Real-world data to improve organ and tissue donation policies: lessons learned from the tissue and organ donor epidemiology study | Health Research Policy and Systems

This effort highlights multiple lessons learned regarding knowledge gaps and challenges of using RWD in assessing the rate of communicable diseases in potential OTE donors (which was selected as a test case to understand the ability to collect donor-related data within the existing OTE workflow) that can, in turn, be used to better inform policy decision-making. Importantly, findings from the data captured by TODES led to precluding its use for policy decisions. First, the data were determined to not be fit-for-purpose, which was not surprising given the data provided by the organizations were collected largely to support business operations rather than to address research and surveillance questions. Specifically, available RWD data could not identify duplicate data among tissue donors, provide a tissue donation denominator or ascertain a representative sample of donors. Second, it was not possible to ascertain a comprehensive understanding of the true infectious disease status of actual donors, and what is particularly lacking are data on potential donors found to have communicable disease risk and therefore the donation did not proceed. From a testing perspective, supplemental (that is, “confirmatory”) tests were rarely performed to verify positive or indeterminate test results, presumably because of the lack of appropriately labelled supplemental tests, lack of adequate specimen volume, inability to sequentially follow deceased donors to document the evolution of infectious disease test markers and lack of regulatory or policy requirements to perform supplemental testing. Furthermore, testing data of potential non-transplantation donors – for example, that likely had positive test results or identified communicable disease risks – were largely unavailable, and if available, data were incomplete. Third, the various testing protocols that estimated infectious disease marker prevalence lacked standardization and included a variety of assay types such as donor screening and diagnostic assays (ST 1). Fourth, donors from OPO- and TE-evaluated datasets cannot be uniquely identified in large part because donors lack a common identifier between the organ and tissue/eye transplantation pathways as well as within the tissue/eye pathway when tissues go to more than one establishment. As such, any assembled dataset contains a mixture of test results (that is, positive results with no further testing, inconclusive results with no further testing, positive results with subsequent testing and negative results with subsequent testing), severely impacting the interpretability and usefulness of the data.

TODES focused on available OTE donor data that might be used to characterize the donor populations to then inform donor screening and testing policy. However, acknowledging how these data are part of biovigilance within an interconnected system needed to maximize overall OTE transplantation safety is also important. Multiple facets contribute to the biovigilance required to maximize transplantation safety [15]. These include (i) donor selection (defining and identifying potential donors, donor screening and testing information), (ii) careful manufacturing practices (processing practices that both prevent contamination and cross-contamination and that remove or inactivate contamination to the extent possible while maintaining utility of the product) and (iii) identifying and investigating adverse events (to learn about the causes to inform improved policies and practice, and to quickly identify other recipients to prevent further adverse event occurrence). These facets of transplant safety require traceability of tissues from the time of considering a potential donor all the way through to the transplantation/implantation to a recipient. Ideally, donor evaluation data and transplantation outcomes data collection could also be used as part of efforts to proactively identify emerging infectious disease threats. The TODES study participants agreed that interventions that can yield benefits to transplantation safety include better communication, better identification methods, better education, etc. A comprehensive list is presented in ST 2. These interventions are consistent with the conclusions of the Transplantation Transmission Sentinel Network (TTSN) pilot program that was developed to collect data on donation, tissue implantation and adverse events [16]. The authors of the TTSN program concluded that eye and tissue tracking from recovery to implantation will be necessary before a sentinel network system can be operable, which would require common identifiers and nomenclature. They further stated that the absence of a US sentinel network may result in future transmission events that could have been otherwise preventable. There is a clear need for such an integrated system for OTE transplantation data collection.

Study limitations

TODES had some limitations. The study was designed to solely address the ability to collect RWD in characterizing the baseline communicable disease epidemiology of potential OTE donors, and was not designed to address any identified challenges, explore other sources of risk from tissue manufacturing, evaluate communicable disease transmission data, or to make policy recommendations. Data integration from different sources (for example, eye banks, large TEs and large laboratories that provide infectious disease testing) was challenging, which resulted in excluding those sources and acquiring tissue donor data only from OPOs that were also tissue recovery establishments. Thus, TODES data are not representative of national organ and tissue donor/donation data. Also, the 2009–2013 donor data collected by TODES reflect the recommendations in the 1994 PHS guidelines [17] that do not address later guideline development (Table 1) in defining “increased risk” organ donors. While the 1994 PHS guidelines were designed to reduce the risk of HIV transmission by screening organ and tissue donors to capture behaviours and medical history placing them at increased risk for HIV infection [17], the subsequent 2013 PHS guideline, limited to organ donors [14], recommends additional donor and recipient screening for HBV and HCV, including use of more sensitive testing methodologies, revised risk factors and more robust informed consent discussions about accepting or rejecting organs from donors known to be infected with HBV or HCV. A new PHS guideline published in June 2020 [18], and was implemented by 1 March 2021 [19, 20]. Changes to the PHS guideline over time highlight two important issues: (1) the same donor data are reviewed when evaluating organ and tissue donors, but differing risk benefit ratios may rightfully result in different donor decisions between organs and tissues/eyes, and (2) it is important to carefully consider unintended availability consequences as the result of any policy or guidance changes [21].

