For orthopedic applications as filler for gaps or voids that are not intrinsic to the stability of the bony structure. Connexus is indicated to be packed gently into bony gaps in the skeletal system as a bone graft extender and as a bone void filler of the extremities and pelvis. These defects may be surgically created or the result of traumatic injury to the bone.

Device Description

IsoTis OrthoBiologics is expanding the range of sizes previously cleared in 510(k) K050690 to include Connexus, 0.5cc. The intended use of this additional size does not change from that previously cleared.

Connexus is derived from selected donated human bone tissue that has been processed into particles. The bone particles are subsequently demineralized using a hydrochloric acid process. The demineralized bone matrix (DBM) is combined with an inert reverse phase carrier and formulated to a putty-like consistency.

The carrier is a solution of polyethylene oxide polypropylene oxide block copolymer dissolved in water exhibiting reverse phase characteristics (i.e., an increase in viscosity as temperature increases).

AI/ML Overview

Here's a breakdown of the acceptance criteria and the study information for the Connexus, 0.5cc device, based on the provided text:

Acceptance Criteria and Device Performance

The provided document, a 510(k) Summary for Connexus, 0.5cc, does not explicitly state quantitative acceptance criteria for its performance. Instead, it focuses on demonstrating substantial equivalence to a predicate device (Connexus, K050690) and adherence to various standards and validated processes.

The "reported device performance" is described in terms of the results of these tests and validations, rather than specific numerical targets met.

Table of Acceptance Criteria and Reported Device Performance

Category / "Acceptance Criteria" (Implicit)	Reported Device Performance / Study Results
Viral Inactivation	Suitable viral inactivation potential: A select panel of viruses representing various types, sizes, shapes, and genomes were evaluated. The testing demonstrated suitable viral inactivation potential of the processing methods for a wide range of potential human viruses.
Osteoinductivity (of DBM component)	Assurance of osteoinductive potential for DBM lots: An in vitro assay measuring alkaline phosphatase activity of myoblast cells is used. This assay has been validated against an in vivo athymic rat muscle pouch model, predicting in vivo osteoinductivity with at least 95% confidence. 67 out of 67 test lots that passed the in vitro assay also passed the in vivo athymic rat assay (confirmed intramuscular bone formation). Note: The specific formulation (DBM + inert carrier) has not been evaluated for osteoinductivity, and correlation of in vitro DBM osteoinductivity to human clinical performance is unknown.
Safety and Effectiveness for Intended Use (Overall Product)	Substantiated in animal models: Performance of Connexus has been evaluated in rabbit and sheep models by radiographic and histological methods for the specified indications. These data substantiate Connexus Putty safety and effectiveness for the indications presented in this Premarket Notification.
Biocompatibility (Implied by ISO 10993-1)	Compliance with ISO 10993-1: The device complies with "Biological Evaluation of Medical Devices Part-1: Evaluation and Testing." (Specific test results or a summary are not provided in this document but are implied by compliance.)
Sterilization (Implied by ISO 11137)	Compliance with ISO 11137: "Sterilization of Health Care Products – Requirements for Validation and Routine Control - Radiation Sterilization" is followed. (Specific validation results are not provided but are implied.)
Human Tissue Compatibility (Implied by 21 CFR 1270, AATB standards)	Meets regulatory and standard requirements: Donor bone in Connexus meets AATB requirements. Also complies with 21 CFR 1270, Human Tissue Intended for Transplantation, and American Association Standards for Tissue Banking (10th Edition).
Quality System Compliance (Implied by various standards)	Compliance with Quality System Standards: IsoTis OrthoBiologics' Quality System complies with FDA Quality System Requirements (21 CFR 820), ISO 13485, and its facility is American Association of Tissue Banks (AATB) accredited.
Package Integrity/Shelf Life (Implied by ASTM 1980 – 02:1999)	Compliance with ASTM 1980-02: "Standard Guide for Accelerated Aging of Sterile Medical Device Packages." (Specific results related to shelf life or packaging integrity are not provided but are implied by compliance with the standard.)
Chemical/Physical Specifications (Implied by USP XXVI/XXVII - NF XXI/XXII)	Meets Pharmacopeia Specifications: Complies with United States Pharmacopeia (USP) XXVI - The National Formulary (NF) Specifications XXI and USP XXVII - The National Formulary (NF) Specifications XXII. (Specific analytical results or specifications are not provided but are implied by compliance.)

Study Details

This document describes a pre-market notification (510(k)) for a medical device, which typically relies on demonstrating substantial equivalence to a legally marketed predicate device rather than conducting large-scale clinical trials. The "studies" mentioned are primarily pre-clinical or in-vitro validations.

