Benchmarking of survival outcomes following Haematopoietic Stem Cell Transplantation (HSCT): an update of the ongoing project of the European Society for Blood and Marrow Transplantation (EBMT) and Joint Accreditation Committee of ISCT and EBMT (JACIE).

From 2016 EBMT and JACIE developed an international risk-adapted benchmarking program of haematopoietic stem cell transplant (HSCT) outcome to provide individual EBMT Centers with a means of quality-assuring the HSCT process and meeting FACT-JACIE accreditation requirements relating to 1-year survival outcomes. Informed by previous experience from Europe, North America and Australasia, the Clinical Outcomes Group (COG) established criteria for patient and Center selection, and a set of key clinical variables within a dedicated statistical model adapted to the capabilities of the EBMT Registry. The first phase of the project was launched in 2019 to test the acceptability of the benchmarking model through assessment of Centers' performance for 1-year data completeness and survival outcomes of autologous and allogeneic HSCT covering 2013-2016. A second phase was delivered in July 2021 covering 2015-2019 and including survival outcomes. Reports of individual Center performance were shared directly with local principal investigators and their responses were assimilated. The experience thus far has supported the feasibility, acceptability and reliability of the system as well as identifying its limitations. We provide a summary of experience and learning so far in this 'work in progress', as well as highlighting future challenges of delivering a modern, robust, data-complete, risk-adapted benchmarking program across new EBMT Registry systems.

The Quality Management Ecosystem in Cell Therapy in Catalonia (Spain): An Opportunity for Integrating Standards and Streamlining Quality Compliance.

Cell therapies are required to meet with compulsory regulations that co-exist with other optional standards and guidelines that together compose a complex quality management system. Indeed, reliable insights on the mechanisms of action and safety of novel cell-based therapies require adherence to solid quality management structures in all steps of the value chain, from early research and tissue procurement to clinical trials and biovigilance, thus guaranteeing reproducibility and solid foundations for better science and improved clinical practice. Herein we present the concept of the quality ecosystem as a tool to understand and assist all stakeholders involved in developing and structuring the integration of standards as novel developments are taking place. We conclude that the various quality management initiatives can all be thought about under the umbrella of an ecosystem.

Worldwide Network for Blood and Marrow Transplantation Special Article on Key Elements in Quality and Accreditation in Hematopoietic Stem Cell Transplantation and Cellular Therapy.

Hematopoietic stem cell transplantation (HSCT) represents an example of a highly complex and costly medical procedure with major applications in hematology and oncology. It is associated with life-threatening complications and, consequently, increased demands on healthcare resources. Although improving quality is an integral component of healthcare strategic planning, drivers of quality may be variable, and there is logical debate as to what drives quality in HSCT. Moreover, HSCT programs differ in structure and availability of resources, which drive the type of transplantations provided and determine what is affordable and/or economically feasible. The complexity of HSCT procedures with involvement of different stakeholders necessitates not only regulatory frameworks, but also robust quality systems to ensure consistent standards, demonstrate transparency for regulators, and define what quality means within the HSCT program. In an era of escalating healthcare complexity and heightened fiscal responsibility, transparency and accountability, accreditation contributes to ensuring that care meets the highest standards and can serve as a risk mitigation strategy. Quality management has become an indispensable tool for the management of a complex medical intervention such as HSCT. It allows the transplantation team to monitor its activities and identify areas for continuous improvement. The Worldwide Network for Blood and Marrow Transplantation invited a group of international experts in HSCT and quality management to work on providing a summary document about the key elements in quality and accreditation in HSCT and highlight the foremost challenges of implementing them, with a special focus on low- and middle-income economies.

Benchmarking survival outcomes: A funnel plot for survival data.

Benchmarking is commonly used in many healthcare settings to monitor clinical performance, with the aim of increasing cost-effectiveness and safe care of patients. The funnel plot is a popular tool in visualizing the performance of a healthcare center in relation to other centers and to a target, taking into account statistical uncertainty. In this paper, we develop a methodology for constructing funnel plots for survival data. The method takes into account censoring and can deal with differences in censoring distributions across centers. Practical issues in implementing the methodology are discussed, particularly in the setting of benchmarking clinical outcomes for hematopoietic stem cell transplantation. A simulation study is performed to assess the performance of the funnel plots under several scenarios. Our methodology is illustrated using data from the European Society for Blood and Marrow Transplantation benchmarking project.

