(252 days)
Not Found
Not Found
No
The device description and performance studies focus on the physical components and their function in facilitating intravaginal culture, with no mention of AI or ML for analysis, decision-making, or image processing.
No.
The devices are used for 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, which are not considered therapeutic.
No.
The device is indicated for preparing, holding, and transferring human gametes or embryos during IVF/IVC and ICSI/IVC procedures. It does not provide any diagnostic information.
No
The device description clearly outlines three physical components: the Culture Device (plastic container), the Retention Device (silicone cup), and the Holding Block (stainless steel block). There is no mention of any software component.
Based on the provided information, the INVOcell Intravaginal Culture System is not an In Vitro Diagnostic (IVD) device.
Here's why:
- Intended Use: The intended use clearly states that the device is used for "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." This describes a device used in the process of creating and culturing embryos, not a device used to diagnose a condition or test a sample for diagnostic purposes.
- Device Description: The description details components for holding, protecting, retaining, and maintaining temperature of gametes and embryos. These are all related to the physical process of culture and transfer, not diagnostic testing.
- Performance Studies: The performance studies evaluate outcomes related to the success of the IVF/ICSI procedure (fertilization rates, embryo quality, pregnancy rates, birth rates), and the comfort and retention of the device. These are measures of the device's effectiveness in facilitating the reproductive process, not its ability to provide diagnostic information.
- Key Metrics: The key metrics are all related to the success and outcomes of the IVF/ICSI procedure, not diagnostic values.
IVD devices are typically used to examine specimens (like blood, urine, tissue) from the human body to provide information for the diagnosis, monitoring, or treatment of a disease or condition. The INVOcell system does not perform this function. It is a device used in a medical procedure (IVF/ICSI) to facilitate the culture of gametes and embryos.
N/A
Intended Use / 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/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.
Product codes
OYO
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
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.
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 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
The INVOcell Holding Block 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.
Mentions image processing
Not Found
Mentions AI, DNN, or ML
Not Found
Input Imaging Modality
Not Found
Anatomical Site
vagina / vaginal cavity
Indicated Patient Age Range
The clinical study included subjects with an age range of 21-45 years.
Intended User / Care Setting
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 care setting is inferred to be a clinical/laboratory setting for assisted reproductive procedures.
Description of the training set, sample size, data source, and annotation protocol
Not Found
Description of the test set, sample size, data source, and annotation protocol
Study 1: INVOcell Outside the US (OUS) Safety and Efficacy
Objective: Evaluate rate of fertilization (IVF only), embryo quality, successful transfer rates, and live birth rates resulting from embryos incubated using the INVOcell device.
Methods: Clinical investigations at assisted reproductive facilities in Peru, Colombia, Bolivia, and Brazil.
Population:
Lima, Peru: 134 subjects, 138 IVF cycles, Age Range 36-43, Average Age 35
Bogota, Colombia: 220 subjects, 125 IVF cycles / 100 ICSI cycles, Age Range 21-45, Average Age 34
Sao Paulo, Brazil: 40 subjects, 20 IVF cycles / 20 ICSI cycles, Age Range 29-44, Average Age 35
Cochabamba, Bolivia: 48 subjects, 48 IVF cycles, Average Age 34
Total cycles: 450 (IVF + ICSI pooled).
Study 2: INVOcell Intravaginal Culture Device Comfort and Retention Study
Objective: 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: Non-random, prospective study of 29 women.
Population: 12/29 women used Intravaginal Culture Device and Retention devices; 17/29 women used Intravaginal Culture Device alone. Instructed to wear devices for 72 hours and report expulsion, readjustment, and comfort.
Summary of Performance Studies
Study 1: INVOcell Outside the US (OUS) Safety and Efficacy
- Study type: Clinical investigation
- Sample size: 450 total cycles (pooled IVF + ICSI from 4 sites, total 442 subjects across 4 sites)
- Key results:
- Effectiveness:
- Fertilization and Cleavage Rates: Compared to literature (Bergh et al., Hum Reprod, 1998), INVOcell incubated embryos showed no statistically significant difference in fertilization and cleavage rates for both IVF and ICSI.
- INVO IVF Total: Fertilization rate 64.6%, Cleavage rate 64.4%
- Bergh IVF: Fertilization rate 67.3%, Cleavage rate 63.1%
- INVO ICSI Colombia: Fertilization rate 78.5%, Cleavage rate 77.1%
- Bergh ICSI: Fertilization rate 72.7%, Cleavage rate 67.4%
- Embryo Quality: Compared to literature (Lundin et al., Reprod, 2001), embryos incubated with INVOcell were of good quality (Grade 1 or 2 with 6 to 8 cells at day 3). Good quality embryo rate for INVO IVF/ICSI Total was 61.5% compared to Lundin IVF/ICSI 41.6%.
- Clinical Outcomes (Pooled data for 450 cycles):
- Clinical Pregnancy Rate: 32.4%
- Miscarriage Rate: 22.6%
- Multiple Pregnancy Rate: 15.1%
- Birth Rate: 23.8%
- Multiple Birth Rate: 17.8%
- Pre-term Birth Rate: 21.4%
- Fertilization and Cleavage Rates: Compared to literature (Bergh et al., Hum Reprod, 1998), INVOcell incubated embryos showed no statistically significant difference in fertilization and cleavage rates for both IVF and ICSI.
