FreezeKit™ Cleave and ThawKit™ Cleave are devices used for freezing of pronuclear (2PN) and cleavage-stage embryos, and thawing of frozen pronuclear (2PN) and cleavage-stage embryos during in vitro fertilization (IVF) procedures.

The proposed devices are two separate kits, containing two and three solutions respectively. The two kits are marketed separately, yet are recommended to be used together to perform freezing and thawing. All solutions in both kits contain MOPS buffered solution, gentamicin as an antibacterial agent, human serum albumin and hyaluronan. The cryoprotectants 1,2 - propanediol and sucrose are included in the freezing solution, and only sucrose is included as a cryoprotectant in the thawing solutions.

AI/ML Overview

The provided document is a 510(k) Premarket Notification for medical devices, specifically for "FreezeKit™ Cleave" and "ThawKit™ Cleave," which are reproductive media used for cryopreservation and thawing of embryos. This type of document focuses on demonstrating substantial equivalence to a legally marketed predicate device rather than undergoing a full clinical efficacy study with robust statistical analysis typically seen in PMAs or studies for AI/software as a medical device.

Therefore, the information required to fully answer the request (especially regarding AI/ML, human expert involvement, ground truth establishment, sample sizes for training/test sets, MRMC studies, and effect sizes) is not present in this document. The "clinical testing" described here is more akin to a performance evaluation rather than a comparative effectiveness study in the context of AI.

I will populate the table and answer the questions based only on the information available in the provided text. Where information is not available or not applicable, I will state "Not available in the provided text" or "Not applicable to this device/study type."

Acceptance Criteria and Device Performance Study

The study performed was a non-inferiority performance evaluation demonstrating that the subject devices (FreezeKit™ Cleave and ThawKit™ Cleave) perform comparably to predicate devices (Cook IVF Cryopreservation Kit and Cook IVF Thawing Kit) for their intended use. The core of this submission is to show substantial equivalence, not necessarily superior performance or to evaluate an AI algorithm.

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

Parameter Measured / Evaluated	Acceptance Criteria (Predefined)	Reported Device Performance (Summary)
Non-Clinical Bench Testing
pH at +20°C and ambient atmosphere	Met predefined acceptance criteria	All bench tests performed met the predefined acceptance criteria. (Specific values not reported)
Osmolality in mOsm/kg	Met predefined acceptance criteria	All bench tests performed met the predefined acceptance criteria. (Specific values not reported)
Sterility	Met predefined acceptance criteria	All bench tests performed met the predefined acceptance criteria. (Specific values not reported)
Bacterial Endotoxins (LAL assay)	Met predefined acceptance criteria	All bench tests performed met the predefined acceptance criteria. (Specific values not reported)
Mouse Embryo Assay (1-cell MEA) [% expanded blastocyst within 96h]	Met predefined acceptance criteria	All bench tests performed met the predefined acceptance criteria. (Specific values not reported)
Mouse Embryo Assay (1-cell MEA) [blastocyst cell number within 96h]	Met predefined acceptance criteria	All bench tests performed met the predefined acceptance criteria. (Specific values not reported)
Clinical Testing
Survival of frozen and thawed human 2PN and cleavage-stage embryos	Demonstrate satisfactory survival and development compared to predicates	Subject device demonstrated satisfactory survival and development of treated 2PN embryos (and implicitly cleavage-stage embryos based on indications).
Development of frozen and thawed human 2PN and cleavage-stage embryos	Demonstrate satisfactory survival and development compared to predicates	Subject device demonstrated satisfactory survival and development of treated 2PN embryos (and implicitly cleavage-stage embryos based on indications).

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

Sample Size for Test Set: Not explicitly stated in the provided text for either non-clinical or clinical testing. For the clinical evaluation, it mentions "human 2PN embryos and cleavage-stage embryos," but no number.
Data Provenance: Not explicitly stated (e.g., country of origin, specific clinics).
Retrospective or Prospective: Not explicitly stated for the clinical evaluation. Given the context of a 510(k) premarket notification for a new version of existing media, it's likely a controlled prospective performance study, but this is an inference.

