BBI Contributing Editor
WASHINGTON – The XVI World Congress of the International Federation of Gynecology and Obstetrics (FIGO; London), held here in early September, covered the wide range of issues typical of OB/GYN conferences, including incontinence, infertility and assisted reproductive technology, oncology, menopause management and birthing issues. However, the center stage of this meeting was grabbed by the field of contraception, as new data on leading-edge technology was provided alongside of the discussion of traditional contraceptive methods.
Contraceptive methodologies have particularly been in the limelight recently, with the FDA approval of the highly controversial abortion pill RU-486. An anti-progestin agent generically called mifepristone and marketed under the brand name of Mifeprex by a small private company, Danco Laboratories (New York), RU-486 now adds another option to the many choices that are available to couples intent on avoiding a pregnancy. Nevertheless, there still appears to be plenty of room for new technology in a significantly underserved market.
As shown in Table 5, the most common contraceptive techniques each have well-known failure rates, compliance requirements and side effects/ drawback profiles. The March/April 1999 issue of Family Planning Perspectives, which contained an article titled "Contraceptive Failure, Method-Related Discontinuation and Resumption of Use: Results from the 1995 National Survey of Family Growth," authored by James Trussell and Barbara Vaughan, noted that almost half of all pregnancies in the U.S. are unintended.
|Table 5:Analysis of Common Contraceptive Methods|
|Method||Failure Rate||Compliance||Side Effects/ Drawbacks|
|Tubal ligations||0.5%||None||Post-operative complications and surgical risks|
|Oral contraceptives||6.9%||Daily||Hormonal changes, stroke, heart attack, ovarian cysts,pulmonary embolism|
|Diaphragm||8.1%||Occurrence||Vaginal infection, bladder infection, cervical cancer|
|Intrauterine||0.5%-2.0%||Monthly self-exam||Uterine perforation, anemia, irregular menses|
|Injectables||3.2%||3 months||Hormonal changes, irregularmenses|
|Implantables||2.3%||3 years||Hormonal changes, irregular menses|
Source: 1995 National Survey of Family Growth
Although most couples who want to avoid pregnancy practice some form of contraception, many women still become pregnant due to either a lack of effectiveness of their contraceptive method or a difficulty in using the method consistently and correctly. Overall, 9% of women experience a pregnancy during 12 months of use of a reversible contraceptive, such as the oral contraceptive pill, condom, spermicides, or diaphragm.
As a result of these significant shortcomings, today's women and their spouses are unhappy with their current choices. According to the 1995 Survey of Family Growth, discontinuing the use of reversible contraceptives is very common. Within the first six months of use, 31% of women discontinue their use, and within 12 months, 44% of women discontinue their use. On average, a woman who uses reversible methods of contraception from the ages of 15 to 45 will discontinue use for a method-related reason almost 10 times.
Although discontinuing contraception is common, most women resume some form of contraception shortly after discontinuation. Within one month of discontinuation, 68% of women resume contraception, with about 17% relying on oral contraceptives, 5% on vasectomy or tubal sterilization, 25% on the male condom, and 20% on other methods. After 12 months of discontinuation, 82% of women resume some form of contraception, with 21% relying on the pill, 6% on vasectomy or tubal sterilization, 32% on the male condom, and 23% on other methods. The studies also revealed that switching to sterilization increases with increasing age.
As shown in Table 6, female surgical sterilization, a permanent form of contraception, is the most common form of contraception currently used in the U.S., with approximately 800,000 surgical tubal ligations performed annually. Some 18% of women use sterilization, followed by 17% who use the oral contraceptive pill, 13% who rely on condom use by their male partners, and 7% who rely on male sterilization (vasectomy). Among women under the age of 30, the birth control pill is the leading method of contraception, while among women 30 to 44 years of age, female sterilization is the leading method. Almost 30% of women between the ages of 30 and 44 use female sterilization.
