The INVOcell Culture Device is indicated for use in preparing, holding, and transferring human gametes or embryos during In Vitro Fertilization/Intravaginal Culture (IVF/IVC) and Intra-Cytoplasmic Sperm Injection Fertilization/ Intravaginal Culture (ICSI/VC) procedures. The INVOcell Culture Device is indicated for use with the INVOcell Retention Device. The INVOcell Culture Device is not indicated for incubation periods exceeding 120h.

The INVOcell Retention Device is indicated for use with the INVOcell Culture Device to aid in retention of the INVOcell Culture Device in the vaginal cavity during the incubation period. The INVOcell Retention Device is not indicated for use exceeding 120h.

Device Description

The INVOcell Intravaginal Culture System consists of the INVOcell Culture Device and the INVOcell Retention Device.

The INVOcell Culture Device is a radiation sterilized, single-use polystyrene container that holds and maintains the gametes and/or embryos during intravaginal culture for a maximum duration of 120 hours. The INVOcell Culture Device consists of three components: Inner Vessel, Outer Rigid Shell, and Retention Device.

The Inner Vessel holds the culture medium along with the gametes and /or embryos. It has a rotating valve at its top, which allows for access to the chamber when loading and retrieving gametes/embryos and provides a seal during incubation. At the bottom of the Inner Vessel, there is a physical stop to limit the penetration depth of the retrieval catheter into the Inner Vessel to protect embryos during retrieval.

The Outer Rigid Shell that is made of polystyrene, protects the Inner Vessel from the vaginal environment when the device is in use. The Inner Vessel fits into the bottom portion of the Outer Rigid Shell and is sealed in position by the top portion of the Outer Rigid Shell cap with a silicone O-ring, which provides a liquid-tight seal to prevent contamination of the Inner Vessel.

The Retention Device aids in the retention of the INVOcell Culture Device during incubation in the vaginal cavity for a maximum duration of 120 hours. The Retention Device is single-use and provided non-sterile. It is a 70 mm diameter cup-shaped silicone retention device that includes holes to allow flow of vaginal secretions during use.

AI/ML Overview

The provided text describes the acceptance criteria and the study that proves the device meets those criteria for the INVOcell Intravaginal Culture System.

Here's the breakdown of the requested information:

1. Table of Acceptance Criteria and Reported Device Performance

The information for "acceptance criteria" and "reported device performance" is primarily found in the "Summary of Non-Clinical Performance Testing" and "Summary of Clinical Performance Testing" sections, as well as the comparison table in Section VI.

Acceptance Criterion (Non-Clinical)	Reported Device Performance
Mouse Embryo Assay (MEA): ≥80% embryos developed to expanded blastocyst at 120h (1-Cell MEA per 2021 FDA guidance)	Met: ≥80% embryos developed to expanded blastocyst at 120h (Confirmed in "Shelf-Life Testing" section; implicitly met for the clinical efficacy as well)
Seal Integrity Testing: No contamination inside and outside the vessel after 120h of incubation.	Met: No contamination inside and outside the vessel after 120h of incubation.
pH Stability: pH of test medium in device remained within the specified range after 120h of incubation.	Met: pH of test medium in device remained within the specified range after 120h of incubation.
Vessel Wall Optical Clarity: No obscured views after 120h of incubation.	Met: No obscured views after 120h of incubation.
Sterilization Validation: Gamma irradiation to achieve sterility.	Met: The gamma irradiation sterilization methods for the predicate device (ISO 11137:2006) are being relied on.
Packaging Integrity Testing: Qualify 6-year expiration date (bubble leak testing per ASTM F2096, seal strength testing per ASTM F88).	Met: Packaging integrity tested after accelerated aging to support 6-year expiration date.
Endotoxin (LAL): < 20 EU/device	Met: < 20 EU/device (from Comparison Table)

Acceptance Criterion (Clinical - Study 1: Comfort and Retention)	Reported Device Performance (Study 1)
Device Retention: Maintain device in vaginal cavity during 120 hours.	Met: 96% overall retention rate (no reports of INVOcell Culture Device expulsion in 29 subjects; one subject successfully readjusted).
Safety - Vaginal Findings: No clinically relevant vaginal findings (e.g., lesions, ulcerations, erythema, or bleeding) after 120 hours.	Met: No clinically relevant vaginal findings identified after device wearing for 120 hours.

