(253 days)
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.
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).
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
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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.
- Test Set Sample Size:
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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.
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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.
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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.
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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.
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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 "ground truth" for the primary and secondary endpoints consisted of clinical outcomes data and standard clinical assessments:
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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.
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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.
§ 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.