The INVOcell Culture Device is indicated for use in preparing, holding, and transferring human gametes or embryos during In Vitro Fertilization/Intra Vaginal 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 INVOcell Retention Device is not indicated for use exceeding 72 hours.

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.

Device Description

The INVOcell Intravaginal Culture System is comprised of three parts: the INVOcell Intravaginal Culture Device, the INVOcell Retention Device, and the INVOcell Holding Block. All devices are designed to be utilized together.

INVOcell Intravaginal Culture Device: a single-use plastic container that serves to house and protect the gametes and/or embryos during intravaginal culture. It is provided sterile. The culture device consists of two components: the inner chamber and the outer shell.

INVOcell Retention Device: aids in the retention of the INVOcell Intravaginal Culture Device during incubation in the vagina. It is a single-use device that is provided nonsterile. The device is a cup-shaped silicone piece that includes to allow flow of vaginal secretions. The device comes in four sizes (65, 70, 75, and 80 mm). It is accompanied by a fitting kit, which is utilized to determine the appropriate diameter of the INVOcell Retention Device to ensure appropriate retention, and is intended to be reprocessed.

INVOcell Holding Block: designed to hold and maintain temperature of the inner vessel of the INVOcell Intravaginal Culture Device during loading and retrieval procedures. The block does this passively by serving as a heat sink. Prior to use, the block is preheated to body temperature. The block then can be utilized to hold the Intravaginal Culture Device inner vessel, and will maintain appropriate temperature for short periods of time. The block is solid stainless steel, with a conical hole in the top for the inner vessel. The block also includes a glass window on the side, to allow viewing of the embryos in the inner vessel during retrieval.

AI/ML Overview

Here's an analysis of the acceptance criteria and the studies that prove the device meets them, based on the provided text:

Key Takeaways:

Device: INVOcell Intravaginal Culture System, comprising the INVOcell Culture Device, INVOcell Retention Device, and INVOcell Holding Block.
Purpose: Intended for preparing, holding, and transferring human gametes or embryos during intravaginal in vitro fertilization (IVF) or intravaginal culture (IVC) procedures.
Approval Basis: FDA De Novo classification. This means there was no existing predicate device, so the manufacturer had to demonstrate safety and effectiveness.
Study Types: Primarily non-clinical bench studies and two clinical studies.

1. Table of Acceptance Criteria and Reported Device Performance

The provided text has an excellent table summarizing the non-clinical/bench studies, their purpose, methods, acceptance criteria, and results. I will reproduce key parts of that table and also synthesize clinical performance criteria from the "Special Controls" section.

Acceptance Criteria and Reported Device Performance for INVOcell Intravaginal Culture System

Test Category	Specific Test	Acceptance Criteria	Reported Device Performance and Results
Non-Clinical/Bench Studies
Sterilization, Cleaning, Disinfection	Sterilization (Culture Device)	Sterility Assurance Level (SAL) shall be 10^-6	Passed
	Reprocessing (Holding Block)	>6-log10 reduction in microorganism counts	Passed
Biocompatibility	Cytotoxicity	Not explicitly stated (implied: non-cytotoxic)	Grade 0 (non-cytotoxic)
	Rabbit Muscle Implantation	Not explicitly stated (implied: no significant toxic effects)	No significant difference from negative control (no signs of toxic response)
	Vaginal Irritation	Not explicitly stated (implied: no irritation)	No signs of macroscopic or microscopic irritation from polar and non-polar extracts
	Sensitization	Not explicitly stated (implied: no sensitization)	No signs of sensitization from polar and non-polar extracts
	Acute Systemic Toxicity	Not explicitly stated (implied: no systemic toxicity)	No evidence of mortality or systemic toxicity from test material extracts
Bench Testing	Volumetric Capacity	Inner vessel volume shall meet specification, and no bubbles or air pockets shall be formed during filling	Passed. No bubbles or air pockets were observed.
	Fluid Contact Surface Finish	No surface imperfections ≥ 50 microns shall be observed	Passed
	Illumination and Optical Properties	Not explicitly stated (implied: ability to observe embryos)	No obscured views, 89% of samples scored 5/5, 11% were 4/5.
	Temperature Maintenance	Media inside inner vessel shall maintain a temperature of >34°C for >10 minutes	Passed; Block maintains temperature of inner vessel (>34°C) for 12 minutes.
	pH Maintenance	pH shall remain within ±0.2 of controls (legally marketed ART labware)	Passed
	Seal Integrity	Culture media within the inner vessel shall remain sterile during incubation and extraction	Passed; 30/30 samples maintained culture media sterility during incubation and extraction.
	Mouse Embryo Assay (Embryo compat.)	>80% embryos shall reach expanded blastocyst stage	Passed; >90% of embryos reached expanded blastocyst stage.
	Endotoxin Testing	The endotoxin level shall be < 20 EU/mL	Passed; < 2.4 EU/device.
Shelf Life	Package Integrity (Bubble emission)	Not explicitly stated (implied: no bubbles)	No bubbles observed in 30 samples.
	Package Integrity (Visual inspect.)	Not explicitly stated (implied: no channels)	No channels observed in 60 samples.
	Physical testing of seals (Peel)	Not explicitly stated (implied: sufficient seal strength)	Seal strengths were in excess of 1.63 lbf/in.
	Mouse Embryo Assay (end of shelf)	>80% of embryos shall reach the blastocyst stage	Passed, >90% reached blastocyst stage.
	pH maintenance (end of shelf)	pH shall remain within ±0.2 of the control	Passed
	Clarity of vessel wall (end of shelf)	Ability to identify and count embryos accurately	Passed
	Seal integrity (end of shelf)	Culture media within the inner vessel shall remain sterile during incubation and extraction (worst-case scenario)	Passed; 30/30 samples maintained culture media sterility during incubation and extraction.
Clinical Performance Testing (from Special Controls)
Performance Characteristics	Comfort and retention of device	Demonstrated retention and minimal discomfort (implied based on study results)	Study 2: Retention for 72hr in 25/29 subjects (100% with Retention Device). Majority reported minimal discomfort.
	Adverse vaginal tissue reactions	Demonstrated absence of significant reactions (implied based on study results)	Study 2: No reports of erythema, ulceration, or lesions.
	Maximum number of gametes/embryos	Indicated for up to 7 oocytes/embryos (based on clinical data supporting this limit)	Majority of clinical data < 5 oocytes/embryos, but up to 7 used with live births.
	Rates of embryo development, imp., pregnancy, live birth, AEs	Comparable to conventional ART (implied acceptable rates and no device-related serious AEs)	Study 1: Fertilization (64.6-78.5%) and cleavage (63.1-77.1%) rates comparable to literature. Good quality embryo rate 61.5%. Clinical pregnancy rate 33.4%, Birth Rate 23.9%. No device-related serious or non-serious AEs.

