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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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