MEDI-CULT FLUSHING MEDIUM by MEDICULT A/S

The product formulation is: Earl's Balanced Salt Solution (EBSS), Sodium Pyruvate, Assisted Reproduction Technology Supplement (ARTS), HEPES, Sodium Bicarbonate, Human Serum Albumin (HSA), Penicillin, Streptomycin, Phenol Red.

AI/ML Overview

The provided text describes specific acceptance criteria for the "Medi-Cult Flushing Medium" products, which are used in In-Vitro Fertilization (IVF) procedures. The study presented aims to demonstrate the safety and effectiveness of these products by comparing their performance to national averages and other clinics.

Here's a breakdown of the requested information:

Acceptance Criteria and Reported Device Performance

The acceptance criteria are implicitly defined by the reported performance metrics of IVF clinics using Medi-Cult media compared to national averages or other clinics. The primary performance metric is the live birth rate.

Acceptance Criteria	Reported Device Performance
Product Testing Controls (QC-test thresholds)
Bioburden	Production-test
Integrity filter testing	Production-test
Sterility	QC-test
pH	QC-test
Osmolarity	QC-test
Endotoxin	QC-test
Mouse Embryo Assay	>80% hatching
Clinical Performance (Implicit)
Live birth rate per started cycle (Norway)	Clinics using Medi-Cult media generally show live birth rates comparable to or exceeding the national average (e.g., Trondheim: 22.2-25.35% vs. National average: 14.6-17.9%).
Live birth rate per embryo replacement (Sweden)	Carl von Linne Clinic (using Medi-Cult) reported 34%, "best in Sweden" and "well above national average of 25.8%".
Live birth rate per embryo replacement (UK)	Clinics using only Medi-Cult products showed live birth rates ranging from 22.3% to 34.5%, with most exceeding the UK national average of 21.8%.
No registered complaints and no serious adverse events	Confirmed as "no registered complaints" and "no evidence...that the product has been the cause of any serious adverse events."

Study Information

Sample size used for the test set and the data provenance:
- Norway (Live birth rates per started cycle):
  - Dept of Ob & Gyn. Univ of Trondheim: Data from 1992-1996. Number of cycles not specified.
  - The National Hospital, Oslo: Data from 1992-1996. Number of cycles not specified.
  - Provenance: Retrospective clinical data from IVF units in Norway.
- Sweden (Birth rate per embryo replacement):
  - Carl von Linne Clinic: Data for 1997. Number of embryo replacements not specified.
  - Provenance: Retrospective clinical data from a specific IVF clinic in Sweden.
- UK (Live birth rates per embryo replacement):
  - A total of 10 clinics using Medi-Cult products were analyzed. The number of IVF cycles for these clinics ranged from 68 to 1434. The total number of IVF cycles represented by these clinics is 5907.
  - UK national average data covered 33520 IVF cycles.
  - Provenance: Retrospective clinical data from IVF units in the UK for the period April 1, 1996 to March 31, 1997, collected by the Human Fertilization and Embryology Authority (HFEA).
Number of experts used to establish the ground truth for the test set and the qualifications of those experts:
- Not applicable in this context. The "ground truth" for clinical performance is real-world live birth rates and national averages, not expert consensus on individual cases. The data collected by national authorities (like HFEA) represent outcomes, not interpretations.
Adjudication method for the test set:
- Not applicable. The data consists of aggregated clinical performance statistics (live birth rates), not individual case 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. This is not an MRMC study. The product is a culture medium, not an AI-assisted diagnostic device, and therefore does not involve human "readers" or AI assistance in that sense.
If a standalone (i.e., algorithm only without human-in-the-loop performance) was done:
- Yes, in a way. The product itself, the culture medium, performs its function (supporting oocytes) without direct human intervention once applied. The clinical data reflects the outcomes achieved when using the product as part of standard IVF protocols. This can be considered a "standalone" performance in the context of the product's function, as it's the medium's intrinsic quality that is being evaluated, albeit within a clinical system.
The type of ground truth used (expert consensus, pathology, outcomes data, etc.):
- Outcomes data: Specifically, live birth rates per started cycle or per embryo replacement, as reported by clinical centers and national registries. For product testing controls, the ground truth is established by specific QC-test results (e.g., Sterility, pH, Osmolarity, Endotoxin, Mouse Embryo Assay >80% hatching).
The sample size for the training set:
- Not applicable. This is not a machine learning model, so there is no concept of a "training set" for the device itself. The historical extensive use of the culture media since the end of the 1980s by many European IVF units can be seen as long-term observational data that informed the current product and its efficacy, but it's not a formal "training set" for an algorithm.
How the ground truth for the training set was established:
- Not applicable, as there is no training set in the context of this device.

Summary

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MAY - 4 2000

510(k) Summary Summary of Safety and Effectiveness Information Supporting a Substantially Equivalent Determination (K991327)

The products:

"Medi-Cult Flushing Medium" Cat.No. 1084, .
"Medi-Cult Flushing Medium w/o Pen/Strep." Cat.No. 1087 -
"Medi-Cult Flushing Medium w/o Phenol Red" Cat.No. 1082 -
-"Medi-Cult Flushing Medium w/o Phenol Red & Pen/Strep." Cat.No. 1080

The indication for use:

"Medi-Cult Flushing Medium" is used for retrieval and washing of human oocytes and holding throughout oocytes recovery.