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

Number of Experts: Not applicable, as this is a device for media used in IVF, not an AI or diagnostic imaging device requiring expert interpretation. The "ground truth" would be the biological outcome (survival, development) measured directly or observed by trained embryologists/laboratory personnel.
Qualifications of Experts: Not explicitly stated, though it would be assumed that the studies were conducted by qualified laboratory personnel and embryologists.

4. Adjudication method (e.g. 2+1, 3+1, none) for the test set

Adjudication Method: Not applicable. The "results" are biological outcomes measured/observed, not subjective interpretations requiring adjudication among multiple readers.

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

MRMC Study: No, an MRMC comparative effectiveness study was not done. This device is not an AI or imaging device that would involve human readers or AI assistance in interpretation.
Effect Size: Not applicable.

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

Standalone Performance: Not applicable. The device is a liquid medium, not an algorithm.

7. The type of ground truth used (expert consensus, pathology, outcomes data, etc.)

Type of Ground Truth: For the non-clinical bench testing, the ground truth was derived from direct measurements (pH, osmolality, sterility, endotoxin levels) and established biological assays (Mouse Embryo Assay results: % expanded blastocyst, blastocyst cell number). For the clinical evaluation, the ground truth was "survival and development of frozen and thawed human 2PN embryos and cleavage-stage embryos." This would be best characterized as outcomes data and direct biological observations/measurements.

8. The sample size for the training set

Sample Size for Training Set: Not applicable. This is a formulation of media, not an AI/ML device that requires a training set. The "training" for such a device would be the product development and optimization process, not data-driven machine learning.

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

Ground Truth for Training Set Establishment: Not applicable, as there is no "training set" in the context of an AI/ML model for this device. The development of the media likely involved iterative testing to achieve optimal performance, and the "ground truth" at that stage would be the desired physical/chemical properties and embryo viability outcomes.

Summary

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

December 21, 2015

Vitrolife Sweden AB % Brett Sonet Glazar Vitrolife, Inc. Embryologist & MEA Laboratory Manager 3601 South Inca Street Englewood, CO 80110

Re: K150950

Trade/Device Name: Freezekit™ Cleave, Thawkit™ Cleave Regulation Number: 21 CFR 884.6180 Regulation Name: Reproductive media and supplements Regulatory Class: Class II Product Code: MOL Dated: November 9, 2015 Received: November 10, 2015

Dear Brett Sonet Glazar,

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 medical device

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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 contact the Division of Industry and Consumer Education 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. 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 Industry and Consumer Education 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,

Image /page/1/Picture/8 description: The image shows the text "Herbert P. Lerner -S" in a large, bold font. The text is arranged horizontally, with the name "Herbert P. Lerner" appearing prominently. The "-S" is slightly smaller and set off to the right. The background is plain and does not distract from the text.

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

Enclosure

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Indications for Use

510(k) Number (if known) K150950

Device Name FreezeKit™ Cleave and ThawKit™ Cleave

Indications for Use (Describe)

FreezeKit™ Cleave is intended for freezing of pronuclear (2PN) and cleavage-stage embryos.

ThawKit™ Cleave is intended for thawing of frozen pronuclear (2PN) and cleavage-stage embryos.

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)

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510(k) Summary

Submitted by:	Vitrolife Sweden ABBox 9080SE-40092 GöteborgSWEDEN
Contact Person:	Brett Sonet Glazar, M.S.Embryologist & MEA Laboratory ManagerVitrolife Inc.3601 South Inca StreetEnglewood, Co. 80110USATel: +1 720 473 5577Fax: +1 303 781 5615E-mail: bglazar@vitrolife.com
Date Prepared:	November 21, 2014
Trade Name:	FreezeKit™ Cleave and ThawKit™ Cleave
Common Name:	Assisted Reproduction Media forcryopreservation
Classification Name:	Reproductive Media and Supplements(21 C.F.R. § 884.6180)
Predicate Devices:	Cook IVF Cryopreservation Kit and Cook IVThawing Kit (K011157)

Devices Description:

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cryoprotectants 1,2 - propanediol and sucrose are included in the freezing solution, and only sucrose is included as a cryoprotectant in the thawing solutions.

