ISM1+: For culture of embryos. To be used in culture after fertilization in Universal IVF Medium (K 991279) up to Day3 to 6- to8-cell stage, followed by extended culture in ISM2+ or by transfer in UTM+.
ISM2+: For culture of embryos. To be used in culture from 6- to 8-cell stage on Day3 to blastocyst stage on day 5, followed by transfer in UTM+. ISM2+ shall be used after ISM1+.
UTM+: For transfer of embryos cultured in ISM1+ or ISM2+.

Device Description

ISM1+, ISM2+, and UTM+ are sequential media for the culture and transfer of embryos. Their composition includes physiological salts, sodium bicarbonate, Penicillin/Streptomycin, HSA, Glucose and derived metabolites, Nucleosides, Non-essential amino acids, Essential amino acids, Phenol Red, and Vitamins. UTM+ also contains Hyaluronate.

AI/ML Overview

Here's a breakdown of the acceptance criteria and the study information for the ISM1+, ISM2+, and UTM+ media, based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

Acceptance Criteria (Set by Sponsor)	Reported Device Performance (from studies)
Product Testing Controls (per batch):
Sterility satisfactory	Certificate of Analysis available for each batch
pH within range	Certificate of Analysis available for each batch
Osmolality within range	Certificate of Analysis available for each batch
Endotoxin ≤ 0.1 EU/ml	Certificate of Analysis available for each batch
Mouse Embryo Assay:
ISM1+ & ISM2+: Blastocyst rate > 70% (one-cell assay)	Certificate of Analysis available for each batch
UTM+: Blastocyst rate > 80% (two-cell assay)	Certificate of Analysis available for each batch
Clinical Equivalence:
Equally effective to original ISM1/ISM2 media (modified versions of which ISM1+/ISM2+ are)	Clinical study concluded "two versions were equally effective." Also, "no registered complaints and no evidence that the product has been the cause of any serious adverse events."
Substantively equivalent to Vitrolife's G1.2-G2.2 sequential culture system	Two prospective studies showed equivalence to G1.2/G2.2 media systems.
Effective for development of embryos for Day 2-3 transfer or Day 5 blastocyst transfer	Demonstrated in original ISM media multicenter trial and supported by equivalence studies.

2. Sample Sizes and Data Provenance

Test Set (Clinical Data for Original ISM):
- Sample Size: 466 cycles.
- Data Provenance: France, prospective multicenter trial.
Test Set (Clinical Data for ISM1+/ISM2+ vs. Original ISM):
- Sample Size: Not specified (referred to as "a clinical study").
- Data Provenance: Not specified (implied to be clinical, likely related to the sponsor's efforts).
Test Set (Clinical Data for ISM+ series vs. G1.2/G2.2):
- Sample Size: Not specified (referred to as "two prospective studies").
- Data Provenance: Not specified (implied to be clinical).
Batch Release Testing (Mouse Embryo Assay):
- Sample Size: Not specified per batch, but it's a routine quality control test.
- Data Provenance: Laboratory testing by the manufacturer.

3. Number of Experts and Qualifications for Ground Truth

This information is not provided in the document. The studies are clinical trials involving patients and their outcomes, which serve as the "ground truth" for effectiveness in supporting embryo development and transfer. The assessment of embryo viability and success is performed by clinicians (e.g., embryologists, IVF specialists), but their specific qualifications and number are not detailed.

4. Adjudication Method for the Test Set

This information is not provided. Clinical outcomes (pregnancies, embryo development) were likely assessed by the involved clinical centers and compiled. There's no mention of a specific adjudication panel or method beyond what's inherent in clinical practice.

5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study

No, an MRMC comparative effectiveness study was not done. The studies described are clinical trials comparing the culture media's efficacy in achieving desired embryo development and pregnancy outcomes, not studies involving human readers interpreting outputs or effects of an AI system.

