The HE4 EIA is an enzyme immunometric assay for the quantitative determination of HE4 in human serum. The assay is to be used as an aid in monitoring recurrence or progressive disease in patients with epithelial ovarian cancer. Serial testing for patient HE4 assay values should be used in conjunction with other clinical methods used for monitoring ovarian cancer.

For In Vitro Diagnostic Use Only.

Fujirebio Diagnostics Tumor Marker Control is intended for use as an assayed control serum to monitor the precision of laboratory testing procedures for the analytes listed in the lot specific assigned values sheet.

Device Description

The Fujirebio Diagnostics Tumor Marker Controls are used for validation of each HE4 EIA assay series. The HE4 EIA results should be considered valid if the mean HE4 values of control duplicates are within the specified HE4 EIA ranges indicated on the Assigned Value Sheet provided with the Fujirebio Diagnostics Tumor Marker Controls.

AI/ML Overview

This submission is for a control device (Fujirebio Diagnostics Tumor Marker Control) intended to replace existing controls for the HE4 EIA kit. Therefore, the "device" in question is the control material itself, not a diagnostic test that detects a medical condition. As such, concepts like "test set," "ground truth," "expert consensus," "MRMC study," and "standalone performance" are not applicable in their usual diagnostic sense. The study focuses on verifying the control's performance to ensure it effectively monitors the precision of the HE4 EIA assay.

Here's an analysis based on the provided document, addressing the closest equivalent concepts for a control device:

Acceptance Criteria and Device Performance Study for Fujirebio Diagnostics Tumor Marker Control

The purpose of this 510(k) submission is to replace the current HE4 EIA kit controls with the Fujirebio Diagnostics Tumor Marker Control. The study focuses on demonstrating that the new control material performs equivalently and reliably to the predicate controls for monitoring the precision of the HE4 EIA assay.

1. Acceptance Criteria and Reported Device Performance

The acceptance criteria and reported performance relate to the value assignment process for the control materials. The key performance indicators are related to the precision and stability of the control material when assayed with the HE4 EIA kit.

Acceptance Criteria (for Value Assignment (K101809))	Reported Device Performance (K101809)
CV < 8% within run.	Not explicitly stated as a direct "result" table, but the methodology implies compliance for the control levels.
Mean value for each run within ± 2SD for other 3 runs.	Not explicitly stated as a direct "result" table, but the methodology implies compliance for the control levels.
Assigned range for HE4 EIA Control Level 1: Total Mean ± 2SD but not less than ± 30%	The assigned ranges for the new controls (K101809) are determined based on this criteria, as indicated on the "Assigned Value Sheet" provided with the controls.
Assigned range for HE4 EIA Control Level 2: Total Mean ± 2SD but not less than ± 25%	The assigned ranges for the new controls (K101809) are determined based on this criteria, as indicated on the "Assigned Value Sheet" provided with the controls.
Predicate (K072939) Acceptance Criteria	Predicate (K072939) Performance
Total CV% ≤ 5	Baseline for comparison, assumed to be met by the predicate.
Assigned range Control Level 1: Total Mean ± 30%	Used for predicate control ranges.
Assigned range Control Level 2: Total Mean ± 20%	Used for predicate control ranges.

Note: The document describes the methodology for establishing the assigned values and ranges for the new controls, rather than presenting a direct "results" table showing statistical verification of each acceptance criterion post-study. The implication is that the study was conducted to meet these criteria. The "Target HE4 Concentrations" for the new device (75 and 500 pM) are different from the predicate (50 and 400 pM), which is explicitly stated as acceptable since the HE4 EIA range is 15-900 pM.

2. Sample size used for the test set and the data provenance

For value assignment of the Fujirebio Diagnostics Tumor Marker Control (K101809):

Sample Size: 24 replicate analyses.
Data Provenance: The replicates were collected in 4 independent runs, using "Different HE4 EIA kit reagent combinations in each run." The country of origin is not specified but implicitly Fujirebio Diagnostics, Inc. (Malvern, PA, USA is the submitter). The data is prospective as it was generated specifically for this submission.

For value assignment of the Predicate HE4 EIA kit controls (K072939):

Sample Size: 26 replicate analyses.
Data Provenance: Collected in 2 independent runs, using the "Same HE4 EIA kit reagent combination in each run." The country of origin is not specified.

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts

This question is not applicable in the traditional sense for a control material. The "ground truth" for a control material is its assigned value, which is established through rigorous laboratory testing and statistical analysis, not expert interpretation of diagnostic images or clinical scenarios. The "experts" involved would be the laboratory scientists and statisticians who designed and executed the value assignment studies according to established protocols. Their specific number and qualifications are not detailed in this summary.

