FEMCAP BARRIER CONTRACEPTIVE

P020041 · Femcap Incorporated · LLQ · Mar 28, 2003 · Obstetrics/Gynecology

Device Facts

• Record ID: P020041
• Device Name: FEMCAP BARRIER CONTRACEPTIVE
• Applicant: Femcap Incorporated
• Product Code: LLQ · Obstetrics/Gynecology
• Decision Date: Mar 28, 2003
• Decision: APPR
• Device Class: Class 3
• Attributes: Therapeutic

Indications for Use

FemCap™ is indicated for use by women of child-bearing age who desire a barrier device to prevent or postpone pregnancy.

Device Story

FemCap™ is a reusable, sailor’s hat-shaped vaginal contraceptive device made of medical-grade silicone. It is designed to fit over the cervix to prevent sperm entry. The device features a dome to cover the cervix, a brim that adheres to the vaginal walls, and a groove to collect semen and hold spermicide. A strap is integrated into the dome to facilitate removal. The device is available in three sizes (22 mm, 26 mm, 30 mm) based on obstetric history. It is used by the patient in a home setting, requiring manual insertion and removal. Spermicide is applied to the inner dome and outer groove before use. The device is washable and intended for extended wear up to 48 hours. By providing a physical barrier and reservoir for spermicide, it reduces the risk of pregnancy. Healthcare providers prescribe the device and instruct patients on proper sizing and insertion techniques.

Clinical Evidence

Pivotal prospective, multi-center, randomized trial (N=841) compared unstrapped FemCap™ to a diaphragm, both with 2% nonoxynol-9. Primary endpoint: pregnancy. 6-month cumulative pregnancy probability: 13.5% (FemCap™) vs 7.9% (diaphragm). 12-month projected probability for FemCap™: 22.8% (95% CI upper limit 30%). Subgroup analysis showed 8.1-8.2% 6-month pregnancy rate for nulliparous/non-vaginal delivery vs 17.3% for vaginal delivery. Safety studies (N=120) on strapped version showed no significant difference in safety or effectiveness compared to unstrapped. Adverse events included bacterial vaginosis, UTI, and vaginal candidiasis. Colposcopy sub-study showed no significant cervical/vaginal irritation differences.

Technological Characteristics

Medical-grade silicone (Applied Silicone LSR-40). Sailor’s hat-shaped design with dome, brim, and removal strap. Three sizes (22 mm, 26 mm, 30 mm). Reusable, washable. Mechanical barrier principle. No energy source. Shelf life 3 years; use life 2 years. Cleaning validation per AAMI TIR No. 1.

Indications for Use

Indicated for women of child-bearing age desiring a barrier contraceptive. Contraindicated in presence of vaginal, cervical, or pelvic infections or lesions.

Reference Devices

• Contraceptive diaphragm

Submission Summary (Full Text)

{0}

# SUMMARY OF SAFETY AND EFFECTIVENESS DATA

## I. General Information

| Device Generic Name | Cervical Cap |
| --- | --- |
| Device Trade Name | FemCap™ |
| Applicant’s Name and Address | FemCap™, Inc.
14058 Mira Montana Drive
Del Mar, CA 92014 |
| PreMarket Approval (PMA) Application Number | P020041 |
| Date of Panel Recommendation | None |
| Date of Notice of Approval to Applicant | March 28, 2003 |

## II. Indications for Use

FemCap™ is indicated for use by women of child-bearing age who desire a barrier device to prevent or postpone pregnancy.

## III. Contraindications

- The device should not be used in the presence of vaginal, cervical, or pelvic infections.
- The device should not be used in the presence of vaginal or cervical lesions.

## IV. Warnings and Precautions

A list of Warnings and Precautions can be found in the device labeling.

## V. Device Description

FemCap™ is a single-patient-use, reusable, vaginal contraceptive and is capable of extended wear up to 48 hours. The device is made of medical grade silicone and designed to fit over the cervix. It is washable and reusable. It has the following design features:

- FemCap™ comes in three sizes. The inner diameter of the rim determines its size. The small 22 mm FemCap™ is intended for women who have never been pregnant. The medium 26 mm device is intended for women who have been pregnant but have not had a vaginal delivery. The large 30 mm, is

{1}

P020041 FemCap™ Summary of Safety and Effectiveness Data

intended for women who have previously had a vaginal delivery of a full-term baby.

- FemCap™ has a sailor’s hat-shaped design to cover the cervix during and following intercourse. The dome of the cap covers the cervix snugly; the brim fits into the vaginal fornices and adheres to the vaginal walls in the upper third of the vagina. The brim is slightly asymmetrical such that one side of it is wider and intended to cover posterior fornix. The groove (or sulcus) between the brim and the dome is intended to collect semen. There is a strap overlying the dome to facilitate removal.


- FemCap™ is designed to prevent sperm from entering the cervix. Approximately one-quarter teaspoon of spermicide is applied to the inside dome of the cap, and one-half teaspoon of spermicide is applied to the outside in the groove of the cap. The cap is then inserted into the vagina by folding the longer side of the brim and is inserted so that it fits in the posterior vaginal fornix. The brim flares outward to help secure the position. The groove acts as reservoir for spermicide and a trap for sperm.

