EmbryoGen® is designed to provide physiological conditions for the embryo from fertilization to Day 3 at the time when the embryo under in vivo conditions would be transported through the oviduct. EmbryoGen® is based on the FDA-cleared culture media EmbryoAssist™(K080473) supplemented with Leukine (sargramostim) GM-CSF. EmbryoGen is supplied in sterilized transparent glass bottles with polypropylene screw top closure in a volume of either 3 mL or 5 mL. The media is colorless, sterile and ready to use by professionals for assisted reproduction. EmbryoGen is quality control tested before release for pH, sterility, Mouse Embryo Assay, endotoxin, osmolality, GM-CSF concentration (by ELISA), GM-CSF potency (TF-1 cell assay) and HSA concentration (by ELISA).

AI/ML Overview

Here's a breakdown of the acceptance criteria and the study that proves the device meets them, based on the provided text:

Acceptance Criteria and Device Performance

The provided document focuses on demonstrating substantial equivalence to a predicate device, rather than explicit acceptance criteria with pre-defined thresholds for performance metrics. The primary "acceptance criteria" here are implicitly tied to proving that EmbryoGen® is as safe and effective as the predicate device, EmbryoAssist™ (K080473), with the added benefit of GM-CSF.

The study aimed to demonstrate a 25% relative increase in ongoing implantation rate at gestational week 7 as its primary hypothesis. While this was the initial goal, the overall study results did not meet this specific statistical significance for the general population. However, the device's performance within a specific subgroup did show a significant improvement.

Here's a table summarizing the implicit acceptance criteria and the device's reported performance within the context of substantial equivalence:

Acceptance Criteria (Implicit, based on substantial equivalence and study goals)	Reported Device Performance (EmbryoGen® with GM-CSF)	Control Device Performance (EmbryoAssist™)	Statistical Significance (p-value)	Notes
Primary Endpoint: Overall Ongoing Implantation Rate (Gestational Week 7) - Demonstrate a 25% relative increase.	23.5%	20.0%	p=0.17	Not statistically significant for the overall unselected population.
Secondary Endpoint: Overall Ongoing Implantation Rate (Gestational Week 12) - Not explicitly defined as a target, but evaluated.	23.0%	18.7%	p=0.02	Statistically significant for the overall unselected population.
Secondary Endpoint: Overall Live Birth Rate - Not explicitly defined as a target, but evaluated.	28.9%	24.1%	p=0.03	Statistically significant for the overall unselected population, attributed primarily to suboptimal performance of the control with low HSA.
Subgroup Performance: Ongoing Implantation Rate (Gestational Week 7) in women with at least one previous miscarriage.	24.5%	17.0%	p=0.001	Statistically significant in this subgroup, regardless of HSA concentration.
Subgroup Performance: Live Birth Rate in women with at least one previous miscarriage.	29.6%	23.1%	p=0.02	Statistically significant in this subgroup.
Safety: No unacceptable clinical risks (miscarriages, abnormalities/malfunctions).	No indications of unacceptable clinical risks; equivalent to control.	Equivalent to test.	Not applicable (safety assessment).	Study with 369 babies born showed no worse outcomes than control in terms of miscarriages and abnormalities. Chromosomal constitution also not worse.
Embryo Quality/Quantity: No negative effect on number of top quality embryos or normally developed Day 3 embryos.	No effect found.	Not applicable (comparison).	Not applicable (no effect).

