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The Eeva System is indicated to provide adjunctive information on events occurring during the first two days of development that may predict further development to the blastocyst stage on Day 5 of development. This adjunctive information aids in the selection of embryo(s) for transfer on Day 3 when, following morphological assessment on Day 3, there are multiple embryos deemed suitable for transfer or freezing. The device may also be used to collect additional time-lapse images until Day 5 of development for embryos not selected for transfer, to allow monitoring of continued embryo development.

The Eeva™ System is an Assisted Reproduction Embryo Image Assessment System (21 CFR 884.6195), installed in an IVF lab and used by embryologists and other IVF professionals. None of the System components have an individual, prior 510(k) clearance. Eeva System, Model EVS210 requires the use of the 12-microwell configuration of the Eeva™ Dish (K141663, also referred to as the "dish"), which is placed on the Eeva Scope (an assisted reproductive microscope). The Eeva Scopes are placed in commercially-available standard-sized incubators. The microscope employs high resolution time-lapse imaging to record an embryo's development during its first two days of incubation. Automated measurements of cell division timing parameters and the Eeva Test results are provided to the user after approximately 42 hours predicting the likelihood of whether an embryo will develop to the blastocyst stage. In Eeva System, Model EVS2210, image recording may continue through Day 5 of embryo development.

The Eeva™ System (EVS2210) provides adjunctive information on early embryo development (first two days) to predict progression to the blastocyst stage by Day 5. This information assists in selecting embryos for transfer on Day 3, especially when multiple suitable embryos are identified through morphological assessment.

1. Table of Acceptance Criteria and Reported Device Performance

The provided document does not explicitly list acceptance criteria for specific performance metrics (like sensitivity, specificity, PPV, NPV) with predefined thresholds. However, it states that "simulated clinical testing (mechanical analysis) demonstrates that the Eeva System Model EVS2210 is informative, and the average specificity, sensitivity, positive predictive value, and negative predictive value performance are substantially equivalent in the adjunctive use of the subject and predicate devices." This implies that the performance of the Eeva System (EVS2210) closely matched that of its predicate device, Eeva System (EVS2000).

The "Algorithm Software Validation" and "Simulated Clinical Use" tests aimed to evaluate the ability of the Eeva System software to predict blastocyst formation and its clinical performance, including determination of sensitivity, specificity, positive predictive value, negative predictive value, and odds ratio.

Since the document asserts substantial equivalence, the implied acceptance criteria are that the EVS2210's performance metrics (sensitivity, specificity, PPV, NPV, odds ratio) should be comparable to or not worse than those of the predicate device (EVS2000).

2. Sample size used for the test set and the data provenance

The document mentions "Simulated Clinical Use" for evaluation but does not explicitly state the sample size used for the test set or the data provenance (e.g., country of origin, retrospective/prospective). It refers to "clinical data submitted for the predicate device" as being "representative of expected safety and effectiveness of the Eeva System Model EVS2210," but this doesn't specify if new data was used for the EVS2210's simulated clinical use or if it entirely leveraged the predicate's data.

3. 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 the ground truth for the "Simulated Clinical Use" test set.

4. Adjudication method for the test set

The document does not describe any adjudication method used for the test set.

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

The document does not mention a multi-reader multi-case (MRMC) comparative effectiveness study, nor does it describe an effect size for human reader improvement with or without AI assistance. The device provides "adjunctive information" to aid embryologists, suggesting it's intended for human-in-the-loop use, but a formal MRMC study is not detailed.

6. If a standalone (i.e. algorithm only without human-in-the-loop performance) was done

The "Simulated Clinical Use" is described as evaluating "clinical performance of the Eeva System software including determination of sensitivity, specificity, positive predictive value, negative predictive value, and odds ratio." This suggests a standalone evaluation of the algorithm's performance in predicting blastocyst formation. The device provides "adjunctive information," implying its output is then used by an embryologist. Therefore, a standalone evaluation of the software's predictive capability appears to have been performed.