## VI. Alternative Practices and Procedures

There are several barrier contraceptive devices that are available, including the cervical cap, diaphragm, female condom, Lea’s Shield and male condom. Other forms of temporary birth control include oral contraceptives, long-acting injections, patches, hormone-containing vaginal ring, spermicide and intra-uterine devices (IUDs).

## VII. Marketing History

FemCap™ received the CE Mark and became commercially available in Europe in July 1999. The device has not been withdrawn from the market for any reason.

8

{2}

P020041 FemCap™ Summary of Safety and Effectiveness Data

# VIII. Adverse Events

The Pivotal Safety and Efficacy Study compared FemCap™ with spermicide to the diaphragm with spermicide. Some of the most commonly reported adverse events in this study are presented below in Table 1.

Table 1: Pivotal Clinical Study of FemCap™¹

| Body System/Symptom | (N=346)
FemCap™ with Spermicide
N % | | (N=396)
Diaphragm with Spermicide
N % | |
| --- | --- | --- | --- | --- |
| Bacterial Vaginosis | 18 | 5.2 | 28 | 7.1 |
| Blood in Device | 31 | 9.0 | 16 | 4.0 |
| Dysmenorrhea | 20 | 5.8 | 16 | 4.0 |
| Genital Irritation | 15 | 4.3 | 23 | 5.8 |
| Leukorrhea | 16 | 4.6 | 29 | 7.3 |
| Menstrual Disorder | 16 | 4.6 | 23 | 5.8 |
| UTI | 26 | 7.5 | 49 | 12.4 |
| Vaginal Candidiasis | 65 | 18.8 | 73 | 18.4 |
| Vaginitis, Etiology Unspecified | 34 | 9.8 | 48 | 12.1 |

¹Some women in both arms of the study reported more than one type of symptom.

The sponsor later added a strap to the FemCap™ to facilitate removal of the device. In addition, the brim on the largest size device (30 mm) was slightly enlarged to improve stability. A second, smaller, safety study was performed on the strapped device. The most commonly reported adverse events from the strapped device study are presented below in Table 2.

Table 2: Follow-up Study of Strapped FemCap™¹

| | Strapped FemCap™ with Spermicide (N=97) | | | Unstrapped FemCap™ with Spermicide from Pivotal Study (N=358)² | | |
| --- | --- | --- | --- | --- | --- | --- |
| Adverse Event | Events | Women | % | Events | Women | % |
| Abdominal or Pelvic Pain | 9 | 6 | 6.2 | 0 | 0 | 0 |
| Genital Irritation Related to Device | 3 | 3 | 3.1 | 14 | 13 | 3.6 |
| Blood in Device | 11 | 5 | 5.2 | 23 | 21 | 5.9 |
| Dysmenorrhea | 6 | 6 | 6.2 | 12 | 10 | 2.8 |
| Leukorrhea | 11 | 5 | 5.2 | 12 | 12 | 3.4 |
| UTI | 8 | 7 | 7.2 | 20 | 15 | 4.2 |
| Vaginal Candidiasis | 7 | 6 | 6.2 | 39 | 33 | 9.2 |
| Vaginal, Etiology Unspecified | 12 | 9 | 7.2 | 28 | 21 | 5.9 |

¹ Some women in both arms of the study reported more than one type of problem.
² The reason that the N=358 for First Generation FemCap™ in Table 2 differs from the N=346 in Table 1, for what appears to be the same population, is that there were slight differences between the studies in the way rules for inclusion in analysis were implemented. The difference in numbers is due to differences in follow-up (observation time) between the two studies.

Please refer to the clinical section for additional information.

9

{3}

P020041 FemCap™ Summary of Safety and Effectiveness Data

In a separate colposcopy study, there was no evidence of greater cervical/vaginal irritation among women who used the strapped FemCap™ compared with those who used the unstrapped FemCap™ (7% vs. 6% respectively).

Only the strapped FemCap™ will be marketed.

## IX. Summary of Preclinical Studies

Over the course of development, the device has been manufactured using the following three types of silicone: Dow Corning Silastic®, Model 7-4810; Wacker Elastosil®, Model#3003-40; and Applied Silicone, Model# LSR-40. The marketed device will be made from Silicone manufactured by Applied Silicone. The Dow Corning and Wacker silicones have been withdrawn from the market for any use in female products. Per FDA’s “Guidance for Manufacturers of Silicone Devices Affected by Withdrawal of Dow Corning Silastic Materials” (June 29, 1993), FemCap™, Inc., provided test results to demonstrate that the Wacker and Applied Silicone products are equivalent to the Dow Corning silicone that was used in the pivotal trial.

### A. Summary of Physical Testing

The following physical tests were performed on the final finished product (manufactured with Applied Silicone material) with satisfactory results:

- Strap Properties: Measured the tensile strength, the percent elongation, and the break distances of the straps with and without the body of the device.
- Cyclic Fatigue Testing: Samples from different manufacturing conditions withstood 800 cycles of specified frequency, elongation and pull force without breaking.

