Embozene® Microspheres are tightly calibrated, compressible microspheres intended to occlude vasculature for the purpose of blocking blood flow to a target tissue such as a hypervascular tumor (HVT) or arteriovenous malformation (AVM). Embozene® Microspheres are manufactured from sodium polymethacrylate and coated with proprietary Polyzene®-F. The microspheres are compressible to enable smooth delivery through the indicated delivery catheter. Embozene® Microspheres are color coded by size to allow easy identification of the different sizes. Embozene® Microspheres are supplied sterile and packaged in 20ml polycycloolefin syringes with a standard 7ml fill volume across the range. Embozene® Microspheres syringes or vials are available in 1 ml or 2 ml microsphere volume.

AI/ML Overview

The acceptance criteria for the Embozene® Microspheres and the study demonstrating its performance are detailed below.
It's important to note that this submission relies heavily on substantial equivalence to previously cleared predicate devices, rather than establishing entirely new performance criteria through a de novo study.

Acceptance Criteria and Reported Device Performance

Acceptance Criteria Category	Specific Criteria	Reported Device Performance	Study Reference
Intended Use	Embolization of arteriovenous malformations and hypervascular tumors (including uterine fibroids)	Device is intended for these uses. Specificity for uterine fibroids is the update from predicate.	Clinical experience reviewed (Smeets et al.)
Technological Characteristics	- Same manufacturer, classification, regulation, product codes (with added NAJ for uterine fibroids). - Same method of delivery, Rx status. - Same mechanism of action (mechanical occlusion). - Same material class, design, and composition (Crosslinked polyacrylate hydrogel with Polyzene-F). - Same size ranges, biocompatibility, microsphere volume, sterility assurance level ($10^{-6}$), pyrogen-free status, packaging, and shelf-life (3 years).	All technological characteristics are identical to the primary predicate device (Embozene® Microspheres, K073417 and K132675). The only difference is the broadened indication for use to explicitly include uterine fibroids, which is supported by clinical data.	Non-Clinical Performance Testing (bench testing) and comparison to predicate device.
Safety	No unique safety concerns regarding use for uterine fibroid embolization.	Review of published and unpublished data regarding adverse events did not identify any unique safety concerns. Adverse events observed in the Smeets et al. study (hysterectomy due to incomplete fibroid expulsion or persistent pain) are documented, but not deemed "unique safety concerns" for the device itself.	Clinical Experience (Smeets et al.)
Clinical Effectiveness (for Uterine Fibroids)	Improvement in fibroid symptoms and/or reduction in fibroid/uterine volume, successful infarction. (Implicitly comparable to predicate device performance)	- UFS-QOL Symptom Severity Scores: Mean score dropped from 64 at baseline to 23 at 3 months (n=85), and to 16 at 12.8 months (n=81). - Fibroid/Uterine Volume Reduction: Mean dominant fibroid volume reduction of 45% at 3 months. Mean total uterine volume reduction of 42% at 3 months. - Fibroid Infarction: 94% rate of >90% infarction of dominant fibroid at 3 months. 91% rate of >90% infarction of total fibroid load at 3 months.	Clinical Experience (Smeets et al.)

Study Details

The submission's primary evidence for meeting acceptance criteria for the expanded indication (uterine fibroids) comes from a review of clinical information, specifically a published study by Smeets et al., and a comparison to predicate devices. No new, prospective, de novo clinical trial was conducted for this 510(k) submission.

1. A table of acceptance criteria and the reported device performance:
See table above.

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

Sample Size for Clinical Data:
- Smeets et al. study: n=85 patients for initial 3-month follow-up on UFS-QOL scores. n=81 patients for extended 12.8-month follow-up on UFS-QOL scores.
Data Provenance:
- Smeets et al. study: Published data, conducted outside the United States. The document states "published and unpublished data on the use of use of Embozene® for the treatment of uterine fibroids (outside the United States)". This indicates a retrospective or prospective observational study conducted previously.