7. The type of ground truth used (expert consensus, pathology, outcomes data, etc.)

The ground truth used for the "Algorithm Software Validation" and "Simulated Clinical Use" tests was the "blastocyst formation." This is an objective biological outcome (whether an embryo develops to the blastocyst stage by Day 5).

8. The sample size for the training set

The document does not provide information regarding the sample size for the training set used for the Eeva System's algorithm.

9. How the ground truth for the training set was established

The document does not provide information on how the ground truth for the training set was established. It only mentions that the device evaluates cell division timing parameters to predict blastocyst formation.

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The Eeva™ Dish is intended to be used to hold human oocytes and embryos during handling and culture.

The Eeva Dish is a round dish with an outer diameter of 38 mm; the inner diameter of the dish is 35mm. The dish is provided with a lid. The interior of the dish contains a large central ring approximately 10mm in diameter, which contains 12 smaller, round microwells, each intended to hold a single human oocyte or embryo. The device allows for the segregation of embryos while they are immersed in the same drop of culture media The microwells are 350 microns in diameter and 134 microns deep, which creates sufficient room for handling of human oocytes and embryos with a pipette. The center ring has a tapered wall to stabilize and minimize embryo movement in the microwells. The dish also contains three smaller outer rings, approximately 8mm in diameter each, that are intended to hold media drops for rinsing oocytes or embryos. The center and three outer rings can each hold 100ul of media. The dish is constructed of virgin polystyrene and is non-pyrogenic and non-embryotoxic. The dish is single use only and is packaged with 3 units per sterile pouch, 12 pouches per corrugated cardboard shipping carton.

Here's an analysis of the Eeva™ Dish's acceptance criteria and the supporting study, based on the provided 510(k) summary:

1. Table of Acceptance Criteria and Reported Device Performance

The device in question (Eeva™ Dish, 12-microwell configuration) is a modification of a previously cleared predicate device (Eeva™ Petri Dish, 16- and 25-microwell configurations). As such, the acceptance criteria are generally aligned with demonstrating "substantial equivalence" to the predicate, particularly in terms of safety and performance for its intended use. The performance criteria largely mirror those established for the original predicate device and testing aims to show the new design doesn't negatively impact these metrics.

Study Details:

The provided document describes a non-clinical testing program conducted on the Eeva™ Dish with 12 microwells to support a determination of substantial equivalence to the predicate devices. The study is a set of tests to ensure the new device functions as intended and safely, similar to the predicate, despite minor design changes.

2. Sample size used for the test set and the data provenance

• Sample Size for Test Set: Not explicitly stated in terms of specific numbers for each test (e.g., how many dishes were tested for pyrogenicity). The document indicates "Non-clinical testing was conducted on the Eeva Dish with 12 microwells." It implies that sufficient samples were used to meet the requirements of the standards/methods for each test.
• Data Provenance: Not explicitly stated (e.g., country of origin). Given it's a 510(k) submission to the FDA, the testing would generally be expected to follow internationally recognized standards, potentially conducted in the US or by accredited labs elsewhere. The timing (July 2014) is for the summary preparation, the tests themselves would have occurred prior. The study is prospective in nature, as the tests were specifically conducted to evaluate the new device.

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts

• This information is not applicable in this context. The Eeva™ Dish is an IVF culture dish, which is a physical labware device. Its performance criteria (e.g., pyrogenicity, embryotoxicity, dimensional accuracy) are assessed through standardized laboratory tests, not through expert interpretation of data or images. "Ground truth" here refers to the quantitative results of these scientific tests against defined criteria.

4. Adjudication method for the test set

• This information is not applicable. As explained above, the tests are objective laboratory assessments with established pass/fail criteria, not subjective 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

• No, an MRMC comparative effectiveness study was not done. This device is a culture dish, not an AI-powered diagnostic tool requiring human reader interaction. Therefore, concepts like "human readers improve with AI" are not relevant to this submission.

