[SUMMARY OF SAFETY AND EFFECTIVENESS DATA]{.underline}

I.  GENERAL INFORMATION

> [Device Generic Name]{.underline}: (Hysteroscopic) Thermal Endometrial
> Ablation Device
>
> [Device Trade Name]{.underline}: Hydro ThermAblator® Endometrial
>
> Ablation System
>
> [Applicant's Name and Address]{.underline}: BEI Medical Systems
> Company, Inc.
>
> 100 Hollister Road
>
> Teterboro, New Jersey 07608
>
> [Premarket Approval Application]{.underline}
>
> [(PMA) Number]{.underline}: P000040
>
> [Date of Panel Recommendation]{.underline}: None
>
> [Date of Notice of Approval to Applicant]{.underline}: April 20, 2001

II. INDICATIONS FOR USE

The Hydro ThermAblator® System (hereinafter called the HTA® System) is a
hysteroscopic thermal ablation device intended to ablate the endometrial
lining of the uterus in premenopausal women with menorrhagia (excessive
uterine bleeding) due to benign causes for whom childbearing is
complete.

III. CONTRAINDICATIONS

The use of this device is contraindicated in a patient:

-   who is pregnant or wants to be pregnant in the future, because
    pregnancy after ablation can be dangerous to both mother and fetus;

-   who has known or suspected endometrial carcinoma (cancer) or
    premalignant change of the endometrium, such as, adenomatous
    hyperplasia;

-   who has active pelvic inflammatory disease or hydrosalpinx;

-   who has any anatomical pathologic condition in which weakness of
    myometrium could exist, such as, prior classic cesarean section or
    transmural myomectomy;

-   who has an intrauterine device in place; or

-   who has active genital or urinary tract infection, e.g., cervicitis,
    endometritis, vaginitis, cystitis, etc., at the time of treatment.

IV. WARNINGS AND PRECAUTIONS

The warnings and precautions can be found in the HTA® Installation and
Operator\'s Manual.

V.  DEVICE DESCRIPTION

The HTA® System is a hysteroscopic, software-controlled, thermal
endometrial ablation system that consists of (a) an operational unit,
(b) a heater canister, and (c) a sterile procedure set. The system also
requires the use of USP 0.9% saline and a standard hysteroscope. The
following is a pictorial representation of the HTA® System:

Figure 1 - HTA® System

![](media/image1.wmf){width="1.913888888888889in" height="3.6in"}

> ![](media/image2.png){width="1.9986111111111111in"
> height="1.3055555555555556in"}
>
> HTA System Sheath Assembly

The device is a closed loop system designed to ablate the endometrial
lining of the uterus by recirculating heated saline within the uterus.
The saline is heated to a temperate of 90 C by a heating element located
in the external heater canister, fed to the uterus by gravity and
recirculated via an aspiration pump. The system includes various alarms
and sensors to monitor the 10-minute treatment cycle.

(a) Operational Unit

The operational unit contains the hardware and software components which
facilitate and control the safe operation of the HTA System. These
components include the user interface display and control buttons, fluid
pump and valves, power connection, cabinet, and IV pole. The user
interface provides instructions to guide the user through the phases of
the ablation procedure.

Fluid management throughout the system is controlled by a peristaltic
pump and series of valves. The pump aspirates fluid from the uterus and
into the fluid reservoir chamber in a continuous manner. Valves are used
to enable and prevent fluid flow within the system during various phases
of the procedure.

The system is supplied with a power cord which provides an input voltage
of 95-135 VAC at 50/60 MHz, with a maximum current of 15 amps.

(b) **Heater Canister**

The heater canister is the plastic (polycarbonate) chamber within which
circulating fluid is heated prior to delivery to the uterus. The
canister houses two redundant thermistors and an electrical connection
to the operational unit. This connection allows the thermistors to
continually measure the temperature of the heater canister in real-time.

The canister consists of a two-layered cylinder within which is housed
the heating element, thermistors and O-ring sealant. The two layers of
the cylinder are separated by an air barrier, which helps minimize the
temperature of the outer surface of the canister. As the fluid within
the inner cylinder reaches temperatures up to 90ºC during treatment, the
outer plastic cylinder mitigates the likelihood of thermal injuries to
the operator in the event of direct contact with the canister. The
heating element is a metal rod which is mechanically connected to the
base of the cylinder and electrically connected to the operational unit.
The O-ring provides a seal to prevent fluid from escaping from the inner
cylinder of the canister.

The heater canister is intended for multiple uses. It is provided
non-sterile and is designed to be cleaned and then resterilized via
autoclave. The specific method for reprocessing has been fully described
and validated.

(c) **Sterile Procedural Set**

The sterile procedural set consists of a patient sheath, tubing lines,
cassette, fluid level measurement reservoir, and fluid collection bag.
The kit is provided sterile for single use.

The patient sheath, constructed of polycarbonate, contains two
concentric lumens to allow for continual fluid flow and provides thermal
insulation. The outer diameter of the sheath is 7.8 mm. The cervix is
dilated to approximately 8 mm in order to accommodate the sheath. The
proximal end of the sheath is attached to a standard 3 mm hysteroscope,
which provides real-time visualization of the ablation procedure.

The tubing lines provide connections between the sheath, operational
unit (peristaltic pump), and fluid reservoir. The tubing segment between
the pump and sheath features an insulating, corrugated tubing line which
acts to prevent accidental burn to the patient or operator, in the event
that the patient/operator contacts the tubing line while it is heated.

