Where the line runs between a laboratory-developed test and an IVD

A test designed, made and used inside a single laboratory falls under 42 CFR Part 493 from the moment the laboratory reports a patient-specific result for the diagnosis, prevention or treatment of disease. Part 493 imposes no premarket review, and it conditions the reporting of results on the laboratory establishing the test’s performance specifications under § 493.1253(b)(2).¹ Separately, the product itself is an in vitro diagnostic product when it meets the definition in 21 CFR 809.3(a), and such products are devices as defined in section 201(h) of the Federal Food, Drug, and Cosmetic Act. The practical boundary therefore runs along two axes: whether patient-specific results are reported at all, and whether the assay is distributed as a product to anyone outside the laboratory that made it.

The two definitions that set the boundary

Section 809.3(a) defines in vitro diagnostic products as reagents, instruments and systems intended for use in the diagnosis of disease or other conditions, including a determination of the state of health. Those products are intended for use in the collection, preparation and examination of specimens taken from the human body. The definition turns on intended use. It was amended on 6 May 2024 and again on 19 September 2025, and the text in force contains no provision addressing tests that a laboratory manufactures for its own use.

On the CLIA side, § 493.1 sets out the conditions all laboratories must meet to be certified to perform testing on human specimens, and the part applies to all laboratories as defined under “laboratory” in § 493.2.¹ Section 493.3(b) removes three activities from the rules.¹

• facilities that only perform testing for forensic purposes
• research laboratories that test human specimens without reporting patient-specific results for the diagnosis, prevention or treatment of any disease or the assessment of health
• SAMHSA-certified drug testing that meets SAMHSA guidelines

All other testing conducted by a SAMHSA-certified laboratory remains subject to the part.¹ An assay used in development therefore sits outside Part 493 for as long as no patient-specific result leaves the laboratory for clinical use.

Complexity categorisation and the certificate held

Section 493.5 divides laboratory tests into waived tests, tests of moderate complexity including the provider-performed microscopy subcategory, and tests of high complexity.¹ Each laboratory must be CLIA-exempt or hold a registration certificate, a certificate of waiver, a certificate for PPM procedures, a certificate of compliance or a certificate of accreditation.¹ Section 493.17(a) provides that notices published in the Federal Register list each specific test system, assay and examination by complexity. The categorisation uses seven criteria scored 1, 2 or 3. Totals of 12 or less are categorised as moderate complexity and totals above 12 as high complexity.¹

A laboratory must obtain a certificate for tests of high complexity if it performs one or more tests meeting those criteria. It must then meet the applicable requirements of subpart C or D. It must also meet those of subparts F, H and J, together with subparts K, M and Q.¹ The certificate of waiver route is closed to an in-house assay: § 493.15(c) limits a waived laboratory to the listed tests and examinations, plus additions published by HHS under § 493.15(d), and no others.¹ Sale of analyte specific reagents to clinical laboratories is likewise limited to those qualified to perform high complexity testing under 42 CFR Part 493.²

What the laboratory must establish before reporting results

Section 493.1253 is the provision that separates a purchased test from a test the laboratory builds. Under § 493.1253(b)(1), a laboratory introducing an unmodified, FDA-cleared or approved test system must demonstrate before reporting patient results that it can obtain accuracy, precision and reportable range comparable to the manufacturer’s specifications, and must verify that the manufacturer’s reference intervals suit its patient population.¹

Section 493.1253(b)(2) applies a heavier obligation in three situations: where the laboratory modifies an FDA-cleared or approved test system, where it introduces a test system not subject to FDA clearance or approval, and where it uses a test system for which the manufacturer provides no performance specifications.¹ The second of these expressly covers methods developed in-house and standardised methods such as textbook procedures.¹ Before reporting patient test results, the laboratory must establish for each such test system, as applicable:

• accuracy
• precision
• analytical sensitivity
• analytical specificity, to include interfering substances
• reportable range of test results for the test system
• reference intervals, that is normal values
• any other performance characteristic required for test performance.¹

The laboratory must then determine calibration and control procedures based on the specifications established, and must document all of this work.¹ Section 493.1253(a) provides that laboratories are not required to verify or establish performance specifications for any test system used by the laboratory before 24 April 2003.¹

What counts as a modification

Section 493.1252(a) requires that test systems be selected by the laboratory and that testing be performed following the manufacturer’s instructions, in a manner that provides results within the laboratory’s stated performance specifications as determined under § 493.1253.¹ A departure from those instructions moves the test out of § 493.1253(b)(1) and into § 493.1253(b)(2). Section 493.1252(e) gives one concrete instance: components of reagent kits of different lot numbers must not be interchanged unless the manufacturer specifies otherwise.¹

The procedure manual rules point the same way. Section 493.1251(c) permits manufacturer’s test system instructions or operator manuals to satisfy the items at § 493.1251(b)(1) through (b)(12), and requires the laboratory to supply any of those items the manufacturer does not provide.¹ For a test developed in-house, the laboratory supplies all of them. That includes the reportable range established under § 493.1253, the control procedures and the limitations of the methodology.¹ Procedures and changes to procedures must be approved, signed and dated by the current laboratory director before use.¹

Analyte specific reagents and the in-house test disclaimer

The one place where the device regulations address tests built inside a laboratory is § 809.30. Analyte specific reagents are restricted devices under section 520(e) of the act.² They may be sold only to in vitro diagnostic manufacturers, to clinical laboratories qualified to perform high complexity testing under 42 CFR Part 493 or regulated under VHA Directive 1106, and to organisations using them for purposes other than providing diagnostic information to patients and practitioners.²

A laboratory that develops an in-house test using an analyte specific reagent must append to the test report the statement: “This test was developed and its performance characteristics determined by (Laboratory Name). It has not been cleared or approved by the U.S. Food and Drug Administration.”² The statement does not apply where results are generated using the test that was cleared or approved in conjunction with review of a class II or III analyte specific reagent.² Ordering of in-house tests developed using these reagents is limited under section 520(e) of the act to physicians and other persons authorised by applicable State law.² Advertising and promotional materials for the reagents must carry the prescribed disclaimer and must not make any statement regarding analytical or clinical performance.² The restrictions in § 809.30(c) through (f) fall away when the reagents are sold to in vitro diagnostic manufacturers or to forensic, academic, research and other non-clinical organisations.²

When the assay leaves the laboratory

Distribution changes the analysis. Reagents, instruments and systems shipped for diagnostic use are in vitro diagnostic products under § 809.3(a). The labeling requirements of § 809.10(a) and (b) then attach, including the intended use statement, the “For In Vitro Diagnostic Use” statement and the prescription limiting statement. Section 809.20(b) requires that in vitro diagnostic products be manufactured in accordance with the good manufacturing practice requirements in 21 CFR Part 820. Section 809.10(c) exempts a shipment for an investigation from those labeling requirements on stated conditions, including the “For Research Use Only. Not for use in diagnostic procedures.” statement for a product in the laboratory research phase and the “For Investigational Use Only.” statement for product testing before full commercial marketing. Part 809 contains no exemption keyed to the status of the institution that makes the test. The institutional carve-out found in the in-house rules of other jurisdictions has no equivalent here.