Study Details

Sample Size used for the test set and the data provenance:
- Test Set Sample Size:
  - Enrolled/Randomized (ITT): 1,332 subjects
  - Per-Protocol (PP) Population: 1,149 subjects
  - Interim Analysis (PP population with embryo transfer & Day 7 data): 301 women
  - Final PP population (Primary Endpoint): The 23.5% vs 20.0% is based on the PP population, which was 1,149 subjects.
  - Subgroup (Previous Miscarriage): 289 patients with embryo transfer.
  - Total Babies Born: 369
- Data Provenance: Multicenter, randomized, parallel group, double-blind, placebo-controlled clinical study. Follow-up data was retrieved from the Danish National Board of Health Register (93%) and supplemented by patient/couple questionnaires (7% for birth data). This indicates a prospective study primarily conducted in Denmark (given the mention of the Danish National Board of Health Register) across 14 study centers.
Number of experts used to establish the ground truth for the test set and the qualifications of those experts:
- The document does not specify the number or qualifications of experts used to establish "ground truth" for the test set.
- The primary endpoint (ongoing implantation rate at gestational week 7) was evaluated by ultrasound scan. Secondary endpoints (embryo quantity/quality) were judged against predefined classification. Follow-up for live birth and health characteristics relied on national registries and questionnaires.
- While medical professionals (e.g., sonographers, clinicians, embryologists) would have been involved in data collection, their specific roles in establishing a "ground truth" for the study endpoints (beyond standard medical practice) are not detailed.
Adjudication method (e.g. 2+1, 3+1, none) for the test set:
- The document does not explicitly describe an adjudication method (like 2+1 or 3+1).
- The double-blind, placebo-controlled, multicenter design suggests efforts to minimize bias. The use of national registries for a large portion of follow-up data implies a standardized, albeit external, source of truth rather than a specific internal adjudication process for every case.
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, a MRMC comparative effectiveness study was not done. This study is evaluating a medical device (culture medium), not an AI or imaging diagnostic tool. Therefore, the concept of "human readers improve with AI" is not applicable here.
If a standalone (i.e. algorithm only without human-in-the-loop performance) was done:
- No, this is not an AI-driven device. It's a culture medium. The concept of "standalone algorithm" is not applicable.
The type of ground truth used (expert consensus, pathology, outcomes data, etc.):
- The "ground truth" for the primary and secondary endpoints consisted of clinical outcomes data and standard clinical assessments:
  - Ongoing implantation rate: Evaluated by ultrasound scan.
  - Live Birth: Confirmed through the Danish National Board of Health Register and patient/couple questionnaires.
  - Abnormalities/Malfunctions: Retrieved from the Danish National Board of Health Register and questionnaires.
  - Embryo quantity and quality parameters: Judged against predefined classifications, likely by embryologists.
The sample size for the training set:
- Not applicable. This study is a clinical trial for a medical culture medium, not a machine learning model. There is no concept of a "training set" in this context.
How the ground truth for the training set was established:
- Not applicable. As a clinical trial for a culture medium, there is no training set or ground truth establishment method for such a set.

Summary

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

Submitted by:

ORIGIO a/s Knardrupvej 2 2760 Måløv Denmark

Contact person:

Eric Gruff, PhD MBA 15696 Oakstand Road Poway, CA 92064

Date Prepared: 2012.Sep.19

Device Identification

Trade Name: EmbryoGen® (Cat. No. 1203)

Classification Name: Reproductive media and supplements (21 CFR 884.6180, Product Code MQL)

Predicate Device

EmbryoAssist (K080473)

Description

EmbryoGen® is designed to provide physiological conditions for the embryo from fertilization to Day 3 at the time when the embryo under in vivo conditions would be transported through the oviduct.

EmbryoGen® is based on the FDA-cleared culture media EmbryoAssist™(K080473) supplemented with Leukine (sargramostim) GM-CSF.

EmbryoGen is supplied in sterilized transparent glass bottles with polypropylene screw top closure in a volume of either 3 mL or 5 mL.

The media is colorless, sterile and ready to use by professionals for assisted reproduction. EmbryoGen is quality control tested before release for pH, sterility, Mouse Embryo Assay, endotoxin, osmolality, GM-CSF concentration (by ELISA), GM-CSF potency (TF-1 cell assay) and HSA concentration (by ELISA).

Indication for use

EmbryoGen is for fertilization and culture until the 2-8 cell stage. EmbryoGen can also be used for embryo transfer at day 2 or 3.

Technological Characteristics

EmbryoGen supports the development and cell division of human embryos. Embryos, which have been exposed to EmbryoGen , are transferred to the woman's uterus, where they potentially implant and result in a pregnancy.

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The technological characteristics of EmbryoGen are essentially similar to the predicate device EmbryoAssist ™ (K080473). They have the same intended use and the same components. The only difference is addition of GM-CSF to EmbryoGen".

EmbryoGen is considered to be functionally equivalent to the predicate device, and is subject to the same quality control tests before release. Further to this a GM-CSF TF-1 cell Assay and an ELISA test are also conducted:

Test on sterility, osmolality, 1-cell Mouse Embryo Assay, pH, Endotoxin, TF-1 cell assay, GM-CSF ELISA and HSA concentration.

Therefore, EmbryoGen is considered substantially equivalent to the predicate device EmbryoAssist (K080473),

Performance and safety data

Clinical Study:

To evaluate the efficiency and safety of EmbryoGen on human embryos, a multicenter, randomized, parallel group, double-blind, placebo-controlled clinical study with adaptive design was conducted at 14 study centers. A total of 1,332 subjects were enrolled/randomized (ITT-population), and of these 1,149 were counted as the PP-population. The objective of this study was to assess whether addition of 2 ng/mL GM-CSF to the embryo culture medium EmbryoAssist™ would significantly increase the chance of a pregnancy after in vitro fertilization. The primary endpoint was ongoing implantation rate at gestational week 7, evaluated by ultrasound scan. The study hypothesis was to demonstrate a 25% relative increase in ongoing implantation rate at gestational week 7, after fertilization, culture until day 3 and transfer in the presence of 2 ng/ml GM-CSF compared to fertilization, culture and transfer in EmbryoAssist™. Secondary endpoints were to assess whether a GM-CSF effect was measurable on embryo quantity and quality parameters, evaluated as number of top quality embryos and number of normally developed day 3 embryos judged against predefined classification. Follow-up was based on data until gestational week 12 and birth data (including abnormalities/malfunctions) retrieved from the Danish National Board of Health Register (93%) supplemented with data from a follow-up questionnaire returned by the patient/couple (7%).

