June 10, 2003
Obstetrics and Gynecology Devices Advisory Panel Meeting
Open Session June 10, 2003
Mary Jo O’Sullivan, M.D.
University of Miami/Jackson Memorial Hospital
Joyce M. Whang, Ph.D.
Division of Reproductive, Abdominal, and Radiological Devices
Evelyn R. Hayes, Ph.D. College of Health and Nursing Sciences University
of Delaware Hugh Miller, M.D. Department of Obstetrics and Gynecology Arizona Health Science Center Jonathan W. Weeks, M.D. Suburban Hospital, Maternal-Fetal Medical Center Louisville, KY
Andrew I. Brill, M.D.
Department of Obstetrics and Gynecology
University of Illinois at Chicago
Charles C. Coddington, III, M.D.
Department of Obstetrics and Gynecology Denver Health Medical Center
Michael P. Diamond, M.D.
Department of Obstetrics and Gynecology
Wayne State University School of Medicine
Kinley Larntz, Ph.D.
School of Statistics, University of Minnesota
Michael Neuman, M.D., Ph.D.
Joint Program of Biomedical Engineering
University of Memphis
Nancy C. Sharts-Hopko, Ph.D.
College of Nursing, Villanova University
Kleia R. Luckner, J.D., M.S.N.
The Toledo Hospital
Mary Lou Mooney, R.A.C.
Nancy C. Brogdon
Director, Division of Reproductive, Abdominal, and Radiological Devices
Chief, Obstetrics and Gynecology Devices Branch
Julia Corrado, M.D.
Obstetrics and Gynecology Devices Branch
CALL TO ORDER
Panel Chair Mary Jo O’Sullivan, M.D., called the meeting to order at 8:31 a.m. and asked the panel members to introduce themselves. Panel Executive Secretary Joyce M. Whang, Ph.D., noted that upcoming panel meetings have been tentatively scheduled for September 8 and 9 and November 3 and 4, 2003. She also stated that three new voting members were present: Evelyn R. Hayes, Ph.D., Hugh Miller, M.D., and Jonathan W. Weeks, M.D. In addition, Andrew I. Brill, M.D., and Charles C. Coddington, III, are new panel consultants. Dr. Whang read the appointment to temporary voting status, which stated that Drs. Brill and Coddington as well as Michael P. Diamond, M.D., Kinley Larntz, Ph.D., Michael Neuman, M.D., Ph.D., and Nancy C. Sharts-Hopko, Ph.D., had been granted temporary voted status for the duration of the meeting. She then read the conflict of interest statement. Full waivers had been granted to Drs. Brill and Larntz for their interests in firms that could be affected by the panel’s recommendations. The Agency took into consideration certain matters regarding Drs. Brill, Miller, Neuman, and Sharts-Hopko, who reported current and/or past interests in firms at issue but in matters not related to the day’s agenda; they could participate fully.
Colin Pollard, Chief, Obstetrics and Gynecology Devices Branch, welcomed the panel and introduced several new branch employees. He read a letter of thanks from Linda Skladany, associate commissioner of external affairs, thanking Dr. Sharts-Hopko for her service over the past 4 years. Finally, he emphasized the importance of the panel’s input in FDA’s review of the device.
No comments were made.
Marc Finch, executive vice president, Microsulis Americas, Inc., said that the company specializes in understanding the effects of microwave-induced dielectric heating of human tissue. The Microwave Endometrial Ablation (MEA) System is a thermal ablation device intended to ablate the endometrial lining of the uterus in premenopausal women with menorrhagia due to benign causes for whom child bearing is complete. The technology for the proposed use has been in development since 1992. Clinical validations include the treatment of 655 subjects by 23 investigators in 11 investigational sites between 1994 and 2001.
Anderson, M.D., Ph.D., FACOG, co-lead investigator, U.S. pivotal trial,
listed treatment objectives for excessive uterine bleeding, then described the
MEA System. The device consists of a microwave generator, an applicator 8 mm in
diameter, and a treatment feedback display. After presenting a video that
illustrated MEA treatment, Dr. Anderson described the treatment process, which
The microwaves have a frequency of 9.2 gHz and penetrate to 3 mm; tissue heating occurs up to 6 mm from the tip. A thermocouple at the applicator tip measures the temperature of adjacent tissue. The temperature should stay in the 70 to 80°C degree range. If the temperature reaches 85°C, an alarm sounds; if it reaches 90°C, the device shuts off. If the temperature rise during the first 5 seconds is abnormal, the system pauses, and a screen prompt appears.
