deaconess Medical Center and Harvard University

Ex-officio Members

Sridhar Basavaraju, Centers for Disease Control (CDC)
Scott Brubaker, Food and Drug Administration (FDA)
Diane Corning, Centers for Medicare & Medicaid Services (CMS)
Marilyn Levi, Health Resources and Services Administration (HRSA)
Nicole Verdun, Food and Drug Administration (FDA)

Additional Attendees

James Berger, Health and Human Services Office of the Assistant Secretary for Health (HHS OASH), Designated Federal Officer (DFO)
Lauren Overman, Health and Human Services Office of the Assistant Secretary for Health (HHS OASH), Alternate Designated Federal Officer (DFO)
Sara Parker, Health and Human Services Office of the Assistant Secretary for Health (HHS OASH)
Christine Durand, Johns Hopkins University School of Medicine
Ghady Haidar, University of Pittsburgh and UPMC
Rebecca Free, Centers for Disease Control (CDC)
Marcus Pereira, Columbia University Irving Medical Center
Timothy L. Pruett, University of Minnesota
Dorry Segev, New York University Langone Health

Christina Deuschle (Meeting Host), Rose Li and Associates, Inc. (RLA)
Mike Kavounis (Meeting Host), RLA
Meghan Walsh (Project Manager), RLA
Jay Weixelbaum (Science Writer), RLA