|Table 6:Types of Contraception Used in the U.S.*|
|Tubal (surgical) ligation||18%|
|Other methods|| |
* Total number of women surveyed: 10,847
Source: 1995 National Survey of Family Growth
The most common method for blocking the fallopian tubes involves tying the tube – using either rings or clips – and then cutting them or cauterizing them in a procedure called tubal ligation. One of the most commonly employed devices is the Filshie Clip, a titanium clip with an inner silicone rubber lining that compresses tissue as the clip locks onto the fallopian tube. It is sold by privately-owned Avalon Medical (Williston, Vermont). Most commonly, the fallopian tubes are accessed by a laparoscope, which enables the procedure to be performed under a local anesthesia and with conscious sedation on a minimally-invasive basis, which is less painful and traumatic to the patient than an open incision procedure. The laparoscopic procedure typically takes about 40 to 60 minutes and requires four to five hours of recovery in the hospital and a few days of post-op recuperation. The cost of surgical tubal ligation ranges from $2,500 to $8,000, depending on the degree of invasiveness.
Tubal ligation is a very effective form of permanent contraception, with a failure rate of only about 0.5%. While these results are attractive, many women desiring permanent contraception do not select tubal ligation due to the risks and discomfort associated with surgery and general anesthesia. The OB/GYN literature contains several references to the fact that anesthesia is an important cause of death from tubal sterilization.
The market opportunity for the prevention of an unwanted pregnancy is large. Worldwide, the United Nations estimates that roughly 58% of couples use some form of contraception, with average levels of use higher in the more-developed regions than in the less-developed regions. According to the 1995 National Survey of Family Growth conducted by the National Center for Health Statistics (Hyattsville, Maryland) and the Centers for Disease Control and Prevention (Atlanta, Georgia), more than 64% of women aged 15 to 44 years in the U.S. were using some form of contraception.
As shown in Table 7, in the developed countries there are an estimated 2.1 million tubal ligation procedures performed annually. Around the world, an estimated 13 million surgical tubal ligations are performed each year, with almost eight million sterilization procedures (including both tubal ligations and vasectomies) performed annually in China alone, bringing the worldwide sterilization market to more than 15 million procedures.
|Table 7: Estimated Annual Number |
of Female Sterilization Procedures
Source: United Nations
The benefit of the high efficacy of tubal sterilization is offset by the disadvantages of its invasiveness and cost. As a result, since the introduction of laparoscopic technology about 25 years ago, there has been a concerted search for a transcervical method of accessing the fallopian tubes and eliminating the trauma, complications and cost associated with tubal surgery. Numerous approaches have been attempted, including the insertion of quinacrine pellets into the uterus, the delivery of methyl-cyanoacrylate and various types of plugs into the fallopian tubes, and the use of radiofrequency energy from within the fallopian tube in an effort to achieve occlusion by scarring. For various reasons, all these methods ultimately have been unsuccessful.
Perhaps the most promising transcervical method yet developed is undergoing clinical evaluation by Conceptus (San Carlos, California). Its device, called the STOP (Selective Tubal Occlusion Procedure), consists of a soft and flexible micro-coil with a maximum length of 4 centimeters and a maximum diameter of 2 millimeters. The inside of the coil contains polyester fibers, a synthetic biocompatible material that is well tolerated in the body and is known to promote tissue growth. Polyester has been safely used in a variety of other medical applications, including artificial heart valves and stent grafts. Table 8provides comparative data between the STOP procedure and surgical tubal ligation.
Table 8: Comparison Between STOP Procedure and Tubal Ligation
|STOP||Surgical Tubal Ligation|
|Where performed||Outpatient||Hospital operating room|
|Procedure time||15 to 20 minutes||40 to 60 minutes|
|Recovery time||1 hour||4 to 5 hours|
|Days off work||Less than 1 day||3 to 4 days|
|Estimated cost||$1,500||$2,500 to $8,000|
|Sources: The BBI Newsletter, Salomon Smith Barney|
The STOP procedure requires the use of a hysteroscope, a device that is used for both diagnostic and operative purposes by some OB/GYN practitioners. Under hysteroscopic viewing of the uterus, the physician gains access to the fallopian tubes using a proprietary transcervical tubal access catheter and guidewire system. First, the STOP catheter is inserted into the uterus through a channel in the hysteroscope. The catheter is then inserted into the fallopian tube until the marker on the catheter reaches the tubal ostium (opening), which indicates proper placement. The outer catheter is withdrawn to expose the wound-down STOP micro-coil, and then the inner catheter is withdrawn to allow the coil to expand. Finally, the delivery wire is removed, leaving the STOP device in place in the fallopian tube. In the hands of an experienced hysteroscopist, the entire STOP procedure takes about 20 minutes.