Ian Feldberg, senior executive vice president of technology, Microsulis, provided an overview of thermal penetration. Heating occurs to a depth of 5 to 6 mm through thermal conduction. Temperatures during the MEA procedure achieve coagulation but are not sufficient to physically remove tissue. The objective is to coagulate 5 to 6 mm of tissue.
analyzing maximum thermal penetration, the most extreme conditions were
assumed. A computer model was developed
, and bench
testing was performed with unperfused porcine liver.
With a maximum applicator temperature of 90°C at the tip and a maximum time of
12 minutes, the depth of thermal penetration was 9 mm. This figure
cannot be exceeded in living tissue due to the presence of blood cooling. In addition to preliminary bench
testing, the sponsor conducted a number of in vivo test in patients
undergoing hysterectomy. The device resulted in tissue necrosis of uniform
depth following treatment.
model predicts that maximum thermal penetration will vary from 6.4
mm to 7.2 mm for the maximum allowable period of 12 minutes.
blood perfusion of at least 50
percent of normal, penetration reaches
up to 8.1
mm. There is no difference
between the sponsor’s and FDA’s methodology in understanding perfusion effects.
The mathematical model represents thermal penetration to 8.1 mm in the case of putting the probe in a single spot and leaving it there for 12 minutes at 90°C; that would not happen clinically. Bench testing is theoretical, however; it is important keep a clinical perspective.
treatment is effective, has minimal risks, and carries limited patient
restrictions. It completely destroys the basal layer, has repeatable and
predictable results, and results in high patient satisfaction. In addition, it
can treat irregular cavities and cavities of many sizes and does not exclude fibroid
uteri. It requires
or operative hysteroscopy.
Claude Fortin, M.D., FACOG, co-lead investigator, presented the pivotal study results. The study took place at eight sites and involved 324 premenopausal women age 30 or older with PBLAC scores of at least 185. Two patients were excluded because the site withdrew from the study. The 107 patients in the control group received rollerball endometrial ablation (REA); the 215 patients in the experimental group received MEA. Follow-up took place at 2 weeks and at 3, 6, and 12 months. Dr. Fortin listed the inclusion and exclusion criteria. He emphasized that patients with myometrial wall thickness of less than 8 mm, as determined by transvaginal ultrasound, were excluded. Patients received 3.75 mg Lupron 3 to 5 weeks before treatment; immediately prior to treatment, hysteroscopy was performed to document normal cavity landmarks and intracavitary pathology. Hysteroscopy has great value as an adverse event mitigator. Five subjects were excluded from treatment following hysteroscopy (2 patients) and ultrasound (3 patients).
primary efficacy endpoint was a reduction in menstrual bleeding to a PBLAC
score of 75 or less at 12 months. The intent-to-treat population was used in
reporting all primary endpoint outcomes. Eighty-seven percent of MEA patients
and 83.2 percent of REA patients were considered treatment successes. Subjects
with lost or missing data were counted as failures. Secondary endpoints were
amenorrhea at 12 months, patient satisfaction, duration of treatment
in terms of anesthesia and procedure time, and anesthesia use. The MEA group
had significantly shorter procedure and anesthesia time than the REA group.
Patients in both groups were comparable in their levels of satisfaction.
Investigator training emphasized the importance of protocol adherence, completion of case report forms, use of the foam simulation unit for multiple practice sessions, and preceptorship of initial cases.
complications were reported. Procedural complications included four cases of
cervical laceration (
1 MEA and 1
REA), one case of cervical stenosis (MEA), and two cases of uterine perforation
during dilation prior to treatment (MEA). The most commonly reported adverse
events in the 24 hours postprocedure were nausea, vomiting, and uterine
cramping; the MEA group was more likely to experience those effects than the
REA group. Adverse events reported between 24 hours and 1 year included
endometritis (5 MEA and 1 REA), bacteremia (1 MEA), and pregnancy (1 REA).
The results of the pivotal trial demonstrate that MEA is safe and effective for its intended use. It can treat normal uterine cavities between 6 and 14 mm and cavities with fibroids smaller than 3 cm.