6. If a standalone (i.e. algorithm only without human-in-the-loop performance) was done

• No, a standalone AI algorithm study was not done. This device is a physical labware product and does not involve an algorithm.

7. The type of ground truth used

The ground truth used for these tests is based on:

• Standardized assay results: For example, Limulus Amoebocyte Lysate (LAL) testing for pyrogenicity, and 1-Cell Mouse Embryo Assay (MEA) for embryotoxicity (where "non-embryotoxic" is defined by ≥ 80% of embryos developing to the expanded blastocyst stage within 96 hours).
• Engineering specifications and measurements: For dimensional accuracy, packaging integrity, sterilization efficacy, and shelf-life verification.
• Verification of compatibility and usability: Against defined functional requirements.

8. The sample size for the training set

• Not applicable. This device is a physical product, not an AI or machine learning model that requires a training set.

9. How the ground truth for the training set was established

• Not applicable. As there is no training set for this device, there is no ground truth for a training set to be established.

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The Eeva System is indicated to provide adjunctive information on events occurring during the first two days of development that may predict further development to the blastocyst stage on Day 5 of development. This adjunctive information aids in the selection of embryo(s) for transfer on Day 3 when, following morphological assessment on Day 3, there are multiple embryos deemed suitable for transfer or freezing.

The Eeva System provides image recording and automated analysis of cell division from high resolution time-lapse images collected until day 3 (72 hours) of development. Results of cell division timing parameters (time from first to second mitosis: and time from second to third mitosis) are provided to the user in addition to a prediction of the likelihood that an embryo will develop to the blastocyst stage. These timing parameters are based on those published in a study by Wong, et. al. (2010).

The Eeva System incorporates: (1) a set of up to four time-lapse image microscopes that automatically take darkfield microscopy images of embryos at regular intervals (every 5 minutes) while the embryos remain in the incubator environment, (2) Eeva Computer and other components (Control Box, Station, Scope Screen and Printer), (3) system software for image capture and recording, user interface, and patient database and (4) image analysis software that automatically identifies embryo development events, compares their times to specified timing parameters and makes a prediction of embryo development to the blastocyst stage. The system is installed in an In Vitro Fertilization (IVF) laboratory, and is to be used as an adjunct to the traditional morphological method to identify the embryos that are more likely to develop into blastocysts.

The Eeva™ System is indicated as an adjunct to traditional morphology evaluation to aid in the selection of embryo(s) for transfer on Day 3 when multiple embryos are deemed suitable for transfer or freezing. It helps predict the likelihood of an embryo developing to the blastocyst stage on Day 5/6.

1. Table of Acceptance Criteria & Reported Device Performance:

The document primarily focuses on clinical performance characteristics rather than specific hard-coded acceptance thresholds for every metric. However, for "Software Validation," a clear acceptance criterion is defined and met. For the primary and secondary endpoints in the Pivotal Adjunct Use Study, the outcome of statistical significance against stated objectives serves as the "acceptance."

2. Sample Sizes and Data Provenance:

• Test Set (Pivotal Adjunct Use Study):
  • Number of Subjects: 54 subjects.
  • Number of Embryos: Not explicitly stated as a total count for the test set, but it refers to "a subject's cohort of embryos" and "multiple embryos per subject."
  • Data Provenance: Prospective, multi-center clinical study conducted at five sites in the United States. Data was collected on embryos cultured to cleavage stage (Day 3) or blastocyst (Day 5/6) stage. This was a non-interventional study, meaning the Eeva output was not used for real-time patient management.