The cassette is loaded onto the cassette plate of the operational unit.
The casing of the cassette contains five contact points where the unit
valves of the unit are actuated. The casing also provides the track
which houses the tubing line for the pump segment.

The fluid level measurement reservoir consists of a cylinder that is
connected to the IV pole of the operational unit. The transparent face
of the reservoir features fluid level markers which display the net
fluid status throughout the procedure in the closed loop system. The
reservoir electronically tracks changes from the 80 mL normal operating
fluid level by means of an electronic strip with fluid sensors and will
alarm when it senses a loss of 10 mL or an increase of 20 mL.

**Principle of Operation**

Once the treating physician determines that a patient is an appropriate
candidate for the ablation procedure with the HTA, the patient should be
given a dose of medication (e.g., Lupron) to thin the lining of the
uterus approximately three weeks prior to the procedure. (However, the
optimum pre-treatment regimen has not been established.)

At the time of the procedure, the components of the HTA are assembled
and connected to a standard hysteroscope. The patient receives some
combination of anesthesia/analgesia at the discretion of the physician.
A bimanual examination of the uterus is performed. A vaginal speculum is
inserted, a tenaculum is placed on the cervix, the cervix is dilated to
8 mm and then the patient sheath is introduced through the cervix and
positioned in the uterus.

The ablation procedure consists of a series of steps which are guided by
the software and user interface of the HTA. During the initial [priming
phase]{.underline}, when the uterine cavity is inspected, room
temperature saline circulates within the system and uterus at a flow
rate of approximately 300 mL/min for 2 minutes. The [active treatment
phase]{.underline} follows, at which time the HTA heating element
activates and begins to elevate the temperature of the saline. When the
saline temperature reaches 80ºC, the treatment period of 10 minutes is
started. The saline temperature continues to elevate, until it reaches
90ºC, and remains there for the duration of the active treatment phase.
Fluid flow through the system is approximately 300 mL/min.

The HTA is designed with components and alarms to monitor the safe
delivery of saline and may interrupt treatment therapy if an unsafe
state is detected. After the entire 10-minute treatment cycle is
successfully completed, the treatment proceeds to the [post-treatment
flush phase]{.underline}. Room-temperature saline is flushed through the
uterus to rapidly reduce the temperature of the fluid in the uterus and
sheath. In the event of interruption of the procedure prior to
completion of the 10-minute treatment phase, the system will proceed to
the same cooling cycle as stated above. After approximately one minute,
the physician removes the sheath from the patient. The procedure is
terminated at this time. The unit then proceeds to a [final system
cool-down phase]{.underline}, during which the room-temperature saline
continues to circulate through the system for an additional period of
time until the temperature of the fluid in the heater canister reaches
45 C.

**VI. ALTERNATIVE PRACTICES OR PROCEDURES**

> The following alternate practices and procedures are currently
> available to treat excessive uterine bleeding due to benign causes:

-   **Drug Therapy**

Drug therapy using estrogen-progestogen combinations, (such as those
found in oral contraceptives) or progestogens (progesterone) by
themselves are most often employed for the treatment of menorrhagia.
Other classes of drugs used include androgens such as danocrine, GnRH
agonists, non-steroidal anti-inflammatory drugs (NSAIDs). Drug therapy
is typically the first order treatment to alleviate menstrual symptoms.
Drug therapies usually require long term treatment. They are successful
for some patients but for others they are ineffective and often
introduce unpleasant side effects. This treatment, however, does allow
the woman to maintain her fertility.

-   **Dilatation and Curettage (D&C)**

D&C is typically the first surgical step if drug therapy is unsuccessful
in eliminating excessive bleeding. The uterine contents are either
scraped away by an instrument or removed through vacuum aspiration. This
may reduce bleeding for a few cycles. If a polyp is present and removed,
the bleeding may stop. In most cases, it does not provide the patient
with long-term definitive results but it is useful for those women who
desire to maintain their fertility. D&C is also useful as a diagnostic
technique to rule out endometrial cancer.

-   **Hysteroscopic Endometrial Ablation**

    Hysteroscopic endometrial ablation is a surgical procedure which
    utilizes a resectoscope or operating hysteroscope, a video monitor,
    a fluid distention medium such as glycine or sorbitol, and a
    surgical ablation device such as an electrode loop, rollerball or
    laser to destroy the inner lining of the uterus, the endometrium.
    The procedure is typically performed under general or epidural
    anesthesia. Dilation of the cervix must accommodate the
    hysteroscopic instrument, usually to a minimum of 9 mm and the
    uterus must be properly distended. The most common risks associated
    with hysteroscopic endometrial ablation are fluid overload, and
    perforation. This treatment is intended for women who no longer
    desire to maintain their fertility.

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-   **Thermal Balloon Ablation**

    The ThermaChoice™ Uterine Balloon Therapy™ (UBT) System is a
    software controlled device designed to ablate endometrial tissue by
    thermal energy heating of sterile injectable fluid (5% dextrose in
    water) within a silicone balloon. The ThermaChoice™ UBT System
    consists of a controller with power cord, single-use sterile
    catheter, and umbilical cable. During the treatment, the fluid
    within the balloon is circulated via an impeller to maintain a
    temperature of 87°C for a period of 8 minutes. This treatment is
    intended for women who no longer desire to maintain their fertility.