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

Non-Clinical/Bench Studies:

Sample sizes vary per test (e.g., 30 samples for seal integrity, 9 INVOcell devices for mouse embryo assay).
Data provenance is retrospective as these are lab tests performed by the manufacturer to establish device performance under controlled conditions. The country of origin is not specified but would be where the manufacturer's R&D/testing facilities are located, presumably the USA given the FDA De Novo filing.

Clinical Studies:

Study 1: INVOcell OUS Safety and Efficacy
- Test Set Sample Size: 450 total cycles (310 IVF, 140 ICSI) involving a total of 442 subjects. This is the pooled data across all sites.
  - Lima, Peru: 134 subjects / 138 cycles (IVF only)
  - Bogota, Colombia: 220 subjects / 225 cycles (125 IVF / 100 ICSI)
  - Sao Paulo, Brazil: 40 subjects / 40 cycles (20 IVF / 20 ICSI)
  - Cochabamba, Bolivia: 48 subjects / 48 cycles (IVF only)
- Data Provenance: Prospective clinical investigations conducted at assisted reproductive facilities in Peru, Colombia, Bolivia, and Brazil.
- For comparison of fertilization, cleavage, and embryo quality, data was compared against retrospective literature reports (Bergh et al. for fertilization/cleavage, Lundin et al. for embryo quality).
Study 2: INVOcell Intravaginal Culture Device Comfort and Retention Study
- Test Set Sample Size: 29 women.
  - 12 women used the Intravaginal Culture Device + Retention Device.
  - 17 women used the Intravaginal Culture Device alone.
- Data Provenance: Non-random, prospective study, country of origin not specified, but likely where primary clinical trials were conducted (e.g., US or one of the OUS sites).

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

Non-Clinical/Bench Studies: The "ground truth" here is objective measurement by qualified lab personnel following standardized protocols (e.g., ISO, ASTM, USP standards). The number and specific qualifications of these experts are not detailed in the text but are inherent to regulatory-compliant lab testing.
Clinical Study 1:
- Ground Truth: Clinical outcomes (fertilization, cleavage, embryo quality, clinical pregnancy rate, miscarriage rate, birth rate).
- Experts: The clinical investigations were conducted by "physicians with expertise in assisted reproductive technology and techniques including oocyte retrieval, clinical embryology, and embryo transfer." The specific number of experts per site or their years of experience are not provided, but the description implies highly qualified fertility specialists. The reported literature (Bergh et al., Lundin et al.) represents consensus in the field (published research) rather than real-time expert adjudication of the INVOcell data.
Clinical Study 2:
- Ground Truth: Patient-reported comfort and objective observation of device retention/expulsion.
- Experts: The study was conducted by clinicians, but the "ground truth" for comfort was self-reported by the 29 women, and retention was observed by clinical staff. No specific expert adjudication process is described beyond the reporting of clinical observations.

4. Adjudication Method for the Test Set

Non-Clinical/Bench Studies: Adjudication is generally not applicable in this context. Results are driven by objective measurements and adherence to acceptance criteria/standards.
Clinical Study 1 (OUS Safety and Efficacy): No formal adjudication method (e.g., 2+1) for clinical outcomes is explicitly described. The outcomes (fertilization, cleavage, pregnancy, birth rates) were calculated from the pooled data collected at the investigational sites. The comparison was against published literature, not simultaneous "gold standard" expert-adjudicated controls from the study.
Clinical Study 2 (Comfort and Retention): No formal adjudication method is mentioned. Retention was observed, and comfort was self-reported by patients.

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 an intravaginal culture system, a physical medical device, not an AI or imaging diagnostic tool that involves "human readers" or AI assistance in interpretation. The provided text does not mention any AI components or MRMC studies.

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

No, a standalone (algorithm only) performance study was not done.
As noted above, this device is a physical system for culturing embryos, not an algorithm.

7. The Type of Ground Truth Used

Non-Clinical/Bench Studies: The ground truth was based on objective measurements and adherence to established and validated laboratory standards (e.g., ISO, ASTM, USP) for sterility, biocompatibility, physical properties, pH, and embryo compatibility (Mouse Embryo Assay).
Clinical Study 1 (OUS Safety and Efficacy):
- Clinical Outcomes Data: The ground truth for effectiveness was derived from observed clinical outcomes such as fertilization rates, cleavage rates, embryo quality assessments (performed by embryologists at the clinical sites), clinical pregnancy rates, miscarriage rates, and live birth rates.
- Expert Consensus/Literature: Comparisons for fertilization, cleavage, and embryo quality were made against published literature/expert consensus from studies by Bergh et al. and Lundin et al.
Clinical Study 2 (Comfort and Retention): The ground truth was a combination of patient self-reported discomfort and observed device retention/expulsion by clinical staff.