### B. Summary of Chemical Testing

Applied Silicone LSR-40 is the raw material silicone provided by Applied Silicone. LSR-40 is a two-part silicone elastomer composed of a vinyldimethyl-terminated polydimethyl siloxane and amorphous (non-crystalline) reinforcing silica. In addition to showing equivalence to the Dow Corning silicone, the sponsor conducted chemical extractions of the final finished product. Samples extracted with saline had negligible weight losses, and no silicones were identified in the extracts. Samples extracted with methylene chloride had weight losses of 3.6-4.1%, and low levels of silicones were identified in the extracts.

10

{4}

P020041 FemCap™ Summary of Safety and Effectiveness Data

## C. Toxicological Studies/Material Safety

Biocompatibility testing was performed on the final finished device made with Applied silicone using standard protocols in accordance with Good Laboratory Practices (GLPs) and in accordance with the FDA medical device biological testing Guidance publication Bluebook Memorandum #G95-1 entitled *Use of International Standardization, ISO-10993-1, Biological Evaluation of Medical Devices Part 1: “Evaluation and Testing”*. The following table summarizes testing done on FemCap™ made with Applied silicone.

Table 3: Biocompatibility Tests and Results

| Test | Test Result |
| --- | --- |
| Cytotoxicity | Not cytotoxic |
| Pyrogen, Rabbit | Non-Pyrogenic |
| Acute Systemic Toxicity | No evidence of systemic toxicity |
| Intracutaneous Toxicity | No evidence of toxicity |
| 6 weeks Muscle Implantation with Histopathology | Microscopic reaction – not significant as compared to the USP negative control implant material, microscopically a non-irritant |
| Vaginal Irritation, Sub Chronic | Not an irritant |
| Sensitization, Maximization Test (Guinea pig) | No evidence of sensitization |
| Genotoxicity, Mouse Bone Marrow Micronucleus | Test article not genotoxic. No evidence of cellular toxicity. |
| Genotoxicity, Mouse Lymphoma, Mammalian Cell Gene Mutation, In Vitro | Not mutagenic |
| Genotoxicity, Ames Test | Not mutagenic. |

## D. Shelf Life

Accelerated and real-time aging studies was used to establish a shelf life of 3 years. Accelerated studies were done by storing devices at 65° C for 49 days; these conditions were designed to simulate 3 years of real-time aging. Real time studies have been done on devices that were aged for 23 and 34 months. Aged devices were checked against dimensional specifications and subjected to the tensile strength and cyclic fatigue tests described in Section IX. A., “Summary of Physical Testing”.

## E. Use Life

FemCap™ is intended to be used with spermicide and to be washed between uses; it is a single-patient-use device. Spermicide and multiple-washing studies have been conducted to support a use life of 2 years.

To determine the effects of the spermicide on the physical properties of the device, accelerated tests were conducted by submerging devices in 2% nonoxynol (N-9) spermicide at 45° C for 31 days. To determine the effects of multiple washing, devices were subjected to 365 cycles of washing, drying and immersion

- 5 -

{5}

P020041 FemCap™ Summary of Safety and Effectiveness Data

in pH 4 acid to mimic the conditions of vaginal environment. After these exposures, the devices were checked against dimensional specifications and subjected to the tensile strength and cyclic fatigue tests described in Section IX. A. "Summary of Physical Testing". FemCap™ passed all the pass/fail criteria.

## F. Cleaning Validation

The cleaning (effectiveness) validation studies were based on the Association for the Advancement of Medical Instrumentation (AAMI) standards (Technical Information Report No. 1, November 1994). The testing company, NAMSA™, conducted the validation protocol for the cleaning. Bioburden recovery validation and soiling/cleaning validation tests were conducted. The cleaning procedure for FemCap™ was determined to be 99.9% effective.

The cleaning method developed is effective in sanitizing the device between uses. The device should be cleaned manually with antimicrobial hand soap, rinsed one minute with tap water, visually inspected for debris, and allowed to air dry. The procedure should be repeated if necessary.

## X. Summary of Clinical Studies

To support the safety and effectiveness FemCap™, the sponsor provided results from six studies: three Phase I feasibility studies (two with the unstrapped FemCap™ and one with the strapped device); a pivotal study of safety and effectiveness (unstrapped FemCap™); a colposcopy study (unstrapped FemCap™); and two safety and acceptability study (strapped FemCap™).

## A. Phase I Feasibility Studies

1. Safety and Efficacy Study of unstrapped FemCap™

The first clinical trial of the unstrapped FemCap™ was a prospective, non-comparative Phase I study of the safety, efficacy and acceptability of the device. Of the 121 women who were enrolled, 106 used unstrapped FemCap™ during 1300 cycles of exposure. A cycle was defined as the interval encompassing a menstrual period and days following bleeding to the next menstrual period. Intercourse could occur at any time within this cycle. On average, each participant provided 12.3 cycles for analysis.

Participants in this study were instructed to use the unstrapped FemCap™ with one-half teaspoon of 3% nonoxynol-9 spermicidal jelly with each act of intercourse and to leave the FemCap™ in place at least 6-8 hours following intercourse. Data were gathered on a single post-coital examination, adverse experiences, contraceptive efficacy and acceptability. The post-coital cervical mucus test, performed on the day following intercourse, failed to reveal any sperm in the cervical mucus.

