By Stacy Freeburg, FACT Accreditation Coordinator
Programs monitor adverse events for patient safety and report events to third party organizations (FDA, Trial Sponsors), who consider the implications of single adverse events and compile the data to identify potential trends. Management of adverse events within an organization related to the administration of cellular therapy products is required by the FACT Standards.
FACT defines an adverse event as any unintended or unfavorable sign, symptom, abnormality, or condition temporally associated with an intervention that may or may not have a causal relationship with the intervention, medical treatment, or procedure. An adverse reaction is classified as a type of adverse event. In the standards, references are made to adverse events that encompass required detection, investigation, documentation, reporting, corrective and preventive action, and the responsibility to report incidents to different entities.
If an unexpected or serious adverse reaction occurs due to cellular therapy product collection or administration for which there is a reasonable possibility that the response may have been caused by the product, the report of the adverse reaction and its outcome and investigation should be communicated to all facilities associated with collection, processing, and/or administration of the product.
Organizations must comply with FACT Standards and policies throughout their accreditation cycle, including submission of the Annual and Renewal Report within 30 days of receipt (refer to the FACT Maintaining Accreditation Policy). The Annual Report is sent on the 12-month anniversary of current accreditation, whereas the Renewal Report is sent 14 months prior to expiration.
These reports allow organizations to update FACT regarding their demographics, changes in key personnel, facilities, or services, and submit required documentation of corrective action, as applicable. The report also requires programs to provide an explanation of any serious or unexpected adverse event that occurs during the reporting period. As defined by the FDA, serious adverse events have a severe impact on an individuals’ health, potentially leading to life-threatening consequences, permanent damage, or extended hospital stays (refer to the FDA, “What is a Serious Adverse Event?”).
When reporting an adverse event, organizations must include an explanation and supporting documentation that demonstrates compliance with the FACT Standards and includes the following:
- A description of relevant patient details. Do not include Protected Health Information (PHI).
- A description of relevant product details, if applicable.
- A summary of how the event was identified and investigated, corrective action(s) implemented, and that appropriate follow-up of implemented corrective action(s) was performed to ensure the corrective action(s) were effective.
- 3.4.8 Management of complications related to the administration of cellular therapy products.
- B/C/D188.8.131.52 Occurrences shall be reported to other facilities performing cellular therapy product functions on the affected cellular therapy product and to the appropriate regulatory and accrediting agencies, registries, grant agencies, sponsors, IRBs, or Ethics Committees,
On December 8, 2023, ISCT hosted the landmark 20th FDA Cell Therapy Liaison Meeting (CTLM), a closed forum strategically designed to facilitate knowledge sharing and discussions between the cell and gene therapy (CGT) community and FDA, with the objective of informing the Agency of specific concerns, challenges and recent developments to advance the regulatory field.
Discussions at the 2023 CTLM covered topics including:
- Cellular and tissue material as raw “starting” material for iPSC clinical products and other cell banks
- Changing the definition of starting material
- QC testing for point of care (POC) manufacturing
- Request for guidance document clarifying which entities are required to register with FDA for the manufacture of human stem cells, HCT/Ps
- Challenges with moving cell and gene therapies into the commercial space for rare diseases
FACT encourages readers to review the entire summary of the meeting and also view the presentation slides. This information is available on the ISCT website at https://www.isctglobal.org/publications/regulatory-quality-initiatives/fda-ctlm.
FACT Professional Relations Encourages Cellular Therapy Stakeholders to Request Extension of Public Comment Period for FDA Proposed Rule on Laboratory Developed Tests
The FACT Professional Relations Committee, chaired by Dr. Navneet Majhail and comprised of 13 cellular therapy stakeholder organizations, has closely followed efforts to change U.S. Food and Drug Association (FDA) regulatory oversight of laboratory-developed tests. There are many such tests that patients receiving stem cell transplantation or other cellular therapies undergo. The FDA currently practices enforcement discretion for these tests but seeks to phase out the discretion approach and begin requiring approval under medical device regulations.
After years of revisions, the Verifying Accurate, Leading-edge IVCT Development (VALID) Act, which was intended to achieve the above, failed to pass through Congress. Subsequently, the FDA announced a proposed rule available for public comment, titled, Medical Devices; Laboratory Developed Tests, which would phase out the discretionary approach via the regulatory process rather than via legislation. Comments are currently due by December 4, 2023.