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

This information is not provided in the summary. The clinical study (Smeets et al.) relied on patient-reported outcomes (UFS-QOL) and objective measurements from MRI (uterine and fibroid volume, fibroid infarction). The interpretation of MRI results would have been by medical professionals (radiologists), but their number and specific qualifications are not specified in this 510(k) summary.

4. Adjudication method for the test set:

This information is not provided in the summary. For the Smeets et al. study, it doesn't mention any specific adjudication method for patient-reported outcomes or MRI interpretations.

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:

No, an MRMC comparative effectiveness study was not done. This device is a vascular embolization device, not an AI-assisted diagnostic tool. Therefore, the concept of "human readers improve with AI assistance" is not applicable.

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

No, this is not an algorithm or AI-based device. It is a physical device (microspheres) for embolization. Therefore, standalone algorithm performance is not relevant.

7. The type of ground truth used:

For the clinical effectiveness concerning uterine fibroids, the ground truth was established through:
- Patient-reported outcomes: Uterine Fibroid Symptom Quality of Life (UFS-QOL) instrument.
- Imaging-based objective measures: Uterine and fibroid volume reduction and percent fibroid infarction as determined by MRI.

8. The sample size for the training set:

Not applicable / Not explicitly stated. This is not an AI/machine learning device that involves a training set in the conventional sense. The "training" for the device's effectiveness is based on the general understanding of embolization therapy and the established performance of predicate devices. The clinical data from Smeets et al. serves as evidence for effectiveness, not as a training set for an algorithm.

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

Not applicable. As mentioned, there isn't a "training set" in the context of an algorithm. The evidence base relies on existing medical knowledge, predicate device performance, and clinical study outcomes.

Summary

{0}------------------------------------------------

FEB 2 4 2014

510(k) Summary of Safety and Effectiveness

February 21, 2014 Summary Date: CeloNova BioSciences, Inc. Submitter: 18615 Tuscany Stone, Ste. 100 San Antonio Texas 78258, USA Nicole C. Barber Contact: Manager, Regulatory Affairs 1. Common name, Trade name & Classification of Subject Device Embozene® Microspheres Trade Name: Common Name(s): Vascular Embolization device, embolization, arterial Product Code: NAJ, KRD, 21 CFR 870.3300 Class II (special control) Classification: 2. 510(k) Numbers and Product Codes of Predicate Devices Embozene® Microspheres Trade Name: CeloNova BioSciences, Inc. Manufacturer: 510(k) Number: K073417/ K132675 KRD, 21 CFR 870.3300 Product Code: Embosphere® Microspheres Trade Name: Manufacturer: BioSphere Medical, Inc. (Acquired by Merit Medical Systems, Inc.) 510(k) Number: K021397 NAJ, 21 CFR 870.3300 Product Code: Contour® PVA Embolization Particles Trade Name: Boston Scientific Corporation Manufacturer: Page 1 of 6 CeloNova BioSciences, Inc.

{1}------------------------------------------------

510(k) Number:	K030966
Product Code:	NAJ, 21 CFR 870.3300

Product Code,

ARM, 21-OPR-3133-S

3. Indications for Use and Intended Purpose

Embozene® Microspheres are intended for embolization of arteriovenous malformations, and hypervascular tumors, including uterine fibroids.

4. Device Description

Embozene® Microspheres are supplied sterile and packaged in 20ml polycycloolefin syringes with a standard 7ml fill volume across the range. Embozene® Microspheres syringes or vials are available in 1 ml or 2 ml microsphere volume. Product configurations are shown in the following tables.