12

{6}

P020041 FemCap™ Summary of Safety and Effectiveness Data

Five out of 106 women became pregnant. Two of these reportedly believed that the device became dislodged during intercourse. The side effects were reported to be minor.

2. Phase I Study: FemCap™ used with and without spermicide in a post-coital study conducted by Contraceptive Research and Development Program (CONRAD)

An open, randomized, comparative cross-over study of the unstrapped FemCap™ (1) with spermicide, (2) without spermicide compared to no device, and (3) to a commercially available contraceptive diaphragm with spermicide. The post-coital study was conducted to evaluate the presence of motile and non-motile sperm in the vagina, especially the cervical canal at mid-cycle.

The study was designed for each subject to undergo five mid-cycle post-coital tests. Two of the five tests were baseline in which mid-cycle intercourse occurred. The other three tests were mid-cycle tests performed within 2.5 hours of intercourse protected by the FemCap™ with KY-Jelly, the FemCap™ with nonoxynol-9, or the diaphragm with nonoxynol-9 (N-9). The order of the tests was randomized.

Eighteen subjects were enrolled; however, only seven completed all five post-coital tests for a total of 43 successfully completed cycles: 20 baseline; 8 FemCap™ with KY-jelly; 7 FemCap™ with nonoxynol-9; and 8 diaphragm with nonoxynol-9. Two subjects using FemCap™ sustained minor cervical lesions: one case of de-epithelialization, and one case of a superficial abrasion. One case of de-epithelialization was noted in a diaphragm cycle. The relationship of these lesions to the contraceptive barrier device is uncertain.

Specimens of vaginal and cervical mucus were obtained. These were examined microscopically by viewing nine high-powered fields for the presence of non-progressively motile sperm, progressively motile sperm and non-motile sperm.

There was reduction of all types of sperm in the cervical mucus for both the FemCap™ group and the diaphragm group. There was little reduction in any vaginal sperm counts with the use of FemCap™. The diaphragm, however, showed excellent results for all types of sperm in the cervix and for the two types of motile sperm in the vagina. In summary, FemCap™ was proven to be safe and, if used with or without spermicide, prevented the sperm entering the mid-cycle cervical mucus.

- 7 -
13

{7}

P020041 FemCap™ Summary of Safety and Effectiveness Data

## 3. Strapped FemCap™ Feasibility Study

The purpose of this study was to evaluate whether the addition of the removal strap would improve user acceptability among women who experienced difficulty inserting or removing the original device.

Forty-seven participants, at 3 centers, were enrolled from the following sources: (a) 18 women discontinued from the Phase III trial of the original FemCap™ due to problems with insertion/removal; and (b) 29 women from the Phase III study who had reported similar difficulties but who either withdrew from the study for other reasons or completed the study.

Each participant was seen in one visit during which she was asked to insert and remove a unstrapped and a strapped FemCap™ and to complete a questionnaire. Twenty-one percent (10/47) of these subjects reported difficulty inserting, positioning, and/or removing one or both of the devices. In contrast, 72% of these women still had trouble inserting, and/or removing the unstrapped device. Eighty one (81%) of subjects reported that the strap made removal easier.

For the 10 subjects who continued to have trouble with insertion and removal, there was little difference between the devices. That is, these subjects did not find either device easier.

Ease of removal was the aspect liked by most about the strapped device; 85% reported that the strapped device was easier to remove. If both devices were available, 60% of volunteers would choose the strapped device over the unstrapped. In 74% of cases, the clinicians would prescribe the strapped device. Only 13% of the clinicians would prescribe the unstrapped device (13% had no preference).

It was concluded that in a small population of women who experienced difficulty inserting/removing the unstrapped device, most preferred the strapped device, most commonly due to easier removal.

## B. Pivotal Safety and Effectiveness Studies

### 1. Phase III Contraceptive Effectiveness Study

This was a prospective, multi-center, randomized trial comparing safety, effectiveness and acceptability of the unstrapped FemCap™ to that of a commercially available diaphragm. Both devices were used with 2% nonoxynol-9 spermicide. The duration of the study was 28 weeks. Eight hundred forty-one (841) subjects were randomized at 10 different centers across the U.S. A subset of 42 subjects underwent colposcopy in one center.

14

{8}

P020041 FemCap™ Summary of Safety and Effectiveness Data

## Study Design

### Primary Efficacy Endpoint:
- Pregnancy

### Primary Safety Endpoints:
- Discontinuation due to medical reasons
- Adverse experiences

### Secondary Endpoints:
- Acceptability
1. Discontinuation due to non-safety device-related reasons
2. Problems reported at follow-up
3. Regularity of device use
4. Responses on participant questionnaire

