FDA plans to demand increasingly tight, phased-in regulation of nearly all laboratory-developed tests between 2025 and 2028. However, a few test categories are exempt (at FDA's discretion on a rolling basis). One is "HLA tests for transplant."
This line of reasoning may have gotten lost in the shuffle when the 160-page rule was released. The FDA discussion is principally at 89 FR 37297-8 (May 6, 2028).
I include (#1) an AI discussion of the FDA's thought process below. and then include (#2) the whole of the (columnar) FDA text at bottom.
It seems the main reason FDA exempts these tests are that the national transplant body (NOTA) mandates controls, but the controls the transplant body mandates are CAP approval. This means FDA has to backpedal and say it doesn't think CAP approval makes tests safe, well, except here, where an old NOTA law endorses the same CAP approval.
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AI Corner: Chat GPT Summarizes FDA on HLA pp. 37297-8.
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The FDA has decided to exercise enforcement discretion for HLA tests used in the context of organ, stem cell, and tissue transplantation, allowing them to operate without direct FDA regulation. Several key reasons contribute to this decision:
Urgency and Need for Rapid Adaptation: HLA tests for transplantation are performed in urgent situations where prompt decisions are crucial. When an organ, stem cell, or tissue becomes available, physicians must quickly assess the compatibility between the donor and recipient. Because new HLA alleles are continuously being identified, modifications to these tests need to be made rapidly to address specific mismatches and respond to the unique needs of each transplant case.
Customization and Individualization: These tests are highly individualized within each medical facility. Laboratories often develop HLA tests that account for local HLA polymorphisms and patient demographics, leading to a level of customization that is necessary for effective transplantation outcomes. This individualization means that a one-size-fits-all approach to regulation may not be suitable for these tests.
Existing Oversight Programs: Several federal programs already provide oversight and help mitigate the risks of harm from inaccurate or unreliable HLA tests:
- National Organ Transplant Act (NOTA): This act established the Organ Procurement and Transplant Network (OPTN), which sets standards for the safe and equitable allocation of organs. The OPTN has requirements for the performance of HLA typing, antibody screening, and crossmatching tests.
- National Marrow Donor Program (NMDP): The NMDP supports patients needing bone marrow or umbilical cord blood transplants and sets minimum requirements for organizations facilitating these transplants. It mandates HLA typing for donors and recipients and requires reporting of test results to maintain quality and accuracy.
- Accreditation Requirements: Both OPTN and NMDP require histocompatibility laboratories to be accredited by either the American Society for Histocompatibility and Immunogenetics (ASHI) or the College of American Pathologists (CAP). These standards have provisions that specifically address OPTN and NMDP requirements, which add a layer of quality control.
Risk Mitigation: The combination of oversight programs like OPTN and NMDP, along with CAP and ASHI accreditation requirements, helps mitigate the risk of inaccurate results. While the FDA does not view CAP or ASHI accreditation alone as sufficient for all in vitro diagnostics (IVDs), it considers the additional protections provided by these programs and the urgency of the situation to justify continued enforcement discretion.
Highly Standardized HLA Tests for Blood Transfusion: The FDA's enforcement discretion does not extend to HLA tests used for blood transfusion, which are more standardized across institutions. This differentiation underscores the unique nature of HLA tests for transplantation and the need for flexibility in their regulation.
In summary, the FDA's decision not to regulate HLA tests for transplantation directly is based on the need for rapid, individualized testing in urgent situations, the presence of existing oversight mechanisms, and the high level of customization required for these tests.
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FDA"s original May 2028 Fed Reg text follows.
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FDA HLA TESTS DISCRETION
89 FR 37297-8 May 6, 2024
clarification in the future.]
FDA intends to consider whether guidance containing additional
discussion and examples of [1976 type] tests that may fall within this category would be
helpful, and would issue any such guidance in accordance with good
guidance practices (see § 10.115).