Visions for a JACIE Quality Management System 4.0.

Quality management has been part of hematopoietic stem cell transplantation (HSCT) from the very beginning. It evolved step-wise from open data exchange up to the introduction of the FACT/JACIE-based quality management system (QMS) 2 decades ago. This formal step has eased cooperation, and improved outcome for patients. Today's expansion of cellular and targeted therapies and new drugs, and the regulatory requirements for advanced therapeutic medicinal products have touched the limits of the current system. Based on the Medicine 4.0 concept, the next step should integrate novel views of QMS. The old definition "Best Quality Transplant" will be replaced by "Optimal Treatment," and encompass the entire health care journey. "Best outcome" will refer to overall survival, quality of life and costs, with or without HSCT, and will be compatible with all requirements by competent authorities. Decisions will be based on high-level evidence, supported by real-time digitized data collection, data analysis, incorporated into artificial-intelligence systems. To reach this goal, EBMT/JACIE will be challenged to start the process by further fostering harmonization within and between organizations at institutional, national, and European levels. Acceleration in information technology and modifications to working practices during the pandemic should facilitate this development to the next stage.

Opportunities and challenges associated with the evaluation of chimeric antigen receptor T cells in real-life.

PURPOSE OF REVIEW: With the approval of the first chimeric antigen receptor (CAR)-T cell products on the market, the European Medicines Agency (EMA) required market authorization holders (MAHs) to monitor the long-term efficacy and safety of CAR-T cells for 15 years after administration. In 2019, the cellular therapy module of the European Society for Blood and Marrow Transplantation (EBMT) registry received a positive qualification opinion from the EMA indicating that the registry fulfills the essential needs to capture such data. We investigated its broader implication. RECENT FINDINGS: Since 2020, the cellular therapy module of the EBMT registry captures data to support postauthorization studies for MAHs and EMA. The process toward a positive qualification opinion has attracted interest from many other stakeholders, such as scientists and Health Technology Assessment bodies, and was the spin-off for a stimulating development which defined the need for a registry to comply with regulatory requirements, and also inspired ways to deal with CAR-T cell programs in terms of center qualifications and educational standards for professionals. SUMMARY: The positive qualified opinion of the EBMT registry by EMA to monitor long-term efficacy and safety of commercial CAR-T cells created opportunities and challenges and was serving as linking-pin to launch a novel CAR-T cell community.

Special report: Summary of the first meeting of African Blood and Marrow Transplantation (AfBMT) group, Casablanca, Morocco, April 19-21, 2018 held under the auspices of the Worldwide Network for Blood and Marrow Transplantation (WBMT).

The first meeting of the African Blood and Marrow Transplantation (AfBMT) was held in Casablanca from April 19, 2018 to April 21, 2018, with the aim of fostering hematopoietic stem cell transplantation (HSCT) activity in Africa. Out of the 54 African countries, HSCT is available only in six (Algeria, Egypt, Morocco, Nigeria, South Africa, and Tunisia). During this meeting, African teams and international experts from the Worldwide Network for Blood and Marrow Transplantation (WBMT) gathered to share their experience and discussed ways to help fill the gap. Nurses and patients held their meeting in parallel. International support and collaboration can help by providing expertise adapted to local resources and regional population needs. Local engagement including government and private participants are necessary to initiate and develop local HSCT capability.

Correction: Benchmarking of survival outcomes following haematopoietic stem cell transplantation: A review of existing processes and the introduction of an international system from the European Society for Blood and Marrow Transplantation (EBMT) and the Joint Accreditation Committee of ISCT and EBMT (JACIE).

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Benchmarking of survival outcomes following haematopoietic stem cell transplantation: A review of existing processes and the introduction of an international system from the European Society for Blood and Marrow Transplantation (EBMT) and the Joint Accreditation Committee of ISCT and EBMT (JACIE).

In many healthcare settings, benchmarking for complex procedures has become a mandatory requirement by competent authorities, regulators, payers and patients to assure clinical performance, cost-effectiveness and safe care of patients. In several countries inside and outside Europe, benchmarking systems have been established for haematopoietic stem cell transplantation (HSCT), but access is not universal. As benchmarking is now integrated into the FACT-JACIE standards, the EBMT and JACIE established a Clinical Outcomes Group (COG) to develop and introduce a universal system accessible across EBMT members. Established systems from seven European countries (United Kingdom, Italy, Belgium, France, Germany, Spain, Switzerland), USA and Australia were appraised, revealing similarities in process, but wide variations in selection criteria and statistical methods. In tandem, the COG developed the first phase of a bespoke risk-adapted international benchmarking model for one-year survival following allogeneic and autologous HSCT based on current capabilities within the EBMT registry core dataset. Data completeness, which has a critical impact on validity of centre comparisons, is also assessed. Ongoing development will include further scientific validation of the model, incorporation of further variables (when appropriate) alongside implementation of systems for clinically meaningful interpretation and governance aiming to maximise acceptance to centres, clinicians, payers and patients across EBMT.