3. Number of Experts and Qualifications for Ground Truth:

• Software Validation Phase (for Eeva System Software's ability to predict blastocyst formation):
  • Number of Experts: A panel of three embryologists.
  • Qualifications: "Embryologists" are mentioned, with no further specific details on their years of experience or board certification. Their role was to review image series and identify start/stop times of development parameters.
• Pivotal Adjunct Use Study (for morphological and adjunct assessments):
  • Number of Experts: A panel of 5 clinical embryologists.
  • Qualifications: "Currently in practice, representing a range of geographical areas and level of experience." No further specific expertise (e.g., years of experience) is provided.

4. Adjudication Method for the Test Set:

• Software Validation: The document states that a panel of three embryologists reviewed the image series to identify start/stop times. The results of their measurements were compared to the Eeva System measurements. This implies a comparison against the consensus or individual expert findings, but it doesn't explicitly detail a formal adjudication method (e.g., majority vote, or a specific process for resolving disagreements between the three). It presents the embryologists' aggregate specificity for comparison.
• Pivotal Adjunct Use Study: For the morphological and adjunct assessments, each of the five panelists independently provided their assessments and embryo selections. There is no mention of an adjudication method to establish a single "expert ground truth" for these assessments among the five panelists. Instead, the study analyzed the impact of the Eeva System on each panelist's predictions and selections, and then reported overall odds ratios and performance metrics that appear to aggregate or model across the panelists' individual responses. The primary endpoint analysis used complex statistical procedures (pre-specified method and GLMM) to address the "complex structure of the data (multiple embryos per subject, five panelists evaluating all embryos by both traditional morphology and sequential adjunctive use of Eeva)."

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

• Yes, a form of MRMC was done. The "Pivotal Adjunct Use Study" serves as this, comparing human readers (embryologists) with and without AI assistance (Eeva System). The "readers" are the 5 clinical embryologists.
• Effect Size:
  • Odds Ratio for Blastocyst Prediction:
    • Traditional Morphology: 1.66 (95% CI: [0.78, 3.51]) by pre-spec analysis; 1.68 (95% CI: [1.29, 2.19]) by GLMM.
    • Adjunct Prediction (with Eeva): 2.56 (95% CI: [1.75, 3.74], p<.0001) by pre-spec analysis; 2.57 (95% CI: [1.88, 3.51]) by GLMM.
    • Improvement: The odds of an embryo forming a blastocyst were 2.56-2.57 times higher with adjunct use compared to traditional morphology alone (1.66-1.68). This is a substantial improvement in the informativeness of the prediction.
  • Specificity: Improved by 37% (from 39% to 76%) with adjunct prediction.
  • Positive Predictive Value (PPV): Improved by 11% (from 43% to 54%) with adjunct prediction.
  • Positive Likelihood Ratio (PLR): Improved (from 1.21 to 1.86) with adjunct prediction.
  • Note on Sensitivity: Sensitivity decreased by 27% (from 72% to 45%). However, the document argues this trade-off is expected and acceptable because the Eeva System's role is to aid in selecting among already morphologically suitable embryos, making specificity and PPV more critical for this use case.

6. Standalone (Algorithm Only) Performance Study:

• Yes, in the "Software Validation" phase. This phase directly assessed the Eeva System Software's ability to predict blastocyst formation independently.
  • The Eeva System software’s specificity was 85.12%, compared to the embryologists’ 82.64%. The lower limit of the 95% CI for Eeva was 77.71%. This demonstrates the algorithm's standalone prediction capability against expert "measurements."
  • The document states, "The results of the embryologists' measurements were compared to the Eeva System measurements to validate the software." This indicates a direct comparison of the software's output against the expert observations.

7. Type of Ground Truth Used:

• For Blastocyst Formation: The ultimate ground truth for blastocyst formation was the actual biological outcome – whether the embryo progressed to the blastocyst stage (Day 5/6) or arrested. This is an objective outcome based on embryo development.
• For Software Validation of Timing Parameters: The ground truth for validating the software's ability to identify cell division start/stop times was based on the measurements/observations of the panel of three embryologists.
• For Clinical Study Assessments: The ground truth for the panels' predictions was the actual blastocyst outcome. The panels were given morphological data collected by clinical site embryologists and, in the adjunct arm, the Eeva parameters.