- Safety: No observed device-related serious or non-serious adverse events.
- Effectiveness:
Study 2: INVOcell Intravaginal Culture Device Comfort and Retention Study
- Study type: Non-random, prospective study
- Sample size: 29 women
- Key results:
- Retention: 25/29 women maintained retention for the full 72 hours. None of the women using the Retention Device reported expulsion or slippage. Expulsions (4 cases) and slippage with repositioning (8 cases) occurred only in women not using the Retention Device.
- Comfort: Majority of subjects experienced minimal discomfort (27/29). Two reported moderate to severe discomfort, with one requesting early device removal. No reports of erythema, ulceration, or lesions.
Summary of Nonclinical/Bench Studies:
- Sterilization, Cleaning, and Disinfection: Passed (Sterility Assurance Level 10^-6, >6-log10 reduction in microorganisms for reprocessing).
- Biocompatibility: Passed (non-cytotoxic, no toxic effects, no irritation, no sensitization, no acute systemic toxicity).
- Bench Testing:
- Volumetric Capacity: Passed (no bubbles or air pockets formed during filling).
- Fluid Contact Surface Finish: Passed (no surfaceimperfections ≥ 50 microns).
- Illumination and Optical Properties: Passed (no obscured views, 89% scored 5/5, 11% scored 4/5 for microsphere visibility).
- Temperature Maintenance of Holding Block: Passed (maintains >34°C for 12 minutes).
- pH maintenance: Passed (pH remained within ±0.2 of controls).
- Seal integrity: Passed (30/30 samples maintained culture media sterility).
- Mouse Embryo Assay (Embryo compatibility): Passed (>90% of embryos reached expanded blastocyst stage).
- Endotoxin Testing: Passed (
§ 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.
0
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 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
1
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.
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 in vitro
b(4)
method; Performed on
Intravaginal Culture
Device and Retention
Device | | Grade 0 (non-
cytotoxic) | |
| Rabbit Muscle
Implantation | Determine the toxic effects of
the Intravaginal Culture Device
or Retention Device in direct
contact with living tissue | ISO 10993-6: Tests
for Local Effects after
Implantation;
Performed on
Intravaginal Culture
Device and Retention
Device | | No significant
difference from
negative control
(no signs of
toxic response) | |
| Vaginal
Irritation | Determine if polar and non-
polar extracts of the
Intravaginal Culture Device or
Retention Device elicit a
hypersensitive response | ISO 10993-10:
Biological Evaluation
of Medical Devices:
Tests for Irritation and
Sensitization;
Performed on
Intravaginal Culture
Device and Retention
Device | - | No signs of
macroscopic or
microscopic
irritation from
polar and non-
polar extracts | |
5
| Sensitization | Determine if polar and non-
polar extracts of the
Intravaginal Culture Device or
Retention Device cause a
hypersensitive response | ISO 10993-10:
Biological Evaluation
of Medical Devices:
Tests for Irritation and
Delayed Type
Hypersensitivity;
Performed on
Intravaginal Culture
Device and Retention
Device | - | No signs of
sensitization
from polar and
non-polar
extracts |
|-------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------|
| Acute Systemic
Toxicity | Determine if polar and non-
polar extracts of the
Intravaginal Culture Device are
acutely systemically toxic | ISO 10993-11:
Biological Evaluation
of Medical Devices
Tests for Systemic
Toxicity;
Intravaginal Culture
Device | - | No evidence of
mortality or
systemic
toxicity from
test material
extracts |
| Bench Testing | | | | |
| Volumetric
Capacity | Determine if the inner vessel
chamber meets volume
specifications and if it can be
filled without formation of air
bubbles. This test ensures that
bubbles/air pockets are not
formed, which may damage the
embryos during incubation. | Inner vessels were
filled to overflow with
water, closed, and
blotted dry. Samples
were observed during
filling for bubble
formation. The water
in the filled vessels
was extracted and
weighed. | 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 | Determine the quality of the
surface finish of the surface of
the inner vessel in contact with
media to ensure that embryos
are not exposed to rough
surfaces, leading them to
"stick" to the vessel walls. | Impression media was
used to create replicas
of the surfaces of
inner vessels.
Scanning electron
microscopy utilized to
visualize the replica
surfaces. | No surface
imperfections
≥ 50 microns
shall be
observed | Passed |
| Illumination and
Optical
Properties | Evaluate if embryos can be
observed post-incubation
through the illumination port of
the Holding Block to ensure
that embryos are appropriately
accounted for after incubation
and during extraction. | 90 micron
microspheres b(4)
Microsphere
solution was added to
the inner vessels of
the Intravaginal
Culture Device, which
were placed in the
Holding Block.
Microspheres were
observed at 12
positions and given a | | No obscured
views, 89% of
samples were
scored 5/5, 11%
were 4/5. |
6
| Temperature
Maintenance of
Holding Block | Evaluate the time required to
heat the Holding Block and the
heat retention time to ensure
that embryo media maintains
appropriate temperature during
loading and extraction
procedures. | clarity.