It is important to emphasize that this proposed rule will have a major impact on transplantation and cellular therapy. It is necessary to carefully review the proposed rule and consider the effects it will have on patient safety and access to treatments. The Professional Relations Committee, in conjunction with member organizations’ individual efforts, will provide more information in the coming weeks. For now, there are two immediate needs for reviewing this proposed rule:
- Submit a request to the FDA to extend the public comment period from 60 days to 120 days. The current public comment period is only 60 days, with only 35 days left at the time of this writing, which many organizations do not feel is adequate time to fully study the impacts of this far-reaching proposed rule. Submitting a comment is relatively simple and can be done anonymously: go to https://www.federalregister.gov/documents/2023/10/03/2023-21662/medical-devices-laboratory-developed-tests, click on “Submit a Formal Comment,” and complete the online form.
- Send a list of laboratory-developed tests utilized by your program to the committee. A hallmark of FACT accreditation is the integration of clinical and laboratory practices. This is a great time to put that integration to action. We encourage clinicians to meet with their laboratory colleagues at their institutions to discuss what tests the laboratories perform for their patients that are considered laboratory-developed tests. Please send those tests to Kara Wacker, Strategic Planning Administrator (firstname.lastname@example.org) for submission to the committee or to member organization AABB, who is leading this compilation effort, at email@example.com.
Allowing additional time to review submitted feedback from accredited programs will help the transplantation and cellular therapy field provide the FDA with useful and relevant information to consider. Thank you for your collaboration.
Provide the Food and Drug Administration Feedback on Distributed and Point-of-Care Manufacturing; Comments Due December 13, 2022
The U.S. Food and Drug Administration (FDA) is seeking input on distributed manufacturing (DM) and point-of-care (POC) manufacturing because of their potential to enable rapid, localized, and timely response to demands for therapies. Although no such manufacturing is currently approved by the FDA, the agency has already seen interest by several technology developers. The FDA Centers for Drug Evaluation and Research (CDER) and Biologics Evaluation and Research (CBER) formed the Framework for Regulatory Advanced Manufacturing Evaluation (FRAME) initiative to determine whether an application using an advanced manufacturing technology can fit within the existing regulatory framework. Findings from this initiative would inform potential future policy development.
The FDA has identified areas of consideration in a discussion paper titled, Distributed Manufacturing and Point-of-Care Manufacturing of Drugs, and is asking for public feedback on key questions identified in the paper, such as:
- How often might a DM unit move to a new location and what might an applicant report to the agency when doing so?
- What locations are envisioned for POC unit operation?
- How might a centralized quality system (i.e., at a “parent location”) ensure each manufacturing unit complies with regulatory requirements and quality standards?
- What type of business relationships are envisioned between companies developing POC manufacturing platforms and health care facilities?
Stakeholders can provide input in various ways:
- Attend the public workshop on November 14-16.
- Submit comments to the public docket under docket number FDA-2022-N-2316.
- If developing direct manufacturing or point-of-care technology, contact CDER’s Emerging Technology Program at CDER-ETT@fda.hhs.gov or CBER’s Advanced Technologies Team at Biologics@fda.hhs.gov (add “CATT” to the subject line).
FDA Publishes Draft Guidance on Voluntary Consensus Standards Recognition Program for Regenerative Medicine Therapies
The United States Food and Drug Administration (FDA) is responding to needs for regulatory predictability and leverage of stakeholder efforts for standardization in regenerative medicine therapies, including cellular therapy, via a draft guidance that introduces a voluntary consensus standards recognition program.
Published in June 2022, Voluntary Consensus Standards Recognition Program for Regenerative Medicine Therapies: Draft Guidance for Industry acknowledges many unique challenges caused by the novelty of regenerative medicine therapy products. The proposed standards recognition program for regenerative medicine therapies (SRP-RMT) is intended to:
- Use agency expertise to evaluate and recognize voluntary consensus standards.
- Provide transparency to industry and other stakeholders regarding CBER’s thinking about a particular method or approach.
- Promote the visibility and use of standards applicable to the agency’s mission.
The draft guidance describes the purpose of the program, procedures for evaluating standards for recognition, documenting the use of a recognized standard, and questions and answers.
