Letter from the President
In a time of turbulence and change, it is more true than ever that knowledge is power. – John F. Kennedy
Change is all around us. It can be as natural as the falling leaves making way for falling snow, or the emergence of blossoms making way for the summer sun for those of us far enough from the equator. It can be as disruptive as a worldwide pandemic as we have all recently experienced. The changes in cellular therapy are a combination of both – the natural progression of science that builds upon past advances in medicine and the disruptive paradigm shifts that require us to do things differently. In this newsletter volume, we aim to clarify a couple of topics that are both natural and disruptive extensions of the work we do.
One is labeling. As cellular therapy products are collected for more uses and produced by a growing field of manufacturing sources, we must be able to adapt how these products are labeled. FACT requires full implementation of ISBT 128 coding and labeling, and the new “split ISBT 128 label” format developed for the “collection for further manufacturing” is also in compliance with FACT Standards. We, therefore, provide assurances that facilities may adopt the use of this label at the request of industry manufacturers and information on how to obtain assistance with the validation process.
Another topic relates to the use of CIBMTR’s Transplant Center-Specific Survival Report to evaluate clinical outcomes for U.S. allogeneic programs. This report is the most objective measure available of one-year survival rates. Its algorithm is transparent and vetted, and it is a resource for transplant Programs, and the field, to improve patient outcomes. We pulled an old article “from the archives” to explain more about this report and how it can be of use to Programs.
We understand that these topics focused on labeling formats and survival scoring for a complex therapy bring about change which may sometimes seem daunting. We hope these clarifications will equip readers with new knowledge that embraces advancements intended to ultimately improve the safety and quality of cellular therapy.
Catherine M. Bollard, MD
Industry, ICCBBA, and FACT hear the calls from apheresis collection facilities to reduce variations in requirements for cellular starting material collection from different companies. One of the most obvious instances of variation that impact patient safety is labeling of the collected cells.
FACT requires full implementation of ISBT 128 coding and labeling. FACT also encourages accredited organizations to participate in clinical trials and provide advanced cellular therapies to their patients. Labels for clinical trial and commercial products are developed by the manufacturer (i.e., the clinical trial sponsor or the commercial manufacturer) and approved by the regulatory authority. Because compliance with Applicable Law is also required, accredited organizations must often use labels outside of ISBT 128. The risks are evident, and near-misses have been reported. Handwritten information, ambiguous identifiers, and variations in processes create risks of product mix-ups and incorrect product information.
Since 2020, FACT has been promoting the work of ICCBBA to develop an ISBT 128 label that will reduce manual transcription errors and promote chain of identity for cells that are collected for further manufacturing by an external entity. Furthermore, the use of ISBT 128 for these collections allows the use of processes, labels, equipment, and software compatible with those already in use for other types of cellular therapy products collected by apheresis facilities.
Following two rounds of public comment, ISBT 128 Standard Labeling of Collection Products for Further Manufacture (ICCBBA ST-018) was published in November 2020. This document is a supplement to the ISBT 128 Standard Technical Specification (ST001) and defines the labeling requirements for cellular therapy apheresis collection products for further processing by a clinical trials sponsor or a manufacturer. The Standard is for use in situations where the sponsor or manufacturer has adopted this Standard and has provided the necessary information to populate the relevant section of the label.
This new ISBT 128 label format, often referred to as a “split label” format, includes all information required by existing ISBT 128 requirements on the left side, and allows manufacturer-specific information on the right side. This format strikes an appropriate balance between internationally standardized information, in both eye- and machine-readable format, and the information individual companies require to maintain chain of identity and regulatory compliance.
The split ISBT 128 label for collected products for further manufacture meets FACT Standards. In fact, FACT prefers use of this label for these situations and is appreciative of the support industry has contributed to adapting their processes and regulatory filings to accommodate it. Companies seeking to adopt this standard acknowledge ISBT 128’s role in patient safety and efficiency in the cellular therapy product supply chain.
We recognize that this new ISBT 128 label format was published during the COVID pandemic, a time of high demand and workforce shortages for our accredited facilities who are still feeling the impacts. Although adopting this change will require additional effort, the long-term savings in patient safety and process efficiencies will pay off. FACT-accredited apheresis collection facilities are encouraged to review this Standard, work with their ISBT 128 vendors and Be the Match regarding implementation and validation, and inquire with clinical trial sponsors and manufacturers about their intentions for adopting it.
