Essure safety a high-priority issue, says FDA

September 30, 2015

The FDA looks at the benefit/risk profile of Essure. And, what place does MRI have in breast cancer treatment? Plus: A look at ovarian stimulating agents.

Establishment of a patient registry, collection of clinical and bench data, and changes to labeling were among the postmarket measures discussed by an expert panel convened by the Food and Drug Administration (FDA) on September 24 to weigh the benefit/risk profile of Essure. The session, which brought together representatives from the National Institutes of Health, the device’s manufacturer, women’s health experts, and patients, was triggered by a dramatic increase in voluntary adverse events reports about the contraceptive implant.

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Essure is a spring-like device that is placed in the proximal section of each fallopian tube lumen. The in-office procedure is performed under hysteroscopic guidance. According to testimony from the manufacturer at the meeting, an estimated 1 million such implantations have been performed worldwide, the majority of them in the United States following its approval for marketing in 2002.

The product was approved by the FDA based on 2 prospective clinical trials performed by the sponsor and reviewed by the agency and its Obstetrics and Gynecology Devices Advisory Panel. The manufacturer was required to continue gathering data from patients in ongoing Phase II and Pivotal studies out to 5 years after discontinuation of alternative contraception and to conduct a new study documenting the bilateral placement rates for newly trained physicians.

Since 2004, more than 5,000 Medical Device Reports (MDRs) about Essure have been submitted to the FDA’s Manufacturer and User Facility Device Experience (MAUDE) database, the majority (4,439) between 2013 and 2015. Of the complaints, 3,516 have been about abdominal or pelvic pain and/or cramping, 1,580 about bleeding irregularities, 878 about allergy/hypersensitivity, 337 about pregnancy, and 227 about migration of the device outside the uterus. 

The panel convened by the FDA was asked to review and discuss data presented by the agency, manufacturer, and members of the clinical and patient communities and specific safety events and potential risk mitigation steps. They also considered possible collection of additional preclinical or clinical data and offered their perspectives on Essure’s overall risk/benefit profile.

Although the panel issued no formal conclusions, the members expressed the potential need for:

·       Changes to the device’s labeling to make clear that Essure is a permanent implant

·       Additional patient counseling around the nature of the implantation procedure and the benefits and risks of the device;

·       Additional training for physicians on how to insert and remove it;

·       More long-term data on patient outcomes with Essure;

·       An “early intervention” protocol for patients with implants who may be experiencing adverse effects; and

·       Bench testing and development of a patient registry to help resolve questions about adverse events in Essure users, such as hypersensitivity issues. 

In preparation for the meeting, the agency created a docket for public comment on Essure, which will remain open until October 24. All interested parties are encouraged to submit comments for consideration by the Agency to http://www.regulations.gov

Said an FDA spokesperson in summing up the proceedings, “Over the past 2 years, the agency has become aware of a growing number of safety concerns with Essure from women and physicians. The FDA considers this to be a high-priority issue and will inform the public about next steps.”

 

NEXT: MRI and breast cancer treatment

 

Does MRI use impact breast cancer treatment?

Preoperative magnetic resonance imaging (MRI) may lead to more aggressive care for breast cancer, including contralateral prophylactic mastectomies, according to the results of a Canadian retrospective cohort study.

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Published in JAMA Oncology, the analysis was of information from  administrative healthcare databases in Ontario that represented 14 geographic regions. The 53,015 women identified by the authors were treated for primary operable breast cancer from 2003 to 2012. Primary measures included the use of preoperative MRI by year, geographic region, and breast cancer stage.

In7824 (14.8%) of the cases assessed, preoperative MRI was performed. Over the course of the study period, the use of the technology increased 8-fold across all cancer stages, from 3% to 24% (P < .001 for trend). Factors tied to MRI usage included higher Charlson morbidity score, surgery performed at a teaching hospital, fewer years of surgeon experience, higher socioeconomic status, and younger age.

Multivariate analyses showed that preoperative breast MRI was linked to a higher likelihood of postdiagnosis breast imaging (odds ratio [OR], 2.09; 95% CI, 1.92-2.28), postdiagnosis breast biopsies (OR, 1.74; 95% CI, 1.57-1.93), postdiagnosis imaging to assess for distant metastatic disease (OR, 1.51; 95% CI, 1.42-1.61), mastectomy (OR, 1.73; 95% CI, 1.62-1.85), contralateral prophylactic mastectomy (OR, 1.48; 95% CI, 1.23-1.77), and a longer than 30-day wait to surgery (OR, 2.52; 95% CI, 2.36-2.70).

Researchers concluded that using preoperative MRI leads to a large increase in ancillary investigations, surgery wait time, and contralateral prophylactic mastectomies. The researchers did note some limitations of their study, including lack of detail on whether treatment decisions were altered based on the test results. Lifetime or baseline cancer risks in the cohort also could not be addressed nor could long-term outcomes of recurrence and survival because of the nature of the databases.

 

NEXT: Looking at ovarian stimulation agents

 

Examining ovarian stimulation agents

The literature to date on aromatase inhibitors suggests that they may produce higher pregnancy rates than drugs that are the standard of care for ovarian stimulation. Results of a new multicenter trial, however, run counter to that thinking, showing significantly lower rates of multiple gestations and live births in women with unexplained infertility who were given letrozole rather than gonadotropin, but not clomiphene.

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The findings are based on an analysis of data from 900 couples with unexplained fertility. The women were aged 18 to 40 years, and had regular menses and a normal uterine cavity with at least one patent fallopian tubes. The male partners had a semen specimen of at least 5 million sperm per milliliter.  The women received either gonadotropin via subcutaneous injection, or clomiphene or letrozole by coated tablet. Usage of clomiphene or letrozole were assigned in a double-blind fashion.

Following treatment with gonadotrophin, clomiphene, or letrozole, clinical pregnancies were reported in 35.5%, 28.3, and 22.4% of all cycles, respectively. Live births occurred in 32.2% of all gonadotrophin cycles, 23.3% of all clomiphene cycles, and 18.7% of all letrozole cycles. Pregnancy rates tied to letrozole were significantly lower than with gonadotropin or clomiphene, (P = 0.003) or gonadotrophin alone (P < .001), but not with clomiphene alone (P = 0.10). The multiple gestation rate for letrozole, which was 9 of 67 pregnancies or 13%, was not significantly different than that seen with gonadotropin or clomiphene (42 of 192, 22%; P = 0.15) or clomiphene alone (8 of 85, 9%; P = 0.44). It was lower than the rate for gonadotrophin alone, which was 34 of 107 pregnancies, 32% (P = 0.006).

In addition, all multiple gestations in the clomiphene and letrozole groups were twin gestations, while the gonadotrophin treatment resulted in 24 twin and 10 triplet gestations. No significant differences were seen across the treatment groups in congenital anomalies, major fetal complications, or major neonatal complications. The rates of loss among established pregnancy also did not differ significantly for the various treatments.

The researchers concluded that ovarian stimulation with letrozole leads to a significantly lower chance of multiple gestation, but also carries a lower frequency of live birth when compared to gonadotrophin. No significant differences were found between letrozole and clomiphene.

Commenting on the limitations of their study, the authors noted the lack of blinding for the gonadotropin group and cautioned that it was not powered comparison of the individual arms.