HemosIL Factor VIII deficient plasma is human plasma, depleted of Factor VIII, which is intended for the in vitro diagnostic quantitative determination of Factor VIII activity in citrated plasma, based on the activated partial thromboplastin time (APTT) assay, on the ACL TOP® Family analyzers. HemosIL Factor VIII deficient plasma is indicated for use on patients who are suspected of congenital or acquired deficiency based on the activated partial thromboplastin time (APTT) assay results.

Device Description

The assay determines the functional activity of Factor VIII by measuring the degree of prolongation of activated partial thromboplastin time in the presence of a contact activator, thromboplastin, phospholipids and calcium ions. Factor VIII activity is correlated with the prolongation of the clotting time of the Factor VIII deficient plasma to which diluted patient sample has been added.

AI/ML Overview

Here's a breakdown of the requested information based on the provided text, focusing on the acceptance criteria and the study that proves the device meets them:

Acceptance Criteria and Device Performance

1. Table of Acceptance Criteria and Reported Device Performance

The provided document primarily details performance characteristics rather than explicit "acceptance criteria" for regulatory approval in every instance. However, it implicitly defines satisfactory performance through comparisons to the predicate device and established linearity/precision targets. Due to the nature of the submission (Reagent formulation change), the primary acceptance criterion is demonstrating comparable performance to the predicate device.

Performance Metric	Acceptance Criteria (Implicit/Explicit)	Reported Device Performance
Precision (CV%)	Within acceptable limits for diagnostic assays (not explicitly stated as a numerical target in this summary, but typical for CLSI EP05-A2). The predicate device's performance would serve as the benchmark.	Within Run CV%: 3.7 - 4.1% (ACL TOP 500 CTS) Total CV%: 3.9 - 6.4% (ACL TOP 500 CTS) (These values are for various control levels with SynthASil reagent and a representative instrument/lot).
Linearity (R², Slope, Intercept)	R² close to 1.0, slope close to 1.0, and intercept close to 0.0, indicating proportional response across the analytical range.	R²: 0.995 - 0.998 Slope: 0.964 - 1.045 Intercept: -1.621 - 2.261 (Demonstrated linearity for activities up to 150% for both reagent lots and ACL TOP Family instruments).
Analytical Range	Defined operational range for Factor VIII activity.	0.1 - 150% (with SynthASil) 0.5 - 150% (with APTT-SP)
Interference	No significant interference from common interferents at specified concentrations (e.g., hemoglobin, triglycerides, bilirubin, FVIII inhibitors, Lupus anticoagulant antibodies).	No effect from hemoglobin up to 530 mg/dL, triglycerides up to 2000 mg/dL, bilirubin up to 150 mg/dL, Factor VIII inhibitors up to 0.1BU, and Lupus anticoagulant antibodies.
Method Comparison (In-House)	Slope: Close to 1.0 Correlation Coefficient (R): Close to 1.0 (indicating strong agreement with the predicate device). "Satisfy the product specifications for method comparison and demonstrate comparable performance."	With SynthASil: Slope: 1.064 (ACL TOP), 1.112 (ACL TOP 500 CTS); R: 0.9885 (ACL TOP), 0.9923 (ACL TOP 500 CTS) With APTT-SP: Slope: 0.893 (ACL TOP), 0.913 (ACL TOP 500 CTS); R: 0.9884 (ACL TOP), 0.9926 (ACL TOP 500 CTS) Conclusion: Satisfies product specifications and demonstrates comparable performance.
Method Comparison (Field Site)	Slope: Close to 1.0 Correlation Coefficient (R): >0.98 "Statistically similar performance to the predicate device."	Slope: 0.871 - 1.138 Correlation Coefficient (R): >0.9829 Conclusion: Performance is statistically similar.
Stability/Shelf Life	Demonstrated shelf life under specified storage conditions. The claimed shelf life would need to be supported by stability data.	12 months when stored at 2-8°C (based on accelerated stability, real-time ongoing).