# # #
Another category of such [enforcement discretion]
tests is HLA tests that are designed, manufactured,
and used within a single laboratory certified under CLIA that meets the
requirements to perform high- complexity histocompatibility testing
when used in connection with
- organ,
- stem cell, ans
- tissue transplantation
- to perform HLA allele typing,
- for HLA antibody screening and monitoring
- or
- for conducting real and ‘‘virtual’’ HLA crossmatch tests
- (hereinafter ‘‘HLA tests for transplantation’’).
transplantation based on medical judgment regarding their patient’s
condition and degree of mismatch between the donor and patient should
an organ, stem cells, or tissue become available. Because new alleles are
continuously identified, and the need for assessing degree of crossmatch is
generally urgent, modifications to HLA tests for transplantation are often made
rapidly in response to urgent situations.
Further, these tests are often individualized within each medical
facility; for example, they include reagents that reflect local HLA
polymorphisms and patient demographics.
In addition, oversight under certain Federal programs helps to mitigate the
risks of harm from inaccurate and unreliable HLA tests for transplantation.
For example, the National Organ Transplant Act (NOTA) of 1984 created
the Organ Procurement and Transplant Network (OPTN).
NOTA, as amended (42 U.S.C. 273 et seq.), and the OPTN
Final Rule, 42 CFR part 121, establish a comprehensive system for the safe and
equitable allocation, distribution, and transplantation of donated organs.
The OPTN Final Rule and OPTN bylaws and policies govern operation of all member
transplant hospitals, organ procurement organizations, and histocompatibility
laboratories in the United States. The Stem Cell Therapeutic and Research Act
of 2005 (Pub. L. 109–129), as amended, authorizes a national registry (‘‘Be the
Match Registry’’) to support patients in need of bone marrow or umbilical cord
blood transplants, which is operated under Federal contracts by the National
Marrow Donor Program® (NMDP) (Ref. 45).
NMDP sets forth minimum requirements for organizations working
through the NMDP to facilitate stem cell transplants (Refs. 46 and 47).
OPTN has requirements for performance of HLA typing, antibody
screening, and crossmatching tests, and NMDP requires HLA typing for donors
and potential recipients for stem cell transplants facilitated by the Be the
Match Registry, as well as reporting of test results to NMDP (Refs. 47 and 48).
Both OPTN and NMDP have procedures in place for identifying, investigating,
and reporting discrepant tests results (Refs. 48 and 49).
In addition to these safeguards designed to identify and resolve
potentially inaccurate results, each OPTN member histocompatibility
laboratory must, among other things, meet specified American Society for
Histocompatibility and Immunogenetics (ASHI) and/or College of American
Pathologists (CAP) standards as a condition of OPTN membership (Ref.
50). NMDP similarly requires histocompatibility laboratories used by
U.S. transplant centers and donor centers to be accredited by CAP and/or
ASHI (Refs. 46, 51 and 52). Both ASHI and CAP standards have provisions that
specifically address OPTN and/or NMDP requirements for
histocompatibility laboratories that perform tests for those programs.
Importantly, as discussed below, FDA does not believe that a CAP or ASHI
accreditation of a laboratory, on its own, is sufficient to mitigate risk and provide
assurance of the safety and effectiveness for all IVDs offered as LDTs by the
accredited laboratory.
However, we consider the fact that OPTN and NMDP
require adherence to CAP and/or ASHI standards, including provisions specific
to OPTN and NMDP requirements, to be one factor that helps mitigate risk of
inaccurate results or unreliable HLA tests for transplantation.
After considering this factor in combination with the protections provided through
tests for transplantation may be modified and performed, as well as the
comments received on our proposed approach to HLA tests for
transplantation, FDA intends to continue the general enforcement
discretion approach for these tests. We note that this enforcement discretion
policy does not apply to HLA tests used for blood transfusion, which are highly
standardized across institutions, nor does it apply to any IVDs identified in
section V.A.2 as falling outside the scope of the phaseout policy or as
discussed in section V.B.