Product REF CodesEmbozene® Color-AdvancedMicrospheres		Volume of Embozene®Color-AdvancedMicrospheres per Syringe		Volume of Embozene®Color-AdvancedMicrospheres per Vial
Nominal Size	Specifications	1ml	2ml	1ml	2ml
40 μm	40 μm ±10 μm	10410-S1	10420-S1	10401-V1	10402-V1
75 μm	75 μm ±15 μm	10710-S1	10720-S1	10701-V1	10702-V1
100 μm	100 μm ±25 μm	11010-S1	11020-S1	11001-V1	11002-V1
250 μm	250 μm ± 50 μm	12010-S1	12020-S1	12001-V1	12002-V1
400 μm	400 μm ± 50 μm	14010-S1	14020-S1	14001-V1	14002-V1
500 μm	530 μm ± 50 μm	15010-S1	15020-S1	15001-V1	15002-V1
700 μm	700 μm ± 50 μm	17010-S1	17020-S1	17001-V1	17002-V1
900 μm	900 μm ± 75 μm	19010-S1	19020-S1	19001-V1	19002-V1
1100 μm	1100 μm ± 75 μm	111010-S1	111020-S1	111001-V1	111002-V1
1300 um	1300 μm ± 75 um	113010-S1	113020-S1	113001-V1	113002-V1

Product REF Codes for Embozene® Color-Advanced Microspheres in Syringe and Vial

{2}------------------------------------------------

Product REF CodesEmbozene® OpaqueMicrospheres		Volume of Embozene®Opaque Microspheres perSyringe		Volume of Embozene®Opaque Microspheres perVial
Nominal Size	Specifications	1ml	2ml	1ml	2ml
40 μm	40 μm ±10 μm	10410-S0	10420-S0	10401-V0	10402-V0
75 μm	75 μm ±15 μm	10710-S0	10720-S0	10701-V0	10702-V0
100 μm	100 μm ±25 μm	11010-S0	11020-S0	11001-V0	11002-V0
250 μm	250 μm ± 50 μm	12010-S0	12020-S0	12001-V0	12002-V0
400 μm	400 μm ± 50 μm	14010-S0	14020-S0	14001-V0	14002-V0
500 μm	530 μm ± 50 μm	15010-S0	15020-S0	15001-V0	15002-V0
700 μm	700 μm ± 50 μm	17010-S0	17020-S0	17001-V0	17002-V0
900 μm	900 μm ± 75 μm	19010-S0	19020-S0	19001-V0	19002-V0
1100 μm	1100 μm ± 75 μm	111010-S0	111020-S0	111001-V0	111002-V0
1300 μm	1300 μm ± 75 μm	113010-S0	113020-S0	113001-V0	113002-V0

Product REF Codes for Embozene® Opaque (Non-Colored) Microspheres in Syringe and Vial

Only microspheres of 500 um or greater should be used for embolization of uterine fibroids.

5. Similarities and Differences Compared to Predicate Devices

To demonstrate substantial equivalence. CeloNova has identified two legally marketed predicate devices; Embozene Microspheres cleared through 510(k)s (K073417 and /K 132675 and Merit Medical's Embospheres Microspheres cleared through 510(k) K021397. The Embozene® Microspheres that are the subject of this 510(k) are the same as the legally marketed Embozene® Microspheres, previously cleared by FDA, in regard to intended use and technological characteristics. The only difference between the subject of this 510(k) and our legally marketed predicate devices relates to the indications for use statement. The indications for use statement related to this 510(k) includes greater specificity than our predicates by explicitly identifying "uterine fibroids" as being among the tumors treated with vascular embolization devices, as established by 21 CFR § 870.3300.

In comparison to the second predicate device, Merit Medical's Embosphere® Microspheres (K021397), the intended use of the subject device is the same. Furthermore, the subject device and the predicate have the same design, specifications, fundamental scientific technology, and packaging.

In comparison to the third predicate device, Boston Scientific's Contour® PVA Embolization Particles (K030966), the intended use of the subject device is the same.

{3}------------------------------------------------

6. Summary of Technological Characteristics

Comparison between the Subject Device (Embozene®) and the Primary Predicate Device (Embozene®)