8. The Sample Size for the Training Set

Not applicable in the context of this device. A "training set" typically refers to data used to train machine learning algorithms. This device is a physical medical device, not an AI system.
For the non-clinical and clinical studies, there isn't a "training set" in the AI sense. The studies are designed to demonstrate performance and safety. The clinical studies establish the safety and effectiveness of the device as used in a real-world setting.

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

Not applicable for this device. As explained above, there is no AI component or "training set" in the sense used for machine learning.

Summary

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DE NOVO CLASSIFICATION REQUEST FOR INVOCELL™ INTRAVAGINAL CULTURE SYSTEM

REGULATORY INFORMATION

FDA identifies this generic type of device as:

Intravaginal Culture System: 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.

NEW REGULATION NUMBER: 21 CFR 884.6165

CLASSIFICATION: II

PRODUCT CODE: OYO

BACKGROUND

DEVICE NAME: INVOCELL INTRAVAGINAL CULTURE SYSTEM

SUBMISSION NUMBER: DEN150008

DATE OF DE NOVO: FEBRUARY 23, 2015

CONTACT: INVO BIOSCIENCE C/O LORI KAHLER THE RC INSIGHT GROUP 743 PASSAIC AVE., SUITE 147 CLIFTON, NJ 07012

REQUESTER'S RECOMMENDED CLASSIFICATION: II

INDICATIONS FOR USE

The INVOcell Intravaginal Culture System consists of the following components:

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

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incubation period. The INVOcell Retention Device is not indicated for use exceeding 72 hours.

LIMITATIONS

The sale, distribution, and use of the device are restricted to prescription use in accordance with 21 CFR §801.109.

The INVOcell Intravaginal Culture Device is indicated to be utilized as part of a system. It is not indicated to be utilized independently of the INVOcell Retention Device and the INVOcell Holding Block.

The device was evaluated for up to 72 hours of incubation. It is not indicated for incubation periods to exceed 72 hours. No data were provided to support longer incubation times.

The INVOcell Intravaginal Culture Device and INVOcell Retention Device are singleuse only. The only components able to be reprocessed are the INVOcell Holding Block and the Retention Device fitting kit.

The INVOcell procedure should only be performed by physicians with expertise in assisted reproductive technology and techniques including oocyte retrieval, clinical embryology, and embryo transfer, and with access to all necessary equipment (listed in the Instructions for Use).

The culture media utilized with the device should have phenol red to aid in the determination of acceptable pH maintenance and antibiotics to mitigate possible contamination of media in the inner chamber.

The INVOcell devices should be handled in an aseptic fashion to reduce the risk of contamination of the culture media.

The device should only house up to 7 oocytes or embryos. The majority of clinical data consisted of cases where < 5 oocytes or embryos were utilized. However, there were cases in which up to 7 were utilized, and live births resulted from the embryos collected.

The INVOcell Intravaginal Culture Device is only compatible with embryo retrieval catheters with tip outer diameters from 1.0mm to 1.85mm.

PLEASE REFER TO THE LABELING FOR A MORE COMPLETE LIST OF WARNINGS, PRECAUTIONS AND CONTRAINDICATIONS.

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DEVICE DESCRIPTION

INVOcell Intravaginal Culture Device

The INVOcell Intravaginal Culture Device is a single-use plastic container that serves to house and protect the gametes and/or embryos during intravaginal culture. It is provided sterile. The culture device consists of two components: the inner chamber and the outer shell (Figure 1).

Image /page/2/Figure/4 description: The image shows three diagrams of a device, labeled as "Inner Chamber", "Outer Shell", and "Combined". The "Inner Chamber" diagram shows a schematic of the inner components, with labels pointing to the rotating valve and micro chamber. The "Outer Shell" diagram shows a transparent outer shell. The "Combined" diagram shows an exploded view of the device, with labels pointing to the top part of the outer rigid shell, the locking system, and the bottom part of the outer rigid shell.

Figure 1: Schematic/Picture of the INVOcell Intravaginal Culture Device, showing the inner chamber, outer shell and combined.

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

The outer shell serves to protect the inner vessel from the vaginal environment. The inner vessel fits into the bottom portion of the outer shell. The top portion of the outer shell can then be screwed onto the bottom portion. A silicone O-ring separates the bottom and top portions of the outer shell, and aids in reducing contamination of the inner vessel.

INVOcell Retention Device

The INVOcell Retention Device (Figure 2) aids in the retention of the INVOcell Intravaginal Culture Device during incubation in the vagina. It is a single-use device that is provided nonsterile. The device is a cup-shaped silicone piece that includes to allow flow of vaginal secretions. The device comes in four sizes (65, 70, 75, and 80 mm). It is accompanied by a fitting kit, which is utilized to determine the appropriate diameter of the INVOcell Retention Device to ensure appropriate retention, and is intended to be reprocessed.

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Image /page/3/Picture/0 description: The image shows two different views of a hemispherical object with holes. The image on the left shows a light pink object with several circular holes on its surface. The object appears to be made of plastic and has a smooth, rounded shape. The image on the right shows a similar object, but it is in black and white and has a different internal structure. The object appears to be made of a different material and has a more complex design.

Figure 2: Picture of the INVOcell Retention Device and the combined INVOcell Intravaginal Culture Device situated inside the INVOcell Retention Device.

INVOcell Holding Block

The INVOcell Holding Block (Figure 3) is designed to hold and maintain temperature of the inner vessel of the INVOcell Intravaginal Culture Device during loading and retrieval procedures. The block does this passively by serving as a heat sink. Prior to use, the block is preheated to body temperature. The block then can be utilized to hold the Intravaginal Culture Device inner vessel, and will maintain appropriate temperature for short periods of time. The block is solid stainless steel, with a conical hole in the top for the inner vessel. The block also includes a glass window on the side, to allow viewing of the embryos in the inner vessel during retrieval.