Ted Anderson, M.D., Ph.D., FACOG, co-chair, Microsulis Clinical Advisory Panel, described the commercial experience with the device outside the United States and the sponsor’s response to the reported adverse events. Commercial experience consists of 15,129 treatments as of the end of the first quarter 2003. A total of 12 perforation- and 13 non-perforation-related adverse events, resulting in 23 cases of bowel injury, were reported. In an additional two cases, investigators were unable to determine whether perforation had occurred. The sponsor has significantly reduced adverse events despite continued increase in the number of treatments and users.
With many adverse events, Microsulis’ internal review found deviations from the protocol. Corrective actions included requirement of Microsulis-certified preceptors in training. In addition, the company made modifications to the instructions for use. Recommendations for mitigation include diagnostic hysteroscopy in all patients prior to insertion of the MEA applicator, strict adherence to contraindications, and ultrasound evaluation of the uterine wall. After implementing the changes, adverse events immediately diminished, and none have been reported since November 2002. Because the applicator is returned to the company after its useful life, communication between company and users is ongoing; underreporting is unlikely.
Dr. Anderson then summarized the evidence for mitigation of adverse events from controlled clinical trials, including the U.S. pivotal study. In more than 3,600 treatments since November 2002 performed in accordance with the proposed instructions for use and incorporating preceptorship, no device-related adverse events have been reported.
Finch, senior executive vice president, Microsulis, described the physician
training used in conducting the clinical trial. The training includes printed
materials and preceptorship, which involves use of a foam uterus simulation
unit as well as observation and mentoring of initial cases. The current instructions
for use are similar to the document used in the clinical trial; they clearly
define the role of ultrasound screening and call attention to the need for
hysteroscopy. The patient assessment form is important because it documents
completion of ultrasound
The sponsor is proposing preceptorship for all U.S. users.
Mr. Finch concluded by emphasizing that when used in patients evaluated, screened, and treated in accordance with the proposed instructions for use, the MEA device is safe and effective for its intended use.
Veronica Price, Lead FDA Reviewer, listed the members of the review team and summarized the history of the PMA review. The agency used a modular approach to the review. Only Module 1 (general information, device design, and description) is closed and accepted; review of other modules is ongoing. A major deficiency letter was sent to the sponsor in December 2002; FDA received a major amendment in March 2003.
Price briefly reviewed the MEA System’s key performance and design attributes.
She noted that after 30 uses, a chip inhibits use of the applicator; the
is then returned to Microsulis. Ms. Price also reviewed key safety
specifications of the device.
Julia A. Corrado, M.D., summarized the FDA clinical review. The proposed indication is essentially the same indication as for recently approved global endometrial ablation devices. The device is in commercial use in Canada, Australia, and the United Kingdom. Although the pivotal trial was designed to be similar to other trials of global endometrial ablation devices, it had some exceptional characteristics: All women received pretreatment ultrasound to locate the thinnest portion of the uterine wall and measure thickness, and they also received CO2 hysteroscopy. Uterine length up to 14 cm was allowed, longer than in other trials. In the U.S. trial, ultrasound was done prior to GnRH (Lupron) administration. In addition, the temperature rise gate (TRG) a software modification was introduced midway during pivotal trial; it detects atypical temperature rise during the first 5 seconds of treatment.
The hypothesis was that there would be a statistical difference of less than 15 percent in patient success rates between MEA and REA groups. Dr. Corrado reviewed the primary and secondary endpoints. No statistically significant differences in success rates were found in the two groups. However, efficacy dropped for women with fibroids in both arms of the study.
The clinical trial met the primary success criterion, and no unanticipated serious adverse events occurred.
Bowel injury following perforation has occurred
with other devices. The
FDA analysis of adverse events from non-U.S. commercial use found a total of 27
14 of those
evidence demonstrated that the uterus was perforated , y et 11 subjects required
Dr. Corrado reviewed the etiology of uterine perforation injuries and the sponsor’s plan for detecting uterine perforation. She also reviewed the plan to reduce the risk of transmural thermal injuries. She noted that mandatory ultrasound is a key part of the mitigation plan. The primary hypothesis is that transmural thermal injuries occurred in patients with evidence of wall thinning. The sponsor is proposing minimum wall thickness of 10 mm.