### Inclusion Criteria:
- Ages of 18 to 40, inclusive
- Sexually active (coital frequency at least 6 times/month)
- Stable, mutually monogamous relationship
- Negative pregnancy test at enrollment
- Regular menstrual cycles for past three months, unless recently pregnant or using hormonal contraception as follows:
1. If recently pregnant, at least 10 weeks since end of last pregnancy. Also, must have had two spontaneous menses 23-38 days apart since end of pregnancy.
2. If recently used oral contraceptives, must have experienced withdrawal bleed at the end of the last pack and one subsequent spontaneous menses 23-38 days after the withdrawal bleed.
3. If recently used injectable hormonal contraception, must have been at least nine months after the last injection, with two spontaneous menses 23-38 days apart since the last injection.
4. If recently used implanted hormonal contraception, must have had at least one spontaneous menses since removal of the implants (withdrawal bleeding occurring within one week of implant removal not considered a menses).
- Not actively desiring pregnancy for 28 weeks and willing to accept an unknown risk of pregnancy

15

{9}

P020041 FemCap™ Summary of Safety and Effectiveness Data

- Willing to be randomly assigned to either FemCap™ or diaphragm and to use that method as her only means of contraception during her participation in the study
- Planning to reside in area for at least 28 weeks after enrolling in the study
- Willing and able to comply with study procedures and to return to the clinic for scheduled follow-up visits

## Exclusion Criteria:

- History suggestive of infertility, defined as
1. known history of a fertility problem or sterilization;
2. previous pelvic surgery, ectopic pregnancy, or antibiotic treatment for PID, unless participant had an intrauterine pregnancy afterwards;
3. abnormalities on pelvic exam at enrollment that might impair fertility; or
4. known history of endometriosis unless participant had an intrauterine pregnancy afterwards.

- Currently breastfeeding unless participant had 2 menses 23-38 days apart before enrolling
- Known sensitivity or allergy to silicone, latex, or spermicide
- History of toxic shock syndrome
- History of 2 or more urinary tract infections requiring treatment during the year preceding enrollment
- At high risk for HIV or other sexually transmitted diseases
- Signs or symptoms of current cervicitis, endometriosis or PID
- Contraindication to pregnancy
- Vaginal or cervical anatomic abnormality identified by examination and precluding proper fit of either device
- Unable to insert, position, and/or remove device
- Other conditions that, in the opinion of the investigator, would constitute contraindications to participation in the study or would compromise ability to comply with the study protocol, such as any major chronic illness including cancer, serious autoimmune disease or a major psychiatric disorder, e.g., schizophrenia
- Currently participating in any other study or previous participation in this study
- UTI, yeast infection, trichomonas, or bacterial vaginosis that could not be resolved within 14 days after enrollment
- Positive gonorrhea or Chlamydia test at enrollment

16

{10}

P020041 FemCap™ Summary of Safety and Effectiveness Data

- Abnormalities on admission Pap smear other than inflammation, infection, or atypical squamous cells of undetermined significance (ASCUS)

In addition, the participant’s partner must have had (by report)

- no history of sensitivity or allergy to silicone, latex or spermicide;
- no known fertility problem or vasectomy; and
- no known risk for STDs including HIV.

Two randomization lists were prepared at each study site, one for women with female barrier experience (diaphragm, Lea’s Shield, FemCap™, cervical cap, female condom, or vaginal sponge) and the other for those without experience with female barrier contraceptives. Subjects were evaluated at enrollment, 2 weeks, 6 weeks, 12 weeks, 20 weeks (telephone contact only), and 28 weeks. Subjects recorded menses, intercourse, type of contraception, and problems (medical and non-medical) before, during or after use with the device in daily diaries. Urine pregnancy tests were performed at each visit. Questionnaires were given to subjects and their partners at the 2-week visit and at the final visit.

Subjects using FemCap™ were instructed not to have intercourse during menses. If they elected to have intercourse while menstruating, they were advised to use condoms instead of FemCap™. Subjects assigned to the diaphragm were told to follow instructions for use for the diaphragm regarding use of the device during menses, i.e., removing the device as soon as possible after intercourse (within 6 hours) to reduce the risk of Toxic Shock Syndrome.

For subjects assigned to use FemCap™ with spermicide, obstetrical history dictated the size of FemCap™ to be used. Nulligravid subjects received the smallest or 22 mm FemCap™, subjects who had been pregnant but had delivered abdominally or who had pregnancy termination received the 26 mm device, and subjects who had delivered vaginally received the 30 mm device.

At the 2-week visit, subjects were asked to demonstrate correct insertion and removal. Additional instructions were offered if the subject was experiencing difficulty. If after additional instruction the subject still could not insert and remove the device correctly, she was discontinued from the study. A subject was considered to have completed the study if she used the assigned device for 28 weeks after enrollment. At the final visit, the following were performed:

- Review of diary
- Interview
- Examination and laboratory tests as in other follow-up visits, including Pap smear and urine pregnancy test
- Return of devices

17

{11}

P020041 FemCap™ Summary of Safety and Effectiveness Data

A total of 841 subjects were enrolled in the pivotal Contraceptive Safety and Effectiveness Study. A total of 419 subjects were randomized to FemCap™ and 422 were randomized to the diaphragm. Of these, 40 FemCap™ and 3 diaphragm subjects could not insert or remove the device and were excluded from the study. Another 29 FemCap™ subjects and 21 diaphragm subjects were also discontinued at baseline or lost to follow-up. Seven hundred forty-one subjects comprised the per-protocol population, 350 FemCap™ and 398 diaphragm subjects.