Image /page/3/Picture/4 description: The image shows a rectangular metal block with several holes. There is a large circular hole in the center of the block, with a smaller hole inside it. On either side of the central hole, there are two smaller circular holes. There is a white, cylindrical object on top of the block.

Figure 3: Picture of the INVOcell Holding Block

Device Usage

In the INVOcell procedure, gametes (for IVF) or intracytoplasmic sperm injected (ICSI) embryos are deposited into the Intravaginal Culture Device inner vessel when the inner vessel is held vertically with the aid of a pre-warmed Holding Block. Once the gametes or embryos are within the inner vessel, the inner vessel is closed and placed within the outer shell. The complete Intravaginal Culture Device is inserted into the patient's vagina, and the Retention Device is placed proximal to the Culture Device in the vagina to ensure the Intravaginal Culture Device stays in place. The devices are left in the vagina for 72 hours, where fertilization and/or development of the embryos occurs. At 72 hours, the retention device and Intravaginal Culture Device are removed from the patient. The Retention Device and the outer shell of the Intravaginal Culture Device are discarded, and the inner vessel is placed into a pre-warmed Holding Block. The embryos are then extracted from the inner vessel via a retrieval catheter, washed and graded Embryos may then be utilized for transplantation, or may be stored for use later.

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For complete detailed instructions, refer to the Instructions for Use.

SUMMARY OF NONCLINICAL/BENCH STUDIES

Test	Purpose	Methods	AcceptanceCriteria	Results
Sterilization, Cleaning, and Disinfection
Sterilization	Evaluate the sterility level ofdevice components providedsterile (outer shell and innervessel of the IntravaginalCulture Device)	ISO 11137:2006Sterilization ofHealthcare Products	The sterilityassurance level(SAL) shall be10-6	Passed
Reprocessing:cleaning anddisinfectionvalidation	Evaluate the cleaning anddisinfection protocols forreprocessed components(Holding Block) to ensure thatbacterial contamination is nottransferred between used andnew devices	Holding blocks weresoiled with test soil,and cleaned anddisinfected per theinstructions for use.After cleaning anddisinfection, surfacesof the devices wereswabbed and testedfor the presence ofmicroorganisms	Greater than 6-log10 reductioninmicroorganismcounts	Passed
Biocompatibility
Cytotoxicity	Determine if the IntravaginalCulture Device or RetentionDevice polar and non-polarextracts elicit a cytotoxicresponse	ISO 10993-5 Tests forCytotoxicity: in vitrob(4)method; Performed onIntravaginal CultureDevice and RetentionDevice		Grade 0 (non-cytotoxic)
Rabbit MuscleImplantation	Determine the toxic effects ofthe Intravaginal Culture Deviceor Retention Device in directcontact with living tissue	ISO 10993-6: Testsfor Local Effects afterImplantation;Performed onIntravaginal CultureDevice and RetentionDevice		No significantdifference fromnegative control(no signs oftoxic response)
VaginalIrritation	Determine if polar and non-polar extracts of theIntravaginal Culture Device orRetention Device elicit ahypersensitive response	ISO 10993-10:Biological Evaluationof Medical Devices:Tests for Irritation andSensitization;Performed onIntravaginal CultureDevice and RetentionDevice	-	No signs ofmacroscopic ormicroscopicirritation frompolar and non-polar extracts

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Sensitization	Determine if polar and non-polar extracts of theIntravaginal Culture Device orRetention Device cause ahypersensitive response	ISO 10993-10:Biological Evaluationof Medical Devices:Tests for Irritation andDelayed TypeHypersensitivity;Performed onIntravaginal CultureDevice and RetentionDevice	-	No signs ofsensitizationfrom polar andnon-polarextracts
Acute SystemicToxicity	Determine if polar and non-polar extracts of theIntravaginal Culture Device areacutely systemically toxic	ISO 10993-11:Biological Evaluationof Medical DevicesTests for SystemicToxicity;Intravaginal CultureDevice	-	No evidence ofmortality orsystemictoxicity fromtest materialextracts
Bench Testing
VolumetricCapacity	Determine if the inner vesselchamber meets volumespecifications and if it can befilled without formation of airbubbles. This test ensures thatbubbles/air pockets are notformed, which may damage theembryos during incubation.	Inner vessels werefilled to overflow withwater, closed, andblotted dry. Sampleswere observed duringfilling for bubbleformation. The waterin the filled vesselswas extracted andweighed.	Inner vesselvolume shallmeetspecificationand no bubblesor air pocketsshall beformed duringfilling	Passed. Nobubbles or airpockets wereobserved
Fluid ContactSurface Finish	Determine the quality of thesurface finish of the surface ofthe inner vessel in contact withmedia to ensure that embryosare not exposed to roughsurfaces, leading them to"stick" to the vessel walls.	Impression media wasused to create replicasof the surfaces ofinner vessels.Scanning electronmicroscopy utilized tovisualize the replicasurfaces.	No surfaceimperfections≥ 50 micronsshall beobserved	Passed
Illumination andOpticalProperties	Evaluate if embryos can beobserved post-incubationthrough the illumination port ofthe Holding Block to ensurethat embryos are appropriatelyaccounted for after incubationand during extraction.	90 micronmicrospheres b(4)Microspheresolution was added tothe inner vessels ofthe IntravaginalCulture Device, whichwere placed in theHolding Block.Microspheres wereobserved at 12positions and given a		No obscuredviews, 89% ofsamples werescored 5/5, 11%were 4/5.