8. Sample Size for the Training Set:

• Software Development Phase: 63 subjects. This data was used to "further develop the Eeva System Software" and identify the parameters for P2 (time from first to second mitosis) and P3 (time from second to third mitosis) that were implemented. This effectively served as the training/development set for the algorithm's specific predictive windows.

9. How the Ground Truth for the Training Set was Established:

• For the "Software Development" phase (training set), "Imaging data was collected on embryos cultured to cleavage stage (Day 3) or blastocyst stage (Day 5/6)." This implies the ground truth for blastocyst formation was established by the actual development outcome of these embryos (i.e., did they reach blastocyst stage or not). This outcome data was then used by the developers to determine the optimal timing parameters (P2 and P3) that formed the basis of the Eeva System's prediction model.

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The Eeva™ Petri Dish is intended to be used to hold human oocytes and embryos during handling and culture.

The Eeva™ Petri Dish is 39mm in diameter with a lid and consists of a large center well containing 16 or 25 micro-wells. The Eeva Petri dish also contains three smaller outer rings, approximately 7mm in diameter each, which are intended to hold media drops for rinsing the oocytes or embryos.

The Eeva™ Petri Dish is constructed of polystyrene and is non-pyrogenic and non-embryotoxic.

The provided text describes the "Eeva™ Petri Dish," which is an IVF tissue culture dish. The document is primarily a 510(k) summary for FDA clearance, focusing on demonstrating substantial equivalence to a predicate device. Therefore, the "acceptance criteria" and "study that proves the device meets the acceptance criteria" are framed in the context of demonstrating safety and effectiveness as an IVF tissue culture dish, rather than a diagnostic AI device with performance metrics like sensitivity/specificity.

Here's an analysis based on the provided text:

1. A table of acceptance criteria and the reported device performance

2. Sample sized used for the test set and the data provenance (e.g. country of origin of the data, retrospective or prospective)

• Non-pyrogenic (LAL test): The sample size for the LAL test is not specified. The data provenance is not mentioned (e.g., country of origin, retrospective/prospective).
• Non-embryotoxic (MEA test): The sample size (number of embryos or tests) for the 1-Cell Mouse Embryo Assay is not specified. The data provenance is not mentioned.

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts (e.g. radiologist with 10 years of experience)

This information is not applicable as the studies performed (LAL and MEA) are laboratory-based tests for material properties and biological compatibility, not expert-opinion-based evaluations of a ground truth.

4. Adjudication method (e.g. 2+1, 3+1, none) for the test set

This information is not applicable for the tests described. The LAL and MEA tests have specific, objective measurement endpoints.

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

There was no MRMC comparative effectiveness study and no AI component mentioned in the provided text. This device is a petri dish, not an AI diagnostic tool.

6. If a standalone (i.e. algorithm only without human-in-the-loop performance) was done

There was no standalone algorithm performance study as this is a physical device, not an algorithm.

7. The type of ground truth used (expert consensus, pathology, outcomes data, etc)

• Non-pyrogenic: Ground truth is established by the LAL (Limulus Amebocyte Lysate) assay, which detects bacterial endotoxins. This is an objective, standardized laboratory test.
• Non-embryotoxic: Ground truth is established by the 1-Cell Mouse Embryo Assay (MEA), which assesses the device's impact on embryo development. The criterion for success is a predefined percentage (e.g., ≥ 80%) of embryos developing to a specific stage (expanded blastocyst). This is an objective, standardized biological assay.
• Substantial Equivalence: The ground truth for this aspect is the comparison of device characteristics (intended use, materials, design) to a legally marketed predicate device, as determined by regulatory review.

8. The sample size for the training set

This information is not applicable as this is not an AI/machine learning device that requires a training set.

9. How the ground truth for the training set was established

This information is not applicable as this is not an AI/machine learning device.

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