EBAA / FDA Executive Liaison Meeting
On April 18, 2024, staff from the Food and Drug Administration (FDA) / Center for Biologics Evaluation and Research (CBER) Office of the Center Director, Super Office of Therapeutic Products, Office of Compliance and Biologics Quality, and Office of Communication, Outreach and Development met with members of EBAA in a virtual EBAA/FDA Executive Liaison Meeting held via Zoom.
EBAA presented how eye banks evaluate donors with a differential diagnosis of sepsis and the use of Infectious Disease consultants to review the medical records to provide an expert opinion, used as part of the donor eligibility (DE) determination. We pointed out that the admitting differential diagnoses are repeated throughout the electronic record, even when clinical evidence is lacking to support the sepsis diagnosis. We also shared our concerns about discordant HBsAg test results and the 2023 increase in ocular tissue not released due to HBsAg test results.
CBER will provide EBAA information regarding who should report donor screening test kit problems and how they can submit them as medical device reports to CBER.
FDA/CBER Attendees:
Office of the Center Director:
- Peter Marks, MD, PhD, Director
- Julie Tierney, JD, Deputy Director for Strategy, Policy, and Legislation
- James Myers, JD, Associate Director for Policy
Super Office of Therapeutic Products (OTP):
Office of Cellular Therapy and Human Tissue CMC (OCTHT):
- Heather Lombardi, PhD, Office Director
- Scott Brubaker, Division Director, Division of Human Tissues (DHT)
Office of Compliance and Biologics Quality (OCBQ):
- Melissa Mendoza, JD, Director
- Vincent Amatrudo, JD, Deputy Director
- Maria Anderson, Deputy Director, Division of Case Management (DCM)
- Cherlita Honeycutt, Branch Chief, Blood and Tissue Compliance Branch (BTCB), DCM
Office of Communication, Outreach and Development (OCOD):
- Ashley Comer, Regulatory Affairs Communication Specialist, Manufacturers Assistance and Technical Training Branch (MATTB), Division of Manufacturers Assistance and Training (DMAT)
- Stacey Rivette, Consumer Safety Officer, MATTB, DMAT
EBAA Attendees:
- Kevin Corcoran, CAE, President & CEO
- Jennifer DeMatteo, MCM, CIC, Director of Regulations & Standards
- Kristin Mathes, MS, MA, VP of Quality Systems, VisionGift, EBAA Legislative & Regulatory Affairs Chair
- Chris Sica, CEBT, Director of Clinical Services, VisionFirst
- Christina A. Cooper, Director of Quality Assurance, CorneaGen.
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FDA Releases 2023 Biological Product & HCT/P Deviation Report Summary
FDA’s annual summary of biological product and human cells, tissues, and cellular and tissue-based product (HCT/P) deviation reports is now available for 2023. FDA requires reporting of certain deviations and unexpected events involving a distributed HCT/P product which is related to a Core Current Good Tissue Practice requirement [21 CFR 1271.150(b)] and related to the prevention of communicable disease transmission or HCT/P contamination [21 CFR 1271.350(b)].
This summary provides an overview of the reports submitted during the fiscal year encompassing October 1, 2022, through September 30, 2023 (FY23), including detailed information regarding the number and types of deviation reports.
Of the 95 reports submitted by tissue 361 HCT/P manufacturers in FY23, 42.1% of the reports involved receipt, pre-distribution, shipment, and distribution; 18.9% of the reports involved donor screening; 16.8% involved donor testing; and 14.7% involved donor eligibility.
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FDA Releases 2023 HCT/P Inspection Summary
The FDA released inspection information for human cells, tissues, and cellular and tissue-based products (HCT/Ps) establishments for fiscal years 2019-23.
CBER is still not back to its pre-pandemic inspection levels, according to the data. There were 563 inspections in 2019, 287 in 2020, 159 in 2021, 379 in 2022 and 445 in 2023.
The summary also includes the number of inspections in which official action was indicated (OAI), voluntary action was indicated (VAI), or no action was indicated (NAI). Despite the increased number of inspections in 2023, FDA noted a decrease in the proportion of inspections classified as OAI, meaning objectionable conditions were found and regulatory action should be recommended.
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FDA Drafts Two Guidances on Safety Testing for Cell and Gene Therapy Products
The first draft guidance is intended to assist sponsors in designing appropriate cell safety testing as part of their regulatory submission for an investigational new drug application or blood license application to ensure the quality and safety of these innovative therapies. Allogeneic cells of human origin may be expanded in culture to manufacture medical products consisting of live cells, inactivated cells, cell lysates or other cell-based materials, including cell-derived particles. The guidance emphasizes the importance of rigorous cell safety testing that accounts for the expansion potential of the cells, the reagents that are used to expand the cells and the number of individuals the cell-based medical product may be capable of treating.