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TemperatureMaintenance ofHolding Block	Evaluate the time required toheat the Holding Block and theheat retention time to ensurethat embryo media maintainsappropriate temperature duringloading and extractionprocedures.	clarity.Blocks were heated to37C and allowed tocool. Temperature ofthe media within theinner vessel wasmonitoredcontinuously	Media insideinner vesselshall maintaina temperatureof >34°C for>10 minutes toallow foradequateprocedure time	Passed; Blockmaintainstemperature ofinner vessel ofthe IntravaginalCulture Device(>34 C) for 12minutes
pH maintenance	Determine if media maintainspH during the incubation periodto ensure that embryos are notexposed to damaging changesin pH during incubation.	pH of media(containing gametes)within the inner vesselof the IntravaginalCulture Device wasmonitored over asimulated incubationperiod of 72 hours	pH shallremain within±0.2 of thecontrols(legallymarketedassistedreproductionlabware)	Passed
Seal integrity	Determine the device's abilityto resist bacterial ingress andmaintain sterility of the culturemedia during incubation andextraction to ensure embryoswill not be exposed to bacteriaduring vaginal incubation.	Sterile bacterial mediawas deposited in theinner vessels of theIntravaginal CultureDevices. b(4)	Culture mediawithin theinner vesselshall remainsterile duringincubation andextraction	Passed; 30/30samplesmaintainedculture mediasterility duringincubation andextraction
Mouse EmbryoAssay (Embryocompatibility)	Determine if the device iscompatible with embryos	Twenty-one 2-cellembryos wereincubated in each of 9(3 samples from 3lots) INVOcellIntravaginal CultureDevices for 72 hours.Legally marketedassisted reproductionlabware were used asthe control (n=3).	>80% embryosshall reachexpandedblastocyststage	Passed; >90%of embryosreachedexpandedblastocyst stage

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		embryos were scoredfor development
EndotoxinTesting	Determine if bacterialendotoxins are withinacceptable limits to ensure thatembryos are not exposed tohigh levels of endotoxins	USP 31 NF 26 2008<85> BacterialEndotoxins Test	The endotoxinlevel shall be <20 EU/mL	Passed; < 2.4EU/ device
Shelf Life
Packageintegrity (Bubbleemission leaktest)	Evaluate the sterile packagingintegrity to ensure that devicesremain sterile throughout theshelf-life	ASTM F2096-11	-	No bubblesobserved in 30samples
Packageintegrity (visualinspection)	Evaluate the sterile packagingintegrity to ensure that devicesremain sterile throughout theshelf-life	ASTM F1886-09	-	No channelsobserved in 60samples
Physical testingof seals (peelstrength)	Evaluate the sterile packagingintegrity to ensure that devicesremain sterile throughout theshelf-life	ASTM F88-09	-	Seal strengthswere in excessof 1.63 lbf/in
Mouse embryoassay	Evaluate the embryocompatibility of the device atthe end of shelf-life to ensurethe device maintains embryocompatibility at the end of shelflife	Twenty-one 2-cellembryos wereincubated in each of 9(3 samples from 3lots) INVOcellIntravaginal CultureDevices for 72 hours.Legally marketedassisted reproductionlabware were used asthe control (n=3).After 72 hours,embryos were scoredfor development	>80% ofembryos shallreach theblastocyststage	Passed, >90%reachedblastocyst stage
pH maintenance	Evaluate media pH during theincubation period to ensure thatthe devices retain their pH-maintaining properties at theend of the shelf life. This test isan indicator for the CO2permeability of the device.	Twenty-one 2-cellembryos wereincubated in each of 9(3 samples from 3lots) INVOcellIntravaginal CultureDevices for 72 hours.The pH of the mediawithin the vesselsafter incubation wasmeasured with anelectrochemical probe.Legally marketedassisted reproductionlabware were used ascontrols.	pH shallremain within±0.2 of thecontrol	Passed

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Clarity of vessel wall	Evaluate the clarity of the vessel wall at the end of the shelf-life to ensure that aging of the plastic does not adversely affect the ability to count embryos	After incubation of mouse embryos during the Mouse Embryo Assay, visually inspect the inner vessels of the Intravaginal Culture Devices and count the number of embryos	Ability to identify and count embryos accurately	Passed
Seal integrity	Determine the device's ability to resist bacterial ingress and maintain sterility of the culture media during incubation and extraction in worst-case scenario (immersion in bacterial broth) at the end of shelf-life	Sterile bacterial media was deposited in the inner vessels of the Intravaginal Culture Devices. Ten samples each from three lots were tested. b(4)	Culture media within the inner vessel shall remain sterile during incubation and extraction	Passed; 30/30 samples maintained culture media sterility during incubation and extraction

SUMMARY OF CLINICAL INFORMATION

The sponsor performed two clinical investigations to demonstrate a reasonable assurance of safety and effectiveness for the INVOcell Intravaginal Culture System.

Study 1: INVOcell Outside the US (OUS) Safety and Efficacy

Objective of the study

Evaluate rate of fertilization (IVF only), embryo quality, successful transfer rates, and live birth rates resulting from embryos incubated using the INVOcell device.

Methods

The sponsor conducted clinical investigations at assisted reproductive facilities in Peru, Colombia, Bolivia, and Brazil. The INVOcell devices (INVOcell Intravaginal Culture Device, Retention Device, and Holding Block) were utilized for both gamete incubation (IVF) and intracytoplasmic sperm injection (ICSI). In all cases, a mild ovarian stimulation protocol was utilized to harvest oocytes. The study population is summarized in Table 1 below:

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Site	Number ofSubjects	IVF cycles/ICSI cycles/Total Cycles	AgeRange	AverageAge
Lima, Peru	134	138/0/138	36-43	35
Bogota,Colombia	220	125/100/225	21-45	34
Sao Paulo, Brazil	40	20/20/40	29-44	35
Cochabamba,Bolivia	48	48/0/48		34

Table 1: Study Population at OUS sites in INVOcell Safety and Efficacy Study

Results

Effectiveness:

For comparison of effectiveness of the INVOcell device to traditional IVF and ICSI procedures, the sponsor pooled the results from the investigational sites. The sponsor examined embryo fertilization and cleavage rates, embryo quality, as well as the clinical outcomes resulting from transfer of embryos.

