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| General |
| Study Status |
Ongoing |
| 522 Number / Requirement Number |
PS160001 / PSS001 |
| Date Original Plan Accepted |
09/02/2016
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| Date Current Plan Accepted |
07/01/2022
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| Study Name |
Postmarket Surveillance Study
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| Device Name |
Essure system for permanent birth control
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| Root Document Number |
P020014
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| General Study Protocol Parameters |
| Study Design |
Prospective Cohort Study
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| Data Source |
New Data Collection
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| Comparison Group |
Concurrent Control
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| Analysis Type |
Descriptive
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| Study Population |
Transit. Adolescent B (as adults) : 18-21 yrs,
Adult: >21
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| Detailed Study Protocol Parameters |
| Study Objectives |
Open-label, non-randomized, prospective observational cohort study of two cohorts of subjects who chose to undergo either hysteroscopic sterilization (Essure) or laparoscopic tubal sterilization.
Interim Data Posting
Information regarding interim study progress (such as number of study sites enrolled and number of patients enrolled) will be posted after the review of each study report as applicable. Study results will be posted at four timepoints, due to the statistical methods required for group comparisons (propensity score matching). An update will occur once enrollment into the Essure arm is completed, once all subjects have reached one-year follow-up, three-year follow-up, and after study completion.
The FDA may also post on its website or otherwise make public postmarket surveillance interim summary data or the FDA’s analyses thereof when appropriate to protect the public health, for example when interim results raise safety concerns or may otherwise impact treatment.
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| Study Population |
The study population includes subjects who are at least 21 years of age who have not been pregnant within the past 6 weeks.
The study population includes women who chose to undergo hysteroscopic sterilization (Essure) or laparoscopic tubal sterilization.
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| Sample Size |
On July 20, 2018, Bayer announced that Essure sales would stop in the United States after December 2018. Health care providers could implant Essure up to one year from the date the device was purchased. The planned sample size of 1,400 women per arm was no longer feasible. The FDA required study enrollment into the Essure arm to continue as long as Essure was available in the U.S. Enrollment into the laparoscopic tubal sterilization arm would stop after it reached approximately 2:1 ratio with the Essure arm.
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| Key Study Endpoints |
Main Safety Endpoints:
• Chronic lower abdominal and/or pelvic pain
• Abnormal uterine bleeding (new onset or worsening)
• Hypersensitivity and allergic reactions, and autoimmune disorders (new onset) or autoimmune- like reactions
• Invasive gynecologic surgery including Essure insert removal
Secondary Safety Endpoints:
• Other adverse events
• In the event of a device removal or event of interest, additional data collection may include bloodwork, pathology, histology, and metallurgic testing, as appropriate
Effectiveness:
• Pregnancy
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| Follow-up Visits and Length of Follow-up |
Follow-up measures include adverse event assessment, medical history including gynecological procedures, patient reported outcome (PRO) measures for chronic pelvic pain and abnormal uterine bleeding, levels of inflammatory markers and human leukocyte antigen (HLA) type, additional bloodwork for women with certain adverse events, and analysis of removed Essure devices.
60 months
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| Interim or Final Data Summary |
| Interim Results |
Database lock of March 10, 2023:
This study is descriptive; therefore, it is not designed or powered to detect statistical differences between the Essure and laparoscopic tubal sterilization (LTS) groups. This study is ongoing, and results reported here are interim and subject to change. Final conclusions should not be made until the study is completed and final adjudication of the data is performed.
The data summarized below are from the first interim analysis performed in 2020 after all patients completed enrollment, the second interim analysis performed in 2021 after all patients completed one year of follow-up, and the third interim analysis performed in 2023 after all patients completed three years of follow-up. Because the patients in the study are at different points in their follow up, the results presented are the overall interim study results from all patients thus far. The final analysis will be performed after all patients have completed 5 years of follow-up.
Study is ongoing and as of the database lock, patients are still completing 48-month and 60-month follow-up visits.
Study enrollment was ended as of December 31, 2019.