Table 4: Patient Accountability
| Number of Patients | FemCap™ with Spermicide | Diaphragm® with Spermicide |
| --- | --- | --- |
| Per-Protocol Population | 350 | 398 |
| Nulligravid | 81 | 98 |
| Non-Vaginal Delivery | 78 | 110 |
| Vaginal Delivery | 191 | 190 |
| Discontinued | 123 | 103 |
| Protocol Violation | 24 | 21 |
| Pregnancy | 39 | 27 |
| Device-Related Reason | 21 | 8 |
| Non-Device Related Reason | 20 | 25 |
| Medical Reasons | 19 | 22 |
| Loss-to-Follow-Up | 13 | 17 |
| Completed 6-Month Study without Becoming Pregnant | 214 | 278 |

In both device groups, the mean age was 29 years. Between 70-72% of subjects were Caucasian. Black women accounted for 19-22% of subjects. Hispanic women accounted for 5-7% of subjects. Between 59-65% of subjects in both groups had prior experience using female barrier contraceptives. The percentage was slightly higher among FemCap™ users, but not by more than four percentage points.

## Effectiveness Results:

The 6-month unadjusted gross cumulative pregnancy probabilities per 100 women in the per-protocol population were 13.5% for FemCap™ users and 7.9% for the diaphragm users. The upper limit of the 95% confidence interval for the 6-month cumulative pregnancy probability for the FemCap™ user was 17.8%. The 12-month pregnancy probability of 22.8% with FemCap™ is a projected probability with an upper limit for the 95% confidence interval for 12 months of 30%.

18

{12}

P020041 FemCap™ Summary of Safety and Effectiveness Data

Out of the 69 nulligravid subjects in this study who used the small $FemCap^{\mathrm{TM}}$, 4 became pregnant for an $8.1\%$ 6-month cumulative Kaplan-Meier pregnancy probability. Of the 61 parous subjects who did not have a vaginal delivery and used the medium sized $FemCap^{\mathrm{TM}}$, 4 became pregnant for an $8.2\%$ 6-month cumulative Kaplan-Meier pregnancy probability. In contrast, of the 184 subjects who had a vaginal delivery and used the large $FemCap^{\mathrm{TM}}$, 28 became pregnant for a $17.3\%$ 6-month cumulative Kaplan-Meier pregnancy probability.

The Table 5 shows pregnancy probabilities from different studies and various types of contraceptives compared to the $FemCap^{\mathrm{TM}}$.

Table 5: Pregnancy Rates
| Contraceptive Method | 6-month Pregnancy Rate | 12-month Pregnancy Rate |
| --- | --- | --- |
| Surgical Sterilization | | |
| Injectable Hormones | Less than 1% | Less than 1% |
| IUDs | | |
| Hormone Pills | 1-2% | 1-2% |
| Vaginal Ring | | |
| Male Condom | 7% | 11%^{1} |
| Contraceptive Diaphragm | 8% | 17% |
| Cervical Cap | 11% | 17% |
| Female Condom | 13% | 21%^{1} |
| Lea’s Shield | 9% | 15%^{1} |
| FemCap™ (All Sizes) | (13.5%) | (23%)^{1} |
| 22 mm, nulligravid | 8.1% | 14%^{1} |
| 26 mm, parous (non-vaginal) | 8.2% | 14%^{1} |
| 30 mm, parous (vaginal) | 17.3% | 29%^{1} |

1 These 1-year rates are projected since most barrier studies today are conducted as 6-month studies.

## Acceptability:

$FemCap^{\mathrm{TM}}$ users most commonly reported dislodgement, difficulty inserting the device, and difficulty removing the device. Diaphragm users most commonly reported vaginal symptoms, difficulty inserting, and inconvenience. $FemCap^{\mathrm{TM}}$ users reported dislodgement for $1.85\%$ of coital acts. Although significantly more $FemCap^{\mathrm{TM}}$ users reported dislodgement or movement, the pregnancy probabilities of these women were not different from pregnancy probabilities of $FemCap^{\mathrm{TM}}$ users who did not complain of dislodgment or movement.

{13}

P020041 FemCap™ Summary of Safety and Effectiveness Data

## Pap Smear Results:

Comparison of Pap smear between baseline and 12 weeks and baseline and discontinuation visit did not reveal significant differences between the two device groups. Because women with abnormal Pap smears were not enrolled into the study, the numbers of subjects with abnormal smears were small at both the 12 weeks and discontinuation visits. There were a greater percentage of “Unsatisfactory” smears (absence of endocervical cells) in the FemCap™ group at discontinuation compared to the diaphragm group, 3.8% versus 0.8% respectively.

## 2. Colposcopy Sub-Study:

Forty-two subjects from the pivotal study were enrolled in single center “nested” colposcopy study. Half of these subjects used the unstrapped FemCap™ with spermicide, and the other half used the diaphragm with spermicide.