Comments on the draft guidance are due by September 14, 2022. Comments may be submitted to https://www.regulations.gov, Docket No. FDA-2022-D-0745-0001.
A public workshop to discuss the guidance will be hosted by the Standards Coordinating Body (SCB) free of charge on August 24, 2022 at 12 pm ET. Register online.
Just like cellular therapy itself, donor registry and regulatory requirements evolve over time. As a voluntary, peer-based accrediting organization, FACT reviews updates to requirements that are relevant to our Standards and affect our accredited organizations. We take every opportunity to provide input on these requirements as a value-added service to the FACT community.
There have been notable requests for public comments in the first half of 2022, and FACT committees, task forces, and leadership have evaluated draft requirements and submitted comments when determined to be appropriate. These include:
- Proposed NMDP/Be the Match Participation Criteria A00960, titled, “U.S. Apheresis and Collection Center Participation Criteria”: FACT expressed support for NMDP/Be the Match’s efforts to simplify and streamline criteria, requested clarification regarding whether the proposed criteria reflect a change in current practice regarding Apheresis Centers’ option to decline the opportunity to share NMDP collection center adult results with other NMDP clients, and reiterated support of retaining this option for NMDP collection centers.
- Draft Version of 25th Edition NMDP Standards: FACT expressed support for the National Marrow Donor Program (NMDP)/Be the Match’s efforts to streamline and simplify its Standards and provided recommendations for increasing clarity regarding the requirements and the scope of related accrediting organizations (e.g., FACT, the Joint Accreditation Committee of ISCT & EBMT (JACIE), and WMDA/NetCord).
- Draft guidance from the FDA proposed rule titled, “Medical Devices; Immunology and Microbiology Classification of Human Leukocyte, Neutrophil and Platelet Antigen and Antibody Tests”: FACT expressed its support of the comments submitted under separate cover by the American Society for Histocompatibility & Immunogenetics (ASHI) and opposed FDA’s proposal to classify HLA devices into class II with special controls.
Read the proposed FDA rule
- Draft guidance from the Food and Drug Administration (FDA), titled: “Considerations for the Development of Chimeric Antigen Receptor (CAR) T Cell Products”: FACT comments focused on the importance of relationships between cellular therapy product manufacturing companies and the health care institutions in their collection and treatment site networks to enhance patient safety, product efficacy, and patient access while minimizing the burdens on the health care institutions. FACT also recommended references to ISBT 128 coding and labeling and ASTCT consensus criteria for grading cytokine release syndrome and neurologic toxicities.
Read the draft FDA guidance
Determining Donor Eligibility for Donor Lymphocyte Infusions Aliquoted from a Product Intended for Transplantation
By Patrick J. Hanley, PhD
Chair, FACT Education Committee
Chief & Director, Cellular Therapy Program
Associate Professor of Pediatrics
Center for Cancer and Immunology Research
Children’s National Hospital & The George Washington University
Haploidentical hematopoietic progenitor cell (HPC) transplantation has increased drastically over the past five years. One reason for this increase is the introduction of T cell Receptor (TCR) α/β and CD19 depletion. In this manufacturing process, the α/β T cells and CD19 B cells are depleted, leaving γ/δ T cells, CD34+ stem cells, and other immune cells that are infused into the patient. The hypothesis is that the γ/δ T cells will provide an anti-tumor effect (in the case of malignancies) and anti-viral immunity, while the lack of α/β T cells will reduce the incidence of graft versus host disease (GVHD). However, the very limited CD3+ alpha beta T cell dose (often less than 1×105 CD3+ α/β /kg) may leave the recipient more susceptible to viral infections, or even engraftment failure. Therefore, clinicians often request that the cell processing facility cryopreserve aliquots of the α/β T cell-containing fraction to be used as a potential donor lymphocyte infusion (DLI).
Donor eligibility gurus may already see the conundrum: the TCR α/β/CD19-depleted cellular therapy product is an HPC product, for which donor infectious disease testing is allowed by the U.S. Food and Drug Administration (FDA) up to 30 days prior to collection; DLI is considered a therapeutic, leukocyte-rich tissue and therefore requires infectious disease testing to be done before or after seven days from collection. Programs can be conservative and simply draw samples for testing within seven days to cover both HPC products and therapeutic products. However, this may not align with the existing process for work-up of the donor in preparation for donation. In some cases, it may require an additional blood draw, which is not in the best interest of the donor.