2. Sample Sizes Used for the Test Set and Data Provenance

Precision Study:
- Sample Size: 80 replicates per instrument/lot per control level (e.g., 4 control levels x 3 lots x 3 instruments x 80 = 2880 individual measurements if all were run, but data is shown for one representative instrument/reagent/lot).
- Data Provenance: Not explicitly stated, but clinical laboratory samples (normal and abnormal types) were used. Implied to be prospective within the context of the study design (20 days, 2 runs/day, 2 replicates/run). Country of origin is not specified, but the applicant is US-based.
Linearity Study:
- Sample Size: 4 replicates for each Factor VIII sample level.
- Data Provenance: Not explicitly stated, but generated in-house using prepared Factor VIII samples ranging from <1% to >150%. Implied prospective within the study.
Interference Study:
- Sample Size: Not specified, but involved testing samples spiked with various interferents.
- Data Provenance: Not specified, likely in-house laboratory testing, prospective.
In-House Method Comparison Study:
- Sample Size: Not explicitly stated for the regression analysis. The table shows 'N' for the ACL TOP 500 CTS as 90 (likely 90 samples tested).
- Data Provenance: "In-House Study," likely prospective laboratory testing.
Field Site Study:
- Sample Size:
  - OUS site: n = 109
  - US #1 site: n = 125
  - US #2 site: n = 102
- Data Provenance: Conducted at "2 US sites and one OUS site." The document states "Both normal and abnormal samples were tested." Implied prospective testing at these sites.

3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of Those Experts

This device is an in vitro diagnostic reagent kit for quantitative determination of Factor VIII activity. The "ground truth" for Factor VIII activity in the test samples is typically established by assigned values from reference materials or by established laboratory methods using calibrated instruments, not by expert human interpretation like in imaging or pathology. The document mentions "assigned values" for the HemosIL Calibration plasma (for calibration curves) and "assigned values" for samples in the linearity study, but does not detail how these assignments were made in terms of human experts. It's a quantitative chemical assay, where "ground truth" is analytical, not based on expert consensus for a "reading."

4. Adjudication Method for the Test Set

Not applicable. This is a quantitative diagnostic assay, not a diagnostic imaging or pathology device where human interpretation and adjudication would be typically required for a "test set" in the sense of establishing truth for diagnostic accuracy. The performance is assessed against known or assigned values for Factor VIII activity.

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

Not applicable. This device is a diagnostic reagent, not an AI-powered diagnostic aid for human readers. It functions as a standalone laboratory test.

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

Yes. This device (HemosIL Factor VIII deficient plasma) is a reagent used in an automated assay on ACL TOP Family analyzers. Its performance characteristics (precision, linearity, interference, method comparison) are evaluated as a standalone component of the in vitro diagnostic system, independent of direct human interpretive "reading" of the results in the same way an imaging device would be read. The "performance" described is the analytical performance of the reagent used with the specified instruments.

7. The Type of Ground Truth Used (expert consensus, pathology, outcomes data, etc.)

For the analytical studies (precision, linearity, method comparison), the "ground truth" is based on:

Reference materials/assigned values: HemosIL Calibration plasma values are assigned for Factor VIII Activity and used to calibrate the standard curve. In the linearity study, samples had "assigned values."
Established methods: The predicate device itself serves as the "truth" for comparative purposes in the method comparison studies.
Known concentrations: For interference studies, samples are spiked with known concentrations of interferents.

This is primarily an analytical ground truth derived from laboratory standards, calibrated materials, and established predicate device performance.

8. The Sample Size for the Training Set

Not applicable. This is an IVD reagent, not a machine learning or AI-based device that requires a "training set" in the context of algorithm development. The reagent itself does not learn or get "trained."

9. How the Ground Truth for the Training Set Was Established

Not applicable, as there is no "training set" for this type of device.

Summary

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510K SUMMARY

ASSAY ONLY TEMPLATE

KI10237

A.	510(k) Number	TBD
B.	Purpose for Submission	Reagent formulation change
C.	Measurand	Factor VIII Activity
D.	Type of Test	Factor VIII Activity Test, based on activatedpartial thromboplastin time (APTT)
E.	Applicant	Instrumentation Laboratory Co.
F.	Proprietary & Established Names	HemosIL Factor VIII deficient plasma
G.	Regulatory Information
1.	Regulation section:	21CFR §864.7290
2.	Classification:	Class II
3.	Product code:	GJT
4.	Device classification name:	Plasma, Coagulation Factor Deficient

H. Intended Use

1. Intended use(s):

Indication(s) for use: 2.
Same as intended use.
1. Special conditions for use statement(s): For in-vitro diagnostic use only. For prescription use.
Special instrument requirements: 4. ACL TOP® Family analyzers

I. Device Description

J. Substantial Equivalence Information:

Predicate device name(s): 1. HemosIL Factor VIII deficient plasma (same name)
1. Predicate 510(k) number(s):

K034007

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3. Comparison with predicate: Similarities

The applicant, HemosIL Factor VIII deficient plasma (PN 00020012800) is substantially equivalent to its predicate, the HemosIL Factor VIII deficient plasma (K034007).

