Medi-Cult Hyaluronidase is for the removal of cumulus and corona radiatacells which must be removed in order to facilitate access to the oocyte and minimize contamination of the injected needle before ICSI.

Device Description

Sperm Preparation Medium supplemented with Hyaluronidase. It is a HEPES buffered salt solution supplemented with Hyaluronidase. It is ready-to-use and contains Synthetic Serum Replacement (SSR) and Human Serum Albumin (HSA). The Hyaluronidase raw material is derived from Bovine testes in the USA. It contains antibiotics - Penicillin and Streptomycin.

AI/ML Overview

The provided text describes the "Medi-Cult Hyaluronidase" device and its intended use, along with some clinical data. However, it does not explicitly define acceptance criteria in a quantitative manner or outline a formal study designed to "prove the device meets acceptance criteria" with specific statistical endpoints and detailed methodologies typically found in studies for diagnostic or AI-driven devices.

The document focuses more on demonstrating substantial equivalence to predicate devices and showing good clinical performance in real-world settings rather than a controlled study against pre-defined acceptance metrics for a novel technology.

Here's an analysis based on the provided text, addressing your points where possible, and noting where information is missing:

1. Table of Acceptance Criteria and Reported Device Performance

The document does not explicitly state quantitative "acceptance criteria" for the device's performance in a formal study. Instead, it relies on historical clinical use and comparisons to national averages. The "performance" is implicitly defined by live birth rates achieved by clinics using the product, which are presented as being "well" or "best" in comparison.

Acceptance Criteria (Implicit/Inferred)	Reported Device Performance (Live birth rates per embryo replacement with ICSI)
Norway: Achieve live birth rates comparable to or better than other established IVF units using similar protocols. (No specific threshold given)	Dept of Ob & Gyn, Univ. of Trondheim: 18.4% (1996), 22.4% (1997)
	The National Hospital, Oslo: 15.9% (1996), 18.4% (1997)
	Haugesund Hospital: 28.6% (1996), 27.1% (1997)
Sweden: Perform comparably to or better than the national average for live birth rates. (No specific threshold given)	Carl von Linne Clinic (using Medi-Cult): 32% (1997)
	Swedish National Average: 25% (1997)
Safety: No registered complaints or serious adverse events in connection with intended use.	No registered complaints or serious adverse events in the last 1.5 years.

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

Test Set (Clinical Data): The "test set" here refers to the clinical usage data presented.
- Norway: Data from "the largest IVF clinics in Norway" that only used Medi-Cult media since the late 1980s for IVF and since 1996 for ICSI. The exact number of cycles or patients is not provided for each clinic, just the aggregated live birth rates for 1996 and 1997.
- Sweden: Data from a single clinic, the Carl von Linne Clinic, for the year 1997. Again, the exact number of cycles or patients is not provided.
Data Provenance:
- Country of Origin: Nordic countries (Norway, Sweden).
- Retrospective or Prospective: The data appears to be retrospective, as it refers to collected live birth rates from past clinical practice (e.g., "The data collected since the introduction of ICSI in Norway in 1996").

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

This information is not applicable as the document describes a medical device (culture medium) used in clinical procedures, not a diagnostic or AI device requiring expert ground truth for image interpretation or similar tasks. The "ground truth" here is the clinical outcome of live birth, directly measurable from patient records.

4. Adjudication Method for the Test Set

This is not applicable for the reasons stated in point 3. The clinical outcomes (live birth rates) are direct observations, not interpretations requiring adjudication.

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 is not applicable. The device is a culture medium used in assisted reproduction, not an AI-assisted diagnostic tool. Therefore, an MRMC study or evaluation of human reader improvement with AI assistance is irrelevant to this submission.

6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) Was Done

This is not applicable. The device is a biological culture medium, not an algorithm.

7. The Type of Ground Truth Used

The ground truth used is outcomes data, specifically "live birth rates per started cycle" or "live birth rates per embryo replacement." This is a direct clinical outcome measure.