6. Standalone (Algorithm Only) Performance

No, a standalone performance study was not done. The device is a culture medium, not an algorithm or AI system. Its performance is directly observed through biological outcomes in embryos.

7. Type of Ground Truth Used

Clinical Outcomes: For the clinical studies, the ground truth was based on:
- Embryo development (cleavage, blastocyst formation).
- Pregnancy rates.
- Singleton vs. twin pregnancies.
- Absence of serious adverse events.
Biological/Laboratory Standards: For the product testing controls (sterility, pH, osmolality, endotoxin, Mouse Embryo Assay), the ground truth was established against predefined acceptable ranges and biological performance thresholds (e.g., blastocyst rate > 70%).

8. Sample Size for the Training Set

Not Applicable. This is a medical device (culture medium), not a machine learning model. Therefore, there is no "training set" in the context of AI.

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

Not Applicable. As there is no AI training set, this question does not apply.

Summary

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K030490

AUG 2 0 2003

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

Indications for use:

ISM1+

For culture of embryos. To be used in culture after fertilization in Universal IVF Medium (K 991279) up to Day3 to 6- to8-cell stage, followed by extended culture in ISM2+ or by transfer in UTM+.

ISM2+

For culture of embryos. To be used in culture from 6- to 8-cell stage on Day3 to blastocyst stage on day 5, followed by transfer in UTM+. ISM2+ shall be used after ISM1+.

UTM+

For transfer of embryos cultured in ISM1+ or ISM2+.

Composition:

ISM1+

l Physiological salts
. Sodium bicarbonate
이 Penicillin/Streptomycin
이 HSA
Glucose and derived . metabolites
l Nucleosides
. Non-essential amino acids
. Essential amino acids
Phenol Red .
I Vitamins

ISM2+

Physiological salts 트
트 Sodium bicarbonate
Penicillin/Streptomycin 미
해 HSA
트 Glucose and derived metabolites
I Nucleosides
t Non-essential amino acids
트 Essential amino acids
l Phenol Red
Vitamins .

UTM+

트 Physiological salts
l Sodium bicarbonate
. Penicillin/Streptomycin
트 HSA
Glucose and derived metabolites
비 Nucleosides
피 Non-essential amino acids
에 Essential amino acids
이 Phenol Red
l Vitamins
I Hyaluronate

Stability, cytotoxicity- and biocompatibility testing

Stability testing of ISM1+/ ISM2+/UTM+ sequential media has been performed for 17 weeks and a shelf life of 8 weeks from shipment date is recommended. Once opened the product is to be used within 28 days.

Furthermore UTM+ was classified as non-toxic according to the Mouse Embryo test, non-irritant according to vaginal irritation test and showed no evidence of delayed contact hypersensitivity.

Product testing controls

1. Sterility
1. pH
1. Osmolality
1. Endotoxin ≤ 0.1 EU/ml
Mouse Embryo Assay, ISM1+ and ISM2+ (one cell assay, Blastocyst rate > 70 %), UTM+ ( two న్ cell assay, blastocyst rate > 80 %)

For each batch a Certificate of Analysis with the results of the above tests is available.

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Clinical Documentation:

Medi-Cult's new ISM1+, ISM2+( Innovative Sequential Media) and UTM + (Uterine Transfer Medium) is a modified version of older ISM1/ISM2/UTM media.

The original ISM media have been tested in a multicenter trial in France. The study included patients, not more than 40 years of age, accepted for IVF and ICSI treatments to a total of 466 cycles. After fertilization in Universal IVF Medium the embryos were cultured in ISM1, ISM2 and either transferred on Day 2/3 or Day 5 using UTM.The data show that the ISM media support development of viable cleavage and blastocyst embryos following either IVF or ICSI and these can be transferred on Day 2/3 or at the blastocyst stage.

All pregnancies in the study were singletons with the exception of one pair of twins. The twins were a result of two individual embryos implanted and therefore no monozygotic twins were seen in the entire study.