	Subject Embozene®Microspheres	PredicateEmbozene®Microspheres
Administrative Elements
Manufacturer	CeloNova BioSciences, Inc.	Same
Premarket Notification	K133447	K073417 andK132675
Classification	Class II (special controls)	Class II (special controls)
ClassificationRegulation	21 CFR 870.3300	21 CFR 870.3300
Product Code	NAJ- Agents, Embolic, ForTreatment Of Uterine FibroidsKRD - Device, Vascular,For Promoting Embolization	KRD - Device, Vascular, ForPromoting Embolization
Intended Use
Indications for UseStatement	Embozene® Microspheresare intended for embolization ofarteriovenous malformations andhypervascular tumors, includinguterine fibroids.	Embozene®Microspheres are intended forembolization of hypervascular tumorsand arteriovenous malformations.
Method of Delivery	Microcatheter underfluoroscopic visualization withcontrast	Same
OTC or Rx	Rx	Same
Technological Characteristics
Mechanism of Action	Mechanical Occlusion	Same
Material Class	Crosslinked polyacrylatehydrogel	Same
Material Design	Spherical	Same
Material Composition	Crosslinked polyacrylatehydrogelwith Polyzene-F	Same

{4}------------------------------------------------

Sizes [µm]	$40 \pm 10$	Same
	$75 \pm 15$
	$100 \pm 25$
	$250 \pm 50$
	$400 \pm 50$
	$530 \pm 50$
	$700 \pm 50$
	$900 \pm 75$
	$1100 \pm 75$
	$1300 \pm 75$
Biocompatibility ofpatient-contactingmaterials	Yes	Same
Microsphere Volume[ml]	1 or 2	Same
Sterility AssuranceLevel	Supplied sterile to SAL $10^{-6}$	Same
Pyrogen-free	Yes	Same
Packaging	Syringe or vial	Same
Shelf-life	3 years	Same

7. Summary of Non-Clinical Performance Testing

There are no performance standards applicable to the device is subject Guidance for Industry and FDA Staff - Class II Special Controls Guidance Document: Vascular and Neurovascular Embolization Devices issued on December, 29 2004. The following non-clinical performance testing was conducted on the primary predicate device:

. Chemical analysis
Size range .
. Catheter compatibility
. Density
Packaging performance .
. Shelf Life
. Sterility
. Biocompatibility

No new testing was conducted since the primary predicate device and the subject device have identical technological characteristics, manufacturing, processing, and sterilization.

{5}------------------------------------------------

Bench testing was conducted to compare Embozene® Microspheres with the predicate Embosphere

8. Summary of Clinical Experience

The clinical information submitted included a review of embolization using various embolic agents to physically occlude vessels to restrict blood flow over the last ten years, published and unpublished data on the use of use of Embozene® for the treatment of uterine fibroids (outside the United States) and postmarket experience with the cleared device.

The published data provided included a study conducted by Smeets et al. [Ref.: Smeets AJ, Nijenhuis RJ, van Rooij WJ et al. Embolization of uterine leiomyomas with Polyzene Fcoated hydrogel microspheres: initial experience. JVIR 2010; 21(12): 1830-1834]. This study included data on fibroid-specific outcomes using the Uterine Fibroid Symptom Quality of Life (UFS-QOL) patient reported outcomes instrument. It also evaluated the uterine and fibroid volume and percent fibroid infarction as determined by MRI. A fibroid-specific quality of life outcomes instrument was used as the primary clinical outcome measure in a previously-cleared device with this indication (i.e., Boston Scientific Contour Emboli PVA, K030966). Results from the Smeets et al. study demonstrated that mean fibroid symptom severity scores on the UFS-QOL instrument dropped from 64 at baseline to 23 at three months (n=85). (A reduction in score constitutes an improvement in patient symptoms.) At a mean follow-up of 12.8 months, mean uterine fibroid symptom severity scores were 16 (n=81). At three months, the mean volume reduction of the dominant fibroid was 45% and the mean volume reduction of the entire uterus was 42%. At three months, there was a 94% rate of >90% infarction of the dominant fibroid and a 91% rate of >90% infarction of the total fibroid load. Regarding adverse events, one subject underwent hysterectomy at two months due to incomplete fibroid expulsion, and two subjects had hysterectomy at five- and seven-months post-procedure due to persistent pain.

Review of published and unpublished data regarding adverse events associated with Embozene® Microspheres did not identify any unique safety concerns regarding use of Embozene® Microspheres for uterine fibroid embolization.