Blocks were heated to
37C and allowed to
cool. Temperature of
the media within the
inner vessel was
monitored
continuously | Media inside
inner vessel
shall maintain
a temperature
of >34°C for
10 minutes to
allow for
adequate
procedure time | Passed; Block
maintains
temperature of
inner vessel of
the Intravaginal
Culture Device
(>34 C) for 12
minutes |
|-------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------|
| pH maintenance | Determine if media maintains
pH during the incubation period
to ensure that embryos are not
exposed to damaging changes
in pH during incubation. | pH of media
(containing gametes)
within the inner vessel
of the Intravaginal
Culture Device was
monitored over a
simulated incubation
period of 72 hours | pH shall
remain within
±0.2 of the
controls
(legally
marketed
assisted
reproduction
labware) | Passed |
| Seal integrity | Determine the device's ability
to resist bacterial ingress and
maintain sterility of the culture
media during incubation and
extraction to ensure embryos
will not be exposed to bacteria
during vaginal incubation. | Sterile bacterial media
was deposited in the
inner vessels of the
Intravaginal Culture
Devices. 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 |
| Mouse Embryo
Assay (Embryo
compatibility) | Determine if the device is
compatible with embryos | Twenty-one 2-cell
embryos were
incubated in each of 9
(3 samples from 3
lots) INVOcell
Intravaginal Culture
Devices for 72 hours.
Legally marketed
assisted reproduction
labware were used as
the control (n=3). | >80% embryos
shall reach
expanded
blastocyst
stage | Passed; >90%
of embryos
reached
expanded
blastocyst stage |
7
| | | embryos were scored
for development | | |
|--------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------|----------------------------------------------------|
| Endotoxin
Testing | Determine if bacterial
endotoxins are within
acceptable limits to ensure that
embryos are not exposed to
high levels of endotoxins | USP 31 NF 26 2008
Bacterial
Endotoxins Test | The endotoxin
level shall be 80% of
embryos shall
reach the
blastocyst
stage | Passed, >90%
reached
blastocyst stage |
| pH maintenance | Evaluate media pH during the
incubation period to ensure that
the devices retain their pH-
maintaining properties at the
end of the shelf life. This test is
an indicator for the CO2
permeability of the device. | Twenty-one 2-cell
embryos were
incubated in each of 9
(3 samples from 3
lots) INVOcell
Intravaginal Culture
Devices for 72 hours.
The pH of the media
within the vessels
after incubation was
measured with an
electrochemical probe.
Legally marketed
assisted reproduction
labware were used as
controls. | pH shall
remain within
±0.2 of the
control | Passed |
8
| 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:
9
| Site | Number of
Subjects | IVF cycles/ICSI cycles/Total Cycles | Age
Range | Average
Age |
|------------------------|-----------------------|-------------------------------------|--------------|----------------|
| 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:
| | Bergh
IVF | INVO
IVF
Total | INVO
IVF
Colombia | INVO
IVF
Peru | INVO
IVF
Bolivia | Bergh
ICSI | INVO
ICSI
Colombia |
|------------------------|--------------|----------------------|-------------------------|---------------------|------------------------|---------------|--------------------------|
| Cycles | 200 | 310 | 125 | 137 | 48 | 175 | 100 |
| Inseminated
Oocytes | 2,279 | 1,388 | 520 | 640 | 228 | 1,880 | 376 |
| Fertilized
Oocytes | 1,536 | 897 | 331 | 404 | 162 | 1,365 | 295 |
| Cleaved
Embryos | 1,437 | 894 | 328 | 404 | 162 | 1,268 | 290 |
| Fertilization
rate | 67.3% | 64.6% | 63.7% | 63.1% | 71% | 72.7% | 78.5% |
| Cleavage
rate | 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
10
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 | Lundin
IVF/ICSI | INVO
IVF/ICSI
Total | INVO
IVF/ICSI
Colombia | INVO
IVF/ICSI
Peru | INVO
IVF
Bolivia |
|-------------------------------------------------|--------------------|---------------------------|------------------------------|--------------------------|------------------------|
| 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 | | 137/410
33.4% | 79
35.1% | 42
30.7% | 16
33.3% |
| Miscarriage rate | 17.3%* | 33/137
24.1% | 15
19% | 14
33.3% | 4
25% |
| Birth rate per cycle | 27.8% | 98/410
23.9% | 63
28%** | 23
16.8%*** | 12
25% |
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 or | |
| disruption of the IVF process | Non-clinical performance testing |
| Shelf life testing | |
| Clinical testing | |
| Sterilization validation | |
| Labeling | |
| Patient injury (e.g., hypersensitivity, | |
| toxicity, abrasion, discomfort) | Non-clinical performance testing |
| Shelf life testing | |
| Biocompatibility |
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:
-
- 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.
-
- 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.
-
- The patient-contacting components of the device must be demonstrated to be biocompatible.
-
- Performance data must demonstrate the sterility of the device components intended to be provided sterile.
-
- 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.
-
- 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.
-
- 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