Total of 1130 patients enrolled in the study at 60 investigational sites in the U.S.
- 340 patients in the Essure group and 790 patients in the LTS group
- 285 (Essure) and 705 patients (LTS) attended the procedure visit
- 280 (Essure) and 705 patients (LTS) had the procedure attempted and serve as the full analysis set to determine rates of events of interest
- mean (+/- SD) age at the time of enrollment was 33.5 (+/- 5.79) years
- majority of patients (788/985, 80.0%) were reported as White
94.6% (265/280) had successful bilateral placement of Essure after 1 or 2 placement attempts
- only patients who had successful bilateral placement and reached 3 months post-Essure placement were eligible for reliance assessment (or confirmation test)
- reliance rate was 92.3% (191/207), which represents the number of patients told to rely out of the number of patients with confirmation testing attempted at the time of the interim database lock
Tubal occlusion was successfully achieved for 99.4% (701/705) LTS patients.
At the time of the interim database lock, approximately half of enrolled patients had discontinued the study mainly due to lost to follow-up and withdrawal from the study. For the Essure group, 51.5% (175/340) of enrolled patients have discontinued the study, with 31.5% (107/340) due to lost to follow-up. For the LTS group, 48.1% (380/790) of enrolled patients have discontinued the study, with 35.7% (282/790) due to lost to follow-up. Per the study protocol, if a patient misses a follow-up visit but returns to a site at a later follow-up time point and wishes to continue participation in the study, they will no longer be considered lost to follow-up. The interim lost to follow-up rates in both groups may be in part due to COVID-19 related challenges, and other external factors. In 2022, the FDA requested that Bayer develop and implement additional strategies to improve follow-up rates in the study. Since 2022, Bayer has taken measures to reduce interim lost to follow-up rates at 3 years in both groups. The current study status is now “ongoing” because the progress of the study is consistent with the study plan. The FDA will continue to closely monitor lost to follow-up rates in the study and work with Bayer to take additional measures as needed.
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| Final Safety Findings |
Interim Results - Safety Endpoints*
*For interim analysis of endpoints, propensity score matching was performed with the full analysis set. The 1:1 propensity-score matched patients serve as the adjusted full analysis set population for comparisons, with 264 patients in each group (unless otherwise noted).
Chronic lower abdominal and/or pelvic pain: For the interim analysis completed in 2020 and 2021, the overall adjusted incidence of patients with reported events of chronic lower abdominal and/or pelvic pain post-sterilization procedure was 9.1% (24/264) and 12.5% (33/264) in the Essure group, and 4.5% (12/264) and 8.7% (23/264) in the LTS treatment group. As of the 2023 interim analysis, the overall adjusted incidence of patients with reported events of chronic lower abdominal and/or pelvic pain was 14.4% (38/264) in the Essure group and 10.2% (27/264) in the LTS group.
Abnormal uterine bleeding (new onset or worsening): Interim analysis completed in 2020 and 2021, the overall adjusted incidence of patients with reported events of abnormal uterine bleeding post-sterilization procedure was 16.3% (43/264) and 20.5% (54/264) in the Essure group, and 10.2% (27/264) and 18.6% (49/264) in the LTS treatment group. As of the 2023 interim analysis, the overall adjusted incidence of patients with reported events of abnormal uterine bleeding was 21.6% (57/264) in the Essure group and 20.8% (55/264) in the LTS group.
