I. Introduction

Around 153 million women around the world have chosen to be sterilized for contraceptive purposes, of these 138 million are in the developing countries. 1 Approximately fifty percent of all female sterilization is performed during the puerperal period or a cesarean section, and the other fifty percent is called “interval sterilization” when there has been no pregnancy for the previous six weeks. The most common surgical procedure today for sterilization is via minilaparotomy. However, the technique of fallopian tube ligation is still being done today largely by a procedure developed at the beginning of the 20 th century. The advent of fiber optic technology led to the introduction of the laparoscope in the 1960’s followed quickly by techniques of electrocoagulation and application of clip/rings to the fallopian tubes to block them. There had been improvements in the design of devices for blocking the tubes, but gains in safety and efficacy were small. Efforts to reach the fallopian tube through the vagina rather then abdominally increased in the 1970’s, but there was a high rate of failure in completing the operation and significant complications. The possibility of reaching the tubes transcervically was recognized in the late 19 th century, but the efforts to perform female sterilization by this method had mixed success.

II. Historical Review of Hysteroscopic Sterilization

In 1869, Pantaleoni published his article entitled “On endoscopic examination of the cavity of the womb” in the medical press. He did this when a woman presented for investigation of abnormal vaginal bleeding. This was the first described hysteroscopic examination of the uterine cavity in recorded history. Then 1878, Kocks attempted to blindly occlude the uterotubal junction by transcervical insertion of electrodes. 2 Similar attempts to improve this rudimentary technique by using guide wire fluoroscopy did not produce significant clinical success. The use of a hysteroscope for direct visualization of the tubal ostia for the purpose of sterilization was initially suggested by Mickulicz-Radecki and Freund in 1927. 3 Schroeder in 1934 performed intramural sterilization of the tubes by electrocoagulation. Although the idea of utilizing hysteroscopy for tubal occlusion goes back to 1920’s, and was explored in clinical trials in the 1950’s, particularly by Japanese investigators, it did not produce acceptable results. Modern hysteroscopy was introduced in the early 1970’s as a method of visualizing the uterine cavity and uterotubal junction. It was not until this period that well designed clinical trials were initiated utilizing electrodes delivered directly under hysteroscopic guidance. These studies were done at several centers; in West Germany by Lindeman, in Japan by Sugimoto, in Mexico by Quinones, and in the United States by Neuwirth. This was a time of growing interest in this new technology which spurred the development of reliable hysteroscopic instrumentation and safe distention medium.

Various methods were evaluated including inert plugs, chemicals, caustic and sclerosing agents; however they often proved difficult, inefficient, and dangerous. 4 Failures were high and serious complications were reported in clinical trials. 2, 5-8 A quarter of a century later, owing to improved technology, new intratubal devices have been designed that achieve sterilization in an ambulatory setting employing a tubal occlusive transcervical method.

After decades of searching for an acceptable hysteroscopic method of permanent birth control, without the need for incisional surgery or general anesthesia, a safe and acceptable form of female sterilization came onto the horizon. The STOP (selective tubal occlusion procedure) device (Conceptus, Inc., Mountain View, CA) was developed and was studied in a clinical trial in pre-hysterectomy patients who wore the device for 1-12 weeks prior to hysterectomy. At hysterectomy hysterosalpingography (HSG) was performed to determine tubal occlusion. 9 Subsequently, the tubes containing the STOP device were processed, sectioned, and evaluated to determine the histological response. Histology showed an acute inflammatory and fibrotic response in the short term that over time, became a chronic inflammatory response with extensive fibrosis, occluding the fallopian tube at the uterotubal junction. This supported the usefulness of the STOP device for pregnancy prevention.

III. Background Study of the Essure ® Permanent Contraceptive Micro-insert

The Essure (previously known as the STOP device) micro-insert underwent several design changes during its evolution. In 1995, there were animal studies with the initial product called the Alpha design which was a static design with curled ends. The second product was Beta 1 and 2 which changed from a curve design to a linear static design. The Beta 2 version was introduced with a delivery catheter. Next a Beta 3 design was developed with an increased quantity of PET (p olyethylene terephthalate) fibers to induce the tissue response. The Gamma, or Essure, design is the model sold commercially today. It is a dynamic coil design with increased length and increased quantity of PET fiber. These various evolutions in the design of the product were progressively more successful in allowing the anchoring of the device in the tubal ostia, and promotion of tissue in-growth, thus occluding the interstitial portion of the tube for permanent contraception.

In 1998 a Phase II FDA IDE clinical trial utilizing the micro-insert for sterilization patients commenced. In the year 2000 a Pivotal Trial to evaluate safety and efficacy of the micro-insert had begun. Both studies are still on-going and data continues to be collected. 2001 saw the commercial sale of the Essure micro-insert in Australia, Singapore and Canada. FDA approval of the micro-insert and commercial sales in Europe and the United States began in 2002.

