Update: Comment Period Ends – AATB Response to FDA Draft Guidance Document Mycobacterium Tuberculosis
Welcome back! As we’ve been following along with the Food and Drug Administration’s (FDA) guidance document, “Recommendations to Reduce the Risk of Transmission of Mycobacterium tuberculosis (Mtb) by Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps)” [1] , the time has finally come where the comment period concludes. The initial release of this document in January 2025 as a “final” guidance document, caused industry uproar, and stakeholders from the tissue banking industry immediately reached out to the FDA to voice their concerns.
The FDA withdrew the “final” guidance document and reissued it as a “draft” to include the public’s comments (comment period ending July 7, 2025), as the concerns over feasibility and practicality of implementing the original recommendations were limited for Mtb testing methods, ambiguous definitions of tuberculosis risk factors, and the potential impact on tissue availability. FDA’s collaboration with stakeholders during the comment period allows for further input to develop a more effective guidance that can be implemented while still ensuring patient safety and reducing the risk of Mtb transmission via HCT/Ps.
Back in May we provided an update on the American Association of Tissue Banks’ (AATB) response to the FDA. With the comment period concluding, here are a few areas the AATB has submitted to FDA to request additional clarification [2] :
Mtb Testing
Issues with sample size, sample location, and sample number to ensure accurate and useful results.
Epidemiology, risk factors, testing considerations, and risk mitigation through product manufacturing choices.
Long implementation period is required to address the potential challenges which includes false negatives.
Performing Mtb cultures on cadaveric human tissue (heart valve, bone, and dura mater), the sensitivity is limited where bacterial loads are low, which is an issue where random sampling of donors without clinical suspicion of tuberculosis and the detection of Mtb is exceedingly low.
Concerns for lack of currently validated culture testing methods for use with solid tissue samples, the low-pretest probability of pre-screened donors, and challenges with determining and obtaining a suitable sample.
Validity of Acid Fast Bacilli (AFB) Culture Testing of Donated Human Tissue
The Clinical Laboratory Standards Institute (CLSI) Standard M48, laboratory Detection and Isolation of Mycobacteria for culture detection of mycobacteria is referenced as a guideline for testing patients with suspected mycobacterial infections, however, AATB states that potential donors suspected of having mycobacterial infections would be deferred and therefore, the remaining population to be tested by definition is not suspected of having a mycobacterial infection. This shows the testing guidance is incompatible for living patients since a potential donor is not suspected of having a mycobacterial infection (with no lesion or tissue sample to test).
The AFB culture method is contrary to the M48 standard and there’s a concern the potential for yielding unreliable results without extensive research and method suitability validation prior to initiating testing.
The Negative Predictive Value of Culturing from Donors Screened to be Free of Risk of Mtb Infection
Concerns of inadequate sampling such as a tissue that is not truly representative or is of insufficient volume could lead to a false negative test result.
Standard Usage and Sampling Challenges
Tissue sampling strategy must be carefully considered and guidelines defined. Currently guidelines lack clarity on items such as inoculum levels for growth results within certain timelines, timelines for positive tests vs incubation periods, sample preparation validation, and reagent impact on assay validation.
Sample specimens are not defined for donor tissues intended for transplantation and lack of clarity for which tissue locations are acceptable or preferable for testing.
Tissues from donors with latent tuberculosis are likely to be so low in bacterial loads that it would be difficult to identify a site for sampling.
Time to Appropriately Validate a Culture-Based Assay
Clarification of a timeframe for performing appropriate assay validation with clinical laboratory culturing practices so tissue establishments can apply these practices efficiently as there is additional validation work required to make mycobacterial culture testing reliable and applicable in context.
General Culturing Practices and Laboratory Testing/Capacity Considerations
Timelines for test results will impact tissue processing and distribution timeframes.
The specimen amount required for testing is expected to be high and therefore sample and volume for laboratory testing will be high which provides operational challenges, this also includes developing media for testing in the amount necessary to support the increase in testing.
Culture Result Reporting and Sharing
Workflows will need to be adjusted based on the sample volume and impact to tissue establishment processing methods will need to be considered.
The longer culture incubation time creates a logistical strain on the industry when multiple tissues from one donor are distributed to several tissue establishments.
Based on the culturing method, consequences for shared donor tissues could result in loss if one laboratory makes an error.
For the full details, check out AATB’s submission here!
We expect that the FDA will respond to the AATB with regard to these comments. Any changes made as a result of these comments will either be communicated by the AATB via bulletin, or in a finalized guidance from the FDA.
Stay tuned for more!
References:
[2] https://www.aatb.org/government-advocacy-correspondences