Be the Match/National Marrow Donor Program (NMDP) Offers Validation Protocol to Apheresis Collection Facilities Implementing ISBT 128 Label for Collection for Further Manufacture
Don’t let the new ISBT 128 apheresis collection split label leave you with a split-ting headache! ICCBBA has recently released the ISBT 128 Standard Labeling of Collection Products for Further Manufacture (ST-018) for use on apheresis collection products. To facilitate implementation, Be the Match (NMDP) has developed a validation protocol for collection centers that plan to utilize the new labels. This will allow users to more readily implement ST-018, which provides standardized, consistent labeling to all apheresis collection bags destined for further manufacturing by a sponsor/manufacturer. Please reach out to Tamara Lengacher at NMDP (tlengach@NMDP.org) for questions and/or to request the protocol. Questions about the ST-018 standard should be sent to ICCBBA’s help desk at firstname.lastname@example.org.
The publication of the 2022 CIBMTR Transplant Center-Specific Survival Report is expected in December 2022. To help Clinical Program Directors prepare to evaluate their programs’ results, this volume’s From the Archives feature is, “Understanding the CIBMTR Outcomes Report,” published in October 2016.
Many of the concerns outlined in this article are still presented to FACT today, and we added more information and updated references to address recent questions. Our hope is that increased understanding of the CIBMTR report will transform its reputation as an anxiety-inducing evaluation into a reputation for what it is meant to be: one of many resources available to transplantation programs to understand and improve one-year survival.
There are many great Just the FACTs newsletter articles related to clinical outcomes, and it was difficult to choose! To see more helpful articles about clinical outcomes, click here.
Understanding the CIBMTR Outcomes Reports
Allogeneic transplant programs in the U.S. are required to submit corrective action plans to FACT when they do not meet the expected range of one-year survival in the annual CIBMTR Transplant Center-Specific Survival Report. To adequately assess lower-than-expected one-year survival, it is necessary to fully understand how the report is generated.
CIBMTR reviews its methodology for the Center-Specific Survival Report every other year at the Center Outcomes Forum. This forum includes a variety of stakeholders, including transplant physicians, and is intended to also increase transparency and understanding. The agendas and summaries of each meeting can be found on the CIBMTR website. CIBMTR also explains the report methodology in the document titled, Methodology Employed for Annual Report on Hematopoietic Cell Transplant Center-Specific Survival Rates, which was last updated in December 2021. The document provides technical information on statistics, but offers the following summary:
“A fixed effects censored data logistic regression model is fitted to survival data for first unrelated and related donor hematopoietic cell transplants at U.S. centers. The model is adjusted for recipient age, recipient race, Karnofsky/Lansky score, Sorror HCT-CI, adult BMI group, pediatric BMI group, recipient CMV status, history of mechanical ventilation, history of invasive fungal infection, prior autologous transplant, disease/stage, AML ELN risk group, AML transformed from MDS or MPN, AML therapy related, number of induction cycles for AML in CR1, interval from diagnosis to transplant in ALL and AML in CR2 and CR3+/relapse, ALL cytogenetic risk group, Philadelphia positive-status in ALL, number of induction cycles for ALL in CR1, MDS IPSS-R risk score at HCT, MDS predisposing condition, CLL and other chronic leukemia disease status, NHL subtype, sensitivity to chemotherapy in NHL and HL, MM ISS stage at diagnosis, plasma cell disorder disease status, year of transplant, donor type/graft type/HLA matching, BM or PBSC donor/recipient sex match, unrelated BM or PBSC donor age at transplant, and recipient median household income. The report on transplant center-specific survival rates helps to identify centers that may have under-performed or over-performed compared to the overall network of transplant centers during this specified time period.”
Each year, CIBMTR provides a comprehensive version of the Center-Specific Survival Report directly to programs prior to publishing the results on the Be the Match website. The report is usually provided to programs annually in mid-December. In each of these reports, CIBMTR outlines in detail the risk factors that are considered and ultimately included in the final multivariate model used to produce the report that year. Each report includes sections on methods, statistical analysis, and results that describe how the model is formulated. Not only does this provide context for individual programs’ results, but it also provides information that any program can use regarding factors that have had a statistically significant impact on one-year survival.