Evolution, trends, outcomes, and economics of hematopoietic stem cell transplantation in severe autoimmune diseases.

Hematopoietic stem cell transplantation (HSCT) has evolved for >20 years as a specific treatment of patients with autoimmune disease (AD). Using European Society for Blood and Marrow Transplantation registry data, we summarized trends and identified factors influencing activity and outcomes in patients with AD undergoing first autologous HSCT (n = 1951; median age, 37 years [3-76]) and allogeneic HSCT (n = 105; median age, 12 years [<1-62]) in 247 centers in 40 countries from 1994 to 2015. Predominant countries of activity were Italy, Germany, Sweden, the United Kingdom, The Netherlands, Spain, France, and Australia. National activity correlated with the Human Development Index (P = .006). For autologous HSCT, outcomes varied significantly between diseases. There was chronological improvement in progression-free survival (PFS, P < 10-5), relapse/progression (P < 10-5), and nonrelapse mortality (P = .01). Health care expenditure was associated with improved outcomes in systemic sclerosis and multiple sclerosis (MS). On multivariate analysis selecting adults for MS, systemic sclerosis, and Crohn disease, better PFS was associated with experience (≥23 transplants for AD, P = .001), learning (time from first HSCT for AD ≥6 years, P = .01), and Joint Accreditation Committee of the International Society for Cellular Therapy and European Society for Blood and Marrow Transplantation accreditation status (P = .02). Despite improved survival over time (P = .02), allogeneic HSCT use remained low and largely restricted to pediatric practice. Autologous HSCT has evolved into a treatment modality to be considered alongside other modern therapies in severe AD. Center experience, accreditation, interspecialty networking, and national socioeconomic factors are relevant for health service delivery of HSCT in AD.

Training practices of cell processing laboratory staff: analysis of a survey by the Alliance for Harmonization of Cellular Therapy Accreditation.

BACKGROUND AIMS: Methods for processing products used for hematopoietic progenitor cell (HPC) transplantation must ensure their safety and efficacy. Personnel training and ongoing competency assessment is critical to this goal. Here we present results from a global survey of methods used by a diverse array of cell processing facilities for the initial training and ongoing competency assessment of key personnel. METHODS: The Alliance for Harmonisation of Cellular Therapy Accreditation (AHCTA) created a survey to identify facility type, location, activity, personnel, and methods used for training and competency. A survey link was disseminated through organizations represented in AHCTA to processing facilities worldwide. Responses were tabulated and analyzed as a percentage of total responses and as a percentage of response by region group. RESULTS: Most facilities were based at academic medical centers or hospitals. Facilities with a broad range of activity, product sources and processing procedures were represented. Facilities reported using a combination of training and competency methods. However, some methods predominated. Cellular sources for training differed for training versus competency and also differed based on frequency of procedures performed. Most facilities had responsibilities for procedures in addition to processing for which training and competency methods differed. Although regional variation was observed, training and competency requirements were generally consistent. CONCLUSIONS: Survey data showed the use of a variety of training and competency methods but some methods predominated, suggesting their utility. These results could help new and established facilities in making decisions for their own training and competency programs.

Economics and Outcome After Hematopoietic Stem Cell Transplantation: A Retrospective Cohort Study.