Based on previous clarification from the FDA (which was confirmed by the FACT office in August 2021), the most straightforward way to address this issue is to recognize that separate eligibility determination is NOT required for the T cell product used as DLI if the lymphocytes were collected as a part of the HPC collection. When the donor of the HPC product is screened and tested in accordance with regulations and determined to be eligible for donation, the donor eligibility determination also applies to the remaining portion of the same product that is used for subsequent therapy.
The following example was presented during a FACT webinar by Safa Karandish, MT(ASCP) from the FDA in 2015 as part of a presentation titled, “FDA presents: Using Donor Screening and Testing to Determine Donor Eligibility,” which can be found on the FACT website at: http://www.factweb.org/forms/store/ProductFormPublic/fda-presents-using-donor-screening-and-testing-to-determine-donor-eligibility.As most of us can attest, with a number of nuances and exceptions to the regulations, donor eligibility determination can be complicated. It’s a relief to hear that in the case of labeling products for DLI from a product collected for an HPC transplant, the regulations are straightforward and the DLI product does not require separate donor eligibility determination.
The United States Food and Drug Administration (FDA) is hosting its annual conference, Regulatory Education for Industry (REdI), virtually next week from July 19-23. Register for this free conference to learn directly from senior leadership at FDA. Continuing education credits for several professional organizations are available, and this conference can also be used toward GxP training now required by the eighth edition FACT-JACIE Hematopoietic Cellular Therapy Standards.
For the first time, this conference will have tracks for three medical products: drugs, devices, and biologics. The biologics track will focus on different aspects of product development of advanced therapies regulated by the Center for Biologics Evaluation and Research (CBER). Topics include regulation of tissue products under 21 CFR part 1271; development and regulation of cellular, gene, and plasma-derived therapies, and expedited programs for advanced therapies.
The U.S. Food and Drug Administration (FDA) continues to provide updates regarding donor eligibility determination amid the COVID-19 pandemic. In January, it posted an announcement with information about considerations for donor eligibility and vaccines.
The FDA does not recommend testing asymptomatic donors of human cells, tissues, and cell and tissue based products (HCT/Ps), but does offer considerations for donor screening based on information known at this time. HCT/P establishments may wish to consider whether the donor in the 28 days prior to collection:
- cared for, lived with, or otherwise had close contact with individuals diagnosed with or suspected of having COVID-19 infection; or
- had been diagnosed with or suspected of having COVID-19 infection; or
- had a positive diagnostic test (e.g., nasopharyngeal swab) for SARS-CoV-2 but never developed symptoms.
The FDA also states that, based on information available at this time, donors who have received non-replicating, inactivated, or RNA-based COVID-19 vaccines are not precluded from donating HCT/Ps.
The Food and Drug Administration (FDA) announced on April 8, 2020 the issuance of final guidance regarding the administration and study of convalescent plasma collected from individuals who have recovered from COVID-19. The use of COVID-19 convalescent plasma is regulated by the FDA as an investigational product, and health care providers wishing to use this therapy as an option must therefore participate in investigational pathways. The guidance provides information on this and a variety of topics as listed below:
- pathways for use of investigational COVID-19 convalescent plasma,
- patient eligibility,
- collection of COVID-19 convalescent plasma, including donor eligibility and donor qualifications,
- labeling, and
The United States Food and Drug Administration (FDA) published Important Information for Human Cell, Tissue, or Cellular or Tissue-based Product (HCT/P) Establishments Regarding the 2019 Novel Coronavirus Outbreak on February 14, 2020. This announcement notes that the FDA has been working closely with the Center for Disease Control (CDC) and other federal and international agencies to monitor the outbreak of coronavirus (COVID-19).
The FDA stated that respiratory viruses are not generally known to be transmitted by HCT/Ps, potential for coronavirus transmission via these products is unknown. Although routine screening measures for infections are already in use, some programs may wish to use additional donor screening in response to this outbreak. Based on limited information available, the FDA says programs may wish to consider the donor history in the 28 days prior to cell collection for potential donors who have:
- traveled to areas with COVID-19 outbreaks, as defined by CDC
- lived with individuals diagnosed with or suspected of having COVID-19 infection; or
- been diagnosed with or suspected of having COVID-19 infection.