The fertilization and cleavage rates of embryos developed with the INVOcell devices was compared to a literature report by Bergh et al. in the journal Human Reproduction. which reports on fertilization and cleavage rates in traditional IVF and ICSI. Fertilization and cleavage rates from the Brazil site were unavailable, as the site did not create individual summary reports of each cycle. The comparison of fertilization and cleavage rates is summarized in Table 2 below:

	BerghIVF	INVOIVFTotal	INVOIVFColombia	INVOIVFPeru	INVOIVFBolivia	BerghICSI	INVOICSIColombia
Cycles	200	310	125	137	48	175	100
InseminatedOocytes	2,279	1,388	520	640	228	1,880	376
FertilizedOocytes	1,536	897	331	404	162	1,365	295
CleavedEmbryos	1,437	894	328	404	162	1,268	290
Fertilizationrate	67.3%	64.6%	63.7%	63.1%	71%	72.7%	78.5%
Cleavagerate	63.1%	64.4%	63.1%	63.1%	71%	67.4%	77.1%

Table 2: Fertilization and Cleavage Rates of Embryos from the INVO Procedure

1 Bergh C, Broden H, Lundin K, Hamberger L. Comparison of fertilization, cleavage and pregnancy rates of oocytes from large and small follicles. Hum Reprod, 1998; 13: 1912-15

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Fertilization rates and cleavage rates of embryos are not statistically different between the INVOcell incubated embryos and those reported in Bergh et al. for traditional IVF and ICSI. In addition, there is no statistical difference between IVF and ICSI fertilization and cleavage rates for the INVOcell procedure. However, there is less data available on ICSI cycles using INVOcell compared to IVF cycles using INVOcell. Overall, cleavage and fertilization data from embryos cultured in the INVOcell device supports that the INVOcell procedure can result in reasonable fertilization and cleavage rates.

The quality of embryos formed and/or incubated utilizing the INVOcell device were compared to results of a study conducted by Lundin et al. in the journal Reproduction.2 It is important to note that the quality of embryos is difficult to compare between centers and studies due to differences in grading systems. However, both the literature study and the INVO study sites utilized similar criteria for the scoring of embryos for quality, which included the grade of fragmentation, cytoplasmic appearance and number of blastomere per embryo. The embryo quality assessment is summarized in Table 3 below:

Embryo Quality	LundinIVF/ICSI	INVOIVF/ICSITotal	INVOIVF/ICSIColombia	INVOIVF/ICSIPeru	INVOIVFBolivia
Number of 6 cells, Grade 1 and 2	192	192	89	63	40
Number of 8 cells, Grade 1 and 2		462	224	191	47
Number of 10 cells or greater,Grade 1 and 2		74	51	16	7
Number of good quality embryos	4,496	728	364	270	94
Number of cleaved embryos	10,798	1,184	618	404	162
Good quality embryo rate	41.6%	61.5%	58%	66.8%	58%
Clinical pregnancy rate per cycle		137/41033.4%	7935.1%	4230.7%	1633.3%
Miscarriage rate	17.3%*	33/13724.1%	1519%	1433.3%	425%
Birth rate per cycle	27.8%	98/41023.9%	6328%**	2316.8%***	1225%

Table 3: Embryo quality after intravaginal incubation in INVOcell device

*Lundin et al. used an ovarian stimulation with a long protocol combining Gn-Rh agonist and FSH. This is in contrast to the mild ovarian stimulation protocol used in the INVOcell study.

**The outcome of one INVO/IVF was unknown.

***The outcome of 5 clinical pregnancies was unknown, which explains in part the low birth rate reported at the Peru site.

In general, embryos incubated with the INVOcell device were of good quality (i.e., being graded 1 or 2 with 6 to 8 cells at day 3). However, the rate of good quality embryos in INVOcell subjects could be due, in part, to the use of the mild ovarian stimulation protocol. The study by Lundin et al.

2 Lundin K, Bergh C, Hardarson T. Early embryo cleavage is a strong indicator of embryo quality in human IVF. Hum Reprod, 2001; 16: 2652-57

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did not utilize the same stimulation protocol. The author instead utilized a hyper-stimulation protocol, which may have resulted in more immature oocytes being harvested for IVF/ICSI, and therefore lower quality embryos. While direct comparisons are difficult given the differences in stimulation protocol, the data support that quality embryos can be produced from the INVOcell procedure at reasonable rates.

Effectiveness indicators such as clinical pregnancy rate, miscarrage rate, multiple pregnancy rate, and birth rates resulting from use of the INVOcell device are presented in Table 4 below:

	INVO cycles (IVF + ICSI)
Cycles	450
Clinical Pregnancies	146
Clinical Pregnancy Rate	32.4%
Miscarriage Rate	22.6%
Multiple Pregnancy Rate	15.1%
Birth Rate	23.8%
Multiple Birth Rate	17.8%
Triplet Births	6
Twin Births	13
Births from Singleton	88
Pregnancies
Triplet Pre-term Births (%)	6 (100%)
Twin Pre-term Births	7 (53.8%)
Singleton Pre-term Births from	0
Single Pregnancies
Pre-term Birth Rate	21.4%

Table 4: Pooled outcomes data from INVOcell clinical use

The relevant effectiveness of the INVOcell device is available to physicians as part of the INVOcell labeling.

Safety:

There were no observed device-related serious or non-serious adverse events associated with the use of the INVOcell Intravaginal Culture Device or the Retention Device during the study. Adverse pregnancy outcomes such as miscarriage and pre-term births were reported in the effectiveness section above as these are primarily related to the effectiveness of the device (i.e., the successful pregnancy and live birth rates).

Study 2: INVOcell Intravaginal Culture Device Comfort and Retention Study

Objective of the studv

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Evaluate the rates at which the INVOcell Intravaginal Culture Device is lost from the vagina during incubation with and without the INVOcell Retention Device. Additionally, the study reported on comfort wearing the device during incubation.