The Phase II study was designed as a prospective, multi-center, single arm non-randomized international study of women seeking permanent contraception. The objectives of the study were to evaluate:

• Women’s tolerance of, and recovery from, the micro-insert placement procedure;
• The safety of the micro-insert placement procedure;
• Women’s tolerance of the implanted micro-inserts
• The long-term safety and stability of the implanted micro-inserts; and
• The effectiveness of the micro-inserts in preventing pregnancy

The Pivotal study was of similar design and used findings from the U.S. Collaborative Review of Sterilization (CREST ) study 10-11 as a qualitative benchmark. The primary endpoints for the study included:

• Prevention of pregnancy
• Safety of device placement procedure, and;
• Safety of device wearing

Secondary endpoints for the study included:

• Participant satisfaction with device placement procedure;
• Participant satisfaction with device wearing;
• Bilateral device placement rate, and;
• Development of a profile for an appropriate candidate for the Essure procedure

The study population of the two studies combined consisted of 664 women in whom bilateral device placement was achieved after one or more attempts (200 in the Phase II study and 464 in the Pivotal trial). All study participants were between 21 and 45 years of age and were seeking permanent contraception prior to enrollment in the study.

Additionally, all women had at least one live birth, had regular cyclical menses and were able and willing to use alternative contraception for the first three months following Essure micro-insert placement.

An Essure device placement procedure was attempted on each fallopian tube. In the Pivotal trial, a pelvic x-ray was performed within 24 hours following device placement to capture a baseline evaluation of device location. Participants were instructed to use either a barrier contraceptive method or oral contraceptives for the first three months following the device placement procedure.

A hysterosalpingogram (HSG) was performed three months post-procedure to evaluate device location and fallopian tube occlusion. If both fallopian tubes were occluded and both devices were in satisfactory location, then the participant was instructed to discontinue use of alternative contraception and rely on the Essure micro-inserts for prevention of pregnancy. Women were evaluated to assess any adverse symptoms or events and post-procedure satisfaction at 1,1½, 2, 3, 4, and 5-year intervals. A Bayesian perspective was adopted to combine efficacy information across trials, and statistically age-adjusted for comparison to the CREST study results.

The most recent data from these ongoing studies was presented at the 2005 Annual Meeting of the American Association of Gynecologic Laparoscopists. 12 Bilateral micro-insert placement and confirmation of tubal occlusion was achieved in 643 women. The mean duration of follow-up was 52.9 months for the Phase II study and 42.5 months for the Pivotal study. Persistent pain or bleeding has not been reported by any of the study participants. Recurrent pain (reported at more than one follow-up visit) pain and bleeding were rarely reported. Sixteen hysterectomies have been reported, none of which was determined to be due to the Essure procedure.

To-date no failures have occurred with up to five years (n=75) and 29,357 women-months of follow-up. The table below provides efficacy rates for the combined trials.

Age-adjusted Posterior cumulative Bayesan efficacy rates (posterior means) for the Essure procedure: Phase II and Pivotal trials combined*

1 year	2 years	3 years	4 years	5 years
99.95%	99.90%	99.84%	99.80%	99.74%**

* Age adjustments are for comparison to the CREST study as a reference population

**Represents 75 Phase II patients who have completed 5-year follow-up. No patients in the Pivotal study have reached the 5-year follow-up visit at this time.

Among women in the Phase II study, 99% rated their tolerance of wearing the Essure micro-insert as “Good” to “Excellent”. Within the Pivotal study group 99% rated their comfort for wearing the Essure micro-insert as “Good” to “Excellent” and 97% rated their satisfaction as “Somewhat” to Very Satisfied”.

These data indicate that hysteroscopic interval tubal sterilization with micro-inserts is well tolerated, results in high patient satisfaction and effective permanent contraception.

Since the introduction of the Essure procedure, extensive physician training has been conducted both in proficiency in hysteroscopy, as well as performance of the procedure. Qualified physicians have been provided with information and skills necessary to select appropriate patients, perform competent procedures and manage technical issues or adverse events related to the placement of the micro-insert. The training requirements include knowledge of hysteroscopy, successful completion of a physician training course at a site approved by Conceptus, Inc., a successful completion of simulated performance of the procedure, and completion of (typically) five cases under a designated preceptor to assure competency. To-date thousands of physicians worldwide have been trained and are performing the Essure procedure routinely in their practices. In the United States, residency programs are increasingly having residents learn this skill along with other routine gynecological procedures. At present there have been tens of thousands successful bilateral placements of Essure micro-inserts worldwide.

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October 2006

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