Acceptance Criterion (Clinical - Study 2: Effectiveness and Safety)	Reported Device Performance (Study 2)
Effectiveness - Embryo Development (Day 5): Embryos suitable for transfer can be formed.	Met: Day 5 embryo development is more advanced compared to day 3 INVOcell.
Effectiveness - Clinical Pregnancy and Live Birth Rates (Day 5): Rates are comparable or improved with 120h incubation and revised loading.	Met: Clinical pregnancy and live birth rates are higher for day 5 incubation in the INVOcell device for both IVF and ICSI cohorts compared to day 3.
Effectiveness - Embryo Transfer, Implantation, Miscarriage, Pre-term birth rates (IVC/ICSI vs. Traditional ICSI): Rates similar.	Met: The rates of embryo transfer, clinical pregnancy, implantation, miscarriage, live birth, and pre-term birth using the IVC/ICSI methods were similar to the day 5 traditional IVF and ICSI methods.
Safety - Adverse Events: No increased adverse events or outcomes (maternal and offspring adverse events).	Met: The type of maternal and offspring adverse events experienced in both the IVC cohort and traditional IVF and ICSI cohort were similar. No increased adverse events or outcomes.

2. Sample Size Used for the Test Set and Data Provenance

Test Set Sample Size:
- Study 1 (Comfort and Retention): 29 subjects.
- Study 2 (Effectiveness and Safety):
  - INVOcell arm (IVC/IVF and IVC/ICSI): 240 fresh embryo transfers.
  - Traditional IVF and ICSI arm: 685 fresh embryo transfers.
Data Provenance:
- Study 1: Single center, location not specified but implies a clinical setting.
- Study 2: Multicenter, retrospective cohort study. Data collected from four fertility clinics in the U.S. for the 3-year period of January 2017 to December 2019.

3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of Those Experts

This document does not specify the number or qualifications of experts used to establish ground truth for the clinical studies. Clinical outcomes (e.g., pregnancy, live birth, birth defects) would typically be recorded by medical professionals in the clinics involved.

4. Adjudication Method for the Test Set

The document does not describe any specific adjudication methods (e.g., 2+1, 3+1) for the clinical data in either study. For a retrospective cohort study like Study 2, data would typically be extracted from existing patient records.

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 is no mention of an MRMC study or AI assistance in this document. The device is an intravaginal culture system, not an imaging or diagnostic AI device that would involve human readers.

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

Not applicable as this is a medical device for in vitro fertilization, not an algorithm or AI system.

7. The Type of Ground Truth Used

Non-Clinical (Lab tests): Ground truth was established by direct measurement against predefined laboratory standards (e.g., blastocyst development percentage, absence of contamination, pH range).
Clinical (Study 1): Ground truth was established by direct observation and patient self-report (e.g., device expulsion, vaginal findings from speculum exam, patient discomfort questionnaire).
Clinical (Study 2): Ground truth was established through retrospective clinical outcomes data (e.g., fresh embryo transfers, embryo development stages, clinical pregnancy rates, live birth rates, implantation rates, miscarriage rates, pre-term birth rates, reported birth defects). This would have come from the patient records at the participating clinics.

8. The Sample Size for the Training Set

Not applicable. This document describes a medical device, not an AI/ML algorithm that requires a training set. The clinical studies described are performance validation studies.

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

Not applicable, as there is no training set for an AI/ML algorithm mentioned.

Summary

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June 22, 2023

INVO Bioscience, Inc. % Wanda Carpinella Regulatory Affairs Consultant Avania, LLC 100 Crowley Drive, Suite 100 Marlborough, MA 01760

Re: K222932

Trade/Device Name: INVOcell Intravaginal Culture System Regulation Number: 21 CFR§ 884.6165 Regulation Name: Intravaginal Culture System Regulatory Class: II Product Code: OYO Dated: May 18, 2023 Received: May 19, 2023

Dear Wanda Carpinella:

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. Although this letter refers to your product as a device, please be aware that some cleared products may instead be combination products. The 510(k) Premarket Notification Database located at https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm identifies combination product submissions. 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. Please note: CDRH does not evaluate information related to contract liability warranties. We remind you, however, that device labeling must be truthful and not misleading.

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.

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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); medical device reporting of medical device-related adverse events) (21 CFR 803) for devices or postmarketing safety reporting (21 CFR 4, Subpart B) for combination products (see https://www.fda.gov/combination-products/guidance-regulatoryinformation/postmarketing-safety-reporting-combination-products); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820) for devices or current good manufacturing practices (21 CFR 4, Subpart A) for combination products; and, if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.

Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR Part 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to https://www.fda.gov/medical-device-safety/medical-device-reportingmdr-how-report-medical-device-problems.