FDA’s second draft guidance includes recommendations for safety and quality testing human- and animal-derived materials used to make cell and gene therapy products and TEMP products. These considerations include donor screening and testing, adventitious agent testing and screening, risk assessment, and materials management. The document also addresses the chemistry, manufacturing, and control (CMC) information submitted in an investigational new drug application (IND) relating to the use of human- and animal-derived materials.
The deadline to comment on both guidances is July 29, 2024.
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FDA Releases Final Rule on Laboratory-Developed Tests
The FDA issued a final rule establishing a regulatory framework for laboratory-developed tests (LDTs). The final rule modifies the definition of in vitro diagnostic products (IVDs), including tests made by laboratories, as medical devices under the FD&C Act.
Since IVDs are defined as devices, all LDTs will now be subject to the regulatory framework governing devices, which includes adverse event reporting, establishment registration, device listing, labeling requirements, investigational use requirements, quality system requirements and premarket review.
Until now, FDA has exercised enforcement discretion and has not enforced applicable requirements for most LDTs. FDA will provide a four-year phaseout period, during which it will gradually step up its requirements for LDTs, until four years from the date of publication of the final rule, when it expects most LDTs to be subject to the same regulatory approach as other IVDs.
Along with the final rule, FDA released an updated LDT webpage and will host a webinar to provide an overview of the final rule, including the phaseout policy on May 14, 2024. Additional information can also be found on:
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NIH and FDA Seek Comment on Draft Glossary of Clinical Research Terms Related to Innovative Clinical Trial Design
The National Institutes of Health (NIH) and the Food and Drug Administration (FDA) have released a request for information including a draft glossary of clinical research terms related to innovative clinical trial design, including studies using real world data (RWD) to generate real world evidence (RWE).
The draft glossary is intended to facilitate communication within the clinical research community by helping establish a common vocabulary to more uniformly characterize clinical research. NIH and FDA will accept comments on the draft glossary until June 24, 2024.
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FDA Recognizes ISBT 128 Version 4.0.0 for Labeling of Blood and Blood Components
In a final guidance, the FDA recognized the United States Industry Consensus Standard for the Uniform Labeling of Blood and Blood Components Using ISBT 128,” Version 4.0.0, dated January 2024, as acceptable for use in the labeling of blood or blood components intended for transfusion or further manufacturing use. This guidance supersedes the guidance of the same title dated June 2014.
Developed by the International Council for Commonality in Blood Banking Automation (ICCBBA), the Consensus Standard helps to facilitate the use of a uniform container label for blood and blood components.
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FDA Issues Final Guidance to Clarify “Remanufacturing” of Devices that Need Maintenance or Repair
FDA issued final guidance to provide the medical device industry clarity on the definition of “remanufacturing” for reusable devices needing maintenance or repair. The guidance aims to clarify the distinction between device "servicing" and "remanufacturing" and activities that constitute a remanufacturing of a device, The guidance also includes recommendations for information that should be included in labeling to help assure the continued quality, safety, and effectiveness of devices that are intended to be serviced over their useful life.
The distinction between “remanufacturing” and “servicing” is important to understand. Remanufacturing is the processing, conditioning, renovating, repackaging, restoring or any other act done to a finished device that significantly changes the finished device’s performance, safety specifications or intended use. Servicing is the repair and/or preventive or routine maintenance of one or more parts in a finished device, after distribution, for purposes of returning it to the safety and performance specifications established by the original equipment manufacturer (OEM) and to meet its original intended use.
The determination of whether the activities an entity performs are remanufacturing affects the applicability and enforcement of regulatory requirements under the FD&C Act, including but not limited to registration and listing, adverse event reporting, the Quality System (QS) regulation, and marketing submissions.
The final guidance sets forth guiding principles that the FDA recommends applying in the context of remanufacturing, a flowchart to help determine whether activities may be remanufacturing and specific examples.
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FDA Releases Draft Guidance on REMS Logic Models
FDA announced the availability of a draft guidance outlining the agency’s risk evaluation and mitigation strategy (REMS) logic model, which are used to control the risks of drugs that have notable safety issues.
The REMS logic model is a framework recommended by the agency, which is a systematic, structured approach to the design, implementation, and evaluation of a REMS, with a goal of having the applicants’ goals, objectives, and strategies line up with intended outcomes.
Examples of a REMS include a communication plan, a package insert for a patient, a medication guide, and technologies associated with packaging and safe disposal for a drug at risk of abuse or overdose. They noted the draft guidance does not focus on the relationship between REMS or risk management and the benefit-risk assessment for a drug, nor does it focus on when the use of a REMS is necessary to determine when the benefits of a drug outweigh its risks.