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-   **Cryosurgical Ablation**

    The HerOption™ Uterine Cryoblation Therapy™ System is a
    software-controlled, cryoablation system that consists of a console,
    cryoprobe, and control unit. The device generates extremely cold
    temperatures by means of pressurized gas, consisting of a mixture of
    common refrigerants, that is expanded through a small orifice in the
    cryoprobe. Deployment of the pressurized gas forms an iceball, whose
    leading (outer) edge reaches temperatures sufficient to destroy
    tissue (-20ºC). In the procedure, the probe is angled toward one
    cornua (side) of the uterus for a period of 4 minutes during which
    the first iceball is formed; the probe is then angled to toward the
    other cornua for a period of 6 minutes during which the second
    iceball is formed. Use of the device must be accompanied by
    ultrasound to enable visualization of the cryoprobe tip placement
    and the leading edge of the iceball. This treatment is not intended
    for a woman who desires to maintain her fertility.

-   **Hysterectomy**

The most common surgical procedure, hysterectomy, is a definitive
treatment for excessive menstrual bleeding. It is, however, a major
surgical procedure performed in the hospital under general anesthesia
that is associated with risks and complications and generally a lengthy
recovery period.

**VII. MARKETING HISTORY**

The HTA® System has been commercially marketed internationally since
January 1996. At time of FDA approval, the HTA System was available in
22 countries and not withdrawn from the market for any reason relating
to the safety and effectiveness of the device.

VIII. **POTENTIAL ADVERSE EFFECTS OF THE DEVICE ON HEALTH**

Adverse effects of the device on health may be categorized as those
observed during the clinical evaluation of the HTA® System and those not
observed in the study, but which may occur.

(a) **Adverse Effects of the Device on Health**

The HTA® System was evaluated in a randomized, prospective, multi-center
clinical trial, comparing the HTA® System (HTA) to roller ball (RB)
ablation. Adverse event data were available from a total of 269 subjects
treated in the study, from the time of procedure through the 1-year
follow-up study period.

The tables below describe these results:

**Table 1a \-- Adverse Events within 24 hours Post-Procedure**

+----------------------------------------+--------------+--------------+
| **Adverse Event**                      | **HTA        | **RB Group** |
|                                        | Group**      |              |
|                                        |              | **n=85**     |
|                                        | **n=184**    |              |
+----------------------------------------+--------------+--------------+
| uterine cramping                       | 51 (28%)     | 21 (25%)     |
+----------------------------------------+--------------+--------------+
| nausea                                 | 20 (11%)     | 2 (2%)       |
+----------------------------------------+--------------+--------------+
| vomiting                               | 20 (11%)     | 2 (2%)       |
+----------------------------------------+--------------+--------------+
| abdominal pain                         | 8 (4%)       | 2 (2%)       |
+----------------------------------------+--------------+--------------+
| urinary tract infection                | 5 (3%)       | 2 (2%)       |
+----------------------------------------+--------------+--------------+
| laceration                             | 2 (1%)       | 2 (2%)       |
+----------------------------------------+--------------+--------------+
| endometritis                           | 2 (1%)       | 1 (1%)       |
+----------------------------------------+--------------+--------------+

**Table 1b \-- Adverse Events at 2 week Post-Procedure**

+----------------------------------------+--------------+--------------+
| **Adverse Event**                      | **HTA        | **RB Group** |
|                                        | Group**      |              |
|                                        |              | **n=85**     |
|                                        | **n=184**    |              |
+----------------------------------------+--------------+--------------+
| uterine cramping                       | 37 (20%)     | 11 (13%)     |
+----------------------------------------+--------------+--------------+
| transient change in appearance of      | 19 (10%)     | 0 (0%)       |
| cervical epithelium                    |              |              |
+----------------------------------------+--------------+--------------+
| vomiting                               | 17 (9%)      | 2 (2%)       |
+----------------------------------------+--------------+--------------+
| nausea                                 | 16 (9%)      | 4 (5%)       |
+----------------------------------------+--------------+--------------+
| abdominal pain                         | 6 (3%)       | 0 (0%)       |
+----------------------------------------+--------------+--------------+
| urinary tract infection (UTI)          | 3 (2%)       | 0 (0%)       |
+----------------------------------------+--------------+--------------+
| endometritis                           | 1 (1%)       | 1 (1%)       |
+----------------------------------------+--------------+--------------+
| thermal injury to extremity            | 1 (1%)       | 0 (0%)       |
+----------------------------------------+--------------+--------------+
| vaginal infection                      | 1 (1%)       | 0 (0%)       |
+----------------------------------------+--------------+--------------+
| cervical laceration                    | 1 (1%)       | 0 (0%)       |
+----------------------------------------+--------------+--------------+

**Table 1c \-- Adverse Events at 3, 6, and 12 months Post-Procedure\***

+----------------------------------------+--------------+--------------+
| **Adverse Event**                      | **HTA        | **RB Group** |
|                                        | Group**      |              |
|                                        |              | **n=85**     |
|                                        | **n=184**    |              |
+----------------------------------------+--------------+--------------+
| uterine cramping                       | 25 (14%)     | 8 (9%)       |
+----------------------------------------+--------------+--------------+
| vaginal infection                      | 6 (3%)       | 2 (2%)       |
+----------------------------------------+--------------+--------------+
| nausea                                 | 3 (2%)       | 0 (0%)       |
+----------------------------------------+--------------+--------------+
| vomiting                               | 3 (2%)       | 0 (0%)       |
+----------------------------------------+--------------+--------------+
| abdominal pain                         | 2 (1%)       | 1 (1%)       |
+----------------------------------------+--------------+--------------+
| hematometra                            | 1 (1%)       | 2 (2%)       |
+----------------------------------------+--------------+--------------+
| urinary tract infection                | 1 (1%)       | 1 (1%)       |
+----------------------------------------+--------------+--------------+

\* This table reports individual events documented at the 3, 6, and 12
month post-

procedure reporting periods. Multiple events may have occurred in the
same patient.