9. Conclusion

The Embozene® Microspheres that are the subject of this 510(k) submission are substantially equivalent to the primary predicate device (Embozene® Microspheres, K073417 and K132675) and the second predicate device (Embosphere® Microspheres, K021397) based on intended use, technological characteristics, and bench performance data. The Embozene® Microspheres that are the subject of this 510(k) submission are substantially equivalent to the third predicate device (Contour® PVA Embolization Particles, K030966) based on intended use and clinical performance data.

CeloNova BioSciences, Inc.

{6}------------------------------------------------

Image /page/6/Picture/1 description: The image shows the logo for the Department of Health & Human Services - USA. The logo consists of a circular seal with the text "DEPARTMENT OF HEALTH & HUMAN SERVICES - USA" arranged around the perimeter. Inside the circle is a stylized graphic of an abstract human figure embracing or protecting another smaller figure, symbolizing the department's mission to protect and promote the health and well-being of the nation.

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

February 24, 2014

CeloNova BioSciences, Inc. Nicole C. Barber Manager, Regulatory Affairs 18615 Tuscany Stone Suite 100 San Antonio, TX 78258

Re: K133447

Trade/Device Name: Embozene® Microspheres Regulation Number: 21 CFR& 870.3300 Regulation Name: Vascular embolization device Regulatory Class: II (special controls) Product Code: NAJ, KRD Dated: November 25, 2013 Received: November 26, 2013

Dear Nicole C. Barber,

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. Please note: CDRH does not evaluate information related to contract liability warranties. We remind you, however, that device labeling must be truthful and not misleading.

If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21, Parts 800 to 898. 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 Part 801); medical device reporting (reporting of

{7}------------------------------------------------

medical device-related adverse events) (21 CFR 803); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820); and if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.

If you desire specific advice for your device on our labeling regulation (21 CFR Part 801), please go to http://www.fda.gov/AboutFDA/CentersOffices/CDRH/CDRHOffices/ucm115809.htm for the Center for Devices and Radiological Health's (CDRH's) Office of Compliance. Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21CFR 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/MedicalDevices/ResourcesforYou/Industry/default.htm.

Sincerely yours,

Herbert P. Lerner -S

for Benjamin R. Fisher, Ph.D. Director Division of Reproductive, Gastro-Renal, and Urological Devices Office of Device Evaluation Center for Devices and Radiological Health

Enclosure

{8}------------------------------------------------

DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration

Indications for Use

Form Approved: OMB No. 0910-0120 Expiration Date: January 31, 2017 See PRA Statement on last page.

510(k) Number (if known)

K133447

Device Name

Embozene® Microspheres

Indications for Use (Describe)

Embozene® Microspheres are indication of arteriovenous malformations and hypervascular turnors, including uterine fibroids.

Type of Use (Select one or both, as applicable)

Prescription Use (Part 21 CFR 801 Subpart D)

Over-The-Counter Use (21 CFR 801 Subpart C)

PLEASE DO NOT WRITE BELOW THIS LINE -- CONTINUE ON A SEPARATE PAGE IF NEEDED.

年度的第一次 FOR FOR FDA USE ONLY . . . . : 标签:: :: Concurrence of Center for Devices and Radiological Health (CDRH) (Signature)

Herbert P. Lerner 2014.02.24 11:29:57 -05'00'

FORM FDA 3881 (1/14)

Regulation Number and Section

§ 870.3300 Vascular embolization device.

(a)
Identification. A vascular embolization device is an intravascular implant intended to control hemorrhaging due to aneurysms, certain types of tumors (e.g., nephroma, hepatoma, uterine fibroids), and arteriovenous malformations. This does not include cyanoacrylates and other embolic agents, which act by polymerization or precipitation. Embolization devices used in neurovascular applications are also not included in this classification, see § 882.5950 of this chapter.(b)
Classification. Class II (special controls.) The special control for this device is the FDA guidance document entitled “Class II Special Controls Guidance Document: Vascular and Neurovascular Embolization Devices.” For availability of this guidance document, see § 870.1(e).