Hematopoietic stem cell transplantation (HSCT) is a lifesaving expensive medical procedure. Hence, more transplants are performed in more affluent countries. The impact of economic factors on patient outcome is less defined. We analyzed retrospectively a defined cohort of 102,549 patients treated with an allogeneic (N = 37,542; 37%) or autologous (N = 65,007; 63%) HSCT. They were transplanted by one of 404 HSCT centers in 25 European countries between 1999 and 2006. We searched for associations between center-specific microeconomic or country-specific macroeconomic factors and outcome. Center patient-volume and center program-duration were significantly and systematically associated with improved survival after allogeneic HSCT (HR 0·87; 0·84-0·91 per 10 patients; p < 0·0001; HR 0·90;0·85-0·90 per 10 years; p < 0·001) and autologous HSCT (HR 0·91;0·87-0·96 per 10 patients; p < 0·001; HR 0·93;0·87-0·99 per 10 years; p = 0·02). The product of Health Care Expenditures by Gross National Income/capita was significantly associated in multivariate analysis with all endpoints (R(2) = 18%; for relapse free survival) after allogeneic HSCT. Data indicate that country- and center-specific economic factors are associated with distinct, significant, systematic, and clinically relevant effects on survival after HSCT. They impact on center expertise in long-term disease and complication management. It is likely that these findings apply to other forms of complex treatments.

Pioneering quality assessment in European cancer centers: a data analysis of the organization for European cancer institutes accreditation and designation program.

PURPOSE: In order to improve the quality of care in Cancer Centers (CC) and designate Comprehensive Cancer Centers (CCCs), the Organization for European Cancer Institutes (OECI) launched an Accreditation and Designation (A&D) program. The program facilitates the collection of defined data and the assessment of cancer center quality. This study analyzes the results of the first 10 European centers that entered the program. METHODS: The assessment included 927 items divided across qualitative and quantitative questionnaires. Data collected during self-assessment and peer-review from the 10 first participating centers were combined in a database for comparative analysis using simple statistics. Quantitative and qualitative results were validated by auditors during the peer review visits. RESULTS: Volumes of various functions and activities dedicated to care, research, and education varied widely among centers. There were no significant differences in resources for radiology, radiotherapy, pathologic diagnostic, and surgery. Differences were observed in the use of clinical pathways but not for the practices of holding multidisciplinary team meetings and conforming to guidelines. Regarding human resources, main differences were in the composition and number of supportive care and research staff. All 10 centers applied as CCCs; five obtained the label, and five were designated as CCs. CONCLUSION: The OECI A&D program allows comparisons between centers with regard to management, research, care, education, and designation as CCs or CCCs. Through the peer review system, recommendations for improvements are given. Assessing the added value of the program, as well as research and patient treatment outcomes, is the next step.

Training practices of hematopoietic progenitor cell-apheresis and -cord blood collection staff: analysis of a survey by the Alliance for Harmonisation of Cellular Therapy Accreditation.

BACKGROUND: As hematopoietic stem cell transplantation expands globally, identification of the key elements that make up high-quality training programs will become more important to optimizing collection practices and quality of the products collected. STUDY DESIGN AND METHODS: Multiple-choice and open questions to identify training practices of those collecting hematopoietic progenitor cell-apheresis [HPC(A)] and -cord blood [HPC(CB)] products were distributed via an electronic survey tool worldwide. Data were collected on facility demographics, job descriptions, and the content of training programs including general practices, staff assessment, retraining, and unique program features. RESULTS: Respondents from more than 50 countries predominantly associating with facilities in North America and Europe represented transplant centers or transfusion services also performing collections. For the majority of staff performing HPC(A) collections (50%), initial training required as many procedures as necessary be done until competency was achieved. Competency was evaluated by direct observation comparing performance to written procedures or protocol steps (47%), combination of written assessment and observation (45%), evaluation of product quality (40%), and written assessment alone (12%). Staff retraining was customized on a case-by-case basis (42%). Similar criteria were placed on HPC(CB) training, with an emphasis on product quality measured by sterility, CD34+ cell collection efficiency, hematocrit, volume, and mononuclear cell count. CONCLUSION: Observation, practice, evaluation, and retraining until competency is achieved marked the training programs. Success was based on the ability of staff to execute procedures ultimately measured in product quality. Identified features may assist facilities in further developing and strengthening their own training programs.

Use of the quality management system "JACIE" and outcome after hematopoietic stem cell transplantation.