FDA reviewed issues related to wall thickness and focused on three considerations. First, thermal damage is related to the temperature at which cell damage occurs and tissue perfusion. Second, no serious adverse events were reported in the study. Third is the ultrasound procedure itself—how should such an important ultrasound be performed? Considerations for performance of ultrasound prior to MEA include the need for standardization of the procedure, inter- and intraobserver variability, and qualifications of the examiner.
A. Chang, Ph.D., Division of Physical Sciences, Office of Science and
Technology, discussed efforts to model the thermal penetration of device.
The goals of computational modeling are to describe the worst-case scenario and
develop a scientific basis for determining minimum wall thickness. He described
the methodology underlying the modeling process. The
gel and excised liver tissues; perfusion rate is an uncertain parameter. The
model suggests a minimum wall
thickness of 7.5 to 11 mm.
members asked Dr. Chang for clarification on different details of the model. He
answered their questions and noted that with regard to the nature of the
tissue, the model assumes homogenous tissue. Fibroids
and so forth can
potentially change the thermal distribution pattern, but that is hard to model.
Microwave effects are related to density, perfusion, and other tissue
properties. When tissue is coagulated, as through microwave, electrical
conductivity tends to increase, causing penetration depth to increase. The
energy is likely to penetrate more deeply as coagulation occurs.
Panel members asked the sponsor a variety of questions related to what would happen if the operator’s motion of the probe is interrupted, whether the endometrium is included in the measurement of uterine thickness, how bowel damage could occur without associated uterine damage, what the company does when it receives an applicator after 30 uses, whether the company analyzed the data to see at what point in the applicator’s 30 uses the adverse events occurred, how often the temperature warning sounded during the trial, why frank curettage was removed from the scheme, why the MEA patients had greater vomiting and cramping, and what the level of provider training and experience was. They also asked the sponsor to provide a sample of the foam uterus used in training.
Jay Cooper, M.D., FACOG, Microsulis (via videoconference) and other sponsor representatives answered the panel’s questions. If the operator discontinued or interrupted operation and the applicator remained in the same place, the reflected temperature would rise to 85°C and an audible alarm would sound. If the applicator did not move after that, the temperature would rise to 90°C, then shut off. In only 6 percent of cases did that happen; only 2.5 percent of cases rose above 85°C.
The sponsor is aware of the issues regarding incorporation of nonhomogeneous tissues into the model. Twenty percent of the patients had fibroids, and 25 percent had had prior uterine surgery; those patients had wall thickness ranging from 9 to 26 mm. Only 1 patient had treatment that lasted longer than 8 min. Concern over the effects of prolonged treatment is not in line with the clinical reality.
of the sponsor’s calculations include endometrial buffer. The effects of Lupron
on the endometrium can be dramatic, but it is rare to see it thinning
1 or 2 mm. The sponsor did not consider the endometrium when considering a 10
mm recommendation, but it adds a margin of safety.
The only possible answer as to why damage occurs to bowel in the absence of perforation is by having the applicator and the source of microwave generation within 6 mm of bowel, which could only occur with a thin uterine wall. In the clinical trial, 3 patients had myometrial thickness of less than 8 mm—about 1 percent. Extrapolating to the number of patients treated worldwide, one could expect about 150 patients to have myometrium thickness of less than 8 mm. Establishment of minimal wall thickness is critical.
Nausea, vomiting, and cramping were the only adverse events that achieved statistical significance. Many of the cases were at a single site that does not routinely use nonsteroidal anti-inflammatory drugs (NSAIDs), so patients had increased cramping posttreatment. Some MEA patients who did not get NSAIDs were prescribed Demerol, which contributes to nausea and vomiting. Of the five patients with endometritis, three were from same site; one had prophylactic antibiotics, and one had a positive culture for strep. Everything resolved with antibiotics.
applicators, regardless of when they are returned (after 30 uses or after
adverse events), are tested for the same parameters as when they come off the
production line. All were operating normally when returned.
was contraindicated in accordance with a recommendation from the clinical trial
advisory panel. Concerning training and preceptorship, it was not until
mid-2001 that the sponsor began mandating preceptors, so the level of expertise
is difficult to assess.