Methods

The study was a non-random, prospective study of 29 women to assess device retention. Of the women in the study, 12/29 used the Intravaginal Culture Device and Retention devices, and the rest (17/29) utilized the Intravaginal Culture Device alone. Women were instructed to wear the device(s) for 72 hours, and report on any expulsion or readjustments/repositioning. In addition, the women were asked to rate their comfort with the device.

Results

The sponsor reported that retention of the device for the full 72 hours occurred in 25/29 women. None of the women utilizing the Retention Device reported device expulsion during the incubation period. Of the expulsions, two were reported during urination or bowel movement, and two were reported without any associated cause. Of the 25 with maintained retention, eight reported slippage with successful repositioning. None of the women using the Retention Device reported slippage.

For the majority of subjects, the device(s) were well tolerated. All but two of the subjects reported minimal discomfort. The remaining two had moderate to severe discomfort, with one asking for device removal prior to the 72 hour wear time. There were no reports of erythema, ulceration or lesions in any of the subjects.

Based upon the results of this study, the Retention Device is effective in retaining the Intravaginal Culture Device for the 72 hour incubation period. For most patients, the device should cause minimal discomfort. The device labeling informs the users that the device may cause discomfort in some patients and discourages its use in patients that may not be able to tolerate the device for the full 72 hour incubation period. Additionally, it is important to note that the INVOcell Retention Device was utilized in the INVOcell Safety and Efficacy Study (Study 1 above) in over 500 subjects, with no reports of serious and non-serious adverse events.

LABELING

The labeling for the INVOcell Intravaginal Culture System comprises physician labeling and patient labeling, which both include the device indications for use, a description of the device, warnings and precautions, clinical data on the performance of the device, and instructions for the safe and effective use of the device.

The labeling satisfies the requirements of 21 CFR 801.109 Prescription devices. The patient labeling also follows the principles identified in FDA's guidance entitled "Medical Device Patient Labeling" (issued April 2001).

The Instructions for Use (IFU) for the INVOcell device includes information on the required equipment/accessories for culturing of gametes and embryos, as well as explicit instructions on

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the handling of each device component and the cleaning/disinfection of the components intended to be reprocessed.

The following warnings and precautions were included in the labeling:

Warnings:

The INVOcell Culture Device and INVOcell Retention Device are single use only. Do . not reuse.
Do not use if product or package appears damaged. If the packaging is damaged, the product may no longer be sterile.
Do not use the INVOcell culture device in patients with demonstrated hypersensitivity to ● medical grade silicone or polystyrene. Ensure that the embryo retrieval catheter complies with the tip outer diameter specifications that are compatible with the INVOcell device.
Proper handling is extremely important to the safe and effective use of the INVOcell . Intravaginal Culture Device. Do not begin clinical use of the INVOcell Intravaginal Culture System without establishing competency by reading and practicing these instructions for use.
INVOcell Intravaginal Culture System should be handled under aseptic conditions at all times.
. After the INVOcell Intravaginal Culture Device has contacted the vaginal environment, the surfaces of the device, including those of the inner vessel, should be handled as if contaminated by vaginal flora.
. Utilize a legally-marketed ART culture medium that will support continued embryonic development for up to 72 hours.
Culture media utilized with the INVOcell system MUST contain antibiotics to mitigate . the risk of contamination of media in the inner chamber.
. Culture media utilized with the INVOcell system should have phenol red to aid in the determination of acceptable pH maintenance.
. Using the INVOcell Culture Device and INVOcell Retention Device, embryo development is first evaluated at the end of the incubation period at 72 hours post fertilization. Any abnormalities that would have been detected at an earlier stage (pronuclei stage) may no longer be apparent when the embryos are evaluated for transfer. As a result, there may be an increased risk that an abnormal embryo could be transferred to the uterus compared to traditional IVF.
Do not use a 0-200 µL tip to add oocytes to the INVOcell Culture Device as the oocytes . may stick in the tip and/or become damaged.
Ensure that the embryo retrieval catheter complies with the list of catheters and the tip . outer diameter requirements listed in the accessory section on page 3 of the IFU.

Precautions:

. INVOcell procedures should only be conducted by physicians with expertise in assisted reproductive technology and techniques including oocyte retrieval, clinical embryology, and embryo transfer, and with access to all equipment listed in the Required Accessories section.

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. It is recommended that the INVOcell Intravaginal Culture system be utilized with a mild ovarian stimulation protocol.
. The recommended upper limit on number of oocytes or ICSI fertilized embryos to be placed in the INVOcell Culture Device is seven. Verify that the outer rigid shell and inner chamber of the INVOcell Culture Device are correctly locked before placement of the INVOcell Culture Device and the INVOcell Retention Device in the vaginal cavity.
. Do not touch the surface of the rotating valve of the inner chamber of INVOcell Culture Device during installation into the outer rigid shell to reduce the potential for contamination of media within the inner chamber via the inner chamber access port of the INVOcell Culture Device.
. Verify that the outer rigid shell and inner chamber of the INVOcell Culture Device are correctly locked before placement of the INVOcell Culture Device and the INVOcell Retention Device in the vaginal cavity.
Advise the patient to avoid the following activities while the INVOcell Culture Device ● and the INVOcell Retention Device are in the vaginal cavity: sexual intercourse. strenuous physical activity, swimming, bathing in a tub (a shower is permissible), use of a douche, sauna, or any activity that may alter the temperature of the vaginal cavity.
. Instruct the patient to contact the physician if any of the following are observed: discomfort, bleeding, movement of the INVOcell Culture Device or INVOcell Retention Device, unusual vaginal secretions, or vaginal odor.
Instruct the patient not to remove the INVOcell Culture Device and the INVOcell . Retention Device from the vaginal cavity and to avoid manipulation of the INVOcell Culture Device and the INVOcell Retention Device.
. Provide the patient with instructions for replacement of the INVOcell Culture Device and the INVOcell Retention Device in the event it moves from its original position.
If obvious contamination of culture medium is observed when the INVOcell Culture Device is removed from the vaginal cavity the embryos should be discarded.
. The working environment in the laboratory should be at a minimum of 22 °C to maintain the culture media temperature in the holding block at or above 34°C for 10 minutes during the loading process and embryo aspiration process.