The mechanism of contraception for the STOP device is based on two features: the deployment and expansion of the micro-coil in the tubal lumen and then local, benign tissue reaction in response to the STOP device. The deployment of the micro-coil begins the process of occluding the tubes, which is similar to the hyperplasic tissue response that causes in-stent restenosis after coronary stenting. Whereas tissue growth in the coronary vessels is an undesirable side effect, in the setting of the fallopian tubes, this excessive tissue growth leads to the desired effect. The polyester fibers within the STOP micro-coil also foster tissue growth from the wall of the fallopian through the micro-coil. Eventually, this tissue response results in total occlusion of the tubal lumen, thereby leading to permanent contraception. Extensive analysis of the STOP histological data has shown that this occlusive tissue response is predictable and localized to the area surrounding the STOP device.
At the FIGO meeting, Dr. Jay Cooper, associate professor of medicine at the University of Arizona College of Medicine (Tucson, Arizona) and the principal investigator for the Conceptus Phase III pivotal trial, reported excellent clinical results from the company's Phase II human clinical studies and noted that this approach could "change the face of female sterilization." At six months, all 207 women who underwent the STOP procedure had successful bilateral occlusion of their fallopian tubes, with the average procedure taking 19 minutes under either intravenous sedation or local anesthetic. Adverse events were uncommon, with 3% of the cases experiencing device placement problems and 1% with problems relating to the malfunctioning of the device itself. Importantly, no pregnancies, a critical endpoint in this trial, have been reported with the current version of the device. Patient satisfaction with this approach has been excellent, with 96% of the women describing their experience as excellent.
Conceptus initiated its Phase III trial in May, plans to enroll a total of 400 patients at 10 to 20 investigational sites in the U.S., Europe and Australia, and complete the trial sometime in the first half of 2001. After a one-year follow-up, the company should be in a position to file its premarket approval application sometime in 2002, with a possible final FDA approval in 2003. The STOP device is eligible for marketing in Australia and the CE mark is expected late this year or early next.
Competition in this attractive market space appears limited. A privately-owned, venture capital-backed company, Adiana (Redwood City, California), also is developing a transcervical tubal occlusion product. Its proprietary device incorporates two separate mechanisms that are designed to achieve tubal occlusion. First, a tiny amount of a material commonly used (but undisclosed by the company) in medicine is implanted by a catheter under hysteroscopic guidance in the proximal end of the fallopian tube. This hysteroscopically guided catheter then delivers a small dose of very low wattage radiofrequency energy that is designed to stimulate the normal tissue within the fallopian tubes to grow. Adiana is performing early human clinical trials on pre-hysterectomy and perihysterectomy patients in Mexico and Australia and hopes to begin its domestic clinical trial sometime in 2001.
The market opportunity for transcervical fallopian tube occlusion is potentially quite large. There are more than 60 million women of reproductive age (15 to 44 years of age) in the U.S. alone, with roughly 23.7 million using some type of long-term contraception. Of those using long-term contraception, some 7.5 million have had two or more children. These 7.5 million women represent the potential domestic market for transcervical fallopian tube occlusion. The tubal surgical sterilization procedure, which causes trauma and discomfort, has been a somewhat unattractive choice for women. Conversely, a minimally invasive, virtually painless, outpatient procedure could easily become an attractive alternative for many women, especially those with two or more children.
Couples whose male partner is open to permanent contraception with a vasectomy may also be candidates for the STOP procedure. Vasectomy also offers permanent contraception with a minimally invasive, outpatient procedure performed under a local anesthesia. It is generally safer and less expensive than surgical tubal ligation for women. About 300,000 vasectomies are performed annually in the U.S.