Hypersensitivity and allergic reactions, and autoimmune disorders or autoimmune- like reactions:
For the interim analysis completed in 2020, only the unadjudicated, adjusted incidence of reported allergic/hypersensitivity type reactions was available. The overall unadjudicated, adjusted incidence of patients with reported events of possible new onset or worsening allergic/hypersensitivity type reactions post-sterilization procedure was 22.3% (59/264) in the Essure group and 12.5% (33/264) in the LTS group. A blinded, independent adjudication committee reviewed the reported events to determine if events represent allergic/hypersensitivity reactions. For the 2021 interim analysis, the incidence of patients with adjudicated new or worsening allergic/hypersensitivity reactions was 1.1% (3/280) in the Essure group and 0.7% (5/705) in the LTS group. The adjudicated, adjusted incidence of new or worsening allergic/hypersensitivity reactions was 0.8% (2/264) in the Essure group and 0.8% (2/264) in the LTS group. As of the 2023 interim analysis, the incidence of patients with adjudicated new or worsening allergic/hypersensitivity reactions was 2.1% (6/280) in the Essure group and 0.9% (6/705) in the LTS group. The adjudicated, adjusted incidence of new or worsening allergic/hypersensitivity reactions was 1.9% (5/264) in the Essure group and 1.1% (3/264) in the LTS group.
For the interim analysis completed in 2020, only the unadjudicated, adjusted incidence of reported newly diagnosed autoimmune disorders post-sterilization procedure was available. The overall unadjudicated, adjusted incidence of patients with reported events of possible newly diagnosed or worsening autoimmune disorders post-sterilization procedure was 0% in the Essure group and 1.5% (4/264) in the LTS group. A blinded, independent adjudication committee reviewed the reported events to determine if events represent autoimmune disorders. For the 2021 interim analysis, the incidence of patients with adjudicated autoimmune disorders was 0% in the Essure group and 0% in the LTS group. As of the 2023 interim analysis, the incidence of patients with adjudicated autoimmune disorders was 0% in the Essure group and 0% in the LTS group.
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| Final Effectiveness Findings |
Interim Results - Safety Endpoints continued*
Gynecologic surgical procedures (excluding second placement attempts; including Essure removal):
For the interim analysis completed in 2020, the overall adjusted incidence of patients undergoing gynecologic surgical procedures after the sterilization procedure was 19.7% (52/264) in the Essure group and 3.0% (8/264) in the LTS group. The higher incidence in the Essure group relative to the LTS group was driven primarily by Essure removal and endometrial ablation procedures in Essure patients. The adjusted incidence of device removal was 6.8% (18/264) in the Essure group and 0% in the LTS group. The adjusted incidence of endometrial ablation was 10.2% (27/264) in the Essure group and 2.3% (6/264) in the LTS group.
For the 2021 interim analysis, the overall adjusted incidence of patients undergoing gynecologic surgical procedures after the sterilization procedures was 20.8% (55/264) in the Essure group and 4.5% (12/264) in the LTS group. The adjusted incidence of device removal was 7.6% (20/264) in the Essure group and 0% in the LTS group. The adjusted incidence of endometrial ablation was 11.0% (29/264) in the Essure group and 3.4% (9/264) in the LTS group.
As of the 2023 interim analysis, the overall adjusted incidence of patients undergoing gynecologic surgical procedures after the sterilization procedures was 23.9% (63/264) in the Essure group and 7.6% (20/264) in the LTS group. The adjusted incidence of device removal was 9.5% (25/264) in the Essure group and 0% in the LTS group. The adjusted incidence of endometrial ablation was 12.1% (32/264) in the Essure group and 6.4% (17/264) in the LTS group.
For the interim analysis completed in 2020, a total of 19 patients had 24 Essure removal events. For the 2021 interim analysis, 21 patients had 26 Essure removal events. As of the 2023 interim analysis, 26 patients have had 34 Essure removal events. Patients may have undergone more than one procedure at the time of device removal (i.e., hysterectomy AND salpingectomy).