4. Adjudication method for the test set

This question is not applicable. Adjudication methods (like 2+1 or 3+1) are used to resolve discrepancies in expert interpretations (e.g., in medical image analysis). For a control material's value assignment, the "adjudication" is inherent in the statistical methods used to calculate the mean and standard deviation from replicate analyses, and the predefined criteria for acceptance (e.g., CV% limits, mean falling within ±2SD).

5. If a multi reader multi case (MRMC) comparative effectiveness study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance

This question is not applicable. An MRMC comparative effectiveness study involving human readers and AI assistance is relevant for diagnostic devices that aid human interpretation. This submission is for a quality control material which does not involve human readers interpreting clinical cases or AI.

6. If a standalone (i.e. algorithm only without human-in-the loop performance) was done

This question is not applicable. This is a control material, not a diagnostic algorithm. Its "performance" is in its ability to reliably produce expected results within defined ranges when tested with the HE4 EIA assay.

7. The type of ground truth used

For a control material, the "ground truth" is its assigned value and accepted range for HE4 concentration, established through a rigorous laboratory testing procedure outlined in item #2 and #9. This is not expert consensus, pathology, or outcomes data, but rather a derived value based on analytical measurements using a validated assay.

8. The sample size for the training set

This concept is not applicable for a control material. There is no "training set" in the context of machine learning or diagnostic algorithm development. The data described in section #2 for value assignment is analogous to characterization data for the control material itself.

9. How the ground truth for the training set was established

This question is not applicable for a control material as there is no "training set." The "ground truth" (assigned values and ranges) for the control materials (both the new and predicate) was established through the following methods as described in the "Value Assignment comparisons" section:

Fujirebio Diagnostics Tumor Marker Control (K101809):
- 24 replicate analyses collected in 4 independent runs.
- Different HE4 EIA kit reagent combinations were used in each run.
- Criteria for value assignment: CV < 8% within run, and the mean value for each run had to be within ± 2SD for the other 3 runs.
- Assigned range for Control Level 1: Total Mean ± 2SD, but not less than ± 30%.
- Assigned range for Control Level 2: Total Mean ± 2SD, but not less than ± 25%.
Predicate HE4 EIA kit controls (K072939):
- 26 replicate analyses collected in 2 independent runs.
- The same HE4 EIA kit reagent combination was used in each run.
- Criteria for value assignment: Total CV% ≤ 5.
- Assigned range for Control Level 1: Total Mean ± 30%.
- Assigned range for Control Level 2: Total Mean ± 20%.

In summary, the study validates a laboratory control material, not a diagnostic algorithm. The "acceptance criteria" and "study" revolve around demonstrating the analytical performance and stability of the control material to ensure it accurately monitors the precision of the HE4 EIA assay.

Summary

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Premarket Notification (510(k)) HE4 EIA Control Replacement

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Image /page/0/Picture/2 description: The image shows the logo for FUJIREBIO Diagnostics, Inc. The logo consists of a stylized graphic to the left of the company name. The graphic is a geometric shape with black and white sections. The text "FUJIREBIO Diagnostics, Inc." is in a bold, sans-serif font.

510(k) SUMMARY

This summary of 510(k) safety and effectiveness information is being submitted in accordance with the requirements of SMDA 1990 and 21 CFR 807.92.

The assigned 510(k) number is: K103676

Submitter Information

Address:	Fujirebio Diagnostics, Inc.201 Great Valley ParkwayMalvern, PA 19355
Contact person:	Diana L Dickson(610) 240-3917dicksond@fdi.com
Summary preparation date:	July 18, 2011
Name of Device:
510(k) number:	K072939
Trade/Proprietary Name:	HE4 EIA Kit
Common/Usual Name:	Tumor-associated Antigen Immunological Test System.
Regulation Number:	21 CFR §866.6010
Regulatory Class:	Class II
Product Code:	OIU, epithelial ovarian tumor associated antigen test (HE4)
510(k) number:	K101809
Trade/Proprietary Name:	Fujirebio Diagnostics Tumor Marker Control
Common/Usual Name:	Quality control material (assayed and unassayed).
Regulation Number:	21 CFR 862.1660
Regulatory Class:	Class I, reserved
Product Code:	JJY, Multi-Analyte Controls, All kinds, (Assayed)
Predicate Device:
HE4 EIA (K072939)

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Image /page/1/Figure/1 description: The image shows the logo for Fujirebio Diagnostics, Inc. The logo consists of a stylized symbol on the left, followed by the company name in bold, sans-serif font. Below the company name is the text "Diagnostics, Inc." in a smaller font size.