Additional information related to some of these events is provided
below:

-   **Peri-operative uterine cramping** - This event typically lasted a
    few days following ablation. Use of NSAIDs prior to and following
    HTA treatment was usually sufficient to manage cramping.

-   **Nausea and Vomiting** - These events were generally attributed to
    certain types of general anesthesia.

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-   **Asymptomatic Alterations** **in Cervical** **Tissue** - This type
    of event ranged from erythema to shallow ulcerations and was
    resolved without treatment within 30 days following ablation.

-   **Endometritis** - This event was resolved with antibiotics in all
    subjects.

-   **Hematometra** - This event was resolved with insertion of a
    uterine sound.

-   **Thermal Injury to Extremity** - This event, consisting of a
    second-degree burn, occurred following prolonged exposure of skin
    (lower leg) to the heated tubing of the HTA during treatment. The
    subject was treated with topical antibiotics and dressing changes.
    The device was modified after the occurrence of this event to reduce
    this risk of injury.

-   **Other Events** - Other events, which occurred in no greater than
    3% of subjects treated with the HTA, included: diarrhea, fever,
    headaches, abdominal distension, and post-ablation tubal
    sterilization syndrome.

**(b) Potential Adverse Effects of the Device on Health**

The following adverse effects may potentially occur, but were not
observed in clinical studies of the HTA:

-   thermal injury to adjacent tissue;

-   heated saline escaping from the device system into the vascular
    spaces, cervix, or abdominal cavity;

-   hemorrhage;

-   perforation of uterus;

-   complications with pregnancy (**NOTE**: pregnancy following
    endometrial ablation is dangerous to both the mother and the fetus);
    and

-   risks associated with hysteroscopy.

**IX. SUMMARY OF PRE-CLINICAL TESTING**

**[A. Thermodynamic Modeling]{.smallcaps}**

(1) Sheath Test - The purpose of the sheath test was to verify the
    sheath design specifications (e.g., temperature on surface, flow
    rate) in a simulated environment. In this test, thermocouples were
    placed on the surface of the sheath, which was wrapped in chicken
    breast. A simulated procedure was performed while the sheath
    temperature was measured. Test results showed that the temperature
    reached a peak of approximately 42ºC after 320 seconds of the
    procedure. A flow meter documented that the inflow and outlet flow
    rates were 0.7 L/min and 3.2 L/min, respectively.

(2) Temperature versus Time: Warm-up and Ablation Phase - The purpose of
    this test was to evaluate the rate at which the temperature of the
    fluid increased from room temperature (approximately 22ºC) to
    ablation temperature (90ºC). In this test, a simulated treatment was
    performed while the fluid temperature within the heater canister was
    monitored. Results showed that the system took approximately 150-180
    seconds to reach ablation temperature.

(3) Temperature versus Time: Heater Canister Temperature - The purpose
    of this test was to measure the temperature of the inner and outer
    surfaces of the heater canister during the treatment period. In this
    test, a simulated 10-minute treatment was performed while the inner
    canister surface was measured with thermocouples and the outer
    canister surface was assessed by human touch. Results showed that
    the inner canister surface remained at 90ºC during the complete
    treatment period and that outer canister surface may be contacted by
    an individual without discomfort.

(4) Temperature versus Time: Cooling Cycle - The purpose of this test
    was to determine the rate at which the temperature reduced after
    termination of the active ablation procedure. In this test, a
    simulated treatment (including post-treatment phase) was performed
    while the temperature inside the heater canister was measured.
    Results showed that upon completion of treatment, circulating fluid
    was cooled to body temperature in approximately 20 seconds. As a
    result of these findings, the HTA was designed to have a 1-minute
    cool down phase before the physician is instructed to remove the
    sheath from the patient.

(5) Simulated Fluid to Patient Temperature - The purpose of this test
    was to determine the temperature differential between the fluid in
    the heater canister, where heating is initiated, and the fluid upon
    contact to the patient. In this test, temperature measurements at
    the canister and sheath were obtained. Results showed that the
    temperature of the fluid dropped approximately 3 to 4ºC from the
    canister to the catheter. These findings characterize the heat sink
    effect in which fluid at an elevated temperature tends to drop to
    the temperature of the surrounding environment. As a result of this
    phenomenon, the device was designed to provide rapid circulation of
    fluid during the ablation procedure, in order to better ensure that
    fluid heated to 90ºC contacts the uterus.