8. The Sample Size for the Training Set

The concept of a "training set" in the context of machine learning or AI is not applicable to this device. The product development and validation were based on established biological and chemical principles, prior clinical use (since the late 1980s), and a "number of trials" (not detailed in this summary, but mentioned in the "Clinical Testing section" which is not provided but alluded to).

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

This is not applicable as there is no "training set" in the AI/ML sense. The "ground truth" for the development of the medium would have been established through a combination of scientific research, in vitro studies demonstrating efficacy in supporting gamete and embryo development, and early clinical observations by pioneering IVF clinics (e.g., "designed in accordance with the specification of the clinic that developed ICSI (Palermo et al. Lancet 1992 340 8810 17-18)"). The overall clinical performance data (like the Nordic data) serves as post-market surveillance evidence rather than a "training set" for an algorithm.

Summary

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JUN 2 0 2000

Page 1 of 2

510(k) Summary Summary of Safety and Effectiveness Information Supporting a Substantially Equivalent Determination

(K991334)

The product:

-"Medi-Cult Hyaluronidase" Cat.No. 1011

Indications for use:

"Medi-Cult Hyaluronidase" is used in assisted reproduction techniques, (ART), such as IVF, GIFT or similar In Vitro procedure to aid in facilitating pregnancy.

"Medi-Cult Hyaluronidase" is for the removal of cumulus and corona radiatacells which must be removed in order to facilitate access to the oocytes and minimize contamination of the injected needle before ICSL

Product formulation:

A number of trials have shown that the products performs well, (see Clinical Testing section). A number of publications in peer-reviewed books or journals have presented data using Medi-Cult media. Often more than one procent from Medi-Cult has been used in the studies listed.

Product testing control contents:

Bioburden, production-test ・
-Integrity filter testing, production-test
-Sterility, QC-test
pH, QC-test
-Osmolarity, QC-test
-Endotoxin, QC-test

The culture media from Medi-Cult have been used by many European IVF-units since the end of the 1980's. (Produced and distributed by GEA-Biotech 1987 to 1989 and by Medi-Cult als from 1989). The first Medi-Cult products for use in conjunction with Intra Cytoplasmic Sperm Injection (ICSI) were introduced in 1993. These products were designed in accordance with the specification of the clinic that developed ICSI (Palermo et al. Lancet 1992 340 8810 17-18).

A number of publications in peer- reviewed books or journals have presented data using Medi-Cult products for ICSI. Often more than one product from Medi-Cult has been used in the studies.

The clinical result of a given IVF-clinic will depend on the patient population treated, the clinical procedures, the laboratory routines and on the various culture media used. A comparison of the clinical performance of clinics using only Medi-Cult products for ICSI with other IVP client using similar clinical and laboratory routines will give an indicate on the performance of the Medi-Cult culture media. In countries were we have access to both national data and data from in incul collected clinics, clinics using Medi-Cult products generally performs well.

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K991334
Page 2 of 2

The IVF-units in the Nordic countries use similar clinical and laboratory protocols and their patient populations are comparable. The clinical data from most Nordic countries are available. In some countries the performance of individual IVF-clinics are available.

The largest IVF clinics in Norway have been using only Medi-Cult media since the end of the 1980'ties and products from Medi-Cult for ICSL The data collected since the introduction of ICSI in Norway in 1996 are shown below as live birth rates per started cycle. Since all clinics (except one) are using products from Medi-Cult, a meaningful comparison to the national average success rate is not meaningful.

Table. Live birth rates per embryo replacement obtained with ICSI in Norway

Clinic	1996	1997
Dept of Ob & Gyn, Univ. of Trondheim	18,4	22,4
The National Hospital, Oslo	15,9	18,4
Haugesund Hospital	28,6	27,1

In Sweden, the Carl von Linne Clinic uses only products from Medi-Cult for ICSI and for culture of gametes and embryos. It is the only Swedish clinic using Medi-Cult products. For the year 1997 their birth rate per embryo replacement was 32% their clinical results were the best in Sweden and well above the national average of 25%.