Purpose of Submission

The purpose of the Fujirebio Diagnostics Tumor Marker Control (for use with HE4 EIA) 510(k) submission is to replace the current HE4 EIA kit controls (cleared under K072939) with the Fujirebio Diagnostics Tumor Marker Control (cleared under K101809).

The Fuiirebio Diagnostics Tumor Marker Controls are used for validation of each HE4 EIA assay series. The HE4 EIA results should be considered valid if the mean HE4 values of control duplicates are within the specified HE4 EIA ranges indicated on the Assigned Value Sheet provided with the Fujirebio Diagnostics Tumor Marker Controls.

Intended Use of the Fujirebio Diagnostics Tumor Marker Control

For In Vitro Diagnostic Use Only.

A comparison of the features of the Fujirebio Diagnostics Turnor Marker Control and the Predicate Device are as follows:

Similarities
	Fujirebio Diagnostics TumorMarker Control(K101809)	HE4 EIA kit controls(K072939)
Intended Purpose	Validation of each HE4 EIA assayseries.The HE4 EIA results should beconsidered valid if the mean HE4values of control duplicates arewithin the specified HE4 E!Aranges	Validation of each HE4 EIA assayseries.The HE4 EIA results should beconsidered valid if the mean HE4values of control duplicates arewithin the specified HE4 EIAranges
Supplier	Manufactured by FujirebioDiagnostics	Manufactured by FujirebioDiagnostics
Matrix	Human Serum	Human Serum
Form	Lyophilized	Lyophilized
HE4 Analyte	Purified, recombinant antigen	Purified, recombinant antigen
Control Levels	2	2
Storage (unopened)	Store the kit at 2-8°C.	Store the kit at 2-8°C.
Shelf Life (unopened)	18 months	18 months

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Premarket Notification (510(k)) HE4 EIA Control Replacement

Image /page/2/Picture/1 description: The image shows the logo for "FUJIREBIO Diagnostics, Inc.". The logo consists of a stylized graphic to the left of the text. The graphic is a combination of black and white shapes with vertical lines. The text "FUJIREBIO" is in bold, and "Diagnostics, Inc." is below it in a smaller font.

Differences
	Fujirebio Diagnostics TumorMarker Control(K101809)	HE4 EIA kit controls(K072939)
Controls Supplied	Sold Separately	Sold with HE4 EIA kit
Analyte (s)	HE4 (Human Epididymis Protein 4)AFP (Alpha-Fetoprotein)CA 15-3CA 19-9CA 125CEA (Carcinoembryonic Antigen)FerritinHE4 (Human Epididymis Protein 4)PSA (Prostate Specific Antigen)Free PSA	HE4 (Human Epididymis Protein 4)
Target HE4Concentrations	75 and 500 pM*	50 and 400 pM*
Target HE4 Ranges	Ranges of expected resultsindicated on the Assigned ValueSheet provided with the FujirebioDiagnostics Tumor MarkerControls.	Ranges of expected results areindicated on the vial labels.
Reconstitution Volume	3.0 mL distilled or deionized water	1.0 mL distilled or deionized water
Stability after	14 days at 2-8°C	4 weeks at 2-8°C
Reconstitution	60 days at -20°C or below	4 months at -20°C or below

*Target concentration differences are acceptable - the claimed HE4 EIA range is 15 – 900 pM, with an upper limit of normal of 150 pM. (Refer to HE4 E!A package insert)

Value Assignment comparisons:

Fujirebio Diagnostics Tumor MarkerControl(K101809)	HE4 EIA kit controls(K072939)
24 replicate analyses collected in 4independent runs	26 replicate analyses collected in 2independent runs
Different HE4 EIA kit reagent combinationsin each run	Same HE4 EIA kit reagent combination ineach run
CV <8% within run.Mean value for each run within ± 2SD forother 3 runs.	Total CV% $≤$ 5
Assigned range for HE4 EIA	Assigned range
Control Level 1:	HE4 EIA kit Control Level 1:
Total Mean ± 2SD but not less than ± 30%	Total Mean ± 30%
Assigned range for HE4 EIA	Assigned range
Control Level 2:	HE4 EIA kit Control Level 2:
Total Mean ± 2SD but not less than ± 25%	Total Mean ± 20%

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DEPARTMENT OF HEALTH & HUMAN SERVICES

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Image /page/3/Picture/1 description: The image shows the seal of the U.S. Department of Health & Human Services. The seal features the words "DEPARTMENT OF HEALTH & HUMAN SERVICES • USA" arranged in a circular pattern. Inside the circle is a stylized image of a human figure, possibly representing a family or individual, with flowing lines suggesting movement or progress.