These colposcopy sub-study subjects underwent colposcopy four times: at enrollment, and at the 2-, 6-, and 28-week visits. Any vaginal or cervical abnormality on colposcopy at enrollment excluded a subject from participation. At the 2-week visit, 4 FemCap™ subjects and 3 diaphragm subjects had lesions. At the 6-week visit, 4 FemCap™ users had lesions and 2 diaphragm users had lesions. At the 28-week visit, 3 subjects in both groups had lesions.

In summary, 29 lesions were seen in the FemCap™ group and 18 in the diaphragm group. Of these, 28 in the FemCap™ group were on the cervix and 14 in the diaphragm group were on the cervix. Of the cervical lesions, there was a difference between the two groups in that 40% of the FemCap™ lesions were within the transformation zone (TZ) and 86% of the diaphragm cervical lesions were in the TZ.

Approximately 40% of the lesions in both groups were classified as aceto-white (non-condyloma) lesions. All of these were squamous metaplasia, a normal finding. Of the other lesions in FemCap™ group: 5 (17%) were classified as ecchymosis; 4 (14%) as abrasive; 2 (7%) each as petechia hemorrhage, edema, and lehkoplakia; and 1 (3%) each as fibrosis and irritation.

## 3. Safety and Acceptability Study of Strapped FemCap™:

Purpose: To compare the strapped FemCap™ device with the unstrapped FemCap™ with respect to safety and acceptability.

A prospective, non-randomized, single-arm study with a historical control was conducted (the FemCap™ with spermicide arm of the pivotal Study of Safety

20

{14}

P020041 FemCap™ Summary of Safety and Effectiveness Data

and Effectiveness of the unstrapped FemCap™). One hundred-twenty subjects were enrolled and fitted with the strapped FemCap™. There were more Caucasian subjects (85%) in this study compared to African American subjects (11%).

Primary Endpoints:

- Safety and acceptability of the strapped FemCap™

Secondary Endpoints:

- Removal difficulty
- Dislodgement
- Participant genital pain or discomfort
- Adverse Events
- Cervical/vaginal irritation
- Acceptability

Participants were given diaries in which to record: dates of intercourse and menses; whether the device was used correctly; other contraceptive devices used; and partner problems. Each subject underwent 3 colposcopies: (1) at enrollment; (2) at 2 weeks; and (3) at 8 weeks into the study.

Removal Difficulty:

Of the 120 subjects enrolled in this study, 20 were discontinued due to inability to insert or remove the device. One subject was discontinued because she could not be fitted successfully. Two were lost to follow-up. Therefore, the treated population for this study was 97 subjects.

At the enrollment visit, 12% of the subjects were unable to remove the strapped FemCap™. These subjects were discontinued from the study. This was greater than the 8% in the pivotal study who were not able to remove the unstrapped FemCap™ at enrollment.

The degree of difficulty in removal is provided in Table 6.

Table 6: Device Removal Problems

| Problem with removal | Strapped FemCap™ (120) | Unstrapped FemCap™ (419) |
| --- | --- | --- |
| Severe Problem | 14 (12%) | 34 (8%) |
| Moderate Problem | 29 (24%) | 148 (35%) |
| Slight Problem | 21 (18%) | 71 (17%) |
| No Problem | 56 (47%) | 166 (40%) |

{15}

P020041 FemCap™ Summary of Safety and Effectiveness Data

Improvements in the above categories for the strapped device were not statistically significant.

## Device Dislodgement:

The correct position of the FemCap™ is covering the cervix such that the entire rim of device is seated within the posterior fornix. When the FemCap™ is no longer in this position, it is considered “dislodged”. Device dislodgment negates contraceptive efficacy. The rate of device dislodgements, though slightly higher in the strapped group compared to the diaphragm, was not significantly different between the two groups.

## Pain/Discomfort/Device “Awareness”:

Emphasis given to these questions in the strapped device study, compared to the pivotal study which tested the unstrapped device, might have heightened participants’ awareness of, memory of, or willingness to report device problems compared to the pivotal study.

Two women discontinued the study because their male partners complained of discomfort from the device. Neither of these two men reported any visible penile injury. The complaints associated with the devices are provided in Table 7.

Table 7: Complaints

| Complaint | Strapped FemCap™ | | Unstrapped FemCap™ | |
| --- | --- | --- | --- | --- |
| | N | % | N | % |
| Female Partner | | | | |
| Pain/Discomfort | 26/97 | 26.8 | 42/348 | 12.1 |
| Awareness of Device | 16/97 | 16.5 | 63/348 | 18.1 |
| Male partner | | | | |
| Pain/Discomfort | * | 31.3 | 13/336 | 3.9 |
| Awareness of Device | * | 34.4 | 128/336 | 38.1 |

*Actual numbers not available

## Cervical/Vaginal Irritation:

Three colposcopic evaluations were performed on each subject: at the enrollment (i.e., baseline) and at 2- and 8-week visits. This corresponded to visits among the Colposcopy Sub-Study subjects. The findings for cervical and vaginal lesions are provided in Table 8.