A specially designed culture medium is necessary to ensure that the oocytes are contained in a solution with stable pH and temperature during oocytes retrieval and transport of oocytes from the operating theatre to the embryology laboratory. Thus enabling successful future fertilisation of human oocytes.

The product formulation: Earl's Balanced Salt Solution (EBSS) Sodium Pyruvate Assisted Reproduction Technology Supplement (ARTS) HEPES Sodium Bicarbonate Human Serum Albumin (HSA) Penicillin Streptomycin Phenol Red

Product testing control contents:

-Bioburden, production-test
-Integrity filter testing, production-test
-Sterility, QC-test
pH, QC-test
-Osmolarity, QC-test
-Endotoxin, OC-test
Mouse Embryo, QC-test (Two cell assay >80 % hatching) -

The culture media from Medi-Cult have been used by many European IVF-units since the end of 1980. (Produced and distributed by GEA-Biotech 1987 to 1989 and by Medi-Cult a/s from 1989). The Medi-Cult media were at that time introduced as a replacement for in-house prepared culture media.

A number of prospective randomized trials have shown that The Medi-Cult-IVF-medium performs equally well or better than alternative culture media. A number of publications in peer- reviewed books or journals have presented data using Medi-Cult media.

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 media with other IVF-clinics using similar clinical and laboratory routines will give an indication on the performance of the Medi-Cult culture media. In countries were we have access to both national data and data from individual clinics, clinics using Medi-Cult media generally perform well.

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 Media since the end of the 1980's. The data collected in the years from 1992 to 1996 are shown below as live birth rates per started cycle.

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Table 1. Live birth rates per started cycle obtained in IVF units in Norway.	Comments of the program and the commend of the comments of the large of the later of the comments of the comments of the comments of the comments of the comments of the contr

Clinic	1992	1993	1994	1995	1996
Dept of Ob & Gyn. Univ of Trondheim	22.2	22.2	19.8	25.35	18.4
The National Hospital, Oslo	13.3	19.0	15.8	11.42	17.4
National average	14.6	17.5	17.9	16.84	16.3

In Sweden, the Carl von Linne Clinic uses only products from Medi-Cult for culture of gametes and embryos, For the year 1997 their birth rate per embryo replacement was 34% their clinical results were the best in Sweden and well above the national average of 25.8%.

The Human Fertilization and Embryology Authority (HFEA) in the UK collects clinical data from all centres licensed to offer treatment for infertility by assisted reproduction. HFEA publishes these data in a booklet and on the web. The clinical data are presented both unadjusted for the demographics of the clinics patient population.

In the Table below the clinical data from some UK-clinics that use only Medi-Cult products is shown. These clinics have all given their consent to be presented as clinics using only Medi-Cult products.

Table 2. Live birth rates per embryo replacement obtained in TVF units in the UK in the period April 1* 1996 to March 31, 1997.

Name of clinic	Number ofIVF- cycles	Live birth rate per embryoreplacement %
Northamptonshire Fertility service	503	26.0
The Bridge Centre	852	27.2
Chelsea and Westminster Hospital	388	22.3
CARE at Park Hospital	650	34.5
BMI Ross Hall Hospital	68	27.5
The Woking Nuffield Hospital	163	32.6
Leeds General Infirmary	1434	24.0
Nurture	1245	28.8
Holly House Fertility and IVF	333	30.5
Guy's and St Thomas Assisted Conception Unit	651	27.1
UK national average	33520	21.8

There have been no registered complaints on the product and no evidence in the last 1.5 years 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 Gynaecologic Devices; Reclassification and Classification of Medical Devices Used for In-Vitro Fertilization and Related 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:

Rute Nunes-Lemadeira 4/20/

Ronald G. Leonardi, Ph. D President R & R REGISTRATIONS P.O. Box 262069 San Diego, CA 92131 619-586-0751

Date

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Public Health Service

Food and Drug Administration 9200 Corporate Boulevard Rockville MD 20850

MAY = 4 2000

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

Re: K991327 Medi-Cult Flushing Medium Dated: April 20, 2000 Received: April 24, 2000

21 CFR §884.6180/Procode: 85 MQL

Requiatory Class: Il

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 provisions of the Federal Food, Drug, and Cosmetic 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 registration, 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 equivalent determination 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 requlation may result in requlation. In addition. FDA may publish further announcements concerning your device in the Federal Register. Please note: this response to your premarket notification submission you might have under sections 531 through 542 of the Act for devices under the Electronic Product Radiation Control provisions, or other Federal laws or requlations.

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 Compiance 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) 443-5597 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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510(k) Number (if known) K991327

Medi-Cult Flushing Medium Device Name:

Indications for Use:

Flushing Medium is used for oocyte retrieval and oocyte washing and for holding throughout oocyte recovery.

(PLEASE DO NO WRITE BELOW THIS LINE - CONTINUE ON ANOTHER PAGE IF NEEDED)

Concurrence of CDRH, Office of Device Evaluation (ODE)

Prescription Use OR Over-The-Counter Use _________________________________________________________________________________________________________________________________________________________ (Per 21 CFR 801.109) ਾ (Optional Format 1-2-96) (Division Sign-Off) Division of Reproductive, Abdominal, ENT, and Radiological Dev 510(k) Number _

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.