Public Health Service

Food and Drug Administration 10903 New Hampshire Avenue Silver Spring, MD 20993

Fujirebio Diagnostics, Inc. c/o Ms. Diana Lyn Dickson Regulatory Affairs Manager 201 Great Valley Parkway Malvern, PA 19355

JUL 1 9 2011

Re: K103676

Trade/Device Name: HE4 EIA kit

Fujirebio Diagnostics Tumor Marker Control Regulation Number: 21 CFR §866.6010 Regulation Name: Tumor-associated Antigen Immunological Test Regulatory Class: Class II Product Code: OIU, JJY Dated: July 7, 2011 Received: July 8, 2011

Dear Ms. Dickson:

We have reviewed your Section 510(k) premarket notification of intent to market the device referenced above and have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to legally marketed predicate devices marketed in interstate commerce prior to May 28, 1976, the enactment date of the Medical Device Amendments, or to devices that have been reclassified in accordance with the provisions of the Federal Food, Drug, and Cosmetic Act (Act) that do not require approval of a premarket approval application (PMA). You may, therefore, market the device, subject to the general controls provisions of the Act. The general controls provisions of the Act include requirements for annual registration, listing of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration.

If your device is classified (see above) into class II (Special Controls), it may be subject to such additional controls. Existing major regulations affecting your device can be found in Title 21, Code of Federal Regulations (CFR), Parts 800 to 895. In addition, FDA may publish further announcements concerning your device in the Federal Register.

Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Parts 801 and 809); medical device reporting (reporting of

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Page 2 - Ms. Diana Lyn Dickson

medical device-related adverse events) (21 CFR 803); and good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820). This letter will allow you to begin marketing your device as described in vour Section 510(k) premarket notification. The FDA finding of substantial equivalence of your device to a legally marketed predicate device results in a classification for your device and thus, permits your device to proceed to the market.

If you desire specific advice for your device on our labeling regulation (21 CFR Parts 801 and 809), please contact the Office of In Vitro Diagnostic Device Evaluation and Safety at (301) 796-5450. Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR Part 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to http://www.fda.gov/MedicalDevices/Safety/ReportaProblem/default.htm for the CDRH's Office of Surveillance and Biometrics/Division of Postmarket Surveillance.

You may obtain other general information on your responsibilities under the Act from the Division of Small Manufacturers, International and Consumer Assistance at its toll-free number (800) 638-2041 or (301) 796-7100 or at its Internet address http://www.fda.gov/cdrh/industry/support/index.html.

Sincerely yours,

é m cham

Maria M. Chan, Ph.D. Director Division of Immunology and Hematology Devices Office of In Vitro Diagnostic Device Evaluation and Safety Center for Devices and Radiological Health

Enclosure

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Indications for Use

510(k) Number (if known): K103676

Device Name: HE4 EIA

Indications For Use:

Prescription Use

(Part 21 CFR 801 Subpart D)

AND/OR

Over-The-Counter Use (21 CFR 807 Subpart C)

(PLEASE DO NOT WRITE BELOW THIS LINE-CONTINUE ON ANOTHER PAGE IF NEEDED)

Concurrence of CDRH, Office of In Vitro Diagnostic Devices (OIVD)

Reena Philip

Division Sign-Off

Office of In Vitro.Diagnostic
Device Evaluation and Safety
510K	K103676

Page 1 of 2

510K __

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Indications for Use

510(k) Number (if known): K103676

Device Name: Fujirebio Diagnostics Tumor Marker Controls

Indications For Use:

For In Vitro Diagnostic Use Only.

Prescription Use X (Part 21 CFR 801 Subpart D) AND/OR

Over-The-Counter Use (21 CFR 807 Subpart C)

(PLEASE DO NOT WRITE BELOW THIS LINE-CONTINUE ON ANOTHER PAGE IF NEEDED)

Concurrence of CDRH, Office of In Vitro Diagnostic Devices (OIVD)

Reena Philip

Division Sign-Off

Office of In Vitro Diagnostic Device Evaluation and Safety

510K

Page 2 of 2

Regulation Number and Section

§ 866.6010 Tumor-associated antigen immunological test system.

(a)
Identification. A tumor-associated antigen immunological test system is a device that consists of reagents used to qualitatively or quantitatively measure, by immunochemical techniques, tumor-associated antigens in serum, plasma, urine, or other body fluids. This device is intended as an aid in monitoring patients for disease progress or response to therapy or for the detection of recurrent or residual disease.(b)
Classification. Class II (special controls). Tumor markers must comply with the following special controls: (1) A guidance document entitled “Guidance Document for the Submission of Tumor Associated Antigen Premarket Notifications (510(k)s) to FDA,” and (2) voluntary assay performance standards issued by the National Committee on Clinical Laboratory Standards.