RISKS TO HEALTH

Table5 below identifies the risks to health that may be associated with use of the Intravaginal Culture System and the measures necessary to mitigate these risks.

Identified Risk	Mitigation Measure
Damage to gametes and/or embryos ordisruption of the IVF process	Non-clinical performance testingShelf life testingClinical testingSterilization validationLabeling
Patient injury (e.g., hypersensitivity,toxicity, abrasion, discomfort)	Non-clinical performance testingShelf life testingBiocompatibility

Table 5: Identified Risks to Health and Mitigation Measures

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	Clinical testing
	Sterilization validation
	Labeling
Infection	Sterilization validation
	Reprocessing validation
	Non-clinical performance testing
	Shelf life testing
	Clinical testing
	Labeling
Transfer of incorrect embryos to patient	Labeling

SPECIAL CONTROLS:

In combination with the general controls of the FD&C Act, the INVOcell Intravaginal Culture System is subject to the following special controls:

1. Clinical performance testing must demonstrate the following:
- a. Comfort and retention of the intravaginal culture device
- b. Adverse vaginal tissue reactions associated with intravaginal culture
- Maximum number of gametes and/or embryos that can be placed in a device C.
- d. Rates of embryo development to the designated stage, implantation rates, clinical pregnancy rates, live birth rates, and any adverse events or outcomes.
1. Non-clinical performance testing must demonstrate that the device performs as intended under anticipated conditions of use. The following performance characteristics must be demonstrated:
- a. Mouse Embryo Assay (MEA) 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
- b. Endotoxin testing on gamete and embryo-contacting components of the device
- Cleaning and disinfection validation of reusable device components C.
- Sterility maintenance of the culture media within the device throughout the d. vaginal incubation period and subsequent embryo extraction
- Ability of the device to permit oxygen and carbon dioxide exchange between the e. media contained within the device and the external environment throughout the vaginal incubation period.
1. The patient-contacting components of the device must be demonstrated to be biocompatible.
1. Performance data must demonstrate the sterility of the device components intended to be provided sterile.
1. 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.
1. Labeling for the device must include:
- a. A detailed summary of the clinical testing. including device effectiveness, devicerelated complications, and adverse events

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b. Validated methods and instructions for reprocessing of reusable components
c. The maximum number of gametes or embryos that can be loaded into the device
d. A warning that informs users that the embryo development is first evaluated following intravaginal culture
e. 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.
1. Patient labeling must be provided and must include:
- a. Relevant warnings, precautions, and adverse effects and complications
- b. Information on how to use the device
- The risks and benefits associated with the use of the device C.
- d. A summary of the principal clinical device effectiveness results.

BENEFIT/RISK DETERMINATION

The risks of the device are based on risks associated with assisted reproductive technology (ART) procedures accompanying the use of the device, as well as the placement of the device in the vagina for 72 hours. No serious adverse events associated with device usage were reported in the clinical studies described above. However, serious risks such as ovarian hyperstimulation syndrome (OHHS) due to elevated response to gonadotropin stimulation utilized in oocyte extraction, pain/discomfort related to oocyte retrieval via transvaginal aspiration, infection related to oocyte aspiration, failure of gametes to fertilize or embryos to develop (requiring additional stimulation protocols and extractions), and psychological injury due to failed embryo development and cancellation of transfer, could occur, but are not directly related to the device. Non-serious risks associated with device usage include discomfort wearing the device, involuntary expulsion of the device, change in vaginal flora secondary to wearing the device, and spotting due to vaginal irritation. In addition, usage of the device carries the risk that embryonic abnormalities that would normally be detected during the 72 hour incubation, may not be noticed, leading to the possible transfer of an abnormal embryo during transplantation. Changes in vaginal flora and spotting were not reported in the clinical evaluation of the device. If they occur, these events would be expected to resolve soon after the 72 hour incubation period. During the device retention study, 14/15 women reported no or mild discomfort while wearing the device. If a woman cannot tolerate wearing the device may be easily removed. but the device will need to be placed in an incubator to maintain temperature. The effectiveness of the device when placed in a laboratory incubator has not been evaluated.

The primary probable benefit of using the device, considering that there are alternative treatments for infertility (depending on the underlying cause) and devices (e.g. traditional ART culture dishes), is the ability for a woman to "carry" the couple's own gametes/embryos. This benefit is psychological in nature, and is based primarily on patient desire for a holistic approach to IVF. Therefore, this benefit will be dependent on patient preference. In addition, this benefit is based upon expert clinical opinion, rather than patient preference data.

Additional factors to be considered in determining probable risks and benefits for the INVOcell Intravaginal Culture System include: the overall risks associated with device use are few and

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minor, and serious adverse events are expected to be rare. The live birth outcomes of the INVOcell Intravaginal Culture System are similar to conventional IVF.

In conclusion, given the available information above, the data support that for intravaginal IVF and culture of gametes/embryos, the probable benefits outweigh the probable risks for the INVOcell Intravaginal Culture System. The device provides substantial benefits to patients desiring a holistic approach to IVF and who are uncomfortable allowing their gametes/embryos to reside in a laboratory environment out of their control. The risks can be mitigated by the use of general and the identified special controls.

CONCLUSION

The de novo request for the INVOcell Intravaginal Culture System is granted and the device is classified under the following:

Product Code: OYO Device Type: Intravaginal Culture System Class: II Regulation: 21 CFR 884.6165

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.