The following are additional details provided by FDA:
In 2018, the United States FDA released six draft guidance documents regarding gene therapy, and the final versions of these documents were released in January 2020. More details can be found in the Just the FACTs newsletter article, FDA Releases Six Draft Guidance Documents for Gene Therapy (2018).
The final documents can be accessed online:
- Chemistry, Manufacturing, and Control Information for Human Gene Therapy Investigational New Drug Applications; Guidance for Industry
- Testing of Retroviral Vector-Based Human Gene Therapy Products for Replication Competent Retrovirus During Product Manufacture and Patient Follow-up; Guidance for Industry
- Long Term Follow-Up After Administration of Human Gene Therapy Products; Guidance for Industry
- Human Gene Therapy for Retinal Disorders; Guidance for Industry
- Human Gene Therapy for Rare Diseases; Guidance for Industry
- Human Gene Therapy for Hemophilia; Guidance for Industry
The United States Food and Drug Administration (FDA) announced a public workshop titled, “Facilitating End-to-End Development of Individualized Therapeutics,” focusing on development of individualized therapeutic products for one or a small number of patients. This workshop will be on March 3, 2020 from 8:30 am to 5:00 pm ET, and can be attended in person or via webcast. Registration is required.
Per the FDA announcement, the objectives of the workshop are:
- “To discuss scientific challenges to development of individualized therapeutics, and ongoing efforts to adapt products manufactured based on a technology platform to treat diseases affecting one individual or a very small number of patients; explore lessons learned, logistical challenges, failures, and successes.
- To examine challenges under the current U.S. regulatory framework that need to be addressed to have a clear pathway for access to individualized therapeutics, including licensed manufacture and consistent delivery of safe and effective products.
- To explore challenges from the patient perspective that limit development and access to individualized therapeutics; consider research and development, ethical, and product availability and access issues.
- To identify new models of collaboration or synergies that may facilitate aspects of development, including manufacturing, preclinical testing, clinical development, and continuing evaluation for consistent production, availability, and delivery of individualized therapeutic products.”
For more details and to register, see the FDA announcement.
Variability in Cell Collection for IEC Products Discussed with FDA during 2019 Cell Therapy Liaison Meeting
The Food and Drug Administration Cell Therapy Liaison Meeting (FDA CTLM) took place on March 5, 2019 and a summary of the meeting is now online. This meeting was made possible by 13 organizations serving the planning committee, led by Olive Sturtevant and the ISCT North America Legal and Regulatory Affairs Committee. Ms. Sturtevant is also a member of the FACT-JACIE Standards Steering Committee.
Four topics were presented to the FDA, including regulation of biobanking material for future products, collection of mononuclear cells (MNCs) for immune effector cell (IEC) products, minimum characterization criteria for clinical grade induced pluripotent stem cell (iPSC) products, and early interaction mechanisms for tool/device developers.
The presentation and discussion regarding the collection of MNCs for IEC products is particularly timely for many FACT-accredited apheresis facilities. The summary outlines the challenges Dr. Jay Raval presented on behalf of the American Society of Apheresis (ASFA) and the discussion with the FDA afterwards.
This summary may be useful to discussions between apheresis facilities and the commercial manufacturers they work with. It also provides ideas that the field could pursue to reduce variability to a meaningful level that will ensure quality IEC products without limiting the ability of experienced apheresis facilities to care for their patients.
This meeting is just one event regarding this issue in which FACT participated. We will continue to provide updates via the Just the FACTs newsletter as appropriate. In the meantime, we have appreciated the spirit of collaboration that has been demonstrated by commercial manufacturers, healthcare providers, related organizations, and many others.
The United States Centers for Medicare & Medicaid Services (CMS) finalized its National Coverage Determination (NCD) for CAR T-cell Therapy for Cancers on August 7, 2019. Among other changes, the decision no longer requires Coverage with Evidence Development (CED) and now allows coverage for indications on FDA-approved indications and uses recommended by a citation in CMS-approved compendia. FACT appreciates CMS’s consideration of our comments and of those submitted by several of our stakeholders. Many of the changes will promote patient access to CAR T-cell therapy.