Ongoing obligations once the test is in routine use

The laboratory director is responsible for the overall operation and administration of the laboratory, and must ensure that the test methodologies selected can provide the quality of results required for patient care and that verification procedures are adequate to determine accuracy, precision and other pertinent performance characteristics.¹ The director must be on site at least once every 6 months, with at least 4 months between the two minimum visits, and may direct no more than five laboratories.¹ In a high complexity laboratory, the technical supervisor is responsible for selection of the test methodology appropriate to the clinical use of the results and for verification of test procedures and establishment of the laboratory’s test performance characteristics.¹

Control and comparison duties follow from the specifications the laboratory established. Section 493.1256(d)(3)(v) requires two control materials for each molecular amplification procedure, with a control capable of detecting inhibition where reaction inhibition is a significant source of false negative results.¹ Calibration verification must be performed at least once every 6 months and on the events listed in § 493.1255(b)(3).¹ Where the same test is performed by different methodologies or instruments or at multiple sites, § 493.1281(a) requires a system that evaluates the relationship between results twice a year.¹ Section 493.1291(e) requires the laboratory to make available to clients on request a list of test methods and, as applicable, the performance specifications established or verified under § 493.1253, together with information affecting interpretation such as test interferences.¹

Questions people also ask

Does a laboratory need FDA clearance before reporting results from a test it developed? The regulations described here condition reporting on CLIA rather than on premarket review. Section 493.1253(b)(2) requires the laboratory to establish the following before reporting patient test results from a test system not subject to FDA clearance or approval.¹

• accuracy
• precision
• analytical sensitivity
• analytical specificity
• reportable range
• reference intervals

The in vitro diagnostic definition in § 809.3(a) turns on the intended use of a product, and the text in force contains no provision addressing tests that a laboratory manufactures for its own use.

What changes when a laboratory modifies an FDA-cleared test system? The test moves from verification under § 493.1253(b)(1) to establishment under § 493.1253(b)(2), so the laboratory must establish the full set of performance characteristics rather than demonstrate comparability with the manufacturer’s figures.¹ Section 493.1252(a) requires testing to follow the manufacturer’s instructions, and § 493.1252(e) prohibits interchanging reagent kit components of different lot numbers unless the manufacturer specifies otherwise.¹

Can an in-house test be run under a certificate of waiver? No. Section 493.15(c) limits a laboratory holding a certificate of waiver to the tests listed in that paragraph and any tests added by HHS under § 493.15(d), and no others.¹ A laboratory performing a test that meets the high complexity criteria in § 493.17(a) must obtain a certificate for high complexity testing.¹

Who may order a test developed in-house from analyte specific reagents? Ordering is limited under section 520(e) of the act to physicians and other persons authorised by applicable State law to order such tests.² The laboratory must also append the prescribed developer statement to the test report.²

When does testing on human specimens fall outside CLIA entirely? Section 493.3(b) excludes the following.¹

• facilities that only perform forensic testing
• research laboratories that test human specimens without reporting patient-specific results for diagnosis, prevention or treatment or for the assessment of health
• SAMHSA-certified drug testing meeting SAMHSA guidelines

Any other testing conducted by a SAMHSA-certified laboratory is subject to the part.¹

Footnotes

1. 42 CFR Part 493, Laboratory Requirements. https://www.ecfr.gov/current/title-42/chapter-IV/subchapter-G/part-493 ↩ ↩² ↩³ ↩⁴ ↩⁵ ↩⁶ ↩⁷ ↩⁸ ↩⁹ ↩¹⁰ ↩¹¹ ↩¹² ↩¹³ ↩¹⁴ ↩¹⁵ ↩¹⁶ ↩¹⁷ ↩¹⁸ ↩¹⁹ ↩²⁰ ↩²¹ ↩²² ↩²³ ↩²⁴ ↩²⁵ ↩²⁶ ↩²⁷ ↩²⁸ ↩²⁹ ↩³⁰ ↩³¹ ↩³² ↩³³ ↩³⁴

2. 21 CFR 809.30, Restrictions on the sale, distribution and use of analyte specific reagents. https://www.ecfr.gov/current/title-21/chapter-I/subchapter-H/part-809/subpart-C/section-809.30 ↩ ↩² ↩³ ↩⁴ ↩⁵ ↩⁶ ↩⁷ ↩⁸ ↩⁹ ↩¹⁰