For comprehensive regulatory information about mediation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/medicaldevices/device-advice-comprehensive-regulatory-assistance) and CDRH Learn (https://www.fda.gov/training-and-continuing-education/cdrh-learn). Additionally, you may contact the Division of Industry and Consumer Education (DICE) to ask a question about a specific regulatory topic. See the DICE website (https://www.fda.gov/medical-device-advice-comprehensive-regulatoryassistance/contact-us-division-industry-and-consumer-education-dice) for more information or contact DICE by email (DICE@fda.hhs.gov) or phone (1-800-638-2041 or 301-796-7100).

Sincerely,

Michael T. Bailey -S

For Monica D. Garcia, Ph.D. Assistant Director DHT3B: Division of Reproductive, Gynecology and Urology Devices OHT3: Office of GastroRenal, ObGyn, General Hospital and Urology Devices Office of Product Evaluation and Quality Center for Devices and Radiological Health

Enclosure

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Indications for Use

510(k) Number (if known) K222932

Device Name INVOcell Intravaginal Culture System

Indications for Use (Describe) The INVOcell Intravaginal Culture System consists of the following components:

Type of Use (Select one or both, as applicable)
Prescription Use (Part 21 CFR 801 Subpart D)	Over-The-Counter Use (21 CFR 801 Subpart C)

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510(k) Summary K222932

INVOcell® Intravaginal Culture System

I.	Submitter	INVO Bioscience, Inc.5582 Broadcast CourtSarasota, FL 34240
	Contact Person	Steven ShumCEO INVO Bioscience, Inc.5582 Broadcast CourtSarasota, FL 34240Tel: 978-878-9505Email: sshum@invobio.com
	Date Prepared	June 20, 2023
II.	Device
	Trade name	INVOcell Intravaginal Culture System
	Common name	Intravaginal Culture System
	Regulatory Name	Intravaginal Culture System

Classification Name: 21 CFR 884.6165 Product Code(s): OYO (Culture, Intravaginal, Assisted Reproduction) Regulatory Class: =

III. Predicate Device

INVOcell Intravaginal Culture System (DEN150008) from INVO Bioscience, Inc.

The predicate device has not been subject to a design-related recall.

IV. Description of the Device

The INVOcell Intravaginal Culture System consists of the INVOcell Culture Device and the INVOcell Retention Device.

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V. Indications for Use

The INVOcell Intravaginal Culture System consists of the following components:

The INVOcell Culture Device is indicated for use in preparing, holding, and transferring human gametes or embryos during In Vitro Fertilization/Intravaginal Culture (IVF/IVC) and Intra-Cytoplasmic Sperm Injection Fertilization/Intravaginal Culture (ICSI/IVC) procedures. The INVOcell Culture Device is indicated for use with the INVOcell Retention Device. The INVOcell Culture Device is not indicated for incubation periods exceeding 120h.

VI. Substantial Equivalence Comparison:

A comparison of the intended use and technological features of the subject and predicate devices are described in the table below:

	K222932Subject Device	DEN150008Predicate Device	Comparison
Indications forUse	The INVOcell Intravaginal Culture System consists of the following components:The INVOcell Culture Device is indicated for use in preparing, holding, and transferring human gametes or embryos during In Vitro Fertilization/Intravaginal Culture (IVF/IVC) and Intra-Cytoplasmic Sperm Injection Fertilization/Intravaginal Culture (ICSI/IVC) procedures. The INVOcell Culture Device is indicated for use with the INVOcell Retention Device. The INVOcell Culture Device is not indicated for incubation periods exceeding 120h.The INVOcell Retention Device is indicated for use with the INVOcell Culture Device to aid in retention of the INVOcell Culture Device in the vaginal cavity during the incubation period. The	The INVOcell Intravaginal Culture System consists of the following components:The INVOcell Culture Device is indicated for use in preparing, holding, and transferring human gametes or embryos during In Vitro Fertilization/Intravaginal Culture (IVF/IVC) and Intra-cytoplasmic Sperm Injection Fertilization/Intravaginal Culture (ICSI/IVC) procedures. The INVOcell Culture Device is indicated for use with the INVOcell Retention Device and the INVOcell Holding Block. The INVOcell Culture Device is not indicated for incubation periods exceeding 72h.The INVOcell Retention Device is indicated for use with the INVOcell Culture Device to aid in retention of the INVOcell Culture Device in the vaginal cavity during the incubation period. The	The indications for use statements for the subject and predicate devices are not identical; however, the intended uses of the subject and predicate devices are the same.