CIBMTR also explains the report, and its tools and resources to help Clinical Programs use their data, during a 2016 FACT webinar recording titled, Using CIBMTR Data to Determine and Evaluate Clinical Outcomes, presented by Stephen Spellman, MBS. This recording gives an overview of how CIBMTR data is used to determine outcomes and how Clinical Programs can use additional data to further evaluate outcomes and improve.
The following are common points Clinical Programs question about the CIBMTR report, and how they can be evaluated in the context of creating corrective action plans to address lower-than-expected one-year survival:
- High-risk patients: Some corrective action plans state the root cause of death to be transplants for high-risk patients. As outlined above, the CIBMTR report is risk-adjusted. High-risk patients should be accounted for within the report. The FACT committee expects corrective actions that specifically address the causes of death. Broad refusal to transplant patients with high risk is not the intent of FACT requirements. As transplants are often the last hope for patients, careful attention to trends in causes of death is particularly important for these patients to improve their outcomes. For example, some programs have determined myeloablative therapy was not necessary or beneficial for a group of frail patients; others adjusted their protocol for preparative regimens.
- Socioeconomic factors: Some programs are located in regions in which their patients have a low socioeconomic status. Social factors do have an impact on a patient’s survival, and FACT understands that these factors are difficult to include in a risk-adjusted methodology. In these cases, FACT would expect to see a corrective action plan that targets social issues identified to be a root cause of patient deaths. Programs have implemented methods to successfully address low resources and lack of caregivers, such as pre-discharge dispensing of prescription medications, bus passes, and expanded clinic hours.
- Small programs: It is difficult to identify trends among a small number of transplants, but FACT will look for a good-faith effort of the program to review data and determine if a trend can be found. One small program found that its patients had a high rate of CNS disease, and educated its network of referring physicians.
- Confidence interval: A common worry is that Clinical Programs will have one-year survival lower than the expected range, through no fault of their own, because of the 95% confidence interval. It is important to realize that each program has its own confidence interval. A defined number does not have to drop out of the curve. Therefore, it is possible for each program to meet expected one-year survival. Small programs typically have a wider expected survival range.
- Delay in reporting: Due to the inherent timeframe of “one-year” survival, the CIBMTR report is delayed by two years because the transplant has to have occurred a year prior, and an additional year is needed to analyze the data. Furthermore, the report uses three years’ worth of data. For example, data analysis may show that a Clinical Program had a particularly bad year in 2019 that resulted in lower-than-expected one-year survival in the 2021 report. That year will affect one-year survival in the next two reports for 2022 and 2023. However, it is still necessary to review the causes of death and their root causes for the timeframe of the report. Programs must submit current internal survival data as part of their corrective action plans. Upward trajectories of internal data are taken into account.
- Overall one-year survival: The CIBMTR report only provides overall one-year survival; however, drilling down into specific diseases will help Clinical Programs determine root causes and which corrective actions may help. This is the same for treatment-related mortality or disease relapse. This type of drill-down has helped programs identify root causes.
- Data errors: Some Clinical Programs have noted that errors in the data submitted to the CIBMTR were the true root of lower than expected one-year survival. Indeed, this can affect results of the algorithm. If data errors are a problem, FACT will want to see corrective actions related to accurate data management and evidence that these corrections have had an impact on the risk-adjusted survival.
The 2023 Advanced Therapies Week will again be on Miami Beach from January 17-20, 2023. This conference is intended to provide networking opportunities from morning until night and thought-provoking content and high-profile speakers. Registrants will include the breadth of the industry, and agenda tracks include:
- Modalities and Indications.
- Patient and Clinical Considerations.
- Supply Chain and Tech Operations.
- New and Enabling Tech.
Phacilitate has offered the FACT community a 15% discount on the registration fee. Take advantage of this cost savings to prepare for the next wave of advancements in cellular therapy. Use the discount code FACT15 when registering.
We invite you to attend the Cellular Therapy Accreditation Workshop in conjunction with the 2023 Tandem Meetings on Tuesday, February 14, from 8:00 am to 5:00 pm, at the World Center Marriott in Orlando, Florida. FACT’s Accreditation Workshops make learning about the accreditation process and related Standards an up-close and personal experience. Accreditation Workshops are collaborative events where you will be able to work through a series of scenario-based case studies supplemented with presentations facilitated by experienced FACT instructors.