Future needs

TODES highlighted the need for a more integrated system for accessing and collecting all OTE donor evaluation data (that is, including data for all potential donors, not just data on donors who were found eligible to donate). Although more burdensome data entry requirements could be considered in policy and regulations, such data entry is currently manual, time consuming and subject to transcription error. The Retrovirus Epidemiological Donor Studies (REDS) research program, which aims to evaluate and propose models for improving the safety of blood donations, provides a model that addresses key challenges in organ and tissue safety. Over the course of 30 years, the National Heart, Lung, and Blood Institute (NHLBI) established the Retrovirus Epidemiological Donor Studies (REDS-I, 1989–2001 [22], REDS-II, 2004–2012 [23]) and the subsequent Recipient Epidemiology and Donor Evaluation Studies (REDS III 2011–2018 [24] and REDS-IV-P 2019–2026 [25]) to conduct research on infectious disease risks to the safety and availability of the blood supply, and with REDS-III and -IV-P, linking donated blood to the safety and effectiveness of transfusions. At the time of the funding of REDS-1 (1989), questions arose about the residual risk of infectious diseases, including HIV, HCV and HBV in the blood supply. Using a distributed research model, multiple entities (blood collectors, hospitals, testing centres and analytical coordinating centres) contributed and analysed data and biospecimens to track blood safety. As a result of the REDS program, donor testing platforms have matured, and new threats have been identified and investigated (for example, West Nile Virus).

Over this time, the risks of acquiring HIV or HCV infection through transfusion have decreased from about 1:200 000–300 000 donations to 1:1.5–2.0 million donations [10]. Much of the decline was attributed to nucleic acid testing (NAT), which was implemented on the basis of data from REDS protocols and analyses of comprehensive donor and donation data captured from participating blood centres. Consequently, the REDS studies have informed regulatory decision-making and public health policies for more than a quarter century. This type of research program enables quick assessment of blood safety risks after a new threat or pathogen has emerged.

Such a model could be used to establish a baseline of infectious risk among OTE donor populations, enabling the evaluation of risk/benefit of interventions upon identification of new threats. To build such an integrated transplant data collection system, an appropriate funding sponsor should be identified, harmonized definitions and testing approaches should be established, unique donor identifiers should be assigned, labelling to facilitate traceability should be implemented, and OPO, TE and eye bank engagement should be assured. In addition, hospitals and clinician users of tissues and organs must understand the need to populate the system with additional data (that is, improve recording of tissue provided to patients, respond to information requests and tissue utilization cards provided by TEs and monitor for and promptly report potential recipient adverse events) [7], the value of additional research and the associated costs. There is no standard for data collection; different establishments use their own systems for data collection. Costs of establishing an integrated transplant data collection system can be daunting. However, standardized and interoperable data that would be used to streamline and optimize donor evaluation, prevent transmission events and identify transmission events quickly to facilitate rapid response to minimize recipient morbidity and mortality could likely decrease overall costs to TEs and the entire healthcare system over time.

Currently, these types of prospective data collection and analyses are viable, and as described below, need not be unduly burdensome because of the evolution of healthcare IT. Automated data collection capacity has now far exceeded the data and testing infrastructure of the 1990s, 2000s and even 2010s. A system could be designed to prospectively collect the data required to estimate incidence, prevalence and risk factors of organ and tissue/eye donors. It could also provide input to benefit–risk assessment models supporting policy evaluation. As described above, data collection and analysis cannot be supported by the electronic information currently available and stored by the organizations surveyed. As described and consistent with the TTSN experience, these issues reinforce the need to involve all stakeholders in the standards and systems development process to ensure the availability and accuracy of the appropriate and consistently defined data elements.

Healthcare IT solutions

Recent healthcare information technology (IT) advancements [26, 27] position RWD as a potential prospect for better informing policy and regulatory decision-making, even as the current system for collecting and tracking donor data remains largely unchanged. The intersection of the following three factors gives rise to RWD as a potential solution: (1) increasing adoption of electronic health records (EHRs) [28]; (2) emerging HL7^® Fast Healthcare Interoperability Resources (FHIR^®) standards [29]; and (3) 21st Century Cures Act mandates to promote interoperability with FHIR R4 as the standard [30]. Embedding information about both the donation/recovery and the transplantation with specific biologically derived product (BDP) codes and donor identifiers in the EHR would enable forward and backward traceability from an impacted (for example, infected) patient or product of concern to other patients or products from the same donor. The US Core Data for Interoperability, the standardized set of health data classes and data elements, is poised to include BDP in a future release, requiring all EHR systems to make these data available to other systems, including those internal and external to the transplanting hospital provider.

The changing landscape of healthcare IT and the continuous development of interoperability standards are the foundation for a sustainable and robust solution to improve organ and tissue safety. Therefore, it is paramount to invite all stakeholders to discuss how these data can be streamlined by standardizing, capturing, storing and transmitting quickly and confidentially to establish RWD for the purposes of donor-to-recipient traceability and to improve transplantation safety.