	indicated for use exceeding 120h.	INVOcell Retention Device is not indicated for use exceeding 72h.The INVOcell Holding Block is indicated for use with the INVOcell Culture Device to aid in temperature maintenance of the INVOcell Culture Device during loading and collection procedures and to aid in positioning and observation of the INVOcell Culture Device during human gamete/embryo loading and collection procedures.
Components	Inner chamber, outside rigid shell, retention device	Inner chamber, outside rigid shell, retention device, holding block	Different: The subject device does not include a holding block. Differences in components do not raise different questions of safety and effectiveness (S&E).
FullyAssembledDimensions	1.8" length x 1.1" diameter	1.8" length x 1.1" diameter	Same
Sterilization	Gamma sterilized	Gamma sterilized	Same
Endotoxin(LAL)	< 20 EU/device	< 20 EU/device	Same
MouseEmbryo Assay	One-cell: ≥ 80% reaching the expanded blastocysts at 120 h	Two-cell: ≥ 80% hatched/expanded blastocysts at 72 h	Different: The subject device uses the one-cell system, and the testing time is longer than that of the predicate device. The differences identified in MEA methods do not raise different questions of S&E.
VaginalIncubationPeriod	120 hours	72 hours	Different: The subject device has a longer vaginal incubation time than the predicate device. Differences in the vaginal incubation time do not raise different questions of S&E.
CultureConditions	0.7 ml of IVF culture medium with mineral oil overlay	1.08 ml of IVF culture medium	Different: The culture conditions for the subject device include a lower volume of medium and a mineral oil overlay. Differences in the culture conditions do not raise different questions of S&E.
Shelf-Life	6 years	3 years	Different: The subject device has a longer shelf-life than
		the predicate device.Differences in shelf-life donot raise different questionsof S&E.

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As shown in the table above, there are differences in the indications for use statements and technological characteristics of the subject and predicate devices. However, as stated in the table, the differences in indications for use do not represent a new intended use and the differences in technological characteristics do not raise different questions of safety and effectiveness.

V. Summary of Non-Clinical Performance Testing

The following non-clinical performance testing was conducted on the INVOcell Culture Device:

Shelf-Life Testing – The following testing was conducted following real-time aging in support of the six-year device shelf-life:
- Mouse Embryo Assay (MEA) per the 2021 FDA guidance Mouse Embryo Assay for Assisted o Reproduction Technology Devices: 1-Cell MEA: ≥80% embryos developed to expanded blastocyst at 120h.
- Seal Integrity Testing: No contamination inside and outside the vessel after 120h of O incubation.
- o pH Stability: pH of test medium in device remained within the specified range after 120h of incubation.
- Vessel Wall Optical Clarity: No obscured views after 120h of incubation. O
Sterilization Validation – The gamma irradiation sterilization methods for the predicate device (ISO 11137:2006) are being relied on in support of this submission.
Packaging Integrity Testing was conducted after accelerated aging. Testing included bubble leak testing (ASTM F2096) and seal strength testing (ASTM F88) on the INVOcell packaging to qualify the 6-year expiration date.

VII. Summary of Clinical Performance Testing

Two clinical studies were conducted to support extension of the culture duration to 120 hours, the revised culture conditions, and substantial equivalence to the predicate device. A summary of the two studies are shown below:

Study 1: INVOcell Culture System Comfort and Retention

This was a single center, open label trial to evaluate Comfort and Retention of the INVOcell Intravaginal Culture System during 120 hours of intravaginal incubation. After device removal and final speculum exam, study participants also completed a questionnaire to assess their discomfort, device expulsion, or incidence of vaginal discharge, spotting, or itching during the 5-day use of the subject device. There were no reports of INVOcell Culture Device expulsion in the 29 subjects evaluated. One subject reported the system was felt to be dislodged and the subject successfully readjusted the device to maintain the system in place. This results in an overall retention rate of 96%, which demonstrated the INVOcell Retention Device performed as intended.

There were no clinically relevant vaginal findings (e.g., lesions, ulcerations, erythema, or bleeding) identified after device wearing for 120 hours. These results demonstrated the safety of wearing the device for the longer 120 hour duration.

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Study #2: Retrospective Analysis of the INVOcell Culture System (IVC) in Comparison with traditional IVF and ICSI for 5 Day Incubation

This was a multicenter, retrospective cohort study that compared safety and effectiveness of the INVOcell Culture System (IVC/IVF and IVC/ICSI) to traditional IVF and ICSI procedures for 5 Day incubation. The study provided real-world evidence to support the expanded indication to 120h incubation and use of the revised device loading procedure, including a lower medium volume and a mineral oil overlay. Data was collected from four fertility clinics in the U.S. for the 3-year period of January 2017 to December 2019.