Selection criteria for subject enrolment were the following: Women referred for standard IVF/ICSI treatment, who agreed to participate in the study and to have their oocytes cultured with or without 2 ng/mL GM-CSF. All women were aged 25-39 years (both inclusive) and characterized by having a regular menstrual cycle, standard GnRH agonist or antagonist protocol, FSH/hMG starting dose between 100 and 300 IU daily, at least 3 follicles with a calculated diameter of ≥14 mm at the day of hCG, and including a leading follicle of minimum 17 mm.

All subjects in the PP-population had their oocytes fertilized and the resulting zygotes/embryos cultured until day 3 and transferred using the allocated study medium. An interim analysis was performed after recruitment of 355 eligible subjects, counting 301 women in the PP-population with embryo transfer and reported data until gestational week 7. The interim analysis did not result in any change of inclusion criteria or hypothesis, but was used for sample size adjustment. Also, because suboptimal performance of the control medium was evident at interim analysis, the concentration of HSA was increased from 2 to 5 mg/mL in both control and GM-CSF test medium just over halfway through the treatment cohort, after 620 includable women with embryo transfer. This alteration increased the ongoing implantation rate gestational week 7 for the control group from 17.9% to 22.4%, but did not affect performance of the GM-CSF medium (23.9% and 23.0% in low and high HSA concentration medium, respectively). 5 mg/mL HSA (0.5%) is the standard concentration used in ART culture media.

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The overall results showed an ongoing implantation rate gestational week 7 (primary endpoint calculated for the PP-population) of 23.5% for women in the GM-CSF group, and 20.0% for women in the control group, which was not statistically significant (p=0.17). However, the results did show a statistical significant difference in gestational week 12 and Live Birth: ongoing implantation rate week 12 was 23.0% for women in the GM-CSF group versus 18.7% in the control group (p=0.02) and Live Birth rate 28.9% versus 24.1% (p=0.03). However, this was primarily attributable to suboptimal performance of the control medium containing a low concentration of HSA.

The secondary endpoints in the study were number of top quality embryos and normally developed day 3 embryos. No effect of GM-CSF was found with regard to the quantity of embryos fulfilling these embryo quality parameters.

Based on follow-up data, live birth and baby health characteristics for the full study cohort, including AE/SAE reports received until gestational week 12, there are no indications of any unacceptable clinical risks when adding 2 ng/mL GM-CSF to the culture medium.

In a predefined subgroup of women who had previously experienced at least one miscarriage (spontaneous abortion) (n=289 patients with embryo transfer), addition of GM-CSF had a significant effect on ongoing implantation rate gestational week 7 (24.5% [GM-CSF] vs. 17.0% [control] (p=0.001)). This effect was seen in the presence of both low (27.3% [GM-CSF]) and high (21.2% [GM-CSF]) HSA concentration. Raising the HSA concentration did not have any impact on control values within this subgroup, with ongoing implantation rates gestational week 7 of 17.4% (low HSA) vs. 16.3% (high HSA). Live birth rate per woman with an embryo transfer was 29.6% (GM-CSF) vs. 23.1% (control) (p=0.02).

In conclusion, we have demonstrated a modest effect of GM-CSF on ongoing implantation rate and live birth rates in unselected women undergoing IVF treatment when compared to a control medium. This positive effect was primarily evident in a culture medium containing 2 mg/mL HSA and disappeared when the concentration of HSA was increased to 5 mg/mL. However, GM-CSF increased ongoing implantation rate, clinical pregnancy and live birth rate in a subgroup of women who had experienced previous miscarriage (~25% of the full study cohort), regardless of HSA concentration. Furthermore, this study, with a total of 369 babies born, also showed that culture medium supplemented with 2 ng/mL GM-CSF was no worse than control medium regarding miscarriages and babies born with abnormalities/malfunctions.

Literature:

Published studies have shown that supplementing culture media for IVF with 2 ng/ml recombinant GM-CSF results in better quality embryos, potentially leading to higher implantation and pregnancy rates. Other studies report lack of an effect of GM-CSF, whereas no inhibitory effects of GM-CSF have been reported when adding 2 ng/mL, which is the concentration of GM-CSF in EmbryoGen . The safety of supplementing the culture medium with 2 ng/mL GM-CSF was examined, and a thorough investigation showed that the chromosomal constitution in humans was no worse in the group of women having their oocytes fertilized and embryos cultured in the presence of 2 ng/mL GM-CSF compared with the control group (Agerholm I, Loft A, Hald F, Lemmen JG, Munding B, Sorensen PD, Ziebe S.: Culture of human oocytes with granulocyte-macrophage colony-stimulating factor has no effect on embryonic chromosomal constitution. Reprod Biomed Online. 2010;20:477-484).