The guidance is designed to help applicants of new drug applications (NDAs), biologics license applications (BLAs), and abbreviated new drug applications (ANDAs) incorporate REMS assessment planning into the design of a REMS. The principles in this guidance apply to designing a REMS, developing a REMS assessment, and modifying a REMS.
FDA’s REMS logic model consists of a design phase, implementation phase, and evaluation phase. The REMS logic model, although described in sequential steps, is an iterative process that involves moving back and forth or toggling between steps and phases to address uncertainties, validating assumptions, incorporating new information, and refining the program.
The agency said it plans to release additional guidances for industry and staff on REMS design and REMS assessment.
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Infectious Disease Updates |
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Tuberculosis Incidence Increasing After Decades of Decline
The CDC reports that after 27 years of declining case counts, the number of tuberculosis cases in the US have been growing every year since 2020 with a 16% increase from 2022 to 2023. The finding was based on data from the agency’s National Tuberculosis Surveillance System, which collects information from state and local health departments.
Although the U.S. has one of the world’s lowest rates of TB, a total of 9,615 TB cases were reported in the United States in 2023, a 16% increase from 2022 and the highest number reported since 2013. The TB incidence rate of 2.9 cases per 100,000 persons represented a 15% increase from 2022. TB incidence increased in every age-group, with the largest increase seen in children ages 5 to 14 years.
As in previous years, most reported TB cases in 2023 (76%) occurred in non–US-born residents. But case counts rose among both US-born and non–US-born residents, who saw increases of 9% and 18%, respectively. Among US-born persons with TB, 33% were Black, 27% Hispanic, 26% White, 6% Asian, 5% American Indian or Native Alaskan, and 3% Native Hawaiian or other Pacific Islander.
Approximately 85% of TB cases in the United States are attributed to reactivation of latent TB infection (LTBI) rather than recent transmission. Therefore, sustained transmission of TB in the United States leading to outbreaks is uncommon. Essential TB elimination activities include TB testing among populations at risk and treating persons with LTBI or TB disease.
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Three Mycobacterium abscessus Infections Tied to Stem-Cell Injections in Mexico
Three people have contracted Mycobacterium abscessus, an intrinsically drug-resistant species of nontuberculosis mycobacterium, after receiving stem cell treatments in Mexico, according to a report published in Morbidity and Mortality Weekly Report (MMWR).
The first patient, a Colorado woman (patient A) with multiple sclerosis, was treated for M abscessus meningitis at two Colorado hospitals (hospitals A and B) in November-December 2022 following an intrathecal donor stem-cell injection in Baja California, Mexico, in October 2022.
Two additional patients were identified at hospital B in the spring of 2023. The first (patient B) was a man from Arizona who developed a right elbow osteoarticular infection following a donor stem-cell injection for psoriatic arthritis at a different clinic in Baja in April 2022. The second was a Colorado man (patient C) who developed infections in both knees after receiving stem-cell injections in his knees at a clinic in Guadalajara in October 2022.
All three patients were still undergoing treatment as of March. No additional cases have been identified.
Isolates from patients A and B were identified as M. abscessus subspecies massiliense of a single clone, nearly identical (with only one single nucleotide polymorphism between the core genomes), and distinct from dominant circulating clones, even though the clinics were 167 miles apart.
A common infected source associated with embryonic stem cell injections is suspected, such as the product, reagents, or equipment used in the procedures. Vigilance for similar cases and guidance for persons considering medical tourism are advised.
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Cefiderocol is Promising Treatment for Extensively-Drug Resistant Eye Infections
Topical cefiderocol could be a new weapon in the ophthalmologist’s arsenal for the treatment of corneal infections caused by highly antibiotic-resistant Pseudomonas aeruginosa, according to research presented at the 2024 annual meeting of the Association for Research in Vision and Ophthalmology (ARVO).
In 2023, there was an outbreak of extensively drug-resistant (XDR) Pseudomonas aeruginosa (PA) infections in 81 patients, associated with contaminated bottles of artificial tears. The eye infections led to loss of vision in 14 patients, surgical removal of the eyeball in four patients, and four deaths. The PA bacteria that caused the infections was resistant to all eye infection antibiotics. However, the strain was susceptible to one antibiotic, cefiderocol, which was approved by FDA in 2019 as a treatment for complicated urinary tract infections but had never been examined as an eye drop.
Eric G. Romanowski, MS, research director of the Charles T. Campbell Ophthalmic Microbiology Laboratory at the University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, described studies that his lab conducted evaluating topical cefiderocol as a potential treatment option for these infections (Abstract 2095). The ‘trojan-horse’ antibiotic, cefiderocol was non-toxic and effective against the highly resistant outbreak strain in an experimental model of infection.
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