The Cellular Therapy Accreditation Workshop provides a high-level overview of topics including requirements and expectations for accreditation, how to position your organization to pursue accreditation, and the most commonly cited Standards. Additional areas of discussion include manufacturer audits and corrective action plans and audits to improve outcomes and data management.
We invite you to attend the FACT Clinical Inspector Training Course in conjunction with the 2023 Tandem Meetings on Tuesday, February 14, from 8:00 am to 5:00 pm, at the World Center Marriott in Orlando, Florida. FACT’s Inspector Training Courses make learning about the inspection process an up-close and personal experience with practical, hands-on sessions simulating performing an inspection supplemented with presentations facilitated by experienced FACT inspectors.
The FACT Inspector Training Course is for clinical inspector trainees only. Trainees must complete all pre-training course requirements before attending. The training course is a collaborative event where the trainee will work with an experienced FACT inspector to review the entire inspection process from beginning to end.
FACT instructors will educate inspector trainees on the following topics during the inspector training course:
- Inspection preparation essentials
- Important technology tools
- Advance review of documents
- Clinical program tour
- Facility documents
- Patient record review
- Post-inspection requirements
We invite you to attend the FACT – ASTCT Quality Boot Camp on Wednesday, February 15, from 8:00 am to 5:00 pm, at the World Center Marriott in Orlando, FL. This is a collaborative event where you will participate in a series of roundtable activities supplemented with presentations facilitated by experienced FACT inspectors and quality personnel.
The theme of the FACT – ASTCT Quality Boot Camp is: Strengthen your Quality Management Program through the Effective Use of Quality Tools. Using the right quality tool can help reduce errors, improve communication, help maintain compliance, and save programs time and resources while improving the overall quality of your program and processes.
During the quality boot camp, FACT instructors will discuss tools and techniques most commonly used in quality management and process improvement including:
- SWOT Analysis (Strengths, Weaknesses, Opportunities, and Threats)
- Risk Assessment and Failure Mode and Effects Analysis (FMEA)
- The Five Whys
- Fishbone/Ishikawa Diagram
FACT Virtual Apheresis Collection and Processing Accreditation Workshop
Virtual, Wednesday, April 19, 2023
8:00 am – 5:00 pm CT
FACT Apheresis Collection Inspector Training Course
Minneapolis, MN April 2023
8:00 am – 5:00 pm CT
FACT Cord Blood Accreditation Workshop
Paris, France, May 30, 2023
8:00 am – 5:00 pm CT
FACT Cord Blood Inspector Training Course
Paris, France, May 30, 2023
8:00 am – 5:00 pm CT
FACT Collection, Processing, and Cord Blood Virtual Quality Boot Camp
Virtual, June 23, 2023
8:00 am – 5:00 pm
FACT Accreditation and Quality Principles Workshop
Perth, Australia, August 15, 2023
8:00 am – 5:00 pm
Registration Open Soon!
FACT Processing Inspector Training Course
Houston, TX, September 7, 2023
8:00 am – 5:00 pm
Quality Immune Effector Cellular Therapy for the Treatment of Solid Tumors Webinar:
Tumor Infiltrating Lymphocytes
Tuesday, January 17, 2023, | 11:00 am ET
Tumor-infiltrating lymphocytes (TILs) can recognize and kill cancer cells. This webinar will provide a broad introduction to TILs and a review of current clinical experience and unique considerations in TIL manufacturing. Presenters will also discuss the need for establishing safety and efficacy quality benchmarks for TILs.
Quality Immune Effector Cellular Therapy for the Treatment of Solid Tumors Webinar:
CAR-T cells and T-cell Receptor Cells in Solid Tumors
Thursday, March 30, 2023, | 11:00 am ET
CAR-T and TCR cell therapy has demonstrated encouraging potential for the treatment of solid tumors. During this webinar, presenters will highlight current clinical experience with CAR-T cells in solid tumors and unique considerations in manufacturing. Presenters will also discuss the need for establishing safety and efficacy quality benchmarks for CAR-T cells and TCRs.