1. Does the panel agree that the results [of the pivotal study] demonstrate the clinical effectiveness of the MEA system?
The panel concurred that clinical
effectiveness had been demonstrated. Dr. Larntz pointed out that the study is a
; however ,
p values are not appropriate for tests of noninferiority. The sponsor
needs to provide confidence intervals in the labeling. The study easily met the
requirement for success. Confidence intervals also need to be reported for the
adverse events; there were significant differences in long-term vomiting and
cramping in the MEA and REA groups.
had some concern that cases
without evidence of perforation were due to thermal penetratio n. The
nausea and vomiting in the MEA group may be associated with undetected bowel
or peritoneal injury. Panel members were concerned that the origin of the bowel
injury is not understood or is due to unidentified thinning
of the uterus.
The panel concurred that the measures will minimize the risk of transmural injury. The panel suggested contraindicating both mechanical and suction preparation and ensuring that physicians, not company representatives, serve as preceptors. Strict adherence to the protocol is critical to safe treatment.
The panel agreed that
mm is a reasonable minimal uterine wall thickness; however, current ultrasound
devices can have 2 to 3 mm of uncertainty in their measurements.
The panel concurred that the
instructions are adequate. Some panel members expressed concern that the
ultrasound measurements were taken prior to administration of Lupron and that
the hormone could
thickness. Most panel members thought any shrinkage would be
The panel members agreed that the safety measures are sufficient.
Panel members suggested that the
instructions should clarify what to do if the physician discovers an
anomaly—e.g., a septate or bicornuate uterus—and
where to take measurements of
the uterine wall. Panel members suggested that the procedure
should be contradindicated for patients with the Essure device
because of the effects of microwave energy on metal. Confidence intervals should
be added to the data in the labeling. Also, the labeling should
emphasize that the operator must sterilize the applicator before use.
The panel concurred that physicians
with pelvic ultrasounds and be able to conduct
The panel suggested continued
evaluation of injuries to the bowel,
Cindy Domecus, executive vice president, government affairs, Conceptus, the maker of the Essure device, stated that the device is not contraindicated for microwave. In Essure’s labeling, it states that no data are available regarding endometrial ablation devices that operate at microwave frequency; use of microwave with metallic implants has been shown to cause injury and should therefore be avoided.
Pollard reminded the panel that the PMA is still under review. Many details,
labeling and the issue of minimal uterine thickness, remain to be
A representative of the sponsor thanked the panel for its comments.
Panel Executive Secretary Whang
read the voting options. The panel voted unanimously to approv
the device with the following conditions:
1. The sponsor should correct the statistical analysis for noninferiority and provide confidence intervals based on the true intent-to-treat population.
2. Only experienced physicians should be preceptors; no mechanical preparation of the uterus will be done in conjunction with the procedure; and operators should perform hysteroscopy on all patients after dilation to confirm that uterus is intact.
3. Myometrium thickness,
as measured by transvaginal ultrasound, should be at least
10 mm; measurement should exclude the endometrium and include the cornua.
4. Operators must be
experienced with diagnostic hysteroscopy.
5. The labeling must be changed in accordance with the above conditions.
When asked to explain the rationale for their votes, panel members stated that the sponsor has taken a responsible approach to ensuring safety. Members expressed concerns about possible bowel injuries, but felt that the company is diligent in working to ensure safety. The data for effectiveness are strong. Panel members suggested that as the device is put into practice, careful scrutiny is needed to determine whether there are continued adverse events, including nausea and vomiting. Less severe bowel injury may be occurring.
Mary Lou Mooney, R.A.C., Industry Representative, commended the manufacturer for improving the quality of life of premenopausal women. Tightening the training requirements and ensuring strict adherence to the instructions for use and indications should ensure safety.
Dr. O’Sullivan thanked the participants and adjourned the meeting at 4:00 p.m.
I certify that I attended this meeting of the Obstetrics and Gynecology Devices Advisory Panel Meeting on June 10, 2003, and that these minutes accurately reflect what transpired.
Joyce M. Whang, Ph.D.
I approve the minutes of this meeting
as recorded in this summary.
Mary Jo O’Sullivan, M.D.
Summary prepared by
Caroline G. Polk
Polk Editorial Services
1112 Lamont St., NW
Washington, DC 20010