Table 8: Cervical and Vaginal Lesions

| | Strapped Device | | | Unstrapped Device | | |
| --- | --- | --- | --- | --- | --- | --- |
| | Baseline
N=97 | 2-Weeks
N=93 | 8-Weeks
N=85 | Baseline
N=20 | 2-Weeks
N=18 | 8-Weeks
N=19 |
| Cervix | 26 | 48 | 42 | 8 | 6 | 6 |
| Vagina | 9 | 9 | 16 | 0 | 0 | 1 |

{16}

P020041 FemCap™ Summary of Safety and Effectiveness Data

The most common adverse events are provided in Table 9.

Table 9: Most Common Adverse Events

| | Strapped Device | | | Unstrapped Device | | |
| --- | --- | --- | --- | --- | --- | --- |
| | Baseline N=97 | 2-Weeks N=93 | 8-Weeks N=85 | Baseline N=20 | 2-Weeks N=18 | 8-Weeks N=19 |
| Petechiae | 17 (13.4%) | 27 (22.6%) | 27 (12.9%) | 1 (5.0%) | 0 (0.0%) | 1 (5.3%) |
| Erythema | 4 (4.1%) | 7 (7.5%) | 13 (11.8%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) |
| De-Epithelialization | 1 (1.0%) | 9 (7.5%) | 3 (2.4%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) |

Female Subject Acceptability Outcomes: Strapped vs. Unstrapped Device

The Table 10 summarizes key device acceptability responses at the two-week follow-up on female subject questionnaires.

Table 10: Female Subject Acceptability Outcomes

| Outcome | Strapped FemCap™ | | Unstrapped FemCap™ | |
| --- | --- | --- | --- | --- |
| | N | % | N | % |
| General Opinion | | | | |
| Liked a Lot | 26/93 | 28.0 | 98/329 | 29.8 |
| Liked Somewhat | 35/93 | 37.6 | 154/329 | 46.8 |
| Problems | 45/92 | 48.9 | 121/327 | 37.0 |
| How Likely to Use Device Alone | | | | |
| Probably Definitely | 29/93 | 31.2 | 98/329 | 29.8 |
| | 35/93 | 37.6 | 165/329 | 50.2 |
| Recommend to a Friend | 76/91 | 83.5 | 280/321 | 87.3 |

Male Partner Acceptability Outcomes: Strapped vs. Unstrapped Device

The general opinion of the male partners at the two-week follow up was approximately the same for the strapped and unstrapped devices. For example, those whose partners used the strapped FemCap™ liked the device somewhat or a lot (45.8%) compared with the unstrapped device (49.5%). However, 62.2% of men whose partners used the strapped FemCap™ were aware of the device, whereas only 50.2% of those whose partners used the unstrapped FemCap™ were aware of the device. As discussed (see Pain/Discomfort/Device Awareness), this difference might be the result of study bias.

23

{17}

P020041 FemCap™ Summary of Safety and Effectiveness Data

Strapped FemCap™ male partners reported 20.7% problems and unstrapped FemCap™ male partners reported 15.5%. Sixty-four percent (64%) of strapped FemCap™ male partners would recommend it to a friend and 72.7% of unstrapped device partners would recommend it to a friend.

The addition of the removal strap had no overall effect on safety and effectiveness of the FemCap™.

## XI. Conclusions Drawn From Studies

The 12-month pregnancy probability of 22.8% with FemCap™ is a projected probability with an upper limit for 95% confidence for 12 months of 30%. There was a difference in the chance of pregnancy depending on whether or not a woman had given birth vaginally and on the size of FemCap™ she used.

For women who had never had a vaginal delivery and who used the small or medium FemCap™, the 6-month chance of pregnancy was about 8.2%. If a woman had given birth vaginally and used the large FemCap™ the chance of pregnancy at 6-months was 17.3%.

Women with a history of vaginal delivery will require special counseling to ensure that they understand that they have a much higher risk of pregnancy than women who are nulliparous or who have had an abdominal delivery. This should be accomplished through labeling.

The pivotal trial demonstrated that FemCap™ is an effective barrier contraceptive device and does not raise any significant clinical safety issues. Only the strapped device will be marketed. FemCap™ is a prescription device.

## XII. Panel Recommendation

In accordance with the provisions of section 515(C)(2) of the act as amended by the Safe Medical Devices Act of 1990, this PMA application was not referred to the Obstetrics and Gynecology Devices Panel, an FDA advisory committee, for review and recommendation because the information in this PMA substantially duplicates information previously reviewed by the panel at previous meetings on vaginal barrier contraceptive devices.

## XIII. CDRH Decision

FDA reviewed the preclinical and clinical data and determined that the device is reasonably safe and effective for its intended use. FDA conducted an inspection of the applicant’s manufacturing facility and determined the facility was in compliance with applicable requirements of the Quality Systems Regulation (21 CFR 820). FDA issued an approval order for the application on March 28, 2003.

24

{18}

P020041 FemCap™ Summary of Safety and Effectiveness Data

## XIV. Approval Specifications

**Directions for Use:** See Labeling (Physicians and Patient Labeling)

**Hazards to Health from Use of Device:** See Indications, Contraindications, Warnings, Precautions, and Adverse Events sections of the labeling.

**Post-Approval Requirements and Restrictions:** There are no post approval study requirements for FemCap™.

- 19 -

25