Table of similarities:

Item	Predicate Device	Applicant
K#	K034007	TBD
Device Name	HemosIL Factor VIII deficient plasma	Same
Manufacturer	Instrumentation Laboratory Co. (self)	Same
Indications forUse	HemosIL Factor VIII deficient plasma is human plasmadepleted of Factor VIII and intended for the in vitrodiagnostic quantitative determination of Factor VIIIactivity in citrated plasma, based on the activatedpartial thromboplastin time (APTT) assay, on the ACLTOP® Family analyzers.	Same
Sample Type	Citrated plasma	Same
Test Principle	Functional clotting assay	Same
Methodology	Abnormalities of the intrinsic pathway factors aredetermined by performing a modified activatedpartial thromboplastin time (APTT) test. Patientplasma is diluted and added to plasma that isdeficient in Factor VIII. Correction of the clotting timeof the deficient plasma is proportional to theconcentration (% activity) of the Factor VIII in thepatient plasma, interpolated from a calibration curve.	Same
Calibration	HemosIL Calibration plasma values are assigned forFactor VIII Activity and used to calibrate the standardcurve.	Same
Kit Composition	Lyophilized human plasma deficient in Factor VIII.	Same

Differences

The difference between the 2 products; the applicant HemosIL Factor VIII deficient plasma and its predicate, is that the applicant contains normal levels of von Willebrand factor, whereas the predicate is deficient not only in Factor VIII but also in von Willebrand Factor. The test results demonstrate that this change does not adversely affect the product's performance.

K. Standard/Guidance Document Referenced (if applicable):

No performance standard or FDA guidance has been established for FVIII deficient plasma.

L. Test Principle

Correction of the clotting time of the deficient plasma is proportional to the concentration (% activity) of the factor VIII in the patient plasma, interpolated from a calibration curve.

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M. Performance Characteristics

1. Analytical performance:

Precision/Reproducibility a.

Precision was assessed utilizing 3 lots of plasma on representative members of the ACL TOP Family (ACL TOP base, ACL TOP 700 and ACL TOP 500 CTS). Precision was evaluated in accordance with CLSI EP05-A2, for 20 days, with 2 runs per day and 2 replicates per run for each sample level (n=80/ instrument/ lot), using a specific lot of APTT reagent (APTT-SP and SynthASil) and both normal and abnormal samples. Test data from a representative instrument, APTT reagent and plasma lot is included below:

Instrument	Control Level	N	MeanFVIII (%)	Within RunCV%	TotalCV%
Controls with SynthASil
ACL TOP 500CTS	Normal Control	80	80.3	3.8	3.9
ACL TOP 500CTS	STC Level 2	80	23.8	4.0	5.5
ACL TOP 500CTS	Low Control I	80	12.1	3.7	5.2
ACL TOP 500CTS	Low Control II	80	6.8	4.1	6.4

Linearity/assay reportable range: b.
Linearity:

The Factor VIII activities of a high sample (level 1) and an intermediate sample (level 2) were determined from the respective means of 8 replicates, using the Factor VIII deficient plasma predicate. These two samples, together with HemosIL® Factor VIII deficient plasma (PN 00020012800), were used to setup samples with Factor VIII activities ranging from <1% to >150%.

All Factor VIII samples were run in 4 replicates, using Factor VIII deficient plasma (PN0020012800) as a substrate, on the ACL TOP with the two reagent lots, and the average activities for all the samples were plotted against their assigned values. The results demonstrated that the Factor VIII assay is linear, with the HemosIL® Factor VIII deficient plasma (PN0020012800) as a substrate, up to 150% activity on the ACL TOP Family.

Instrument	FVIIIDP	Reagent	Slope	Intercept	R2
ACL TOP	Lot 1	SynthASil	0.971	0.528	0.995
ACL TOP		APTT SP	1.045	2.261	0.997
ACL TOP 500 CTS	Lot 2	SynthASil	1.040	-0.526	0.998
ACL TOP 500 CTS		APTT SP	0.964	-1.621	0.996

Analytical Range:

System

ACL TOP Family with SynthASil	0.1 - 150%
ACL TOP Family with APTT-SP	0.5 - 150%

C. Traceability, Stability, Expected values (controls, calibrators, or methods): Based on the accelerated stability study, which projects 3 years of shelf life, a shelf life of 12 months is claimed for the product when stored at 2-8°C. Real-time stability testing is ongoing, and will be used to update the shelf life as more data becomes available.

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d. Interference Study:

Factor VIII results on the ACL TOP Family are not affected by hemoglobin up to 530 mg/dL, triglycerides up to 2000 mg/dL, bilirubin up to 150 mg/dL, and Factor VIII inhibitors up to 0.1BU. Results are not affected by the presence of Lupus anticoagulant antibodies.