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B.  **[Biocompatibility]{.smallcaps}**

> Biocompatibility information was supplied to provide assurance that
> the patient-contacting materials of the HTA were safe for use in a
> medical device. The HTA contains components which may be categorized
> as those which provide direct contact to patient tissue (e.g., patient
> sheath catheter) and those which contact the fluid flow path which
> comes into contact with patient tissue (e.g., canister, tubing lines).
>
> To support the biocompatibility of the polycarbonate material, the
> sponsor submitted the results of these tests:

-   cytotoxicity (USP 23 \"Elution Cytotoxicity test\") - sheath
    catheter, fluid pathway

-   sensitization (ISO 10993-10 \"Maximization sensitization test\") -
    sheath catheter, fluid pathway

-   intracutaneous reactivity - sheath catheter

-   intracutaneous injection (USP 23) - fluid pathway

-   systemic injection (USP)- fluid pathway

-   hemolysis (rabbit blood)- fluid reservoir

> Results submitted for these tests demonstrated that the test material
> device successfully passed each test.
>
> In addition to these tests, the sponsor conducted leach testing on
> internal fluid pathway of the device system. During clinical use,
> device components that contact the internal fluid pathway are exposed
> to temperatures of up to 90ºC, a state which may elicit the release of
> leachables. In this test, the sponsor operated the system such that
> fluid was circulated at 90ºC for 2 hours. Extractions were obtained
> and analyzed via Fourier Transform Infrared (FTIR) spectroscopy for
> presence of unknown leachables. Results did not identify any unknown
> leachables in the product extract.

C.  **[Sterility]{.smallcaps}**

> The procedural set is supplied sterile and intended for single use.
> The heater canister is not supplied sterile. It is designed to be
> cleaned and sterilized by the end user and is intended to be reused.
>
> The procedural set is sterilized with 100% ethylene oxide (EtO) to a
> sterility assurance level of 10^-6^. The sterilization process is
> validated in accordance with ANSI/AAMI/ISO 11135-1994. Maximum
> residual level of EtO, ethylene
>
> chlorohydrin, and ethylene glycol were identified as 25, 25 and 250
> parts per million, respectively.
>
> The heater canister is a reusable component. (The number of reuses is
> specified in the device labeling.) The canister must be cleaned with
> warm water and a mild soap using an appropriate brush or cloth. The
> canister must be autoclave sterilized with either a flash method
> (270ºC for four minutes) or wrap method (250ºC for the length of time
> appropriate for sterilizer load and components of load, consistent
> with hospital guidelines). Adequate validation of the protocols for
> reprocessing was supplied.
>
> The shelf life of the procedural set was established at two years.
> This duration was based on real-time evaluation of product, in which
> aged product was subjected to sterility/package integrity and
> functional testing.

D.  **[Electrical Safety/Electromagnetic Compatibility]{.smallcaps}**

> Electrical safety and electromagnetic compatibility testing was
> performed in accordance with the following standards by an independent
> test facility:

-   EN 60601-1: electrical safety

-   UL 2601-1: electrical safety

-   CSA 22.2 No. 601-1 (safety of medical electrical equipment - part 1)

-   EN 60601-1-2: collateral standard, electromagnetic compatibility
    requirements of medical electrical equipment

-   IEC 801-2: electrostatic discharge requirement

-   IEC 801-2: radiated susceptibility

-   IEC 801-4: conducted transient susceptibility

-   EN 55011B/CISPR 11: emissions limits for medical RF equipment

-   IEC 801-5: surge immunity

> Certification of compliance of the HTA to these standards was
> provided.

**E. [Software Validation]{.smallcaps}**

> In accordance with the FDA document \"Guidance for the Content of
> Premarket Submissions for Software Contained in Medical Devices,\" the
> level of risk of the HTA was considered to be **moderate**, as the
> software contained in the device controls delivery of thermal energy,
> which, if not properly controlled, may cause injury to the patient.
> The hazard analysis and documentation submitted on the device system
> reflect this level of risk and consist of the following documents:

-   system specification requirement plan;

-   software requirement specification;

-   software validation plan;

-   software test plan;

-   software test results;

-   architectural design chart;

-   traceability matrix; and

-   hazard and failure mode effects analysis.

> Test results demonstrated that the device performed in accordance with
> the specifications defined for the device. Based on these results, the
> software contained in the device should function safely and
> effectively.

**F. [Animal Testing ]{.smallcaps}**

Animal testing was performed in a series of two studies conducted on
porcine models. The objective of these studies was to evaluate the
safety and feasibility of the device for use in the human uterus. In
particular, the studies allowed assessment of two characteristics of the
device\'s principle of operation: (1) target and non-target tissue
temperature exposure; and (2) effect of uterine circulation on
temperature dissipation. A porcine model was chosen because of
similarities to the human cervix and uterus, including the approximate
thickness of cervix and uterine blood supply.

**Initial Study**

Two pigs were used in this study. A laparotomy was performed, the cervix
and uterus were exteriorized, and ligatures were placed at the vagina
and uterine horns to isolate section of tissue to be tested.
Thermocouples were placed in each pig in the uterine lumen (target
tissue) and on the cervical serosa (non-target tissue). Saline was
heated to approximately 85ºC and cycled through the isolated uterine
space through insulated tubing and inflow channel of the hysteroscope.
Heated saline was allowed to flow by gravity for three minutes, during
which uterine and serosal temperatures were measured. Tissues were
examined histologically and histochemically to assess nuclear
destruction and depth of tissue necrosis. Results showed that internal
uterine temperature ranged from 71 - 81ºC and external serosal
temperature ranged from 38 - 43ºC. Internal uterine tissue necrosis was
approximately 4 mm, while external serosal tissue and uterine myometrium
were undamaged.

