What one assay has to prove under FDA and under the IVDR

The same assay faces two different structures of proof. In the United States the manufacturer establishes that the assay falls within a classification regulation for its generic type and meets the controls attached to the class assigned there, in most cases by demonstrating substantial equivalence to a legally marketed device.¹ In the European Union the manufacturer must generate clinical evidence composed of scientific validity, analytical performance and clinical performance data, assessed and documented in a performance evaluation report that forms part of the technical documentation.²

How the FDA classification regulations set the burden

Part 862 sets out the classification of clinical chemistry and clinical toxicology devices intended for human use that are in commercial distribution.¹ The identification text in each section is a general description rather than a precise account of every device that falls under it. A manufacturer filing a premarket notification must state why the device is substantially equivalent to other devices, as required in § 807.87.¹ A match between the device and the section title and identification wording is not sufficient on its own.

Class determines the review pathway. A class III device listed in Part 862 cannot be commercially distributed after the date shown in its classifying regulation without an approval under section 515 of the Federal Food, Drug, and Cosmetic Act, meaning an order approving a premarket approval application or declaring a product development protocol complete.¹ Human chorionic gonadotropin test systems show how intended use splits a single analyte across classes. An HCG test system for early detection of pregnancy is class II. An HCG test system for any other use, such as aiding diagnosis, prognosis and management of treatment of persons with certain tumours, is class III and has required premarket approval since 28 May 1976.¹

Calibrators receive their own treatment. Because of the central role a calibrator plays in the measurement process and its effect on the accuracy of results, all three forms of calibrator are classified into class II regardless of the classification of the device with which they are used.¹ This holds whether the calibrator is distributed separately, supplied as a kit component or built into the instrument. A device and its calibrator may therefore carry different classifications.¹

The limits on exemption from premarket notification

Many Part 862 devices are exempt from premarket notification, and the exemption is bounded. For in vitro diagnostics the exemption reaches only as far as misdiagnosis resulting from use of the device would not be associated with high morbidity or mortality.¹ A premarket notification must still be submitted where the device has a different intended use from a legally marketed device of that generic type, or where the modified device operates on a different fundamental scientific technology.¹

A submission is also required where the in vitro device is intended for any of the following.¹

• Diagnosis, monitoring or screening of neoplastic diseases, with the exception of immunohistochemical devices.
• Screening or diagnosis of familial or acquired genetic disorders, including inborn errors of metabolism.
• Measuring an analyte that serves as a surrogate marker for screening, diagnosis or monitoring of life-threatening diseases, or to monitor therapy.
• Assessing the risk of cardiovascular diseases.
• Use in diabetes management.
• Identifying or inferring the identity of a microorganism directly from clinical material.
• Detection of antibodies to microorganisms other than immunoglobulin G, or IgG assays where the results are not qualitative or are used to determine immunity or the assay is intended for use in matrices other than serum or plasma.
• Noninvasive testing as defined in § 812.3(k).
• Near patient testing at the point of care.

Special controls as the performance specification

For class II devices in Part 862 the substantive evidence requirements sit in the special controls, and they differ sharply from one device type to another. Some special controls are a single FDA guidance document, as for cardiac allograft gene expression profiling test systems under § 862.1163 and drug metabolizing enzyme genotyping systems under § 862.3360.¹ Others are numerical. A hemoglobin A1c test system must undergo initial and annual standardization verification by a certifying glycohemoglobin standardization organization deemed acceptable by FDA.¹ Its accuracy testing must use at least 120 blood samples spanning the measuring interval, and total error compared with the standardized method must be 6 percent or less.¹

The integrated continuous glucose monitoring system regulation goes further. Design verification and validation must include clinical data comparing iCGM values with blood glucose values measured in parallel on an FDA-accepted laboratory method traceable to a higher order reference.¹ The acceptance criteria are stated as lower one-sided 95 percent confidence bounds, for example exceeding 85 percent for measurements within plus or minus 15 mg/dL below 70 mg/dL and exceeding 87 percent for measurements within plus or minus 20 percent across the measuring range.¹ Total 25-hydroxyvitamin D mass spectrometry test systems require a minimum of 115 serum or plasma samples for accuracy and a reference range study drawn from at least three distinct climatic regions of the United States in different seasons.¹

Special controls also reach labelling and training. The prognostic test for development or progression of preeclampsia, classified at § 862.1602, requires documentation of clinical performance across multiple intended use sites and broad demographics representative of intended use patients in the United States.¹ Its § 809.10(b) labelling must carry limiting statements, including that the result is an aid in patient management and that it is not to be used to aid decisions on hospital discharge or delivery.¹ The acute kidney injury test system regulation at § 862.1220 requires the end user training programme to be documented as part of risk management performed under the design and development activities in 21 CFR 820.10(c).¹

What the IVDR requires in evidence

Article 56(1) ties conformity with the general safety and performance requirements in Annex I to scientific validity, analytical performance and clinical performance data providing sufficient clinical evidence.² The manufacturer specifies and justifies the level of clinical evidence needed, and that level must be appropriate to the characteristics of the device and its intended purpose.² The performance evaluation follows a defined and methodologically sound procedure and must demonstrate all three elements.² Clinical evidence must scientifically demonstrate, by reference to the state of the art in medicine, that the intended clinical benefits will be achieved and that the device is safe.²

Each strand has its own report. Scientific validity is demonstrated from one or a combination of information on devices measuring the same analyte or marker, peer-reviewed literature, consensus expert positions, proof of concept studies and clinical performance studies, and is recorded in the scientific validity report.² Analytical performance must be shown for all parameters in point (a) of Section 9.1 of Annex I unless an omission is justified, as a general rule on the basis of analytical performance studies.² Where a novel marker has no certified reference material or reference measurement procedure, trueness may not be demonstrable, and a clinical performance study comparing the device to current clinical standard practice is required where no alternative approach exists.² Clinical performance covers the parameters in point (b) of Section 9.1 and may draw on studies, peer-reviewed literature or published experience from routine diagnostic testing.²