Overall conclusion:

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K120136

The conclusion from the performance and safety data, intended use comparison, product formulation comparison and test specification comparison as well as the nonclinical data demonstrates that the EmbryoGen is suitable for its intended use, and meets the criteria in the comparison to predicate device (EmbryoAssist, K080473) in which substantial equivalence has been demonstrated, and meets the criteria outlined in the Notice of Final Rule, 63 FR 48428, Docket Number 97N-0335.

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DEPARTMENT OF HEALTH & HUMAN SERVICES

Image /page/4/Picture/1 description: The image shows the logo for the U.S. Department of Health and Human Services. The logo features a stylized eagle with three tail feathers. The words "DEPARTMENT OF HEALTH & HUMAN SERVICES - USA" are arranged in a circular fashion around the eagle.

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

ORIGIO a/s
% Eric Gruff, Ph.D., MBA
President
E4 Consulting
15696 Oakstand Road
POWAY CA 92064

SEP 26 2012

Re: K120136

Trade/Device Name: EmbryoGen® Regulation Number: 21 CFR§ 884.6180 Regulation Name: Reproductive media and supplements Regulatory Class: II Product Code: MQL Dated: September 12, 2012 Received: September 13, 2012

Dear Dr. Gruff:

We have reviewed your Section 5.10(k) premarket notification of intent to market the device we nave reviewed your becaon 310(x) premiere is substantially equivalent (for increations for use stated in the enclosure) to legally marketed predicate devices marketed in interstate for use stated in the enclosure) to regarly manatical Device Amendments, or to commerce prior to May 26, 1970, the encordance with the provisions of the Federal Food, Drug, and Cosmetic Act (Act) that do not require approval of a premarket approval application (PMA).
and Cosmetic Act (Act) that do not require approval of a previsions of the Act and Cosment Act (Act) that do not require appro ral controls provisions of the Act. The Act. The Act. The Act. The Y ou may, therefore, market the device, sucject to the genirements for annual registration, listing of general controls of the her her her her meading, and prohibitions against misted to septem lisbility adulteration. Please note: CDRH does not evaluate information related to contract fiability adulteration. Please note: CDITT does not evaluate must be truthful and not misleading.

If your device is classified (see above) into either class II (Special Controls) or class III (PMA), If your device is classified (see above) mio ontiner major regulations affecting your device can be
it may be subject to additional controls. Existing major regulations affe it may be subject to additional controls. Extraing migor s 800 to 898. In addition, FDA may
found in the Code of Federal Regulations, Title 21, Parts 800 to 898. In addit Touria in the Code of I odean resguinering your device in the Federal Register.

Please be advised that FDA's issuance of a substantial equivalence determination does not mean Please be advised that IDA's issuated on a such other requirements of the Act
that FDA has made a determination that your devices Enderal accepcies. You must that FDA has made a decemmanon that 70 in week by other Federal agencies. You must of any Federal statutes and regulations assimilating, but not limited to: registration and listing of medit comply with an the Act STEquilements, mendang, com.
(21 CFR Part 807); labeling (21 CFR Part 801); medical device reporting of medical

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device-related adverse events) (21 CFR 803); good manufacturing practice requirements as set de vice-iclated adverse ovents) (21 CFR Part 820); and if applicable, the electronic forul in the quality by sound (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 IT you desire specific advice for your as november offices/CDRH/CDRHOffices/ucm115809.html for go to mq.7/www.lua.gov/rtbound27.b Schlick's (CDRH's) Office of Compliance. Also, please, please the Concertion entitled, "Misbranding by reference to premarket notification" (21CFR Patters (2) note the regulation entitled, "informations 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 Tou may obtain other general mornational and Consumer Assistance at its toll-free number (800) 638-2041 or (301) 796-7100 or at its Internet address http://www.fda.gov/MedicalDevices/Resourcesfor You/Industry/default.htm.

Sincerely yours,

Benjamin K. Twitchell

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

Enclosure

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Indication for Use

510(k) Number (if known): (Not yet assigned) (

Device Name:

EmbryoGen®

Indication for Use:

EmbryoGen® is for fertilization and culture until the 2-8 cell stage. EmbryoGen® can also be used for embryo transfer at day 2 or 3.

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

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

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

Concurrence of CDRH, Office of Device Evaluation (ODE)

Beusink 25 Sept 2012

sion Sign-Off

Page 1 of _

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.