FDA and Why HLA Tests Won't Be Regulated Right Now

 AI discussion then original FDA text follows.

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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:

1. 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.

2. 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.

3. 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.

4. 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.

5. 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 HLA TESTS DISCRETION

 

 

89 FR 37297-8     May 6, 2024

 

 

[FDA discusses “1976 type tests”

and how they are defined and foresees further

clarification in the future.]

 

FDA intends to consider whether

guidance containing additional

discussion and examples of 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, and

·        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’’).

 

[Bullets BQ]

 

Physicians must

often make prompt decisions about

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

 

the programs described above and the

urgent circumstances in which HLA

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.