Competent authorities, healthcare payers and hospitals devote increasing resources to quality management systems but scientific analyses searching for an impact of these systems on clinical outcome remain scarce. Earlier data indicated a stepwise improvement in outcome after allogeneic hematopoietic stem cell transplantation with each phase of the accreditation process for the quality management system "JACIE". We therefore tested the hypothesis that working towards and achieving "JACIE" accreditation would accelerate improvement in outcome over calendar time. Overall mortality of the entire cohort of 107,904 patients who had a transplant (41,623 allogeneic, 39%; 66,281 autologous, 61%) between 1999 and 2006 decreased over the 14-year observation period by a factor of 0.63 per 10 years (hazard ratio: 0.63; 0.58-0.69). Considering "JACIE"-accredited centers as those with programs having achieved accreditation by November 2012, at the latest, this improvement was significantly faster in "JACIE"-accredited centers than in non-accredited centers (approximately 5.3% per year for 49,459 patients versus approximately 3.5% per year for 58,445 patients, respectively; hazard ratio: 0.83; 0.71-0.97). As a result, relapse-free survival (hazard ratio 0.85; 0.75-0.95) and overall survival (hazard ratio 0.86; 0.76-0.98) were significantly higher at 72 months for those patients transplanted in the 162 "JACIE"-accredited centers. No significant effects were observed after autologous transplants (hazard ratio 1.06; 0.99-1.13). Hence, working towards implementation of a quality management system triggers a dynamic process associated with a steeper reduction in mortality over the years and a significantly improved survival after allogeneic stem cell transplantation. Our data support the use of a quality management system for complex medical procedures.

Introduction of a quality management system and outcome after hematopoietic stem-cell transplantation.

PURPOSE: A comprehensive quality management system called JACIE (Joint Accreditation Committee International Society for Cellular Therapy and the European Group for Blood and Marrow Transplantation), was introduced to improve quality of care in hematopoietic stem-cell transplantation (HSCT). We therefore tested the hypothesis that the introduction of JACIE improved patient survival. PATIENTS AND METHODS: Data on 41,623 allogeneic (39%) and 66,281 autologous (61%) HSCTs for an acquired hematologic disorder performed between 1999 and 2007 by 421 teams in Europe were used to assess the outcomes of patients who received a transplantation at baseline (> 3 years before application or no application), during preparation (3 years before application), during application (time from application to accreditation), and after JACIE accreditation. The analysis was clustered by team and stratified for year of HSCT, donor type, disease, conditioning, and gross national income per capita of the respective country. Patient's risks were adjusted for by their European Group for Blood and Marrow Transplantation score. RESULTS: Patient outcome was systematically better when the transplantation center was at a more advanced phase of JACIE accreditation, independent of year of transplantation and other risk factors. Improvement was robust as quantified for relapse-free survival after allogeneic HSCT compared with baseline by a hazard ratio (HR) of 0.96 (95% CI, 0.90 to 1.03; P = .22) for preparation, 0.95 (95% CI, 0.88 to 1.03; P = .20) for application, and 0.86 (95% CI, 0.78 to 0.95; P = .01) for the accreditation (test for trend P = .01). Improvement from baseline was similar after autologous HSCT (HR for accreditation, 0.83; 95% CI, 0.74 to 0.93; P < .01). CONCLUSION: Even with all the limitations of an observational study, these findings support the hypothesis that introduction of a comprehensive clinical quality management system is associated with improved outcome of patients after HSCT.

JACIE accreditation in 2008: demonstrating excellence in stem cell transplantation.

JACIE was initiated as a small pilot project in Spain in 2000 and launched as a formal Europe-wide inspection program in January 2004. Since 2000, over 150 applications for accreditation have been received by the JACIE Office and more than 130 inspections have been completed in European centers and facilities. Almost all of these were found to be functioning at a high level of excellence, with the majority having only minor deficiencies in compliance with the standards. In one-third of centers there were more significant deficiencies. The most common deficiencies were in quality management. Following correction of deficiencies 86 centers have to date achieved full accreditation and many more are nearing the completion of the process. Implementation of JACIE involves a significant investment of time and resources by applicant centers. The majority require at least 18 months to prepare for accreditation and 85% have needed to employ a quality manager and/or data manager on an ongoing basis. However, all centers felt their program had benefited from the implementation of JACIE. JACIE is also working closely with other international organisations related to cellular therapy as part of the Alliance for the Harmonisation of Cell Therapy Accreditation (AHCTA), which is examining the differences in existing standards and aiming to develop international standards for all aspects of stem cell transplantation. In particular the requirements for safety of imported tissues and cells has emphasised the need for global harmonisation. The recent implementation of Directive 2004/23/EC and the associated Commission Directives 2006/17/EC and 2006/86/EC has provided an impetus for the implementation of JACIE in European Union (EU) member states. It will be important in the future to examine how JACIE can co-operate with the EU Competent Authorities (CA) to ease the burden of the inspection process for haemopoietic stem cell (HSC) transplant programs.