Here's a breakdown of the specific points requested:

Sample size used for the test set and the data provenance:
- Viral Inactivation Validation: "A select panel of viruses representing various virus types, sizes, shapes, and genomes were evaluated." (Specific number not provided). Data provenance is from in vitro laboratory validation.
- Osteoinductivity Potential (DBM component):
  - In vitro assay: Not specified, but each lot of DBM is tested.
  - In vivo athymic rat model validation: "67 out of 67 test lots" that passed the in vitro assay were confirmed in the in vivo model. This indicates a sample size of 67 athymic rat tests. Data provenance is from in vivo animal testing.
- Overall Product Performance: Evaluated in "rabbit and sheep models." (Specific sample sizes not provided). Data provenance is from in vivo animal testing.
Number of experts used to establish the ground truth for the test set and the qualifications of those experts:
- The document does not mention human experts establishing ground truth for the presented studies.
- For the osteoinductivity study, the "ground truth" (or validation reference) for the in vitro assay was the in vivo athymic rat model (confirmation of intramuscular bone formation).
- For animal performance studies, ground truth was established by "radiographic and histological methods" which would typically involve qualified veterinary pathologists or radiologists, but no specific number or qualifications are mentioned.
Adjudication method (e.g. 2+1, 3+1, none) for the test set:
- Not applicable/Not mentioned. The studies described are lab validations and animal studies, not human reader assessments requiring adjudication.
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 MRMC or AI-assisted studies are mentioned. This device is a bone void filler, not an AI-powered diagnostic tool.
If a standalone (i.e. algorithm only without human-in-the-loop performance) was done:
- Not applicable. This device is a physical bone void filler, not an algorithm.
The type of ground truth used (expert consensus, pathology, outcomes data, etc):
- Viral Inactivation: Laboratory validation of viral reduction efficacy (presumably based on standard laboratory assays and controls).
- Osteoinductivity Potential:
  - In vitro: Alkaline phosphatase activity assay (biochemical marker).
  - In vivo (for validation of in vitro assay): Histological confirmation of intramuscular bone formation in athymic rats (pathology).
- Overall Product Performance (animal models): Radiographic and histological methods (imaging and pathology).
The sample size for the training set:
- Not applicable as this is not an AI/machine learning product requiring a training set in the conventional sense. The "training" for the DBM osteoinductivity assay involved validating it against 67 athymic rat cases.
How the ground truth for the training set was established:
- If we consider the validation of the in vitro osteoinductivity assay as a "training" of the assay to predict in vivo performance, then the ground truth for its validation was established by histological confirmation of intramuscular bone formation in athymic rats.

Summary

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K 052098

510(k) Summary of Safety and Effectiveness 1.4

1. Sponsor

IsoTis OrthoBiologics, Inc. 2 Goodyear, Suite B Irvine, CA 92618 U.S.A

Contact Person:	Paul Doner
Telephone:	949 855-7168
Facsimile:	949 595-8711

Date Prepared: August 2, 2005

2. Device Name

Proprietary Name:	Connexus, 0.5cc
Common/Usual Name:	Bone Void Filler
Classification Name:	Sec. 888.3045 Resorbable calcium salt bone void fillerdevice.

3. Predicate Devices

Connexus (K050690, July 7, 2005)

4. Device Description

5. Intended Use

Technological Characteristics and Substantial Equivalence 6.

Connexus and its predicate devices are similar in design, materials of construction and function. The proposed and predicate devices are osteoconductive and osteoinductive. The Connexus product and its predicate devices provide an interconnected, porous scaffold and an environment for new bone ingrowth and stimulate bone growth. The only differences between the proposed device and its predicates are the percentage of demineralized bone and the inert carriers used. Connexus is provided sterile and for single patient use. The donor bone in the Connexus product meets the requirements of the AATB. Product safety and effectiveness is adequately supported by the substantial

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equivalence information, materials data, and test results provided in this Premarket Notification.

Viral Inactivation Validation -
The methods for processing the DBM contained in Connexus were evaluated for their viral inactivation potential. A select panel of viruses representing various virus types, sizes, shapes, and genomes were evaluated. The viral inactivation testing demonstrated suitable viral inactivation potential of the processing methods for a wide range of potential human viruses.
Osteoinductivity Potential
The osteoinductive potential of the DBM used in Connexus is determined via an in vitro assay. The assay measures the alkaline phosphatase activity of myoblast cells. The level of alkaline phosphatese induction is compared to positive and negative DBM controls. Results from the assay were correlated with results from implantation of DBM into an athymic rat muscle pouch. Analysis of these results shows that the in vitro assay has been validated against the in vivo athymic rat model and predicts with at least 95% confidence the in vivo osteoinductivity of the test material. 67 out of 67 test lots that passed the in vitro assay passed the in vivo athymic rat assay via confirmation of intramuscular bone formation.