- Essure removal procedures included salpingectomy (19 events), hysterectomy (9 events), salpingotomy (5 events), and cornual resection (1 event)
- primary reasons for Essure removal, as described by the investigators, were the following: patient request (6 patients), management of adverse events related to Essure (8 patients), management of adverse events not related to Essure (3 patients), in conjunction with other gynecologic surgery (5 patients), device failure/pregnancy (1 patient), and “unable to rely and no associated adverse event” (3 patients)
- category of “management of adverse events related to Essure” included 1 patient with Essure micro-insert outside of the fallopian tube, 4 patients with pelvic pain, 1 patient with pelvic and back pain, 1 patient with abdominal pain, and 1 patient with perforation of fallopian tube
- overall cumulative probability of device removal for any reason is 15.7% at approximately 56 months
- for patients who were told to rely, cumulative probability of device removal is 12.3% at approximately 54 months after insertion
- device removal procedures ranged from 1 day to 56 months after Essure placement
Other adverse events:
For the interim analysis completed in 2020, 2021, and 2023, the overall adjusted incidence of patients with unintentional perforation of the uterus, fallopian tubes or cervix by any surgical instrument or sterilization device was 1.9% (5/264) in the Essure group and 1.1% (3/264) in the LTS group.
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| Study Strengths and Weaknesses |
Interim Results - Safety Endpoints continued*
For the interim analysis completed in 2020, 2021, and 2023, the overall adjusted incidence of patients with expulsion (insert displaced toward the cervix or vagina and retrieved through the vagina hysteroscopically) was 0.4% (1/264) in the Essure group and 0% (0/264) in the LTS group.
For the interim analysis completed in 2020, 2021, and 2023, the overall adjusted incidence of patients with dislocation (insert displaced out of the uterus, fallopian tube, or in the intraperitoneal cavity and retrieved via laparoscopy) was 0.4% (1/264) in the Essure group and 0% (0/264) in the LTS group.
Interim Results - Effectiveness Endpoint
Pregnancy:
For the interim analysis completed in 2020, one patient in the Essure group became pregnant after being told she could rely on the device for permanent birth control, and 5 patients in the LTS group became pregnant after tubal occlusion was successfully achieved. For the 2021 interim analysis, one patient in the Essure group and 7 patients in the LTS group became pregnant. As of the 2023 interim analysis, two patients in the Essure group and 6 patients in the LTS group became pregnant.
- cumulative probability of no pregnancy after sterilization procedure is 98.9% at approximately 12 months and beyond for the Essure group and 99.1% at approximately 12 months and beyond for the LTS group
Interim Results - Limitations
This study is not randomized and women are not blinded to their treatment group. The five year follow-up of patients in the study is ongoing and these results are interim. As such, results reported are subject to change and final conclusions should not be made based on these interim results. Final analyses of endpoints will not be completed until the study concludes and final adjudication of the data is performed.
Previous Update- Database lock of April 28, 2022:
Study is ongoing and as of the database lock, patients are still completing 36-month, 48-month, and 60-month follow-up visits. A total of 1130 patients were enrolled in the study, with 340 patients in the Essure group and 790 patients in the LTS group. All patients have completed two years of follow-up. Since the last database lock of March 11, 2021*, more enrolled patients have discontinued the study mainly due to lost to follow-up and withdrawal from the study. For the Essure group, 47.4% (161/340) of enrolled patients have discontinued the study, with 29% (100/340) due to lost to follow-up. For the LTS group, 43.5% (344/790) of enrolled patients have discontinued the study, with 33% (257/790) due to lost to follow-up. The FDA changed the study status to “progress inadequate” due to the increase in interim lost to follow-up rates in both groups from the previous database lock in 2021. "Progress Inadequate" means that the progress of the study is not consistent with the study plan. The interim lost to follow-up rates in both groups may be in part due to COVID-19 related challenges, and other external factors. Per the study protocol, if a patient misses a follow up visit but returns to a site at a later follow up time point and wishes to continue participation in the study, they will no longer be considered lost to follow-up. The FDA requested Bayer develop and implement additional strategies to improve follow-up rates in the study. The next interim analysis will be performed after all patients have completed 3 years of follow-up. The final analysis will be performed after all patients have completed 5 years of follow-up.
*(Database lock of March 11, 2021: At the time of the interim database lock, approximately one-third of enrolled patients had discontinued the study (Essure group: 125/340, 36.8%; LTS group: 247/789, 31.3%), mainly due to lost to follow-up and withdrawal from the study.)
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