Furthermore, a clinical study has been performed where Medi-Cult's original ISM1/ISM2 have been compared to ISM1+/1SM2+. The conclusion was that the two versions were equally effective.

Two prospective studies where the ISM series and ISM+ series respectively have been compared to G1.2/G2.2 media systems have been performed.

Based on the results of these studies it is concluded that Medi-Cult's ISM+ series comprising ISM1+, ISM2+ and UTM+ media are substantial equivalent to Vitrolife's G1,2-G2.2 sequential culture system and is effective for development of embryos for Day 2-3 transfer or for developing blastocysts for Day 5 transfer in patients for IVF or ICSI

During our studies there has been no registered complaints and no evidence that the product has been the cause of any serious adverse events in connection with its intended use.

Thus based on the clinical data presented and our experience with the ISM products we feel that the safety and effectiveness of the product for its intended use is shown in the present submission and the products are substantially equivalent to the predicated devices G1.2 media ( K 000625) and G2.2 media ( K 000619).

Prepared and Submitted by:

forther

02-/53-23

Date

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

accella

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Image /page/2/Picture/1 description: The image shows the logo for the U.S. Department of Health & Human Services. The logo consists of a stylized depiction of an eagle or bird-like figure with three curved lines forming its body and wings. The bird is facing to the left. Encircling the bird is the text "DEPARTMENT OF HEALTH & HUMAN SERVICES - USA" in a circular arrangement.

Public Health Service

AUG 2 0 2003

Food and Drug Administration 9200 Corporate Boulevard Rockville MD 20850

Medi-Cult a/s % Ronald G. Leonardi, Ph.D. President R & R Registrations P.O. Box 262069 SAN DIEGO CA 92196-2069 Re: K030490

Trade/Device Name: Innovative Sequential Media System (ISM1"", ISM2"") and Uterine Transfer Medium (UTM"") Regulation Number: 21 CFR 884.6180 Regulation Name: Reproductive media and supplements Regulatory Class: II Product Code: 85 MQL Dated: June 11, 2003 Received: June 11, 2003

Dear Dr. Leonardi:

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 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

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 one of the following numbers, based on the regulation number at the top of the letter:

8xx.1xxx	(301) 594-4591
876.2xxx, 3xxx, 4xxx, 5xxx	(301) 594-4616
884.2xxx, 3xxx, 4xxx, 5xxx, 6xxx	(301) 594-4616
892.2xxx, 3xxx, 4xxx, 5xxx	(301) 594-4654
Other	(301) 594-4692

Additionally, for questions on the promotion 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 Part 807.97) you may obtain. Other general information on your responsibilities under the Act may be obtained 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/dsma/dsmamain.html.

Sincerely yours,

Nancy C. Brogdon

Nancy C. Brogdon Director, Division of Reproductive, Abdominal and Radiological Devices Office of Device Evaluation Center for Devices and Radiological Health

Enclosure

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510(k) Number (if known)

K030490

Device Name: ISM1+™, ISM2+™ and UTM+™

INDICATIONS FOR USE:

ISMI+

For culture of embryos. To be used in culture after fertilization in Universal IVF Medium (K 991279) up to Day 3 to 6- to 8-cell stage, followed by extended culture in ISM2+ or by transfer in UTM+.

ISM2+

For culture of embryos. To be used in culture from 6- to 8-cell stage on Day 3 to blastocyst stage on Day 5, followed by transfer in UTM+. ISM2+ shall be used after ISM1+.

UTM+ For transfer of embryos cultured in ISM1+ or ISM2+.

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

Concurrence of CDRH, Office of Device Evaluation (ODE)

Prescription Use J (Per 21 CFR 801.109)

Over-The-Counter Use

(Optional Format 1-2-96)

David A. Lessem

(Division Sign-Om
Division of Reproductive, Abdominal,
and Radiological Devices
510(k) Number K030490

iii

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.