Clinical performance studies must be carried out unless reliance on other sources of clinical performance data is duly justified.² Where they are conducted they run on a clinical performance study plan setting out the following.²

• rationale
• objectives
• design
• analysis
• methodology
• monitoring
• conduct
• record-keeping

The performance evaluation plan

The plan is the document that fixes what the evaluation will generate, and Annex XIII lists its minimum content. As a general rule it includes the following.²

• A specification of the intended purpose, the intended use and the characteristics of the device.
• A specification of the analyte or marker to be determined.
• Identification of certified reference materials or reference measurement procedures allowing metrological traceability.
• Clear identification of specified target patient groups with indications, limitations and contra-indications.
• Identification of the general safety and performance requirements in Sections 1 to 9 of Annex I needing support from data.
• A specification of methods and statistical tools used to examine analytical and clinical performance.
• A description of the state of the art, including relevant standards, common specifications and guidance.
• An outline of development phases with milestones and potential acceptance criteria, and the post-market performance follow-up planning.

Where an element is not appropriate for a given device, the plan must carry a justification.²

Evidence after launch

Both regimes keep obligations running after market entry, through different instruments. Under Article 56(6) the performance evaluation and its documentation are updated throughout the life cycle with data from the post-market performance follow-up plan and the post-market surveillance plan.² For class C and class D devices the performance evaluation report is updated when necessary and at least annually.² The summary of safety and performance referred to in Article 29(1) is updated as soon as possible where needed.² On the FDA side the continuing obligation is embedded in particular special controls, such as the annual standardization verification required for hemoglobin A1c and total 25-hydroxyvitamin D test systems.¹

Dates that decide when IVDR evidence binds

The Regulation has applied since 26 May 2022, with derogations listed in Article 113(3).² Legacy devices holding a valid Directive 98/79/EC certificate may be placed on the market until 31 December 2027.² Devices that needed no notified body under the Directive but do under the Regulation may be placed on the market until 31 December 2027 for class D, 31 December 2028 for class C and 31 December 2029 for class B and sterile class A.² Those extensions depend on the conditions in Article 110(3c), including a quality management system in place under Article 10(8) by 26 May 2025 and a formal application to a notified body by the applicable date.² The written agreement with the notified body was due by 26 September 2026 for class C devices and is due by 26 September 2027 for class B and sterile class A devices.² Article 110(3d) provides that the post-market surveillance, market surveillance, vigilance and registration requirements of the Regulation apply to those devices in place of the corresponding Directive provisions.² Under Article 113(3)(f) that provision applies from six months after publication of the notice that the relevant electronic system is functional.²

Questions people also ask

Does a 510(k) require clinical performance data?

It depends on the classification regulation. The general requirement in a premarket notification is a statement of why the device is substantially equivalent to other devices, under § 807.87.¹ Where the classifying section imposes special controls, those controls can require clinical data, as with the acute kidney injury test system at § 862.1220 and the integrated continuous glucose monitoring system at § 862.1355.¹

Does the IVDR have an equivalent to substantial equivalence?

The IVDR builds conformity on performance evaluation against the general safety and performance requirements in Annex I.² Data on devices measuring the same analyte or marker may support scientific validity under Annex XIII, Section 1.2.1.² Analytical and clinical performance must be demonstrated for the device itself, in relation to the parameters in Section 9.1 of Annex I.²

What is the difference between scientific validity and clinical performance under the IVDR?

Scientific validity concerns the association of an analyte or marker with a clinical condition or physiological state, demonstrated from the sources listed in Annex XIII, Section 1.2.1 and recorded in the scientific validity report.² Clinical performance concerns the device’s ability to yield results correlated with that condition, addressed against the parameters in point (b) of Section 9.1 of Annex I and recorded in the clinical performance report.²

Can a calibrator be exempt from premarket notification in the United States?

A calibrator under § 862.1150 is class II with special controls and is exempt from the premarket notification procedures in subpart E of part 807, subject to the limitations in § 862.9.¹ The clinical toxicology calibrator under § 862.3200 carries the same classification and the same exemption with the same limitations.¹

When must a legacy IVD in the European Union hold a notified body certificate under the Regulation?

Article 110 sets the end dates by class. Devices covered by a valid Directive certificate may be placed on the market until 31 December 2027, and devices moving into notified body scope for the first time have until 31 December 2027, 31 December 2028 or 31 December 2029 depending on class.² Each date is conditional on the application and written agreement deadlines in Article 110(3c).²

Footnotes

1. 21 CFR Part 862, Clinical Chemistry and Clinical Toxicology Devices. https://www.ecfr.gov/current/title-21/chapter-I/subchapter-H/part-862 ↩ ↩² ↩³ ↩⁴ ↩⁵ ↩⁶ ↩⁷ ↩⁸ ↩⁹ ↩¹⁰ ↩¹¹ ↩¹² ↩¹³ ↩¹⁴ ↩¹⁵ ↩¹⁶ ↩¹⁷ ↩¹⁸ ↩¹⁹ ↩²⁰ ↩²¹ ↩²² ↩²³ ↩²⁴

2. Regulation (EU) 2017/746 of the European Parliament and of the Council of 5 April 2017 on in vitro diagnostic medical devices and repealing Directive 98/79/EC and Commission Decision 2010/227/EU. Consolidated version of 2025-01-10. https://eur-lex.europa.eu/legal-content/EN/TXT/?uri=CELEX:02017R0746-20250110 ↩ ↩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