Indications for Use:

FreezeKit™ Cleave is intended for freezing of pronuclear (2PN) and cleavage stage embryos.

ThawKit™ Cleave is intended for thawing of frozen pronuclear (2PN) and cleavage-stage embryos.

The subject device indications for use are slightly different from the predicate device, which is indicated more generally for cryopreservation and thawing of zygotes and embryos. However, this difference does not alter the intended use of the subject device from that of the predicate. The intended use of the subject and predicate devices are comparable.

Technological Characteristics Comparison

The formulation of the subject devices are similar to that of the predicates. The compositions of the proposed devices and predicate devices contain antibiotics (gentamicin) and human serum albumin (HSA), as well as the same cryoprotectants (sucrose and 1,2 -propanediol). However, hyaluronan is included only in the proposed devices. In addition, the subject devices have a different buffer base compared to the predicate devices. The addition of hyaluronan in the subject device and the different buffer base do not raise any different types of safety and effectiveness questions.

The subject and predicate devices have similar specifications, including pH, osmolality, endotoxin levels and MEA performance. In addition, both the subject and predicate devices are sterilized by aseptic filtration. The subject device includes one additional specification for the MEA analysis is evaluated for the proposed devices. However, this does not represent a difference in technological characterisicts and does not raise any different types of safety and effectiveness questions.

Non-Clinical Bench Testing

The following parameters were measured and evaluated to assure satisfactory operating performance of FreezeKit™ Cleave and ThawKit™ Cleave:

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pH at +20°C and ambient atmosphere
Osmolality in mOsm/kg ●
. Sterility
Bacterial Endotoxins (LAL assay) in EU/mL
Mouse embryo assay (1-cell MEA) [% expanded blastocyst within 96h|
Mouse embryo assay (1-cell MEA) [blastocyst cell number within 96h]

All bench tests performed met the predefined acceptance criteria.

Clinical Testing

A clinical evaluation was performed to assure satisfactory performance of FreezeKit™ Cleave and ThawKit™ Cleave. The testing assessed survival and development of frozen and thawed human 2PN embryos and cleavage-stage embryos after being cryopreserved with the subject devices as compared to the predicates. Results for the subject device demonstrated satisfactory survival and development of treated 2PN embryos.

Conclusions

The comparison of indications for use / intended purposes, product characteristics, specifications, composition and performance between the predicate devices (Cook IVF Cryopreservation Kit and Cook IVF Thawing Kit) and the proposed devices (FreezeKit™ Cleave and ThawKit™ Cleave) demonstrates that they are substantially equivalent. Although there are differences in the terminology of the indications for use, as well as minor differences in the composition, none of these differences render the subject device not substantially equivalent.

Pre-clinical and clinical evaluation studies demonstrate that the subject device performs comparably to the predicate device and support a determination of substantial equivalence.

Therefore, FreezeKit™ Cleave and ThawKit™ Cleave are as safe and effective as Cook IVF Cryopreservation Kit and Cook IVF Thawing Kit. FreezeKit™ Cleave and ThawKit™ Cleave are substantially equivalent to Cook IVF Cryopreservation Kit and Cook IVF Thawing Kit.

Regulation Number and Section

§ 884.6180 Reproductive media and supplements.

(a)
Identification. Reproductive media and supplement are products that are used for assisted reproduction procedures. Media include liquid and powder versions of various substances that come in direct physical contact with human gametes or embryos (including water, acid solutions used to treat gametes or embryos, rinsing solutions, sperm separation media, supplements, or oil used to cover the media) for the purposes of preparation, maintenance, transfer or storage. Supplements are specific reagents added to media to enhance specific properties of the media (e.g., proteins, sera, antibiotics, etc.).(b)
Classification. Class II (special controls) (mouse embryo assay information, endotoxin testing, sterilization validation, design specifications, labeling requirements, biocompatibility testing, and clinical testing). The device, when it is phosphate-buffered saline used for washing, and short-term handling and manipulation of gametes and embryos; culture oil used as an overlay for culture media containing gametes and embryos; and water for assisted reproduction applications, is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 884.9.