The American Society for Transplantation and Cellular Therapy (ASTCT), one of FACT’s parent organizations, indicated that it is also pleased with many of the changes from the proposed decision memo and responded with a comment letter about suggestions for continuing to improve reimbursement for this therapy.
We believe in the utility of FACT Standards to promote safety and efficacy of CAR T-cell therapies; increase harmonization across requirements of regulators, payers, and manufacturers; and reduce burden on hospitals. We will continue to work with all of these stakeholders to do our part to promote patient access.
The Cellular Therapy Community Corner provides a forum for the cell therapy community that includes educational opportunities, recent publications, and upcoming events.
ASGCT Debuts Patient Education Program
The American Society of Gene & Cell Therapy (ASGCT) announced the first release of the Society’s Patient Education program, a new initiative for 2019. Designed by ASGCT committee volunteers in coordination with patient advocacy groups, the new patient-centered portal is designed to educate and inform patients, families, and the public on the status and promise of gene and cell therapies.
The following Sessions are now live on ASGCT.org:
Gene Therapy 101, which includes the following information:
Disease Treatments, which includes the following information:
- Spinal Muscular Atrophy
- X-Linked Myotubular Myopathy
- Leukodystrophy (coming February 15)
- Blood Disorders (coming February 22)
- Inherited Retinal Disorders (coming February 28)
All topics ultimately provide patients and patient advocates with video, text, and infographic resources to share with various stakeholders. ASGCT encourages people to share these resources with their friends and family.
FDA Outlines Planned Policies to Advance Development of Safe and Effective Cell and Gene Therapies
Statement from FDA Commissioner Scott Gottlieb, M.D. and Peter Marks, M.D., Ph.D., Director of the Center for Biologics Evaluation and Research
On January 15, 2019, FDA announced its plans to provide policy guidance and advance its drug development network over the coming year in response to increases in cell and gene therapy investigational new drug (IND) applications. The FDA anticipates receiving more than 200 INDs per year by 2020 and approving 10 to 20 cell and gene products a year by 2025.
The full statement outlines FDA’s policy agenda as it relates to these technologies.
Find a clinical trial through the Jason Carter Clinical Trials Program Offered by The National Marrow Donor Program®/Be The Match®
The National Marrow Donor Program®/Be The Match® is offering a new program, The Jason Carter Clinical Trials Program, designed to help patients with blood cancers or blood disorders and their families find and join clinical trials. Funding was provided by the Carter family, in memory of their son and brother, Jason Carter. This free program offers:
- One-on-one telephone support and information from a clinical trial nurse to help patients and families navigate their clinical trial search.
- Easy-to-use, web-based search tool to find relevant clinical trials: JasonCarterClinicalTrialsProgram.org
- Easy-to-understand educational resources for patients and families to learn about cancer treatment options and clinical trials.
On the JCCTP.org website, there are patient-friendly clinical trial descriptions related to leukemia, lymphoma, MDS, aplastic anemia, and more. Treatments in some of these clinical trials include blood or marrow transplant, but many others trials include the latest cell therapies such as CAR T and immunotherapies.
Patients can also apply for financial assistance from the Drs. Jeffrey and Isabel Chell Clinical Trials Travel Grant. This grant works to offset the cost of travel related to clinical trial participation. Grant eligibility information and application are available on JasonCarterClinicalTrialsProgram.org.
The United States Food and Drug Administration (FDA) released six draft guidance documents related to gene therapy. Three of the guidance documents are disease-specific, and three are related to manufacturing. According to Scott Gottlieb, MD, FDA Commissioner, these documents are the building blocks of the FDA’s framework for advancing gene therapy while requiring safety and effectiveness. The guidance is part of the FDA’s efforts to provide clear recommendations to sponsors and researchers.
The FDA highlights the importance of establishing standardized procedures for cell collection and handling across all collection sites for multi-center clinical trials to assure the quality and safety of the final product as well as ensuring control of the manufacturing process. A list of collection sites, the FDA Establishment Identifier, and accreditations for compliance with established standards (e.g., Foundation for the Accreditation of Cellular Therapy) should be included in the IND.
Additional Manufacturing Draft Guidance Documents
Disease-Specific Draft Guidance Documents