The data collection effort was focused on evaluating the outcomes of INVOcell day 5 transfer (IVC/IVF and IVC/ICSI) compared to historical outcomes of INVOcell day 3 transfer (IVC/IVF and IVC/ICSI). Rates of embryo development to the designated stage were also examined after day 5 incubation.

The four sites contributed a total of 240 fresh embryo transfers in the INVOcell arm (IVC/IVF and IVC/ICSI) and 685 fresh embryo transfers in the traditional IVF and ICSI arm. Patient demographics and fertility diagnoses were comparable between both cohorts.

Effectiveness

When comparing the data of day 3 INVOcell (IVC/IVF and IVC/ICSI) using the original loading procedure to day 5 INVOcell (IVC/IVF and IVC/ICSI), which used the revised loading methods, the day 5 embryo development is more advanced, and the clinical pregnancy and live birth rates are higher for day 5 incubation in the INVOcell device for both IVF and ICSI cohorts.

While the INVOcell ICSI (IVC/ICSI) method produced lower rates of embryos developed to the blastocyst stage than traditional ICSI produced, the rates of embryos developed to the blastocyst stage using the IVC/IVF and traditional IVF methods were similar. The rates of embryo transfer, clinical pregnancy, implantation, miscarriage, live birth, and pre-term birth using the IVC/ICSI methods were similar to the day 5 traditional IVF and ICSI methods. The data supports that embryos suitable for transfer can be formed by incubation in the INVOcell device with 120h incubation and use of the revised device loading methods.

Safety

The type of maternal and offspring adverse events experienced in both the IVC (IVF and ICSI) cohort and traditional IVF and ICSI cohort were similar. There were a total of 2 birth defects reported in 2 subjects in the IVC (IVF and ISCI) cohort (out of 104 births with known outcomes) and 9 birth defect in 9 subjects in the traditional IVF and ICSI cohort (out of 273 births with known outcomes). The data supports that incubation in the INVOcell device with 120h incubation and use of the revised device loading methods did not result in increased adverse events or outcomes.

VIII. Conclusion

The results of the performance testing described above demonstrate that INVOcell Culture System is as safe and effective as the predicate device and supports a determination of substantial equivalence.

Regulation Number and Section

§ 884.6165 Intravaginal culture system.

(a)
Identification. An intravaginal culture system is a prescription device intended for preparing, holding, and transferring human gametes or embryos during intravaginal in vitro fertilization or intravaginal culture procedures.(b)
Classification. Class II (special controls). The special controls for this device are:(1) Clinical performance testing must demonstrate the following:
(i) Comfort and retention of the intravaginal culture device;
(ii) Adverse vaginal tissue reactions associated with intravaginal culture;
(iii) Maximum number of gametes and/or embryos that can be placed in a device; and
(iv) Rates of embryo development to the designated stage, implantation rates, clinical pregnancy rates, live birth rates, and any adverse events or outcomes.
(2) Nonclinical performance testing must demonstrate that the device performs as intended under anticipated conditions of use. The following performance characteristics must be demonstrated:
(i) Mouse embryo assay testing to assess embryotoxicity by evaluating the gamete and embryo-contacting device components effect on the growth and development of mouse embryos to the blastocyst stage;
(ii) Endotoxin testing on gamete and embryo-contacting components of the device;
(iii) Cleaning and disinfection validation of reusable device components;
(iv) Sterility maintenance of the culture media within the device throughout the vaginal incubation period and subsequent embryo extraction; and
(v) Ability of the device to permit oxygen and carbon dioxide exchange between the media contained within the device and the external environment throughout the vaginal incubation period.
(3) The patient-contacting components of the device must be demonstrated to be biocompatible.
(4) Performance data must demonstrate the sterility of the device components intended to be provided sterile.
(5) Shelf life testing must demonstrate that the device maintains its performance characteristics and the packaging of device components labeled as sterile maintain integrity and sterility for the duration of the shelf life.
(6) Labeling for the device must include:
(i) A detailed summary of the clinical testing, including device effectiveness, device-related complications, and adverse events;
(ii) Validated methods and instructions for reprocessing of reusable components;
(iii) The maximum number of gametes or embryos that can be loaded into the device;
(iv) A warning that informs users that the embryo development is first evaluated following intravaginal culture; and
(v) A statement that instructs the user to use legally marketed assisted reproductive technology media that contain elements to mitigate the contamination risk (
e.g., antibiotics) and to support continued embryonic development over the intravaginal culture period.(7) Patient labeling must be provided and must include:
(i) Relevant warnings, precautions, and adverse effects and complications;
(ii) Information on how to use the device;
(iii) The risks and benefits associated with the use of the device; and
(iv) A summary of the principal clinical device effectiveness results.