**Follow-up Study**

Two pigs were used in this study. Thermocouples were placed in uterine
tissue, superficial myometrium, peripheral myometrium and serosa. Saline
was heated to approximately 85ºC and introduced in the same manner as
the initial study. Treatment time was 3 minutes for the first pig and 8
minutes for the second pig. Measurements were taken at 3 minutes (both
animals) and 5 and 8 minutes (second pig only). Tissues were examined
macroscopically and microscopically. Results showed that temperatures at
3 minutes ranged from 68 - 76ºC for uterine tissue, 64 - 66ºC for
superficial myometrium, 38 - 47ºC for peripheral myometrium, and 24 -
36ºC for serosa. At 5 minutes, target tissues ranged from 68 - 76ºC and
non-target tissue were 48ºC or lower. Gross visual examination,
histology and histochemistry indicated tissue necrosis in the
endometrium and superficial myometrium (5 mm) with no evidence of
necrosis in the peripheral myometrium or serosa at 48 hours.

Overall findings from the studies demonstrated that introduction of
heated saline induced tissue necrosis within the target tissue without
concomitant necrosis of non-target tissue.

**X. SUMMARY OF CLINICAL STUDIES**

Clinical evaluation of the HTA® System was conducted in studies
categorized as Phase I (feasibility safety), Phase II (feasibility
safety and effectiveness), and Phase III (pivotal safety and
effectiveness). These studies are described below.

**A. Phase I (Feasibility Safety) Study**

Phase I (feasibility safety) testing of the device evaluated the
preliminary safety of heated, free-flowing saline as a medium to
thermally ablate the endometrium in pre-menopausal women with excessive
uterine bleeding. This testing was conducted in a series of three
stages, which are described below.

[First Stage]{.underline}

The purpose of the first stage was to evaluate (1) the concept of
free-flowing saline as a medium for ablation and (2) the design of the
HTA in the control of potential fluid loss through the fallopian tubes.
A total of four subjects, who were scheduled for tubal ligation,
received a mock ablation procedure with unheated, dyed saline. The
procedure was observed via laparoscopy. In all procedures, no fluid loss
alarms were triggered by the machine and no fluid loss through the
fallopian tubes was observed with the laparoscope.

[Second Stage]{.underline}

The purpose of the second stage was to investigate the treatment
parameters (i.e., temperature of saline and time of procedure) of HTA
ablation. Twenty-four subjects were enrolled in this stage. Enrolled
study subjects received the ablation procedure and then underwent a
laparoscopic-assisted hysterectomy. The ablation procedure was completed
on 16 of 24 subjects. Treatment times ranged from 3-8 minutes and
treatment temperature was approximately 85ºC. Histological data
available from 11 of 16 subjects documented that depth of destruction
ranged from 1 to 3 mm. In addition, complications with the procedure
(e.g., fluid leakage, heater canister leakage) resulted in modifications
to the device.

[Third Stage]{.underline}

The purpose of the third stage was to investigate the treatment
parameters of the HTA that contained design modifications made in
response to observations from the second stage. Nine subjects were
enrolled. The ablation was completed on 8 of 9 subjects. Treatment times
ranged from 4-6 minutes and treatment temperature was approximately
85ºC. Results demonstrated that the modified device appeared to perform
safely.

**B. Phase II (Feasibility Safety and Effectiveness) Study**

Phase II (feasibility safety and effectiveness) testing of the device
evaluated safety and preliminary effectiveness of heated, free-flowing
saline as a medium to thermally ablate the endometrium in pre-menopausal
women with excessive uterine bleeding. This testing was conducted in two
stages.

[First Stage]{.underline}

The first stage of Phase II testing was conducted outside the United
States. Its purpose was to investigate the effectiveness of the device
with several different treatment parameters (e.g., treatment times
ranged from 5 to 10 minutes, and treatment temperatures ranged from 85ºC
to 90ºC). Twenty-five subjects were enrolled in these studies. Treatment
effectiveness and adverse event information was documented. Results
showed that ablation performed with saline at 90ºC for a period of 10
minutes was as safe and potentially more effective than ablation
performed at lower temperature and shorter treatment times, based on a
level of destruction of the endometrium to 4 mm.

[Second Stage]{.underline}

The second stage of Phase II testing was conducted in the United States.
Its purpose was to investigate the effectiveness of the device with
saline heated to 90ºC at a total treatment time of 10 minutes. Twenty
subjects were enrolled in this study. Study subjects had a baseline
bleeding diary score of at least 150 (adapted from *Janssen CAH,
Scholten PC, et al. based on "A Simple Visual Assessment Technique to
Discriminate Between Menorrhagia and Normal Menstrual Blood Loss".
Obstetrics & Gynecology, Vol. 85, No. 6, June 1995*). No adverse events
were reported. Of the 19 subjects for whom 6-month post-treatment
information was available, 14 reported bleeding diary scores within
normal levels (≤75). Results demonstrated that the device, when used
with treatment parameters of 90ºC for 10 minutes, provided preliminary
evidence of safety and effectiveness in treatment of excessive uterine
bleeding.

**C. Phase III (Pivotal Safety and Effectiveness) Study**

Phase III testing was conducted in the United States. This pivotal
safety and effectiveness study was a multi-center, randomized,
concurrently-controlled clinical trial in which subjects were randomized
between the test device (HTA) and the control device (roller ball
\[RB\]) at a 2 to 1 ratio.

**Objective**

The objective of the study was to assess the safety and effectiveness of
HTA ablation, relative to RB ablation in terms of safety and
effectiveness in the treatment of patients with menorrhagia due to
benign causes in an anatomically normal uterine cavity.