There have been no registered complaints for the product and no evidence in the last 1.5 year that the product has been the cause of any serious adverse events in connection with its intended use.

Thus based on the Federal Register Notice (Final Rule, Vol. 63, No. 175, page 48429, September 10, 1998), "Obstetric and Gynecologic Devices; Reclassification and Classification of Medical Devices Used for In-Vitro Fertilization and Related Assisted Reproduction Procedures" effective on October 13, 1998 and the supportive clinical data we feel that the safety and effectiveness of the product for its intended use is shown in the present submission.

Prepared and Submitted by:

Ronald G. Leonardi, Ph. D. 12/14/99
Date

Ronald &. Leonardi, Ph. D. President R & R Registrations P.O. Box 262069 San Diego CA 92196 1-619-586-0751

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Image /page/2/Picture/15 description: The image shows the logo for the Department of Health & Human Services - USA. The logo features a stylized eagle with three lines representing its body and wings. The text "DEPARTMENT OF HEALTH & HUMAN SERVICES - USA" is arranged in a circular pattern around the eagle.

JUN 2 0 2000

Food and Drug Administration 9200 Corporate Boulevard Rockville MD 20850

Medi-Cult A/S c/o Ronald G. Leonardi, Ph.D. President R & R Registrations P.O. Box 262069 San Diego, CA 92196-2069

Re: K991334 Medi-Cult Hyaluronidase Dated: May 22, 2000 Received: May 23, 2000 Requiatory Class: II 21 CFR §884.6180/Procode: 85 MQL

Dear Dr. Leonardi:

We have reviewed your Section 510(k) notification of intent to market the device referenced above and we 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 Federal Food, Grug, and Cosmelic Act (Act). 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 recistration, listing of devices, good manufacturing and prohibitions against misbranding and adulteration.

If your device is classified (see above) into either class II (Premarket Approval), 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 895. A substantially equivalion assumes compliance with the Current Good Manufacturing Practice requirements, as set forth in the Quality System Regulation (QS) for Medical Devices: General regulation (21 CFR Part 820) and that, through periodic QS inspections, the Food and Drug Administration (FDA) will verify such assumptions. Failure to comply with the GMP regulation may result in regulatory action, FDA may publish further announcements concerning your device in the Federal Register. Please note: this response to your premarket notfication submission does not affect any obligation you might have under sections 531 through 542 of the Act for devices under Radiation Control provisions, or other Federal laws or regulations.

This letter will allow you to begin marketing your device as described in your 510(k) premarket notification. The FDA finding of substantial equivalence of your device to a legally marketed predication 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 and additionally 809.10 for in vitro diagnostic devices), please contact the Office of Compliance at (301) 594-4591. Additionally, for question and advertising of your device, please contact the Office of Compliance at (301) 594-4639. Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21CFR 807.97). Other general information on your responsibilities under the Act may be obtained from the Division of Small Manufacturers Assistance at its toll-free number (800) 638-2041 or (301) 443-6597 or at its internet address "http://www.fda.gov/cdrh/dsmaldsmamain.html".

Sincerely yours,

Daniel G. Schultz, M.D.

Captain, USPHS Director, Division of Reproductive, Abdominal, and Radiological Devices Office of Device Evaluation Center for Devices and Radiological Health

Enclosure(s)

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B4. Indication for Use Statement

510(k) Number (if know) K991334

Device Name: Medi-Cult Hyaluronidase

Indications for use:

For use in assisted reproduction techniques, (ART), such as IVF, GIFT or similar in vitro procedure to aid in facilitating pregnancy.

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

Concurrence of CDRH, Office of Device Evaluation (ODE)
Prescription Use	✓
(Per 21 CFR 801.109)	OR
	Over-The-Counter Use
	(Optional Format 1-2-96)
	(Division Sign-Off)
	Division of Reproductive, Abdominal, ENT,and Radiological Devices

510(k) Number K991334

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.