Each lot of DBM incorporated in the Connexus is evaluated for osteoinductive potential using an in vitro assay. Testing each lot of DBM assures that only DBM with ostoeinductive potential is used in Connexus. Although DBM used in the final product has been shown to be osteoinductive using an in vitro assay, the combination of DBM and inert carrier has not been evaluated for osteoinductivity: therefore, it is unknown to what extent the formulation components may alter the osteoinductivity character of the DBM. Additionally, it is unknown how osteoinductivity of the DBM component, measured via the in vitro assay, will correlate with human clinical performance of Connexus.

Product Performance Testing

Performance of Connexus has been evaluated in rabbit and sheep models by radiographic and histological methods for the indications specified in the Premarket Notification.

These data substantiate Connexus Putty safety and effectiveness for the indications presented in this Premarket Notification.

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1.5 Performance Standards

No performance standards applicable to Connexus bone void filler material have been adopted under Section 514 of the Act. Connexus complies where appropriate with the applicable requirement of the following voluntary/consensus standards:

ISO 10993-1: Biological Evaluation of Medical Devices Part-1: Evaluation and Testing .
. 21 CFR 1270, Human Tissue Intended for Transplantation
. United States Pharmacopeia (USP) XXVI - The National Formulary (NF) Specifications XXI
. United States Pharmacopeia (USP) XXVII - The National Formulary (NF) Specifications XXII
. ISO 11137:1997; Sterilization of Health Care Products – Requirements for Validation and Routine Control - Radiation Sterilization
. ASTM 1980 – 02:1999 (current edition approved Jan. 2002); Standard Guide for Accelerated Aging of Sterile Medical Device Packages
American Association Standards for Tissue Banking, (10" Edition printing date: April . 2002)

Additionally, IsoTis OrthoBiologics' Quality System complies with the FDA Quality System Requirements (21 CFR 820), ISO 13485 and its facility is American Association of Tissue Banks (AATB) accredited.

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SEP - 7 2005

Food and Drug Administration 9200 Corporate Boulevard Rockville MD 20850

Mr. Paul Doner Director of Regulatory Affairs and Quality Assurance IsoTis OthoBiologics Inc. 2 Goodyear, Suite B Irvine, California 92618

Re: K052098 Trade Name: Connexus™, 0.5cc Regulation Number: 21 CFR 888.3045 Regulation Name: Resorbable calcium salt bone void filler device Regulatory Class: II Product Code: MQV Dated: August 2, 2005 Received: August 11, 2005

Dear Mr. Doner:

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 either class II (Special Controls) or class III (PMA), it may be subject to such 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); 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.

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Page 2- Mr. Paul Doner

This letter 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 Part 801), please contact the Office of Compliance at (240) 276-0120. Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21CFR Part 807.97). 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) 443-6597 or at its Internet address http://www.fda.gov/cdrh/industry/support/index.html.

Sincerely yours,

Mali A-McMillan

Mark Melkerson Acting Director Division of General, Restorative and Neurological Devices Office of Device Evaluation Center for Devices and Radiological Health

Enclosure

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Statement of Indications for Use 1.3

510(k) Number (if known):

Device Name:

Connexus ™, 0.5cc

Indications for Use:

Connexus is an osteoinductive and osteoconductive bone filiing material indicated:

For orthopedic applications as filler for gaps or voids that are not intrinsic to the stability of the bony structure. Connexus is indicated to be packed gently into bony gaps in the skeletal system as a bone graft extender and as bony void filler of the extremities and pelvis. These defects may be surgically created or from the result of traumatic injury to the bone.

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

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

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

Concurrence of CDRH, Office of Device Evaluation (ODE)

Mark A. Mckinnon

(Division Sign-( Division of General. Sestorative, and Neurologica

510(k) Number

Regulation Number and Section

§ 888.3045 Resorbable calcium salt bone void filler device.

(a)
Identification. A resorbable calcium salt bone void filler device is a resorbable implant intended to fill bony voids or gaps of the extremities, spine, and pelvis that are caused by trauma or surgery and are not intrinsic to the stability of the bony structure.(b)
Classification. Class II (special controls). The special control for this device is the FDA guidance document entitled “Class II Special Controls Guidance: Resorbable Calcium Salt Bone Void Filler Device; Guidance for Industry and FDA.” See § 888.1(e) of this chapter for the availability of this guidance.