**Study Endpoints**

The primary effectiveness endpoint was the *Janssen* diary scoring
system (see above reference) Treatment success was defined as reduction
in menses to a diary score of ≤ 75 in order to assure a return to
eumenorrhea. Overall study success was a statistical difference of \<
20% in the success rate between HTA® and RB in the reduction of
excessive menstrual bleeding to at least normal levels. Secondary
effectiveness endpoints evaluated were overall percent decrease in diary
scores and responses from a quality-of-life questionnaire. Safety
endpoints were adverse events associated with each procedure, including
device-related complications, time of procedure, and type of anesthesia
used.

**Study Methods**

A randomized, prospective, multi-center clinical investigation was
conducted at nine sites using investigators experienced with
hysteroscopic roller ball endometrial ablation. Prior to acceptance in
the study, subjects underwent a series of screening examinations which
primarily documented bleeding status and uterine structure. Demographic
information and gynecological history was recorded. Subjects were
required to meet a set of entry criteria.

[Inclusion Criteria]{.underline}

Subjects were enrolled in the study if they had the following:

-   excessive uterine bleeding, as documented by the menstrual diary and
    calculation worksheet defined by Janssen (with a minimum score of
    150);

-   endometrial cavity measuring ≤ 10.5 cm;

-   age ≥ 30 years; and

-   previously failed, did not tolerate, or refused medical therapy.

[Exclusion Criteria]{.underline}

Subjects were excluded from the study if they had the following:

-   age \> 50 years;

-   active or recurrent chronic pelvic inflammatory disease;

-   active genital or urinary tract infection;

-   clotting defects, bleeding disorders, or anticoagulant treatments;

-   abnormal pap smear that showed evidence of dysplasia;

-   malignant pathology and/or simple hyperplasia, as documented by
    endometrial biopsy;

-   history of gynecologic malignancy within the past 5 years;

-   submucous myomas and/or polyps;

-   intramural fibroids \> 4cm, as documented on ultrasonogram, thought
    to be contributing to menorrhagia, such as those deforming the
    uterine cavity;

-   congenital uterine anatomical anomaly, such as full septate or
    bicornate uterus;

-   previous endometrial ablation procedure;

-   previous classic Cesarean section;

-   current pregnancy or desire for future pregnancy;

-   desire for complete amenorrhea; and

-   known hydrosalpinx.

Subjects received one dose of Lupron 7.5mg on Cycle Day 21 ± 2 days.
Treatment took place on Cycle Day 19 - 27 after injection. After
completion of treatment, subjects were followed at 2 weeks, and 3, 6,
and 12 months post-treatment.

**Description of Subjects**

Two hundred seventy-six subjects were enrolled in the study. Baseline
demographic and gynecological variables were statistically equivalent
between the two groups with regard to age, race, body mass index, mean
baseline diary score and other criteria. The table below summarizes some
key demographic information and gynecological history on study subjects:

**Table 2 \-- Demographics and Gynecological History**^†^

+-------------------------------------+---------------+---------------+
| **Baseline                          | **HTA®**      | **RB**        |
| Characteristics/Gynecological       |               |               |
| History**                           |               |               |
+-------------------------------------+---------------+---------------+
| Race                                | 84%           | 76%           |
|                                     |               |               |
| Caucasian                           | 15%           | 19%           |
|                                     |               |               |
| African-American                    | 2%            | 5%            |
|                                     |               |               |
| Other                               |               |               |
+-------------------------------------+---------------+---------------+
| Age (years)                         | 40.7 ± 5.2    | 40.6 ± 5.3    |
+-------------------------------------+---------------+---------------+
| Body Mass Index (BMI kg/m^2^)       | 29.0 ± 7.4    | 28.8 ± 7.8    |
+-------------------------------------+---------------+---------------+
| Baseline Diary Scores               | 596.6 ± 787.6 | 585.5 ± 565.2 |
+-------------------------------------+---------------+---------------+
| Hemoglobin (g/mL)                   | 12.6 ± 1.3    | 12.5 ± 1.7    |
+-------------------------------------+---------------+---------------+
| Hematocrit                          | 37.4 ± 3.3    | 37.6 ± 4.3    |
+-------------------------------------+---------------+---------------+
| Uterine Sound Length (cm)           | 8.5 ± 1.3     | 8.6 ± 1.2     |
+-------------------------------------+---------------+---------------+

† All values, except for race, are expressed in terms of mean ± standard
deviation.

**Subject Accountability**

The table below describes the accountability of subjects throughout the
study period.

Table 3 \-- Subject Accountability

+-------------------------------------+----------+----------+----------+
| Subjects:                           | **HTA®** | **RB**   | *        |
|                                     |          |          | *Total** |
+-------------------------------------+----------+----------+----------+
| enrolled in study                   | 187      | 89       | 276      |
+-------------------------------------+----------+----------+----------+
| received no treatment               | 3        | 4        | 7        |
+-------------------------------------+----------+----------+----------+
| received incomplete treatment       | 7        | 0        | 7        |
+-------------------------------------+----------+----------+----------+
| for whom 12-month data not          | 10       | 2        | 12       |
| available:                          |          |          |          |
|                                     | 2        | 0        | 2        |
| received hysterectomy^†^            |          |          |          |
|                                     | 2        | 0        | 2        |
| died in non-device-related events   |          |          |          |
|                                     | 6        | 2        | 8        |
| lost to follow-up                   |          |          |          |
+-------------------------------------+----------+----------+----------+
| for whom 12-month data available    | 167      | 83       | 250      |
+-------------------------------------+----------+----------+----------+

> † Both subjects were ≥ 40 years old; reasons for hysterectomy were
> bleeding (1) and

pain/myoma (1)