Detection limit: e. Not Applicable
f Analytical specificity: Not Applicable
Assay cut-off: g. Not Applicable
1. Comparison studies:
- Method comparison with predicate device: a.

In-House Study

An in-house method comparison study was performed to compare the performance of the new Factor VIII deficient plasma with its predicate.

The Deming regression analysis for the ACL TOP shows that the slope and correlation coefficient (r) are 1.064 and 0.9885 respectively, with the SynthASil reagent, and 0.893 and 0.9884 respectively, with the APTT-SP reagent.

The Deming regression analysis for the ACL TOP 500 CTS shows that the slope and correlation coefficient (r) are 1.112 and 0.9923 respectively, with the SynthASil reagent, and 0.913 and 0.9926 respectively, with the APTT-SP reagent.

The above results satisfy the product specifications for method comparison and demonstrate comparable performance is achieved for the 2 reagents.

Reagent	Instrument	N	Slope	Intercept	R
SynthASil	ACL TOP 500 CTS	90	1.112	-3.57	0.9923
APTT SP	ACL TOP 500 CTS	90	0.913	0.56	0.9926

Field Site Study

A field site study was conducted at 2 US sites and one OUS site, comparing the new Factor VIII depleted plasma with its predicate. Both normal and abnormal samples were tested on an ACL TOP analyzer. The results showed a correlation (R) >0.9829 and a slope of 0.871-1.138 indicating that the performance of the two tests is statistically similar.

Within Lin. Range (1st Replicate)	OUS	US #1	US #2
Slope	1.074	0.871	1.138
Intercept	-4.83	-0.25	-9.31
Correlation coefficient (R)	0.9829	0.9935	0.9842
n	109	125	102

b. Matrix comparison: NA

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1. Clinical studies:
- Clinical Sensitivity: NA a.
- b. Clinical Specificity: NA
- Other clinical supportive data (when a. and b. are not applicable): NA C.
1. Clinical cut-off: NA
Expected values/Reference range*: 5.

Factor VIII: 50-150% (0.50-1.50 IU)

*Due to the many variables which may affect clotting times (including the population age), each laboratory should establish its own normal range.

N. Proposed Labeling

The labeling is sufficient and satisfies the requirements of 21 CFR Part 809.10.

0. Conclusion

The submitted information in this premarket notification is complete and supports a substantial equivalence decision.

P. Administrative Information

Applicant Contact Information

Name of applicant:	Instrumentation Laboratory Co.
Mailing address:	180 Hartwell Road
	Bedford, MA 01730, USA
Phone #:	781-861-4350
Fax #:	781-861-4207
E-mail address:	jemery@ilww.com
Contact:	Jacqueline Emery, BSEE
	Regulatory Affairs Manager
Date Prepared	July 5, 2011

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Food and Drug Administration 10903 New Hampshire Avenue Document Mail Center-WO66-G609 Silver Spring, MD 20993-0002

Instrumentation Laboratory Co. c/o Ms. Jacqueline Emery Regulatory Affairs Manager 180 Hartwell Rd. Bedford, MA 01730

JUL 0 8 2011

Re: K110237

Trade/Device Name: HemosIL® Factor VIII Deficient Plasma Regulation Number: 21 CFR 864.7290 Regulation Name: Factor deficiency test Regulatory Class: Class II Product Code: GJT Dated: June 27, 2011 Received: June 29, 2011

Dear Ms. Emery,

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 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

Image /page/5/Picture/11 description: The image shows the logo for the U.S. Department of Health & Human Services. The logo features the department's name arranged in a circular fashion around the perimeter. In the center is a stylized graphic of an abstract symbol, consisting of three angled lines that resemble a person with outstretched arms.

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Page 2 - Ms. Jacqueline Emery

will allow you to begin marketing your device as described in your 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.

Reena Philip

Tota

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 Statement

510(k) Number (if known): K110237

Device Name: HemosIL* Factor VIII deficient plasma

Indications for Use:

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

Over-The-Counter Use (21 CFR 801 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)

Division Sign-Off

Office of In Vitro Diagnestic Device Evaluation and Safety

510(k) K110237

Regulation Number and Section

§ 864.7290 Factor deficiency test.

(a)
Identification. A factor deficiency test is a device used to diagnose specific coagulation defects, to monitor certain types of therapy, to detect coagulation inhibitors, and to detect a carrier state (a person carrying both a recessive gene for a coagulation factor deficiency such as hemophilia and the corresponding normal gene).(b)
Classification. Class II (performance standards).