**Results**

A. [Primary Effectiveness Endpoint]{.underline}

Patient success was based on a reduction in diary score from
[\>]{.underline}150 pre-treatment to [\<]{.underline}75 at one year. The
results are presented below:

Table 4a \-- Effectiveness: Diary Scores at 1 year

+--------------------------------------------+------------+------------+
|                                            | **HTA®**   | **RB**     |
|                                            |            |            |
|                                            | **n =      | **n =      |
|                                            | 187**^†^   | 89**^†^    |
+--------------------------------------------+------------+------------+
| number of successful subjects (diary score | 128        | 68         |
| ≤ 75)                                      |            |            |
+--------------------------------------------+------------+------------+
| study success rate (# successful/total     | 68.4%      | 76.4%      |
| subjects)                                  |            |            |
+--------------------------------------------+------------+------------+
| number of subjects with amenorrhea (diary  | 66         | 42         |
| score = 0)                                 |            |            |
+--------------------------------------------+------------+------------+
| amenorrhea rate (# with diary score =      | 35.3%      | 47.1%      |
| 0/total subjects)                          |            |            |
+--------------------------------------------+------------+------------+

† This table presents the intent-to-treat results of the study data. See
\"Subject Accountability\" section above for accountability of all
subjects enrolled in study.

B. [Secondary Effectiveness Endpoint]{.underline}

Results with respect to the secondary endpoint of quality of life (QoL)
compared QoL scores at pre-treatment and 12-months post-treatment for
both HTA® and RB study groups, and are presented in the table below:

#### Table 4b \-- Effectiveness: Quality of Life (QoL) at 1 year

+-----------------------------------------+-----------+----------------+
|                                         | **HTA®**  | **RB**         |
+-----------------------------------------+-----------+----------------+
| number of subjects who responded to     | 167       | 83             |
| questionnaire                           |           |                |
+-----------------------------------------+-----------+----------------+
| QoL score (mean ± SD)**^†^**            | 54.2 ±    | 53.3 ± 13.5    |
|                                         | 13.5      |                |
| @ baseline                              |           | 11.4 ± 15.2    |
|                                         | 13.0 ±    |                |
| @ 1 year                                | 15.0      |                |
+-----------------------------------------+-----------+----------------+
| leisure activities affected             | 70.1%     | 66.3%          |
|                                         |           |                |
| @ baseline                              | 21.6%     | 28.9%          |
|                                         |           |                |
| @ 1 year                                |           |                |
+-----------------------------------------+-----------+----------------+
| work and activities of daily life       | 90.4%\    | 91.0%          |
| affected                                | 19.8%     |                |
|                                         |           | 20.0%          |
| @ baseline                              |           |                |
|                                         |           |                |
| @ 1 year                                |           |                |
+-----------------------------------------+-----------+----------------+

† The QoL information was obtained from the Ruta QoL questionnaire
(*Ruta DA, Garratt*

*AM, Chadha YC, et al. Assessment of patients with menorrhagia: how
valid is a structured*

*clinical history as a measure of health status? Qual Life Res 4:33-40,
1995.*). The scoring

scale range was 2.6 - 89.5. A higher score is associated with increased
menorrhagia (e.g.,

mild = 37.6; moderate = 46.7; and severe = 50.7).

C. [Safety Endpoints]{.underline}

Results related to safety information were provided in terms of adverse
event information, overall time of treatment, and type of anesthesia
provided. Adverse event information is described in the \"Adverse
Events\" section above. Overall treatment time was 26.4 ± 12.1 minutes
for HTA® and 32.2 ± 12.2 minutes for RB.

Anesthesia was delivered at the discretion of the investigator and
attending anesthesiologist. General anesthesia was administered to 55%
and 76% of HTA and RB subjects, respectively. Thirty percent of HTA
subjects received a paracervical block with IV sedation as compared to
13% of RB subjects. Fifteen percent of HTA subjects received
paracervical block without IV sedation, as compared to 9% of RB
subjects.

**XI. CONCLUSIONS DRAWN FROM THE STUDIES**

The pre-clinical and clinical studies provide reasonable assurance that
the HTA® is safe and effective, when used in accordance with the
directions for use in the ablation of the endometrial lining of the
uterus in premenopausal women with menorrhagia due to benign causes for
whom childbearing is complete.

XII. **PANEL RECOMMENDATION**

In accordance with the provisions of section 515(c)(2) of the Federal
Food, Drug and Cosmetic Act as amended by the Safe Medical Devices Act
of 1990, this PMA was not referred to the Obstetrics and Gynecology
Devices Advisory Panel, an FDA advisory committee, for review and
recommendation because the information in the PMA substantially
duplicates information previously reviewed by this panel.

**XIII. FDA DECISION**

FDA issued an approval order on April 20, 2001.

The applicant\'s manufacturing facilities were inspected on October 16,
23, and 24, 2000 and found to be in compliance with Quality Systems
Regulation.

XIV. **APPROVAL SPECIFICATIONS**

Directions for use: See the labeling.

Hazards to Health from Use of the Device: See Indications,
Contraindications, Warnings, Precautions, and Adverse Events in the
labeling.

Post-approval Requirements and Restrictions: The applicant is required
to follow subjects from the Phase III (pivotal safety and effectiveness)
study for a period of three years from the time of treatment in order to
collect long-term safety and effectiveness data on the HTA. In addition,
the device is restricted to physicians trained in diagnostic
hysteroscopy.